WO2018045966A1 - 含咪唑稠合三环类化合物及其应用 - Google Patents

含咪唑稠合三环类化合物及其应用 Download PDF

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WO2018045966A1
WO2018045966A1 PCT/CN2017/100722 CN2017100722W WO2018045966A1 WO 2018045966 A1 WO2018045966 A1 WO 2018045966A1 CN 2017100722 W CN2017100722 W CN 2017100722W WO 2018045966 A1 WO2018045966 A1 WO 2018045966A1
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alkyl
substituted
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group
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蔡雄
钱长庚
翁运幄
卿远辉
刘斌
林明生
王艳艳
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广州必贝特医药技术有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the invention relates to the technical field of medicine, in particular to an imidazole-containing fused tricyclic compound and application thereof.
  • protein antigens are processed by antigen-presenting cells (APC), degraded into polypeptides, bound to MHC and moved to the surface of APC, and combined with TCR surface TCR to generate activated TCR signals.
  • APC antigen-presenting cells
  • the binding of the antigen to the relevant receptors on the surface of T lymphocytes produces co-stimulatory signals, co-stimulatory signals and co-inhibitory signals, which perform positive and negative regulation, respectively.
  • T lymphocytes are activated.
  • the vast majority of tumor immunotherapy exerts anti-tumor effects by indirectly or directly activating human T cells to clear tumor cells.
  • Tumor cells can evade immune killing by inhibiting the immune checkpoint and its related ligands by abnormally up-regulating and inhibiting T cell activation. Blocking immune checkpoints and enhancing T cell activation is the focus of anti-tumor drug development in recent years.
  • Cytotoxic T lymphocyte-associated antigen (CTLA-4), Programmed Death-1 (PD-1) Programmed death-ligand 1 (PD-L1) is a recent year.
  • An important immunological checkpoint for clinical validation Approved by the US FDA, the immunological checkpoint PD-1 monoclonal antibody Nivolumab is used for Hodgkin's lymphoma, advanced renal cell carcinoma, advanced non-small cell lung cancer, melanoma and head and neck squamous cell carcinoma; another PD-1 antibody Pembrolizumab For the treatment of advanced non-small cell lung cancer, melanoma, head and neck squamous cell carcinoma, Hodgkin's lymphoma and bladder cancer; PD-L1 antibody atezolizumab as a second-line drug for the treatment of advanced bladder cancer and metastatic non-small cell lung cancer;
  • the CTLA-4 antibody Ipilimumab is used to treat unresectable or metastatic melanoma.
  • IDO inoleamine-(2,3) plus dioxygenase
  • TDO tryptophan-2,3-dioxygenase
  • IDO1 and TDO are the rate-limiting enzymes for the degradation of tryptophan into the kynurenine pathway. Tryptophan consumption and kynurenine accumulation induce effector T cell apoptosis or dysfunction and immunosuppression.
  • kynurenine and its metabolites (3-hydroxy kynurenine and 3-hydroxyanthranilic acid) are elevated, producing lymphocyte toxicity, causing cell cycle arrest and apoptosis; and also inducing naive T cells Immunosuppressive regulatory T cell (Tregs) differentiation. Similar to other immunological checkpoints, IDO1 and TDO are important targets for immunotherapy (Nat. Immunol. 14, 1014–1022, 2013; Nat Rev Drug Discov 14, 603–622 (2015).
  • IDO1 inhibitors Indoximod (NLG-8189), Epacadostat (INCB24360) and GDC-0919 (NLG919) are in clinical trials. According to clinicaltrials.gov, IDO1 inhibitors are being used in a variety of clinical trials for the treatment of hematological and solid tumors, including glioblastoma, glioma, glioma, malignant brain tumors, ependymoma, Medulloblastoma, breast cancer, melanoma, pancreatic cancer, non-small cell lung cancer, head and neck cancer, stomach cancer, esophageal cancer, colorectal cancer, prostate cancer, cancer bladder cancer, urinary transitional cell carcinoma, ovarian tumor, fallopian tube Cancer, endometrial cancer, renal cell carcinoma, primary peritoneal cancer, acute myeloid leukemia, lymphoma, and the like. Early clinical studies have shown that IDO1 inhibitors have excellent safety and can be used in combination with antibody drugs for checkpoint proteins
  • the present invention provides an imidazole-containing fused tricyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof, which can be used as an IDO1 inhibitor and has better Antitumor activity.
  • n is selected from: 0, 1, 2, 3 or 4;
  • X is selected from CR 6 or N;
  • Y is selected from (CH 2 ) y or CR 7 R 8 , wherein y is selected from 0 or 1;
  • W is selected from (CH 2 ) z , CR 7 R 8 or -N(R) 2 , wherein z is selected from 0 or 1;
  • R 1 is selected from the group consisting of: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkane a hydroxy-substituted C1-C6 alkyl group, an alkoxy-substituted C1-C6 alkyl group, an amino-substituted C1-C6 alkyl group, an alkylamino group-substituted C1-C6 alkyl group, a nitro group, a cyano group, OR, -N(R) 2 , -SR, -C(O)OR, -C(O)N(R) 2 , -C(O)R, -S(O)R, -S(O) 2 R,-S(O) 2 N(R) 2
  • R 2 and R 3 are each independently selected from the group consisting of: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, alkylamino substituted C1-C6 alkyl, nitro , cyano, -OR, -N(R) 2 , -SR, -C(O)R, -C(O)OR, -C(O)N(R) 2 , -S(O)R,- S(O) 2 R, -S(O) 2 N(R) 2 , -N(R)C(O)R;
  • R 6 is selected from the group consisting of: H, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl, -OR;
  • R 7 and R 8 are each independently selected from the group consisting of: C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl, -OR,-N (R) 2 , -SR, -S(O) 2 R;
  • R is selected from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxy Substituted C1-C6 alkyl, alkoxy substituted C1-C6 alkyl, amino substituted C1-C6 alkyl, alkylamino substituted C1-C6 alkyl;
  • Ring A is selected from an 8-16 membered substituted or unsubstituted bicyclic and tricyclic ring which is a saturated, partially unsaturated or aromatic bicyclic or tricyclic ring.
  • the atom on the ring of the bicyclic and tricyclic ring is selected from one of C, O, N and S or a combination of several chemically acceptable ones.
  • ring A is selected from:
  • n is selected from 0, 1 or 2;
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 are each independently selected from CR 9 or N;
  • R 9 is selected from the group consisting of: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkane a hydroxy-substituted C1-C6 alkyl group, an alkoxy-substituted C1-C6 alkyl group, an amino-substituted C1-C6 alkyl group, an alkylamino group-substituted C1-C6 alkyl group, an aryl group, a heteroaryl group, Nitro, cyano, -OR, -N(R) 2 , -SR, -C(O)OR, -C(O)N(R) 2 , -C(O)R, -S(O)R , -S(O) 2 R, -S
  • R 10 is selected from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, a hydroxy-substituted C1-C6 alkyl group, an alkoxy-substituted C1-C6 alkyl group, an amino-substituted C1-C6 alkyl group, an alkylamino group-substituted C1-C6 alkyl group;
  • R is selected from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxy Substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, alkylamino-substituted C1-C6 alkyl.
  • ring A is selected from:
  • ring A is selected from:
  • ring A is selected from:
  • ring A is selected from:
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 are each independently selected from CR 9 .
  • R 9 is selected from the group consisting of: H, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxy substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, alkylamino substituted C1-C6 alkyl, aryl, nitro, cyano, -OR,- N(R) 2 , -SR, -C(O)OR, -C(O)N(R) 2 , -C(O)R;
  • R is selected from the group consisting of: H, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, alkoxy substituted A C1-C6 alkyl group, an amino-substituted C1-C6 alkyl group, an alkylamino group-substituted C1-C6 alkyl group.
  • R 9 is selected from the group consisting of: H, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, phenyl, nitro, cyano, - OR, -N(R) 2 , -C(O)OR, -C(O)N(R) 2 , -C(O)R.
  • R 9 is selected from the group consisting of: H, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, phenyl, -OR, -C(O OR, -C(O)N(R) 2 ; R is selected from the group consisting of: H, C1-C6 alkyl.
  • R 9 is selected from the group consisting of: H, halogen, methyl, trifluoromethyl, methoxy, hydroxymethyl, hydroxyisopropyl, phenyl, -C(O)OC 2 H 5 , -C(O)NH 2 .
  • R 10 is selected from the group consisting of: H, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen substituted C1-C6 alkyl, hydroxy substituted C1-C6 alkyl
  • the alkoxy group is substituted with a C1-C6 alkyl group, an amino-substituted C1-C6 alkyl group, and an alkylamino group substituted for a C1-C6 alkyl group.
  • R 10 is selected from H or C1-C6 alkyl.
  • the imidazole-containing fused tricyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof has the structure of Formula II or Formula III:
  • X is CR 6 ;
  • Y is selected from CH 2 or CR 7 R 8 ;
  • W is (CH 2 ) z , z is selected from 0 or W is -N(R) 2 ;
  • R 6 is selected from H or C1-C6 alkyl
  • R 7 and R 8 are each independently selected from the group consisting of: C 1 -C 6 alkyl, -OR, -N(R) 2 , -SR;
  • R is selected from the group consisting of: H, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, alkoxy substituted A C1-C6 alkyl group, an amino-substituted C1-C6 alkyl group, an alkylamino group-substituted C1-C6 alkyl group.
  • the imidazole-containing fused tricyclic compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof has the structure of Formula IV:
  • n is selected from 0, 1 or 2;
  • R 1 is selected from the group consisting of: H, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, nitro, cyano, -OR, -N(R) 2 ,- SR, -C(O)OR, -C(O)N(R) 2 , -C(O)R, -S(O)R, -S(O) 2 R, -S(O) 2 N( R) 2 , -N(R)C(O)R;
  • R is selected from the group consisting of: H, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, alkoxy substituted A C1-C6 alkyl group, an amino-substituted C1-C6 alkyl group, an alkylamino group-substituted C1-C6 alkyl group.
  • R 2 and R 3 are each independently selected from the group consisting of: H, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, nitro, cyano , -OR, -N(R) 2 , -SR, -S(O)R, -S(O) 2 R, -S(O) 2 N(R) 2 , -N(R)C(O) R;
  • R is selected from the group consisting of: H, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, alkoxy substituted A C1-C6 alkyl group, an amino-substituted C1-C6 alkyl group, an alkylamino group-substituted C1-C6 alkyl group.
  • R 2 and R 3 are each independently selected from the group consisting of: H, halogen.
  • R is selected from the group consisting of: H, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, alkoxy substituted A C1-C6 alkyl group, an amino-substituted C1-C6 alkyl group, an alkylamino group-substituted C1-C6 alkyl group.
  • one of R 4 and R 5 is selected from H and the other is selected from -OH.
  • the compound is selected from the group consisting of
  • the invention also provides the use of the above compounds.
  • the tumor is a solid tumor or a blood tumor.
  • the solid tumor is breast cancer, pancreatic cancer, lung cancer, liver cancer, gastric cancer, colon cancer, kidney cancer, prostate cancer, head and neck cancer, esophageal cancer, ovarian cancer or cervical cancer; Lymphoma, leukemia or myeloma.
  • breast cancer, pancreatic cancer, lung cancer, liver cancer, stomach cancer, colon cancer, kidney cancer, prostate cancer, head and neck cancer, lymphoma and the like is especially breast cancer, pancreatic cancer, lung cancer, liver cancer, stomach cancer, colon cancer, kidney cancer, prostate cancer, head and neck cancer, lymphoma and the like.
  • the present invention also provides a pharmaceutical composition for preventing and treating tumors.
  • a pharmaceutical composition for controlling tumors comprising the above-mentioned imidazole-containing fused tricyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof.
  • the active ingredient of the pharmaceutical composition may also comprise other checkpoint protein inhibiting drugs or other anti-tumor drugs; including other checkpoint protein inhibitors including, but not limited to, PD1 monoclonal antibody drugs, PD-L1 monoclonal antibody drugs, and CTLA -4 monoclonal antibody drugs; said other anti-tumor drugs include, but are not limited to, chemotherapeutic drugs, hormonal drugs, targeted therapeutic drugs, and immunotherapeutic drugs.
  • the above-mentioned imidazole-containing fused tricyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof can be combined with other checkpoint protein inhibiting drugs or other antitumor drugs to enhance antitumor activity.
  • the tumor comprises: breast cancer, pancreatic cancer, lung cancer, liver cancer, stomach cancer, colon cancer, Kidney cancer, prostate cancer, head and neck cancer, esophageal cancer, ovarian cancer, cervical cancer, lymphoma, leukemia and myeloma.
  • the imidazole-containing fused tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof is a series of novel compounds which have an action of regulating IDO1 activity.
  • the compound By blocking the immune checkpoint IDO1, the compound can enhance T cell activation and is used to treat IDO1-mediated immunosuppression, thereby becoming an effective drug for treating malignant tumors. It can be combined with antibody drugs for checkpoint proteins or other anticancer drugs to enhance anticancer effects. At the same time, it has the potential to effectively treat immunosuppressive diseases associated with IDO1 abnormalities, and has great application value.
  • Figure 3 is a graph showing the blood concentration of a compound NLG919, Compounds 2, 8, 11, 36 and 42 administered intragastrically (20 mg/kg).
  • any variable e.g., R1, R2, etc.
  • the definition of each occurrence thereof is independent of the definition of each occurrence.
  • combinations of substituents and variables are allowed as long as such combinations stabilize the compound.
  • a line drawn from a substituent into the ring system means that the bond referred to can be attached to any ring atom that can be substituted. It will be appreciated that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the present invention to provide compounds which are chemically stable and which are readily synthesized from readily available starting materials by techniques in the art and from the methods set forth below. If the substituent itself is substituted by more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stabilized.
  • alkyl as used herein is meant to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C1-C6 in “C1-C6 alkyl” includes a group having 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight chain or a branched chain.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • cycloalkyl includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl and the like.
  • halogen as used herein is meant to include chloro, fluoro, bromo and iodo.
  • the invention includes free forms of the compounds of Formulas I-IV, as well as pharmaceutically acceptable salts thereof, stereoisomers thereof, and prodrug molecules thereof.
  • Some specific exemplary compounds herein are protonated salts of amine compounds.
  • the term "free form" refers to an amine compound in a non-salt form. Included pharmaceutically acceptable salts include not only the indications of the particular compounds described herein Exemplary salts also include all typical pharmaceutically acceptable salts of the free forms of the compounds of formula I-IV.
  • the free form of the particular salt of the compound can be isolated using techniques known in the art.
  • the free form can be regenerated by treating the salt with a suitable dilute aqueous base such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate.
  • a suitable dilute aqueous base such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate.
  • the free form differs somewhat from its respective salt form in solubility in certain physical properties, such as in polar solvents, but for purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods.
  • the salt of the basic compound is prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric or excess amount of the desired salt or mixture of the inorganic or organic acid in a suitable solvent or combination of solvents.
  • a salt of an acidic compound is formed by reaction with a suitable inorganic or organic base.
  • pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention which are formed by the reaction of a basic compound of the invention with an inorganic or organic acid.
  • conventional non-toxic salts include those prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid.
  • stearic acid lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2
  • a salt prepared from monoacetoxybenzoic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid or the like.
  • a suitable "pharmaceutically acceptable salt” refers to a salt prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, zinc salts and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred.
  • a salt derived from a pharmaceutically acceptable organic non-toxic base comprising a salt of a primary, secondary and tertiary amine, the substituted amine comprising a naturally occurring substituted amine, a cyclic amine and a basic ion exchange resin such as a fine Amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, B Diamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine , piperidine, guanidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine, t
  • the compounds of the invention can be prepared by the following synthetic schemes (methods in Schemes 1-13. In combination with the synthetic schemes described below, which can be described in the present invention A better understanding of the compounds and synthetic methods is described.
  • the synthetic schemes described are described for the preparation of the compounds described in the present invention, which are merely illustrative for illustrative purposes and do not constitute a The scope of the invention is limited.
  • Step 1a Preparation of 4-iodo-1-trityl-1H-imidazole (Compound 0102-1): 4-Iodoimidazole (0101-1) (10.0 ⁇ , 51.6 mmol, 1.0 eq.) was dissolved in 150 mL of THF, triphenylchloromethane (17.2 g, 61.7 mmol, 1.2 eq.) and triethylamine (14.5 mL, 10.4 mmol, 2.0 eq.). The reaction was carried out overnight at 80 °C. The mixture was cooled to room temperature, then evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The white solid 4-iodo-1-trityl-1H-imidazole (16 g, yield: 71%) was obtained. LCMS (ESI): m / z 437 [M + 1] +.
  • Step 1b 2-(1-Trityl-1H-imidazol-4-yl)benzaldehyde (2-(1-trityl-1H-imidazol-4-yl)benzaldehyde (Preparation of Compound 0105-1): Tetrakistriphenylphosphine palladium (2.0 g, 1.7 mmol, 0.074 equivalent), 4-iodo-1-trityl-1H-imidazole (0102-1) (10.0 g, 23.0 mmol, under nitrogen) 1.0 equivalent), 2-aldehyde phenylboronic acid (0103-1) (4.1 g, 27.5 mmol, 1.2 eq.) and tripotassium phosphate (12.0 g, 46 mmol, 2.0 eq.) were added to 180 ml of dimethylformamide.
  • Step 1c Preparation of 4-hydroxy-3-iodobenzoic acid (Compound 0203-1).
  • P-Hydroxybenzoic acid (0201-1) (3.45 g, 25 mmol, 1.0 eq.) was dissolved in 60 mL of methanol, then sodium iodide (3.75 g, 25 mmol, 1.0 eq.) and sodium hydroxide (2.0). Grams, 50 mmol, 2.0 equivalents).
  • a saturated sodium hypochlorite solution 45 ml, 25 mmol, 1.0 eq.
  • Step 1d Preparation of methyl 4-hydroxy-3-iodobenzoate (Compound 0204-1): Compound 4-hydroxy-3-iodobenzoic acid (0203-1) (2.5 Grams, 9.47 mmol, 1.0 eq.) were dissolved in 30 mL of dry methanol. Then a solution of methanolic hydrochloric acid (10 ml, 3 mol/L methanol solution, 30 mmol, 3.2 eq.) was added. The mixture was stirred at 65 ° C overnight.
  • Step 1e Preparation of methyl 4-hydroxy-3-((trimethylsilyl)ethynyl)benzoate (compound 0205-1): in a nitrogen atmosphere
  • the compound 4-hydroxy-3-iodobenzoic acid methyl ester (0204-1) (2.78 mg, 9.98 mmol, 1.0 equivalent)
  • cuprous iodide 28 mg, 0.15 mmol, 0.015 equivalent
  • double three Phenylphosphine palladium dichloride 210 mg, 0.3 mmol, 0.03 equivalent
  • trimethylsilylacetylene (1.37 g, 13.997 mmol, 1.4 equivalent
  • Step 1f Preparation of methyl benzofuran-5-carboxylate (compound 0206-1): the compound 4-hydroxy-3-(trimethylsilylethynyl)benzoate (0205-1) (1.5 g, 6.046 mmol, 1.0 eq.) was dissolved in 50 mL of methanol then EtOAc (57 mg, 0.302 mmol, 0.05 eq.) and diisopropylethylamine (. , 6.79 mmol, 1.1 equivalent). The mixture was stirred at 60 ° C for 16 hours. After completion of the reaction, the mixture was cooled, and the solvent was evaporated, evaporated, mjjjjjj (400 mg, yield: 37.56%). LCMS (ESI): m / z 177 [M + 1] +.
  • Step 1g (2-(benzofuran-5-yl)-2-oxoethyl)phosphonate) (Compound 0207- Preparation of 1).
  • Dimethyl methyl phosphate (211 mg, 1.703 mmol, 1.5 eq.) was dissolved in 10 mL of dry tetrahydrofuran under a nitrogen atmosphere. Dry ice/ethanol was cooled to -60 ° C, and n-butyllithium (0.7 mL, 2.5 mol/L n-hexane solution, 1.703 mmol, 1.5 eq.) was slowly added dropwise.
  • Step 1h (Z)-1-(benzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-ene-1 -keto[(Z)-1-(benzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one] (Compound 0208 Preparation of -1): 60% sodium hydride (34 mg, 0.844 mmol, 1.0 equivalent) was dissolved in 15 ml of tetrahydrofuran under a nitrogen atmosphere and an ice bath.
  • Step 1i 1-(benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (1-(benzofuran-5) -yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) [Compound 1 (Compound 0209-1)]: Compound (Z)-1- (benzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (0208-1) (350 Methanol, 0.63 mmol, 1.0 eq.) and acetic acid (5 mL) were combined in methanol (100 mL).
  • Step 3a Preparation of benzo[b]thiophene-5-carboxylic acid (compound 0302-7): 5-bromine in a round bottom flask under nitrogen protection Benzothiophene (0301-7) (1.0 g, 4.69 mmol, 1.0 eq.) and 35 ml of anhydrous tetrahydrofuran were cooled to -72 ° C in a dry ice-ethanol bath, and a solution of 2.5 M n-butyllithium tetrahydrofuran (2.8) was added dropwise. Milliliter, 7.04 mmol, 1.5 eq.), stirred for one hour, passed carbon dioxide, and stirred for 1 hour. 2M aqueous hydrochloric acid was added dropwise to the aqueous phase to pH 1 and extracted with ethyl acetate. EtOAc was evaporated. ).
  • Step 3b Preparation of benzo[b]thiophene-5-carboxylate methyl benzo[b]thiophene-5-carboxylate (compound 0303-7): benzo[b]thiophene-5-carboxylic acid (0302- 7) (1.0 g, 5.6 mmol, 1.0 eq.) was dissolved in 30 mL of MeOH. EtOAc (EtOAc, EtOAc, EtOAc, EtOAc Stir under 4 hours. The organic layer was concentrated under reduced pressure. EtOAcjjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH
  • Step 3c dimethyl (2-(benzo[b]thiophen-5-yl)-2-oxoethyl) Preparation of phosphonate) (Compound 0304-7): Under a nitrogen atmosphere, dimethyl methylphosphonate (513 mg, 4.14 mmol, 1.5 eq.) and 30 mL of anhydrous tetrahydrofuran were added to dry ice in a round bottom flask.
  • Step 3d (E)-1-(Benzo[b]thiophen-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propane-2- Iso-1-one [(E)-1-(benzo[b]thiophen-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en- Preparation of 1-one] (Compound 0305-7): dimethyl 2-(benzo[b]thiophen-5-yl)-2-oxoethyl)phosphate (0304-7) (267 mg, 0.97 mmol, 1.1 equivalents), 2-(1-trityl-1H-imidazol-4-yl)benzaldehyde (0105-1) (350 mg, 0.85 mmol, 1.0 eq.) and cesium carbonate (418 mg) , 1.28 mmol, 1.5 eq.) was added to 30 ml of
  • Step 3e 1-(Benzo[b]thiophen-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (1-( Preparation of benzo[b]thiophen-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0306-7): (E)- 1-(Benzo[b]thiophen-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (0305 -7) (500 mg, 0.88 mmol, 1.0 eq.) was dissolved in 30 ml of methanol, and then 5 ml of acetic acid was added and the mixture was heated to reflux overnight.
  • Step 3f 1-(Benzo[b]thiophen-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol (1-( Preparation of benzo[b]thiophen-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 7): 1-(Benzene[ b] thiophen-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0306-7) (200 mg, 0.60 mmol, 1.0 equivalent) dissolved in 30 ml of methanol, cooled to 0 ° C in an ice bath, added sodium borohydride (34 mg, 0.9 mmol, 1.5 eq.), stirred for half an hour, added acetone, concentrated under reduced pressure, and added dichloro The mixture is extracted with
  • Step 4a Preparation of 2-fluoro-4-hydroxy-5-iodobenzoic acid (compound 0203-8).
  • Potassium carbonate (2.65 g, 19.2 mmol, 3 equivalents) was dissolved in 5 ml, iodine (1.625 g, 6.4 mmol, 1 eq.) was added, stirred for 1 hour, and the compound 2-fluoro-4-hydroxybenzene was added dropwise.
  • Formic acid (0201-8) (1 g, 6.4 mmol, 1 eq.) in 15 mL aqueous ammonia. The mixture was stirred at room temperature for 2 hours.
  • Step 4b Preparation of methyl 2-fluoro-4-hydroxy-5-iodobenzoate (Compound 0204-8): Compound 2-fluoro-4-hydroxyl -5-iodobenzoic acid (0203-8) (1.6 g, 5.67 mmol, 1 when The amount) was dissolved in 30 ml of methanol. Thionyl chloride (1.5 ml) was slowly added dropwise under ice bath. The mixture was stirred under reflux for 2 hours. After completion of the reaction, the mixture was evaporated tolulululululululululululu 53.57%).
  • Step 4c 2-fluoro-4-hydroxy-5-(trimethylsilyl)ethynylbenzoate (compound 0205-8)
  • methyl 2-fluoro-4-hydroxy-5-iodobenzoate (0204-8) (900 mg, 3.04 mmol, 1.0 eq.), trimethylsilylacetylene (417 mg) under nitrogen. , 4.26 mmol, 1.4 eq.), cuprous iodide (8.6 mg, 0.04 mmol, 0.015 eq.) and tetrakistriphenylphosphine palladium (64 mg, 0.09 mmol, 0.03 eq.) were added to 10 ml of tetrahydrofuran and 20 ml.
  • Triethylamine (921.1 mg, 9.12 mmol, 3 equivalents) was added dropwise to a mixture of chloroform, and the mixture was heated to 50 ° C, and the reaction was stirred for 4 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to give ethyl 2-fluoro-4-hydroxy-5-(trimethylsilylethynyl)benzoate, which was directly used for the next reaction.
  • Step 4d Preparation of methyl 6-fluorobenzofuran-5-carboxylate (compound 0206-8): dilute 2-fluoro-4-hydroxyl with 50 ml of anhydrous methanol Concentrate of methyl 5-(trimethylsilylethynyl)benzoate (0205-8) (3.04 mmol, 1.0 eq.), N,N-diisopropylethylamine (784 mg, 6.08 mmol, 2.0 Ethylene oxide (57 mg, 0.304 mmol, 0.1 eq.) was reacted at 60 ° C for 4 hr. The mixture was cooled to room temperature, suction filtered, and the filtrate was evaporated. mjjjjjjjjjjjjj Methyl ester (180 mg, yield: 30.52%). LCMS (ESI): m / z 195 [M + 1] +.
  • Step 4e (2-(6-fluorobenzofuran-5-yl)-2-oxoethyl)phosphonate (dimethyl(2-(6-fluorobenzofuran-5-yl)-2-oxoethyl)phosphonate
  • Dimethyl methylphosphonate (173 mg, 1.395 mmol, 1.5 eq.) was dissolved in 5 mL of dry tetrahydrofuran under a nitrogen atmosphere. Dry ice/ethanol was cooled to -60 ° C, and n-butyllithium (0.7 ml, 2.5 mol/ml n-hexane solution, 1.86 mmol, 2 eq.) was slowly added dropwise.
  • Step 4f 1-(6-Fluorobenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-ene-1- Ketone (1-(6-fluorobenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en-1-one) (Compound 0208-8) Preparation: 2-(1-trityl-1H-imidazol-4-yl)benzaldehyde (0105-1) (263 mg, 0.635 mmol, 1 eq.), compound (2-(6-fluorobenzene) And furan-5-yl)-2-oxoethyl)phosphate (0207-8) (200 mg, 0.699 mmol, 1.1 equivalent) and cesium carbonate (619 mg, 1.905 mmol, 2 equivalents) The mixture was mixed in isopropyl alcohol (10 ml
  • Step 4g 1-(6-Fluorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (1-( Preparation of 6-fluorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0209-8): Compound 1-(6- Fluorobenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (0208-8) (304 Methanol, 0.529 mmol, 1 eq.) and acetic acid (2 mL) were combined in methanol (4 mL).
  • Step 4h 1-(6-Fluorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol (1-( Preparation of 6-fluorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 8): 1-(6-Fluorobenzo) Furan-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0209-8) (150 mg, 0.45 mmol, 1.0 eq.
  • Step 5a Preparation of methyl 3-fluoro-4-hydroxybenzoate (compound 0202-14): 3-fluoro-4-hydroxybenzoic acid (0201-14) (1.0 Grams, 6.41 mmol, 1.0 eq.) were dissolved in 50 mL of methanol, and concentrated sulfuric acid (3 mL) was slowly added dropwise. The mixture was stirred at 50 ° C overnight. After the reaction was completed, the solvent was evaporated, the residue was evaporated, evaporated, evaporated, evaporated Ester (1.25 g, crude). LCMS (ESI): m / z 171 [M + 1] +.
  • Step 5b Preparation of methyl 3-fluoro-4-hydroxy-5-iodobenzoate (compound 0204-14): potassium carbonate (1.62 g, 11.74 m) Mole, 2.0 equivalents) and the compound 3-fluoro-4-hydroxybenzoic acid methyl ester (0202-14) (1.0 g, 5.87 mmol, 1.0 eq.) were dissolved in 50 mL of tetrahydrofuran and added with iodine (1.79 g, 7.05) Millimol, 1.2 eq.), stirred at room temperature overnight. After the reaction was completed, 15 ml of an aqueous solution of sodium hydrogensulfite was added. The mixture was extracted with EtOAc. EtOAc (EtOAc m. LCMS (ESI): m / z 297 [M + 1] +.
  • Step 5c methyl 3-fluoro-4-hydroxy-5-(trimethylsilyl)ethynylbenzoate (compound 0205-14)
  • Step 5d methyl 7-fluorobenzofuran-5-carboxylate (preparation of compound 0206-14): 3-fluoro-4-hydroxy-diluted with 50 ml of anhydrous methanol Methyl 5-(trimethylsilylethynyl)benzoate (0205-14) crude (1.73 g, 6.49 mmol, 1.0 eq.), N,N-diisopropylethylamine (722 mg, 7.14 mmol) , 1.1 equivalents) and cuprous iodide (62 mg, 0.32 mmol, 0.05 equivalents). After reacting at 60 ° C for 4 hours, a small amount of potassium carbonate was added and stirred at 60 ° C overnight.
  • Step 5e (2-(7-fluorobenzofuran-5-yl)-2-oxoethyl)phosphonate (dimethyl(2-(7-fluorobenzofuran-5-yl)-2-oxoethyl)phosphonate
  • Dimethyl methylphosphonate (192 mg, 1.55 mmol, 1.5 eq.) was dissolved in 10 mL of dry tetrahydrofuran under a nitrogen atmosphere. Dry ice/ethanol was cooled to -60 ° C, and n-butyllithium (0.62 mL, 2.5 mol/L n-hexane solution, 1.55 mmol, 1.5 eq.) was slowly added dropwise.
  • Step 5f 1-(7-Fluorobenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-ene-1- Ketone (1-(7-fluorobenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en-1-one) (Compound 0208-14) Preparation: 60% sodium hydride (38 mg, 0.97 mmol, 1.0 eq.) was dissolved in 15 ml of tetrahydrofuran under nitrogen atmosphere and ice bath, and then slowly added (2-(7-fluorobenzene) A solution of dimethylfuran-5-yl)-2-oxoethyl)phosphate (0207-14) (278 mg, 0.97 mmol, 1.0 eq.) in THF (15 mL).
  • Step 5g 1-(7-Fluorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanone (1-(7-fluorobenzofuran-) Preparation of 5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0209-14): Compound 1-(7-Fluorobenzofuran) -5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (0208-14) (252 mg, 0.44 m Mole, 1.0 eq.) and acetic acid (4 mL) were combined in methanol (80 mL).
  • Step 5h 1-(7-Fluorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol (1-( Preparation of 7-fluorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 14): Compound 1-(7-fluorobenzene) And furan-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanone (0209-14) (122 mg, 0.367 mmol, 1.0 eq.) Sodium borohydride (28 mg, 0.734 mmol, 2.0 eq.) was added slowly in 50 mL of methanol.
  • Step 6a Preparation of 2-chloro-4-hydroxy-5-iodobenzoic acid (compound 0203-17): 2-chloro-4-hydroxybenzoic acid ( 0201-17) (100 mg, 0.581 mmol, 1.0 eq.) was added to 10 ml of water, then aqueous ammonia (1 ml) was added. After cooling in an ice bath, an aqueous solution (20 ml) of potassium iodide (0.319 g, 1.94 mmol, 3.0 eq.) and iodine (0.146 g, 0.581 mmol, 1.0 eq.) was slowly added dropwise, and the dropping temperature was controlled below 5 °C.
  • Step 6b Preparation of methyl 4-hydroxy-5-iodo-2-chloro-benzoate (compound 0204-17): Compound 2-chloro-4- Hydroxy-5-iodobenzoic acid (0203-17) (0.17 g) was dissolved in 30 ml of anhydrous methanol, then concentrated sulfuric acid (0.05 g) was added, and the mixture was stirred at 65 ° C overnight. The methanol was removed, the residue was suspended in 100 ml of water, and a saturated aqueous sodium hydrogencarbonate solution was added to bring the pH to about 4, and the solid was collected by filtration, washed with water and dried to give the desired product, 4-hydroxy-5-iodo-2-chlorobenzoic acid methyl ester. (1.80 g, yield 100%) as a white solid .LCMS (ESI): m / z 313 [m + 1] +.
  • Step 6c methyl 4-hydroxy-2-hydroxy-5-(trimethylsilyl)ethynylbenzoate (compound 0205-17)
  • Step 6d Preparation of methyl 6-chlorobenzofuran-5-carboxylate (compound 0206-17): Diluting 2-chloro-4-hydroxyl with 50 ml of anhydrous methanol Methyl 5-(trimethylsilylethynyl)benzoate (0205-17) (0.100 g, 0.320 mmol, 1.0 eq.), N,N-diisopropylethylamine (35.3 mg, 0.352 mmol, 1.1 equivalents) and cuprous iodide (3 mg, 0.016 mmol, 0.05 equivalents). After reacting at 60 ° C for 4 hours, a small amount of potassium carbonate was added and stirred at 60 ° C overnight.
  • Step 6e (2-(6-chlorobenzofuran-5-yl)-2-oxoethyl)phosphonate (2-(6-chlorobenzofuran-5-yl)-2-oxoethyl)phosphonate
  • Dimethyl methylphosphonate (186 mg, 1.5 mmol, 1.5 eq.) was dissolved in 5 mL of dry tetrahydrofuran under nitrogen atmosphere. Dry ice/ethanol cooled to -60 °C, n-butyl lithium (0.8 ml, 2.5 mol / ml of n-hexane solution, 1.86 mmol, 2 equivalents) was slowly added dropwise.
  • Step 6f 1-(6-Chlorobenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-5-yl)phenyl)propan-2-ene-1- Ketone (1-(6-chlorobenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en-1-one) (Compound 0208-17)
  • 2-(1-trityl-1H-imidazol-4-yl)benzaldehyde (0105-1) (266 mg, 0.644 mmol, 1 eq.), (2-(6-chlorobenzo) Dimethylfuran-5-yl)-2-oxoethyl)phosphate (0207-17) (200 mg, 0.709 mmol, 1.1 eq.) and cesium carbonate (460 mg, 1.418 mmol, 2 eq.)
  • the mixture was stirred at room temperature for 16 hours
  • Step 6g 1-(6-Chlorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (1-( Preparation of 6-chlorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0209-17): Compound 1-(6- Chlorobenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-5-yl)phenyl)propan-2-en-1-one (0208-17) (290 Methanol, 0.490 mmol, 1 eq.) and acetic acid (2 mL) were combined in methanol (4 mL).
  • Step 6h 1-(6-Chlorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol (1-( Preparation of 6-chlorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 17): 1-(6-Chlorobenzophthalate) Furan-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0209-17) (200 mg, 0.573 mmol, 1.0 eq.
  • Step 7a Preparation of methyl 4-hydroxy-2-methoxybenzoate (compound 0202-22): Compound 2,4-dihydroxybenzoic acid methyl ester (0201- 22) (800 mg, 4.76 mmol, 1 eq.) and potassium carbonate (4 g, 28.56 mmol, 6 eq.) were mixed in 50 ml of acetone, and then p-toluenesulfonyl chloride (900 mg, 4.76 mmol) was slowly added. 1 equivalent). The mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was filtered.
  • Step 7b Preparation of methyl 4-hydroxy-5-iodo-2-methoxybenzoate (compound 0204-22): Compound 4-hydroxy-2 Methyl methoxybenzoate (0202-22) (500 mg, 2.74 mmol, 1 eq.), iodine (835 mg, 3.29 mmol, 1.2 eq.) and potassium carbonate (570 mg, 4.11 mmol, 1.5 Equivalent) was mixed in 10 ml of DMF. The mixture was stirred at room temperature for 3 hours.
  • Step 7c Methyl 4-hydroxy-2-methoxy-5-(trimethylsilyl)ethynylbenzoate (compound 0205- Preparation of 22): 4-hydroxy-5-iodo-2-methoxybenzoic acid methyl ester (0204-22) (845 mg, 2.74 mmol, 1.0 eq.), trimethylsilylacetylene under nitrogen atmosphere (537 mg, 5.48 mmol, 2 equivalents), cuprous iodide (7.8 mg, 0.04 mmol, 0.015) Equivalent) and tetrakistriphenylphosphine palladium (57 mg, 0.08 mmol, 0.03 equivalent) were added to a mixture of 10 ml of tetrahydrofuran and 20 ml of chloroform, followed by dropwise addition of triethylamine (830 mg, 8.22 mmol, 3 equivalents) The mixture was heated to 50 ° C and stirred for 4 hours. It was cooled to room temperature and concentrated under reduced pressure,
  • Step 7d methyl 6-methoxybenzofuran-5-carboxylate (preparation of compound 0206-22): diluted 4-hydroxy-2- with 50 ml of anhydrous methanol Concentrate of methyl methoxy-5-(trimethylsilylethynyl)benzoate (0205-22) (2.74 mmol, 1.0 eq.), N,N-diisopropylethylamine (559 mg, 5.48) Millimol, 2.0 equivalents) and cuprous iodide (52 mg, 0.274 mmol, 0.1 eq.) were reacted at 60 ° C for 4 hours. After completion of the reaction, the mixture was cooled to room temperature and filtered with suction.
  • Step 7e (2-(6-methoxybenzofuran-5-yl)-2-oxoethyl)phosphoric acid dimethyl (dimethyl(2-(6-methoxybenzofuran-5-yl)-2-oxoethyl)phosphoric acid dimethyl (dimethyl(2-(6-methoxybenzofuran-5-yl)-2-oxoethyl)phosphoric acid dimethyl (dimethyl(2-(6-methoxybenzofuran-5-yl)-2-oxoethyl)
  • Dimethyl methylphosphonate (451 mg, 3.64 mmol, 1.5 eq.) was dissolved in 5 mL of dry THF. Dry ice/ethanol was cooled to -60 ° C, and n-butyllithium (2 mL, 2.5 mol/ml n-hexane solution, 4.86 mmol, 2 eq.) was slowly added dropwise.
  • Step 7f 1-(6-Methoxybenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-5-yl)phenyl)propan-2-ene- 1-keto(1-(6-methoxybenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en-1-one) (Compound 0208- Preparation of 22): 2-(1-Trityl-1H-imidazol-4-yl)benzaldehyde (0105-1) (207 mg, 0.5 mmol, 1 eq.), compound (2-(6-) Dimethyl methoxybenzofuran-5-yl)-2-oxoethyl)phosphate (0207-22) (179 mg, 0.6 mmol, 1.2 eq.) and cesium carbonate (325 mg, 1 mmol, 2 equivalents) were mixed in isopropanol (10 ml
  • Step 7g 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(6-methoxybenzofuran-5-yl)ethane-1-one (2 -(5H-imidazo[5,1-a]isoindol-5-yl)-1-(6-methoxybenzofuran-5-yl)ethan-1-one) (Compound 0209-22)
  • Step 7h 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(6-methoxybenzofuran-5-yl)ethane-1-ol (2 -(5H-imidazo[5,1-a]isoindol-5-yl)-1-(6-methoxybenzofuran-5-yl)ethan-1-ol) (Compound 22)
  • 2-(5H-Imidazole [5,1-a]isoindoline-5-yl)-1-(6-methoxybenzofuran-5-yl)ethane-1-one (0209-22) 210 mg, 0.6 m Molar, 1.0 eq.
  • sodium borohydride 45 mg, 1.2 mmol, 2 eq.
  • Example 8 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(7-methoxybenzofuran-5-yl)ethane-1-ol (Preparation of 2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(7-methoxybenzofuran-5-yl)ethan-1-ol) (Compound 23) (Prepared according to Scheme 2)
  • Step 8a Preparation of methyl 4-hydroxy-3-iodo-5-methoxybenzoate (compound 0204-23): 4-hydroxy-3- Methyl methoxybenzoate (0202-23) (1.82 g, 0.01 mol, 1.0 eq.) was dissolved in 15 mL of trifluoroacetic acid and N-iodosuccinimide (2.7 g, 0.012 mol, 1.2 eq. The reaction was stirred at room temperature for 3 hours. Water was added, and the mixture was extracted with EtOAc. EtOAcjjjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Methyl 5-5-methoxybenzoate (840 mg, yield: 27.2%).
  • Step 8b Methyl 4-hydroxy-3-methoxy-5-(trimethylsilyl)ethynylbenzoate) (Compound 0205- Preparation of 23): 4-Hydroxy-3-iodo-5-methoxybenzoic acid methyl ester (0204-23) (800 mg, 2.6 mmol, 1.0 eq.), trimethylsilylacetylene under nitrogen atmosphere (1.27 g, 13.0 mmol, 5.0 eq.), diisopropylamine (657 mg, 6.5 mmol, 2.5 eq.), cuprous iodide (10 mg, 0.05 mmol, 0.02 eq.) and tetratriphenylphosphine palladium ( 140 mg, 0.13 mmol, 0.05 eq.) was added to 45 ml of tetrahydrofuran and heated to reflux overnight. Cool to room temperature and concentrate under reduced pressure to give the product 4-cyl Methyl 3-methoxy-5-(trimethyls
  • Step 8c Preparation of methyl 7-methoxybenzofuran-5-carboxylate (compound 0206-23): 4-hydroxy-3- diluted with 50 ml of anhydrous methanol a concentrate of methyl methoxy-5-(trimethylsilylethynyl)benzoate (0205-23) (2.6 mmol, 1.0 eq.), diisopropylamine (0.71 mL, 5.2 mmol, 2.0 eq.) Cuprous iodide (152 mg, 0.8 mmol, 0.3 eq.) was heated and refluxed for 8 hr. then cooled to 50.degree.
  • Step 8d (2-(7-Methoxybenzofuran-5-yl)-2-oxoethyl)phosphoric acid dimethyl (dimethyl(2-(7-methoxybenzofuran-5-yl)-2-oxoethyl Preparation of phosphonate) (Compound 0207-23): Under a nitrogen atmosphere, dimethyl methylphosphonate (308 mg, 2.48 mmol, 2.0 eq.) and 20 mL of anhydrous tetrahydrofuran were added to a round bottom flask.
  • Step 8e 1-(7-Methoxybenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-ene- 1-keto(1-(7-methoxybenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one) (Compound 0208- Preparation of 23): dimethyl (2-(7-methoxybenzofuran-5-yl)-2-oxoethyl)phosphate (0207-23) (317 mg, 1.1 mmol, 1.25 eq.
  • Step 8f 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(7-methoxybenzofuran-5-yl)ethane-1-one (2 -(5H-imidazo[5,1-a]isoindol-5-yl)-1-(7-methoxybenzofuran-5-yl)ethan-1-one) (Compound 0209-23)
  • Step 8g 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(7-methoxybenzofuran-5-yl)ethane-1-ol (2 -(5H-imidazo[5,1-a]isoindol-5-yl)-1-(7-methoxybenzofuran-5-yl)ethan-1-ol) (Compound 23) Preparation: 2-(5H-Imidazole [5,1-a]isoindoline-5-yl)-1-(7-methoxybenzofuran-5-yl)ethane-1-one (0209-23) (150 mg, 0.43 m Molar, 1.0 eq.) was dissolved in 30 mL of methanol, cooled in ice-cooled to 0 ° C, sodium borohydride (25 mg, 0.65 mmol, 1.5 eq.) was added, the reaction was stirred for half an hour, acetone was added and concentrated under reduced
  • Step 9a Preparation of 4-hydroxy-5-iodo-2-methylbenzoic acid (compound 0203-25): 4-hydroxy-2-methylbenzene Formic acid (0201-25) (1.0 g, 6.6 mmol, 1.0 eq.) was added to 10 (ml) water and then aqueous ammonia (1 mL) was added. After cooling in an ice bath, an aqueous solution (20 ml) of potassium iodide (3.26 g, 19.8 mmol, 3.0 eq.) and iodine (1.66 g, 6.6 mmol, 1.0 eq.) was slowly added dropwise, and the temperature was controlled below 5 degrees. Finally, the mixture was stirred at room temperature for 2 hours.
  • Step 9b Preparation of methyl 4-hydroxy-5-iodo-2-methylbenzoate (compound 0204-25): Compound 4-hydroxy-5- Iodo-2-methylbenzoic acid (0203-25) (1.8 g) was dissolved in 30 ml of anhydrous methanol, then concentrated sulfuric acid (0.5 g) was added. The mixture was stirred at 65 ° C overnight. After completion of the reaction, methanol was removed under reduced pressure, the residue was suspended in 100 ml of water, and a saturated aqueous sodium hydrogen carbonate aqueous solution was added to bring the pH to about 4, and the solid was collected by filtration, washed with water and dried to give the desired product 4-hydroxy-5-iodo-2. Methyl methylbenzoate (1.90 g, yield 100%) was obtained as a white solid. LCMS (ESI): m / z 293 [M + 1] +.
  • Step 9c methyl 4-hydroxy-2-methyl-5-((trimethylsilyl)ethynyl)benzoate (compound 0205) -25)
  • Step 9d Preparation of methyl 6-methylbenzofuran-5-carboxylate (compound 0206-25): 4-hydroxy-2-methyl diluted with 50 ml of anhydrous methanol Methyl 5-(trimethylsilylethynyl)benzoate (0205-25) (1.0 g, 3.4 mmol, 1.0 eq.), N,N-diisopropylethylamine (378 mg, 3.74 mmol, 1.1 eq.) and cuprous iodide (30 mg, 0.17 mmol, 0.05 eq.). After reacting at 60 ° C for 4 hours, a small amount of potassium carbonate was added and stirred at 60 ° C overnight.
  • Step 9e (2-(6-methylbenzofuran-5-yl)-2-oxoethyl)phosphonic acid dimethyl (dimethyl(2-(6-methylbenzofuran-5-yl)-2-oxoethyl Preparation of phosphonate) (Compound 0207-25): Dimethyl methylphosphonate (186 mg, 1.5 mmol, 1.5 eq.) was dissolved in 5 mL of dry tetrahydrofuran under a nitrogen atmosphere.
  • Step 9f 1-(6-Methylbenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-5-yl)phenyl)propan-2-ene-1 -keto(1-(6-methylbenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en-1-one)
  • Compound 0208-25 Preparation: 2-(1-trityl-1H-imidazol-4-yl)benzaldehyde (0105-1) (266 mg, 0.644 mmol, 1 eq.), compound (2-(6-A) Dimethyl benzofuran-5-yl)-2-oxoethyl)phosphonate (0207-25) (200 mg, 0.709 mmol, 1.1 eq.) and cesium carbonate (460 mg, 1.418 mmol, 2 Equivalent) was mixed in isopropanol (10 m
  • Step 9g 1-(6-Methylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (2- Preparation of (5H-imidazo[5,1-a]isoindol-5-yl)-1-(6-methylbenzofuran-5-yl)ethan-1-one) (Compound 0209-25): Compound 1-(6 -methylbenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-5-yl)phenyl)propan-2-en-1-one (0208-25) (310 mg, 0.543 mmol, 1 eq.) and acetic acid (2 mL) were combined in methanol (4 mL).
  • Step 9h 1-(6-Methylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol
  • (1- Preparation of (6-methyl benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol)
  • Compound 25 1-(6-methylbenzofuran) -5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0209-25) (200 mg, 0.609 mmol, 1.0 eq) Dissolve in 30 ml of methanol, cool in ice-cooled to 0 ° C, add sodium borohydride (35 mg, 0.915 mmol, 1.5 eq.), stir the reaction for half an hour, add acetone, concentrate under reduced pressure, and add dichloromethane to extract.
  • Step 10a Preparation of methyl 4-hydroxy-2-(trifluoromethyl)benzoate (compound 0202-30): 2-trifluoromethyl-4-hydroxyl Benzoic acid (0201-30) (600 mg, 2.91 mmol, 1.0 eq.) was dissolved in 30 mL of methanol, and then thionyl chloride (2 mL) was slowly added dropwise. The mixture was stirred at 50 °C overnight. After the reaction was completed, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated Methyl ester (612 mg, yield: 95.6%). LCMS (ESI): m / z 221 [M + 1] +.
  • Step 10b Preparation of methyl 4-hydroxy-5-iodo-2-(trifluoromethyl)benzoate (compound 0204-30): potassium carbonate ( 891 mg, 6.46 mmol, 2.0 eq.) and the compound 2-trifluoromethyl-4-hydroxybenzoic acid methyl ester (0202-30) (712 mg, 3.23 mmol, 1.0 eq) were dissolved in 50 mL of THF. Iodine (985 mg, 3.88 mmol, 1.2 eq.) was added and stirred at room temperature overnight. After the reaction was completed, 15 ml of an aqueous solution of sodium hydrogensulfite was added. The mixture was extracted with EtOAc. EtOAc (EtOAc m.) . LCMS (ESI): m / z 347 [M + 1] +.
  • Step 10c Preparation of methyl 6-(trifluoromethyl)benzofuran-5-carboxylate (compound 0206-30): under the protection of nitrogen, 2-3 Methyl fluoromethyl-4-hydroxy-5-iodobenzoate (0204-30) (800 mg, 2.31 mmol, 1.0 eq.), trimethylsilylacetylene (341 mg, 3.46 mmol, 1.5 eq.), iodine Cuprous (7 mg, 0.035 mmol, 0.015 equivalent) and bistriphenylphosphine palladium dichloride (48 mg, 0.07 mmol, 0.03 equivalent) were added to 30 ml of tetrahydrofuran, followed by dropwise addition of triethylamine (701 Mg, 6.93 mmol, 3.0 eq.), the mixture was heated to 50 ° C and stirred for 3 hours.
  • Step 10d (2-oxo-2-(6-trifluoromethylbenzofuran-5-yl)ethyl) dimethyl phosphate (dimethyl(2-oxo-2-(6-(trifluoromethyl)benzofuran-) Preparation of 5-yl)ethyl)phosphonate)
  • Compound (0207-30) Dimethyl methylphosphonate (152 mg, 1.23 mmol, 1.5 eq.) was dissolved in 15 mL of dry tetrahydrofuran under a nitrogen atmosphere. in.
  • Step 10e 1-(6-Trifluoromethylbenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-ene 1-(6-(trifluoromethyl)benzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en-1-one)
  • (Compound 0208-30) Compound (2-oxo-2-(6-trifluoromethylbenzofuran-5-yl)ethyl)phosphoric acid dimethyl ester (0207-30) (262 mg, 0.78 mmol, 1.2 eq.), 2-(1-trityl-1H-imidazol-4-yl)benzaldehyde (0105-1) (270 mg, 0.65 mmol, 1.0 eq.) and cesium carbonate (847 mg) The mixture was mixed with isopropyl alcohol (20 ml), and
  • Step 10f 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(6-trifluoromethylbenzofuran-5-yl)ethane-1-one ( Preparation of 2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(6-(trifluoromethyl)benzofuran-5-yl)ethan-1-one) (Compound 0209-30): Compound 1-(6-trifluoromethylbenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-ene-1 - Ketone (0208-30) (173 mg, 0.277 mmol, 1.0 eq.) and EtOAc (2 mL).
  • Step 10g 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(6-trifluoromethylbenzofuran-5-yl)ethane-1-ol ( Preparation of 2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(6-(trifluoromethyl)benzofuran-5-yl)ethan-1-ol) (Compound 30): Compound 2 -(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(6-trifluoromethylbenzofuran-5-yl)ethane-1-one (0209-30) (93 mg, 0.24 mmol, 1.0 eq.) was dissolved in 40 mL of ethanol.
  • Step 11a 5-methoxy-2-pinacol borate benzaldehyde (5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde
  • (Compound 0104-31) Compound 2-bromo-5-methoxybenzaldehyde (1 g, 4.65 mmol, 1 eq.), bis-pinacol borate (1.77 g) , 6.975 mmol, 1.5 eq.), potassium acetate (1.37 g, 3 eq.), tetratriphenylphosphine palladium (538 mg, 0.465 mmol, 0.1 eq.) was mixed in 10 ml of toluene, and the reaction was stirred at 110 ° C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered, and the filtrate was evaporated. mjjjjjj
  • Step 11b 5-methoxy-2-(1-tritylmethyl-1H-imidazol-5-yl)benzaldehyde (5-methoxy-2-(1-trityl-1H-imidazol-5-yl)benzaldehyde
  • Compound 0105-31 Compound 5-methoxy-2-pinacol borate benzaldehyde (0104-31) (610 mg, 2.32 mmol, 1.4 eq.) -Iodo-1-trityl-1H-imidazole (0101-1) (725 mg, 1.66 mmol, 1 eq.), tetratriphenylphosphine palladium (192 mg, 0.166 mmol, 0.1 eq.), phosphoric acid Potassium (865 mg, 3.32 mmol, 2 eq.) was mixed in DMF / H 2 O (50/10 mL), and the reaction was stirred at 95 ° C for 3 hours.
  • Step 11c 1-(benzofuran-5-yl)-3-(5-methoxy-2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-ene
  • Preparation of compound 0208-31) dimethyl (2-(benzofuran-5-yl)-2-oxoethyl)phosphate (0207-1) (175 mg, 0.652 mmol, 1.3 eq.)
  • Compound 5-methoxy-2-(1-trityl-1H-imidazol-5-yl)benzaldehyde (0105-31) (220 mg, 0.5 mmol, 1 eq.) and bismuth carbonate (325 mg, 1 mmol, 2 equivalents) were mixed in isopropyl alcohol (10 ml),
  • Step 11d 1-(1H-benzofuran-5-yl)-2-(7-methoxy-5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-
  • ketone (1-(benzofuran-5-yl)-2-(7-methoxy-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0209-31)) : The compound 1-(benzofuran-5-yl)-3-(5-methoxy-2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-ene 1- Ketone (0208-31) (280 mg, 0.478 mmol, 1 eq.) and EtOAc (2 mL).
  • Step 11e 1-(1H-benzofuran-5-yl)-2-(7-methoxy-5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-
  • alcohol (1-(benzofuran-5-yl)-2-(7-methoxy-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)
  • Compound 31 1 -(1H-benzofuran-5-yl)-2-(7-methoxy-5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0209- 31) (1 60 mg, 0.465 mmol, 1.0 eq.) was dissolved in 10 ml of methanol, cooled in ice-cooled to 0 ° C, sodium borohydride (35 mg, 0.93 mmol, 2 eq.
  • Example 12 1-(1H-benzofuran-5-yl)-2-(7-fluoro-5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol Preparation of (1-(b enzofuran-5-yl)-2-(7-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 32) One and two line preparation)
  • Step 12a 5-fluoro-2-pinacol borate benzaldehyde (5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde) ( Preparation of compound 0104-32): Compound 2-bromo-5-fluorobenzaldehyde (500 mg, 2.46 mmol, 1 eq.), bis-pinacol boron ester (937 mg, 3.69 mmol, 1.5 equivalents, potassium acetate (724 g, 7.38 mmol, 3 equivalents), tetrakistriphenylphosphine palladium (284 mg, 0.246 mmol, 0.1 eq.), mixed in 10 ml of toluene, and stirred at 110 ° C. hour. After completion of the reaction, the mixture was cooled to room temperature, filtered, and the filtrate was evaporated. mjjjjjj
  • Step 12b 5-fluoro-2-(1-trityl-1H-imidazol-5-yl)benzaldehyde (5-fluoro-2-(1-trityl-1H-imidazol-5-yl)benzaldehyde)
  • compound 0105-32 Compound 5-fluoro-2-pinacol borate benzaldehyde (0104-32) (1.5 g, 2.46 mmol, 1.4 eq.), 5-iodo-1 -Trityl-1H-imidazole (0101-1) (715 mg, 1.64 mmol, 1 eq.), tetratriphenylphosphine palladium (189 mg, 0.164 mmol, 0.1 eq.), tripotassium phosphate (854 mg) 3.28 mmol, 2 eq.) was mixed with DMF / H 2 O (50/10 ml), and the reaction was stirred at 95 ° C for 3 hours.
  • Step 12c 1-(benzofuran-5-yl)-3-(5-fluoro-2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-ene-1 -keto(1-(benzofuran-5-yl)-3-(5-fluoro-2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one) (Compound 0208 -32) Preparation: dimethyl (2-(benzofuran-5-yl)-2-oxoethyl)phosphate (0207-1) (175 mg, 0.652 mmol, 1.3 eq.), Compound 5 -Fluoro-2-(1-trityl-1H-imidazol-5-yl)benzaldehyde (0105-32) (216 mg, 0.5 mmol, 1 eq.) and cesium carbonate (325 mg, 1 mmol, 2 equivalents) were mixed in isoprop
  • Step 12d 1-(1H-benzofuran-5-yl)-2-(7-fluoro-5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one ( Preparation of 1-(benzofuran-5-yl)-2-(7-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0209-32): Compound 1-(benzofuran-5-yl)-3-(5-fluoro-2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one ( 0208-32) (200 mg, 0.35 mmol, 1 eq.) and EtOAc (2 mL).
  • Step 12e 1-(1H-benzofuran-5-yl)-2-(7-fluoro-5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol ( Preparation of 1-(benzofuran-5-yl)-2-(7-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 32): 1-(() 1H-benzofuran-5-yl)-2-(7-fluoro-5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0209-32) (110 ⁇ / RTI> ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> ⁇ /RTI
  • Example 13 1-(benzofuran-5-yl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol (1 -(benzofuran-5-yl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 33) (According to Schemes 1 and 2) Line preparation)
  • Step 13a 2-fluoro-6-pinacol borate benzaldehyde (2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde)
  • compound 0104-33 Compound 2-bromo-6-fluorobenzaldehyde (2.0 g, 9.84 mmol, 1.0 eq.), bis-pinacol borate (3.75 g, 14.76 mmol, 1.5 eq.) , potassium acetate (2.89 g, 29.52 mmol, 3.0 eq.), tetrakistriphenylphosphine palladium (568 mg, 0.49 mmol, 0.05 eq.) was mixed in 50 ml of toluene, replaced with nitrogen three times or more, then at 110 ° C The reaction was stirred overnight. After completion of the reaction, the mixture was cooled to room temperature, filtered, and the filtrate was evaporated. m
  • Step 13b 2-fluoro-6-(1-trityl-1H-imidazol-5-yl)benzaldehyde (2-fluoro-6-(1-trityl-1H-imidazol-5-yl)benzaldehyde)
  • 2-fluoro-6-pinacol borate benzaldehyde (0104-33) (3.23 g, 12.9 mmol, 1.5 equivalents)
  • 5-iodo-1 - Trityl-1H-imidazole (0101-1) (3.75 g, 8.6 mmol, 1.0 eq.)
  • tetratriphenylphosphine palladium (994 mg, 0.86 mmol, 0.1 eq.
  • tripotassium phosphate (3.65 g) , 17.2 mmol, 2.0 eq.) was mixed with DMF / H 2 O (80/10 mL) and stirred at 95 ° C overnight.
  • Step 13c 1-(benzofuran-5-yl)-3-(2-fluoro-6-(1-tritylmethyl-1H-imidazol-5-yl)phenyl)propan-2-ene-1 -keto(1-(benzofuran-5-yl)-3-(2-fluoro-6-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en-1-one) (Compound 0208 -33)
  • Compound 2 -Fluoro-6-(1-trityl-1H-imidazol-5-yl)benzaldehyde (0105-33) (100 mg, 0.23 mmol, 1.0 eq.) and cesium carbonate (150 mg, 0.46 mmol, 2.0 equivalents) were mixed in is
  • Step 13d 1-(benzofuran-5-yl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (1- Preparation of (benzofuran-5-yl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0209-33): Compound 1- (benzofuran-5-yl)-3-(2-fluoro-6-(1-tritylmethyl-1H-imidazol-5-yl)phenyl)propan-2-en-1-one (0208- 33) (108 mg, 0.188 mmol, 1.0 eq.) and EtOAc (2 mL).
  • Step 13e 1-(benzofuran-5-yl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol
  • (1- Preparation of (benzofuran-5-yl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)
  • Compound 33 Compound 1-(Benzene) And furan-5-yl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0209-33) (61 mg, 0.18 1 mmol) was dissolved in 20 ml of ethanol, cooled to 0 ° C in an ice bath, sodium borohydride (14 mg, 0.36 mmol, 2.0 eq.) was added, the reaction was stirred for 1 hour, acetone was added and concentrated under reduced pressure.
  • Step 14a Preparation of methyl 2,3-dihydrobenzofuran-5-carboxylate (compound 0403-36): Compound 2,3-dihydrobenzofuran -5-carboxylic acid (0401-36) (900 mg, 5.5 mmol, 1.0 eq.) was dissolved in 50 mL methanol. After cooling in an ice bath, thionyl chloride (0.8 ml, 11.0 mmol, 2.0 eq.) was slowly added dropwise. The mixture was stirred at room temperature overnight. After the reaction was completed, it was concentrated under reduced pressure. The residue was dissolved in dichloromethane, and a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was adjusted to basic. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness crystals.
  • Step 14b dimethyl (2-(2,3-dihydrobenzofuran-5-yl)-2-oxoethyl)phosphate (dimethyl(2-(2,3-dihydrobenzofuran-5-yl)- Preparation of 2-oxoethyl)phosphonate)
  • Compound 0403-36 Dimethyl methyl phosphate (888 mg, 7.16 mmol, 1.5 eq.) was dissolved in 20 mL of dry tetrahydrofuran under nitrogen and cooled.
  • n-Butyllithium (3.8 ml, 2.5 mol/L tetrahydrofuran solution, 9.5 mmol, 2.0 eq.) was slowly added dropwise at -70 ° C, the mixture was stirred at this temperature for 30 minutes, and the compound 2, 3- was slowly added dropwise.
  • Step 14c (Z)-1-(2,3-Dihydrobenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propane 2-(2-(1-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2 -en-1-one] (Compound 0040-36)
  • 2-(1-Trityl-1H-imidazol-4-yl)benzaldehyde (0105-1) (500 mg, 1.2 mmol, 1.0 equivalents, dimethyl 2-(2,3-dihydrobenzofuran-5-yl)-2-oxoethyl)phosphate (0402-36) (420 mg, 1.5 mmol, 1.3 eq.
  • Step 14d 1-(2,3-Dihydrobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one ( Preparation of 1-(2,3-dihydrobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0405-36): Compound (Z)-1-(2,3-dihydrobenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propane-2- The ene-1-one (0404-36) (500 mg, 0.9 mmol, 1.0 eq.) and acetic acid (10 ml) were combined in methanol (40 ml), and the mixture was stirred at 90 ° C overnight.
  • Step 14e 1-(2,3-Dihydrobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol ( Preparation of 1-(2,3-dihydrobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 36): Compound 1- (2,3-dihydrobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0405-36) ( 250 mg, 0.79 mmol, 1.0 eq.) was dissolved in 10 mL of methanol, then sodium borohydride (121 mg, 3.2 mmol, 4.0 eq.) was slowly added and cooled to 0 °C.
  • Example 15 1-(6-Fluoro-2,3-dihydrobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane
  • Step 15a Preparation of methyl 6-fluoro-2,3-dihydrobenzofuran-5-carboxylate (compound 0402-42): compound Methyl 6-fluorobenzofuran-5-carboxylate (300 mg, 1.54 mmol, 1 eq.) was dissolved in 10 ml of methanol, then 30 mg of palladium carbon was added, and the mixture was replaced with hydrogen, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was filtered, and then evaporated tolulululululululululululululululululululululululululululululululululululululululululululululululululululululululululu LCMS (ESI): m / z 197 [M + 1] +.
  • ESI tolulululululululululululululululululululululululululululululul
  • Step 15b (2-(6-Fluoro-2,3-dihydrobenzofuran-5-yl)-2-oxoethyl)phosphoric acid dimethyl ester (dimethyl(2-(6-fluoro-2,3) Preparation of -dihydrobenzofuran-5-yl)-2-oxoethyl)phosphonate) (Compound 0403-42): Dissolving dimethyl methylphosphonate (286 mg, 2.31 mmol, 1.5 eq.) in a nitrogen atmosphere 5 ml of dry tetrahydrofuran.
  • Step 15c 1-(6-Fluoro-2,3-dihydrobenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-5-yl)phenyl)propane 1-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2 -en-1-one) (Compound 0404-42) Preparation: 2-(1-trityl-1H-imidazol-4-yl)benzaldehyde (0105-1) (263 mg, 0.635 mmol, 1 equivalent), compound (2-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-oxoethyl)phosphoric acid dimethyl ester (0403-42) (377 mg, 1.3 m Mole, 1.3 equivalents) and cesium carbonate (412 mg, 1.27 mmol,
  • Step 15d 1-(6-Fluoro-2,3-dihydrobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane- 1-keto(1-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0405) -42)
  • Step 15e 1-(6-Fluoro-2,3-dihydrobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane- 1-Alcohol (1-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 42 Preparation: 1-(6-Fluoro-2,3-dihydrobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl) Alkan-1-one (0405-42) (150 mg, 0.45 mmol, 1.0 eq.) was dissolved in 30 mL methanol, cooled in ice-cooled to 0 ° C, and sodium borohydride (34 mg, 0.9 mmol, 2 Equivalent
  • Step 16a Preparation of methyl 6-hydroxy-5-iodonicotinate (compound 0204-49): 6-hydroxynicotinic acid (0201-49) (2.8 g, 20 m) Molar, 1.0 eq.) was dissolved in 50 mL of methanol. Concentrated sulfuric acid (3 ml) was added dropwise slowly. The mixture was stirred at 60 ° C overnight. After cooling to room temperature, iodosuccinimide (5.4 g, 24 mmol, 1.2 equivalent) was added, and the mixture was heated to 60 ° C for 4 hours. After the reaction was completed, 15 ml of an aqueous solution of sodium hydrogensulfite was added. The mixture was extracted with EtOAc. EtOAc (EtOAc m. LCMS (ESI): m / z 280 [M + 1] +.
  • Step 16b Preparation of methyl furo[2,3-b]pyridine-5-carboxylate (compound 0206-49): under nitrogen protection, Methyl 6-hydroxy-5-iodonicotinate (0204-49) (1.45 g, 5.2 mmol, 1.0 eq.), trimethylsilylacetylene (2.55 g, 26 mmol, 5.0 eq.), cuprous iodide ( 494 mg, 2.6 mmol, 0.5 eq.) and tetrakistriphenylphosphine palladium (168 mg, 0.16 mmol, 0.03 equivalent) were added to 30 ml of tetrahydrofuran, then diisopropylethylamine (1.3 g, 13 m) was added dropwise.
  • Step 16c (2-(furo[2,3-b]pyridin-5-yl)-2-oxoethyl)phosphate dimethyl ester (dimethyl(2-(furo[2,3-b]pyridin-) Preparation of 5-yl)-2-oxoethyl)phosphonate)
  • Compound 0207-49 Dissolve dimethyl methylphosphonate (42 mg, 0.338 mmol, 1.5 eq.) in 5 mL under a nitrogen atmosphere Dry in toluene.
  • Step 16d 1-(furo[2,3-b]pyridin-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2- 1-(furo[2,3-b]pyridin-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en-
  • 1-one Compound 0208-49
  • 60% sodium hydride (9.5 mg, 0.394 mmol, 2.0 eq.) was dissolved in 10 ml of tetrahydrofuran under nitrogen atmosphere and ice bath.
  • Step 16e 1-(furo[2,3-b]pyridin-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-one ( 1-(furo[2,3-b]pyridin-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0209-49)
  • Step 16f 1-(furo[2,3-b]pyridin-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-ol ( Preparation of 1-(furo[2,3-b]pyridin-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 49): The compound 1-(furo[2,3-b]pyridin-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-one (0209 -49) (16 mg, 0.05 mmol, 1.0 eq.) was dissolved in 10 mL methanol.
  • Step 17a methyl 4-hydroxy-3-(3-hydroxyprop-1-yn-1-yl)benzoate
  • 4-hydroxy-3-iodobenzoic acid methyl ester (1 g, 3.6 mmol) and propargyl alcohol (0.24 g, 4.3 mmol) were dissolved in tetrahydrofuran (15 ml) at room temperature.
  • Step 17b 2-(((tert-Butoxycarbonyl)oxy)methyl)benzofuran-5-carboxylic acid methyl ester (I-6-57-A4) (methyl 2-((tert-butoxycarbonyl)oxy)
  • methyl benzofuran-5-carboxylate compound 0206-50: methyl 4-hydroxy-3-(3-hydroxyprop-1-en-1-yl)benzoate (0205-50) (0.25 g, 1.2 mmol) was dissolved in N,N-dimethylformamide (5 ml), then iodide (23 mg, 0.12 mmol) and diisopropylamine (100 mg) were added and heated to 120 ° C overnight.
  • Step 17c ((5-(2-(dimethoxyphosphonyl))acetyl)benzofuran-2-yl)methyl)carbonate tert-butyl (tert-butyl((5-(2-(dimethoxyphosphoryl))) Preparation of acetyl)benzofuran-2-yl)methyl)carbonate)
  • Compound 0207-50 Dimethyl methyl phosphate (0.13 g, 1 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to minus 78 ° C Then, n-butyllithium (2.5 moles per liter of n-hexane solution, 0.5 ml) was added dropwise, and the temperature was kept for half an hour, and then 2-(((tert-butoxycarbonyl)oxy)methyl)benzofuran was added dropwise.
  • Step 17d ((5-(3-(2-(1-tritylmethyl-1H-imidazol-5-yl)phenyl)acryloyl)benzofuran-2-yl)methyl)carbonate tert-butyl ester
  • tert-butyl((5-(3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)acryloyl)benzofuran-2-yl)methyl)carbonate) (Compound 0208-50): 2-(1-Trityl-1H-imidazol-5-yl)benzaldehyde (0105-1) (200 mg, 0.483 mmol, 1 eq.), Compound ((5-(2-)) Phosphate) acetyl)benzofuran-2-yl)methyl)carbonate tert-butyl ester (0207-50) (211 mg, 0.531 mmol, 1.1 eq.) and cesium carbonate (314 mg
  • Step 17e 1-(2-(Hydroxymethyl)benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one
  • (1-(2-(hydroxymethyl)benzofuran-5-yl)-2-(5H-pyrrolo[2,1-a]isoindol-5-yl)ethan-1-one) (Compound 0209-50): The compound ((6-(3-(2-(1-tritylmethyl-1H-imidazol-5-yl)phenyl)acryloyl)benzofuran-2-yl)methyl)carbonate tert-butyl ester ( (208 mg, 0.445 mmol, 1 eq.) and acetic acid (2 mL) were combined in methanol (4 mL).
  • Step 17f 1-(2-(Hydroxymethyl)benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol
  • 1-(2-(hydroxymethyl)benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) Compound 50: 1 -(2-(hydroxymethyl)benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0209-50 (210 mg, 0.61 mmol, 1.0 eq.) was dissolved in 30 mL of methanol, cooled in ice-cooled to 0 ° C, sodium borohydride (27 mg, 0.70 mmol, 1.15 eq.).
  • Step 18a methyl 2-(2-hydroxypropan-2-yl)benzofuran-5-carboxylate (compound 0206-59)
  • 3-iodo-4-hydroxybenzoic acid methyl ester (0204-1) (1.0 g, 3.6 mmol, 1.0 eq.), cuprous iodide (10 mg, 0.05 mmol, 0.015).
  • cuprous iodide (10 mg, 0.05 mmol, 0.015).
  • Equivalent bistriphenylphosphine palladium dichloride (76 mg, 0.11 mmol, 0.03 equivalent) and 2-methyl-3-butyn-2-ol (424 mg, 5.0 mmol, 1.4 eq.) dissolved in Mix 20 ml of tetrahydrofuran and 20 ml of chloroform.
  • Step 18b (2-(2-(2-Hydroxypropan-2-yl)benzofuran-5-yl)-2-oxoethyl)phosphate dimethyl ester (dimethyl(2-(2-(2-) Preparation of hydroxypropan-2-yl)benzofuran-5-yl)-2-oxoethyl)phosphonate) (Compound 0207-59).
  • Dimethyl methylphosphonate (265 mg, 2.13 mmol, 2.5 eq.) was dissolved in 15 mL of dry tetrahydrofuran under a nitrogen atmosphere.
  • Step 18c 1-(2-(2-Hydroxypropan-2-yl)benzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl ) propan-2-en-1-one (1-(2-(2-hydroxypropan-2-yl)benzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl) Preparation of pheny l)prop-2-en-1-one) (Compound 0208-59): Compound (2-(2-(2-hydroxypropan-2-yl)benzofuran-5-yl)-2 -Oxoethyl)dimethyl phosphate (0207-59) (391 mg, 1.2 mmol, 2.0 eq.), compound 2-(1-trityl-1H-imidazol-4-yl)benzaldehyde (0105 (1) (250 mg, 0.6 mmol, 1.0 eq.) and cesium carbonate
  • Step 18d 1-(2-(2-Hydroxypropan-2-yl)benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)B 1-(2-(2-hydroxypropan-2-yl)benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1- Preparation of one) (Compound 0209-59): The compound 1-(2-(2-hydroxypropan-2-yl)benzofuran-5-yl)-3-(2-(1-tritylmethyl)- 1H-imidazol-4-yl)phenyl)propan-2-en-1-one (0208-59) (273 mg, 0.44 mmol, 1.0 eq.) and acetic acid (3 mL) .
  • Step 18e 2-(5-(1-Hydroxy-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethyl)benzofuran-2-yl)propane-2- Alcohol (2-(5-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)benzofuran-2-yl)propan-2-ol) (Compound 59) Preparation: the compound 1-(2-(2-hydroxypropan-2-yl)benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl) Ethyl-1-one (0209-59) (70 mg, 0.188 mmol, 1.0 eq.) was dissolved in 30 mL methanol.
  • Step 19a methyl 6-fluoro-2-(2-hydroxypropan-2-yl)benzofuran-5-carboxylate (methyl 6-fluoro-2-(2-hydroxypropan-2-yl)benzofuran-5- Carboxylate (preparation of compound 0206-60): methyl 2-fluoro-4-hydroxy-5-iodobenzoate (0204-1) (700 mg, 2.36 mmol, 1.0 eq.) 2-methyl-3-butyn-2-ol (595 mg, 7.08 mmol, 3.0 eq.), triethylamine (0.99 ml, 7.08 mmol, 3.0 eq.), cuprous iodide (9 mg, 0.05 mM) Mole, 0.02 equivalents), tetrabutylammonium fluoride (870 mg, 2.36 mmol) and tetrakistriphenylphosphine palladium (136 mg, 0.12 mmol, 0.05 eq.) were added to 25 ml of t
  • Step 19b (2-(6-Fluoro-2-(2-hydroxypropan-2-yl)benzofuran-5-yl)-2-oxoethyl)phosphate dimethyl ester (dimethyl(2-(6) Preparation of -fluoro-2-(2-hydroxypropan-2-yl)benzofuran-5-yl)-2-oxoethyl)phosphonate)
  • Compound 0207-60 Add methyl in a round bottom flask under nitrogen atmosphere Dimethyl phosphonate (912 mg, 7.35 mmol, 5.0 eq.) and 30 mL of anhydrous tetrahydrofuran were cooled to -72 ° C in dry ice-ethanol bath and 2.5 M n-butyllithium n-hexane solution (3.53 mL, 8.82 mmol, 6.0 eq.), stirring for one hour, dropwise adding methyl 6-fluoro-2-(2-hydroxypropan-2-yl)benzofuran-5-carboxy
  • Step 19c 1-(6-Fluoro-2-(2-hydroxypropan-2-yl)benzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazole-4- Phenyl)propan-2-en-1-one (1-(6-fluoro-2-(2-hydroxypropan-2-yl)benzofuran-5-yl)-3-(2-(1-trityl-) Preparation of 1H-imidazol-4-yl)phenyl)prop-2-en-1-one) (Compound 0208-60): (2-(6-Fluoro-2-(2-hydroxypropan-2-yl)) Dimethyl benzofuran-5-yl)-2-oxoethyl)phosphate (0207-60) (400 mg, 1.47 mmol, 3.3 eq.), 2-(1-tritylmethyl-1H-imidazole 4-yl)benzaldehyde (0105-1) (180 mg, 0.44 mmol, 1.0
  • Step 19d 1-(6-Fluoro-2-(2-hydroxypropan-2-yl)benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5 -yl-6-fluoro-2-(2-hydroxypropan-2-yl)benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-
  • 5-yl)ethan-1-one Compound 0209-60
  • Step 19e 2-(6-Fluoro-5-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethyl)benzofuran-2-yl) Propane-2-ol (2-(6-fluoro-5-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)benzofuran-2-yl)propan-2 -ol) (Preparation of Compound 60): 1-(6-Fluoro-2-(2-hydroxypropan-2-yl)benzofuran-5-yl)-2-(5H-imidazole [5,1- a] Isoindoline-5-yl)ethane-1-one (0209-60) (150 mg, 0.38 mmol, 1.0 eq.) was dissolved in 30 mL of methanol, cooled to 0 ° C Sodium borohydride (29 mg
  • Step 20a Preparation of 5-bromo-2-methylbenzofuran (Compound 0301-68): ethyl 2-bromopropionate (2.7 g, 15 mmol, 1.5 eq. It was added to a solution of 5-bromo salicylaldehyde (2 g, 10 mmol, 1.0 eq.) and potassium carbonate (2.8 g, 20 mmol, 2.0 eq.) in 70 ml of acetonitrile and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to remove acetonitrile, and then 70 ml of methanol was added, and the reaction was stirred at 70 ° C for 4 hours.
  • Step 20b Preparation of 2-methylbenzofuran-5-carboxylic acid (Compound 0302-68): Add 5-bromine in a round bottom flask under nitrogen protection 2-methylbenzofuran (0301-68) (1.4 g, 6.6 mmol, 1.0 eq.) and 50 ml of anhydrous tetrahydrofuran, cooled to -72 ° C in dry ice-ethanol bath, and 2.5 M n-butyllithium was added dropwise. A solution of n-hexane (4.8 ml, 11.9 mmol, 1.8 eq.) was stirred for one hour, carbon dioxide was passed, and the reaction was stirred for 1 hour. 2M hydrochloric acid aqueous solution was added dropwise to the aqueous phase to pH 1. The mixture was extracted with ethyl acetate. ,Crude).
  • Step 20c Preparation of methyl 2-methylbenzofuran-5-carboxylate (compound 0303-68): 2-methylbenzofuran-5-carboxylic acid ( 0302-68) (1.5 g, 6.6 mmol, 1.0 eq.) was dissolved in 40 ml of methanol, and then thionyl chloride (1.8 ml, 25.5 mmol, 3.0 eq.) and two drops of DMF were slowly added dropwise, and refluxed for three hours. . Cooled to room temperature, concentrated under reduced pressure, extracted with ethyl acetate, washed with water and brine The organic phase was dried over anhydrous sodium sulfate (MgSO4). .
  • MgSO4 anhydrous sodium sulfate
  • Step 20d (2-(2-methylbenzofuran-5-yl)-2-oxoethyl) dimethyl phosphate (dimethyl(2-(2-methylbenzofuran-5-yl)-2-oxoethyl) Preparation of phosphonate) (Compound 0304-68): In a round bottom flask, dimethyl methylphosphonate (645 mg, 5.2 mmol, 2.0 eq.) and 30 mL of anhydrous tetrahydrofuran were added to dry ice under nitrogen.
  • Step 20e 1-(2-Methylbenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-ene-1 -keto(1-(2-methylbenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)
  • Compound 0305-68 Preparation of (2-(2-methylbenzofuran-5-yl)-2-oxoethyl)phosphoric acid dimethyl ester (0304-68) (226 mg, 0.80 mmol, 1.1 eq.)
  • 2-(1-Trityl-1H-imidazol-4-yl)benzaldehyde (0105-1) (300 mg, 0.73 mmol, 1.0 eq.) and cesium carbonate (473 mg, 1.45 mmol, 2.0 eq.) After adding to 40 ml of isopropy
  • Step 20f 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(2-methylbenzofuran-5-yl)ethane-1-one (2- Preparation of (5H-imidazo[5,1-a]isoindol-5-yl)-1-(2-methylbenzofuran-5-yl)ethan-1-one) (0306-68): 1-(2-A) Benzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (0305-68) (500 Methanol, 0.73 mmol, 1.0 eq.) was dissolved in 30 mL of methanol.
  • Step 20g 2-(5H-Imidazo[5,1-a]isoindoline-5-yl)-1-(2-methylbenzofuran-5-yl)ethane-1-ol (2- Preparation of (5H-imidazo[5,1-a]isoindol-5-yl)-1-(2-methylbenzofuran-5-yl)ethan-1-ol)
  • Compound 68 2-(5H-Imidazole [ 5,1-a]isoindoline-5-yl)-1-(2-methylbenzofuran-5-yl)ethane-1-one (0306-68) (200 mg, 0.61 mmol, 1.0 equivalent) dissolved in 30 ml of methanol, cooled to 0 ° C in an ice bath, sodium borohydride (47 mg, 1.22 mmol, 2.0 eq.), stirred for half an hour, added acetone, concentrated under reduced pressure, and added to dichloro The mixture was extracted with methylene chloride (b
  • Step 21a Preparation of methyl 2-phenylbenzofuran-5-carboxylate (compound 0206-79): Compound 4-hydroxy-3- under nitrogen atmosphere Methyl iodobenzoate (0204-1) (2.78 g, 9.98 mmol, 1.0 eq.), cuprous iodide (28 mg, 0.15 mmol, 0.015 eq.), bistriphenylphosphine palladium dichloride (210 mg) , 0.3 mmol, 0.03 equivalent) and phenylacetylene (1.42 g, 13.997 mmol, 1.4 equivalent) were dissolved in a mixture of 20 ml of tetrahydrofuran and 40 ml of chloroform.
  • Step 21b dimethyl (2-(2-phenylbenzofuran-5-yl)-2-oxoethyl)phosphate (dimethyl(2-oxo-2-(2-phenylbenzofuran-5-yl)ethyl) Preparation of phosphonate) (Compound 0207-79): Dimethyl methyl phosphate (211 mg, 1.703 mmol, 1.5 eq.) was dissolved in 10 mL of dry THF.
  • Step 21c 1-(2-Phenylbenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-ene-1 -keto(1-(2-phenylbenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)
  • Compound 0208-79 Preparation of (2-(2-phenylbenzofuran-5-yl)-2-oxoethyl)phosphoric acid dimethyl ester (0207-79) (254 mg, 0.738 mmol, 1.0 eq.)
  • 2-(1-Trityl-1H-imidazol-4-yl)benzaldehyde (0105-1) (305 mg, 0.738 mmol, 1.0 eq.) and cesium carbonate (480 mg, 1.476 mmol, 2.0 eq.)
  • Step 21d 1-(2-Phenylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (1- Preparation of (2-phenylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0209-79): Compound 1-(2 -Phenylbenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (0208-79) (306 mg, 0.484 mmol, 1.0 eq.) and acetic acid (5 mL) were combined in methanol (200 mL).
  • Step 21e 1-(2-Phenylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol (1- Preparation of (2-phenylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 79): Compound 1-(2-Benzene) Benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0209-79) (157 mg, 0.402 mmol) , 1.0 equivalent) was dissolved in 50 ml of methanol.
  • Example 22 1-(6-Fluoro-2-phenylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1 -Alcohol (1-(6-fluoro-2-phenylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 80) (prepared according to the scheme 2)
  • Step 22a Preparation of methyl 6-fluoro-2-phenylbenzofuran-5-carboxylate (compound 0206-80): under nitrogen protection, Methyl 2-fluoro-4-hydroxy-5-iodobenzoate (0204-8) (800 mg, 2.7 mmol, 1.0 eq.), phenylacetylene (408 mg, 4.056 mmol, 1.5 eq.), cuprous iodide (7.6 mg, 0.04 mmol, 0.015 equivalent), tetrabutylammonium iodide (1.49 g, 4.056 mmol, 1.5 eq.) and tetrakistriphenylphosphine palladium (56 mg, 0.09 mmol, 0.03 eq.) were added to 10 A mixed solution of THF and 20 ml of chloroform was added dropwise triethylamine (816 mg, 8.11 mmol, 3 eq.), and the mixture was heated to 55 ° C and
  • Step 22b (2-(6-fluoro-2-phenylbenzofuran-5-yl)-2-oxoethyl)phosphoric acid dimethyl ester (dimethyl(2-(6-fluoro-2-phenylbenzofuran-5) Preparation of -yl)-2-oxoethyl)phosphonate)
  • Step 22c 1-(6-Fluoro-2-phenylbenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-5-yl)phenyl)propane-2 1-(6-fluoro-2-phenylbenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en-1 -one) (Compound 0208-80): 2-(1-trityl-1H-imidazol-4-yl)benzaldehyde (0105-1) (287 mg, 0.693 mmol, 1 eq) Compound (2-(6-fluoro-2-phenylbenzofuran-5-yl)-2-oxoethyl)phosphoric acid dimethyl ester (0207-80) (300 mg, 0.83 mmol, 1.2 eq.) Cesium carbonate (450 mg, 1.386 mmol, 2 eq.)
  • Step 22d 1-(6-Fluoro-2-phenylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1- Ketone (1-(6-fluoro-2-phenylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (compound 0209-80)
  • Preparation the compound 1-(6-fluoro-2-phenylbenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-5-yl)phenyl)propane - 2-En-1-one (0208-80) (250 mg, 0.38 mmol, 1 eq.) and EtOAc (2 mL) The mixture was stirred at 90 ° C for 16 hours.
  • Step 22e 1-(6-Fluoro-2-phenylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-
  • Alcohol (1-(6-fluoro-2-phenylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)
  • Compound 80 1-(6-Fluoro-2-phenylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one ( 0209-80) (200 mg, 0.49 mmol, 1.0 eq.) was dissolved in 30 mL of methanol, cooled in ice-cooled to 0 ° C, sodium borohydride (37 mg, 0.9 mmol, 2 eq.
  • Step 23a Preparation of methyl 4-acetoxybenzoate (compound 1002-95): acetyl chloride (10.4 g, 132 mmol, 2.0 eq.) was added dropwise to p-hydroxybenzene under ice bath. Methyl formate (1001-95) (10 g, 66 mmol, 1.0 eq.) and triethylamine (20 g, 198 mmol, 3.0 eq.) The organic layer was dried (MgSO4), evaporated LCMS (ESI): m / z 195 [M + 1] +.
  • Step 23b Preparation of 3-acetyl-4-hydroxybenzoic acid (Compound 1003-95): methyl 4-acetylbenzoate (1002-95) (14 g, After crushing into a powder, 66 mmol, 1.0 eq. of aluminum trichloride (26.3 g, 198 mmol, 3.0 eq.) was stirred at 140 ° C for 5 hours. After completion of the reaction, a dark brown solid was solidified and cooled to room temperature. It was crushed with a spoon, added to 300 ml of an aqueous solution, and heated under reflux for 3 hours. The reaction mixture became clear, cooled to room temperature, concentrated hydrochloric acid was added dropwise to pH 1.
  • Step 23c Preparation of methyl 3-acetyl-4-hydroxybenzoate (compound 1004-95): 3-acetyl-4-hydroxybenzoic acid (1003-95) (4 g, 22.2 mmol, 1.0 eq.) was dissolved in 50 ml of methanol. The organic solvent was concentrated under reduced pressure, and the mixture was evaporated to ethyl ether. Methyl formate (4.5 g, crude). LCMS (ESI): m / z 195 [M + 1] +.
  • Step 23d Preparation of 3-methylbenzofuran-5-carboxylic acid (Compound 1005-95): methyl 2-bromoacetate (2.36 g, 15.4 mmol, 1.5) Equivalent), added to 3-acetyl-4-hydroxybenzoic acid (1004-95) (2.0 g, 10.3 mmol, 1.0 eq.) and potassium carbonate (2.84 g, 20.6 mmol, 2.0 eq.) in 70 ml of acetonitrile Stir at room temperature overnight. After the reaction liquid was concentrated under reduced pressure to remove acetonitrile, 15 ml of tetrahydrofuran and 2N sodium hydroxide solution were added, and the mixture was stirred at 70 ° C for 4 hours.
  • Step 23e Preparation of methyl 3-methylbenzofuran-5-carboxylate (compound 1006-95): 3-methylbenzofuran-5-carboxylic acid ( 1005-95) (2.5 g, crude) was dissolved in 50 mL of methanol. The organic solvent was concentrated under reduced pressure, and ethyl acetate and water were evaporated. - Methyl carboxylate (1.7 g, total yield of 86.9% in two steps). LCMS (ESI): m / z 191 [M + 1] +.
  • Step 23f (2-(3-methylbenzofuran-5-yl)-2-oxoethyl) dimethyl phosphate (dimethyl(2-(3-methylbenzofuran-5-yl)-2-oxoethyl) Preparation of phosphonate) (Compound 1007-95): In a round bottom flask, dimethyl methylphosphonate (372 mg, 3.0 mmol, 1.5 eq.) and 30 mL of anhydrous tetrahydrofuran were added to dry ice under nitrogen.
  • Step 23g 1-(3-Methylbenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-ene-1 -keto(1-(3-methylbenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)
  • Compound 1008-95 Preparation: dimethyl (2-(3-methylbenzofuran-5-yl)-2-oxoethyl)phosphate (1007-95) (400 mg, crude), 2-(1- Trityl-1H-imidazol-4-yl)benzaldehyde (0105-1) (300 mg, 0.73 mmol, 1.0 eq.) and cesium carbonate (473 mg, 1.45 mmol, 2.0 eq.).
  • Step 23h 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(3-methylbenzofuran-5-yl)ethane-1-one (2- Preparation of (5H-imidazo[5,1-a]isoindol-5-yl)-1-(3-methylbenzofuran-5-yl)ethan-1-one) (Compound 1009-95): 1-(3- Methylbenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (1008-95) ( 2.0 g of crude product was dissolved in 30 ml of methanol, 15 ml of acetic acid was added, and the mixture was heated to reflux overnight.
  • Step 23i 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(3-methylbenzofuran-5-yl)ethane-1-ol (2- Preparation of (5H-imidazo[5,1-a]isoindol-5-yl)-1-(3-methylbenzofuran-5-yl)ethan-1-ol) (Compound 95): 2-(5H-Imidazole [ 5,1-a]isoindoline-5-yl)-1-(3-methylbenzofuran-5-yl)ethane-1-one (1009-95) (120 mg, 0.37 mmol, 1.0 eq.), dissolved in 30 ml of methanol, chilled to 0 ° C, EtOAc (55.6 mg, 1.46 mmol, 4.0 eq.), stirred for 2 hr.
  • Example 24 1-(Diphenyl[b,d]furan-2-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol ( Preparation of 1-(dibenzo[b,d]furan-2-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 96) Six line preparation)
  • Step 24a Preparation of diphenyl[b,d]furan-2-carboxylic acid (compound 0602-96): 2-bromo-diphenyl [b,d ] furan (0601-96) (1.0 g, 4.0 mmol, 1.0 eq.) was dissolved in 50 ml of dry THF, cooled to -70 ° C under nitrogen, and slowly added dropwise n-butyllithium (2.5 ml, 2.5 mol/L of a solution of n-hexane, 6.0 mmol, 1.5 eq.), the mixture was stirred at this temperature for 30 minutes, and dried carbon dioxide gas was passed for 15 minutes to stop the introduction of carbon dioxide, and the reaction was continued for 1 hour.
  • n-butyllithium 2.5 ml, 2.5 mol/L of a solution of n-hexane, 6.0 mmol, 1.5 eq.
  • Step 24b Preparation of methyl dibenzo[b,d]furan-2-carboxylate (compound 0603-96): compound diphenyl [b,d] Furan-2-carboxylic acid (0602-96) (1.2 g, 5.66 mmol, 1.0 eq.) was dissolved in 50 ml of methanol, cooled in ice-cooling, and slowly added thionyl chloride (0.82 ml, 11.3 mmol, 2.0 eq. ), heated to 80 ° C, and reacted for 4 hours. After the reaction was completed, it was concentrated under reduced pressure.
  • Step 24c (2-(diphenyl[b,d]furan-2-yl)-2-oxoethyl)phosphate dimethyl ester (dimethyl(2-(dibenzo[b,d]furan-2-yl)) Preparation of -2-oxoethyl)phosphonate) (Compound 0604-96): Dissolve dimethyl methyl phosphate (536 mg, 4.3 mmol, 1.5 eq.) in 50 mL of dry tetrahydrofuran under cooling with nitrogen.
  • n-butyl lithium (2.3 ml, 2.5 mol / liter of n-hexane solution, 5.74 mmol, 2.0 eq.) was slowly added dropwise, the mixture was stirred at this temperature for 30 minutes, and the compound diphenyl was slowly added dropwise.
  • a solution of methyl furan-2-carboxylate (0603-96) (650 mg, 2.87 mmol, 1.0 eq.) in 5 mL of THF. After completion of the reaction, the mixture was combined with EtOAc EtOAc.
  • Step 24d 1-(Diphenyl[b,d]furan-2-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-ene- 1-ketone (1-(dibenzo[b,d]furan-2-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)
  • (Compound 0605-96) 2-(1-Trityl-1H-imidazol-4-yl)benzaldehyde (0105-1) (200 mg, 0.483 mmol, 1.0 eq.), Compound (2) -(Diphenyl[b,d]furan-2-yl)-2-oxoethyl)phosphate dimethyl ester (0604-96) (170 mg, 0.53 mmol, 1.1 eq.) and cesium carbonate (315 mg, 0.966 mmol, 2.0
  • Step 24e 1-(Diphenyl[b,d]furan-2-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (1 -(dibenzo[b,d]furan-2-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0606-96) Preparation: Compound 1-(diphenyl[b,d]furan-2-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-ene-1- Ketone (0605-96) (300 mg, 0.49 mmol, 1.0 eq.) and acetic acid (10 ml) were combined in methanol (40 ml), and the mixture was stirred at 90 ° C overnight.
  • Step 24f 1-(Diphenyl[b,d]furan-2-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol (1 -(dibenzo[b,d]furan-2-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 96) Preparation: Compound 1 -(diphenyl[b,d]furan-2-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0606-96) ( 150 mg, 0.41 mmol, 1.0 eq.) was dissolved in 10 mL of methanol and then sodium borohydride (62 mg, 1.64 mmol, 4.0 eq.) was slowly added and cooled to 0 °C.
  • Example 25 1-(Furan[3,2-b]pyridin-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol Preparation of (1-(furo[3,2-b]pyridin-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 98) (Prepared according to Scheme 1 and 5)
  • Step 25a (Z)-3-(2-(1-Triphenylmethyl-1H-imidazol-4-yl)phenyl)acrylate (ethyl(Z)-3-(2-(1-trityl-) Preparation of 1H-imidazol-4-yl)phenyl)acrylate)
  • Compound 0106-98 2-(1-Triphenylmethyl-1H-imidazol-4-yl)benzaldehyde (0105-1) (480 mg) , 1.2 mmol, 1.0 eq.), triethyl phosphonoacetate (528 mg, 2.4 mmol, 2.0 eq.) and cesium carbonate (786 mg, 2.4 mmol, 2.0 eq.) in isopropyl alcohol (30 mL) The reaction was stirred at room temperature overnight.
  • Step 25b 2-(5H-imidazo[5,1-a]isoindoline-5-yl)acetate (ethyl2-(5H-imidazo[5,1-a]isoindol-5-yl)acetate)
  • (Compound 0107-98) Compound (Z)-3-(2-(1-Triphenylmethyl-1H-imidazol-4-yl)phenyl)acrylate (0106-98) (600 mg , 1.24 mmol, 1.0 eq.) and acetic acid (10 ml) were combined in methanol (40 ml), and the mixture was stirred at 90 ° C overnight. After the reaction was completed, it was concentrated under reduced pressure.
  • Step 25c 2-(5H-imidazo[5,1-a]isoindol-5-yl)acetic acid)
  • Preparation of Compound 0108-98 2-(5H-Imidazo[5,1-a]isoindoline-5-yl)acetate (0107-98) (250 mg, 1.03 mmol, 1.0 eq) Dissolved in 10 ml of tetrahydrofuran, added 3 ml of 1 M NaOH solution, and stirred at room temperature overnight.
  • Step 25d 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-N-methoxy-N-methylacetamide (2-(5H-imidazo[5,1- Preparation of a]isoindol-5-yl)-N-methoxy-N-methylacetamide (Compound 0109-98): Compound 2-(5H-Imidazo[5,1-a]isoindoline-5-yl) Acetic acid (0108-98) (400 mg, 1.8 mmol, 1.0 eq.) was dissolved in 30 mL of tetrahydrofuran and added 2-(7-benzotriazole)-N,N,N',N'-tetra Methylurea hexafluorophosphate (1.42 g, 3.6 mmol, 2.0 eq.), N,O-dimethylhydroxylamine hydrochloride (351 mg, 3.6 mmol, 2.0 eq.) and tri
  • Step 25e Preparation of 6-bromo-3-iodopyridin-3-ol (Compound 0502-98): Potassium carbonate (3.18 g, 22.98 mmol, 2.0 eq. And 2-bromo-5-hydroxypyridine (0501-98) (2.0 g, 11.49 mmol, 1.0 eq.) was dissolved in 50 ml of tetrahydrofuran, and iodine (6.41 g, 25.28 mmol, 2.2 eq.) was added and stirred at room temperature. overnight. After the reaction was completed, 25 ml of an aqueous sodium hydrogensulfite solution was added. The mixture was extracted with EtOAc. EtOAc (EtOAc)EtOAc. LCMS (ESI): m / z 300 [M + 1] +.
  • Step 25f Preparation of 3-hydroxy-6-bromo-2-(trimethylsilylethynyl)pyridine (6-bromo-2-((trimethylsilyl)ethynyl)pyridin-3-ol) (Compound 0503-98): 6-Bromo-3-hydroxy-2-iodopyridine (0502-98) (2.0 g, 6.67 mmol, 1.0 eq.), trimethylsilylacetylene (655 mg, 6.67 mmol, 1.0 eq.) under N2.
  • cuprous iodide (19 mg, 0.1 mmol, 0.015 equivalent) and bistriphenylphosphine palladium dichloride (140 mg, 0.2 mmol, 0.03 equivalent) were added to a mixture of 30 ml of tetrahydrofuran and 15 ml of chloroform.
  • Triethylamine (2.02 g, 20 mmol, 3.0 eq.) was added dropwise to the solution, and the mixture was heated to 50 ° C and stirred for 3 hr. The mixture was cooled to room temperature, filtered, and evaporated tolulululululululululululululululululululululululu Silylethynyl)pyridine (1.21 g, yield: 67.2%).
  • Step 25g Preparation of 5-bromofuro[3,2-b]pyridine (Compound 0505-98): Dissolve compound 3-hydroxy-6 with 50 ml of anhydrous methanol -Bromo-2-(trimethylsilylethynyl)pyridine (0503-98) (1.21 g, 4.48 mmol, 1.0 eq.), N,N-diisopropylethylamine (636 mg, 4.92 mmol, 1.1 equivalents) and cuprous iodide (43 mg, 0.22 mmol, 0.05 eq.) were reacted at 60 ° C for 4 hours, then a small amount of potassium carbonate was added and stirred at 60 ° C overnight. The mixture was cooled to room temperature and filtered with suction. EtOAcjjjjjjjjjjj %). LCMS (ESI): m / z 198/200 [M + 1] +.
  • Step 25h 1-(furo[3,2-b]pyridin-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one ( 1-(furo[3,2-b]pyridin-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)
  • Compound (0507-98) Preparation: The compound 5-bromofuran [3,2-b]pyridine (0505-98) (100 mg, 0.5 mmol, 1.0 eq.) was dissolved in 10 ml of dry THF.
  • Step 25i 1-(furo[3,2-b]pyridin-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol ( Preparation of 1-(furo[3,2-b]pyridin-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 98): The compound 1-(furan[3,2-b]pyridin-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0507 -98) (43 mg, 0.136 mmol, 1.0 eq.) was dissolved in 20 ml of ethyl alcohol, and sodium borohydride (10 mg, 0.272 mmol, 2.0 eq.) was slowly added.
  • Example 26 1-(benzofuran-6-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol (1-(benzofuran-) Preparation of 6-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 101) (prepared according to Scheme 3)
  • Step 26a (2-(benzofuran-6-yl)-2-oxoethyl)phosphonate (compound 0304-(2-(benzofuran-6-yl)-2-oxoethyl)phosphonate) Preparation of 101): Under a nitrogen atmosphere, dimethyl methylphosphonate (521 mg, 4.2 mmol, 2.0 eq.) and 20 ml of anhydrous tetrahydrofuran were added to a round bottom flask and cooled in a dry ice-ethanol bath.
  • Step 26b 1-(benzofuran-6-yl)-2-(1-trityl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (1-(benzofuran) -6-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one) (Preparation of Compound 030-1-1: (2-(Benzene) And furan-6-yl)-2-oxoethyl)phosphate (0304-101) (161 mg, 0.6 mmol, 1.0 eq.), 2-(1-trityl-1H-imidazole- 4-yl)benzaldehyde (0105-1) (250 mg, 0.6 mmol, 1.0 eq.) and cesium carbonate (392 mg, 1.2 mmol, 2.0 eq.) were added to 40 ml of isopropanol and stirred at room temperature.
  • Step 26c 1-(benzofuran-6-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (1-(benzofuran-6) -yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0306-101)
  • 1-(benzofuran-6-yl) 2-(1-Trityl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (0305-101) (370 mg, 0.6 mmol, 1.0 eq.) dissolved in 30 In ml of methanol, 6 ml of acetic acid was added and heated to reflux overnight.
  • Step 26d 1-(benzofuran-6-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol (1-(benzofuran-6) -yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 101)
  • 1-(benzofuran-6-yl)-2 -(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0306-101) 160 mg, 0.51 mmol, 1.0 eq.
  • Example 27 5-(1-Hydroxy-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethyl)-1,3-dihydro-2H-benzo[d Imidazol-2-one (5-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-1,3-dihydro-2H-benzo[d]imidazol- Preparation of 2-one) (Compound 102) (prepared according to Scheme 7)
  • Step 27a (2-(3-fluoro-4-nitrophenyl)-2-oxoethyl)phosphonate (dimethyl(2-fluoro-4-nitrophenyl)-2-oxoethyl)phosphonate) (Compound 0702-102)
  • Dimethyl methyl phosphate (607 mg, 4.9 mmol, 1.3 eq.) was dissolved in 20 mL of dry tetrahydrofuran under nitrogen, cooled to -70 ° C, slowly drip Add n-butyllithium (2.26 ml, 2.5 mol / liter of n-hexane solution, 5.65 mmol, 1.5 equivalents), the mixture was stirred at this temperature for 30 minutes, and the compound 3-fluoro-4-nitrobenzene was slowly added dropwise.
  • Step 27b (Z)-1-(3-Fluoro-4-nitrophenyl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propane-2- Iso-1-one [(Z)-1-(3-fluoro-4-nitrophenyl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1- Preparation of one] (Compound 0703-102): 2-(1-trityl-1H-imidazol-4-yl)benzaldehyde (0105-1) (1.4 g, 3.37 mmol, 1.0 eq.), compound (2-(3-Fluoro4-nitrophenyl)-2-oxoethyl)phosphate dimethyl ester (0702-102) (1.36 g, 4.38 mmol, 1.3 eq.) and cesium carbonate (2.2 g, 6.74) The mixture was stirred in is
  • Step 27c 1-(3-Fluoro-4-nitrophenyl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (1-( Preparation of 3-fluoro-4-nitrophenyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 704-102): Compound (Z)-1 -(3-Fluoro-4-nitrophenyl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (703- 102) (1.8 g, 3.1 mmol, 1.0 eq.) and acetic acid (20 ml) were combined in methanol (80 ml), and the mixture was stirred at 90 ° C overnight.
  • Step 27d 1-(3-Amino-4-nitrophenyl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (1- Preparation of (3-amino-4-nitrophenyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0705-102): Compound 1-(3) -fluoro-4-nitrophenyl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0704-102) (1.1 g, 3.26 m Mole, 1.0 equivalents) and aqueous ammonia (15 ml) were dissolved in tetrahydrofuran (20 ml), and the mixture was heated to 85 ° C for 5 hours.
  • Step 27e 1-(3,4-Diaminophenyl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (1-(3) , 4-diaminophenyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0706-102)
  • Step 27f 5-(2-(5H-Imidazo[5,1-a]isoindoline-5-yl)acetyl)-1,3-dihydro-2H-benzo[d]imidazole-2- Ketone (5-(2-(5H-imidazo[5,1-a]isoindol-5-yl)acetyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one) (Compound 0707-102 Preparation: 1-(3,4-Diaminophenyl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0706- 102) (800 mg, 2.6 mmol, 1.0 eq.) was dissolved in 50 mL of THF.
  • N,N'-carbonyldiimidazole (1.26 g, 7.8 mmol, 3.0 eq.) was added under nitrogen and heated to 35 ° C overnight. After completion of the reaction, the mixture was extracted with methylene chloride (m.hhhhhhhhhhhhhhhhhhh 5H-imidazo[5,1-a]isoindoline-5-yl)acetyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (400 mg, yield: 46 %).
  • Step 27g 5-(1-Hydroxy-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethyl)-1,3-dihydro-2H-benzo[d] Imidazolyl-2-one (5-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-1,3-dihydro-2H-benzo[d]imidazol-2 -one) (Compound 102)
  • Compound 5-(2-(5H-Imidazo[5,1-a]isoindoline-5-yl)acetyl)-1,3-dihydro-2H- Benzo[d]imidazol-2-one (0707-102) 400 mg, 1.2 mmol, 1.0 eq.
  • sodium borohydride 182 mg, 4.8 Mol
  • sodium borohydride 182 mg, 4.8 Mol.
  • Example 28 5-(1-Hydroxy-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethyl)porphyrin-2-one (5-(1-hydroxy) Preparation of -2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)indolin-2-one) (Compound 103) (prepared according to Scheme 7)
  • Step 28a 1-(3-Fluoro-4-nitrophenyl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethyl)-1-ol
  • (1- Preparation of (3-fluoro-4-nitrophenyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 0710-103): 1-(3- Fluoro-4-nitrophenyl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethyl)-1-one (0704-102) (310 mg, 0.92 m Molar, 1.0 eq.) was dissolved in 30 mL of methanol, cooled in ice-cooled to 0 ° C, sodium borohydride (53 mg, 1.38 mmol, 1.5 eq.), and the reaction was stirred for half an hour, acetone was added and concentrated under reduced
  • Step 28b 2-(5-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-2-nitrophenyl)malonic acid
  • Diethyl 2-(5-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-2-nitrophenyl)malonate) (Compound 0710-31) : 1-(3-Fluoro-4-nitrophenyl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethyl)-1-ol (0710-103) (350 mg, 0.92 mmol, 1.0 eq.) was dissolved in 5 ml of dimethylformamide, and potassium carbonate (358 mg, 2.6 mmol, 2.8 eq.) and diethyl malonate (207) were added at room temperature.
  • Step 28c 5-(1-Hydroxy-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethyl)-2-nitrobenzoic acid (5-(1-hydroxy-) Preparation of 2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-2-nitrobenzoic acid) (Compound 0712-103): 2-(5-(1-hydroxy-2-() 5H-Imidazo[5,1-a]isoindoline-5-yl)ethyl)-2-nitrophenyl)malonic acid diethyl ester (0711-103) (410 mg, 0.92 mmol, 1.0 Equivalent) dissolved in 5 ml of tetrahydrofuran, added with 30 ml of 6M aqueous hydrochloric acid, and the reaction was heated at 95 ° C overnight, cooled to room temperature and concentrated to dryness under reduced pressure to give the product 5-(1-hydroxy-2
  • Step 28d 5-(1-Hydroxy-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethyl)porphyrin-2-one (5-(1-hydroxy-) Preparation of 2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)indolin-2-one) (Compound 103): 5-(1-hydroxy-2-(5H-imidazole) , 1-a]isoindoline-5-yl)ethyl)-2-nitrobenzoic acid (0712-103) (0.92 mmol, 1.0 eq.) was dissolved in a mixture of 10 ml of water and 10 ml of acetic acid.
  • Step 29a Preparation of methyl 1-methyl-1H-indole-5-carboxylate (compound 0303-104).
  • the compound 5-carboxylic acid hydrazine (0302-104) (1 g, 6.2 mmol, 1 eq.) was dissolved in 10 mL of DMF under nitrogen atmosphere and ice bath, and sodium hydride was slowly added. Mg, 18.6 mmol, 3 equivalents).
  • methyl iodide 2.2 g, 15.5 mmol, 2.5 eq.
  • Step 29b dimethyl (2-(1-methyl-1H-indol-5-yl)-2-oxoethyl)phosphate dimethyl(2-(1-methyl-1H-indol-5-yl)
  • -2-oxoethyl)phosphonate (0304-104): Dimethyl methyl phosphate (600 mg, 4.8 mmol, 1.5 eq.) was dissolved in 5 mL of dry tetrahydrofuran under a nitrogen atmosphere.
  • Step 29c (E)-1-(1-Methyl-1H-indol-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propane -2-en-1-one [(E)-1-(1-methyl-1H-indol-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop Preparation of -2-en-1-one] (Compound 0305-104): Compound (2-(1-methyl-1H-indol-5-yl)- under a nitrogen atmosphere and an ice bath Dimethyl 2-oxoethyl)phosphate (0304-104) (309 mg, 1.1 mmol, 1.2 eq.) was dissolved in 10 mL of THF.
  • Step 29d 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(1-methyl-1H-indol-5-yl)ethane-1-one ( Preparation of 2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(1-methyl-1H-indol-5-yl)ethan-1-one) (Compound 0306-104): Compound (E)-1-(1-methyl-1H-indol-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propane - 2-En-1-one (0305-104) (692 mg, 1.216 mmol, 1 eq.) and acetic acid (2 mL) were combined in methanol (4 mL).
  • Step 29e 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(1-methyl-1H-indol-5-yl)ethane-1-ol ( Preparation of 2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(1-methyl-1H-indol-5-yl)ethan-1-ol) (Compound 104): Compounds 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(1-methyl-1H-indol-5-yl)ethane-1-one (0306-104 (179 mg, 0.544 mmol, 1 eq.) was dissolved in 5 mL of methanol and sodium borohydride (41 mg, 1.088 mmol, 2 eq.).
  • Example 30 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(1H-indazol-5-yl)ethane-1-ol (2-(5H) -imidazo[5,1-a]isoindol-5-yl)-1-(1H-indazol-5-yl)ethan-1-ol) (Preparation of compound 105) (prepared according to the scheme three lines)
  • Step 30a Preparation of 1H-indazole-5-carboxylate (compound 0303-105): carbazole-5-formate (0302-105) (420 mg, 2.11 mmol, 1.0 eq.) was dissolved in 20 mL of MeOH. EtOAc (EtOAc, EtOAc, EtOAc (EtOAc) 3 hours. The mixture was cooled to room temperature, EtOAc was evaporated, evaporated, evaporated, evaporated. 376 mg, crude). LCMS (ESI): m / z 177 [M + 1] +.
  • Step 30b 5-(2-(Dimethoxyphosphoryl)acetyl)-1H-indazole-1-carboxylic acid tert-butyl ester (tert-butyl5-(2-(dimethoxyphosphoryl)acetyl)-1H-indazole- 1-carboxylate) (Preparation of compound 0304-105): tert-methyl 1H-indazole-5-carboxylate (376 mg, 2.11 mmol, 1.0 eq.), triethylamine (0.51 mL, 3.66 mmol, 3.0 eq.) and di-tert-butyl dicarbonate (920 mg, 4.22 mmol, 2.0 eq.) were added to 40 ml of tetrahydrofuran and allowed to react at room temperature for 2 hours.
  • Step 30c 5-(3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)acryloyl)-1H-indazole-1-carboxylic acid tert-butyl ester (tert-butyl) Preparation of 5-(3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)acryloyl)-1H-indazole-1-carboxylate) (Compound 0305-105): 5-(2-( Dimethoxyphosphoryl)acetyl)-1H-indazole-1-carboxylic acid tert-butyl ester (0304-105) (375 mg, 1.0 mmol, 1.4 eq.), 2-(1-tritylmethyl- 1H-imidazol-4-yl)benzaldehyde (0105-1) (300 mg, 0.73 mmol, 1.0 eq.) and cesium carbonate (900 mg, 2.8 mmol, 3.8
  • Step 30d 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(1H-indazol-5-yl)ethane-1-one (2-(5H-) Preparation of imidazo[5,1-a]isoindol-5-yl)-1-(1H-indazol-5-yl)ethan-1-one) (Compound 0306-105): 5-(3-(2) -(1-Trityl-1H-imidazol-4-yl)phenyl)acryloyl)-1H-indazole-1-carboxylic acid tert-butyl ester (0305-105) (490 mg, 0.73 mmol, 1.0 Equivalent) was dissolved in 30 ml of methanol, added with 5 ml of acetic acid and heated to reflux overnight.
  • Step 30e 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(1H-indazol-5-yl)ethane-1-ol (2-(5H-) Preparation of imidazo[5,1-a]isoindol-5-yl)-1-(1H-indazol-5-yl)ethan-1-ol) (Compound 105): 2-(5H-imidazole [5,1] -a]isoindoline-5-yl)-1-(1H-indazol-5-yl)ethane-1-one (0306-105) (150 mg, 0.48 mmol, 1.0 eq.) dissolved in 30 In methanol, in an ice bath, cooled to 0 ° C, sodium borohydride (22 mg, 0.58 mmol, 1.2 eq.) was added, and the reaction was stirred for half an hour, acetone was added, concentrated under reduced pressure, extracted with dich
  • Step 31a 1-(1H-Benzo[d]imidazol-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (1 Preparation of (1H-benzo[d]imidazol-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0708-106).
  • Step 31b 1-(1H-Benzo[d]imidazol-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol (1 -(1H-benzo[d]imidazol-6-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 106)
  • Compound 1 -(1H-benzo[d]imidazol-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0708-106) 130 mg, 0.414 mmol, 1 eq. was dissolved in 5 mL of methanol.
  • Example 32 1-(1H-Benzo[d][1,2,3]triazol-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl Ethyl-1-ol 1-(1H-benzo[d][1,2,3]triazol-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan Preparation of -1-ol (Compound 107) (prepared according to Scheme 7)
  • Step 32a 1-(1H-Benzo[d][1,2,3]triazol-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl) Ethyl-1-one (1-(1H-benzo[d][1,2,3]triazol-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan Preparation of -1-one) (Compound 0709-107): 1-(3,4-Diaminophenyl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl Ethyl-1-one (0706-102) (200 mg, 0.65 mmol, 1.0 eq.) was dissolved in 50 mL of aq.
  • Step 32b 1-(1H-Benzo[d][1,2,3]triazol-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl) Ethyl-1-ol (1-(1H-benzo[d][1,2,3]triazol-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan Preparation of -1-ol) (Compound 107): Compound 1-(1H-benzo[d][1,2,3]triazol-5-yl)-2-(5H-imidazole [5,1- a] Isoindoline-5-yl)ethane-1-one (0709-107) (120 mg, 0.38 mmol, 1.0 eq.) was dissolved in 10 mL of methanol and then sodium borohydride (58 mg, 1.52 mmol, 4.0 eq.), cooled to 0 °C
  • Example 33 1-(Benzo[d]isoxazol-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol (Preparation of 1-(benzo[d]isoxazol-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 108) preparation)
  • Step 33a Preparation of 5-bromobenzo[d]isoxazole (Compound 0310-18): 5-Bromo Salicylaldehyde (2.0 g, 10.0 mmol, 1.0 eq.) Dissolved in 25 ml of methanol, added 50% aqueous hydroxylamine solution (1.32 g, 20.0 mmol, 2.0 eq.) and sodium acetate (2.46 g, 30.0 mmol, 3.0 eq.), stirred at 50 ° C for one hour and cooled to room temperature.
  • Step 33b Preparation of benzo[d]isoxazole-5-carboxylic acid (compound 302-108): under a nitrogen atmosphere, in a round bottom flask, add 5 -Bromobenzo[d]isoxazole (0301-108) (1.0 g, 5.0 mmol, 1.0 eq.) and 30 ml of anhydrous tetrahydrofuran, cooled to -72 ° C in dry ice-ethanol bath, dropwise 2.5 M. A solution of butyllithium in n-hexane (3.6 ml, 9.0 mmol, 1.8 eq.) was stirred for one hour, carbon dioxide was passed, and the reaction was stirred for 1 hour.
  • Step 33c Preparation of benzo[d]isoxazole-5-carboxylate methyl benzo[d]isoxazole-6-carboxylate (compound 0303-108): benzo[d]isoxazol-5-carboxylate
  • the acid (0302-108) 1.0 g, 5.0 mmol, 1.0 eq.
  • toluene 1.1 ml, 15.0 mmol, 3.0 eq.
  • the organic layer was concentrated under reduced pressure.
  • EtOAcjjjjjjjjjjjjjjjjjjjjjjjj The product benzo[d]isoxazole-5-carboxylic acid methyl ester (930 mg, crude product).
  • Step 33d (2-(benzo[d]isoxazol-5-yl)-2-oxoethyl)phosphoric acid dimethyl (dimethyl(2-(benzo[d]isoxazol-5-yl)-2) Preparation of -oxoethyl)phosphonate) (Compound 0304-108): Add dimethyl methylphosphonate (525 mg, 4.23 mmol, 1.5 eq.) and 14 mL of anhydrous toluene in a round bottom flask under nitrogen.
  • Step 33e 1-(Benzo[d]isoxazol-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-ene- 1-keto(1-[benzo[d]isoxazol-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)
  • 0305-108 dimethyl (2-(benzo[d]isoxazol-5-yl)-2-oxoethyl)phosphate (0304-108) (0.97 mmol, 1.2 eq.) , 2-(1-trityl-1H-imidazol-4-yl)benzaldehyde (0105-1) (389 mg, 0.94 mmol, 1.0 eq.) and cesium carbonate (612 mg, 1.88 mmol, 2.0 eq.
  • Step 33f 1-(Benzo[d]isoxazol-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (1 -(benzo[d]isoxazol-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0306-108)
  • Step 33g 1-(Benzo[d]isoxazol-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol (1 -(benzo[d]isoxazol-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 108) Preparation: 1-(Benzene) And [d]isoxazol-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0306-108) (0.94 mmol) , 1.0 equivalent), dissolved in 30 ml of methanol, cooled to 0 ° C in an ice bath, added sodium borohydride (54 mg, 1.41 mmol, 1.5 eq.), stirred for half an hour, added acetone, concentrated under reduced pressure, added two The methyl
  • Example 34 1-(Benzo[d][1,3]dioxolan-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)B Alken-1-ol (1-(benzo[d][1,3]dioxol-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) Preparation of (Compound 113) (prepared according to Scheme 4)
  • Step 34a Preparation of methyl benzo[d][1,3]dioxole-5-carboxylate (compound 0402-113): The compound benzo[d][1,3]dioxolane-5-carboxylic acid (0401-113) (1 g, 6 mmol, 1 eq.) and potassium carbonate (1.65 g, 12 mmol, 2 eq. Dissolved in 10 ml of DMF, and then added dropwise methyl iodide (1.02 g, 7.2 mmol, 1.2 eq.). The mixture was stirred at room temperature for 4 hours.
  • Step 34b (2-(Benzo[d][1,3]dioxolan-5-yl)-2-oxoethyl)phosphoric acid dimethyl (2-(benzo[d][1 ,3]dioxol-5-yl)-2-oxoethyl)phosphonate)
  • Compound 0403-113 Dissolve dimethyl methyl phosphate (824 mg, 6.64 mmol, 1.5 eq.) in a nitrogen atmosphere In 5 ml of dry tetrahydrofuran, cool to -60 ° C with dry ice / ethanol, slowly add dropwise n-butyl lithium (5.3 ml, 2.5 mol / ml of n-hexane solution, 13.28 mmol, 2 equivalents), the mixture is here The reaction was stirred at the temperature for 30 minutes, and then the compound benzo[d][1,3]dioxolane-5-carboxylate (0402-113) (800 mg, 4.44 mmol, 1
  • Step 34c (E)-1-(Benzo[d][1,3]dioxolan-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl) Phenyl)propan-2-en-1-one [(E)-1-(benzo[d][1,3]dioxol-5-yl)-3-(2-(1-trityl-1H-imidazol) Preparation of -4-yl)phenyl)prop-2-en-1-one] (Compound 0404-113): Compound (2-(benzo[d][1] under nitrogen atmosphere and ice bath , 3] Dioxol-5-yl)-2-oxoethyl) dimethyl phosphate (0403-113) (350 mg, 1.28 mmol, 1.5 eq.) was dissolved in 10 mL of tetrahydrofuran, then slowly Sodium hydride (52 mg, 1.28 mmol, 1.5 eq.) was
  • Step 34d 1-(Benzo[d][1,3]dioxolan-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane 1-ketone (1-(benzo[d][1,3]dioxol-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)( Preparation of Compound 0405-113): Compound (E)-1-(Benzo[d][1,3]dioxolan-5-yl)-3-(2-(1-tritylmethyl)- 1H-imidazol-4-yl)phenyl)propan-2-en-1-one (0404-113) (680 mg, 1.214 mmol, 1 eq.) and acetic acid (2 mL) .
  • Step 34e 1-(Benzo[d][1,3]dioxolan-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane 1-propanol (1-(benzo[d][1,3]dioxol-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)( Preparation of Compound 113): Compound 1-(Benzo[d][1,3]dioxolan-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5 Ethyl-l- ketone (0405-113) (160 mg, 0.503 mmol, 1 eq.) was dissolved in 5 ml of methanol and sodium borohydride (37.8 mg, 1.0 mmol, 2 eq.) was slowly added.
  • Example 35 1-(benzodioxan-6-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol (1- (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 119) Preparation (prepared according to the scheme four lines)
  • Step 35a Preparation of methyl 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (compound 0402-119): compound benzo Dioxane-6-carboxylic acid (0401-119) (500 mg, 2.78 mmol, 1 eq.) was dissolved in 15 ml of methanol, and then slowly added dropwise 1.5 ml of thionyl chloride, and the mixture was refluxed. The reaction was stirred for 2 hours. After completion of the reaction, the mixture was evaporated to dryness. The ester (538 mg, yield: 99.26%) was a yellow solid.
  • Step 35b (2-(2,3-dihydrobenzo[b][1,4]dioxin) Preparation of -6-yl)-2-oxoethyl)phosphonate)
  • Compound 0403-19 Dissolve dimethyl methyl phosphate (514 mg, 4.15 mmol, 1.5 eq.) in 5 mL under a nitrogen atmosphere. In dry tetrahydrofuran, it was cooled to -60 ° C with dry ice/ethanol, and n-butyllithium (2.2 ml, 2.5 mol/ml n-hexane solution, 5.54 mmol, 2 eq.) was slowly added dropwise, and the mixture was stirred at this temperature.
  • Step 35c 1-(benzodioxan-6-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-ene-1- Ketone (1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en Preparation of -1-one) (Compound 0041-119): Compound 0403-19 (397 mg, 1.39 mmol, 1.9 eq.), compound 2-(1-trityl-1H-imidazol-4-yl) Benzaldehyde (0105-1) (300 mg, 0.72 mmol, 1 eq.) and cesium carbonate (468 mg, 1.44 mmol, 2 eq.) were mixed in isopropyl alcohol (10 mL) and the mixture was stirred at room temperature.
  • Step 35d 1-(benzodioxan-6-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (1-( 2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0405-119) Preparation of the compound: 1-(benzodioxan-6-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-ene 1- Ketone (0404-119) (413 mg, 0.72 mmol, 1 eq.) and EtOAc (5 mL).
  • Step 35e 1-(benzodioxan-6-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol (1-( 2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 119) Preparation: the compound 1-(benzodioxan-6-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0405- 119) (110 mg, 0.332 mmol, 1 eq.) was dissolved in EtOAc (5 mL) and then sodium borohydride (25 mg, 0.664 mmol, 2 eq.).
  • Example 36 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(in-2-yl)ethane-1-ol (2-(5H-imidazo[ Preparation of 5,1-a]isoindol-5-yl)-1-(naphthalen-2-yl)ethan-1-ol) (Compound 123) (prepared according to Scheme 8)
  • Step 36a Preparation of 2-methyl 2-naphthoate (compound 0802-123).
  • Compound 2-naphthalenecarboxylic acid (0801-123) (1 g, 5.8 mmol, 1 eq.) and potassium carbonate (1.60 g, 11.6 mmol, 2 eq.) were dissolved in 10 mL of DMF (0.99 g, 6.96 mmol, 1.2 eq.). The mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was quenched with water and filtered to give the title compound 2-methyl-carboxylate (1 g, yield: 93.28%) as a white solid.
  • Step 36b (2-(naphthalen-2-yl)-2-oxoethyl)phosphonate (compound 0803-123)
  • Dimethyl methyl phosphate 500 mg, 4.04 mmol, 1.5 eq.
  • n-Butyllithium 2.15 ml, 2.5 mol/ml n-hexane solution, 5.38 mmol, 2 eq.
  • the mixture was stirred at this temperature for 30 minutes, and the compound 2-methylcarboxylate (0802-) was slowly added dropwise.
  • Step 36c (E)-1-(N--2-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one [(E)-1-(naphthalen-2-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one] (Compound 0804-123 Preparation: 2-(1-trityl-1H-imidazol-4-yl)benzaldehyde (0105-1) (474 mg, 1.15 mmol, 1 eq.), compound (2-(N-2) -Methyl 2-oxoethyl)phosphate (0803-123) (350 mg, 1.26 mmol, 1.1 eq.) and cesium carbonate (407 mg, 1.15 mmol, 2 eq.) mixed with isopropanol (10 ml), the mixture was stirred at room temperature for 16 hours.
  • Step 36d 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(in-2-yl)ethane-1-one (2-(5H-imidazo[5] , 1-a]isoindol-5-yl)-1-(naphthalen-2-yl)ethan-1-one) (Compound 0805-123)
  • Step 36e 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(in-2-yl)ethane-1-ol (2-(5H-imidazo[5] , 1-a]isoindol-5-yl)-1-(naphthalen-2-yl)ethan-1-ol) (Compound 123)
  • Compound 2-(5H-Imidazole[5,1-a] Porphyrin-5-yl)-1-(n-2-yl)ethane-1-one (0805-123) (300 mg, 0.926 mmol, 1 eq.) was dissolved in 5 mL of methanol and then slowly.
  • Step 37a Preparation of methyl quinoline-6-carboxylate (compound 0802-125): Dissolve quinoline-6-carboxylic acid (510 mg, 2.95 mmol, 1.0 eq.) in In 20 ml of methanol, 1 ml of concentrated sulfuric acid was added, and the reaction was stirred at 50 ° C overnight. After cooling to room temperature, aq. aq. , yield: 89%).
  • Step 37b (2-oxo-2-(quinolin-6-yl)ethyl)phosphonate) (Compound 0803- Preparation of 125): Under a nitrogen atmosphere, dimethyl methylphosphonate (716 mg, 5.78 mmol, 2.0 eq.) and 20 ml of anhydrous tetrahydrofuran were added to a round bottom flask and cooled in a dry ice-ethanol bath.
  • Step 37c 1-(Quinolin-6-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (1- Preparation of (quinolin-6-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one) (Compound 0804-125): (2 -Oxo-2-(quinolin-6-yl)ethyl)phosphoric acid dimethyl ester (0803-125) (267 mg, 0.96 mmol, 1.1 eq.), 2-(1-tritylmethyl-1H- Imidazolyl-4-yl)benzaldehyde (0105-1) (360 mg, 0.87 mmol, 1.0 eq.) and cesium carbonate (706 mg, 2.17 mmol, 2.5 eq.) were added to 60 ml of isopropanol at room temperature The reaction was stirred overnight, EtOA
  • Step 37d 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(quinolin-6-yl)ethane-1-one (2-(5H-imidazo[ Preparation of 5,1-a]isoindol-5-yl)-1-(quinolin-6-yl)ethan-1-one)
  • Compound 0805-125 1-(Quinolin-6-yl)-3 -(2-(1-Trityl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (0804-125) (490 mg, 0.86 mmol, 1.0 eq.) dissolved In 30 ml of methanol, 5 ml of acetic acid was added and heated to reflux overnight.
  • Step 37e 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(quinolin-6-yl)ethane-1-ol (2-(5H-imidazo[ Preparation of 5,1-a]isoindol-5-yl)-1-(quinolin-6-yl)ethan-1-ol) (Compound 125): 2-(5H-imidazole [5,1-a] Porphyrin-5-yl)-1-(quinolin-6-yl)ethane-1-one (0805-125) (227 mg, 0.70 mmol, 1.0 eq.) was dissolved in 30 mL methanol, ice bath The mixture was cooled to 0 ° C, sodium borohydride (32 mg, 0.84 mmol, 1.2 eq.) was added, the reaction was stirred for half an hour, acetone was added, concentrated under reduced pressure, extracted with dichloromethane, washed with water and saturated brine
  • Example 38 2-(5H-Imidazo[5,1-a]isoindoline-5-yl)-1-(isoquinolin-6-yl)ethane-1-ol (2-(5H-) Preparation of imidazo[5,1-a]isoindol-5-yl)-1-(isoquinolin-6-yl)ethan-1-ol) (Compound 127) (prepared according to Scheme 8)
  • Step 38a Preparation of methyl isoquinoline-6-carboxylate (compound 0802-127): Compound 6-isoquinolinecarboxylic acid (0801-127) (450 mg, 2.6 mmol) 1.0 equivalents were dissolved in 50 ml of N,N-dimethylformamide, potassium carbonate was added, and then methyl iodide (443 mg, 3.12 mmol, 1.2 eq.) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, ethyl acetate was evaporated, evaporated, evaporated, evaporated, LCMS (ESI): m / z 188 [M + 1] +.
  • Step 38b dimethyl (2-(isoquinolin-6-yl)-2-oxoethyl)phosphonate (compound 0803-127)
  • dimethyl methyl phosphate 550 mg, 4.3 mmol, 1.5 equivalents
  • n-butyllithium 2.2 mL, 2.5 mol/L n-hexane solution, 5.5 mmol, 2.0 eq.
  • Step 38c 1-(Isoquinolin-6-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (1 -(isoquinolin-6-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one) (Compound 0804-127)
  • Compound (2-(isoquinolin-6-yl)- Dimethyl 2-oxoethyl)phosphate (0803-127) (400 mg, 1.4 mmol, 2.3 eq.) and cesium carbonate (391 mg, 1.2 mmol, 2.0 eq.) in isopropyl alcohol (30 mL) The reaction was stirred at
  • Step 38d 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(isoquinolin-6-yl)ethane-1-one (2-(5H-imidazo) Preparation of [5,1-a]isoindol-5-yl)-1-(isoquinolin-6-yl)ethan-1-one)
  • Compound 0805-127 Compound 1-(isoquinolin-6-yl) --3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (0804-127) (300 mg, 0.53 mmol, 1.0 eq.
  • Step 38e 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(isoquinolin-6-yl)ethane-1-ol (2-(5H-imidazo) Preparation of [5,1-a]isoindol-5-yl)-1-(isoquinolin-6-yl)ethan-1-ol) (Compound 127): Compound 2-(5H-imidazole [5,1-a] Isoindolin-5-yl)-1-(isoquinolin-6-yl)ethane-1-one (0805-127) (170 mg, 0.52 mmol, 1.0 eq.) was dissolved in 10 mL of methanol.
  • Step 39a Preparation of methyl isoquinoline-6-carboxylate (compound 0802-128): Compound 7-quinolinecarboxylic acid (0801-128) (1.0 g, 5.78 mmol, 1.0) Equivalent) was dissolved in 30 mL of methanol, then sulfuric acid (0.5 mL) was added and refluxed overnight. After the reaction was completed, the mixture was adjusted to pH 8 with sodium hydrogen carbonate solution, extracted with dichloromethane, and then evaporated. The organic phase was dried over anhydrous sodium sulfate and evaporated to afford compound 7-- ).
  • Step 39b 1-(Quinolin-7-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (1- Preparation of (quinolin-7-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one) (Compound 0804-128): Protection under nitrogen Next, dimethyl methyl phosphate (345 mg, 2.78 mmol, 1.3 equivalent) was dissolved in 30 ml of dry toluene, cooled to -70 ° C, and n-butyllithium (1.28 ml, 2.5 mol / A solution of n-hexane (3.21 mmol, 1.5 eq.), the mixture was stirred at this temperature for 30 minutes, and then the compound 7-quinolinecarboxylic acid methyl ester (0802-128) (400 mg, 2.14 mmol) was slowly added dropwise.
  • Step 39c 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(quinolin-7-yl)ethane-1-one (2-(5H-imidazo[ Preparation of 5,1-a]isoindol-5-yl)-1-(isoquinolin-6-yl)ethan-1-one) (Compound 0805-128): Compound 1-(Quinolin-7-yl)- 3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (0804-128) (300 mg, 0.53 mmol, 1.0 eq.) Acetic acid (10 ml) was mixed in methanol (40 ml), and the mixture was stirred at 90 ° C overnight.
  • Step 39d 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(quinolin-7-yl)ethane-1-ol (2-(5H-imidazo[ Preparation of 5,1-a]isoindol-5-yl)-1-(isoquinolin-6-yl)ethan-1-ol) (Compound 128): Compound 2-(5H-Imidazole [5,1-a] Isoporphyrin-5-yl)-1-(quinolin-7-yl)ethane-1-one (0804-128) (120 mg, 0.37 mmol, 1.0 eq.) was dissolved in 10 mL methanol.
  • Step 40a 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(quinoxalin-6-yl)ethane-1-one (2-(5H-imidazo) Preparation of [5,1-a]isoindol-5-yl)-1-(quinoxalin-6-yl)ethan-1-one) (Compound 0805-130): Compound 1-(3-Amino-4- Nitrophenyl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0705-102) (200 mg, 0.597 mmol, 1 eq.) Ammonium chloride (271 mg, 5.075 mmol, 8.5 equivalents) was dissolved in ethanol/water (8/2 mL).
  • Step 40b 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(quinoxalin-6-yl)ethane-1-ol (2-(5H-imidazo) Preparation of [5,1-a]isoindol-5-yl)-1-(quinoxalin-6-yl)ethan-1-ol)
  • Compound 130 Compound 2-(5H-Imidazole [5,1-a] Isoindolin-5-yl)-1-(quinoxalin-6-yl)ethane-1-one (0805-130) (120 mg, 0.368 mmol, 1 eq.) was dissolved in 5 mL methanol Sodium borohydride (28 mg, 0.736 mmol, 2 eq.) was added slowly.
  • Step 41a Preparation of methyl quinoline-3-carboxylate (compound 0802-131): compound 3-quinolinecarboxylic acid (0801-131) (1.0 g, 5.78 mmol, 1.0) Equivalent) was dissolved in 30 mL of methanol, then sulfuric acid (0.5 mL) was added and refluxed overnight. After the reaction was completed, the pH was adjusted to 8 with sodium hydrogen carbonate solution, extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. ). LCMS (ESI): m / z 188 [M + 1] +.
  • Step 41b dimethyl(2-oxo-2-(quinolin-3-yl)ethyl)phosphonate (compound 0803-(3-oxo-2-(quinolin-3-yl)ethyl)phosphonate)
  • 131) Under a nitrogen atmosphere, dimethyl methyl phosphate (345 mg, 2.78 mmol, 1.3 equivalents) was dissolved in 30 ml of dry toluene, cooled to -70 ° C, slowly added dropwise n-butyl Lithium (1.28 ml, 2.5 mol/L n-hexane solution, 3.21 mmol, 1.5 eq.).
  • Step 41c 1-(Quinolin-3-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (1- Preparation of (quinolin-3-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one) (Compound 0804-131): 2- (1-Trityl-1H-imidazol-4-yl)benzaldehyde (0105-1) (250 mg, 0.6 mmol, 1.0 eq.), Compound (2-(quinolin-3-yl)-2- Oxyethylethyl dimethyl phosphate (0803-131) (420 mg, 1.5 mmol, 2.5 eq.) and cesium carbonate (698 mg, 2.14 mmol, 3.6 eq.) were combined in isopropyl alcohol (30 mL).
  • Step 41d 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(quinolin-3-yl)ethane-1-one (2-(5H-imidazo[ Preparation of 5,1-a]isoindol-5-yl)-1-(quinolin-3-yl)ethan-1-one)
  • Compound 0805-131 Compound 1-(quinolin-3-yl)- 3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (0804-131) (220 mg, 0.39 mmol, 1.0 eq.) Acetic acid (10 ml) was mixed in methanol (40 ml), and the mixture was stirred at 90 ° C overnight.
  • Step 41e 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(quinolin-3-yl)ethane-1-ol (2-(5H-imidazo[ Preparation of 5,1-a]isoindol-5-yl)-1-(quinolin-3-yl)ethan-1-ol) (Compound 131): Compound 2-(5H-Imidazole [5,1-a] Isoporphyrin-5-yl)-1-(quinolin-3-yl)ethane-1-one (0805-131) (100 mg, 0.3 mmol, 1.0 eq.) was dissolved in 10 mL of methanol.
  • Example 42 2-(5H-Imidazo[5,1-a]isoindoline-5-yl)-1-(isoquinolin-3-yl)ethane-1-ol (2-(5H-) Preparation of imidazo[5,1-a]isoindol-5-yl)-1-(isoquinolin-3-yl)ethan-1-ol) (Compound 132) (prepared according to Scheme 8)
  • Step 42a Preparation of methyl isoquinoline-3-carboxylate (compound 0802-132): Compound 3-isoquinolinecarboxylic acid (0801-132) (1.0 g, 5.78 mmol) , 1.0 equivalent) was dissolved in 30 ml of methanol, then sulfuric acid (0.5 ml) was added and refluxed overnight. After the reaction was completed, the pH was adjusted to 8 with sodium hydrogen carbonate solution, extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and evaporated to afford compound 3-isoquinolinecarboxylic acid methyl ester (810 mg, 75 %).
  • Step 42b dimethyl (2-(isoquinolin-3-yl)-2-oxoethyl)phosphonate (compound 0803) Preparation of 132): Under a nitrogen atmosphere, dimethyl methyl phosphate (345 mg, 2.78 mmol, 1.3 eq.) was dissolved in 30 ml of dry toluene, cooled to -70 ° C, slowly added dropwise n-butyl Lithium (1.28 ml, 2.5 mol/L n-hexane solution, 3.21 mmol, 1.5 eq.).
  • Step 42c 1-(Isoquinolin-3-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (1 -(isoquinolin-3-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one) (Compound 0804-132)
  • Compound (2-(isoquinolin-3-yl)- Dimethyl 2-oxoethyl)phosphate (0803-132) (350 mg, 1.25 mmol, 2.2 eq.) and cesium carbonate (391 mg, 1.2 mmol, 2.0 eq.) in isopropyl alcohol (30 mL)
  • the reaction was stir
  • Step 42d 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(isoquinolin-3-yl)ethane-1-one (2-(5H-imidazo) Preparation of [5,1-a]isoindol-5-yl)-1-(isoquinolin-3-yl)ethan-1-one) (Compound 0805-132): Compound 1-(Isoquinolin-3-yl) --3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (0804-132) (200 mg, 0.35 mmol, 1.0 eq.
  • Step 42e 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(isoquinolin-3-yl)ethane-1-ol (2-(5H-imidazo) Preparation of [5,1-a]isoindol-5-yl)-1-(isoquinolin-3-yl)ethan-1-ol) (Compound 132): Compound 2-(5H-Imidazole [5,1-a] Isoindolin-5-yl)-1-(isoquinolin-3-yl)ethane-1-one (0805-132) (80 mg, 0.14 mmol, 1.0 eq.) was dissolved in 10 mL methanol Sodium borohydride (53.5 mg, 1.4 mmol, 10.0 eq.) was added slowly and cooled to 0 °C.
  • Step 43a Preparation of 2-quinoline-2-carboxylic acid (compound 0802-133): Compound 2-quinolinecarboxylic acid (0801-133) (1.0 g, 5.77 mmol, 1.0) Ethyl acetate and potassium carbonate (1.59 g, 11.54 mmol, 2.0 eq.) were added to 30 ml of DMF, then methyl iodide (0.98 g, 6.93 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 4 hours. After the completion of the reaction, 100 ml of water was added, and the mixture was combined with EtOAc. EtOAc (EtOAc) White solid. LCMS (ESI): m / z 174 [M + 1] +.
  • Step 43b (2-(2-oxo-2-(quinolin-2-yl)ethyl)phosphonate) (Compound 0803-(2-oxo-2-(quinolin-2-yl)ethyl)phosphonate) Preparation of 133): Methyl dimethyl phosphate (494 mg, 4.00 mmol, 1.5 eq.) was dissolved in 10 mL of dry THF. Dry ice/ethanol was cooled to -60 ° C, n-butyl lithium (2.14 ml, 2.5 mol / liter of tetrahydrofuran solution, 5.34 mmol, 2.0 equivalents) was slowly added dropwise, and the mixture was stirred at this temperature for 30 minutes, and then slowly added dropwise.
  • Step 43c 1-(Quinolin-2-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (1- Preparation of (quinolin-2-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one) (Compound 0804-133): (2 -(Quinolin-2-yl)-2-oxoethyl)phosphate dimethyl ester (0803-133) (279 mg, 1.0 mmol, 1.0 eq.), 2-(1-tritylmethyl-1H- Imidazolyl-4-yl)benzaldehyde (0105-1) (414 mg, 1.0 mmol, 1.0 eq.) and cesium carbonate (651 mg, 2.0 mmol, 2.0 eq.) isopropyl alcohol (10 mL) at room temperature The reaction was stirred overnight.
  • Step 43d 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(quinolin-2-yl)ethane-1-one (2-(5H-imidazo[ Preparation of 5,1-a]isoindol-5-yl)-1-(quinolin-2-yl)ethan-1-one) (Compound 0805-133): Compound 1-(quinolin-2-yl)- 3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (0804-133) (200 mg, 0.353 mmol, 1.0 eq.) Acetic acid (5 ml) was mixed in methanol (10 ml), and the mixture was stirred at 90 ° C overnight.
  • Step 43e 2-(5H-imidazo[5,1-a]isoindoline-5-yl)-1-(quinolin-2-yl)ethane-1-ol (1-(quinolin-2- Preparation of yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 133): Compound 2-(5H-Imidazole [5,1-a] Isoporphyrin-5-yl)-1-(quinolin-2-yl)ethane-1-one (0805-133) (100 mg, 0.308 mmol, 1.0 eq.) was dissolved in 10 mL of methanol.
  • Step 44b dimethyl (2-oxo-2-(quinoxalin-2-yl)ethyl)phosphonate (compound 0803) -134)
  • dimethyl methylphosphonate 500 mg, 4.0 mmol, 1.5 eq.
  • 20 ml of anhydrous toluene were added and cooled in a dry ice-ethanol bath.
  • Step 44c 1-(Quinoxalin-2-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (1 -(quinoxalin-2-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one) (Compound 0804-134)
  • 2-(Quinoxalin-2-yl)-2-oxoethyl)phosphate dimethyl ester (0803-134) (224 mg, 0.80 mmol, 1.1 eq.)
  • 2-(1-tritylmethyl)- 1H-imidazol-4-yl)benzaldehyde (0105-1) (300 mg, 0.73 mmol, 1.0 eq.) and cesium carbonate (472 mg, 1.45 mmol, 2.0 eq.) were added to 40 ml of isopropanol.
  • Step 44d 2-(5H-Imidazo[5,1-a]isoindoline-5-yl)-1-(quinoxalin-2-yl)ethane-1-one (2-(5H-imidazo) Preparation of [5,1-a]isoindol-5-yl)-1-(quinoxalin-2-yl)ethan-1-one) (Compound 0805-134): 1-(Quinoxalin-2-yl) -3-(2-(1-Trityl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (0804-134) (400 mg, 0.80 mmol, 1.0 eq) Dissolved in 30 ml of methanol, added 5 ml of acetic acid, and heated to reflux overnight.
  • Step 44e 2-(5H-Imidazo[5,1-a]isoindoline-5-yl)-1-(quinoxalin-2-yl)ethane-1-ol (2-(5H-imidazo) [5,1-a]isoindol-5-yl)-1-(quinoxalin-2-yl)ethan-1-ol) (Preparation of compound 134: 2-(5H-imidazole [5,1-a]) Porphyrin-5-yl)-1-(quinoxalin-2-yl)ethane-1-one (0805-134) (200 mg, 0.61 mmol, 1.0 eq.) dissolved in 30 mL of methanol, ice In a bath, cooled to 0 ° C, sodium borohydride (35 mg, 0.92 mmol, 1.5 eq.) was added, the reaction was stirred for half an hour, acetone was added, concentrated under reduced pressure, extracted with dichloromethane, washed with water and
  • Example 45 1-(Benzofuran-2-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol (1-(benzofuran-) Preparation of 2-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 135) (prepared according to Scheme 9)
  • Step 45a Preparation of methyl benzofuran-2-carboxylate (compound 0902-135): compound benzofuran-2-carboxylic acid (0901-135) (1.0 g, 6.1 Millimol, 1.0 eq.) was dissolved in 50 mL of methanol. After cooling in an ice bath, thionyl chloride (1.3 ml, 18.3 mmol, 3.0 eq.) was slowly added dropwise. The mixture was stirred at 40 ° C for 6 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. The organic phase was dried over anhydrous sodium sulfate (m.hhhhhhhhhhhhhh 900 mg, yield: 82%). LCMS (ESI): m / z 177 [M + 1] +.
  • Step 45b dimethyl (2-(benzofuran-2-yl)-2-oxoethyl)phosphonate (compound 0903- Preparation of 135): Under a nitrogen atmosphere, dimethyl methyl phosphate (420 mg, 3.38 mmol, 1.5 eq.) was dissolved in 20 ml of dry tetrahydrofuran, cooled to -70 ° C, slowly added dropwise n-butyl Lithium (1.8 mL, 2.5 mol/L n-hexane solution, 4.5 mmol, 2.0 eq.).
  • Step 45c 1-(benzofuran-2-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (1 -(benzofuran-2-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one) (Compound 0904-135)
  • Compound (2-(benzofuran-2-yl)-2 -Oxoethyl)phosphoric acid dimethyl ester (0903-135) (257 mg, 0.96 mmol, 2.0 eq.) and cesium carbonate (313 mg, 0.96 mmol, 2.0 eq.) in isopropyl alcohol (30 mL) The reaction was stirred at room temperature
  • Step 45d 1-(benzofuran-2-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (1-(benzofuran-2) -yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0905-135)
  • Step 45e 1-(benzofuran-2-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol (1-(benzofuran-2) -yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 135)
  • Compound 1-(benzofuran-2-yl)- 2-(5H-Imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0905-135) (148 mg, 0.47 mmol, 1.0 eq.) was dissolved in 10 mL methanol Cool to 0 ° C and slowly add sodium borohydride (70 mg, 1.88 mmol, 4.0 eq.).
  • Example 46 1-(Benzothiophen-2-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol (1-(benzo[ Preparation of b]thiophen-2-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) Compound 137) (prepared according to Scheme 9)
  • Step 46a Preparation of methyl benzo[b]thiophene-2-carboxylate (compound 0902-137): compound 2-benzothiophenecarboxylic acid (0901-137) (1.0 g , 5.61 mmol, 1.0 eq.) was added to 20 ml of methanol, then concentrated sulfuric acid (0.1 g) was added, and the mixture was stirred at 60 ° C for 16 hours. After completion of the reaction, 50 ml of a saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was evaporated. Gram, yield 97.4%) was a white solid.
  • Step 46b (2-(benzothiophen-2-yl)-2-oxoethyl)phosphonate (dimethyl(2-(benzo[b]thiophen-2-yl)-2-oxoethyl)phosphonate)
  • Dimethyl methyl phosphate (480 mg, 3.9 mmol, 1.5 eq.) was dissolved in 10 mL of dry tetrahydrofuran under nitrogen atmosphere and cooled with dry ice/ethanol to - At 60 ° C, n-butyllithium (2.08 ml, 2.5 mol / liter of tetrahydrofuran solution, 5.2 mmol, 2.0 equivalents) was slowly added dropwise, and the mixture was stirred at this temperature for 30 minutes, and the compound 2-benzothiophene was slowly added dropwise.
  • Step 46c 1-(Benzothiophen-2-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-en-1-one (1 -(benzo[b]thiophen-2-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one) (compound 0904-137)
  • Step 46d 1-(Benzothiophen-2-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (1-(benzo[b] Preparation of thiophen-2-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0905-137).
  • Step 46e 1-(Benzothiophen-2-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol (1-(benzo[b] Preparation of thiophen-2-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 137): Compound 1-(benzothiophene-2) -yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0905-137) (100 mg, 0.303 mmol, 1.0 eq.) Sodium borohydride (22 mg, 0.606 mmol, 2.0 eq.) was added slowly in 10 mL of methanol.
  • Example 47 1-(benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one oxime methyl (O- Preparation of methyl oxime 1-(benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one O-methyl oxime) (Compound 146) Two line preparation)
  • the listed compounds have two chiral centers with four stereoisomers that can be separated in a high performance liquid phase (HPLC) using a chiral column.
  • HPLC high performance liquid phase
  • the chiral column chromatography method is as follows:
  • Compound 8 was isolated by the above HPLC method, and was sequentially subjected to Compound 9, Compound 10, Compound 11 and Compound 12 in the order of the peak.
  • the retention times of the components using the above analytical methods are as follows (as shown in Figure 2):
  • Step 49a Preparation of 2-fluoro-4-hydroxy-5-iodobenzaldehyde (Compound 1102-11): Compound 2 under ice bath and stirring -Fluoro-4-hydroxybenzaldehyde (1101-11) (20 g, 142.86 mmol, 1 equivalent) was slowly added to 200 ml of concentrated sulfuric acid, the ice bath was removed, stirred at room temperature, and dissolved in the compound, then placed on ice. In the bath. A solution of NIS (32.14 g, 142.86 mmol, 1 eq.) in tetrahydrofuran (50 mL) was slowly added dropwise, keeping the internal temperature below 10 °C.
  • NIS 32.14 g, 142.86 mmol, 1 eq.
  • Step 49b Preparation of 6-fluorobenzofuran-5-carbaldehyde (compound 1104-11): 2-fluoro-4-hydroxy-5-iodobenzaldehyde under nitrogen protection (1102-11) (29 g, 109 mmol, 1 equivalent), trimethylsilylacetylene (16 g, 163.5 mmol, 1.4 eq.), cuprous iodide (311 mg, 1.635 mmol, 0.015 eq.) Tetrakistriphenylphosphine palladium (2.3 g, 3.27 mmol, 0.03 equivalent) was added to 150 ml of tetrahydrofuran and 75 ml of chloroform, then triethylamine (33 g, 327 mmol, 3 eq.) was added and the mixture was heated to 55 ° C.
  • Step 49c 3-(6-Fluorobenzofuran-5-yl)-3-hydroxy-1-(2-iodophenyl)propan-1-one (3-(6-fluorobenzofuran-5-yl)-3 Preparation of -hydroxy-1-(2-iodophenyl)propan-1-one) (Compound 1106-11): Diisopropylamine (5.0 g, 49.35 mmol, 1.5 eq.) was dissolved in anhydrous tetrahydrofuran under nitrogen atmosphere.
  • Step 49d 3-((tert-Butyldimethylsilyl)oxy)-3-(6-fluorobenzofuran-5-yl)-1-(2-iodophenyl)propan-1-one (3 -((tert-butyldimethylsilyl)oxy)-3-(6-fluorobenzofuran-5-yl)-1-(2-iodophenyl)propan-1-one) (Compound 1107-11): Under nitrogen protection conditions, 3-(6-fluorobenzofuran-5-yl)-3-hydroxy-1-(2-iodophenyl)propan-1-one (1106-11) (7.1 g, 17.3 mmol, 1.0 eq.) 2,6-lutidine (7.4 g, 69.2 mmol, 4.0 eq.) was dissolved in dichloromethane (80 mL).
  • Step 49e (1R,3S)-3-((tert-Butyldimethylsilyl)oxy)-3-(6-fluorobenzofuran-5-yl)-1-(2-iodophenyl)propane -1,3,6-fluorobenzofuran-5-yl-1-(2-iodophenyl)propan-1-ol) (Compound 1108) -11) and (1R,3R)-3-((tert-butyldimethylsilyl)oxy)-3-(6-fluorobenzofuran-5-yl)-1-(2-iodophenyl) Propane-1-ol ((1R,3R)-3-((tert-butyldimethylsilyl)oxy)-3-(6-fluorobenzofuran-5-yl)-1-(2-iodophenyl)propan-1-ol) Preparation of 1109-11): S-CBS (0.42 g, 1.53 mmol, 0.1 e
  • Step 49f 1-((1S,3S)-3-((tert-Butyldimethylsilyl)oxy)-3-(6-fluorobenzofuran-5-yl)-1-(2-iodobenzene) Ethyl)-1H-imidazole-2-carboxylic acid ethyl ester (1-((1S,3S)-3-((tert-butyldimethylsilyl)oxy)-3-(6-fluorobenzofuran-5-yl)-1- Preparation of (2-iodophenyl)propyl)-1H-imidazole-2-carboxylate) (Compound 1111-11): (1R,3S)-3-((tert-Butyldimethylsilyl)oxy)-3- (6-Fluorobenzofuran-5-yl)-1-(2-iodophenyl)propan-1-ol (1108-11) (2.65 g, 5 mmol, 1.0 eq.),
  • Step 49g (S)-5-((S)-2-((tert-Butyldimethylsilyl)oxy)-2-(6-fluorobenzofuran-5-yl)ethyl)-5H- Imidazo[5,1-a]isoporphyrin-3-carboxylic acid ethyl ester (ethyl(S)-5-((S)-2-((tert-butyldimethylsilyl)oxy)-2-(6-fluorobenzofuran-) Preparation of 5-yl)ethyl)-5H-imidazo[5,1-a]isoindole-3-carboxylate (Compound 1112-11): 1-((1S,3S)-3-(( Ethyl tert-butyldimethylsilyloxy)-3-(6-fluorobenzofuran-5-yl)-1-(2-iodophenyl)propane)-1H-imidazol-2-carboxylate (
  • Step 49h (S)-5-((S)-2-(6-fluorobenzofuran-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)-5H- Imidazo[5,1-a]isoporphyrin ((S)-2-(6-fluorobenzofuran-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)-5H Preparation of -imidazo[5,1-a]isoindole) (Compound 1113-11): (S)-5-((S)-2-((tert-Butyldimethylsilyl)oxy)-2- (6-Fluorobenzofuran-5-yl)ethyl)-5H-imidazole [5,1-a]isoindoline-3-carboxylic acid ethyl ester (1112-11) (2.85 g, 4.5 mmol, 1.0 equivalent), tributy
  • Step 49i (S)-1-(6-fluorobenzofuran-5-yl)-2-((S)-5H-imidazo[5,1-a]isoindoline-5-yl)ethane -1-(6)-(6-fluorobenzofuran-5-yl)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)
  • Step 50a (1R)-3-((tert-Butyldimethylsilyl)oxy)-3-(6-fluorobenzofuran-5-yl)-1-(2-iodophenyl)propane - 1-(1R)-3-((tert-butyldimethylsilyl)oxy)-3-(6-fluorobenzofuran-5-yl)-1-(2-iodophenyl)propan-1-ol) (Compound 1401-11) Preparation: Under the protection of nitrogen, S-CBS (0.42 g, 1.53 mmol, 0.1 eq.) was dissolved in tetrahydrofuran (50 ml), and 10 mol per liter of borane was added dropwise under ice bath.
  • Step 50b 1-((1S)-3-((tert-Butyldimethylsilyl)oxy)-3-(6-fluorobenzofuran-5-yl)-1-(2-iodophenyl) Propane)-1H-imidazole-2-carboxylic acid ethyl ester (1-((1S)-3-((tert-butyldimethylsilyl)oxy)-3-(6-fluorobenzofuran-5-yl)-1-(2-iodophenyl) Preparation of propyl)-1H-imidazole-2-carboxylate) (Compound 1402-11): (1R)-3-((tert-Butyldimethylsilyl)oxy)-3-(6-fluorobenzo) Furan-5-yl)-1-(2-iodophenyl)propan-1-ol (1401-11) (5.3 g, 10 mmol, 1.0 eq.) and triphenylphosphine (9.7
  • Step 50c 1-((1S)-3-(6-fluorobenzofuran-5-yl)-3-hydroxy-1-(2-iodophenyl)propyl)-1H-imidazole-2-carboxylic acid Ethyl (ethyl 1-((1S)-3-(6-fluorobenzofuran-5-yl)-3-hydroxy-1-(2-iodophenyl)propyl)-1H-imidazole-2-carboxylate) (Compound 1403-11) Preparation: 1-((1S)-3-((tert-butyldimethylsilyl)oxy)-3-(6-fluorobenzofuran-5-yl)-1-(2-iodobenzene) Ethyl)propane)-1H-imidazole-2-carboxylic acid ethyl ester (1402-11) (700 mg, 1.08 mmol, 1.0 eq.) and tetrabutylammonium fluoride trihydrate (3
  • Step 50d (S)-1-(3-(6-fluorobenzofuran-5-yl)-1-(2-iodophenyl)-3-oxopropyl)-1H-imidazol-2-carboxylate Ethyl ethyl ester (ethyl(S)-1-(3-(6-fluorobenzofuran-5-yl)-1-(2-iodophenyl)-3-oxopropyl)-1H-imidazole-2-carboxylate (compound 1404-11) Preparation: 1-((1S)-3-(6-fluorobenzofuran-5-yl)-3-hydroxy-1-(2-iodophenyl)propyl)-1H-imidazol-2-carboxylate Ethyl ester (1403-11) (500 mg, 0.94 mmol, 1.0 eq.) and IBX (524 mL, 1.88 mmol, 2.0 eq.) were dissolved in DMSO (10
  • Step 50e 1-((1S,3S)-3-(6-fluorobenzofuran-5-yl)-3-hydroxy-1-(2-iodophenyl)propane)-1H-imidazol-2-carboxylate
  • Ethyl ethyl ester ethyl 1-((1S,3S)-3-(6-fluorobenzofuran-5-yl)-3-hydroxy-1-(2-iodophenyl)propyl)-1H-imidazole-2-carboxylate
  • Step 50f 1-((1S,3S)-3-(6-fluorobenzofuran-5-yl)-1-(2-iodophenyl)-3-((trimethylsilyl)oxy)propane -1H-Imidazole-2-carboxylic acid ethyl ester (ethyl 1-((1S,3S)-3-(6-fluorobenzofuran-5-yl)-1-(2-iodophenyl)-3-((trimethylsilyl)oxy) Preparation of propyl)-1H-imidazole-2-carboxylate) (Compound 1111-11): 1-((1S,3S)-3-(6-fluorobenzofuran-5-yl) under nitrogen protection Ethyl 3-hydroxy-1-(2-iodophenyl)propane)-1H-imidazol-2-carboxylate (1405-11) (290 mg, 0.54 mmol, 1.0 eq.) and trimethylcyanosilane
  • Step 50g (S)-5-((S)-2-(6-fluorobenzofuran-5-yl)-2-((trimethylsilyl)oxy)ethyl)-5H-imidazole [5 ,1-a]ethyl(S)-5-((S)-2-(6-fluorobenzofuran-5-yl)-2-((trimethylsilyl)oxy)ethyl
  • -5H-imidazo[5,1-a]isoindole-3-carboxylate) Compound 1112-11): 1-((1S,3S)-3-(6-fluorobenzo) under nitrogen protection Ethyl furan-5-yl)-1-(2-iodophenyl)-3-((trimethylsilyl)oxy)propane)-1H-imidazol-2-carboxylate (1111-11) (140 mg , 0.23 mmol, 1.0 eq.), palladium acetate (8 mg, 0.035 mmol
  • Step 50h (S)-5-((S)-2-(6-fluorobenzofuran-5-yl)-2-((trimethylsilyl)oxy)ethyl)-5H-imidazole [5 ,1-a]iso-porphyrin ((S)-5-((S)-2-(6-fluorobenzofuran-5-yl)-2-((trimethylsilyl))oxy)ethyl)-5H-imidazo[5 ,1-a]isoindole) (Compound 1113-11) Preparation: (S)-5-((S)-2-((Trimethylsilyl)oxy)-2-(6-fluorobenzofuran) -5-yl)ethyl)-5H-imidazo[5,1-a]isoindoline-3-carboxylic acid ethyl ester (1112-11) (55 mg, 0.12 mmol, 1.0 eq.), tributyl Tin oxide (68.5 g, 0.
  • Step 50i (S)-1-(6-fluorobenzofuran-5-yl)-2-((S)-5H-imidazo[5,1-a]isoindoline-5-yl)ethane -1-(6)-(6-fluorobenzofuran-5-yl)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)
  • (Compound 11) (S)-5-((S)-2-(6-fluorobenzofuran-5-yl)-2-((tert-butyldimethylsilyl)oxy)B 5)-H-imidazole [5,1-a]isoindoline (1113-11) (30 mg, 0.07 mmol, 1.0 eq.) was dissolved in 2 mL of absolute ethanol, and 0.15 ml of concentrated hydrochloric acid was added and reacted at room temperature.
  • Step 51a Preparation of methyl 3-chloro-2-fluoro-4-hydroxy-5-iodobenzoate (compound 0204-19): Methyl 2-fluoro-4-hydroxy-5-iodobenzoate (700 mg, 2.36 mmol, 1.0 eq.) was dissolved in dichloromethane (50 mL) and diisopropylethylamine (. 2.0 equivalent), bromomethyl methyl ether (0.3 ml, 3.54 mmol, 1.5 eq.) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The organic phase was washed with EtOAc EtOAc.
  • Methylfluoro-5-iodo-4-(methoxymethoxy)benzoate 800 mg, yield: 99.1%.
  • Tetramethyl piperidine (466 mg, 3.3 mmol, 1.5 eq.) was added to 30 ml of tetrahydrofuran under a nitrogen atmosphere, cooled to -40 ° C, and 2.5 M n-butyllithium n-hexane solution (1.6 ml, 3.96) was added dropwise. Millimol, 1.8 equivalents). The temperature was naturally raised to room temperature and stirring was continued for half an hour.
  • Methyl benzoate (800 mg, crude product).
  • the above methyl 3-chloro-2-fluoro-5-iodo-4-(methoxymethoxy)benzoate was dissolved in tetrahydrofuran, and a 3 M aqueous hydrochloric acid solution was added thereto, and the mixture was stirred at 50 ° C for 3 hours.
  • the mixture was extracted with EtOAc.
  • EtOAc EtOAc (EtOAc m.
  • Step 51b Preparation of methyl 7-chloro-6-fluorobenzofuran-5-carboxylate (compound 0206-19): under nitrogen protection, 3 -Chloro-2-fluoro-4-hydroxy-5-iodobenzoic acid methyl ester (0204-19) (760 mg, 2.13 mmol, 1.0 eq.), trimethylsilylacetylene (626 mg, 6.39 mmol, 3.0) Equivalent), triethylamine (645 mg, 6.39 mmol, 3.0 eq.), cuprous iodide (8 mg, 0.043 mmol, 0.02 eq.) and dichloroditriphenylphosphine palladium (75 mg, 0.11 mmol, 0.05 equivalent) was dissolved in 50 ml of tetrahydrofuran, and the reaction was stirred at 60 ° C overnight.
  • Step 51c (2-(7-Chloro-6-fluorobenzofuran-5-yl)-2-oxoethyl)phosphate dimethyl dimethyl(2-(7-chloro-6-fluorobenzofuran-5-yl)
  • 2-oxoethyl)phosphonate (Compound 0207-19): In a round bottom flask, dimethyl methylphosphonate (136 mg, 1.1 mmol, 2.0 eq.) and 20 mL of Water tetrahydrofuran, cooled to -72 ° C in a dry ice-ethanol bath, 2.5 M n-butyl lithium n-hexane solution (0.51 mL, 1.3 mmol, 2.3 eq.) was added dropwise, stirred for 1 hour, and added dropwise at -72 ° C.
  • Step 51d 1-(7-Chloro-6-fluorobenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propane-2- 1-(7-chloro-6-fluorobenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-
  • Preparation of one) (Compound 0208-19): dimethyl (2-(7-chloro-6-fluorobenzofuran-5-yl)-2-oxoethyl)phosphate (0207-19) (185 Mg, 0.55 mmol, 1.0 eq.), 2-(1-trityl-1H-imidazol-4-yl)benzaldehyde (0105-1) (228 mg, 0.55 mmol, 1.0 eq.) 359 mg, 1.1 mmol, 2.0 eq.), EtOAc, EtOAc (E
  • Step 51e 1-(7-Chloro-6-fluorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one
  • (1-(7-chloro-6-fluorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 209-19) : 1-(7-Chloro-6-fluorobenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propan-2-ene 1- Ketone (0208-19) (150 mg, 0.25 mmol, 1.0 eq.) was dissolved in 30 mL of methanol and added with acetic acid 6 Cc, heated to reflux overnight.
  • Step 51f 1-(7-Chloro-6-fluorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol
  • 1-(7-chloro-6-fluorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 19): 1-(7-chloro-6-fluorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0209- 19) (100 mg, 0.28 mmol, 1.0 eq.) was dissolved in 30 ml of methanol, cooled in ice-cooled to 0 ° C, sodium borohydride (21 mg, 0.56 mmol, 2.0 eq.).
  • Example 52 1-(6-Fluoro-2-hydroxymethylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane- 1-(6-fluoro-2-(hydroxymethyl)benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-o l)( Preparation of compound 51) (prepared according to Scheme 2)
  • Step 52a 2-(((tert-butoxycarbonyl)oxy)methyl)-6-fluorobenzofuran-5-carboxylic acid methyl ester (methyl 2-((tert-butoxycarbonyl)oxy)methyl)-6- Preparation of fluorobenzofuran-5-carboxylate) (Compound 0206-51).
  • Methyl 2-fluoro-5-iodo-4-hydroxybenzoate (0204-51) (900 mg, 3.04 mmol, 1.0 eq.), propanol (340 mg, 6.08 mmol, 1.5).
  • cuprous iodide (8 mg, 0.046 mmol, 0.015 equivalent) and tetrakistriphenylphosphine palladium (64 mg, 0.09 mmol, 0.03 equivalent) were added to 10 ml of tetrahydrofuran and 20 ml of chloroform, then added dropwise Triethylamine (921 mg, 9.12 mmol, 3 eq.), mixture was heated to 55 ° C and stirred overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. EtOAc (EtOAc:EtOAc:EtOAc Methyl 5-carboxylate (600 mg, crude). LCMS (ESI): m / z 225 [M + 1] +.
  • Step 52b ((5-(2-(Dimethoxyphosphoryl)acetyl)-6-fluorobenzofuran-2-yl)methyl)carbonate tert-butyl ester (tert-butyl((5-(2) Preparation of (dimethoxyphosphoryl)acetyl)-6-fluorobenzofuran-2-yl)methyl)carbonate)
  • Compound 0207-51 Dimethyl methylphosphonate (345 mg, 2.78 mmol, under a nitrogen atmosphere) 1.5 equivalents were dissolved in 15 ml of dry tetrahydrofuran.
  • Step 52c ((6-Fluoro-5-(3-(2-(1-tritylmethyl-1H-imidazol-5-yl)phenyl)acryloyl)benzofuran-2-yl)methyl) Tert-butyl(tert-butyl((6-fluoro-5-(3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)acryloyl)benzofuran-2-yl)methyl)carbonate)( Preparation of compound 0208-51): 2-(1-trityl-1H-imidazol-4-yl)benzaldehyde (0105-1) (696 mg, 1.68 mmol, 1 eq.), compound (5 -(2-(Dimethoxyphosphoryl)acetyl)-6-fluorobenzofuran-2-yl)methyl)carbonate tert-butyl ester (0207-51) (772 mg, 1.85 mmol, 1.1 eq.) It was mixed
  • Step 52d 1-(6-Fluoro-2-hydroxymethylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1 -keto(1-(6-fluoro-2-(hydroxymethyl)benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0209 -51) Preparation.
  • Step 52e 1-(6-Fluoro-2-hydroxymethylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1 -1-(6-fluoro-2-(hydroxymethyl)benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 51 Preparation: 1-(6-fluoro-2-hydroxymethylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane 1- Ketone (0209-51) (250 mg, 0.688 mmol, 1.0 eq.) was dissolved in 10 mL MeOH.
  • Step 53a Preparation of methyl 6-fluoro-2-methylbenzofuran-5-carboxylate (compound 0303-69): under nitrogen protection, 5 -Bromo-6-fluoro-2-methylbenzofuran (0301-69) (0.7 g, 3.0 mmol, 1.0 eq.) was added to 10 ml of anhydrous tetrahydrofuran, cooled to -78 ° C, then added dropwise Lithium (1.8 ml, 4.5 mmol, 1.5 eq.) was stirred for 0.5 h.
  • Step 53b 1-(6-Fluoro-2-methylbenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-4-yl)phenyl)propane-2 1-(6-fluoro-2-methylbenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1 -one) (Compound 0305-69). Dimethyl methylphosphonate (402 mg, 3.24 mmol, 1.5 eq.) was dissolved in 5 mL of dry tetrahydrofuran under a nitrogen atmosphere.
  • Step 53c 1-(6-Fluoro-2-methylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1- Ketone (1-(6-fluoro-2-methylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)-ethan-1-one) (Compound 0306-69) Preparation.
  • Step 53d 1-(6-Fluoro-2-methylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-
  • Preparation of alcohol (1-(6-fluoro-2-methylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)
  • Compound 69 1-(6-Fluoro-2-methylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one ( 0306-69) (350 mg, 1.01 mmol, 1.0 eq.) was dissolved in 30 mL of MeOH.
  • Example 54 5-(1-Hydroxy-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethyl)benzofuran-2-carboxylic acid ethyl ester (ethyl5-( Preparation of 1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)benzofuran-2-carboxylate) (Compound 89) (prepared according to Scheme 5)
  • Step 54a Preparation of ethyl 5-bromobenzofuran-2-carboxylate (compound 0505-89): 5-bromo salicylaldehyde (0504-89) (5 g , 25 mmol, 1.0 eq.) and cesium carbonate (8.2 g, 25 mmol, 1.0 eq.) were mixed in 80 ml of DMF, and ethyl bromoacetate (8.3 g, 50 mmol, 2.0 eq.) was added dropwise. After completion, the reaction was carried out for half an hour at room temperature.
  • Step 54b Preparation of ethyl 5-acetylbenzofuran-2-carboxylate (compound 0506-89): compound 5-bromobenzofuran-2 under nitrogen protection Ethyl carboxylate (0505-89) (2 g, 7.43 mmol, 1.0 eq.), butyl vinyl ether (7.4 g, 74.3 mmol, 10 eq.), palladium acetate (33 mg, 0.15 mmol, 0.02 Equivalent), bis(2-diphenylphosphinophenyl)ether (120 mg, 0.22 mmol, 0.03 equivalent) and diisopropylethylamine (2.4 mg, 18.6 mmol, 2.5 equivalents) in 50 ml of n-butyl alcohol.
  • Step 54c 5-(2-(5H-Imidazo[5,1-a]isoindoline-5-yl)acetyl)benzofuran-2-carboxylic acid ethyl ester (ethyl5-(2-(5H-) Preparation of imidazo[5,1-a]isoindol-5-yl)acetyl)benzofuran-2-carboxylate) (Compound 0507-89): methyl 5-acetylbenzofuran-2-carboxylate (0506-89) (200 mg, 0.86 mmol, 1.0 eq.) and 2-(1-trityl-1H-imidazol-4-yl)benzaldehyde (0105-1) (534 mg, 1.3 mmol, 1.5 eq.) In ethanol (10 ml), 5 ml of concentrated sulfuric acid was added dropwise thereto under ice-cooling, and the mixture was warmed to 90 ° C, and the mixture was stirred for 18 hours
  • Step 54d 5-(1-Hydroxy-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethyl)benzofuran-2-carboxylic acid ethyl ester (ethyl5-(1) Preparation of -hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)benzofuran-2-carboxylate) (Compound 89): 5-(2-(5H-imidazole [5, Ethyl 1-a]isoindoline-5-yl)acetyl)benzofuran-2-carboxylate (0507-89) (40 mg, 0.1 mmol, 1.0 eq.) was dissolved in 5 mL of ethanol and added Sodium borohydride (19 mg, 0.5 mmol, 5.0 eq.), the reaction was stirred for half an hour, and the liquid was taken to the reaction mixture.
  • Example 55 5-(1-Hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)benzofuran-2-carboxylic acid amide (5-(1) -hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)benzofuran-2-carboxamide) Preparation of 90) (prepared according to Scheme 5)
  • Step 55a 5-(2-(5H-Imidazo[5,1-a]isoindoline-5-yl)acetyl)benzofuran-2-carboxylic acid amide (5-(2-(5H-imidazo) Preparation of [5,1-a]isoindol-5-yl)acetyl)benzofuran-2-carboxamide) (Compound 0507-90).
  • Step 55b 5-(1-Hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)benzofuran-2-carboxylic acid amide (5-(1- Preparation of hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)benzofuran-2-carboxamide) (Compound 90): 5-(2-(5H-imidazole [5,1] -a]Isoindoline-5-yl)acetyl)benzofuran-2-carboxylic acid amide (0507-90) (25 mg, 0.07 mmol, 1.0 eq.) was dissolved in 4 mL of methanol and hydrobor.
  • Example 56 1-(6-Bromobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol (1- Preparation of (6-bromobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 156) (prepared according to Scheme 2)
  • Step 56a Preparation of 2-bromo-4-hydroxybenzoic acid (Compound 0201-156): 2-bromo-4-hydroxybenzaldehyde (1.7 g, 8.46 mmol, 1.0) Equivalent) was dissolved in 2 mol of aqueous sodium hydroxide solution (30 ml), and potassium permanganate (2.7 g, 616.92 mmol, 2.0 eq.) was added portionwise in an ice bath and stirred at room temperature for 2 hr. Filtration, the filtrate was washed once with dichloromethane, and the filtrate was added with 2 moles of aqueous hydrochloric acid to adjust to pH 1 and extracted with ethyl acetate. Bromo-4-hydroxybenzoic acid (1.6 g, 88%). LCMS (ESI): m / z 217 [M + 1] +.
  • Step 56b Preparation of methyl 2-bromo-4-hydroxybenzoate (Compound 0202-156): Under the protection of nitrogen, the compound 2-bromo-4-hydroxybenzoic acid (0201- 156) (1.6 g, 7.4 mmol, 1 eq.) was dissolved in methanol (30 ml), and then th. The mixture was heated to 55 ° C, and the mixture was evaporated. Rate: 100%).
  • Step 56c Preparation of methyl 2-bromo-4-hydroxy-5-iodobenzoate (compound 0204-156): 2-bromo-4-hydroxybenzene Methyl formate (0202-156) (1.0 g, 4.33 mmol, 1.0 eq.) and potassium carbonate (1.2 g, 8.66 mmol, 2.0 eq.) were mixed in tetrahydrofuran (50 ml), and iodine was added dropwise (1.43) Grams, 5.63 mmol, 1.3 eq.) were dissolved in 20 mL of tetrahydrofuran. After the addition was completed, the reaction was carried out at room temperature for 18 hours. The reaction mixture was washed with aq.
  • Step 56d Preparation of methyl 6-bromobenzofuran-5-carboxylate (compound 0206-156): 2-bromo-4-hydroxy-5 under nitrogen protection Methyl iodobenzoate (0204-156) (1 g, 2.8 mmol, 1.0 eq.), trimethylsilylacetylene (550 mg, 5.6 mmol, 2.0 eq.), cuprous iodide (8.0 mg, 0.042 m) Mole, 0.015 equivalents, ditriphenylphosphine palladium dichloride (60 mg, 0.084 mmol, 0.03 equivalent) and triethylamine (2 ml) were added to 50 ml of tetrahydrofuran, heated to 60 ° C, and stirred for 18 hours.
  • Methyl iodobenzoate (1 g, 2.8 mmol, 1.0 eq.)
  • trimethylsilylacetylene 550 mg, 5.6 mmol, 2.0 eq.
  • Step 56e (2-(6-bromobenzofuran-5-yl)-2-oxoethyl)phosphonate (2-(6-bromobenzofuran-5-yl)-2-oxoethyl)phosphonate
  • Dimethyl methylphosphonate (119 mg, 0.96 mmol, 1.5 eq.) was dissolved in 10 mL of dry THF. After cooling to -70 ° C with dry ice/ethanol, n-butyllithium (0.4 mL, 0.96 mmol, 1.5 eq.) was slowly added dropwise.
  • Step 56f 1-(6-Bromobenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-5-yl)phenyl)propan-2-ene-1- Ketone (1-(6-bromobenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en-1-one) (Compound 0208-156)
  • 2-(1-trityl-1H-imidazol-4-yl)benzaldehyde (0105-1) (240 mg, 0.58 mmol, 1.0 eq.), (2-(6-bromobenzo) Dimethylfuran-5-yl)-2-oxoethyl)phosphate (0207-156) (200 mg, 0.58 mmol, 1.0 eq.) and cesium carbonate (378 mg, 1.16 mmol, 2.0 eq.)
  • the reaction was carried out for 18 hours at room temperature in is
  • Step 56g 1-(6-Bromobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (1-( Preparation of 6-bromobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0209-156): Compound 1-(6- Bromobenzofuran-5-yl)-3-(2-(1-tritylmethyl-1H-imidazol-5-yl)phenyl)propan-2-en-1-one (0208-156) (350 Methanol, 0.55 mmol, 1 eq.) and acetic acid (8 mL) were combined in methanol (16 mL).
  • Step 56h 1-(6-Bromobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol (1-( Preparation of 6-bromobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 156): 1-(6-Bromobenzo) Furan-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (130 mg, 0.33 mmol, 1.0 eq.) dissolved in 10 mL In methanol, in an ice bath, sodium borohydride (25 mg, 0.66 mmol, 2.0 eq.) was added, and the mixture was stirred for half an hour, and then quenched with water, extracted with dichloromethane, and washed with water and brin
  • Example 57 1-(2-Chlorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol (1- Preparation of (2-chlorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 157) (prepared according to Scheme 5)
  • Step 57a Preparation of 1-(2-chlorobenzofuran-5-yl)ethan-1-one (Compound 0506-157): Compound 5-bromobenzofuran (0505-157) (1 g, 5.1 mmol, 1.0 eq.), butyl vinyl ether (2.55 g, 25.5 mmol, 5 eq.), palladium acetate (114) Mg, 0.51 mmol, 0.1 eq.), 1,3-bis(diphenylphosphino)propane (210 mg, 0.51 mmol, 0.1 eq.) and triethylamine (1.55 g, 1.53 mmol, 3.0 eq.) 30 ml of ethylene glycol.
  • Step 57b 1-(2-Chlorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (1-( Preparation of 2-chlorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one) (Compound 0507-157): 1-(2-Chlorine Benzofuran-5-yl)ethane-1-one (0506-157) (120 g, 0.61 mmol, 1.0 eq.) and 2-(1-trityl-1H-imidazol-4-yl)benzene Formaldehyde (0105-1) (380 mg, 0.92 mmol, 1.5 equivalent) was dissolved in 10 ml of dioxane, and 1 ml of concentrated sulfuric acid was added dropwise thereto under ice-cooling, and the mixture was warmed to 90 ° C,
  • Step 57c 1-(2-Chlorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-ol (1-( Preparation of 2-chlorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol) (Compound 157): 1-(2-Chlorobenzophthalate) Furan-5-yl)-2-(5H-imidazo[5,1-a]isoindoline-5-yl)ethane-1-one (0507-157) (30 mg, 0.086 mmol, 1.0 eq.
  • test compound was tested for IDO1 enzyme conversion of L-tryptophan (L-Trp) to produce kynurenine (Kyn). Inhibition activity.
  • test compound or reference compound (NLG919) was dissolved and diluted to different concentrations in DMSO using a 96-well plate (Corning, Cat. No. 3635) with 2 ul of compound and 98 ul 2 x IDO-1 (BPS, Cat) per well. #71182) Enzyme solution, incubate for 15 minutes at room temperature. 100 ul of 2 x L-tryptophan (Sigma, Cat. No. 93659-10G) substrate solution was added. The above 200 ul reaction solution contained 50 mM pH 6.5 potassium phosphate buffer, 0.02 mM methylene blue (Sigma, Cat. No. M9140-100G), 20 mM ascorbate (Sigma, Cat. No.
  • the compound-free control wells were 0.2 ml of reaction solution containing enzyme and substrate and 1% DMSO (positive control), and the enzyme-free control wells were 0.2 ml of enzyme-free substrate mixture and 1% DMSO (negative control).
  • % inhibition rate (positive control - compound well value) / (positive control - negative control) x 100.
  • the imidazole-containing fused tricyclic compound of the present invention can inhibit IDO1 enzyme activity.
  • IDO1 kinase inhibition assay using the following levels: For IC 50 concerned, I> 3000nM, 3000nM ⁇ II > 1000nM, 1000nM ⁇ III> 500nM, 500nM ⁇ IV> 200nM, V ⁇ 200nM. The results are shown in Table 1.
  • Hela cells were purchased from Shanghai Fudan IBS Cell Resource Center. After the cells were trypsinized from the cell culture plate and resuspended in DPBS medium, the cell density was determined by counting with a Scepter automatic cell counter (Millipore, Cat. No. PHCC00000). The cells were diluted with a cell culture medium into a solution containing 56,000 cells per ml. The adjusted cell fluid was added to a 96-well plate at 180 ⁇ L per well, and 20 ul of 10 ng/ml recombinant human interferon gamma (R&D, Cat. No. CAA31639) and various concentrations of the test compound or reference compound were added to each well.
  • Scepter automatic cell counter Millipore, Cat. No. PHCC00000
  • Cell culture medium; maximum enzyme activity control wells were added 20 ul of cell culture medium containing 10 ng/ml of interferon gamma and 10% DMSO; and 20 ul of cell culture medium containing 10% DMSO and no interferon gamma was added to the blank control wells. After culturing for 24 hours at 37 ° C in a 5% CO 2 incubator, 140 ul of the culture supernatant was taken out from each well into a new 96-well plate, and 10 ⁇ l of 6.1 N trichloroacetic acid was added thereto to mix.
  • a wavelength of 480 nm signal was detected using a microplate reader Thermo Scientific MULTISKAN MK3.
  • Inhibition rate % (signal value of the maximum enzyme activity control well - signal value of the compound well) / (signal value of the maximum enzyme activity control well - signal value of the blank control well) x 100%.
  • the curves were fitted using the GraphPad Prism 5.0 software and the IC50 was calculated.
  • Human cervical cancer Hela cells can induce endogenous IDO1 expression by pro-inflammatory cytokines. Although IDO1, IDO2 and TDO both catalyze the production of kynurenine by tryptophan, in Hela cells, interferon gamma stimulates IDO1 expression without affecting IDO2 and TDO (Blood, 115: 3520, 2010). In the assay, the imidazole-containing fused tricyclic compound of the present invention inhibits the IDO1 enzyme activity of HeLa cells.
  • the compound 2, the compound 8, the compound 11, the compound 36 and the compound 42 provided by the present invention have good absorption and high blood exposure after oral administration in rats.
  • the results are shown in Fig. 3 and Table 3.
  • the Tmax of the imidazole-containing fused tricyclic compound of the present invention is 0.5-1.1 hours, the Cmax is 930-2769 ng/ml, which is 7.1-21.1 times of the reference compound NLG919Cmax; the AUC 0-24h is 1538. -11099 ng/ml*h, which is 3.6-26.3 times the reference compound NLG919AUC 0-24h .
  • Cmax refers to the maximum blood concentration
  • T1/2 is the half-life
  • AUC 0-24 refers to the area under the time-concentration curve of 0-24 hours
  • AUC 0-inf refers to the area under the time-concentration curve of 0-Inf.
  • the Caco-2 cell model is a human cloned colon adenocarcinoma cell used for experiments simulating intestinal transit in vivo (J Mass Spectrom 35: 71-76, 2000).
  • Compound 11 (10 uM) and Caco-2 monolayer cells were incubated at 37 ° C for 90 minutes, and the compound transport was measured by LC-/MS/MS.
  • the apparent permeability coefficient of the compound from the top to the outside of the substrate ( Papp AB) and basolateral to apical permeability coefficient (Papp BA), respectively, indicate the ability of the compound to transport in both directions.

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Abstract

本发明公开了具有式(I)所示结构的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子。该类化合物具有调节IDO1活性的作用，这类化合物通过阻断免疫检查点IDO1，可以增强T细胞激活，用于治疗IDO1介导的免疫抑制，从而能够成为治疗恶性肿瘤的有效药物。与检查点蛋白的抗体药物或其他抗癌药物合用，可以增强抗癌效果。同时也有潜力有效治疗与IDO1异常有关的免疫抑制性疾病，有较大的应用价值。

Description

含咪唑稠合三环类化合物及其应用 技术领域
本发明涉及医药技术领域，特别是涉及一种含咪唑稠合三环类化合物及其应用。
背景技术
在细胞免疫中蛋白类抗原经抗原提呈细胞(APC)加工处理、降解为多肽，与MHC结合并移至APC表面，并与T细胞表面TCR结合，产生活化TCR信号。而抗原与T淋巴细胞表面的有关受体结合就产生协同刺激信号，即共刺激信号(co-stimulatory)和共抑制信号(co-inhibitory)，分别行使正向、负向调节功能。在双信号刺激下，T淋巴细胞被激活。绝大多数肿瘤免疫治疗都是通过间接或者直接激活人体T细胞清除肿瘤细胞发挥抗肿瘤作用。肿瘤细胞可以通过异常上调抑制信号免疫检查点及其相关配体，抑制T细胞激活，从而逃避免疫杀伤。阻断免疫检查点，增强T细胞激活，是近些年抗肿瘤药物开发聚焦点。
细胞毒性T淋巴细胞相关抗原(CTLA-4)、程序性死亡蛋白-1(Programmed Death-1,PD-1)程序性死亡蛋白配体1(Programmed death-ligand 1，PD-L1)是近年来临床验证的重要免疫检查点。经美国FDA批准，免疫检查点PD-1单克隆抗体Nivolumab用于霍奇金淋巴瘤、晚期肾细胞癌、晚期非小细胞肺癌、黑色素瘤和头颈鳞状细胞癌；另一个PD-1抗体Pembrolizumab用于晚期非小细胞肺癌、黑色素瘤、头颈鳞状细胞癌、霍奇金淋巴瘤和膀胱癌的治疗；PD-L1抗体atezolizumab作为二线药物用于治疗晚期膀胱癌和转移性非小细胞肺癌；CTLA-4抗体Ipilimumab用于治疗不可切除的或转移性的黑色素瘤。
吲哚胺-(2,3)加双氧酶(IDO)和色氨酸-2,3-双加氧酶(TDO)是参与肿瘤免疫逃逸的另一个免疫检查点。IDO在前列腺癌、结直肠癌、胰腺癌、非小细胞肺癌、卵巢肿瘤、肾癌、黑色素瘤等肿瘤表达(Nat Med.9:1269-74，2003)。IDO1和TDO是色氨酸降解成犬尿氨酸通路的限速酶。色氨酸消耗和犬尿氨酸积聚诱导效应T细胞凋亡或功能障碍和免疫抑制。当色氨酸浓度的降低，升高T细胞内的不带电荷的tRNA水平，导致GCN2(amino acid-sensitive general control nondepressible 2)应激激酶通路激活和外周T细胞的无反应状态。而犬尿氨酸及其代谢产物(3-羟基犬尿氨酸和3-羟基邻氨基苯甲酸)升高，产生淋巴细胞毒性，引起细胞周期阻断和凋亡；还可诱导幼稚T细胞向免疫抑制调节T细胞 (Tregs)分化。和其他免疫检查点相似，IDO1和TDO是免疫治疗的重要靶点(Nat.Immunol.14,1014–1022,2013；Nat Rev Drug Discov 14,603–622(2015)。
IDO1抑制剂Indoximod(NLG-8189)、Epacadostat(INCB24360)和GDC-0919(NLG919)等正在临床试验阶段。根据clinicaltrials.gov信息,IDO1抑制剂用于多种血液肿瘤和实体瘤治疗临床试验正在进行，包括胶质母细胞瘤、神经胶质瘤、神经胶质肉瘤、恶性脑肿瘤、室管膜瘤、髓母细胞瘤、乳腺癌、黑色素瘤，胰腺癌、非小细胞肺癌、头颈部癌、胃癌、食管癌、结直肠肿瘤、前列腺癌、癌膀胱癌、泌尿系统移行细胞癌、卵巢肿瘤、输卵管癌、子宫内膜癌、肾细胞癌、原发性腹膜癌、急性髓细胞白血病、淋巴瘤等。早期临床研究结果证明IDO1抑制剂具有很好的安全性，与检查点蛋白的抗体药物或其它抗肿瘤药物联合使用，可显著增强抗肿瘤活性。
发明内容
基于此，本发明提供了一种含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，该类化合物能作为IDO1抑制剂，具有较好的抗肿瘤活性。
具体技术方案如下：
具有式(I)所示结构的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子：
Figure PCTCN2017100722-appb-000001
其中：
n选自：0，1，2，3或4；
X选自CR6或N；
Y选自(CH2)y或CR7R8，其中，y选自0或1；
W选自(CH2)z，CR7R8或-N(R)2，其中，z选自0或1；
R1选自：H，卤素，C1-C6烷基，C2-C6烯基，C2-C6炔基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代的C1-C6烷基，硝基，氰基，-OR，-N(R)2，-SR，-C(O)OR， -C(O)N(R)2，-C(O)R，-S(O)R，-S(O)2R，-S(O)2N(R)2，-N(R)C(O)R；
R2和R3分别独立选自：H，卤素，C1-C6烷基，C2-C6烯基，C2-C6炔基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代的C1-C6烷基，硝基，氰基，-OR，-N(R)2，-SR，-C(O)R,-C(O)OR,-C(O)N(R)2,-S(O)R，-S(O)2R，-S(O)2N(R)2,-N(R)C(O)R；
R4和R5分别独立选自：H，卤素，C1-C6烷基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，-OR，-N(R)2，-SR，氰基，硝基，-C(O)OR，-C(O)N(R)2，-C(O)R，-S(O)R，-S(O)2R，-S(O)2N(R)2,-N(R)C(O)R；或R4和R5一起形成G，G选自＝O或＝N-OR；
R6选自：H，卤素，C1-C6烷基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，-OR；
R7和R8分别独立选自：C1-C6烷基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，-OR，-N(R)2，-SR，-S(O)2R；
R选自：H，C1-C6烷基，C2-C6烯基，C2-C6炔基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基的取代C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代的C1-C6烷基；
环A选自8-16元取代的或未取代的双环并环或三环并环，所述双环并环或三环并环为饱和、部分不饱和或芳香的双环并环或三环并环，所述双环并环或三环并环的环上的原子选自C、O、N和S中的一种或化学上可接受的几种的组合。
在其中一些实施例中，环A选自：
Figure PCTCN2017100722-appb-000002
其中：
m选自0,1或2；
X1、X2、X3、X4、X5、X6、X7分别独立选自CR9或N；
R9选自：H，卤素，C1-C6烷基，C2-C6烯基，C2-C6炔基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代的C1-C6烷基，芳基，杂芳基，硝基，氰基，-OR，-N(R)2，-SR，-C(O)OR，-C(O)N(R)2，-C(O)R，-S(O)R，-S(O)2R，-S(O)2N(R)2，-N(R)C(O)R；
R10选自：H，C1-C6烷基，C2-C6烯基，C2-C6炔基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代的C1-C6烷基；
R选自：H，C1-C6烷基，C2-C6烯基，C2-C6炔基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代的C1-C6烷基。
在其中一些实施例中，环A选自：
Figure PCTCN2017100722-appb-000003
在其中一些实施例中，环A选自：
Figure PCTCN2017100722-appb-000004
在其中一些实施例中，环A选自：
Figure PCTCN2017100722-appb-000005
在其中一些实施例中，环A选自：
Figure PCTCN2017100722-appb-000006
在其中一些实施例中，X1、X2、X3、X4、X5、X6、X7分别独立选自CR9。
在其中一些实施例中，R9选自：H，卤素，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代C1-C6烷基，芳基，硝基，氰基，-OR，-N(R)2，-SR，-C(O)OR，-C(O)N(R)2，-C(O)R；
R选自：H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代的C1-C6烷基。
在其中一些实施例中，R9选自：H，卤素，C1-C6烷基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，苯基，硝基，氰基，-OR，-N(R)2，-C(O)OR，-C(O)N(R)2，-C(O)R。
在其中一些实施例中，R9选自：H，卤素，C1-C6烷基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，苯基，-OR，-C(O)OR，-C(O)N(R)2；R选自：H，C1-C6烷基。
在其中一些实施例中，R9选自：H，卤素，甲基，三氟甲基，甲氧基，羟甲基，羟基异丙基，苯基，-C(O)OC2H5，-C(O)NH2。
在其中一些实施例中，R10选自：H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代C1-C6烷基，羟基取代C1-C6烷基，烷氧基取代C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代C1-C6烷基。
在其中一些实施例中，R10选自H或C1-C6烷基。
在其中一些实施例中，所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子具有式Ⅱ或式III所示结构：
Figure PCTCN2017100722-appb-000007
在其中一些实施例中，
X为CR6；
Y选自CH2或CR7R8；
W为(CH2)z，z选自0或W为-N(R)2；
R6选自H或C1-C6烷基；
R7和R8分别独立选自：C1-C6烷基，-OR，-N(R)2，-SR；
R选自：H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代的C1-C6烷基。
在其中一些实施例中，所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子具有式IV所示结构：
Figure PCTCN2017100722-appb-000008
在其中一些实施例中，
n选自0，1或2；
R1选自：H，卤素，C1-C6烷基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，硝基，氰基，-OR，-N(R)2，-SR，-C(O)OR，-C(O)N(R)2，-C(O)R，-S(O)R，-S(O)2R，-S(O)2N(R)2，-N(R)C(O)R；
R选自：H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代的C1-C6烷基。
在其中一些实施例中，n选自0，1或2；R1选自：H，卤素，-OR，R为C1-C6烷基。
在其中一些实施例中，R2和R3分别独立选自：H，卤素，C1-C6烷基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，硝基，氰基，-OR，-N(R)2，-SR，-S(O)R，-S(O)2R，-S(O)2N(R)2,-N(R)C(O)R；
R选自：H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代的C1-C6烷基。
在其中一些实施例中，R2和R3分别独立选自：H，卤素。
在其中一些实施例中，R4和R5分别独立选自：H，羟基取代的C1-C6烷基，-OR，-N(R)2，-SR，氰基，硝基，-C(O)OR，-C(O)N(R)2，-C(O)R，-S(O)R，-S(O)2R，-S(O)2N(R)2,-N(R)C(O)R；或R4和R5一起形成G，G选自＝O或＝N-OR；
R选自：H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代的C1-C6烷基。
在其中一些实施例中，R4和R5分别独立选自：-OR，或R4和R5一起形成G，G选自＝O或＝N-OR；R选自：H，C1-C6烷基。
在其中一些实施例中，R4和R5中的一个选自H，另一个选自-OH。
在其中一些实施例中，所述化合物选自：
Figure PCTCN2017100722-appb-000009
Figure PCTCN2017100722-appb-000010
Figure PCTCN2017100722-appb-000011
Figure PCTCN2017100722-appb-000012
Figure PCTCN2017100722-appb-000013
Figure PCTCN2017100722-appb-000014
Figure PCTCN2017100722-appb-000015
Figure PCTCN2017100722-appb-000016
Figure PCTCN2017100722-appb-000017
Figure PCTCN2017100722-appb-000018
本发明还提供了上述化合物的应用。
具体技术方案如下：
上述含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备IDO1抑制剂中的应用。
上述含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备防治肿瘤的药物中的应用。
在其中一些实施例中，所述肿瘤为实体肿瘤或血液肿瘤。
在其中一些实施例中，所述实体肿瘤为乳腺癌、胰腺癌、肺癌、肝癌、胃癌、结肠癌、肾癌、前列腺癌、头颈肿瘤、食道癌、卵巢癌或宫颈癌；所述血液肿瘤为淋巴瘤、白血病或骨髓瘤。尤其是乳腺癌、胰腺癌、肺癌、肝癌、胃癌、结肠癌、肾癌、前列腺癌、头颈肿瘤、淋巴瘤等。
本发明白还提供了一种防治肿瘤的药物组合物。
具体技术方案如下：
一种防治肿瘤的药物组合物，其活性成分包含上述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子。所述药物组合物的活性成分还可以包含其它检查点蛋白抑制药物或其它抗肿瘤药物；所述其它检查点蛋白抑制剂包括但是不限于PD1单克隆抗体药、PD-L1单克隆抗体药和CTLA-4单克隆抗体药；所述其它抗肿瘤药物包括但是不限于化疗药、激素药、靶向治疗药和免疫治疗药。上述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子与其它检查点蛋白抑制药物或其它抗肿瘤药物联用可以增强抗肿瘤活性。
在其中一些实施例中，所述肿瘤包括：乳腺癌、胰腺癌、肺癌、肝癌、胃癌、结肠癌、 肾癌、前列腺癌、头颈肿瘤、食道癌、卵巢癌、宫颈癌、淋巴瘤、白血病和骨髓瘤。
本发明的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，是一系列新的化合物，该类化合物具有调节IDO1活性的作用，这类化合物通过阻断免疫检查点IDO1，可以增强T细胞激活，用于治疗IDO1介导的免疫抑制，从而能够成为治疗恶性肿瘤的有效药物。与检查点蛋白的抗体药物或其他抗癌药物合用，可以增强抗癌效果。同时也有潜力有效治疗与IDO1异常有关的免疫抑制性疾病，有较大的应用价值。
附图说明
图1为实施例48中化合物2的立体异构体分离的HPLC图；
图2为实施例48中化合物8的立体异构体分离的HPLC图；
图3为化合物NLG919、化合物2、8、11、36和42的大鼠灌胃给药(20mg/kg)的血药浓度图。
具体实施方式
本发明所述化合物中，当任何变量(例如R1、R2等)在任何组分中出现超过一次，则其每次出现的定义独立于其它每次出现的定义。同样，允许取代基及变量的组合，只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易合成的化合物。如果取代基自身被超过一个基团取代，应理解这些基团可在相同碳原子上或不同碳原子上，只要使结构稳定。
本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如，“C1-C6烷基”中“C1-C6”的定义包括以直链或支链排列的具有1、2、3、4、5或6个碳原子的基团。术语“环烷基”指具有特定碳原子数目的单环饱和脂肪烃基。例如“环烷基”包括环丙基、甲基-环丙基、2,2-二甲基-环丁基、2-乙基-环戊基、环己基等。
正如本领域技术人员所理解的，本文中所用“卤素”意指包括氯、氟、溴和碘。
本发明包括式Ⅰ-IV化合物的游离形式，也包括其药学上可接受的盐、其立体异构体及其前药分子。本文中一些特定的示例性化合物为胺类化合物的质子化了的盐。术语“游离形式”指以非盐形式的胺类化合物。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示 例性盐，也包括所有式Ⅰ-IV化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如，可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别，但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常，通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的，通过和适当的无机或有机碱反应形成酸性化合物的盐。
因此，本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如，常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等制备的盐，也包括得自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2一乙酰氧基一苯甲酸、富马酸、苯磺酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
如果本发明化合物为酸性的，则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐。得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐，所述碱包括伯胺、仲胺和叔胺的盐，取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'－二苄基乙二胺、二乙胺、2一二乙基氨基乙醇、2一二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N一乙基吗啉、N一乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪,哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
除在文献中已知的或在实验程序中例证的标准方法外，可采用如下合成方案(方案1-13中的方法制备本发明化合物。结合下述的合成方案，能够对本发明中所述的化合物以及合成方法进行更好的理解。所述的合成方案描述了可以用于制备本发明中所述的化合物的方法，所述的方法仅仅是为说明目的的说明性方案描述，并不构成对本发明所具有的范围的限制。
Figure PCTCN2017100722-appb-000019
Figure PCTCN2017100722-appb-000020
Figure PCTCN2017100722-appb-000021
Figure PCTCN2017100722-appb-000022
Figure PCTCN2017100722-appb-000023
Figure PCTCN2017100722-appb-000024
Figure PCTCN2017100722-appb-000025
Figure PCTCN2017100722-appb-000026
以下结合实施例对本发明做进一步的描述，但该实施例并非用于限制本发明的保护范围。
实施例1：1-(苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物1)的制备(按照方案一和二线路制备)
步骤1a:4-碘-1-三苯甲基-1H-咪唑(4-iodo-1-trityl-1H-imidazole)(化合物0102-1)的制备:4-碘咪唑(0101-1)(10.0克，51.6毫摩尔，1.0当量)溶解于150毫升四氢呋喃中，加入三苯基氯甲烷(17.2克，61.7毫摩尔，1.2当量)和三乙胺(14.5毫升，10.4毫摩尔，2.0当量)，加热至80℃，反应过夜。冷却至室温，减压浓缩，加入乙酸乙酯，水洗，无水硫酸钠干燥，减压浓缩，加入甲醇和少量二氯甲烷搅拌半小时，抽滤，所得固体，用甲醇洗两次，真空干燥，得到白色固体4-碘-1-三苯甲基-1H-咪唑(16克，收率：71％)。LCMS(ESI):m/z 437[M+1]+。
步骤1b:2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(2-(1-trityl-1H-imidazol-4-yl)benzaldehyde(化合物0105-1的制备):在氮气保护下，将四三苯基膦钯(2.0克，1.7毫摩尔，0.074当量)、4-碘-1-三苯甲基-1H-咪唑(0102-1)(10.0克，23.0毫摩尔，1.0当量)、2-醛基苯硼酸(0103-1)(4.1克，27.5毫摩尔，1.2当量)和磷酸三钾(12.0克，46毫摩尔，2.0当量)加入到180毫升二甲基甲酰胺和水(5：1)的混合液中，加热至90℃，反应6小时。冷却至室温，经过硅藻土抽滤，所得滤液用乙酸乙酯稀释至1000毫升，用饱和食盐水洗三次，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝8：1和石油醚：二氯甲烷＝2：1)，得到白色固体2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(5.2克，收率：54％)。LCMS(ESI):m/z 415[M+1]+。
步骤1c:4-羟基-3碘苯甲酸(4-hydroxy-3-iodobenzoic acid)(化合物0203-1)的制备。将对羟基苯甲酸(0201-1)(3.45克，25毫摩尔，1.0当量)溶于60毫升甲醇中，然后加入碘化钠(3.75克，25毫摩尔，1.0当量)和氢氧化钠(2.0克，50毫摩尔，2.0当量)。冰浴下冷却后，缓慢滴加饱和次氯酸钠溶液(45毫升，25毫摩尔，1.0当量)，控制温度在5℃以下。最后混合物在室温下搅拌反应2小时。反应结束后，加入亚硫酸氢钠饱和溶液(100毫升)淬灭，加入100毫升水，搅拌过夜。浓盐酸调pH值到3-4，析出固体，过滤，水洗，固体溶于乙酸乙酯，无水硫酸钠干燥，过滤，减压浓缩得到白色固体化合物4-羟基-3碘苯甲酸(5.71克，收率：86.5％)。LCMS(ESI):m/z 265[M+1]+。
步骤1d:4-羟基-3-碘苯甲酸甲酯(methyl 4-hydroxy-3-iodobenzoate)(化合物0204-1)的制备:将化合物4-羟基-3碘苯甲酸(0203-1)(2.5克，9.47毫摩尔，1.0当量)溶解于30毫升的无水甲醇中。然后加入盐酸甲醇溶液(10毫升，3摩尔/升的甲醇溶液，30毫摩尔，3.2当量)。混 合物在65℃下搅拌反应过夜。反应结束后，减压除去甲醇，残留物混悬在100毫升水中，加入饱和碳酸氢钠水溶液使pH到4左右，过滤收集固体，水洗一遍，干燥得到白色固体4-羟基-3-碘苯甲酸甲酯(2.86克，粗品)。LCMS(ESI):m/z 279[M+1]+。
步骤1e:4-羟基-3-(三甲基硅乙炔基)苯甲酸甲酯(methyl 4-hydroxy-3-((trimethylsilyl)ethynyl)benzoate)(化合物0205-1)的制备:在氮气的氛围下，将化合物4-羟基-3-碘苯甲酸甲酯(0204-1)(2.78毫克，9.998毫摩尔，1.0当量)，碘化亚铜(28毫克，0.15毫摩尔，0.015当量)，双三苯基磷二氯化钯(210毫克，0.3毫摩尔，0.03当量)和三甲基硅乙炔(1.37克，13.997毫摩尔，1.4当量)溶解于20毫升四氢呋喃和40毫升氯仿的混合液中。置换氮气三次，再缓慢滴入三乙胺(3.15克，31.14毫摩尔，3.0当量)。混合物加热到50℃反应4小时。反应结束后，降至室温，加入100毫升氯仿，用稀盐酸水溶液洗两遍，无水硫酸钠干燥，减压浓缩，得到褐色固体4-羟基-3-(三甲基硅乙炔基)苯甲酸甲酯(2.35克，粗品)。LCMS(ESI):m/z 248[M+1]+。
步骤1f:苯并呋喃-5-羧酸甲酯(methyl benzofuran-5-carboxylate)(化合物0206-1)的制备:将化合物4-羟基-3-(三甲基硅乙炔基)苯甲酸甲酯(0205-1)(1.5克，6.046毫摩尔，1.0当量)溶于50毫升甲醇中，然后加入碘化亚铜(57毫克，0.302毫摩尔，0.05当量)和二异丙基乙胺(687毫克，6.79毫摩尔，1.1当量)。混合物在60℃下搅拌反应16小时。反应结束后，降温，减压除去溶剂，所得残留物用硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝100/1)纯化，得到白色固体苯并呋喃-5-羧酸甲酯(400毫克，收率：37.56％)。LCMS(ESI):m/z 177[M+1]+。
步骤1g:(2-(苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(benzofuran-5-yl)-2-oxoethyl)phosphonate)(化合物0207-1)的制备。在氮气的氛围下，将甲基磷酸二甲酯(211毫克，1.703毫摩尔，1.5当量)溶解于10毫升的干燥的四氢呋喃中。干冰/乙醇冷却到-60℃，缓慢滴加入正丁基锂(0.7毫升，2.5摩尔/升的正己烷溶液，1.703毫摩尔，1.5当量)。混合物在-60℃下搅拌反应30分钟，再缓慢滴加化合物苯并呋喃-5-羧酸甲酯(0206-1)(200毫克，1.135毫摩尔，1.0当量)的四氢呋喃(10毫升)溶液。混合物在-60℃下搅拌反应0.5小时再升至室温反应4小时。反应结束后，加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到无色油状液体(2-(苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(226毫克，收率：74.2％)。LCMS(ESI):m/z 269[M+1]+。
步骤1h:(Z)-1-(苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮[(Z)-1-(benzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one](化合物0208-1)的制备:在氮气的氛围和冰浴的条件下，将60％的氢化钠(34毫克，0.844毫摩尔，1.0当量)溶 解于15毫升的四氢呋喃中。再缓慢加入(2-(苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(0207-1)(226毫克，0.844毫摩尔，1.0当量)的四氢呋喃溶液(15毫升)。混合物搅拌15分钟后，滴加2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(350毫克，0.844毫摩尔，1.0当量)的四氢呋喃(20毫升)溶液。混合物在冰浴条件下搅拌反应0.5小时。升至室温搅拌反应过夜。反应结束后，用饱和氯化铵水溶液淬灭，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到黄色油状物。所得黄色油状物通过硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝1/2)纯化，得到黄色油状物(Z)-1-(苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(356毫克，收率：75.7％)。LCMS(ESI):m/z 557[M+1]+。
步骤1i:1-(苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)[化合物1(化合物0209-1)]的制备:将化合物(Z)-1-(苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0208-1)(350毫克，0.63毫摩尔，1.0当量)和醋酸(5毫升)混合于甲醇(100毫升)中。混合物在90℃下搅拌反应过夜。反应结束后，降至室温。用饱和碳酸钠水溶液调节pH值至10，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，浓缩液用硅胶柱层析(二氯甲烷/甲醇＝100/1)纯化，得到黄色固体目标产物1-(苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(165毫克，收率：83.4％)。LCMS(ESI):m/z 315[M+1]+。1H NMR(300MHz,DMSO)δ8.46(d,J＝1.6Hz,1H),8.14(d,J＝2.2Hz,1H),8.06(dd,J＝8.7,1.8Hz,1H),7.75(m,2H),7.63(t,J＝7.1Hz,2H),7.44-7.27(m,2H),7.16(s,1H),7.09(m,1H),5.82(dd,J＝8.5,4.0Hz,1H),4.11(dd,J＝18.5,4.1Hz,1H),3.74(dd,J＝18.5,8.5Hz,1H)。
实施例2：1-(苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物2)的制备(按照方案二线路制备)
将化合物1-(苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0209-1)(165毫克，0.525毫摩尔，1.0当量)溶解于50毫升甲醇中。再缓慢加入硼氢化钠(40毫克，1.05毫摩尔，2.0当量)。混合物在室温下搅拌反应3小时。反应结束后，加入饱和氯化铵水溶液淬灭，搅拌10分钟，减压除去乙醇，加入饱和碳酸钠水溶液(50毫升)，用二氯甲烷(100毫升)萃取，有机相用饱和食盐水洗一遍，无水硫酸钠干燥，浓缩，浓缩物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1至100/8)纯化，得到米白色固体目标产物1-(苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(126毫克，收率：75.9％)。LCMS(ESI):m/z 317[M+1]+。熔点：58～62℃；1H NMR(500MHz,DMSO)δ7.99-7.83(m,2H),7.70-7.47(m,4H),7.40-7.23(m,3H),7.17-7.09(m,1H),6.93(m,1H),5.81-5.70(m,1H),5.52-5.35(m,1H),5.10(m,1H), 2.55-1.82(m,2H).
实施例3：1-(苯并[b]噻吩-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(benzo[b]thiophen-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物7)的制备(按照方案三线路制备)
步骤3a:苯并[b]噻吩-5-羧酸(benzo[b]thiophene-5-carboxylic acid)(化合物0302-7)的制备:在氮气保护下，在圆底烧瓶中，加入5-溴苯并噻吩(0301-7)(1.0克，4.69毫摩尔，1.0当量)和35毫升无水四氢呋喃，于干冰-乙醇浴中冷却至-72℃，滴加2.5M正丁基锂四氢呋喃溶液(2.8毫升，7.04毫摩尔，1.5当量)，搅拌一个小时，通入二氧化碳，搅拌反应1小时。滴加2M盐酸水溶液至水相呈pH为1，加入乙酸乙酯萃取，无水硫酸钠干燥有机相，减压浓缩，得到黄色固体苯并[b]噻吩-5-羧酸(924毫克，粗品)。
步骤3b:苯并[b]噻吩-5-羧酸甲酯methyl benzo[b]thiophene-5-carboxylate(化合物0303-7)的制备:将苯并[b]噻吩-5-羧酸(0302-7)(1.0克，5.6毫摩尔，1.0当量)溶解于30毫升甲醇中，加入HATU(2.56克，6.7毫摩尔，1.2当量)和三乙胺(1.0毫升，7.1毫摩尔，1.3当量)，室温下搅拌4小时。减压浓缩，加入乙酸乙酯和水，分液，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝8：1)，得到黄色固体产物苯并[b]噻吩-5-羧酸甲酯(584毫克，收率：54％)。
步骤3c:(2-(苯并[b]噻吩-5-基)-2-氧代乙基)磷酸二甲酯dimethyl(2-(benzo[b]thiophen-5-yl)-2-oxoethyl)phosphonate)(化合物0304-7)的制备:在氮气保护下，在圆底烧瓶中，加入甲基膦酸二甲酯(513毫克，4.14毫摩尔，1.5当量)和30毫升无水四氢呋喃，于干冰-乙醇浴中冷却至-72℃，滴加2.5M正丁基锂正己烷溶液(2.2毫升，5.52毫摩尔，2.0当量)，搅拌一个小时，于-72℃滴加苯并[b]噻吩-5-羧酸甲酯(0303-7)(530毫克，2.76毫摩尔，1.0当量)的四氢呋喃溶液，搅拌反应2小时。加水和乙酸乙酯，分液，无水硫酸钠干燥有机相，减压浓缩，经过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝8：1)，得到微黄色液体产物(2-(苯并[b]噻吩-5-基)-2-氧代乙基)磷酸二甲酯(1.06克，粗品)。LCMS(ESI):m/z 285[M+1]+。
步骤3d:(E)-1-(苯并[b]噻吩-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮[(E)-1-(benzo[b]thiophen-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en-1-one](化合物0305-7)的制备:将(2-(苯并[b]噻吩-5-基)-2-氧代乙基)磷酸二甲酯(0304-7)(267毫克，0.97毫摩尔，1.1当量)、2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(350毫克，0.85毫摩尔，1.0当量)和碳酸铯(418毫克，1.28毫摩尔，1.5当量)加入到30毫升异丙醇中，在室温下搅拌反应8小时，减压浓缩，加入乙酸乙酯和水，分液，无水硫酸钠干燥，减压浓缩，得到 微黄色固体产物(E)-1-(苯并[b]噻吩-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(500毫克，收率：90％)。LCMS(ESI):m/z 573[M+1]+。
步骤3e:1-(苯并[b]噻吩-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(benzo[b]thiophen-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0306-7)的制备:将(E)-1-(苯并[b]噻吩-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0305-7)(500毫克，0.88毫摩尔，1.0当量)溶解到30毫升甲醇中，加入乙酸5毫升，加热回流过夜。冷却到室温，减压浓缩，加入水，用2M氢氧化钠水溶液调节pH至12，加入二氯甲烷萃取，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝15：1)，得到黄色固体产物1-(苯并[b]噻吩-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(200毫克，收率：68％)。LCMS(ESI):m/z 331[M+1]+。
步骤3f:1-(苯并[b]噻吩-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(benzo[b]thiophen-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物7)的制备:将1-(苯并[b]噻吩-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0306-7)(200毫克，0.60毫摩尔，1.0当量)溶解到30毫升甲醇中，冰浴中，冷却至0℃，加入硼氢化钠(34毫克，0.9毫摩尔，1.5当量)，搅拌反应半小时，加入丙酮，减压浓缩，加入二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝30:1～15:1)，得到黄色固体产物1-(苯并[b]噻吩-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(28毫克，收率：14％)。LCMS(ESI):m/z 333[M+1]+。熔点：78～80℃；1H NMR(400MHz,DMSO)δ8.00-7.91(m,2H),7.76-7.72(m,1H),7.62-7.52(m,2H),7.42-7.28(m,5H),7.18-7.11(m,1H),6.39-6.27(m,1H),5.53-5.38(m,1H),5.34(m,1H),2.49-2.01(m,2H).
实施例4：1-(6-氟苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(6-fluorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物8)的制备(按照方案二线路制备)
步骤4a：2-氟-4-羟基-5-碘苯甲酸(2-fluoro-4-hydroxy-5-iodobenzoic acid)(化合物0203-8)的制备。将碳酸钾(2.65克，19.2毫摩尔，3当量)溶解于5毫升，加入碘单质(1.625克，6.4毫摩尔，1当量)，搅拌1小时，再滴加化合物2-氟-4-羟基苯甲酸(0201-8)(1克，6.4毫摩尔，1当量)的15毫升氨水溶液。混合物在室温下搅拌反应2小时。反应结束后，用2N盐酸水溶液调节pH至1，再加入亚硫酸氢钠水溶液5毫升。最后用乙酸乙酯和水萃取，有机相用饱和食盐水洗，减压浓缩，得到白色固体2-氟-4-羟基-5-碘苯甲酸(1.6克，粗品)。
步骤4b：2-氟-4-羟基-5-碘苯甲酸甲酯(methyl 2-fluoro-4-hydroxy-5-iodobenzoate)(化合物0204-8)的制备:将化合物2-氟-4-羟基-5-碘苯甲酸(0203-8)(1.6克，5.67毫摩尔，1当 量)溶解于30毫升甲醇。冰浴下缓慢滴加入氯化亚砜(1.5毫升)。混合物在回流的条件下搅拌反应2小时。反应结束后，减压浓缩，再用硅胶柱层析纯化(洗脱剂：二氯甲烷)，得到白色固体2-氟-4-羟基-5-碘苯甲酸甲酯(900毫克，收率：53.57％)。
步骤4c：2-氟-4-羟基-5-(三甲基硅乙炔基)苯甲酸甲酯(methyl 2-fluoro-4-hydroxy-5-((trimethylsilyl)ethynyl)benzoate)(化合物0205-8)的制备:在氮气保护下，将2-氟-4-羟基-5-碘苯甲酸甲酯(0204-8)(900毫克，3.04毫摩尔，1.0当量)，三甲基硅乙炔(417毫克，4.26毫摩尔，1.4当量)，碘化亚铜(8.6毫克，0.04毫摩尔，0.015当量)和四三苯基膦钯(64毫克，0.09毫摩尔，0.03当量)加入到10毫升四氢呋喃和20毫升氯仿的混合液中，然后滴加三乙胺(921.1毫克，9.12毫摩尔，3当量)，混合物加热至50℃，搅拌反应4小时。冷却至室温，减压浓缩得产物2-氟-4-羟基-5-(三甲基硅乙炔基)苯甲酸甲酯，直接用于下一步反应。
步骤4d：6-氟苯并呋喃-5-羧酸甲酯(methyl 6-fluorobenzofuran-5-carboxylate)(化合物0206-8)的制备:用50毫升无水甲醇稀释2-氟-4-羟基-5-(三甲基硅乙炔基)苯甲酸甲酯(0205-8)浓缩液(3.04毫摩尔，1.0当量)，加入N，N-二异丙基乙胺(784毫克，6.08毫摩尔，2.0当量)和碘化亚铜(57毫克，0.304毫摩尔，0.1当量)，于60℃下反应4小时，加入碳酸钾(839毫克，6.08毫摩尔，2.0当量)，于60℃下搅拌过夜。冷却至室温，抽滤，所得滤液减压浓缩，经过硅胶柱层析分离纯化(洗脱剂：石油醚：乙酸乙酯＝25：1)，得到白色固体6-氟苯并呋喃-5-羧酸甲酯(180毫克，收率：30.52％)。LCMS(ESI):m/z 195[M+1]+。
步骤4e：(2-(6-氟苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(6-fluorobenzofuran-5-yl)-2-oxoethyl)phosphonate)(化合物0207-8)的制备:在氮气的氛围下，将甲基膦酸二甲酯(173毫克，1.395毫摩尔，1.5当量)溶解于5毫升的干燥的四氢呋喃中。干冰/乙醇冷却到-60℃，缓慢滴加入正丁基锂(0.7毫升，2.5摩尔/毫升的正己烷溶液，1.86毫摩尔，2当量)。混合物在-60℃下搅拌反应30分钟，再缓慢滴加化合物6-氟苯并呋喃-5-羧酸甲酯(180毫克，0.93毫摩尔，1当量)的四氢呋喃(1毫升)溶液。混合物在-60℃下搅拌反应1小时。反应结束后，加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物(2-(6-氟苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(200毫克，收率：75.47％)为透明油状物。LCMS(ESI):m/z 287[M+1]+。
步骤4f：1-(6-氟苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(6-fluorobenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en-1-one)(化合物0208-8)的制备:将2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(263毫克，0.635毫摩尔，1当量),化合物(2-(6-氟苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(0207-8)(200毫克，0.699毫摩尔，1. 1当量)和碳酸铯(619毫克，1.905毫摩尔，2当量)混合于异丙醇(10毫升)中，混合物在室温下搅拌反应16小时。反应结束后，用水淬灭，过滤，得到目标产物1-(6-氟苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(304毫克，收率：83.38％)为黄色固体。L CMS(ESI):m/z 575[M+1]+。
步骤4g：1-(6-氟苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(6-fluorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0209-8)的制备:将化合物1-(6-氟苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0208-8)(304毫克，0.529毫摩尔，1当量)和醋酸(2毫升)混合于甲醇(4毫升)中。混合物在90℃下搅拌反应16小时。反应结束后，用2N氢氧化钠水溶液调节pH值至12，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物1-(6-氟苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(300毫克，粗品)为黄色固体。LCMS(ESI):m/z 333[M+1]+。
步骤4h：1-(6-氟苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(6-fluorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物8)的制备:将1-(6-氟苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0209-8)(150毫克，0.45毫摩尔，1.0当量)溶解到30毫升甲醇中，冰浴中，冷却至0℃，加入硼氢化钠(26毫克，0.68毫摩尔，1.5当量)，搅拌反应半小时，加入丙酮，减压浓缩，加入二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝30:1～15:1)，得到黄色固体1-(6-氟苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(75毫克，收率：49.7％)。LCMS(ESI):m/z 335[M+1]+。熔点：77～79℃；1H NMR(400MHz,DMSO)δ8.01-7.79(m,3H),7.62-7.29(m,5H),7.18-7.10(m,1H),7.00(m,1H),5.96-5.86(m,1H),5.55-5.45(m,1H),5.32(m,1H),2.38-1.81(m,2H).
实施例5：1-(7-氟苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(7-fluorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物14)的制备(按照方案二线路制备)
步骤5a：3-氟-4-羟基苯甲酸甲酯(methyl 3-fluoro-4-hydroxybenzoate)(化合物0202-14)的制备：将3-氟-4-羟基苯甲酸(0201-14)(1.0克，6.41毫摩尔，1.0当量)溶解于50毫升甲醇，缓慢滴加入浓硫酸(3毫升)。混合物在50℃的条件下搅拌反应过夜。反应结束后，除去溶剂，将残留物加入冰水中，用乙酸乙酯萃取，再用饱和食盐水洗两遍，无水硫酸钠干燥，浓缩得到米白色固体产物3-氟-4-羟基苯甲酸甲酯(1.25克，粗品)。LCMS(ESI):m/z 171[M+1]+。
步骤5b：3-氟-4-羟基-5-碘苯甲酸甲酯(methyl 3-fluoro-4-hydroxy-5-iodobenzoate)(化合物0204-14)的制备：将碳酸钾(1.62克，11.74毫摩尔，2.0当量)和化合物3-氟-4-羟基苯甲酸甲酯(0202-14)(1.0克，5.87毫摩尔，1.0当量)溶解于50毫升的四氢呋喃中，加入碘单质(1.79克，7.05毫摩尔，1.2当量)，室温搅拌过夜。反应结束后，加入亚硫酸氢钠水溶液15毫升。最后用乙酸乙酯萃取，有机相用饱和食盐水洗，减压浓缩，得到米白色固体产物3-氟-4-羟基-5-碘苯甲酸甲酯(1.25克，收率：71.9％)。LCMS(ESI):m/z 297[M+1]+。
步骤5c：3-氟-4-羟基-5-(三甲基硅乙炔基)苯甲酸甲酯(methyl3-fluoro-4-hydroxy-5-((trimethylsilyl)ethynyl)benzoate)(化合物0205-14)的制备:在氮气保护下，将3-氟-4-羟基-5-碘苯甲酸甲酯(0204-14)(1.57克，5.3毫摩尔，1.0当量)，三甲基硅乙炔(729毫克，7.42毫摩尔，1.4当量)，碘化亚铜(15毫克，0.08毫摩尔，0.015当量)和双三苯基磷二氯化钯(112毫克，0.16毫摩尔，0.03当量)加入到30毫升四氢呋喃和15毫升氯仿中，然后滴加三乙胺(1.61克，15.9毫摩尔，3.0当量)，混合物加热至50℃，搅拌反应3小时。冷却至室温，过滤，减压浓缩得到产物3-氟-4-羟基-5-(三甲基硅乙炔基)苯甲酸甲酯(1.73g，粗品)，直接用于下一步反应。LCMS(ESI):m/z 267[M+1]+。
步骤5d：7-氟苯并呋喃-5-羧酸甲酯(methyl 7-fluorobenzofuran-5-carboxylate)(化合物0206-14的制备)：用50毫升无水甲醇稀释3-氟-4-羟基-5-(三甲基硅乙炔基)苯甲酸甲酯(0205-14)粗品(1.73克，6.49毫摩尔，1.0当量)，加入N，N-二异丙基乙胺(722毫克，7.14毫摩尔，1.1当量)和碘化亚铜(62毫克，0.32毫摩尔，0.05当量)。于60℃下反应4小时后，加入少量碳酸钾，于60℃下搅拌过夜。冷却至室温，抽滤，所得滤液减压浓缩，经过硅胶柱层析分离纯化(洗脱剂：石油醚：乙酸乙酯＝25：1)，得到白色固体产物7-氟苯并呋喃-5-羧酸甲酯(728毫克，收率：61.9％)。LCMS(ESI):m/z 195[M+1]+。
步骤5e：(2-(7-氟苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(7-fluorobenzofuran-5-yl)-2-oxoethyl)phosphonate)(化合物0207-14)的制备:在氮气的氛围下，将甲基膦酸二甲酯(192毫克，1.55毫摩尔，1.5当量)溶解于10毫升的干燥的四氢呋喃中。干冰/乙醇冷却到-60℃，缓慢滴加入正丁基锂(0.62毫升，2.5摩尔/升的正己烷溶液，1.55毫摩尔，1.5当量)。混合物在-60℃下搅拌反应30分钟，再缓慢滴加化合物7-氟苯并呋喃-5-羧酸甲酯(0206-14)(200毫克，1.03毫摩尔，1.0当量)的四氢呋喃(10毫升)溶液。混合物在-60℃下搅拌反应0.5小时。升至室温反应4小时，反应结束后，加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物(2-(7-氟苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(278毫克，收率：94.3％)为无色油状液体。LCMS(ESI):m/z 287[M+1]+。
步骤5f：1-(7-氟苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(7-fluorobenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en-1-one)(化合物0208-14)的制备:在氮气的氛围和冰浴的条件下，将60％的氢化钠(38毫克，0.97毫摩尔，1.0当量)溶解于15毫升的四氢呋喃中，再缓慢加入(2-(7-氟苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(0207-14)(278毫克，0.97毫摩尔，1.0当量)的四氢呋喃溶液(15毫升)。混合物搅拌15分钟后，将2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(402毫克，0.97毫摩尔，1.0当量)的四氢呋喃(20毫升)溶液滴加入其中。混合物在冰浴条件下搅拌反应0.5小时。升至室温搅拌反应过夜。反应结束后，用饱和氯化铵水溶液淬灭，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到黄色油状物。所得物通过硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝1/2)纯化，得到目标产物1-(7-氟苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(252毫克，收率：45.2％)为黄色油状物。LCMS(ESI):m/z 575[M+1]+。
步骤5g：1-(7-氟苯并呋喃-5-基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酮(1-(7-fluorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0209-14)的制备:将化合物1-(7-氟苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0208-14)(252毫克，0.44毫摩尔，1.0当量)和醋酸(4毫升)混合于甲醇(80毫升)中。混合物在90℃下搅拌反应过夜。反应结束后，降至室温。用饱和碳酸钠水溶液调节pH值至10，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得物用硅胶柱层析(二氯甲烷/甲醇＝100/1)纯化，得到目标产物1-(7-氟苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(122毫克，收率：83.5％)为黄色固体。LCMS(ESI):m/z 333[M+1]+。
步骤5h：1-(7-氟苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(7-fluorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物14)的制备:将化合物1-(7-氟苯并呋喃-5-基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酮(0209-14)(122毫克，0.367毫摩尔，1.0当量)溶解于50毫升甲醇中，再缓慢加入硼氢化钠(28毫克，0.734毫摩尔，2.0当量)。混合物在室温下搅拌反应3小时。反应结束后，加入饱和氯化铵水溶液淬灭，搅拌10分钟，减压除去乙醇，加入饱和碳酸钠水溶液(50毫升)，用二氯甲烷(100毫升)萃取，有机相用饱和食盐水洗一遍，无水硫酸钠干燥，浓缩，所得物硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1至100/8)纯化，得到目标产物1-(7-氟苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(107毫克，收率：87.2％)为白色固体。LCMS(ESI):m/z 335[M+1]+。熔点：165～168℃；1H NMR(400MHz,DMSO)δ8.09-8.08(m,1H),8.07-7.89(m,1H),7.64-7.48(m,3H),7.42-7.27(m,3H),7.25-7.03(m,2H),5.98-5.85(m,1H),5.38-4.35(m,1H),5.06(m,1H),2.35-1.99(m,2H).
实施例6：1-(6-氯苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(6-chlorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物17)的制备(按照方案二线路制备)
步骤6a:2-氯-4-羟基-5-碘苯甲酸(2-chloro-4-hydroxy-5-iodobenzoic acid)(化合物0203-17)的制备:将2-氯-4-羟基苯甲酸(0201-17)(100毫克，0.581毫摩尔，1.0当量)加入10毫升水中，然后加入氨水(1毫升)。冰浴下冷却后，缓慢滴加碘化钾(0.319克，1.94毫摩尔，3.0当量)和碘(0.146克，0.581毫摩尔，1.0当量)的水溶液(20毫升)，控制滴加温度在5℃以下。最后混合物在室温下搅拌反应2小时。反应结束后，加入亚硫酸氢钠饱和溶液(10毫升)淬灭，加入50毫升水，搅拌过夜。浓盐酸调pH到3-4，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物2-氯-4-羟基-5-碘苯甲酸(0.17克粗品)。LCMS(ESI):m/z 299[M+1]+。
步骤6b:4-羟基-5-碘-2-氯苯甲酸甲酯(methyl 4-hydroxy-5-iodo-2-chloro-benzoate(化合物0204-17)的制备:将化合物2-氯-4-羟基-5-碘苯甲酸(0203-17)(0.17克)溶解于30毫升的无水甲醇中。然后加入浓硫酸(0.05克)。混合物在65℃下搅拌反应过夜。反应结束后，减压除去甲醇，残留物混悬在100毫升水中，加入饱和碳酸氢钠水溶液使pH到4左右，过滤收集固体，水洗一遍，干燥得到目标产物4-羟基-5-碘-2-氯苯甲酸甲酯(1.80克，收率100％)为白色固体。LCMS(ESI):m/z 313[M+1]+。
步骤6c:2-氯-4-羟基-5-(三甲基硅乙炔基)苯甲酸甲酯(methyl 4-hydroxy-2-chloro-5-((trimethylsilyl)ethynyl)benzoate(化合物0205-17)的制备:在氮气保护下，将4-羟基-5-碘-2-氯苯甲酸甲酯(0204-17)(0.100克，0.320毫摩尔，1.0当量)，三甲基硅乙炔(47毫克，0.48毫摩尔，1.5当量)，碘化亚铜(3.8毫克，0.02毫摩尔，0.015当量)和双三苯基磷二氯化钯(7.1毫克，0.01毫摩尔，0.03当量)加入到10毫升四氢呋喃和10毫升氯仿的混合液中，然后滴加三乙胺(0.098克，0.96毫摩尔，3.0当量)，混合物加热至50℃，搅拌反应3小时。冷却至室温，过滤，减压浓缩得到残留物2-氯-4-羟基-5-(三甲基硅乙炔基)苯甲酸甲酯(0.10g，粗品)，直接用于下一步。LCMS(ESI):m/z 283[M+1]+。
步骤6d:6-氯苯并呋喃-5-羧酸甲酯(methyl 6-chlorobenzofuran-5-carboxylate(化合物0206-17)的制备)：用50毫升无水甲醇稀释2-氯-4-羟基-5-(三甲基硅乙炔基)苯甲酸甲酯(0205-17)(0.100克，0.320毫摩尔，1.0当量)，加入N，N-二异丙基乙胺(35.3毫克，0.352毫摩尔，1.1当量)和碘化亚铜(3毫克，0.016毫摩尔，0.05当量)。于60℃下反应4小时后，加入少量碳酸钾，于60℃下搅拌过夜。冷却至室温，抽滤，所得滤液减压浓缩，经过硅胶柱层析分离纯化(洗脱剂：石油醚：乙酸乙酯＝25：1)，得到白色固体6-氯苯并呋喃-5-羧 酸甲酯(45毫克，收率：66.6％)。LCMS(ESI):m/z 211[M+1]+。
步骤6e:(2-(6-氯苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(6-chlorobenzofuran-5-yl)-2-oxoethyl)phosphonate(化合物0207-17)的制备:在氮气的氛围下，将甲基膦酸二甲酯(186毫克，1.5毫摩尔，1.5当量)溶解于5毫升干燥的四氢呋喃中。干冰/乙醇冷却到-60℃，缓慢滴加入正丁基锂(0.8毫升，2.5摩尔/毫升的正己烷溶液，1.86毫摩尔，2当量)。混合物在-60℃下搅拌反应30分钟，再缓慢滴加化合物6-氯苯并呋喃-5-羧酸甲酯(0206-17)(211毫克，1.0毫摩尔，1当量)的四氢呋喃(5毫升)溶液。混合物在-60℃下搅拌反应1小时。反应结束后，加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物(2-(6-氯苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(200毫克，收率70.7％)为透明油状物。LCMS(ESI):m/z 303[M+1]+。
步骤6f:1-(6-氯苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烷-2-烯-1-酮(1-(6-chlorobenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en-1-one)(化合物0208-17)的制备:将2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(266毫克，0.644毫摩尔，1当量),(2-(6-氯苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(0207-17)(200毫克，0.709毫摩尔，1.1当量)和碳酸铯(460毫克，1.418毫摩尔，2当量)混合于异丙醇(10毫升)中，混合物在室温下搅拌反应16小时。反应结束后，用水淬灭，过滤，得到目标产物1-(6-氯苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烷-2-烯-1-酮(290毫克，收率：70.1％)为黄色固体。LCMS(ESI):m/z 591[M+1]+。
步骤6g:1-(6-氯苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(6-chlorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0209-17)的制备:将化合物1-(6-氯苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烷-2-烯-1-酮(0208-17)(290毫克，0.490毫摩尔，1当量)和醋酸(2毫升)混合于甲醇(4毫升)中。混合物在90℃下搅拌反应16小时。反应结束后，用2N氢氧化钠水溶液调节pH至12，用二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物1-(6-氯苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(200毫克，粗品)为黄色固体。LCMS(ESI):m/z 349[M+1]+。
步骤6h:1-(6-氯苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(6-chlorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物17)的制备:将1-(6-氯苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0209-17)(200毫克，0.573毫摩尔，1.0当量)溶解到30毫升甲醇中，冰浴中冷却至0℃后，加入硼氢化钠(33毫克，0.859毫摩尔，1.5当量)，搅拌反应半小时，加入丙酮，减压浓缩，加入二氯甲烷萃取， 用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝30:1～15:1)，得到化合物1-(6-氯苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(100毫克，收率：49.8％)黄色固体。LCMS(ESI):m/z 351[M+1]+。熔点：110～112℃；1H NMR(400MHz,DMSO)δ8.15-7.92(m,3H),7.72-7.33(m,5H),7.30-7.01(m,2H),6.12-5.98(m,1H),5.59(s,1H),5.42(m,1H),2.42-2.12(m,2H).
实施例7：2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(6-甲氧基苯并呋喃-5-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(6-methoxybenzofuran-5-yl)ethan-1-ol)(化合物22)的制备(按照方案二线路制备)
步骤7a:4-羟基-2-甲氧基苯甲酸甲酯(methyl 4-hydroxy-2-methoxybenzoate)(化合物0202-22)的制备:将化合物2,4-二羟基苯甲酸甲酯(0201-22)(800毫克，4.76毫摩尔，1当量)和碳酸钾(4克，28.56毫摩尔，6当量)混合于50毫升的丙酮中，再缓慢加入对甲苯磺酰氯(900毫克，4.76毫摩尔，1当量)。混合物在室温下搅拌反应过夜。反应结束后，过滤，滤液减压浓缩，得到白色固体1.5克。所得固体用10毫升DMF溶解，再加入碳酸钾(1.28克，9.32毫摩尔，2当量)和碘甲烷(793.8毫克，5.59毫摩尔，1.2当量)，混合物在室温下搅拌反应1小时。反应结束后，用乙酸乙酯和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，用硅胶柱层析(洗脱剂：石油醚:乙酸乙酯＝10:1)纯化，得到白色固体2-甲氧基-4-对甲苯磺酰基苯甲酸甲酯(1.5克，收率：93.75％)。LCMS(ESI):m/z 337[M+1]+。将上述得到的化合物2-甲氧基-4-对甲苯磺酰基苯甲酸甲酯(1.5克，4.46毫摩尔，1当量)溶解在15毫升甲醇中，再加入甲醇钠(361毫克，6.69毫摩尔，1.5当量)。混合物在回流的条件下，搅拌反应2小时。反应结束后，减压浓缩，硅胶柱层析纯化(洗脱剂：石油醚:乙酸乙酯＝5:1)，得到白色固体4-羟基-2-甲氧基苯甲酸甲酯(600毫克，收率：73.44％)。LCMS(ESI):m/z 183[M+1]+。
步骤7b:4-羟基-5-碘-2-甲氧基苯甲酸甲酯(methyl 4-hydroxy-5-iodo-2-methoxybenzoate)(化合物0204-22)的制备:将化合物4-羟基-2-甲氧基苯甲酸甲酯(0202-22)(500毫克，2.74毫摩尔，1当量)，碘单质(835毫克，3.29毫摩尔，1.2当量)和碳酸钾(570毫克，4.11毫摩尔，1.5当量)混合于10毫升DMF中。混合物在室温下搅拌反应3小时。反应结束后，用亚硫酸氢钠水溶液淬灭，再加入水，析出固体，过滤，滤渣用水洗，干燥，得到白色固体4-羟基-5-碘-2-甲氧基苯甲酸甲酯(845毫克，粗品)。LCMS(ESI):m/z 309[M+1]+。
步骤7c:4-羟基-2-甲氧基-5-(三甲基硅乙炔基)苯甲酸甲酯(methyl4-hydroxy-2-methoxy-5-((trimethylsilyl)ethynyl)benzoate)(化合物0205-22)的制备:在氮气保护下，将4-羟基-5-碘-2-甲氧基苯甲酸甲酯(0204-22)(845毫克，2.74毫摩尔，1.0当量)，三甲基硅乙炔(537毫克，5.48毫摩尔，2当量)，碘化亚铜(7.8毫克，0.04毫摩尔，0.015 当量)和四三苯基膦钯(57毫克，0.08毫摩尔，0.03当量)加入到10毫升四氢呋喃和20毫升氯仿的混合液中，然后滴加三乙胺(830毫克，8.22毫摩尔，3当量)，混合物加热至50℃，搅拌反应4小时。冷却至室温，减压浓缩，所得浓缩液直接用于下一步反应。
步骤7d:6-甲氧基苯并呋喃-5-羧酸甲酯(methyl 6-methoxybenzofuran-5-carboxylate)(化合物0206-22的制备):用50毫升无水甲醇稀释4-羟基-2-甲氧基-5-(三甲基硅乙炔基)苯甲酸甲酯(0205-22)浓缩液(2.74毫摩尔，1.0当量)，加入N，N-二异丙基乙胺(559毫克，5.48毫摩尔，2.0当量)和碘化亚铜(52毫克，0.274毫摩尔，0.1当量)，于60℃下反应4小时。反应结束后，冷却至室温，抽滤，所得滤液减压浓缩，经过硅胶柱层析分离纯化(洗脱剂：石油醚：乙酸乙酯＝25：1)，得到黄色固体。所得固体用四氢呋喃溶解，再加入四丁基氟化铵三水化合物(30毫克)。室温下搅拌5分钟，用乙酸乙酯和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到黄色油状物6-甲氧基苯并呋喃-5-羧酸甲酯(503毫克，粗品)。LCMS(ESI):m/z 207[M+1]+。
步骤7e:(2-(6-甲氧基苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(6-methoxybenzofuran-5-yl)-2-oxoethyl)phosphonate)化合物(0207-22)的制备:在氮气的氛围下，将甲基膦酸二甲酯(451毫克，3.64毫摩尔，1.5当量)溶解于5毫升的干燥的四氢呋喃中。干冰/乙醇冷却到-60℃，缓慢滴加入正丁基锂(2毫升，2.5摩尔/毫升的正己烷溶液，4.86毫摩尔，2当量)。混合物在-60℃下搅拌反应30分钟，再缓慢滴加化合物6-甲氧基苯并呋喃-5-羧酸甲酯(0206-22)(503毫克，2.43毫摩尔，1当量)的四氢呋喃(1毫升)溶液。混合物在-60℃下搅拌反应1小时。反应结束后，加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物(2-(6-甲氧基苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(638毫克，粗品)为黄色油状物。LCMS(ESI):m/z 299[M+1]+。
步骤7f:1-(6-甲氧基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烷-2-烯-1-酮(1-(6-methoxybenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en-1-one)(化合物0208-22)的制备:将2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(207毫克，0.5毫摩尔，1当量),化合物(2-(6-甲氧基苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(0207-22)(179毫克，0.6毫摩尔，1.2当量)和碳酸铯(325毫克，1毫摩尔，2当量)混合于异丙醇(10毫升)中，混合物在室温下搅拌反应16小时。反应结束后，用水淬灭，过滤，得到目标产物1-(6-甲氧基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烷-2-烯-1-酮(248毫克，粗品)为黄色固体。LCMS(ESI):m/z 587[M+1]+。
步骤7g:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(6-甲氧基苯并呋喃-5-基)乙烷-1-酮(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(6-methoxybenzofuran-5-yl)ethan-1-one)(化合物 0209-22)的制备:将化合物1-(6-甲氧基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烷-2-烯-1-酮(0208-22)(248毫克，0.422毫摩尔，1当量)和醋酸(2毫升)混合于甲醇(4毫升)中。混合物在90℃下搅拌反应16小时。反应结束后，用2N氢氧化钠水溶液调节pH至12，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(6-甲氧基苯并呋喃-5-基)乙烷-1-酮(210毫克，粗品)为黄色固体。LCMS(ESI):m/z 345[M+1]+。
步骤7h:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(6-甲氧基苯并呋喃-5-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(6-methoxybenzofuran-5-yl)ethan-1-ol)(化合物22)的制备:将2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(6-甲氧基苯并呋喃-5-基)乙烷-1-酮(0209-22)(210毫克，0.6毫摩尔，1.0当量)溶解到30毫升甲醇中，冰浴中冷却至0℃，加入硼氢化钠(45毫克，1.2毫摩尔，2当量)，搅拌反应半小时，加入丙酮，减压浓缩，加入二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝30:1～15:1)，得到黄色固体2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(6-甲氧基苯并呋喃-5-基)乙烷-1-醇(100毫克，收率：47.39％)。LCMS(ESI):m/z 347[M+1]+。熔点：92～95℃；1H NMR(400MHz,DMSO)δ7.99-7.10(m,9H),6.90(s,1H),5.78-5.33(m,3H),3.77-3.71(m,3H),2.33-1.82(m,2H).
实施例8：2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(7-甲氧基苯并呋喃-5-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(7-methoxybenzofuran-5-yl)ethan-1-ol)(化合物23)的制备(按照方案二线路制备)
步骤8a:4-羟基-3-碘-5-甲氧基苯甲酸甲酯(methyl 4-hydroxy-3-iodo-5-methoxybenzoate)(化合物0204-23)的制备:将4-羟基-3-甲氧基苯甲酸甲酯(0202-23)(1.82克，0.01摩尔，1.0当量)溶解于15毫升三氟乙酸中，加入N-碘代丁二酰亚胺(2.7克，0.012摩尔，1.2当量)，于室温下搅拌反应3小时。加入水，用乙酸乙酯萃取，干燥，减压浓缩，经硅胶柱层析分离纯化(洗脱剂：石油醚：二氯甲烷＝4：3)，得到白色固体产物4-羟基-3-碘-5-甲氧基苯甲酸甲酯(840毫克，收率：27.2％)。
步骤8b:4-羟基-3-甲氧基-5-(三甲基硅乙炔基)苯甲酸甲酯(methyl4-hydroxy-3-methoxy-5-((trimethylsilyl)ethynyl)benzoate)(化合物0205-23)的制备:在氮气保护下，将4-羟基-3-碘-5-甲氧基苯甲酸甲酯(0204-23)(800毫克，2.6毫摩尔，1.0当量)，三甲基硅乙炔(1.27克，13.0毫摩尔，5.0当量)，二异丙胺(657毫克，6.5毫摩尔，2.5当量)，碘化亚铜(10毫克，0.05毫摩尔，0.02当量)和四三苯基膦钯(140毫克，0.13毫摩尔，0.05当量)加入到45毫升四氢呋喃中，加热回流反应过夜。冷却至室温，减压浓缩得产物4-羟基 -3-甲氧基-5-(三甲基硅乙炔基)苯甲酸甲酯，直接用于下一步反应。
步骤8c:7-甲氧基苯并呋喃-5-羧酸甲酯(methyl 7-methoxybenzofuran-5-carboxylate)(化合物0206-23)的制备:用50毫升无水甲醇稀释4-羟基-3-甲氧基-5-(三甲基硅乙炔基)苯甲酸甲酯(0205-23)浓缩液(2.6毫摩尔，1.0当量)，加入二异丙胺(0.71毫升，5.2毫摩尔，2.0当量)和碘化亚铜(152毫克，0.8毫摩尔，0.3当量)，加热回流反应8小时，冷却至50℃加入碳酸钾(718毫克，5.2毫摩尔，2.0当量)，于50℃下搅拌过夜。冷却至室温，抽滤，所得滤液减压浓缩，经过硅胶柱层析分离纯化(洗脱剂：石油醚：乙酸乙酯＝4：1)，得到白色固体产物7-甲氧基苯并呋喃-5-羧酸甲酯(256毫克，收率：47.8％)。LCMS(ESI):m/z207[M+1]+。
步骤8d:(2-(7-甲氧基苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(7-methoxybenzofuran-5-yl)-2-oxoethyl)phosphonate)(化合物0207-23)的制备:在氮气保护下，在圆底烧瓶中，加入甲基膦酸二甲酯(308毫克，2.48毫摩尔，2.0当量)和20毫升无水四氢呋喃，于干冰-乙醇浴中冷却至-72℃，滴加2.5M正丁基锂正己烷溶液(1.3毫升，3.1毫摩尔，2.5当量)，搅拌一个小时，于-72℃滴加7-甲氧基苯并呋喃-5-羧酸甲酯(0206-23)(256毫克，1.24毫摩尔，1.0当量)的四氢呋喃溶液，搅拌反应2小时。加入氯化铵水溶液和乙酸乙酯，分液，无水硫酸钠干燥有机相，减压浓缩，经过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝2：1)，得到微黄色油状液体产物(2-(7-甲氧基苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(317毫克，收率：85.9％)。LCMS(ESI):m/z 299[M+1]+。
步骤8e:1-(7-甲氧基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(7-methoxybenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)(化合物0208-23)的制备:将(2-(7-甲氧基苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(0207-23)(317毫克，1.1毫摩尔，1.25当量)、2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(331毫克，0.8毫摩尔，1.0当量)和碳酸铯(553毫克，1.6毫摩尔，2.0当量)加入到40毫升异丙醇中，在室温下搅拌反应过夜，减压浓缩，加入乙酸乙酯和水，分液，无水硫酸钠干燥，减压浓缩，得到微黄色固体产物1-(7-甲氧基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(390毫克，收率：62.6％)。LCMS(ESI):m/z 587[M+1]+。
步骤8f:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(7-甲氧基苯并呋喃-5-基)乙烷-1-酮(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(7-methoxybenzofuran-5-yl)ethan-1-one)(化合物0209-23)的制备:将1-(7-甲氧基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0208-23)(390毫克，0.66毫摩尔，1.0当量)溶解到25毫升甲醇中，加入乙酸5毫升，加热回流过夜。冷却到室温，减压浓缩，加入水，用2M氢氧化钠水溶液调节pH至 12，加入二氯甲烷萃取，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝15：1)，得到微黄色固体产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(7-甲氧基苯并呋喃-5-基)乙烷-1-酮(160毫克，收率：70.4％)。LCMS(ESI):m/z 345[M+1]+。
步骤8g:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(7-甲氧基苯并呋喃-5-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(7-methoxybenzofuran-5-yl)ethan-1-ol)(化合物23)的制备:将2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(7-甲氧基苯并呋喃-5-基)乙烷-1-酮(0209-23)(150毫克，0.43毫摩尔，1.0当量)溶解到30毫升甲醇中，冰浴中，冷却至0℃，加入硼氢化钠(25毫克，0.65毫摩尔，1.5当量)，搅拌反应半小时，加入丙酮，减压浓缩，加入二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝30:1～15:1)，得到微黄色固体产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(7-甲氧基苯并呋喃-5-基)乙烷-1-醇(116毫克，收率：77.8％)。LCMS(ESI):m/z 347[M+1]+。熔点：64～66℃；1H NMR(400MHz,DMSO)δ8.00-7.87(m,2H),7.63-7.49(m,2H),7.42-7.24(m,3H),7.18-7.10(m,1H),6.98-6.90(m,2H),5.89-5.76(m,1H),5.38-5.35(m,1H),5.07(m,1H),2.30-2.20(m,2H).
实施例9：1-(6-甲基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(6-methyl benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol)(化合物25)的制备(按照方案二线路制备)
步骤9a：4-羟基-5-碘-2-甲基苯甲酸(4-hydroxy-5-iodo-2-methylbenzoic acid)(化合物0203-25)的制备:将4-羟基-2-甲基苯甲酸(0201-25)(1.0克，6.6毫摩尔，1.0当量)加入10(毫升)水中，然后加入氨水(1毫升)。冰浴下冷却后，缓慢滴加碘化钾(3.26克，19.8毫摩尔，3.0当量)和碘(1.66克，6.6毫摩尔，1.0当量)的水溶液(20毫升)，控制温度在5度以下。最后混合物在室温下搅拌反应2小时。反应结束后，加入亚硫酸氢钠饱和溶液(10毫升)淬灭，加入50毫升水，搅拌过夜。浓盐酸调PH值到3-4，析出固体，过滤，水洗，固体溶于乙酸乙酯，无水硫酸钠干燥，过滤，减压浓缩得到化合物4-羟基-5-碘-2-甲基苯甲酸(1.8克，粗品)。LCMS(ESI):m/z 278[M+1]+。
步骤9b：4-羟基-5-碘-2-甲基苯甲酸甲酯(methyl 4-hydroxy-5-iodo-2-methylbenzoate)(化合物0204-25)的制备:将化合物4-羟基-5-碘-2-甲基苯甲酸(0203-25)(1.8克)溶解于30毫升的无水甲醇中，然后加入浓硫酸(0.5克)。混合物在65度下搅拌反应过夜。反应结束后，减压除去甲醇，残留物混悬在100毫升水中，加入饱和碳酸氢钠水溶液使pH到4左右，过滤收集固体，水洗一遍，干燥得到目标产物4-羟基-5-碘-2-甲基苯甲酸甲酯(1.90克，收率100％) 为白色固体。LCMS(ESI):m/z 293[M+1]+。
步骤9c：4-羟基-2-甲基-5–(三甲基甲硅乙炔基)苯甲酸甲酯(methyl 4-hydroxy-2-methyl-5-((trimethylsilyl)ethynyl)benzoate)(化合物0205-25)的制备:在氮气保护下，将4-羟基-5-碘-2-甲基苯甲酸甲酯(0204-25)(1.0克，3.4毫摩尔，1.0当量)，三甲基硅乙炔(500毫克，5.1毫摩尔，1.5当量)，碘化亚铜(38毫克，0.2毫摩尔，0.015当量)和双三苯基磷二氯化钯(71毫克，0.1毫摩尔，0.03当量)加入到10毫升四氢呋喃和10毫升氯仿的混合液中，然后滴加三乙胺(1.04克，10.2毫摩尔，3.0当量)，混合物加热至50℃，搅拌反应3小时。冷却至室温，过滤，减压浓缩得到残留物4-羟基-2-甲基-5–(三甲基甲硅乙炔基)苯甲酸甲酯(1.0g，粗品)，直接用于下一步反应。LCMS(ESI):m/z 263[M+1]+。
步骤9d：6-甲基苯并呋喃-5-羧酸甲酯(methyl 6-methylbenzofuran-5-carboxylate)(化合物0206-25)的制备:用50毫升无水甲醇稀释4-羟基-2-甲基-5–(三甲基甲硅乙炔基)苯甲酸甲酯粗品(0205-25)(1.0克，3.4毫摩尔，1.0当量)，加入N，N-二异丙基乙胺(378毫克，3.74毫摩尔，1.1当量)和碘化亚铜(30毫克，0.17毫摩尔，0.05当量)。于60℃下反应4小时后，加入少量碳酸钾，于60℃下搅拌过夜。冷却至室温，抽滤，所得滤液减压浓缩，经过硅胶柱层析分离纯化(洗脱剂：石油醚：乙酸乙酯＝25：1)，得到白色固体产物6-甲基苯并呋喃-5-羧酸甲酯(450毫克，收率：69.6％)。LCMS(ESI):m/z 191[M+1]+。
步骤9e：(2-(6-甲基苯并呋喃-5-基)-2-氧代乙基)膦酸二甲酯(dimethyl(2-(6-methylbenzofuran-5-yl)-2-oxoethyl)phosphonate)(化合物0207-25)的制备:在氮气的氛围下，将甲基膦酸二甲酯(186毫克，1.5毫摩尔，1.5当量)溶解于5毫升的干燥的四氢呋喃中。干冰/乙醇冷却到-60度，缓慢滴加入正丁基锂(0.8毫升，2.5摩尔/毫升的正己烷溶液，1.86毫摩尔，2当量)，混合物在此温度下搅拌反应30分钟，再缓慢滴加化合物6-甲基苯并呋喃-5-羧酸甲酯(0206-25)(190毫克，1.0毫摩尔，1当量)的四氢呋喃(1毫升)溶液。混合物在-60度下搅拌反应1小时。反应结束后，加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物(2-(6-甲基苯并呋喃-5-基)-2-氧代乙基)膦酸二甲酯(200毫克，收率70.9％)为透明油状物。LCMS(ESI):m/z 283[M+1]+。
步骤9f：1-(6-甲基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烷-2-烯-1-酮(1-(6-methylbenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en-1-one)(化合物0208-25)的制备:将2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(266毫克，0.644毫摩尔，1当量),化合物(2-(6-甲基苯并呋喃-5-基)-2-氧代乙基)膦酸二甲酯(0207-25)(200毫克，0.709毫摩尔，1.1当量)和碳酸铯(460毫克，1.418毫摩尔，2当量)混合于异丙醇(10毫升)中，混合物在室温下搅拌反应16小时。反应结束后，用水淬灭，过滤，得到目标产物1-(6-甲基苯并 呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烷-2-烯-1-酮(310毫克，收率：84.4％)为黄色固体。LCMS(ESI):m/z 571[M+1]+。
步骤9g：1-(6-甲基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(6-methylbenzofuran-5-yl)ethan-1-one)(化合物0209-25)的制备:将化合物1-(6-甲基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烷-2-烯-1-酮(0208-25)(310毫克，0.543毫摩尔，1当量)和醋酸(2毫升)混合于甲醇(4毫升)中。混合物在90℃下搅拌反应16小时。反应结束后，用2N氢氧化钠水溶液调节pH值至12，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物1-(6-甲基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(200毫克，粗品)为黄色固体。LCMS(ESI):m/z 329[M+1]+。
步骤9h：1-(6-甲基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(6-methyl benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol)(化合物25)的制备:将1-(6-甲基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0209-25)(200毫克，0.609毫摩尔，1.0当量)溶解到30毫升甲醇中，冰浴中，冷却至0℃，加入硼氢化钠(35毫克，0.915毫摩尔，1.5当量)，搅拌反应半小时，加入丙酮，减压浓缩，加入二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝30:1～15:1)，得到化合物1-(6-甲基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(110毫克，收率：54.56％)黄色固体。LCMS(ESI):m/z 331[M+1]+。熔点：95～97℃；1H NMR(300MHz,DMSO)δ8.25-8.05(m,1H),7.87～7.21(m,8H),6.89(m,1H),5.65(m,2H),5.29(m,1H),2.43～2.10(m,5H)。
实施例10：2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(6-三氟甲基苯并呋喃-5-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(6-(trifluoromethyl)benzofuran-5-yl)ethan-1-ol)(化合物30)的制备(按照方案二线路制备)
步骤10a：2-三氟甲基-4-羟基苯甲酸甲酯(methyl 4-hydroxy-2-(trifluoromethyl)benzoate)(化合物0202-30)的制备:将2-三氟甲基-4-羟基苯甲酸(0201-30)(600毫克，2.91毫摩尔，1.0当量)溶解于30毫升甲醇，缓慢滴加入氯化亚砜(2毫升)。混合物在50度的条件下搅拌反应过夜。反应结束后，除去溶剂，将残留物加入冰水中，用乙酸乙酯萃取，再用饱和食盐水洗两遍，无水硫酸钠干燥，浓缩得到褐色固体2-三氟甲基-4-羟基苯甲酸甲酯(612毫克，收率：95.6％)。LCMS(ESI):m/z 221[M+1]+。
步骤10b：2-三氟甲基-4-羟基-5-碘苯甲酸甲酯(methyl4-hydroxy-5-iodo-2-(trifluoromethyl)benzoate)(化合物0204-30)的制备:将碳酸钾(891毫克， 6.46毫摩尔，2.0当量)和化合物2-三氟甲基-4-羟基苯甲酸甲酯(0202-30)(712毫克，3.23毫摩尔，1.0当量)溶解于50毫升的四氢呋喃中，加入碘单质(985毫克，3.88毫摩尔，1.2当量)，室温搅拌过夜。反应结束后，加入亚硫酸氢钠水溶液15毫升。最后用乙酸乙酯萃取，有机相用饱和食盐水洗，减压浓缩，得到黄色油状体2-三氟甲基-4-羟基-5-碘苯甲酸甲酯(1.02克，收率：91.3％)。LCMS(ESI):m/z 347[M+1]+。
步骤10c:6-三氟甲基苯并呋喃-5-羧酸甲酯(methyl 6-(trifluoromethyl)benzofuran-5-carboxylate)(化合物0206-30)的制备:在氮气保护下，将2-三氟甲基-4-羟基-5-碘苯甲酸甲酯(0204-30)(800毫克，2.31毫摩尔，1.0当量)，三甲基硅乙炔(341毫克，3.46毫摩尔，1.5当量)，碘化亚铜(7毫克，0.035毫摩尔，0.015当量)和双三苯基磷二氯化钯(48毫克，0.07毫摩尔，0.03当量)加入到30毫升四氢呋喃中，然后滴加三乙胺(701毫克，6.93毫摩尔，3.0当量)，混合物加热至50℃，搅拌反应3小时。冷却至室温，加入10毫升甲醇和碳酸钾(956毫克，6.93毫摩尔，3.0当量)。于60℃下反应过夜。冷却至室温，抽滤，所得滤液减压浓缩，经过硅胶柱层析分离纯化(洗脱剂：石油醚：乙酸乙酯＝25：1)，得到白色固体产物6-三氟甲基苯并呋喃-5-羧酸甲酯(203毫克，收率：35.99％)。LCMS(ESI):m/z 245[M+1]+。
步骤10d:(2-氧代-2-(6-三氟甲基苯并呋喃-5-基)乙基)磷酸二甲酯(dimethyl(2-oxo-2-(6-(trifluoromethyl)benzofuran-5-yl)ethyl)phosphonate)化合物(0207-30)的制备：在氮气的氛围下，将甲基膦酸二甲酯(152毫克，1.23毫摩尔，1.5当量)溶解于15毫升的干燥的四氢呋喃中。干冰/乙醇冷却到-60℃，缓慢滴加入正丁基锂(0.5毫升，2.5摩尔/升的正己烷溶液，1.23毫摩尔，1.5当量)，混合物在此温度下搅拌反应30分钟，再缓慢滴加化合物0206-30(200毫克，0.819毫摩尔，1.0当量)的四氢呋喃(15毫升)溶液。混合物在-60℃搅拌反应0.5小时。升至室温反应4小时，反应结束后，加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物6-三氟甲基苯并呋喃-5-羧酸甲酯(262毫克，粗品)为黄色油状液体，直接用于下一步反应。LCMS(ESI):m/z 337[M+1]+。
步骤10e:1-(6-三氟甲基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(6-(trifluoromethyl)benzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en-1-one)(化合物0208-30)的制备:将化合物(2-氧代-2-(6-三氟甲基苯并呋喃-5-基)乙基)磷酸二甲酯(0207-30)(262毫克，0.78毫摩尔，1.2当量)，2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(270毫克，0.65毫摩尔，1.0当量)和碳酸铯(847毫克，2.6毫摩尔，4.0当量)混合于异丙醇(20毫升)中，混合物在室温下搅拌反应16小时。反应结束后，用水淬灭，乙酸乙酯萃取， 有机相用无水硫酸钠干燥，过滤，减压浓缩得到残留物通过柱层析纯化(石油醚/乙酸乙酯＝5/1～1/1)得到目标产物(176毫克，收率：43.3％)为黄色胶状体。LCMS(ESI):m/z 625[M+1]+。
步骤10f:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(6-三氟甲基苯并呋喃-5-基)乙烷-1-酮(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(6-(trifluoromethyl)benzofuran-5-yl)ethan-1-one)(化合物0209-30)的制备:将化合物1-(6-三氟甲基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0208-30)(173毫克，0.277毫摩尔，1.0当量)和醋酸(2毫升)混合于甲醇(30毫升)中。混合物在90℃下搅拌反应过夜。反应结束后，降至室温。用饱和碳酸钠水溶液调节pH值至10，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得物用硅胶柱层析(二氯甲烷/甲醇＝100/1)纯化，得到目标产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(6-三氟甲基苯并呋喃-5-基)乙烷-1-酮(93毫克，收率：87.8％)为黄色固体。LCMS(ESI):m/z 383[M+1]+。
步骤10g:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(6-三氟甲基苯并呋喃-5-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(6-(trifluoromethyl)benzofuran-5-yl)ethan-1-ol)(化合物30)的制备:将化合物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(6-三氟甲基苯并呋喃-5-基)乙烷-1-酮(0209-30)(93毫克，0.24毫摩尔，1.0当量)溶解于40毫升乙醇中。再缓慢加入硼氢化钠(18毫克，0.48毫摩尔，2.0当量)。混合物在室温下搅拌反应3小时。反应结束后，加入饱和氯化铵水溶液淬灭，搅拌10分钟，减压除去乙醇，加入饱和碳酸钠水溶液(50毫升)，用二氯甲烷(100毫升)萃取，有机相用饱和食盐水洗一遍，无水硫酸钠干燥，浓缩，所得物硅胶柱层析(二氯甲烷/甲醇＝100/1至100/8)纯化，得到目标产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(6-三氟甲基苯并呋喃-5-基)乙烷-1-醇(82毫克，收率：88.1％)为白色固体。LCMS(ESI):m/z 385[M+1]+。熔点：124～126℃；1H NMR(400MHz,DMSO)δ8.26-8.13(m,3H),7.94-7.91(m,1H),7.69(m,1H),7.56(m,1H),7.44-7.11(m,4H),6.15-6.08(m,1H),5.69(m,1H),5.49-5.33(m,1H),2.61-2.43(m,1H),2.01-1.72(m,1H).
实施例11：1-(1H-苯并呋喃-5-基)-2-(7-甲氧基-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(benzofuran-5-yl)-2-(7-methoxy-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物31)的制备(按照方案一和二线路制备)
步骤11a:5-甲氧基-2-频哪醇硼酸酯苯甲醛(5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde)(化合物0104-31)的制备:氮气保护下，将化合物2-溴-5-甲氧基苯甲醛(1克，4.65毫摩尔，1当量)，双联频哪醇硼酸酯(1.77克，6.975毫摩尔，1.5当量)，醋酸钾(1.37克，3当量)，四三苯基磷钯(538毫克， 0.465毫摩尔，0.1当量)混合于10毫升甲苯中，并在110℃下搅拌反应16小时。反应结束后，冷却至室温，过滤，滤液减压浓缩，得到黑色油状物产物5-甲氧基-2-频哪醇硼酸酯苯甲醛(1.5克，粗品)，直接用于下一步反应。
步骤11b:5-甲氧基-2-(1-三苯甲基-1H-咪唑-5-基)苯甲醛(5-methoxy-2-(1-trityl-1H-imidazol-5-yl)benzaldehyde)(化合物0105-31)的制备:氮气保护下，将化合物5-甲氧基-2-频哪醇硼酸酯苯甲醛(0104-31)(610毫克，2.32毫摩尔，1.4当量)，5-碘-1-三苯甲基-1H-咪唑(0101-1)(725毫克，1.66毫摩尔，1当量)，四三苯基磷钯(192毫克，0.166毫摩尔，0.1当量)，磷酸三钾(865毫克，3.32毫摩尔，2当量)混合于DMF/H2O(50/10毫升)中，并在95℃下搅拌反应3小时。反应结束后，冷却至室温，过滤，减压浓缩，浓缩液用硅胶柱层析纯化(石油醚/乙酸乙酯/二氯甲烷＝10/1/1)，得到白色固体产物5-甲氧基-2-(1-三苯甲基-1H-咪唑-5-基)苯甲醛(440毫克，收率：59.62％)。
步骤11c:1-(苯并呋喃-5-基)-3-(5-甲氧基-2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(benzofuran-5-yl)-3-(5-methoxy-2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)(化合物0208-31)的制备:将(2-(苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(0207-1)(175毫克，0.652毫摩尔，1.3当量)，化合物5-甲氧基-2-(1-三苯甲基-1H-咪唑-5-基)苯甲醛(0105-31)(220毫克，0.5毫摩尔，1当量)和碳酸铯(325毫克，1毫摩尔，2当量)混合于异丙醇(10毫升)中，混合物在室温下搅拌反应16小时。反应结束后，用水淬灭，过滤，得到目标产物1-(苯并呋喃-5-基)-3-(5-甲氧基-2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(280毫克，收率：96.55％)为黄色固体。LCMS(ESI):m/z 587[M+1]+。
步骤11d:1-(1H-苯并呋喃-5-基)-2-(7-甲氧基-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(benzofuran-5-yl)-2-(7-methoxy-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0209-31))的制备:将化合物1-(苯并呋喃-5-基)-3-(5-甲氧基-2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0208-31)(280毫克，0.478毫摩尔，1当量)和醋酸(2毫升)混合于甲醇(4毫升)中。混合物在90℃下搅拌反应16小时。反应结束后，用2N氢氧化钠水溶液调节pH值至12，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(二氯甲烷/甲醇/氨水＝150/1/1),得到目标产物1-(1H-苯并呋喃-5-基)-2-(7-甲氧基-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(160毫克，收率：97.08％)为黄色固体。LCMS(ESI):m/z 345[M+1]+。
步骤11e:1-(1H-苯并呋喃-5-基)-2-(7-甲氧基-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(benzofuran-5-yl)-2-(7-methoxy-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物31)的制备:将1-(1H-苯并呋喃-5-基)-2-(7-甲氧基-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0209-31)(1 60毫克，0.465毫摩尔，1.0当量)溶解到10毫升甲醇中，冰浴中，冷却至0℃，加入硼氢化钠(35毫克，0.93毫摩尔，2当量)，搅拌反应半小时，加入丙酮，减压浓缩，加入二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇/氨水＝150/1/1)，得到黄色固体1-(1H-苯并呋喃-5-基)-2-(7-甲氧基-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(51毫克，收率：31.69％)。LCMS(ESI):m/z 347[M+1]+。熔点：180～181℃；1H NMR(500MHz,DMSO)δ7.94-7.93(m,1H),7.89-7.73(m,1H),7.69-7.65(m,1H),7.50-7.44(m,2H),7.37-7.32(m,1H),7.16-7.03(m,1H),6.99-7.86(m,3H),5.80-5.70(m,1H),5.44-5.25(m,1H),5.05(m,1H),3.79-3.70(m,3H),2.53-1.75(m,2H).
实施例12：1-(1H-苯并呋喃-5-基)-2-(7-氟-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(b enzofuran-5-yl)-2-(7-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物32)的制备(按照方案一和二线路制备)
步骤12a:5-氟-2-频哪醇硼酸酯苯甲醛(5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde)(化合物0104-32)的制备:氮气保护下，将化合物2-溴-5-氟苯甲醛(500毫克，2.46毫摩尔，1当量)，双联频哪醇硼酯(937毫克，3.69毫摩尔，1.5当量)，醋酸钾(724克，7.38毫摩尔，3当量)，四三苯基磷钯(284毫克，0.246毫摩尔，0.1当量)混合于10毫升甲苯中，并在110℃下搅拌反应16小时。反应结束后，冷却至室温，过滤，滤液减压浓缩，得到黄色油状物产物5-氟-2-频哪醇硼酸酯苯甲醛(1.5克，粗品)，直接用于下一步反应。
步骤12b:5-氟-2-(1-三苯甲基-1H-咪唑-5-基)苯甲醛(5-fluoro-2-(1-trityl-1H-imidazol-5-yl)benzaldehyde)(化合物0105-32)的制备:氮气保护下，将化合物5-氟-2-频哪醇硼酸酯苯甲醛(0104-32)(1.5克，2.46毫摩尔，1.4当量)，5-碘-1-三苯甲基-1H-咪唑(0101-1)(715毫克，1.64毫摩尔，1当量)，四三苯基磷钯(189毫克，0.164毫摩尔，0.1当量)，磷酸三钾(854毫克，3.28毫摩尔，2当量)混合于DMF/H2O(50/10毫升)中，并在95℃下搅拌反应3小时。反应结束后，冷却至室温，过滤，减压浓缩，所得物用硅胶柱层析纯化(石油醚/乙酸乙酯/二氯甲烷＝10/1/1)，得到黄色固体产物5-氟-2-(1-三苯甲基-1H-咪唑-5-基)苯甲醛(300毫克，收率：42.37％)LCMS(ESI):m/z 433[M+1]+。
步骤12c:1-(苯并呋喃-5-基)-3-(5-氟-2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(benzofuran-5-yl)-3-(5-fluoro-2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)(化合物0208-32)的制备:将(2-(苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(0207-1)(175毫克，0.652毫摩尔，1.3当量),化合物5-氟-2-(1-三苯甲基-1H-咪唑-5-基)苯甲醛 (0105-32)(216毫克，0.5毫摩尔，1当量)和碳酸铯(325毫克，1毫摩尔，2当量)混合于异丙醇(10毫升)中，混合物在室温下搅拌反应16小时。反应结束后，用水淬灭，过滤，得到目标产物1-(苯并呋喃-5-基)-3-(5-氟-2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(200毫克，收率：69.57％)为黄色固体。LCMS(ESI):m/z 575[M+1]+。
步骤12d:1-(1H-苯并呋喃-5-基)-2-(7-氟-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(benzofuran-5-yl)-2-(7-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0209-32)的制备:将化合物1-(苯并呋喃-5-基)-3-(5-氟-2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0208-32)(200毫克，0.35毫摩尔，1当量)和醋酸(2毫升)混合于甲醇(4毫升)中。混合物在90℃下搅拌反应16小时。反应结束后，用2N氢氧化钠水溶液调节pH值至12，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(二氯甲烷/甲醇/氨水＝150/1/1),得到目标产物1-(1H-苯并呋喃-5-基)-2-(7-氟-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(110毫克，收率：94.83％)为黄色固体。LCMS(ESI):m/z 333[M+1]+。
步骤12e:1-(1H-苯并呋喃-5-基)-2-(7-氟-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(benzofuran-5-yl)-2-(7-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物32)的制备:将1-(1H-苯并呋喃-5-基)-2-(7-氟-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0209-32)(110毫克，0.331毫摩尔，1.0当量)溶解到10毫升甲醇中，冰浴中，冷却至0℃，加入硼氢化钠(25毫克，0.662毫摩尔，2当量)，搅拌反应半小时，加入丙酮，减压浓缩，加入二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇/氨水＝150/1/1)，得到产物黄色固体(61毫克，收率：54.95％)。LCMS(ESI):m/z 335[M+1]+。熔点：83～85℃；1H NMR(500MHz,DMSO)δ8.05-7.91(m,2H),7.77-7.74(m,1H),7.70-7.68(m,1H),7.62-7.44(m,3H),7.32-7.30(m,1H),7.20-7.13(m,1H),7.00-6.98(m,1H),5.91-5.76(m,1H),5.60-5.44(m,1H),5.11(m,1H),2.64-1.93(m,2H).
实施例13：1-(苯并呋喃-5-基)-2-(6-氟-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(benzofuran-5-yl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物33)的制备(按照方案一和二线路制备)
步骤13a:2-氟-6-频哪醇硼酸酯苯甲醛(2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde)(化合物0104-33)的制备:将化合物2-溴-6-氟苯甲醛(2.0克，9.84毫摩尔，1.0当量)，双联频哪醇硼酸酯(3.75克，14.76毫摩尔，1.5当量)，醋酸钾(2.89克，29.52毫摩尔，3.0当量)，四三苯基磷钯(568毫克，0.49毫摩尔，0.05当量)混合于50毫升甲苯中，置换氮气3次以上，然后在110℃下搅拌反应过夜。反应结束后，冷却至室温，过滤，滤液减压浓缩，得到黑色油状物产物2-氟-6-频哪醇硼酸酯苯甲醛(3.23克，粗品)，直 接用于下一步反应。LCMS(ESI):m/z 251[M+1]+。
步骤13b:2-氟-6-(1-三苯甲基-1H-咪唑-5-基)苯甲醛(2-fluoro-6-(1-trityl-1H-imidazol-5-yl)benzaldehyde)(化合物0105-33)的制备:氮气保护下，将化合物2-氟-6-频哪醇硼酸酯苯甲醛(0104-33)(3.23克，12.9毫摩尔，1.5当量)，5-碘-1-三苯甲基-1H-咪唑(0101-1)(3.75克，8.6毫摩尔，1.0当量)，四三苯基磷钯(994毫克，0.86毫摩尔，0.1当量)，磷酸三钾(3.65克，17.2毫摩尔，2.0当量)混合于DMF/H2O(80/10毫升)中，并在95℃下搅拌反应过夜。反应结束后，冷却至室温，一边搅拌，一边将反应液加进水中，用乙酸乙酯萃取，分液，有机相用饱和食盐水洗两遍，干燥，过滤，滤液减压浓缩，所得残留物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝10/1～1/1)，得到黄色油状物产物2-氟-6-(1-三苯甲基-1H-咪唑-5-基)苯甲醛(220毫克，收率：5.9％)。LCMS(ESI):m/z 433[M+1]+。
步骤13c:1-(苯并呋喃-5-基)-3-(2-氟-6-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烷-2-烯-1-酮(1-(benzofuran-5-yl)-3-(2-fluoro-6-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en-1-one)(化合物0208-33)的制备:将(2-(苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(0207-1)(81毫克，0.3毫摩尔，1.3当量),化合物2-氟-6-(1-三苯甲基-1H-咪唑-5-基)苯甲醛(0105-33)(100毫克，0.23毫摩尔，1.0当量)和碳酸铯(150毫克，0.46毫摩尔，2.0当量)混合于异丙醇(10毫升)中，混合物在室温下搅拌反应16小时。反应结束后，用水淬灭，乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩得到残留物通过柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1～1/1)得到目标产物1-(苯并呋喃-5-基)-3-(2-氟-6-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烷-2-烯-1-酮(108毫克，收率：81.8％)为黄色固体。LCMS(ESI):m/z 575[M+1]+。
步骤13d:1-(苯并呋喃-5-基)-2-(6-氟-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(benzofuran-5-yl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0209-33)的制备:将化合物1-(苯并呋喃-5-基)-3-(2-氟-6-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烷-2-烯-1-酮(0208-33)(108毫克，0.188毫摩尔，1.0当量)和醋酸(2毫升)混合于甲醇(20毫升)中。混合物在90℃下搅拌反应16小时。反应结束后，用2N氢氧化钠水溶液调节pH值至12，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝50/1～10/1),得到目标产物1-(苯并呋喃-5-基)-2-(6-氟-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(61毫克，收率：97.6％)为黄色固体。LCMS(ESI):m/z 333[M+1]+。
步骤13e:1-(苯并呋喃-5-基)-2-(6-氟-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(benzofuran-5-yl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物33)的制备:将化合物1-(苯并呋喃-5-基)-2-(6-氟-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0209-33)(61毫克，0.18毫摩尔，1.0当量)溶解到20毫升乙醇中，冰浴中，冷却至0℃，加入硼氢 化钠(14毫克，0.36毫摩尔，2.0当量)，搅拌反应1小时，加入丙酮，减压浓缩，加入二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝50/1～10/1)，得到产物白色固体(40毫克，收率：66.6％)。LCMS(ESI):m/z 335[M+1]+。熔点：68～70℃；1H NMR(500MHz,DMSO)δ7.99-7.91(m,2H),7.58(m,1H),7.50-7.45(m,1H),7.41-7.35(m,2H),7.26-6.95(m,3H),6.90-6.87(m,1H),5.81-5.69(m,1H),5.50-5.44(m,1H),4.97-4.78(m,1H),2.55-1.84(m,2H).
实施例14：1-(2,3-二氢苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(2,3-dihydrobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物36)的制备(按照方案四线路制备)
步骤14a:2,3-二氢苯并呋喃-5-甲酸甲酯(methyl 2,3-dihydrobenzofuran-5-carboxylate)(化合物0402-36)的制备:将化合物2,3-二氢苯并呋喃-5-甲酸(0401-36)(900毫克，5.5毫摩尔，1.0当量)溶解于50毫升甲醇中。冰浴冷却，缓慢滴加氯化亚砜(0.8毫升，11.0毫摩尔，2.0当量)。混合物在室温下搅拌反应过夜。反应结束后，减压浓缩。将残留物溶解在二氯甲烷中，加入饱和碳酸氢钠溶液，调至碱性，分液。有机相用无水硫酸钠干燥，旋干得到产物2,3-二氢苯并呋喃-5-甲酸甲酯(900毫克，收率：91.6％)。LCMS(ESI):m/z 179[M+1]+。
步骤14b:(2-(2,3-二氢苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(2,3-dihydrobenzofuran-5-yl)-2-oxoethyl)phosphonate)(化合物0403-36)的制备:在氮气保护下，将甲基磷酸二甲酯(888毫克，7.16毫摩尔，1.5当量)溶解于20毫升的干燥的四氢呋喃中，冷却到-70℃，缓慢滴加入正丁基锂(3.8毫升，2.5摩尔/升的四氢呋喃溶液，9.5毫摩尔，2.0当量)，混合物在此温度下搅拌反应30分钟，再缓慢滴加化合物2,3-二氢苯并呋喃-5-甲酸甲酯(0402-36)(850毫克，4.77毫摩尔，1.0当量)的1毫升四氢呋喃溶液，搅拌反应过夜。反应结束后，加水淬灭，二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1～50/1)纯化，得到产物(2-(2,3-二氢苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(600毫克，收率：47％)。LCMS(ESI):m/z 271[M+1]+。
步骤14c:(Z)-1-(2,3-二氢苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮[(Z)-1-(2,3-dihydrobenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one](化合物0404-36)的制备:将2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(500毫克，1.2毫摩尔，1.0当量),化合物(2-(2,3-二氢苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(0402-36)(420毫克，1.5毫摩尔，1.3当量)和碳酸铯(782毫克，2.4毫摩尔，2.0当量)混合于异丙醇(30毫升)中，在室温下搅拌反应过夜。反应结束后，用水淬灭，二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1～50/1)纯化，得到产物(Z)- 1-(2,3-二氢苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(500毫克，收率：74％)。LCMS(ESI):m/z 559[M+1]+。
步骤14d:1-(2,3-二氢苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(2,3-dihydrobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0405-36)的制备:将化合物(Z)-1-(2,3-二氢苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0404-36)(500毫克，0.9毫摩尔，1.0当量)和醋酸(10毫升)混合于甲醇(40毫升)中，混合物在90℃下搅拌反应过夜。反应结束后，减压浓缩。残留物溶解于二氯甲烷中，用饱和碳酸氢钠溶液中和剩余的酸，二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1～50/1)纯化，得到产物1-(2,3-二氢苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(250毫克，收率：88％)。LCMS(ESI):m/z 317[M+1]+。
步骤14e:1-(2,3-二氢苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(2,3-dihydrobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物36)的制备:将化合物1-(2,3-二氢苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0405-36)(250毫克，0.79毫摩尔，1.0当量)溶解于10毫升甲醇中，再缓慢加入硼氢化钠(121毫克，3.2毫摩尔，4.0当量)，冷却至0℃。混合物在室温下搅拌反应1小时。反应结束后，加入2毫升丙酮淬灭，减压浓缩，所得物硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1～50/1)纯化，得到产物1-(2,3-二氢苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(100毫克，收率：40％)，黄色固体。LCMS(ESI):m/z 319[M+1]+。熔点60℃；1H NMR(400MHz,DMSO)δ7.94-7.83(m,1H),7.60-7.46(m,2H),7.40-7.24(m,3H),7.15-7.09(m,2H),6.70-6.67(m,1H),5.63-5.52(m,1H),5.47-5.30(m,1H),4.93-4.89(m,1H),4.52-4.47(m,2H),3.14(m,2H),2.48-1.70(m,2H).
实施例15：1-(6-氟-2,3-二氢苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物42)的制备(按照方案四线路制备)
步骤15a:6-氟-2,3-二氢苯并呋喃-5-羧酸甲酯(methyl 6-fluoro-2,3-dihydrobenzofuran-5-carboxylate)(化合物0402-42)的制备:将化合物6-氟苯并呋喃-5-羧酸甲酯(300毫克，1.54毫摩尔，1当量)溶解于10毫升甲醇中，再加入30毫克钯碳，氢气置换，混合物在室温下搅拌反应2小时。反应结束后，过滤，滤液减压浓缩，得到淡黄色固体6-氟-2,3-二氢苯并呋喃-5-羧酸甲酯(303毫克，粗品)。LCMS(ESI):m/z 197[M+1]+。
步骤15b:(2-(6-氟-2,3-二氢苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-oxoethyl)phosphonate)(化合物0403-42)的制备:在氮气的氛围下，将甲基膦酸二甲酯(286毫克，2.31毫摩尔，1.5当量)溶解于5毫升的干燥的四氢呋喃中。干冰/乙醇冷却到-60℃，缓慢滴加入正丁基锂(1.2毫升，2.5摩尔/毫升的正己烷溶液，3.08毫摩尔，2当量)。混合物在-60℃下搅拌反应30分钟，再缓慢滴加化合物6-氟-2,3-二氢苯并呋喃-5-羧酸甲酯(0402-42)(303毫克，1.54毫摩尔，1当量)的四氢呋喃(1毫升)溶液。混合物在-60℃下搅拌反应1小时。反应结束后，加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物(2-(6-氟-2,3-二氢苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(377毫克，粗品)为黄色油状物。LCMS(ESI):m/z 289[M+1]+。
步骤15c:1-(6-氟-2,3-二氢苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烷-2-烯-1-酮(1-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en-1-one)(化合物0404-42)的制备:将2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(263毫克，0.635毫摩尔，1当量),化合物(2-(6-氟-2,3-二氢苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(0403-42)(377毫克，1.3毫摩尔，1.3当量)和碳酸铯(412毫克，1.27毫摩尔，2当量)混合于异丙醇(10毫升)中，混合物在室温下搅拌反应16小时。反应结束后，用水淬灭，过滤，得到目标产物1-(6-氟-2,3-二氢苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烷-2-烯-1-酮(280毫克，粗品)为黄色固体。LCMS(ESI):m/z 577[M+1]+。
步骤15d:1-(6-氟-2,3-二氢苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0405-42)的制备:将化合物1-(6-氟-2,3-二氢苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烷-2-烯-1-酮(0404-42)(280毫克，0.486毫摩尔，1当量)和醋酸(2毫升)混合于甲醇(4毫升)中。混合物在90度下搅拌反应16小时。反应结束后，用2N氢氧化钠水溶液调节pH至12，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物1-(6-氟-2,3-二氢苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(150毫克，粗品)为黄色固体。LCMS(ESI):m/z 335[M+1]+。
步骤15e:1-(6-氟-2,3-二氢苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物42)的制备:将1-(6-氟-2,3-二氢苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0405-42)(150毫克，0.45毫摩尔，1.0当量)溶解到30毫升甲醇中，冰浴中，冷却至0℃，加入硼氢化钠(34毫克，0.9毫摩尔，2当量)，搅拌反应半小时，加入丙酮，减压浓缩，加 入二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝30:1～15:1)，得到白色固体1-(6-氟-2,3-二氢苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(148毫克，收率：97.36％)。LCMS(ESI):m/z 337[M+1]+。熔点：67-70℃；1H NMR(400MHz,DMSO)δ7.96-7.80(m,1H),7.61-7.30(m,5H),7.16-7.09(m,1H),6.56(m,1H),5.67(s,1H),5.50-5.36(m,1H),5.16(m,1H),4.57(m,2H),3.14(m,2H),2.47-1.71(m,2H).
实施例16：1-(呋喃并[2,3-b]吡啶-5-基)-2-(5H-咪唑并[5,1-a]异吲哚啉-5-基)-1-醇(1-(furo[2,3-b]pyridin-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物49)的制备(按照方案二线路制备)
步骤16a:6-羟基-5-碘烟酸甲酯(methyl 6-hydroxy-5-iodonicotinate)(化合物0204-49)的制备:将6-羟基烟酸(0201-49)(2.8克，20毫摩尔，1.0当量)溶解于50毫升甲醇。缓慢滴加入浓硫酸(3毫升)。混合物在60℃的条件下搅拌反应过夜。冷却至室温，加入碘代丁二酰亚胺(5.4克，24毫摩尔，1.2当量)，加热到60摄氏度，反应4小时。反应结束后，加入亚硫酸氢钠水溶液15毫升。最后用乙酸乙酯萃取，有机相用饱和食盐水洗，减压浓缩，得到黄色固体产物6-羟基-5-碘烟酸甲酯(1.6克，收率：28.6％)。LCMS(ESI):m/z 280[M+1]+。
步骤16b:呋喃并[2,3-b]吡啶-5-碳酸甲酯(methyl furo[2,3-b]pyridine-5-carboxylate)(化合物0206-49)的制备：在氮气保护下，将6-羟基-5-碘烟酸甲酯(0204-49)(1.45克，5.2毫摩尔，1.0当量)，三甲基硅乙炔(2.55克，26毫摩尔，5.0当量)，碘化亚铜(494毫克，2.6毫摩尔，0.5当量)和四三苯基磷钯(168毫克，0.16毫摩尔，0.03当量)加入到30毫升四氢呋喃中，然后滴加二异丙基乙胺(1.3克，13毫摩尔，2.5当量)，混合物加热至65℃，搅拌反应过夜。冷却至室温，过滤，减压浓缩得到残留物用50毫升无水甲醇稀释，加入碳酸钾(1.07克，7.8毫摩尔，1.5当量)和碘化亚铜(1.0克，5.2毫摩尔，1.0当量)。于60℃下反应4小时后，冷却至室温，抽滤，所得滤液减压浓缩，经过硅胶柱层析分离纯化(洗脱剂：石油醚：乙酸乙酯＝25：1)，得到产物黄色固体(150毫克，收率：16.2％)。LCMS(ESI):m/z 178[M+1]+。
步骤16c:(2-(呋喃并[2,3-b]吡啶-5-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(furo[2,3-b]pyridin-5-yl)-2-oxoethyl)phosphonate)(化合物0207-49)的制备:在氮气的氛围下，将甲基膦酸二甲酯(42毫克，0.338毫摩尔，1.5当量)溶解于5毫升的干燥的甲苯中。干冰/乙醇冷却到-60℃，缓慢滴加入正丁基锂(0.14毫升，2.5摩尔/升的正己烷溶液，0.338毫摩尔，1.5当量)。混合物在-60℃下搅拌反应30分钟，再缓慢滴加化合物呋喃并[2,3-b]吡啶-5-碳酸甲酯(0206-49)(40毫克，0.225毫摩尔，1.0当量)的甲苯(5毫升)溶液。混合物在-60℃下搅 拌反应0.5小时。升至室温反应1小时，反应结束后，加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物(2-(呋喃并[2,3-b]吡啶-5-基)-2-氧代乙基)磷酸二甲酯(53毫克，粗品)为无色油状液体。LCMS(ESI):m/z 270[M+1]+。
步骤16d:1-(呋喃并[2,3-b]吡啶-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(furo[2,3-b]pyridin-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en-1-one)(化合物0208-49)的制备:在氮气的氛围和冰浴的条件下，将60％的氢化钠(9.5毫克，0.394毫摩尔，2.0当量)溶解于10毫升的四氢呋喃中。再缓慢加入(2-(呋喃并[2,3-b]吡啶-5-基)-2-氧代乙基)磷酸二甲酯(0207-49)(53毫克，0.197毫摩尔，1.0当量)的四氢呋喃溶液(10毫升)。混合物搅拌15分钟后，将2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(82毫克，0.197毫摩尔，1.0当量)的四氢呋喃(10毫升)溶液滴加入其中。混合物在冰浴条件下搅拌反应0.5小时。升至室温搅拌反应过夜。反应结束后，用饱和氯化铵水溶液淬灭，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到黄色油状物。所得黄色油状物通过硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝1/2)纯化，得到目标产物1-(呋喃并[2,3-b]吡啶-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(22毫克，收率：20％)为黄色油状物。LCMS(ESI):m/z 558[M+1]+。
步骤16e:1-(呋喃并[2,3-b]吡啶-5-基)-2-(5H-咪唑并[5,1-a]异吲哚啉-5-基)-1-酮(1-(furo[2,3-b]pyridin-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0209-49)的制备:将化合物1-(呋喃并[2,3-b]吡啶-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0208-49)(22毫克，0.039毫摩尔，1.0当量)和醋酸(0.5毫升)混合于甲醇(10毫升)中。混合物在70℃下搅拌反应过夜。反应结束后，降至室温。用饱和碳酸钠水溶液调节pH值至10，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得目标粗产物1-(呋喃并[2,3-b]吡啶-5-基)-2-(5H-咪唑并[5,1-a]异吲哚啉-5-基)-1-酮(16毫克，粗品)为黄色油状体，直接用于下一步反应。LCMS(ESI):m/z 316[M+1]+。
步骤16f:1-(呋喃并[2,3-b]吡啶-5-基)-2-(5H-咪唑并[5,1-a]异吲哚啉-5-基)-1-醇(1-(furo[2,3-b]pyridin-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物49)的制备:将化合物1-(呋喃并[2,3-b]吡啶-5-基)-2-(5H-咪唑并[5,1-a]异吲哚啉-5-基)-1-酮(0209-49)(16毫克，0.05毫摩尔，1.0当量)溶解于10毫升甲醇中。再缓慢加入硼氢化钠(4毫克，0.1毫摩尔，2.0当量)。混合物在室温下搅拌反应3小时。反应结束后，加入饱和氯化铵水溶液淬灭，搅拌10分钟，减压除去乙醇，用二氯甲烷(10毫升)萃取，有机相用饱和食盐水洗一遍，无水硫酸钠干燥，浓缩，所得物通过大薄层析板(洗脱剂：二氯甲烷/甲醇＝10/1)纯化，得到目 标产物1-(呋喃并[2,3-b]吡啶-5-基)-2-(5H-咪唑并[5,1-a]异吲哚啉-5-基)-1-醇(11毫克，收率：69.3％)为米白色固体。LCMS(ESI):m/z 318[M+1]+。1H NMR(400MHz,DMSO)δ8.30(m,1H),8.13-8.05(m,3H),7.67-7.50(m,2H),7.43-7.22(m,3H),6.99(m,1H),5.99-5.89(m,1H),5.57-5.45(m,1H),5.12(m,1H),2.47-1.91(m,2H).
实施例17：1-(2-(羟甲基)苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(2-(hydroxymethyl)benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物50)的制备(按照方案二线路制备)
步骤17a:4-羟基-3-(3-羟基丙烷-1-炔-1-基)苯甲酸甲酯(methyl 4-hydroxy-3-(3-hydroxyprop-1-yn-1-yl)benzoate)(化合物0205-50)的制备：常温下将4-羟基-3-碘苯甲酸甲酯(1克，3.6毫摩尔)和丙炔醇(0.24克，4.3毫摩尔)溶于四氢呋喃(15毫升)中，然后加入三乙胺(0.73克，7.2毫摩尔)、碘化亚酮(69毫克，0.36毫摩尔)和双三苯基膦二氯化钯(0.25克，0.36毫摩尔)，氮气保护下加热到55℃反应过夜，然后真空条件下除去溶剂，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝3:1)后得到黄色固体产物1-(2-(羟甲基)苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(0.33克，产率44.5％)。LCMS(ESI):m/z 207[M+1]+。
步骤17b:2-(((叔丁氧羰基)氧基)甲基)苯并呋喃-5-甲酸甲酯(I-6-57-A4)(methyl 2-(((tert-butoxycarbonyl)oxy)methyl)benzofuran-5-carboxylate(化合物0206-50)的制备：将4-羟基-3-(3-羟基丙烷-1-炔-1-基)苯甲酸甲酯(0205-50)(0.25克，1.2毫摩尔)溶于N,N-二甲基甲酰胺(5毫升)中，然后加入碘化亚酮(23毫克，0.12毫摩尔)和二异丙胺(100毫克)。加热到120℃反应过夜，萃取干燥后，通过柱层析分离(洗脱剂：石油醚：乙酸乙酯＝3:1)得到产物黄色固体2-(羟甲基)苯并呋喃-5-甲酸甲酯(0.17克，产率68％)。LCMS(ESI):m/z 207[M+1]+。常温下将上述得到的2-(羟甲基)苯并呋喃-5-甲酸甲酯(0.16克，0.78毫摩尔)和碳酸二叔丁酯(0.25克，1.2毫摩尔)溶于四氢呋喃(10毫升)，然后加热对二甲氨基吡啶(10毫克)和三乙胺(0.24克，2.3毫摩尔)，常温下反应2小时，萃取，旋干后，通过柱层析分离(洗脱剂：石油醚：乙酸乙酯＝3:1)得到黄色液体产物2-(((叔丁氧羰基)氧基)甲基)苯并呋喃-5-甲酸甲酯(0.23克，产率100％)。LCMS(ESI):m/z 307[M+1]+。
步骤17c:((5-(2-(二甲氧基磷酸酯)乙酰基)苯并呋喃-2-基)甲基)碳酸叔丁酯(tert-butyl((5-(2-(dimethoxyphosphoryl)acetyl)benzofuran-2-yl)methyl)carbonate)(化合物0207-50)的制备：将甲基磷酸二甲酯(0.13克，1毫摩尔)溶于四氢呋喃(10毫升)中，冷却至负78℃，然后滴加正丁基锂(2.5摩尔每升的正己烷溶液，0.5毫升)，保持温度反应半小时，然后滴加2-(((叔丁氧羰基)氧基)甲基)苯并呋喃-5-甲酸甲酯(0206-50)(0.23克，0.78毫摩尔)，-78℃反应2 小时，常温反应过夜，萃取旋干后，通过柱层析分离(洗脱剂：二氯甲烷：甲醇＝50:1)得到黄色油状物产物((5-(2-(二甲氧基磷酸酯)乙酰基)苯并呋喃-2-基)甲基)碳酸叔丁酯(0.16克，产率100％)。LCMS(ESI):m/z 399[M+1]+。
步骤17d:((5-(3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烯酰基)苯并呋喃-2-基)甲基)碳酸叔丁酯(tert-butyl((5-(3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)acryloyl)benzofuran-2-yl)methyl)carbonate)(化合物0208-50)的制备：将2-(1-三苯甲基-1H-咪唑-5-基)苯甲醛(0105-1)(200毫克，0.483毫摩尔，1当量)，化合物((5-(2-(二甲氧基磷酸酯)乙酰基)苯并呋喃-2-基)甲基)碳酸叔丁酯(0207-50)(211毫克，0.531毫摩尔，1.1当量)和碳酸铯(314毫克，0.966毫摩尔，2当量)混合于异丙醇(10毫升)中，混合物在室温下搅拌反应16小时。反应结束后，用水淬灭，过滤，得到目标产物(305毫克，收率：92.14％)为黄色固体。LCMS(ESI):m/z 687[M+1]+。
步骤17e:1-(2-(羟甲基)苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(2-(hydroxymethyl)benzofuran-5-yl)-2-(5H-pyrrolo[2,1-a]isoindol-5-yl)ethan-1-one)(化合物0209-50)的制备：将化合物((6-(3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烯酰基)苯并呋喃-2-基)甲基)碳酸叔丁酯(0208-50)(305毫克，0.445毫摩尔，1当量)和醋酸(2毫升)混合于甲醇(4毫升)中。混合物在90℃下搅拌反应16小时。反应结束后，用2N氢氧化钠水溶液调节pH值至12，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，浓缩液用5毫升甲醇溶解，滴加入0.5毫升浓盐酸，混合物搅拌反应2小时。反应结束后，用2N氢氧化钠水溶液调节pH值至12，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物(300毫克，粗品)为黄色固体。LCMS(ESI):m/z 345[M+1]+。
步骤17f:1-(2-(羟甲基)苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(2-(hydroxymethyl)benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物50)的制备：将1-(2-(羟甲基)苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0209-50)(210毫克，0.61毫摩尔，1.0当量)溶解到30毫升甲醇中，冰浴中，冷却至0℃，加入硼氢化钠(27毫克，0.70毫摩尔，1.15当量)，搅拌反应半小时，加入丙酮，减压浓缩，加入二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝30:1～15:1)，得到黄色固体产物1-(2-(羟甲基)苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(88毫克，收率：41.6％)。LCMS(ESI):m/z 347[M+1]+。熔点：68～70℃；1H NMR(400MHz,DMSO)δ7.99-7.82(m,1H),7.65-7.22(m,7H),7.17-7.10(m,1H),6.73(s,1H),5.87-5.76(m,1H),5.49-5.35(m,2H),5.09(m,1H),4.56(m,2H),2.37-1.79(m,2H).
实施例18：2-(5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)苯并呋喃-2-基)丙烷-2-醇 2-(5-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)benzofuran-2-yl)propan-2-ol(化合物59)的制备(按照方案二线路制备)
步骤18a:2-(2-羟基丙烷-2-基)苯并呋喃-5-羧酸甲酯(methyl 2-(2-hydroxypropan-2-yl)benzofuran-5-carboxylate)(化合物0206-59)的制备:在氮气的氛围下，将3-碘-4羟基苯甲酸甲酯(0204-1)(1.0克，3.6毫摩尔，1.0当量)，碘化亚铜(10毫克，0.05毫摩尔，0.015当量)，双三苯基磷二氯化钯(76毫克，0.11毫摩尔，0.03当量)和2-甲基-3-丁炔-2-醇(424毫克，5.0毫摩尔，1.4当量)溶解于20毫升的四氢呋喃和20毫升的氯仿的混合液中。置换氮气三次，再缓慢滴入三乙胺(1.09克，10.8毫摩尔，3.0当量)。混合物加热到50℃反应4小时。然后在80℃下回流过夜。反应结束后，降至室温，加入100毫升氯仿，用稀盐酸水溶液洗两遍，无水硫酸钠干燥，减压浓缩，所得残留物用硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝50/1～4/1)纯化，得到目标产物2-(2-羟基丙烷-2-基)苯并呋喃-5-羧酸甲酯(624毫克，收率：74％)为黄色油体。LCMS(ESI):m/z 235[M+1]+。
步骤18b:(2-(2-(2-羟基丙烷-2-基)苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(2-(2-hydroxypropan-2-yl)benzofuran-5-yl)-2-oxoethyl)phosphonate)(化合物0207-59)的制备。在氮气的氛围下，将甲基膦酸二甲酯(265毫克，2.13毫摩尔，2.5当量)溶解于15毫升的干燥的四氢呋喃中。干冰/乙醇冷却到-60℃，缓慢滴加入正丁基锂(0.85毫升，2.5摩尔/升的正己烷溶液，2.13毫摩尔，2.5当量)。混合物在-60℃下搅拌反应30分钟，再缓慢滴加化合物2-(2-羟基丙烷-2-基)苯并呋喃-5-羧酸甲酯(0206-59)(200毫克，0.85毫摩尔，1.0当量)的四氢呋喃(15毫升)溶液。混合物在-60℃下搅拌反应0.5小时。升至室温反应1小时，反应结束后，加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物(2-(2-(2-羟基丙烷-2-基)苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(426毫克，粗品)为黄色油状液体。LCMS(ESI):m/z 327[M+1]+。
步骤18c:1-(2-(2-羟基丙烷-2-基)苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(2-(2-hydroxypropan-2-yl)benzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)pheny l)prop-2-en-1-one)(化合物0208-59)的制备：将化合物(2-(2-(2-羟基丙烷-2-基)苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(0207-59)(391毫克，1.2毫摩尔，2.0当量)，化合物2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(250毫克，0.6毫摩尔，1.0当量)和碳酸铯(489毫克，1.5毫摩尔，2.5当量)混合于异丙醇(30毫升)中，混合物在室温下搅拌反应16小时。反应结束后，用水淬灭，乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩得到残留物通过柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1～1/1)得到目标产物1-(2-(2-羟基丙烷-2-基)苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(273毫克，收率：74％)为黄色胶状体。LCMS (ESI):m/z 615[M+1]+。
步骤18d:1-(2-(2-羟基丙烷-2-基)苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(2-(2-hydroxypropan-2-yl)benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0209-59)的制备:将化合物1-(2-(2-羟基丙烷-2-基)苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0208-59)(273毫克，0.44毫摩尔，1.0当量)和醋酸(3毫升)混合于甲醇(50毫升)中。混合物在90℃下搅拌反应过夜。反应结束后，降至室温。用饱和碳酸钠水溶液调节pH值至10，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1～10/1)纯化，得到目标产物1-(2-(2-羟基丙烷-2-基)苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(143毫克，收率：87.3％)为黄色固体。LCMS(ESI):m/z 373[M+1]+。
步骤18e:2-(5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)苯并呋喃-2-基)丙烷-2-醇(2-(5-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)benzofuran-2-yl)propan-2-ol)(化合物59)的制备:将化合物1-(2-(2-羟基丙烷-2-基)苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0209-59)(70毫克，0.188毫摩尔，1.0当量)溶解于30毫升甲醇中。再缓慢加入硼氢化钠(14毫克，0.376毫摩尔，2.0当量)。混合物在室温下搅拌反应3小时。反应结束后，加入饱和氯化铵水溶液淬灭，搅拌10分钟，减压除去乙醇，加入饱和碳酸钠水溶液(50毫升)，用二氯甲烷(80毫升)萃取，有机相用饱和食盐水洗一遍，无水硫酸钠干燥，浓缩，所得物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1至100/8)纯化，得到目标产物2-(5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)苯并呋喃-2-基)丙烷-2-醇(57毫克，收率：80.9％)为米白色固体。LCMS(ESI):m/z 375[M+1]+。熔点：187～189℃；1H NMR(400MHz,DMSO)δ8.22-8.16(m,1H),7.70-7.24(m,8H),6.62(m,1H),5.83-5.76(m,1H),5.58-5.49(m,1H),5.38(s,1H),5.13-5.02(m,1H),2.34-1.90(m,2H),1.50(s,6H).
实施例19：2-(6-氟-5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)苯并呋喃-2-基)丙烷-2-醇(2-(6-fluoro-5-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)benzofuran-2-yl)propan-2-ol)(化合物60)的制备(按照方案二线路制备)
步骤19a:6-氟-2-(2-羟基丙烷-2-基)苯并呋喃-5-羧酸甲酯(methyl 6-fluoro-2-(2-hydroxypropan-2-yl)benzofuran-5-carboxylate)(化合物0206-60)的制备):在氮气保护下，将2-氟-4-羟基-5-碘苯甲酸甲酯(0204-1)(700毫克，2.36毫摩尔，1.0当量)，2-甲基-3-丁炔-2-醇(595毫克，7.08毫摩尔，3.0当量)，三乙胺(0.99毫升，7.08毫摩尔，3.0当量)，碘化亚铜(9毫克，0.05毫摩尔，0.02当量)，四丁基氟化铵(870毫克，2.36毫摩尔，)和四三苯基膦钯(136毫克，0.12毫摩尔，0.05当量)加入到25毫升四氢呋喃中，于60℃ 下，反应过夜。冷却至室温，减压浓缩，冷却至室温，加入乙酸乙酯萃取，干燥，减压浓缩，经过硅胶柱层析分离纯化(洗脱剂：石油醚：乙酸乙酯＝8：1)，得到黄色固体6-氟-2-(2-羟基丙烷-2-基)苯并呋喃-5-羧酸甲酯(400毫克，收率：67.2％)。LCMS(ESI):m/z 253[M+1]+。
步骤19b:(2-(6-氟-2-(2-羟基丙烷-2-基)苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(6-fluoro-2-(2-hydroxypropan-2-yl)benzofuran-5-yl)-2-oxoethyl)phosphonate)(化合物0207-60)的制备:在氮气保护下，在圆底烧瓶中，加入甲基膦酸二甲酯(912毫克，7.35毫摩尔，5.0当量)和30毫升无水四氢呋喃，于干冰-乙醇浴中冷却至-72℃，滴加2.5M正丁基锂正己烷溶液(3.53毫升，8.82毫摩尔，6.0当量)，搅拌一个小时，于-72℃滴加6-氟-2-(2-羟基丙烷-2-基)苯并呋喃-5-羧酸甲酯(0206-60)(370毫克，1.47毫摩尔，1.0当量)的四氢呋喃溶液，搅拌反应2小时。加入氯化铵水溶液和乙酸乙酯，分液，无水硫酸钠干燥有机相，减压浓缩，得到微黄色油状液体(2-(6-氟-2-(2-羟基丙烷-2-基)苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(400毫克，粗产品)。LCMS(ESI):m/z 345[M+1]+。
步骤19c:1-(6-氟-2-(2-羟基丙烷-2-基)苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(6-fluoro-2-(2-hydroxypropan-2-yl)benzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)(化合物0208-60)的制备:将(2-(6-氟-2-(2-羟基丙烷-2-基)苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(0207-60)(400毫克，1.47毫摩尔，3.3当量)、2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(180毫克，0.44毫摩尔，1.0当量)和碳酸铯(958毫克，2.94毫摩尔，2.0当量)加入到40毫升异丙醇中，在室温下搅拌反应过夜，减压浓缩，加入乙酸乙酯和水，分液，无水硫酸钠干燥，减压浓缩，得到黄色固体1-(6-氟-2-(2-羟基丙烷-2-基)苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(540毫克，粗品)。LCMS(ESI):m/z 633[M+1]+。
步骤19d:1-(6-氟-2-(2-羟基丙烷-2-基)苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(6-fluoro-2-(2-hydroxypropan-2-yl)benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0209-60)的制备:将1-(6-氟-2-(2-羟基丙烷-2-基)苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0208-60)(370毫克，0.59毫摩尔，1.0当量)溶解到30毫升甲醇中，加入乙酸6毫升，加热回流过夜。冷却到室温，减压浓缩，加入水，用2M氢氧化钠水溶液调节pH至12，加入二氯甲烷萃取，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝15：1)，得到微黄色固体1-(6-氟-2-(2-羟基丙烷-2-基)苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(150毫克，收率：65.2％)。LCMS(ESI):m/z 391[M+1]+。
步骤19e:2-(6-氟-5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)苯并呋喃-2-基)丙烷-2- 醇(2-(6-fluoro-5-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)benzofuran-2-yl)propan-2-ol)(化合物60的制备)：将1-(6-氟-2-(2-羟基丙烷-2-基)苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0209-60)(150毫克，0.38毫摩尔，1.0当量)溶解到30毫升甲醇中，冰浴中，冷却至0℃，加入硼氢化钠(29毫克，0.76毫摩尔，2.0当量)，搅拌反应半小时，加入丙酮，减压浓缩，加入二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝30:1～15:1)，得到微黄色固体2-(6-氟-5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)苯并呋喃-2-基)丙烷-2-醇(40毫克，收率：26.8％)。LCMS(ESI):m/z 393[M+1]+。熔点：122～124℃；1H NMR(400MHz,DMSO)δ8.23-8.09(m,1H),7.79-7.62(m,3H),7.48-7.24(m,4H),6.70-6.78(m,1H),5.89(m,1H),5.57(m,1H),5.47-5.40(m,1H),5.34-5.18(m,1H),2.40-1.97(m,2H),1.50(s,6H).
实施例20：2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(2-甲基苯并呋喃-5-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(2-methylbenzofuran-5-yl)ethan-1-ol)(化合物68的制备)(按照方案三线路制备)
步骤20a:5-溴-2-甲基苯并呋喃(5-bromo-2-methylbenzofuran)(化合物0301-68)的制备:将2-溴丙酸乙酯(2.7克，15毫摩尔，1.5当量)，加入到5-溴水杨醛(2克，10毫摩尔，1.0当量)和碳酸钾(2.8克，20毫摩尔，2.0当量)的70毫升乙腈溶液中，室温下搅拌过夜。将反应液减压浓缩除去乙腈后，加入70毫升甲醇，70℃下搅拌反应4小时。冷却至室温，加入水100毫升，滴加浓盐酸至水相呈pH为1，加入二氯甲烷萃取，无水硫酸钠干燥有机相，减压浓缩，得到白色固体。将白色固体溶于50毫升醋酸酐中，加入醋酸钠(2.5克，30毫摩尔，3.0当量)，140℃下搅拌过夜，将反应液冷却至室温，用乙酸乙酯萃取，无水硫酸钠干燥有机相，减压浓缩，得到无色油状物产物5-溴-2-甲基苯并呋喃(1.5克，收率71.1％)。
步骤20b:2-甲基苯并呋喃-5-羧酸(2-methylbenzofuran-5-carboxylic acid)(化合物0302-68)的制备:在氮气保护下，在圆底烧瓶中，加入5-溴-2-甲基苯并呋喃(0301-68)(1.4克，6.6毫摩尔，1.0当量)和50毫升无水四氢呋喃，于干冰-乙醇浴中冷却至-72℃，滴加2.5M正丁基锂正己烷溶液(4.8毫升，11.9毫摩尔，1.8当量)，搅拌一个小时，通入二氧化碳，搅拌反应1小时。滴加2M盐酸水溶液至水相呈pH为1，加入乙酸乙酯萃取，无水硫酸钠干燥有机相，减压浓缩，得到黄色固体产物2-甲基苯并呋喃-5-羧酸(1.6克，粗品)。
步骤20c:2-甲基苯并呋喃-5-羧酸甲酯(methyl 2-methylbenzofuran-5-carboxylate)(化合物0303-68)的制备:将2-甲基苯并呋喃-5-羧酸(0302-68)(1.5克，6.6毫摩尔，1.0当量)溶解于40毫升甲醇中，缓慢滴加二氯亚砜(1.8毫升，25.5毫摩尔，3.0当量)和两滴DMF，加热回流反应三小时。冷却至室温，减压浓缩，加入乙酸乙酯萃取，用水和饱和食盐水洗有 机相，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝6：1)，得到产物黄色固体(1.08克，收率：86.1％)。
步骤20d:(2-(2-甲基苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(2-methylbenzofuran-5-yl)-2-oxoethyl)phosphonate)(化合物0304-68)的制备:在氮气保护下，在圆底烧瓶中，加入甲基膦酸二甲酯(645毫克，5.2毫摩尔，2.0当量)和30毫升无水四氢呋喃，于干冰-乙醇浴中冷却至-72℃，滴加2.5M正丁基锂正己烷溶液(2.6毫升，6.5毫摩尔，2.5当量)，搅拌一个小时，于-72℃滴加2-甲基苯并呋喃-5-羧酸甲酯(500毫克，2.6毫摩尔，1.0当量)的四氢呋喃溶液，搅拌反应2小时。加水和乙酸乙酯，分液，无水硫酸钠干燥有机相，减压浓缩，经过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝1：1)，得到微黄色液体产物(2-(2-甲基苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(635毫克，收率：86.6％)。LCMS(ESI):m/z 283[M+1]+。
步骤20e:1-(2-甲基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(2-methylbenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)(化合物0305-68)的制备:将(2-(2-甲基苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(0304-68)(226毫克，0.80毫摩尔，1.1当量)、2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(300毫克，0.73毫摩尔，1.0当量)和碳酸铯(473毫克，1.45毫摩尔，2.0当量)加入到40毫升异丙醇中，在室温下搅拌反应8小时，减压浓缩，加入乙酸乙酯和水，分液，无水硫酸钠干燥，减压浓缩，得到黄色固体产物1-(2-甲基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(500毫克，粗品)。LCMS(ESI):m/z 571[M+1]+。
步骤20f:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(2-甲基苯并呋喃-5-基)乙烷-1-酮(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(2-methylbenzofuran-5-yl)ethan-1-one)(0306-68)的制备:将1-(2-甲基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0305-68)(500毫克，0.73毫摩尔，1.0当量)溶解到30毫升甲醇中，加入乙酸5毫升，加热回流过夜。冷却到室温，减压浓缩，加入水，用2M氢氧化钠水溶液调节pH至12，加入二氯甲烷萃取，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝15：1)，得到黄色固体2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(2-甲基苯并呋喃-5-基)乙烷-1-酮(200毫克，收率：84.0％)。LCMS(ESI):m/z 329[M+1]+。
步骤20g:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(2-甲基苯并呋喃-5-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(2-methylbenzofuran-5-yl)ethan-1-ol)(化合物68)的制备:将2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(2-甲基苯并呋喃-5-基)乙烷-1-酮(0306-68)(200毫克，0.61毫摩尔，1.0当量)溶解到30毫升甲醇中，冰浴中，冷却至0℃，加入硼氢化钠(47 毫克，1.22毫摩尔，2.0当量)，搅拌反应半小时，加入丙酮，减压浓缩，加入二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝30:1～15:1)，得到黄色固体产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(2-甲基苯并呋喃-5-基)乙烷-1-醇(150毫克，收率：74.6％)。LCMS(ESI):m/z 331[M+1]+。熔点：92～94℃；1H NMR(400MHz,DMSO)δ8.08-7.97(m,1H),7.65-7.49(m,3H),7.42-7.17(m,5H),6.54(s,1H),5.83-5.75(m,1H),5.54-5.42(m,1H),5.07(m,1H),2.42(s,3H),2.38-2.18(m,2H).
实施例21：1-(2-苯基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(2-phenylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物79)的制备(按照方案二线路制备)
步骤21a:2-苯基苯并呋喃-5-羧酸甲酯(methyl 2-phenylbenzofuran-5-carboxylate)(化合物0206-79)的制备：在氮气的氛围下，将化合物4-羟基-3-碘苯甲酸甲酯(0204-1)(2.78克，9.998毫摩尔，1.0当量)，碘化亚铜(28毫克，0.15毫摩尔，0.015当量)，双三苯基磷二氯化钯(210毫克，0.3毫摩尔，0.03当量)和苯乙炔(1.42克，13.997毫摩尔，1.4当量)溶解于20毫升四氢呋喃和40毫升氯仿的混合液中。置换氮气三次，再缓慢滴入三乙胺(3.15克，31.14毫摩尔，3.0当量)。混合物加热到50℃反应16小时。反应结束后，降至室温，加入100毫升氯仿，用稀盐酸水溶液洗两遍，无水硫酸钠干燥，减压浓缩，所得残留物用硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝100/1)纯化得到目标产物2-苯基苯并呋喃-5-羧酸甲酯(450毫克，收率：49.61％)为白色固体。LCMS(ESI):m/z 253[M+1]+。
步骤21b:(2-(2-苯基苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-oxo-2-(2-phenylbenzofuran-5-yl)ethyl)phosphonate)(化合物0207-79)的制备:在氮气的氛围下，将甲基磷酸二甲酯(211毫克，1.703毫摩尔，1.5当量)溶解于10毫升的干燥的四氢呋喃中。干冰/乙醇冷却到-60℃，缓慢滴加入正丁基锂(0.7毫升，2.5摩尔/升的正己烷溶液，1.703毫摩尔，1.5当量)，混合物在此温度下搅拌反应30分钟，再缓慢滴加化合物2-苯基苯并呋喃-5-羧酸甲酯(0206-79)(286毫克，1.135毫摩尔，1.0当量)的四氢呋喃(10毫升)溶液。混合物在-60℃下搅拌反应0.5小时。升至室温反应4小时，反应结束后，加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物(2-(2-苯基苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(254毫克，收率：65.1％)为无色油状液体。LCMS(ESI):m/z 345[M+1]+。
步骤21c:1-(2-苯基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(2-phenylbenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)(化合物0208-79)的制备:将(2-(2-苯基苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(0207-79)(254毫克， 0.738毫摩尔，1.0当量)，2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(305毫克，0.738毫摩尔，1.0当量)和碳酸铯(480毫克，1.476毫摩尔，2.0当量)的异丙醇溶液(10毫升)在室温下搅拌反应过夜。反应结束后，用水淬灭，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到黄色油状物。所得黄色油状物通过硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝1/2)纯化，得到目标产物1-(2-苯基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(306毫克，收率：65.7％)为黄色油状物。LCMS(ESI):m/z 633[M+1]+。
步骤21d:1-(2-苯基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(2-phenylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0209-79)的制备:将化合物1-(2-苯基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0208-79)(306毫克，0.484毫摩尔，1.0当量)和醋酸(5毫升)混合于甲醇(200毫升)中。混合物在90℃下搅拌反应过夜。反应结束后，降至室温。用饱和碳酸钠水溶液调节pH值至10，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1)纯化，得到目标产物1-(2-苯基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(157毫克，收率：83.4％)为黄色固体。LCMS(ESI):m/z 391[M+1]+。
步骤21e:1-(2-苯基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(2-phenylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物79)的制备:将化合物1-(2-苯基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0209-79)(157毫克，0.402毫摩尔，1.0当量)溶解于50毫升甲醇中。再缓慢加入硼氢化钠(30毫克，0.804毫摩尔，2.0当量)。混合物在室温下搅拌反应2小时。反应结束后，加入饱和氯化铵水溶液淬灭，搅拌10分钟，减压除去乙醇，加入饱和碳酸钠水溶液(50毫升)，用二氯甲烷(100毫升)萃取，有机相用饱和食盐水洗一遍，无水硫酸钠干燥，浓缩，所得物硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1至100/8)纯化，得到目标产物1-(2-苯基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(126毫克，收率：80.9％)为淡黄色固体。LCMS(ESI):m/z 393[M+1]+。熔点：92-94℃；1H NMR(300MHz,DMSO)δ8.20-8.11(m,1H),7.99-7.96(m,2H),7.76-7.24(m,12H),5.94-5.86(m,1H),5.63-5.54(m,1H),5.17(m,1H),2.44-1.90(m,2H).
实施例22：1-(6-氟-2-苯基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(6-fluoro-2-phenylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物80)的制备(按照方案二线路制备)
步骤22a:6-氟-2-苯基苯并呋喃-5-羧酸甲酯(methyl  6-fluoro-2-phenylbenzofuran-5-carboxylate)(化合物0206-80)的制备:在氮气保护下，将2-氟-4-羟基-5-碘苯甲酸甲酯(0204-8)(800毫克，2.7毫摩尔，1.0当量)，苯乙炔(408毫克，4.056毫摩尔，1.5当量)，碘化亚铜(7.6毫克，0.04毫摩尔，0.015当量)，四丁基碘化铵(1.49克，4.056毫摩尔，1.5当量)和四三苯基膦钯(56毫克，0.09毫摩尔，0.03当量)加入到10毫升四氢呋喃和20毫升氯仿混合溶液中，然后滴加三乙胺(816毫克，8.11毫摩尔，3当量)，混合物加热至55℃，搅拌反应过夜。冷却至室温，减压浓缩，所得浓缩液经过硅胶柱层析分离纯化(洗脱剂：石油醚：乙酸乙酯＝50：1)，得到黄色固体6-氟-2-苯基苯并呋喃-5-羧酸甲酯(358毫克，收率：49.10％)。LCMS(ESI):m/z 271[M+1]+。
步骤22b:(2-(6-氟-2-苯基苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(6-fluoro-2-phenylbenzofuran-5-yl)-2-oxoethyl)phosphonate)化合物(0207-80)的制备:在氮气的氛围下，将甲基膦酸二甲酯(105毫克，0.83毫摩尔，1.5当量)溶解于5毫升的干燥的四氢呋喃中。干冰/乙醇冷却到-60℃，缓慢滴加入正丁基锂(0.45毫升，2.5摩尔/毫升的正己烷溶液，1.2毫摩尔，2当量)。混合物在-60℃下搅拌反应30分钟，再缓慢滴加化合物6-氟-2-苯基苯并呋喃-5-羧酸甲酯(0206-80)(150毫克，0.56毫摩尔，1当量)的四氢呋喃(1毫升)溶液。混合物在-60℃下搅拌反应1小时。反应结束后，加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物(2-(6-氟-2-苯基苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(300毫克，粗品)为黄色油状物。LCMS(ESI):m/z 363[M+1]+。
步骤22c:1-(6-氟-2-苯基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烷-2-烯-1-酮(1-(6-fluoro-2-phenylbenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en-1-one)(化合物0208-80)的制备:将2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(287毫克，0.693毫摩尔，1当量),化合物(2-(6-氟-2-苯基苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(0207-80)(300毫克，0.83毫摩尔，1.2当量)和碳酸铯(450毫克，1.386毫摩尔，2当量)混合于异丙醇(10毫升)中，混合物在室温下搅拌反应16小时。反应结束后，用水淬灭，过滤，得到目标产物1-(6-氟-2-苯基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烷-2-烯-1-酮(250毫克，粗品)为黄色固体。LCMS(ESI):m/z 651[M+1]+。
步骤22d:1-(6-氟-2-苯基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(6-fluoro-2-phenylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0209-80)的制备:将化合物1-(6-氟-2-苯基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烷-2-烯-1-酮(0208-80)(250毫克，0.38毫摩尔，1当量)和醋酸(2毫升)混合于甲醇(4毫升)中。混合物在90℃下搅拌反应16小时。反应结束后，用2N氢氧化钠水溶液调节pH 至12，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物1-(6-氟-2-苯基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(200毫克，粗品)为黄色固体。LCMS(ESI):m/z 409[M+1]+。
步骤22e:1-(6-氟-2-苯基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(6-fluoro-2-phenylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物80)的制备:将1-(6-氟-2-苯基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0209-80)(200毫克，0.49毫摩尔，1.0当量)溶解到30毫升甲醇中，冰浴中，冷却至0℃，加入硼氢化钠(37毫克，0.9毫摩尔，2当量)，搅拌反应半小时，加入丙酮，减压浓缩，加入二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝30:1～15:1)，得到白色固体1-(6-氟-2-苯基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(51毫克，收率：25.37％)。LCMS(ESI):m/z 411[M+1]+。熔点：116～118℃；1H NMR(400MHz,DMSO)δ8.08-7.82(m,4H),7.65-7.62(m,2H),7.54-7.33(m,7H),7.21-7.13(m,1H),5.98-5.89(m,1H),5.58-5.49(m,1H),5.31(m,1H),2.45-1.98(m,2H).
实施例23:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(3-甲基苯并呋喃-5-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(3-methylbenzofuran-5-yl)ethan-1-ol)(化合物95)的制备(按照方案十线路制备)
步骤23a:4-乙酰基苯甲酸甲酯(methyl 4-acetoxybenzoate)(化合物1002-95)的制备：冰浴下，将乙酰氯(10.4克，132毫摩尔，2.0当量)滴加到对羟基苯甲酸甲酯(1001-95)(10克，66毫摩尔，1.0当量)和三乙胺(20克，198毫摩尔，3.0当量)的200毫升二氯甲烷溶液中，室温下搅拌过夜。加入二氯甲烷萃取，无水硫酸钠干燥有机相，减压浓缩，得到黄色固体4-乙酰基苯甲酸甲酯(14克，粗品)。LCMS(ESI):m/z 195[M+1]+。
步骤23b:3-乙酰基-4-羟基苯甲酸(3-acetyl-4-hydroxybenzoic acid)(化合物1003-95)的制备:将4-乙酰基苯甲酸甲酯(1002-95)(14克，66毫摩尔，1.0当量)碾成粉末后加入三氯化铝(26.3克，198毫摩尔，3.0当量)，于140℃下搅拌5小时，反应完后成深褐色凝结固体，冷却至室温。用勺子碾碎，加到300毫升水溶液当中，加热回流3小时，反应液成澄清状，冷却至室温，滴加浓盐酸至pH为1，大量白色固体析出，过滤，干燥得到白色固体3-乙酰基-4-羟基苯甲酸(11.5克，两步总收率96.8％)。LCMS(ESI):m/z 181[M+1]+。
步骤23c:3-乙酰基-4-羟基苯甲酸甲酯(methyl 3-acetyl-4-hydroxybenzoate)(化合物1004-95)的制备:将3-乙酰基-4-羟基苯甲酸(1003-95)(4克，22.2毫摩尔，1.0当量)溶解于50毫升甲醇中，加入0.3毫升浓硫酸，回流搅拌反应过夜。减压浓缩出去甲醇，加入乙酸 乙酯和水溶解，用碳酸氢钠调节pH至中性，萃取，无水硫酸钠干燥有机相，减压浓缩，得到黄色固体3-乙酰基-4-羟基苯甲酸甲酯(4.5克，粗品)。LCMS(ESI):m/z 195[M+1]+。
步骤23d:3-甲基苯并呋喃-5-羧酸(3-methylbenzofuran-5-carboxylic acid)(化合物1005-95)的制备:将2-溴乙酸甲酯(2.36克，15.4毫摩尔，1.5当量)，加入到3-乙酰基-4-羟基苯甲酸(1004-95)(2.0克，10.3毫摩尔，1.0当量)和碳酸钾(2.84克，20.6毫摩尔，2.0当量)的70毫升乙腈溶液中，室温下搅拌过夜。将反应液减压浓缩除去乙腈后，加入30毫升四氢呋喃和2N氢氧化钠溶液15毫升，70℃下搅拌反应4小时。冷却至室温，加入水100毫升，滴加浓盐酸至水相呈pH为1，加入二氯甲烷萃取，无水硫酸钠干燥有机相，减压浓缩，得到白色固体。将此白色固体溶于50毫升醋酸酐中，加入醋酸钠(2.6克，30.9毫摩尔，3.0当量)，140℃下搅拌过夜，将反应液冷却至室温，用乙酸乙酯萃取，无水硫酸钠干燥有机相，减压浓缩，得到黄色油状物3-甲基苯并呋喃-5-羧酸(2.5克，粗品)。LCMS(ESI):m/z 177[M+1]+。
步骤23e:3-甲基苯并呋喃-5-羧酸甲酯(methyl 3-methylbenzofuran-5-carboxylate)(化合物1006-95)的制备:将3-甲基苯并呋喃-5-羧酸(1005-95)(2.5克，粗品)溶解于50毫升甲醇中，加入0.5毫升浓硫酸，回流搅拌反应过夜。减压浓缩出去甲醇，加入乙酸乙酯和水溶解，用碳酸氢钠调节pH至中性，萃取，无水硫酸钠干燥有机相，减压浓缩，得到黄色固体3-甲基苯并呋喃-5-羧酸甲酯(1.7克，两步总收率86.9％)。LCMS(ESI):m/z 191[M+1]+。
步骤23f:(2-(3-甲基苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(3-methylbenzofuran-5-yl)-2-oxoethyl)phosphonate)(化合物1007-95)的制备:在氮气保护下，在圆底烧瓶中，加入甲基膦酸二甲酯(372毫克，3.0毫摩尔，1.5当量)和30毫升无水四氢呋喃，于干冰-乙醇浴中冷却至-72℃，滴加2.5M正丁基锂正己烷溶液(2.0毫升，5毫摩尔，2.5当量)，搅拌一个小时，于-72℃滴加3-甲基苯并呋喃-5-羧酸甲酯(1006-95)(380毫克，2.0毫摩尔，1.0当量)的四氢呋喃溶液，搅拌反应2小时。加水和乙酸乙酯，分液，无水硫酸钠干燥有机相，减压浓缩，得到黄色液体(2-(3-甲基苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(400毫克，粗品)。LCMS(ESI):m/z 283[M+1]+。
步骤23g:1-(3-甲基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(3-methylbenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)(化合物1008-95)的制备:将(2-(3-甲基苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(1007-95)(400毫克，粗品)、2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(300毫克，0.73毫摩尔，1.0当量)和碳酸铯(473毫克，1.45毫摩尔，2.0当量)加入到40毫升异丙醇中，在室温下搅拌反应8小时，加入1g苯甲醛反应掉剩余的磷试剂，减压浓缩，加入乙酸乙酯和水，分液，无水硫酸 钠干燥，减压浓缩，得到黄色液体1-(3-甲基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(2.0克，粗品)。LCMS(ESI):m/z 571[M+1]+。
步骤23h:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(3-甲基苯并呋喃-5-基)乙烷-1-酮(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(3-methylbenzofuran-5-yl)ethan-1-one)(化合物1009-95)的制备:将1-(3-甲基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1008-95)(2.0克，粗品)溶解到30毫升甲醇中，加入乙酸15毫升，加热回流过夜。冷却到室温，减压浓缩，加入水，用2M氢氧化钠水溶液调节pH至12，加入二氯甲烷萃取，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝15：1)，得到黄色固体2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(3-甲基苯并呋喃-5-基)乙烷-1-酮(120毫克，两步收率：50.0％)。LCMS(ESI):m/z 329[M+1]+。
步骤23i:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(3-甲基苯并呋喃-5-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(3-methylbenzofuran-5-yl)ethan-1-ol)(化合物95)的制备:将2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(3-甲基苯并呋喃-5-基)乙烷-1-酮(1009-95)(120毫克，0.37毫摩尔，1.0当量)溶解到30毫升甲醇中，冰浴中，冷却至0℃，加入硼氢化钠(55.6毫克，1.46毫摩尔，4.0当量)，搅拌反应2小时，减压浓缩，加入二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝30:1～15:1)，得到黄色固体2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(3-甲基苯并呋喃-5-基)乙烷-1-醇(50毫克，收率：41％)。LCMS(ESI):m/z 331[M+1]+。熔点：67～70℃；1H NMR(400MHz,DMSO)δ8.09-7.98(m,1H),7.73(m,1H),7.65-7.61(m,3H),7.51-7.22(m,4H),7.15(s,1H),5.85-5.76(m,1H),5.56-5.42(m,1H),5.32-5.09(m,1H),2.36(m,1H),2.25-2.17(m,4H).
实施例24：1-(二苯[b,d]呋喃-2-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(dibenzo[b,d]furan-2-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物96)的制备(按照方案六线路制备)
步骤24a:二苯[b,d]呋喃-2-羧酸(dibenzo[b,d]furan-2-carboxylic acid)(化合物0602-96)的制备:将2-溴-二苯[b,d]呋喃(0601-96)(1.0克，4.0毫摩尔，1.0当量)溶解于50毫升的干燥的四氢呋喃中，在氮气保护下，冷却到-70℃，缓慢滴加入正丁基锂(2.5毫升，2.5摩尔/升的正己烷溶液，6.0毫摩尔，1.5当量)，混合物在此温度下搅拌反应30分钟，通入干燥的二氧化碳气体，反应15分钟，停止通入二氧化碳，继续反应1小时。反应结束后，加饱和氯化铵水溶液淬灭，用1.0摩尔/升的稀盐酸将体系pH调至6，二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，得到产物二苯[b,d]呋喃-2-羧酸(1.2克，粗品)。LCMS(ESI):m/z 213[M+1]+。
步骤24b:二苯[b,d]呋喃-2-羧酸甲酯(methyl dibenzo[b,d]furan-2-carboxylate)(化合物0603-96)的制备:将化合物二苯[b,d]呋喃-2-羧酸(0602-96)(1.2克，5.66毫摩尔，1.0当量)溶解于50毫升甲醇中，冰浴冷却，缓慢滴加氯化亚砜(0.82毫升，11.3毫摩尔，2.0当量)，加热至80℃，反应4小时。反应结束后，减压浓缩。将残留物溶解在二氯甲烷中，加入饱和碳酸氢钠溶液，调至碱性，分液。有机相用无水硫酸钠干燥，旋干，残留物用硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝1/5)纯化，得到产物二苯[b,d]呋喃-2-羧酸甲酯(650毫克，收率：55％)。LCMS(ESI):m/z 227[M+1]+。
步骤24c:(2-(二苯[b,d]呋喃-2-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(dibenzo[b,d]furan-2-yl)-2-oxoethyl)phosphonate)(化合物0604-96)的制备:在氮气保护下，将甲基磷酸二甲酯(536毫克，4.3毫摩尔，1.5当量)溶解于50毫升的干燥的四氢呋喃中，冷却到-70℃，缓慢滴加入正丁基锂(2.3毫升，2.5摩尔/升的正己烷溶液，5.74毫摩尔，2.0当量)，混合物在此温度下搅拌反应30分钟，再缓慢滴加化合物二苯[b,d]呋喃-2-羧酸甲酯(0603-96)(650毫克，2.87毫摩尔，1.0当量)的5毫升四氢呋喃溶液，搅拌反应2小时。反应结束后，加水淬灭，二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(二氯甲烷/甲醇＝50/1)纯化，得到产物(2-(二苯[b,d]呋喃-2-基)-2-氧代乙基)磷酸二甲酯(500毫克，收率：54.7％)。LCMS(ESI):m/z 319[M+1]+。
步骤24d:1-(二苯[b,d]呋喃-2-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(dibenzo[b,d]furan-2-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)(化合物0605-96)的制备:将2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(200毫克，0.483毫摩尔，1.0当量),化合物(2-(二苯[b,d]呋喃-2-基)-2-氧代乙基)磷酸二甲酯(0604-96)(170毫克，0.53毫摩尔，1.1当量)和碳酸铯(315毫克，0.966毫摩尔，2.0当量)混合于异丙醇(30毫升)中，在室温下搅拌反应过夜。反应结束后，加水，有固体析出，过滤，将滤饼干燥，得到产物1-(二苯[b,d]呋喃-2-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(300毫克，粗品)。LCMS(ESI):m/z 607[M+1]+。
步骤24e:1-(二苯[b,d]呋喃-2-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(dibenzo[b,d]furan-2-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0606-96)的制备：将化合物1-(二苯[b,d]呋喃-2-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0605-96)(300毫克，0.49毫摩尔，1.0当量)和醋酸(10毫升)混合于甲醇(40毫升)中，混合物在90℃下搅拌反应过夜。反应结束后，减压浓缩。残留物溶解于二氯甲烷中，用饱和碳酸氢钠溶液中和剩余的酸，二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1-50/1)纯化，得到产物1-(二苯[b,d]呋喃-2- 基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(150毫克，收率：83％)。LCMS(ESI):m/z 365[M+1]+。
步骤24f:1-(二苯[b,d]呋喃-2-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(dibenzo[b,d]furan-2-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物96)的制备:将化合物1-(二苯[b,d]呋喃-2-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0606-96)(150毫克，0.41毫摩尔，1.0当量)溶解于10毫升甲醇中，再缓慢加入硼氢化钠(62毫克，1.64毫摩尔，4.0当量)，冷却至0℃。混合物在室温下搅拌反应1小时。反应结束后，加入2毫升丙酮淬灭，减压浓缩，所得物硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1-30/1)纯化，得到产物1-(二苯[b,d]呋喃-2-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(100毫克，收率：66％)，黄色固体。LCMS(ESI):m/z 367[M+1]+。熔点：113～115℃；1H NMR(300MHz,DMSO)δ8.18～8.08(m,3H),7.70-7.19(m,10H),6.00-5.91(m,1H),5.62-5.50(m,1H),5.19(m,1H),2.65-1.94(m,2H).
实施例25：1-(呋喃[3,2-b]吡啶-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(furo[3,2-b]pyridin-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物98)的制备(按照方案一和五线路制备)
步骤25a:(Z)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烯酸乙酯(ethyl(Z)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)acrylate)(化合物0106-98)的制备:将2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(480毫克，1.2毫摩尔，1.0当量)，膦酰基乙酸三乙酯(528毫克，2.4毫摩尔，2.0当量)和碳酸铯(786毫克，2.4毫摩尔，2.0当量)混合于异丙醇(30毫升)中，在室温下搅拌反应过夜。反应结束后，用水淬灭，二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，得到产物(Z)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烯酸乙酯(600毫克，粗品)。LCMS(ESI):m/z 485[M+1]+。
步骤25b:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙酸乙酯(ethyl2-(5H-imidazo[5,1-a]isoindol-5-yl)acetate)(化合物0107-98)的制备:将化合物(Z)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烯酸乙酯(0106-98)(600毫克，1.24毫摩尔，1.0当量)和醋酸(10毫升)混合于甲醇(40毫升)中，混合物在90℃下搅拌反应过夜。反应结束后，减压浓缩。残留物溶解于二氯甲烷中，用饱和碳酸氢钠溶液中和剩余的酸，二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝50/1)纯化，得到产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙酸乙酯(250毫克，收率：83％)。LCMS(ESI):m/z 243[M+1]+。
步骤25c:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙酸(2-(5H-imidazo[5,1-a]isoindol-5-yl)acetic acid)(化合物0108-98)的制备:将2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙酸乙酯(0107-98)(250 毫克，1.03毫摩尔，1.0当量)溶解于10毫升的四氢呋喃中，加入3毫升1M的NaOH溶液，室温搅拌反应过夜。加入50毫升的四氢呋喃稀释，无水硫酸钠干燥，过滤，将滤液减压浓缩，得到产品2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙酸(400毫克，粗品)。LCMS(ESI):m/z 215[M+1]+。
步骤25d:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-N-甲氧基-N-甲基乙酰胺(2-(5H-imidazo[5,1-a]isoindol-5-yl)-N-methoxy-N-methylacetamide)(化合物0109-98)的制备:将化合物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙酸(0108-98)(400毫克，1.8毫摩尔，1.0当量)溶解于30毫升四氢呋喃中，分别加入2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.42克，3.6毫摩尔，2.0当量)，N,O-二甲基羟胺盐酸盐(351毫克，3.6毫摩尔，2.0当量)和三乙胺(1毫升，7.2毫摩尔，4.0当量)，室温搅拌反应2小时。反应结束后，二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，所得物硅胶柱层析(洗脱剂：二氯甲烷/甲醇50/1-20/1)纯化，得到产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-N-甲氧基-N-甲基乙酰胺(300毫克，收率：62％)，黄色粘稠液体。LCMS(ESI):m/z 258[M+1]+。
步骤25e:6-溴-3-羟基-2-碘吡啶(6-bromo-2-iodopyridin-3-ol)(化合物0502-98)的制备:将碳酸钾(3.18克，22.98毫摩尔，2.0当量)和2-溴-5羟基吡啶(0501-98)(2.0克，11.49毫摩尔，1.0当量)溶解于50毫升的四氢呋喃中，加入碘单质(6.41克，25.28毫摩尔，2.2当量)，室温搅拌过夜。反应结束后，加入亚硫酸氢钠水溶液25毫升。最后用乙酸乙酯萃取，有机相用饱和食盐水洗，减压浓缩，得到米白色固体产物6-溴-3-羟基-2-碘吡啶(3.24克，收率：94％)。LCMS(ESI):m/z 300[M+1]+。
步骤25f:3-羟基-6-溴-2-(三甲基硅乙炔基)吡啶(6-bromo-2-((trimethylsilyl)ethynyl)pyridin-3-ol)(化合物0503-98)的制备:在氮气保护下，将6-溴-3-羟基-2-碘吡啶(0502-98)(2.0克，6.67毫摩尔，1.0当量)，三甲基硅乙炔(655毫克，6.67毫摩尔，1.0当量)，碘化亚铜(19毫克，0.1毫摩尔，0.015当量)和双三苯基磷二氯化钯(140毫克，0.2毫摩尔，0.03当量)加入到30毫升四氢呋喃和15毫升氯仿的溶合液中，然后滴加三乙胺(2.02克，20毫摩尔，3.0当量)，混合物加热至50℃，搅拌反应3小时。冷却至室温，过滤，减压浓缩得到残留物，经过硅胶柱层析分离纯化(洗脱剂：石油醚：乙酸乙酯＝25：1)得到3-羟基-6-溴-2-(三甲基硅乙炔基)吡啶(1.21克，收率：67.2％)。LCMS(ESI):m/z 270[M+1]+。
步骤25g:5-溴呋喃[3,2-b]吡啶(5-bromofuro[3,2-b]pyridine)(化合物0505-98)的制备:用50毫升无水甲醇溶解化合物3-羟基-6-溴-2-(三甲基硅乙炔基)吡啶(0503-98)(1.21克，4.48毫摩尔，1.0当量)，加入N，N-二异丙基乙胺(636毫克，4.92毫摩尔，1.1当量)和碘化亚铜(43毫克，0.22毫摩尔，0.05当量)，于60℃下反应4小时后，再加入少量碳酸钾，于60℃ 下搅拌过夜。冷却至室温，抽滤，所得滤液减压浓缩，经过硅胶柱层析分离纯化(洗脱剂：石油醚：乙酸乙酯＝25：1)，得到产物浅黄色固体(400毫克，收率：45.1％)。LCMS(ESI):m/z 198/200[M+1]+。
步骤25h:1-(呋喃[3,2-b]吡啶-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(furo[3,2-b]pyridin-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)化合物(0507-98)的制备:在氮气的氛围下，将化合物5-溴呋喃[3,2-b]吡啶(0505-98)(100毫克，0.5毫摩尔，1.0当量)溶解于10毫升的干燥的四氢呋喃中。干冰/乙醇冷却到-60℃，缓慢滴加入正丁基锂(0.22毫升，2.5摩尔/升的正己烷溶液，0.55毫摩尔，1.1当量)，混合物在此温度下搅拌反应60分钟，再缓慢滴加化合物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-N-甲氧基-N-甲基乙酰胺(0109-98)(193毫克，0.75毫摩尔，1.5当量)的四氢呋喃(10毫升)溶液。混合物在-60℃下搅拌反应1小时。升至室温反应4小时，反应结束后，加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到的残留物通过薄层析板纯化(展开剂：二氯甲烷/甲醇＝10:1)得到目标产物1-(呋喃[3,2-b]吡啶-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(43毫克，收率：27.3％)为褐色油状体。LCMS(ESI):m/z 316[M+1]+。
步骤25i:1-(呋喃[3,2-b]吡啶-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(furo[3,2-b]pyridin-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物98)的制备:将化合物1-(呋喃[3,2-b]吡啶-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0507-98)(43毫克，0.136毫摩尔，1.0当量)溶解于20毫升乙醇中，再缓慢加入硼氢化钠(10毫克，0.272毫摩尔，2.0当量)。混合物在室温下搅拌反应3小时。反应结束后，加入饱和氯化铵水溶液淬灭，搅拌10分钟，减压除去乙醇，加入饱和碳酸钠水溶液(10毫升)，用二氯甲烷(50毫升)萃取，有机相用饱和食盐水洗一遍，无水硫酸钠干燥，浓缩，所得物通过薄层析(展开剂：二氯甲烷/甲醇＝10/1)纯化，得到目标产物98(8毫克，收率：18.6％)为白色固体。LCMS(ESI):m/z 318[M+1]+。1H NMR(500MHz,DMSO)δ8.36(m,1H),8.15-8.11(m,2H),7.73-7.25(m,6H),7.14-7.11(m,1H),6.13-6.05(m,1H),5.65-5.49(s,1H),5.23-5.16(m,1H),2.41(m,2H).
实施例26：1-(苯并呋喃-6-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(benzofuran-6-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物101)的制备(按照方案三线路制备)
步骤26a:(2-(苯并呋喃-6-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(benzofuran-6-yl)-2-oxoethyl)phosphonate)(化合物0304-101)的制备:在氮气保护下，在圆 底烧瓶中，加入甲基膦酸二甲酯(521毫克，4.2毫摩尔，2.0当量)和20毫升无水四氢呋喃，于干冰-乙醇浴中冷却至-72℃，滴加2.5M正丁基锂的正己烷溶液(2.5毫升，6.3毫摩尔，3.0当量)，搅拌一个小时，于-72℃滴加苯并呋喃-6-羧酸甲酯(0303-101)(370毫克，2.1毫摩尔，1.0当量)的四氢呋喃溶液，搅拌反应2小时。加入氯化铵水溶液和乙酸乙酯，分液，无水硫酸钠干燥有机相，减压浓缩，经过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝2：1)，得到微黄色油状液体产物(2-(苯并呋喃-6-基)-2-氧代乙基)磷酸二甲酯(410毫克，收率：72.8％)。LCMS(ESI):m/z 269[M+1]+。
步骤26b:1-(苯并呋喃-6-基)-2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(benzofuran-6-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)(化合物0305-101的制备:将(2-(苯并呋喃-6-基)-2-氧代乙基)磷酸二甲酯(0304-101)(161毫克，0.6毫摩尔，1.0当量)、2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(250毫克，0.6毫摩尔，1.0当量)和碳酸铯(392毫克，1.2毫摩尔，2.0当量)加入到40毫升异丙醇中，在室温下搅拌反应过夜，减压浓缩，加入乙酸乙酯和水，分液，无水硫酸钠干燥，减压浓缩，得到微黄色固体1-(苯并呋喃-6-基)-2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(370毫克，粗品)。LCMS(ESI):m/z 557[M+1]+。
步骤26c:1-(苯并呋喃-6-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(benzofuran-6-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0306-101)的制备:将1-(苯并呋喃-6-基)-2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0305-101)(370毫克，0.6毫摩尔，1.0当量)溶解到30毫升甲醇中，加入乙酸6毫升，加热回流过夜。冷却到室温，减压浓缩，加入水，用2M氢氧化钠水溶液调节pH至12，加入二氯甲烷萃取，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝15：1)，得到微黄色固体产物1-(苯并呋喃-6-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(160毫克，收率：84.6％)。LCMS(ESI):m/z 315[M+1]+。
步骤26d:1-(苯并呋喃-6-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(benzofuran-6-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物101)的制备:将1-(苯并呋喃-6-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0306-101)(160毫克，0.51毫摩尔，1.0当量)溶解到30毫升甲醇中，冰浴中，冷却至0℃，加入硼氢化钠(29毫克，0.76毫摩尔，1.5当量)，搅拌反应半小时，加入丙酮，减压浓缩，加入二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝30:1～15:1)，得到产物微黄色固体1-(苯并呋喃-6-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(70毫克，收率：43.4％)。LCMS(ESI):m/z 317[M+1]+。熔点：52～54℃；1H NMR(400 MHz,DMSO)δ8.00-7.85(m,2H),7.65-7.28(m,7H),7.18-7.10(m,1H),6.93-6.92(m,1H),5.92-5.80(m,1H),5.53-5.36(m,1H),5.11(m,1H),2.55-1.85(m,2H).
实施例27：5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)-1,3-二氢-2H-苯并[d]咪唑-2-酮(5-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one)(化合物102)的制备(按照方案七线路制备)
步骤27a:(2-(3-氟4-硝基苯基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(3-fluoro-4-nitrophenyl)-2-oxoethyl)phosphonate)(化合物0702-102)的制备:在氮气保护下，将甲基磷酸二甲酯(607毫克，4.9毫摩尔，1.3当量)溶解于20毫升的干燥的四氢呋喃中，冷却到-70℃，缓慢滴加入正丁基锂(2.26毫升，2.5摩尔/升的正己烷溶液，5.65毫摩尔，1.5当量)，混合物在此温度下搅拌反应30分钟，再缓慢滴加化合物3-氟-4-硝基苯甲酸甲酯(0701-102)(750毫克，3.77毫摩尔，1.0当量)的5毫升四氢呋喃溶液，搅拌反应3小时。反应结束后，加水淬灭，二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，得到产物(2-(3-氟4-硝基苯基)-2-氧代乙基)磷酸二甲酯(1.36克，粗品)。LCMS(ESI):m/z 292[M+1]+。
步骤27b:(Z)-1-(3-氟-4-硝基苯基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮[(Z)-1-(3-fluoro-4-nitrophenyl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one](化合物0703-102)的制备:将2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(1.4克，3.37毫摩尔，1.0当量)，化合物(2-(3-氟4-硝基苯基)-2-氧代乙基)磷酸二甲酯(0702-102)(1.36克，4.38毫摩尔，1.3当量)和碳酸铯(2.2克，6.74毫摩尔，2.0当量)混合于异丙醇(30毫升)中，在室温下搅拌反应过夜。反应结束后，用水淬灭，二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1～50/1)纯化，得到产物(Z)-1-(3-氟-4-硝基苯基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1.8克，收率：92％)。LCMS(ESI):m/z 580[M+1]+。
步骤27c:1-(3-氟-4-硝基苯基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(3-fluoro-4-nitrophenyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物704-102)的制备:将化合物(Z)-1-(3-氟-4-硝基苯基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(703-102)(1.8克，3.1毫摩尔，1.0当量)和醋酸(20毫升)混合于甲醇(80毫升)中，混合物在90℃下搅拌反应过夜。反应结束后，减压浓缩。残留物溶解于二氯甲烷中，用饱和碳酸氢钠溶液中和剩余的酸，二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(二氯甲烷/甲醇＝100/1～50/1)纯化，得到产物1-(3-氟-4-硝基苯基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1.1克，粗品)。LCMS(ESI):m/z 338[M+1]+。
步骤27d:1-(3-胺基-4-硝基苯基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮 (1-(3-amino-4-nitrophenyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0705-102)的制备:把化合物1-(3-氟-4-硝基苯基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0704-102)(1.1克，3.26毫摩尔，1.0当量)和氨水(15毫升)溶于四氢呋喃(20毫升)，在闷罐中，升温到85℃反应5小时。反应液冷却到室温，二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，即得到产物1-(3-胺基-4-硝基苯基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(800毫克，粗品)。LCMS(ESI):m/z 335[M+1]+。
步骤27e:1-(3,4-二胺基苯基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(3,4-diaminophenyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0706-102)的制备:将1-(3-胺基-4-硝基苯基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0705-102)(800毫克，2.4毫摩尔，1.0当量)和氯化铵(1.12克，20.4毫摩尔，8.5当量)混合于60毫升乙醇和15毫升水的混合液中，加热至50℃，然后加入还原铁粉(1.07克，19.2毫摩尔，8.0当量)。加热至80℃，反应2小时。反应完成后，过滤，将滤液浓缩，再用二氯甲烷萃取，有机相用无水硫酸钠干燥，减压旋干，得到产物1-(3,4-二胺基苯基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(800毫克，粗品)。LCMS(ESI):m/z 305[M+1]+。
步骤27f:5-(2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙酰基)-1,3-二氢-2H-苯并[d]咪唑-2-酮(5-(2-(5H-imidazo[5,1-a]isoindol-5-yl)acetyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one)(化合物0707-102)的制备:将1-(3,4-二胺基苯基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0706-102)(800毫克，2.6毫摩尔，1.0当量)溶解于50毫升四氢呋喃中，加入0.72毫升三乙胺(5.2毫摩尔，2.0当量)。在氮气保护下，加入N,N'-羰基二咪唑(1.26克，7.8毫摩尔，3.0当量)，加热至35℃，反应过夜。反应完成后，用二氯甲烷萃取，减压浓缩，残留物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1～50/1)纯化，得到产品5-(2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙酰基)-1,3-二氢-2H-苯并[d]咪唑-2-酮(400毫克，收率：46％)。LCMS(ESI):m/z 331[M+1]+。
步骤27g:5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)-1,3-二氢-2H-苯并[d]咪唑-2-酮(5-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one)(化合物102)的制备:将化合物5-(2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙酰基)-1,3-二氢-2H-苯并[d]咪唑-2-酮(0707-102)(400毫克，1.2毫摩尔，1.0当量)溶解于30毫升甲醇中，冷却至0℃，再缓慢加入硼氢化钠(182毫克，4.8毫摩尔，4.0当量)。混合物在室温下搅拌反应1小时。反应结束后，加入2毫升丙酮淬灭，减压浓缩，所得物硅胶柱层析(二氯甲烷/甲醇＝100/1～50/1)纯化，得到产物5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)-1,3-二氢-2H-苯并[d]咪唑-2-酮(80毫克，收率：20％)，黄色固体。LCMS(ESI):m/z 333[M+1]+。熔点：245℃； 1H NMR(400MHz,DMSO)δ10.53(d,J＝18.8Hz,2H),7.94-7.80(m,1H),7.60-7.57(m,2H),7.48-7.23(m,2H),7.09(s,1H),7.01(s,H),6.97-6.84(m,2H),5.75-5.58(m,1H),5.49-5.31(m,1H),4.96(m,1H),2.31-1.99(m,2H).
实施例28：5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)吲哚啉-2-酮(5-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)indolin-2-one)(化合物103)的制备(按照方案七线路制备)
步骤28a:1-(3-氟-4-硝基苯基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)-1-醇(1-(3-fluoro-4-nitrophenyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物0710-103)的制备:将1-(3-氟-4-硝基苯基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)-1-酮(0704-102)(310毫克，0.92毫摩尔，1.0当量)溶解到30毫升甲醇中，冰浴中，冷却至0℃，加入硼氢化钠(53毫克，1.38毫摩尔，1.5当量)，搅拌反应半小时，加入丙酮，减压浓缩，加入二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到产物1-(3-氟-4-硝基苯基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)-1-醇(350毫克，粗产品)，为棕色固体。LCMS(ESI):m/z 340[M+1]+。
步骤28b:2-(5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)-2-硝基苯基)丙二酸二乙酯(diethyl 2-(5-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-2-nitrophenyl)malonate)(化合物0711-103)的制备:将1-(3-氟-4-硝基苯基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)-1-醇(0710-103)(350毫克，0.92毫摩尔，1.0当量)溶解到5毫升二甲基甲酰胺中，于室温下，加入碳酸钾(358毫克，2.6毫摩尔，2.8当量)和丙二酸二乙酯(207毫克，1.29毫摩尔，1.4当量)，搅拌反应过夜，加入乙酸乙酯稀释，用饱和食盐水洗三次，无水硫酸钠干燥，减压浓缩，得到红棕色液体产物2-(5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)-2-硝基苯基)丙二酸二乙酯(410毫克，粗产品)。LCMS(ESI):m/z 480[M+1]+。
步骤28c:5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)-2-硝基苯甲酸(5-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-2-nitrobenzoic acid)(化合物0712-103)的制备:将2-(5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)-2-硝基苯基)丙二酸二乙酯(0711-103)(410毫克，0.92毫摩尔，1.0当量)溶解到5毫升四氢呋喃中，加入30毫升6M盐酸水溶液，于95℃下加热反应过夜，冷却至室温，减压浓缩至干，所得残留物为产物5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)-2-硝基苯甲酸的粗品，直接用于下一步反应。LCMS(ESI):m/z 366[M+1]+。
步骤28d:5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)吲哚啉-2-酮(5-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)indolin-2-one)(化合物103)的制备:将 5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)-2-硝基苯甲酸(0712-103)(0.92毫摩尔，1.0当量)溶解到10毫升水和10毫升乙酸的混合液中，加入还原性铁粉(258毫克，4.6毫摩尔，5.0当量)，于85℃下，搅拌反应2小时，冷却至室温，加入2M氢氧化钠水溶液调节pH至10，用二氯甲烷萃取，用水和饱和食盐水洗有机相，干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝12：1～8：1)，得到棕黄色固体5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)吲哚啉-2-酮(30毫克，收率：9.8％)。LCMS(ESI):m/z 332[M+1]+。熔点：72～74℃；1H NMR(400MHz,DMSO)δ10.33(m,1H),7.98-7.87(m,1H),7.63-7.10(m,8H),6.75(m,1H),5.70-5.59(m,1H),5.48-5.32(m,1H),4.91(m,1H),3.45(m,2H),2.49-1.72(m,2H).
实施例29：2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(1-甲基-1H-吲哚-5-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(1-methyl-1H-indol-5-yl)ethan-1-ol)(化合物104)的制备(按照方案三线路制备)
步骤29a:1-甲基-1H-吲哚-5-甲酸甲酯(methyl 1-methyl-1H-indole-5-carboxylate)(化合物0303-104)的制备。在氮气的氛围和冰浴的条件下，将化合物5-羧酸吲哚(0302-104)(1克，6.2毫摩尔，1当量)溶解于10毫升的DMF中，再缓慢加入氢化钠(744毫克，18.6毫摩尔，3当量)。混合物搅拌15分钟后，将碘甲烷(2.2克，15.5毫摩尔，2.5当量)滴加入其中。混合物在冰浴条件下搅拌反应1小时。反应结束后，加入水淬灭，过滤，得到目标化合物1-甲基-1H-吲哚-5-甲酸甲酯(780毫克，收率：66.43％)为黄色固体。LCMS(ESI):m/z 190[M+1]+。
步骤29b:(2-(1-甲基-1H-吲哚-5-基)-2-氧代乙基)磷酸二甲酯dimethyl(2-(1-methyl-1H-indol-5-yl)-2-oxoethyl)phosphonate(0304-104)的制备:在氮气的氛围下，将甲基磷酸二甲酯(600毫克，4.8毫摩尔，1.5当量)溶解于5毫升的干燥的四氢呋喃中。干冰/乙醇冷却到-60℃，缓慢滴加入正丁基锂(2.5毫升，2.5摩尔/毫升的正己烷溶液，6.4毫摩尔，2当量)，混合物在此温度下搅拌反应30分钟，再缓慢滴加化合物1-甲基-1H-吲哚-5-甲酸甲酯(0303-104)(609毫克，3.2毫摩尔，1当量)的四氢呋喃(1毫升)溶液。混合物在-60℃下搅拌反应1小时。反应结束后，加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝25/1)纯化，得到目标产物(2-(1-甲基-1H-吲哚-5-基)-2-氧代乙基)磷酸二甲酯(387毫克，收率：42.76％)为黄色油状物。LCMS(ESI):m/z 281[M+1]+。
步骤29c:(E)-1-(1-甲基-1H-吲哚-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮[(E)-1-(1-methyl-1H-indol-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one](化合物0305-104)的制备:在氮气的氛围和冰浴的条件下，将化合物(2-(1-甲基-1H-吲哚-5-基)-2-氧代乙基)磷酸二甲酯(0304-104)(309毫克，1.1毫摩尔，1.2当量)溶解于10毫升的四氢呋喃 中。再缓慢加入氢化钠(44毫克，1.1毫摩尔，1.2当量)。混合物搅拌15分钟后，滴加2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(379毫克，0.92毫摩尔，1当量)的四氢呋喃(1毫升)溶液。混合物在冰浴条件下搅拌反应4小时。反应结束后，用水淬灭，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物(E)-1-(1-甲基-1H-吲哚-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(692毫克，粗品)为黄色油状物。LCMS(ESI):m/z 570[M+1]+。
步骤29d:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(1-甲基-1H-吲哚-5-基)乙烷-1-酮(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(1-methyl-1H-indol-5-yl)ethan-1-one)(化合物0306-104)的制备:将化合物(E)-1-(1-甲基-1H-吲哚-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0305-104)(692毫克，1.216毫摩尔，1当量)和醋酸(2毫升)混合于甲醇(4毫升)中。混合物在90℃下搅拌反应16小时。反应结束后，用2N氢氧化钠水溶液调节pH值至12，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1)纯化，得到目标产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(1-甲基-1H-吲哚-5-基)乙烷-1-酮(185毫克，收率：46.60％)为黄色油状物。LCMS(ESI):m/z 328[M+1]+。
步骤29e:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(1-甲基-1H-吲哚-5-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(1-methyl-1H-indol-5-yl)ethan-1-ol)(化合物104)的制备:将化合物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(1-甲基-1H-吲哚-5-基)乙烷-1-酮(0306-104)(179毫克，0.544毫摩尔，1当量)溶解于5毫升甲醇中，再缓慢加入硼氢化钠(41毫克，1.088毫摩尔，2当量)。混合物在室温下搅拌反应1小时。反应结束后，加入2毫升丙酮淬灭，减压浓缩，所得物硅胶柱层析(二氯甲烷/甲醇＝50/1)纯化，得到目标产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(1-甲基-1H-吲哚-5-基)乙烷-1-醇(140毫克，收率：77.95％)为黄色固体。LCMS(ESI):m/z 331[M+1]+。熔点：73～76℃；1H NMR(400MHz,DMSO)δ7.95-7.80(m,1H),7.62–7.48(m,3H),7.41–7.21(m,5H),7.16-7.10(m,1H),6.38(m,1H),5.66-5.55(m,1H),5.49–5.30(m,1H),5.10(m,1H),3.77(m,3H),2.36–1.80(m,2H).
实施例30：2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(1H-吲唑-5-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(1H-indazol-5-yl)ethan-1-ol)(化合物105的制备)(按照方案三线路制备)
步骤30a:1H-吲唑-5-羧酸叔甲酯(methyl 1H-indazole-5-carboxylate)(化合物0303-105)的制备):将吲唑-5-甲酸盐酸盐(0302-105)(420毫克，2.11毫摩尔，1.0当量)溶解于20毫升甲醇中，于冰浴下加入二氯亚砜(0.45毫升，6.33毫摩尔，3.0当量)，加入二甲基甲酰胺， 加热回流反应3小时。冷却至室温，减压浓缩，加入饱和碳酸氢钠水溶液，调pH至12，用乙酸乙酯萃取，分液，用无水硫酸钠干燥有机相，过滤浓缩，减压浓缩，得到产物黄色固体(376毫克，粗品)。LCMS(ESI):m/z 177[M+1]+。
步骤30b:5-(2-(二甲氧基磷酰基)乙酰基)-1H-吲唑-1-羧酸叔丁酯(tert-butyl5-(2-(dimethoxyphosphoryl)acetyl)-1H-indazole-1-carboxylate)(化合物0304-105)的制备):将1H-吲唑-5-羧酸叔甲酯(376毫克，2.11毫摩尔，1.0当量)，三乙胺(0.51毫升，3.66毫摩尔，3.0当量)和二碳酸二叔丁酯(920毫克，4.22毫摩尔，2.0当量)加入到40毫升四氢呋喃中，于室温下反应2小时。减压浓缩，经过硅胶柱层析分离纯化(洗脱剂：石油醚：乙酸乙酯＝8:1)，得到微黄色固体产物1H-吲唑-1-羧酸叔丁酯-5-羧酸叔甲酯(571毫克，收率：97.9％)。LCMS(ESI):m/z 277[M+1]+。取一圆底烧瓶在氮气保护下加入甲基膦酸二甲酯(514毫克，4.14毫摩尔，2.0当量)和20毫升无水四氢呋喃，于干冰-乙醇浴中冷却至-72℃，滴加2.5M正丁基锂正己烷溶液(2.5毫升，6.21毫摩尔，3.0当量)，搅拌一个小时，于-72℃滴加上述得到的1H-吲唑-1-羧酸叔丁酯-5-羧酸叔甲酯(571毫克，2.07毫摩尔，1.0当量)的四氢呋喃溶液，搅拌反应2小时。加入氯化铵水溶液和乙酸乙酯，分液，无水硫酸钠干燥有机相，减压浓缩，经过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝8：1)，得到产物微黄色油状液体(375毫克，收率：49.2％)。LCMS(ESI):m/z 369[M+1]+。
步骤30c:5-(3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烯酰基)-1H-吲唑-1-羧酸叔丁酯(tert-butyl 5-(3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)acryloyl)-1H-indazole-1-carboxylate)(化合物0305-105)的制备:将5-(2-(二甲氧基磷酰基)乙酰基)-1H-吲唑-1-羧酸叔丁酯(0304-105)(375毫克，1.0毫摩尔，1.4当量)、2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(300毫克，0.73毫摩尔，1.0当量)和碳酸铯(900毫克，2.8毫摩尔，3.8当量)加入到60毫升异丙醇中，在室温下搅拌反应过夜，减压浓缩，加入乙酸乙酯和水，分液，无水硫酸钠干燥，减压浓缩，得到黄色固体产物5-(3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烯酰基)-1H-吲唑-1-羧酸叔丁酯(490毫克，粗品)。LCMS(ESI):m/z 657[M+1]+。
步骤30d:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(1H-吲唑-5-基)乙烷-1-酮(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(1H-indazol-5-yl)ethan-1-one)(化合物0306-105)的制备):将5-(3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烯酰基)-1H-吲唑-1-羧酸叔丁酯(0305-105)(490毫克，0.73毫摩尔，1.0当量)溶解到30毫升甲醇中，加入乙酸5毫升，加热回流过夜。冷却到室温，减压浓缩，加入水，用2M氢氧化钠水溶液调节pH至12，加入二氯甲烷萃取，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝15：1)，得到黄色固体产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(1H-吲唑-5-基)乙烷-1-酮(150毫克， 收率：65.5％)。LCMS(ESI):m/z 315[M+1]+。
步骤30e:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(1H-吲唑-5-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(1H-indazol-5-yl)ethan-1-ol)(化合物105)的制备:将2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(1H-吲唑-5-基)乙烷-1-酮(0306-105)(150毫克，0.48毫摩尔，1.0当量)溶解到30毫升甲醇中，冰浴中，冷却至0℃，加入硼氢化钠(22毫克，0.58毫摩尔，1.2当量)，搅拌反应半小时，加入丙酮，减压浓缩，加入二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝30:1～15:1)，得到黄色固体产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(1H-吲唑-5-基)乙烷-1-醇(138毫克，收率：90.9％)。LCMS(ESI):m/z 317[M+1]+。熔点：70～72℃；1H NMR(400MHz,DMSO)δ13.01(s,1H),8.03-8.00(m,1H),7.85-7.79(m,2H),7.62-7.29(m,6H),7.18-7.10(m,1H),5.82-5.71(m,1H),5.52-5.34(m,1H),5.11(m,1H),2.57-1.81(m,2H).
实施例31：1-(1H-苯并[d]咪唑-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(1H-benzo[d]imidazol-6-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物106)的制备(按照方案七线路制备)
步骤31a:1-(1H-苯并[d]咪唑-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(1H-benzo[d]imidazol-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0708-106)的制备。将化合物1-(3-胺基-4-硝基苯基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0705-102)(200毫克，0.597毫摩尔，1当量)溶解于甲酸(5毫升)中，升温至50℃，加入还原铁粉(100毫克，1.79毫摩尔，3当量)。然后混合物升温至125℃，搅拌反应30分钟。LC-MS监测反应完全后，冷却至室温，过滤，滤液用二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标化合物1-(1H-苯并[d]咪唑-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(130毫克，粗品)为黄色油状物。LCMS(ESI):m/z 315[M+1]+。
步骤31b:1-(1H-苯并[d]咪唑-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(1H-benzo[d]imidazol-6-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物106)的制备:将化合物1-(1H-苯并[d]咪唑-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0708-106)(130毫克，0.414毫摩尔，1当量)溶解于5毫升甲醇中。再缓慢加入硼氢化钠(31毫克，0.828毫摩尔，2当量)。混合物在室温下搅拌反应1小时。反应结束后，加入2毫升丙酮淬灭，减压浓缩，所得物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇/氨水＝20/1/1)纯化，得到目标产物106(45毫克，收率：34.35％)为黄色固体。LCMS(ESI):m/z 317[M+1]+。熔点：240～241℃；1H NMR(400MHz,DMSO)δ12.41(s,1H),8.19-8.18(m,1H),7.99-7.83(m,1H),7.72–7.49(m,4H),7.41–7.25(m,3H),7.17-7.10(m,1H),5.82-5.72(m,1H),5.51–5.36(m, 1H),5.13(m,1H),2.37–1.80(m,2H).
实施例32：1-(1H-苯并[d][1,2,3]三唑-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇1-(1H-benzo[d][1,2,3]triazol-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol(化合物107)的制备(按照方案七线路制备)
步骤32a:1-(1H-苯并[d][1,2,3]三唑-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(1H-benzo[d][1,2,3]triazol-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0709-107)的制备:将1-(3,4-二胺基苯基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0706-102)(200毫克，0.65毫摩尔，1.0当量)溶解于50毫升0.2M盐酸水溶液中，冷却至0℃。将亚硝酸钠(136毫克，19.5毫摩尔，3.0当量)溶解于10毫升水中，缓慢滴加到反应体系中，0℃反应1小时。反应结束后，用饱和碳酸氢钠溶液调节pH至碱性，二氯甲烷萃取，有机相用无水硫酸钠干燥，所得物硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1-10/1)纯化，得到产物1-(1H-苯并[d][1,2,3]三唑-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(120毫克，收率：58％)。LCMS(ESI):m/z 316[M+1]+。
步骤32b:1-(1H-苯并[d][1,2,3]三唑-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(1H-benzo[d][1,2,3]triazol-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物107)的制备:将化合物1-(1H-苯并[d][1,2,3]三唑-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0709-107)(120毫克，0.38毫摩尔，1.0当量)溶解于10毫升甲醇中，再缓慢加入硼氢化钠(58毫克，1.52毫摩尔，4.0当量)，冷却至0℃。混合物在室温下搅拌反应1小时。反应结束后，加入2毫升丙酮淬灭，减压浓缩，所得物硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1-10/1)纯化，得到产物1-(1H-苯并[d][1,2,3]三唑-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(30毫克，收率：25％)，黄色固体。LCMS(ESI):m/z 318[M+1]+。熔点：45～46℃；1H NMR(400MHz,DMSO)δ8.16-8.04(m,1H),7.88-7.86(m,3H),7.65-7.59(m,2H),7.51-7.48(m,1H),7.46–7.19(m,2H),7.18-7.08(m,1H),6.04-5.90(m,1H),5.61–5.35(m,1H),5.15(m,1H),2.41–2.20(m,2H).
实施例33：1-(苯并[d]异恶唑-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(benzo[d]isoxazol-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物108)的制备(按照方案三线路制备)
步骤33a:5-溴苯并[d]异恶唑(6-bromobenzo[d]isoxazole)(化合物0301-108)的制备:将5-溴水杨醛(2.0克，10.0毫摩尔，1.0当量)溶解于25毫升甲醇中，加入50％羟胺水溶液(1.32克，20.0毫摩尔，2.0当量)和醋酸钠(2.46克，30.0毫摩尔，3.0当量)，于50℃下加热搅拌一小时，冷却至室温，减压浓缩，加入乙酸乙酯和水，分液，无水硫酸钠干燥有机相，浓 缩，经过硅胶柱层析分离(洗脱剂：石油醚：乙酸乙酯＝15：1)，得到白色固体5-溴-2-羟基苯甲肟(2.1克，收率：97.2％)。LCMS(ESI):m/z 215[M+1]+。在氮气的保护下，将上述反应得到的5-溴-2-羟基苯甲肟(2.0克，9.26毫摩尔，1.0当量)及三苯基膦(3.4克，12.96毫摩尔，1.4当量)溶解于70毫升无水四氢呋喃溶液中，一次加入2，3-二氯-5，6二氰苯醌(3.2克，13.89毫摩尔，1.5当量)，于室温下搅拌15分钟，加入乙酸乙酯和水，分液，无水硫酸钠干燥有机相，减压浓缩，经过硅胶柱层析分离(洗脱剂：石油醚：乙酸乙酯＝20：1)，得到白色固体产物5-溴苯并[d]异恶唑(1.5克，收率：81.9％)。LCMS(ESI):m/z 198[M+1]+。
步骤33b:苯并[d]异恶唑-5-羧酸(benzo[d]isoxazole-5-carboxylic acid)(化合物302-108)的制备:在氮气保护下，在圆底烧瓶中，加入5-溴苯并[d]异恶唑(0301-108)(1.0克，5.0毫摩尔，1.0当量)和30毫升无水四氢呋喃，于干冰-乙醇浴中冷却至-72℃，滴加2.5M正丁基锂正己烷溶液(3.6毫升，9.0毫摩尔，1.8当量)，搅拌一个小时，通入二氧化碳，搅拌反应1小时。滴加2M盐酸水溶液至水相呈pH为1，加入乙酸乙酯萃取，无水硫酸钠干燥有机相，减压浓缩，得到黄色固体产物苯并[d]异恶唑-5-羧酸(1.0克，粗产品)。
步骤33c:苯并[d]异恶唑-5-羧酸甲酯methyl benzo[d]isoxazole-6-carboxylate(化合物0303-108)的制备:将苯并[d]异恶唑-5-羧酸(0302-108)(1.0克，5.0毫摩尔，1.0当量)溶解于30毫升甲醇中，加入二氯亚砜(1.1毫升，15.0毫摩尔，3.0当量)，加热回流下搅拌3小时。减压浓缩，加入乙酸乙酯和水，分液，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝4：1)，得到黄色固体产物苯并[d]异恶唑-5-羧酸甲酯(930毫克，粗产品)。
步骤33d:(2-(苯并[d]异恶唑-5-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(benzo[d]isoxazol-5-yl)-2-oxoethyl)phosphonate)(化合物0304-108)的制备:在氮气保护下，在圆底烧瓶中，加入甲基膦酸二甲酯(525毫克，4.23毫摩尔，1.5当量)和14毫升无水甲苯，于干冰-乙醇浴中冷却至-72℃，滴加2.5M正丁基锂正己烷溶液(2.26毫升，5.64毫摩尔，2.0当量)，搅拌一个小时，于-72℃滴加苯并[d]异恶唑-5-羧酸甲酯(0303-108)(500毫克，2.82毫摩尔，1.0当量)的四氢呋喃溶液，搅拌反应2小时。加入几滴水，加入无水硫酸钠干燥，过滤，减压浓缩所得到的产物(2-(苯并[d]异恶唑-5-基)-2-氧代乙基)磷酸二甲酯粗品直接用于下一步反应。(ESI):m/z 270[M+1]+。
步骤33e:1-(苯并[d]异恶唑-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(benzo[d]isoxazol-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)(化合物0305-108)的制备:将(2-(苯并[d]异恶唑-5-基)-2-氧代乙基)磷酸二甲酯(0304-108)(0.97毫摩尔，1.2当量)、2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(389毫克，0.94毫摩尔，1.0 当量)和碳酸铯(612毫克，1.88毫摩尔，2.0当量)加入到30毫升异丙醇中，在室温下搅拌反应过夜，减压浓缩，加入乙酸乙酯和水，分液，无水硫酸钠干燥，减压浓缩，得到微黄色固体产物1-(苯并[d]异恶唑-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(600毫克，粗品)。LCMS(ESI):m/z 558[M+1]+。
步骤33f:1-(苯并[d]异恶唑-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(benzo[d]isoxazol-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0306-108)的制备:将1-(苯并[d]异恶唑-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0305-108)(600毫克，0.94毫摩尔，1.0当量)溶解到30毫升甲醇中，加入乙酸5毫升，加热回流过夜。冷却到室温，减压浓缩，用2M氢氧化钠水溶液调节pH至7，加入二氯甲烷洗水相，水相减压浓缩，得到黄色固体产物1-(苯并[d]异恶唑-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(850毫克，粗产品)。LCMS(ESI):m/z 316[M+1]+。
步骤33g:1-(苯并[d]异恶唑-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(benzo[d]isoxazol-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物108)的制备:将1-(苯并[d]异恶唑-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0306-108)(0.94毫摩尔，1.0当量)溶解到30毫升甲醇中，冰浴中，冷却至0℃，加入硼氢化钠(54毫克，1.41毫摩尔，1.5当量)，搅拌反应半小时，加入丙酮，减压浓缩，加入二氯甲烷洗水相，水相减压浓缩，经过薄层硅胶板制备分离(洗脱剂：二氯甲烷：甲醇：氨水＝10:1：0.02)，得到黄色固体产物1-(苯并[d]异恶唑-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(13毫克，收率：4.5％)。LCMS(ESI):m/z 318[M+1]+。熔点：95～97℃；1H NMR(400MHz,DMSO)δ10.97(s,1H),7.98-7.86(m,1H),7.60-7.22(m,6H),7.18-7.09(m,1H),6.98-6.94(m,1H),5.82-5.69(m,1H),5.48-5.31(m,1H),4.88(m,1H),2.45-1.78(m,2H).
实施例34：1-(苯并[d][1,3]二氧戊环-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(benzo[d][1,3]dioxol-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物113)的制备(按照方案四线路制备)
步骤34a:苯并[d][1,3]二氧戊环-5-羧酸甲酯(methyl benzo[d][1,3]dioxole-5-carboxylate)(化合物0402-113)的制备:将化合物苯并[d][1,3]二氧戊环-5-羧酸(0401-113)(1克，6毫摩尔，1当量)和碳酸钾(1.65克，12毫摩尔，2当量)溶解于10毫升的DMF中，再滴加碘甲烷(1.02克，7.2毫摩尔，1.2当量)。混合物在室温下搅拌反应4小时。反应结束后，加入水淬灭，过滤，得到目标产物苯并[d][1,3]二氧戊环-5-羧酸甲酯(900毫克，收率：83.02％)为黄色固体。LCMS(ESI):m/z 181[M+1]+。
步骤34b:(2-(苯并[d][1,3]二氧戊环-5-基)-2-氧代乙基)磷酸二甲酯(dimethyl (2-(benzo[d][1,3]dioxol-5-yl)-2-oxoethyl)phosphonate)(化合物0403-113)的制备:在氮气的氛围下，将甲基磷酸二甲酯(824毫克，6.64毫摩尔，1.5当量)溶解于5毫升的干燥的四氢呋喃中，用干冰/乙醇冷却到-60℃，缓慢滴加入正丁基锂(5.3毫升，2.5摩尔/毫升的正己烷溶液，13.28毫摩尔，2当量)，混合物在此温度下搅拌反应30分钟，再缓慢滴加化合物苯并[d][1,3]二氧戊环-5-羧酸甲酯(0402-113)(800毫克，4.44毫摩尔，1当量)的四氢呋喃(1毫升)溶液。混合物在-60℃下搅拌反应1小时。反应结束后，加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝25/1)纯化，得到目标产物(2-(苯并[d][1,3]二氧戊环-5-基)-2-氧代乙基)磷酸二甲酯(750毫克，收率：62.50％)为白色固体。LCMS(ESI):m/z 273[M+1]+。
步骤34c:(E)-1-(苯并[d][1,3]二氧戊环-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮[(E)-1-(benzo[d][1,3]dioxol-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one](化合物0404-113)的制备:在氮气的氛围和冰浴的条件下，将化合物(2-(苯并[d][1,3]二氧戊环-5-基)-2-氧代乙基)磷酸二甲酯(0403-113)(350毫克，1.28毫摩尔，1.5当量)溶解于10毫升的四氢呋喃中，再缓慢加入氢化钠(52毫克，1.28毫摩尔，1.5当量)。混合物搅拌15分钟后，再滴加2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(355毫克，0.86毫摩尔，1当量)的四氢呋喃(1毫升)溶液。混合物在冰浴条件下搅拌反应4小时。反应结束后，用水淬灭，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物(E)-1-(苯并[d][1,3]二氧戊环-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(680毫克，粗品)为黄色油状物。LCMS(ESI):m/z 561[M+1]+。
步骤34d:1-(苯并[d][1,3]二氧戊环-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(benzo[d][1,3]dioxol-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0405-113)的制备:将化合物(E)-1-(苯并[d][1,3]二氧戊环-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0404-113)(680毫克，1.214毫摩尔，1当量)和醋酸(2毫升)混合于甲醇(4毫升)中。混合物在90℃下搅拌反应16小时。反应结束后，用2N氢氧化钠水溶液调节pH值至12，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1)纯化，得到目标产物1-(苯并[d][1,3]二氧戊环-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(160毫克，收率：41.45％)为黄色油状物。LCMS(ESI):m/z 319[M+1]+。
步骤34e:1-(苯并[d][1,3]二氧戊环-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(benzo[d][1,3]dioxol-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物113)的制备:将化合物1-(苯并[d][1,3]二氧戊环-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮 (0405-113)(160毫克，0.503毫摩尔，1当量)溶解于5毫升甲醇中，再缓慢加入硼氢化钠(37.8毫克，1.0毫摩尔，2当量)。混合物在室温下搅拌反应1小时。反应结束后，加入2毫升丙酮淬灭，减压浓缩，所得物硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝50/1)纯化，得到目标产物1-(苯并[d][1,3]二氧戊环-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(60毫克，收率：37.26％)为黄色固体。LCMS(ESI):m/z 321[M+1]+。熔点：65～68℃；1H NMR(400MHz,DMSO)δ7.95-7.85(m,1H),7.60-7.47(m,2H),7.40-7.25(m,2H),7.15-7.09(m,1H),7.00(m,1H),6.89-6.82(m,2H),5.97(m,2H),5.72-5.60(m,1H),5.46-5.29(m,1H),4.90(m,1H),2.33-1.99(m,2H).
实施例35：1-(苯并二氧六环-6-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物119)的制备(按照方案四线路制备)
步骤35a:苯并二氧六环-6-羧酸甲酯(methyl 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate)(化合物0402-119)的制备:将化合物苯并二氧六环-6-羧酸(0401-119)(500毫克，2.78毫摩尔，1当量)溶解于15毫升的甲醇中，再缓慢滴加入1.5毫升氯化亚砜，混合物在回流的条件下搅拌反应2小时。反应结束后，减压浓缩，所得物用乙酸乙酯和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标化合物苯并二氧六环-6-羧酸甲酯(538毫克，收率：99.26％)为黄色固体。LCMS(ESI):m/z 195[M+1]+。
步骤35b:(2-(苯并二氧六环-6-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxoethyl)phosphonate)(化合物0403-119)的制备:在氮气的氛围下，将甲基磷酸二甲酯(514毫克，4.15毫摩尔，1.5当量)溶解于5毫升的干燥的四氢呋喃中，用干冰/乙醇冷却到-60℃，缓慢滴加入正丁基锂(2.2毫升，2.5摩尔/毫升的正己烷溶液，5.54毫摩尔，2当量)，混合物在此温度下搅拌反应30分钟，再缓慢滴加化合物苯并二氧六环-6-羧酸甲酯(0402-119)(538毫克，2.77毫摩尔，1当量)的四氢呋喃(1毫升)溶液。混合物在-60℃下搅拌反应1小时。反应结束后，加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物(2-(苯并二氧六环-6-基)-2-氧代乙基)磷酸二甲酯(754毫克，粗品)为黄色油状物。LCMS(ESI):m/z 287[M+1]+。
步骤35c:1-(苯并二氧六环-6-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)(化合物0404-119)的制备:将化合物0403-119(397毫克，1.39毫摩尔，1.9当量)，化合物2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(300毫克，0.72毫摩尔，1当量)和碳酸铯 (468毫克，1.44毫摩尔，2当量)混合于异丙醇(10毫升)中，混合物在室温下搅拌反应16小时。反应结束后，用水淬灭，过滤，得到目标产物1-(苯并二氧六环-6-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(413毫克，收率：99.27％)为黄色固体。LCMS(ESI):m/z 575[M+1]+。
步骤35d:1-(苯并二氧六环-6-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0405-119)的制备:将化合物1-(苯并二氧六环-6-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0404-119)(413毫克，0.72毫摩尔，1当量)和醋酸(5毫升)混合于甲醇(10毫升)中。混合物在90℃下搅拌反应16小时。反应结束后，用2N氢氧化钠水溶液调节pH值至12，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1)纯化，得到目标产物1-(苯并二氧六环-6-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(160毫克，收率：66.67％)为黄色固体。LCMS(ESI):m/z 333[M+1]+。
步骤35e:1-(苯并二氧六环-6-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物119)的制备:将化合物1-(苯并二氧六环-6-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0405-119)(110毫克，0.332毫摩尔，1当量)溶解于5毫升甲醇中，再缓慢加入硼氢化钠(25毫克，0.664毫摩尔，2当量)。混合物在室温下搅拌反应1小时。反应结束后，加入2毫升丙酮淬灭，减压浓缩，所得物厚制备板层析(展开剂：二氯甲烷/甲醇＝15/1)纯化，得到目标产物1-(苯并二氧六环-6-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(68毫克，收率：61.26％)为白色固体。LCMS(ESI):m/z 335[M+1]+。熔点：69～70℃；1H NMR(500MHz,DMSO)δ7.91-7.81(m,1H),7.56-7.43(m,2H),7.36-7.19(m,2H),7.12-7.05(m,1H),6.88-6.73(m,3H),5.65-5.54(m,1H),5.41-5.26(m,1H),4.84(m,1H),4.17(s,4H),2.47-1.67(m,2H).
实施例36：2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(奈-2-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(naphthalen-2-yl)ethan-1-ol)(化合物123)的制备(按照方案八线路制备)
步骤36a:2-奈羧酸甲酯(methyl 2-naphthoate)(化合物0802-123)的制备。将化合物2-奈羧酸(0801-123)(1克，5.8毫摩尔，1当量)和碳酸钾(1.60克，11.6毫摩尔，2当量)溶解于10毫升的DMF中，再滴加碘甲烷(0.99克，6.96毫摩尔，1.2当量)。混合物在室温下搅拌反应4小时。反应结束后，加入水淬灭，过滤，得到目标化合物2-奈羧酸甲酯(1克，收率：93.28％)为白色固体。LCMS(ESI):m/z 187[M+1]+。
步骤36b:(2-(奈-2-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(naphthalen-2-yl)-2-oxoethyl)phosphonate)(化合物0803-123)的制备:在氮气的氛围下，将甲基磷酸二甲酯(500毫克，4.04毫摩尔，1.5当量)溶解于5毫升的干燥的四氢呋喃中，用干冰/乙醇冷却到-60℃，缓慢滴加入正丁基锂(2.15毫升，2.5摩尔/毫升的正己烷溶液，5.38毫摩尔，2当量)，混合物在此温度下搅拌反应30分钟，再缓慢滴加化合物2-奈羧酸甲酯(0802-123)(500毫克，4.04毫摩尔，1.5当量)的四氢呋喃(1毫升)溶液。混合物在-60℃下搅拌反应1小时。反应结束后，加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝25/1)纯化，得到目标产物(2-(奈-2-基)-2-氧代乙基)磷酸二甲酯(740毫克，收率：98.67％)为透明油状物。LCMS(ESI):m/z 279[M+1]+。
步骤36c:(E)-1-(奈-2-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮[(E)-1-(naphthalen-2-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one](化合物0804-123)的制备：将2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(474毫克，1.15毫摩尔，1当量),化合物(2-(奈-2-基)-2-氧代乙基)磷酸二甲酯(0803-123)(350毫克，1.26毫摩尔，1.1当量)和碳酸铯(407毫克，1.15毫摩尔，2当量)混合于异丙醇(10毫升)中，混合物在室温下搅拌反应16小时。反应结束后，用水淬灭，过滤，得到目标产物(E)-1-(奈-2-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(538毫克，收率：81.64％)为白色固体。LCMS(ESI):m/z 577[M+1]+。
步骤36d:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(奈-2-基)乙烷-1-酮(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(naphthalen-2-yl)ethan-1-one)(化合物0805-123)的制备:将化合物(E)-1-(奈-2-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0804-123)(538毫克，0.934毫摩尔，1当量)和醋酸(2毫升)混合于甲醇(4毫升)中。混合物在90℃下搅拌反应16小时。反应结束后，用2N氢氧化钠水溶液调节pH值至12，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(奈-2-基)乙烷-1-酮(300毫克，粗品)为白色固体。LCMS(ESI):m/z 325[M+1]+。
步骤36e:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(奈-2-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(naphthalen-2-yl)ethan-1-ol)(化合物123)的制备:将化合物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(奈-2-基)乙烷-1-酮(0805-123)(300毫克，0.926毫摩尔，1当量)溶解于5毫升甲醇中，再缓慢加入硼氢化钠(70毫克，1.85毫摩尔，2当量)。混合物在室温下搅拌反应1小时。反应结束后，加入2毫升丙酮淬灭，减压浓缩，所得物硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝50/1)纯化，得到目标产物2-(5H-咪唑[5,1-a]异吲哚啉-5- 基)-1-(奈-2-基)乙烷-1-醇(252毫克，收率：83.50％)为黄色固体。LCMS(ESI):m/z 327[M+1]+。熔点：68～70℃；1H NMR(400MHz,DMSO)δ8.03-7.86(m,5H),7.65-7.30(m,7H),7.18-7.10(m,1H),5.94-5.83(m,1H),5.55-5.40(m,1H),5.16(m,1H),2.57-1.88(m,2H).
实施例37：2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-6-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(quinolin-6-yl)ethan-1-ol)(化合物125)的制备(按照方案八线路制备)
步骤37a:喹啉-6-羧酸甲酯(methyl quinoline-6-carboxylate)(化合物0802-125)的制备:将喹啉-6-羧酸(510毫克，2.95毫摩尔，1.0当量)溶解于20毫升甲醇中，加入1毫升浓硫酸，在50℃下搅拌反应过夜。冷却至室温，加入饱和碳酸氢钠水溶液，用乙酸乙酯萃取，分液，用无水硫酸钠干燥有机相，过滤，减压浓缩，得到白色固体喹啉-6-羧酸甲酯(540毫克，收率：89％)。
步骤37b:(2-氧代-2-(喹啉-6-基)乙基)磷酸二甲酯(dimethyl(2-oxo-2-(quinolin-6-yl)ethyl)phosphonate)(化合物0803-125)的制备:在氮气保护下，在圆底烧瓶中，加入甲基膦酸二甲酯(716毫克，5.78毫摩尔，2.0当量)和20毫升无水四氢呋喃，于干冰-乙醇浴中冷却至-72℃，滴加2.5M正丁基锂正己烷溶液(2.31毫升，5.78毫摩尔，2.0当量)，搅拌一个小时，于-72℃滴加喹啉-6-羧酸甲酯(0802-125)(540毫克，2.89毫摩尔，1.0当量)的四氢呋喃溶液，搅拌反应2小时。加氯化铵水溶液和乙酸乙酯，分液，无水硫酸钠干燥有机相，减压浓缩，经过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝8：1)，得到微黄色油状液体产物(2-氧代-2-(喹啉-6-基)乙基)磷酸二甲酯(926毫克，收率：77.4％)。LCMS(ESI):m/z 279[M+1]+。
步骤37c:1-(喹啉-6-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(quinolin-6-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)(化合物0804-125)的制备:将(2-氧代-2-(喹啉-6-基)乙基)磷酸二甲酯(0803-125)(267毫克，0.96毫摩尔，1.1当量)、2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(360毫克，0.87毫摩尔，1.0当量)和碳酸铯(706毫克，2.17毫摩尔，2.5当量)加入到60毫升异丙醇中，在室温下搅拌反应过夜，减压浓缩，加入乙酸乙酯和水，分液，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝5：1)，得到黄色固体产物1-(喹啉-6-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(490毫克，收率：99％)。LCMS(ESI):m/z 568[M+1]+。
步骤37d:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-6-基)乙烷-1-酮(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(quinolin-6-yl)ethan-1-one)(化合物0805-125)的制备:将1-(喹啉-6-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0804-125)(490毫克， 0.86毫摩尔，1.0当量)溶解到30毫升甲醇中，加入乙酸5毫升，加热回流过夜。冷却到室温，减压浓缩，加入水，用2M氢氧化钠水溶液调节pH至12，加入二氯甲烷萃取，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝15：1)，得到黄色固体产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-6-基)乙烷-1-酮(227毫克，收率：80.7％)。LCMS(ESI):m/z 326[M+1]+。
步骤37e:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-6-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(quinolin-6-yl)ethan-1-ol)(化合物125)的制备:将2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-6-基)乙烷-1-酮(0805-125)(227毫克，0.70毫摩尔，1.0当量)溶解到30毫升甲醇中，冰浴中，冷却至0℃，加入硼氢化钠(32毫克，0.84毫摩尔，1.2当量)，搅拌反应半小时，加入丙酮，减压浓缩，加入二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝30:1～15:1)，得到黄色固体产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-6-基)乙烷-1-醇(155毫克，收率：67.7％)。LCMS(ESI):m/z 328[M+1]+。熔点：56～58℃；1H NMR(400MHz,DMSO)δ8.86(m,1H),8.33(m,1H),8.00-7.96(m,2H),7.91-7.83(m,2H),7.67-7.61(m,2H),7.53-7.50(m,1H),7.41-7.32(m,2H),7.18-7.10(m,1H),6.05-5.94(m,1H),5.57-5.43(m,1H),5.18(m,1H),2.44-1.91(m,2H).
实施例38：2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(异喹啉-6-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(isoquinolin-6-yl)ethan-1-ol)(化合物127)的制备(按照方案八线路制备)
步骤38a:6-异喹啉羧酸甲酯(methyl isoquinoline-6-carboxylate)(化合物0802-127)的制备:将化合物6-异喹啉羧酸(0801-127)(450毫克，2.6毫摩尔，1.0当量)溶解于50毫升N,N-二甲基甲酰胺中，加入碳酸钾，然后加入碘甲烷(443毫克，3.12毫摩尔，1.2当量)。混合物在室温下搅拌反应1小时。反应结束后，乙酸乙酯萃取，分液，有机相用无水硫酸钠干燥，旋干得到化合物6-异喹啉羧酸甲酯(540毫克，粗品)。LCMS(ESI):m/z 188[M+1]+。
步骤38b:2-(异喹啉-6-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(isoquinolin-6-yl)-2-oxoethyl)phosphonate)(化合物0803-127)的制备:在氮气保护下，将甲基磷酸二甲酯(550毫克，4.3毫摩尔，1.5当量)溶解于30毫升的干燥的四氢呋喃中，冷却到-70℃，缓慢滴加入正丁基锂(2.2毫升，2.5摩尔/升的正己烷溶液，5.5毫摩尔，2.0当量)。混合物在此温度下搅拌反应30分钟，再缓慢滴加化合物6-异喹啉羧酸甲酯(0802-127)(540毫克，2.88毫摩尔，1.0当量)的5毫升四氢呋喃溶液，搅拌反应2小时。反应结束后，加水淬灭，无水硫酸钠干燥，减压浓缩，得到化合物(2-(异喹啉-6-基)-2-氧代乙基)磷酸二甲酯(600 毫克，粗品)。LCMS(ESI):m/z 280[M+1]+。
步骤38c:1-(异喹啉-6-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(isoquinolin-6-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)(化合物0804-127)的制备:将2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(250毫克，0.6毫摩尔，1.0当量),化合物(2-(异喹啉-6-基)-2-氧代乙基)磷酸二甲酯(0803-127)(400毫克，1.4毫摩尔，2.3当量)和碳酸铯(391毫克，1.2毫摩尔，2.0当量)混合于异丙醇(30毫升)中，在室温下搅拌反应过夜。反应结束后，用水淬灭，二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1-50/1)纯化，得到产物1-(异喹啉-6-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(300毫克，收率：87％)。LCMS(ESI):m/z 568[M+1]+。
步骤38d:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(异喹啉-6-基)乙烷-1-酮(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(isoquinolin-6-yl)ethan-1-one)(化合物0805-127)的制备:将化合物1-(异喹啉-6-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0804-127)(300毫克，0.53毫摩尔，1.0当量)和醋酸(10毫升)混合于甲醇(40毫升)中，混合物在90℃下搅拌反应过夜。反应结束后，减压浓缩。残留物溶解于二氯甲烷中，用饱和碳酸氢钠溶液中和剩余的酸，二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1-50/1)纯化，得到产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(异喹啉-6-基)乙烷-1-酮(170毫克，收率：98.8％)。LCMS(ESI):m/z 326[M+1]+。
步骤38e:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(异喹啉-6-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(isoquinolin-6-yl)ethan-1-ol)(化合物127)的制备:将化合物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(异喹啉-6-基)乙烷-1-酮(0805-127)(170毫克，0.52毫摩尔，1.0当量)溶解于10毫升甲醇中，再缓慢加入硼氢化钠(79毫克，2.09毫摩尔，4.0当量)，冷却至0℃。混合物在室温下搅拌反应1小时。反应结束后，加入2毫升丙酮淬灭，减压浓缩，所得物硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1-30/1)纯化，得到产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(异喹啉-6-基)乙烷-1-醇(100毫克，收率：40％)，黄色固体。LCMS(ESI):m/z 328[M+1]+。熔点：62～63℃；1H NMR(400MHz,DMSO)δ9.27(s,1H),8.48(d,J＝5.5Hz,1H),8.11-7.94(m,3H),7.80-7.12(m,7H),6.11-6.01(m,1H),5.57-5.49(m,1H),5.18(m,1H),2.44-1.95(m,2H).
实施例39：2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-7-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(isoquinolin-6-yl)ethan-1-ol)(化合物128)的制备(按照方案八线路制备)
步骤39a:7-喹啉羧酸甲酯(methyl isoquinoline-6-carboxylate)(化合物0802-128)的制备:将 化合物7-喹啉羧酸(0801-128)(1.0克，5.78毫摩尔，1.0当量)溶解于30毫升甲醇中，然后加入硫酸(0.5毫升)，回流反应过夜。反应结束后，加碳酸氢钠溶液调pH至8，用二氯甲烷萃取，分液，有机相用无水硫酸钠干燥，旋干得到化合物7-喹啉羧酸甲酯(760毫克，70％)。LCMS(ESI):m/z 188[M+1]+。
步骤39b:1-(喹啉-7-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(quinolin-7-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)(化合物0804-128)的制备:在氮气保护下，将甲基磷酸二甲酯(345毫克，2.78毫摩尔，1.3当量)溶解于30毫升的干燥的甲苯中，冷却到-70℃，缓慢滴加入正丁基锂(1.28毫升，2.5摩尔/升的正己烷溶液，3.21毫摩尔，1.5当量)，混合物在此温度下搅拌反应30分钟，再缓慢滴加化合物7-喹啉羧酸甲酯(0802-128)(400毫克，2.14毫摩尔，1.0当量)的2毫升甲苯溶液，搅拌反应2小时(LCMS(ESI):m/z 280[M+1]+)。反应结束后，加异丙醇30毫升，碳酸铯(1.46克，4.5毫摩尔，2.0当量)，2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(250毫克，0.6毫摩尔，0.28当量)，在室温下搅拌反应过夜。反应结束后，用水和二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(二氯甲烷/甲醇＝100/1-50/1)纯化，得到化合物1-(喹啉-7-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(300毫克，收率：24.7％)。LCMS(ESI):m/z 568[M+1]+。
步骤39c:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-7-基)乙烷-1-酮(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(isoquinolin-6-yl)ethan-1-one)(化合物0805-128)的制备:将化合物1-(喹啉-7-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0804-128)(300毫克，0.53毫摩尔，1.0当量)和醋酸(10毫升)混合于甲醇(40毫升)中，混合物在90℃下搅拌反应过夜。反应结束后，减压浓缩，残留物溶解于二氯甲烷中，用饱和碳酸氢钠溶液中和剩余的酸，二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(二氯甲烷/甲醇＝100/1-50/1)纯化，得到产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-7-基)乙烷-1-酮(120毫克，收率：69.4％)。LCMS(ESI):m/z 326[M+1]+。
步骤39d:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-7-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(isoquinolin-6-yl)ethan-1-ol)(化合物128)的制备:将化合物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-7-基)乙烷-1-酮(0804-128)(120毫克，0.37毫摩尔，1.0当量)溶解于10毫升甲醇中，再缓慢加入硼氢化钠(58毫克，1.48毫摩尔，4.0当量)，冷却至0℃。混合物在室温下搅拌反应1小时。反应结束后，加入0.4毫升水淬灭，减压浓缩，所得物硅胶柱层析(二氯甲烷/甲醇＝100/1-30/1)纯化，得到化合物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-7-基)乙烷-1-醇(10毫克，收率：8.2％)，黄色固体。LCMS(ESI):m/z 328[M+ 1]+。1H NMR(500MHz,DMSO)δ8.80-8.78(m,1H),8.26-8.18(m,1H),8.00-7.85(m,3H),7.61-7.56(m,3H),7.43-7.40(m,1H),7.34(t,J＝7.5Hz,1H),7.26(t,J＝7.6Hz,1H),7.09(s,1H),5.89(d,J＝4.3Hz,1H),5.44(s,1H),5.12(m,1H),2.42-1.89(m,2H).
实施例40：2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹喔啉-6-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(quinoxalin-6-yl)ethan-1-ol)(化合物130)的制备(按照方案八线路制备)
步骤40a:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹喔啉-6-基)乙烷-1-酮(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(quinoxalin-6-yl)ethan-1-one)(化合物0805-130)的制备:将化合物1-(3-胺基-4-硝基苯基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0705-102)(200毫克，0.597毫摩尔，1当量)和氯化铵(271毫克，5.075毫摩尔，8.5当量)溶解于乙醇/水(8/2毫升)中。升温至50℃，加入还原铁粉(266.7毫克，4.776毫摩尔，8当量)。然后混合物升温至回流，搅拌反应30分钟。LC-MS监测反应完全后，冷却至室温，过滤，滤液用二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得化合物用5毫升异丙醇溶解，在室温的条件下，缓慢滴加入乙二醛(69毫克，1.194毫摩尔，2当量)。混合物在室温下搅拌反应2小时。反应结束后，减压浓缩，得到目标化合物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹喔啉-6-基)乙烷-1-酮(120毫克，粗品)为黄色油状物。LCMS(ESI):m/z 327[M+1]+。
步骤40b:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹喔啉-6-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(quinoxalin-6-yl)ethan-1-ol)(化合物130)的制备:将化合物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹喔啉-6-基)乙烷-1-酮(0805-130)(120毫克，0.368毫摩尔，1当量)溶解于5毫升甲醇中，再缓慢加入硼氢化钠(28毫克，0.736毫摩尔，2当量)。混合物在室温下搅拌反应1小时。反应结束后，加入2毫升丙酮淬灭，减压浓缩，所得物用厚制备板层析(洗脱剂：二氯甲烷/甲醇＝15/1)纯化，得到目标产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹喔啉-6-基)乙烷-1-醇(20毫克，收率：16.67％)为黄色固体。LCMS(ESI):m/z 329[M+1]+。1H NMR(500MHz,DMSO)δ8.92-8.89(m,2H),8.07-8.02(m,4H),7.67-7.47(m,2H),7.41-7.05(m,3H),6.13-6.00(m,1H),5.56-5.43(m,1H),5.20(m,1H),2.58-2.34(m,2H).
实施例41：2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-3-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(quinolin-3-yl)ethan-1-ol)(化合物131)的制备(按照方案八线路制备)
步骤41a:3-喹啉羧酸甲酯(methyl quinoline-3-carboxylate)(化合物0802-131)的制备:将化合物3-喹啉羧酸(0801-131)(1.0克，5.78毫摩尔，1.0当量)溶解于30毫升甲醇中，然后加入硫酸(0.5毫升)，回流反应过夜。反应结束后，加碳酸氢钠溶液调pH至8，用二氯甲烷萃 取，分液，有机相用无水硫酸钠干燥，旋干得到产物3-喹啉羧酸甲酯(800毫克，74％)。LCMS(ESI):m/z 188[M+1]+。
步骤41b:(2-(喹啉-3-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-oxo-2-(quinolin-3-yl)ethyl)phosphonate)(化合物0803-131)的制备:在氮气保护下，将甲基磷酸二甲酯(345毫克，2.78毫摩尔，1.3当量)溶解于30毫升的干燥的甲苯中，冷却到-70℃，缓慢滴加入正丁基锂(1.28毫升，2.5摩尔/升的正己烷溶液，3.21毫摩尔，1.5当量)。混合物在此温度下搅拌反应30分钟，再缓慢滴加化合物3-喹啉羧酸甲酯(0802-131)(400毫克，2.14毫摩尔，1.0当量)的2毫升甲苯溶液，搅拌反应2小时。反应结束后，加水淬灭，无水硫酸钠干燥，减压浓缩，得到产物黄色油状化合物(2-(喹啉-3-基)-2-氧代乙基)磷酸二甲酯(420毫克，粗品)。LCMS(ESI):m/z 280[M+1]+。
步骤41c:1-(喹啉-3-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(quinolin-3-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)(化合物0804-131)的制备:将2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(250毫克，0.6毫摩尔，1.0当量)，化合物(2-(喹啉-3-基)-2-氧代乙基)磷酸二甲酯(0803-131)(420毫克，1.5毫摩尔，2.5当量)和碳酸铯(698毫克，2.14毫摩尔，3.6当量)混合于异丙醇(30毫升)中，在室温下搅拌反应过夜。反应结束后，用水淬灭，二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1-50/1)纯化，得到产物黄色固体化合物1-(喹啉-3-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(220毫克，收率：64.5％)。LCMS(ESI):m/z 568[M+1]+。
步骤41d:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-3-基)乙烷-1-酮(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(quinolin-3-yl)ethan-1-one)(化合物0805-131)的制备:将化合物1-(喹啉-3-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0804-131)(220毫克，0.39毫摩尔，1.0当量)和醋酸(10毫升)混合于甲醇(40毫升)中，混合物在90℃下搅拌反应过夜。反应结束后，减压浓缩。残留物溶解于二氯甲烷中，用饱和碳酸氢钠溶液中和剩余的酸，二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1-50/1)纯化，得到产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-3-基)乙烷-1-酮(100毫克，收率：78.9％)。LCMS(ESI):m/z 326[M+1]+。
步骤41e:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-3-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(quinolin-3-yl)ethan-1-ol)(化合物131)的制备:将化合物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-3-基)乙烷-1-酮(0805-131)(100毫克，0.3毫摩尔，1.0当量)溶解于10毫升甲醇中，再缓慢加入硼氢化钠(45.6毫克，1.2毫摩尔，4.0当量)，冷 却至0℃。混合物在室温下搅拌反应1小时。反应结束后，加入2毫升丙酮淬灭，减压浓缩，所得物硅胶柱层析(二氯甲烷/甲醇＝100/1-30/1)纯化，得到产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-3-基)乙烷-1-醇(70毫克，收率：71.4％)，黄色固体。LCMS(ESI):m/z 328[M+1]+。熔点：154～157℃；1H NMR(300MHz,DMSO)δ9.03(d,J＝2.2Hz,1H),8.36(d,J＝2.0Hz,1H),8.13-8.00(m,3H),7.79-7.65(m,4H),7.51-7.39(m,2H),7.20(s,1H),6.18-6.08(d,J＝4.4Hz,1H),5.59(t,J＝6.0Hz,1H),5.27(m,1H),2.55-2.43(m,2H).
实施例42：2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(异喹啉-3-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(isoquinolin-3-yl)ethan-1-ol)(化合物132)的制备(按照方案八线路制备)
步骤42a:3-异喹啉羧酸甲酯(methyl isoquinoline-3-carboxylate)(化合物0802-132)的制备:将化合物3-异喹啉羧酸(0801-132)(1.0克，5.78毫摩尔，1.0当量)溶解于30毫升甲醇中，然后加入硫酸(0.5毫升)，回流反应过夜。反应结束后，加碳酸氢钠溶液调pH至8，用二氯甲烷萃取，分液，有机相用无水硫酸钠干燥，旋干得到化合物3-异喹啉羧酸甲酯(810毫克，75％)。LCMS(ESI):m/z 188[M+1]+。
步骤42b:(2-(异喹啉-3-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(isoquinolin-3-yl)-2-oxoethyl)phosphonate)(化合物0803-132)的制备:在氮气保护下，将甲基磷酸二甲酯(345毫克，2.78毫摩尔，1.3当量)溶解于30毫升的干燥的甲苯中，冷却到-70℃，缓慢滴加入正丁基锂(1.28毫升，2.5摩尔/升的正己烷溶液，3.21毫摩尔，1.5当量)。混合物在此温度下搅拌反应30分钟，再缓慢滴加化合物3-异喹啉羧酸甲酯(0802-132)(400毫克，2.14毫摩尔，1.0当量)的2毫升甲苯溶液，搅拌反应2小时。反应结束后，加水淬灭，无水硫酸钠干燥，减压浓缩，得到产物黄色油状化合物(2-(异喹啉-3-基)-2-氧代乙基)磷酸二甲酯(350毫克，粗品)。LCMS(ESI):m/z 280[M+1]+。
步骤42c:1-(异喹啉-3-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(isoquinolin-3-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)(化合物0804-132)的制备:将2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(250毫克，0.6毫摩尔，1.0当量),化合物(2-(异喹啉-3-基)-2-氧代乙基)磷酸二甲酯(0803-132)(350毫克，1.25毫摩尔，2.2当量)和碳酸铯(391毫克，1.2毫摩尔，2.0当量)混合于异丙醇(30毫升)中，在室温下搅拌反应过夜。反应结束后，倒入100毫升水中，过滤所得固体即产物1-(异喹啉-3-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(200毫克，收率：58.7％)。LCMS(ESI):m/z 568[M+1]+。
步骤42d:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(异喹啉-3-基)乙烷-1-酮 (2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(isoquinolin-3-yl)ethan-1-one)(化合物0805-132)的制备:将化合物1-(异喹啉-3-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0804-132)(200毫克，0.35毫摩尔，1.0当量)和醋酸(10毫升)混合于甲醇(40毫升)中，混合物在90℃下搅拌反应过夜。反应结束后，减压浓缩，残留物溶解于二氯甲烷中，用饱和碳酸氢钠溶液中和剩余的酸，二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，得到产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(异喹啉-3-基)乙烷-1-酮(80毫克，粗品)。LCMS(ESI):m/z 326[M+1]+。
步骤42e:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(异喹啉-3-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(isoquinolin-3-yl)ethan-1-ol)(化合物132)的制备:将化合物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(异喹啉-3-基)乙烷-1-酮(0805-132)(80毫克，0.14毫摩尔，1.0当量)溶解于10毫升甲醇中，再缓慢加入硼氢化钠(53.5毫克，1.4毫摩尔，10.0当量)，冷却至0℃。混合物在室温下搅拌反应1小时。反应结束后，加入2毫升丙酮淬灭，减压浓缩，所得物硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1-30/1)纯化，得到产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(异喹啉-3-基)乙烷-1-醇(20毫克，收率：43.7％)，黄色固体。LCMS(ESI):m/z 328[M+1]+。1H NMR(500MHz,DMSO)δ9.21(s,1H),8.07(d,J＝8.1Hz,1H),7.97-7.92(m,3H),7.74(m,1H),7.61-7.59(m,3H),7.38(t,J＝7.6Hz,1H),7.28(t,J＝7.5Hz,1H),7.10(s,1H),6.07-5.98(m,1H),5.47-5.43(m,1H),5.18(m,1H),2.45-2.28(m,2H).
实施例43：2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-2-基)乙烷-1-醇(1-(quinolin-2-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物133)的制备(按照方案八线路制备)
步骤43a:2-喹啉羧酸甲酯(quinoline-2-carboxylic acid)(化合物0802-133)的制备:将化合物2-喹啉羧酸(0801-133)(1.0克，5.77毫摩尔，1.0当量)和碳酸钾(1.59克，11.54毫摩尔，2.0当量)加入30毫升的DMF中，然后加入碘甲烷(0.98克，6.93毫摩尔，1.2当量)，混合物在常温下搅拌反应4小时。反应结束后，加入100毫升水，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物2-喹啉羧酸甲酯(0.80克，粗品)为白色固体。LCMS(ESI):m/z 174[M+1]+。
步骤43b:(2-(喹啉-2-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-oxo-2-(quinolin-2-yl)ethyl)phosphonate)(化合物0803-133)的制备：在氮气的氛围下，将甲基磷酸二甲酯(494毫克，4.00毫摩尔，1.5当量)溶解于10毫升的干燥的四氢呋喃中。干冰/乙醇冷却到-60℃，缓慢滴加入正丁基锂(2.14毫升，2.5摩尔/升的四氢呋喃溶液，5.34毫摩尔，2.0当量)，混合物在此温度下搅拌反应30分钟，再缓慢滴加化合物2-喹啉羧酸甲酯(0802-133)(286毫克，1.135毫摩尔，1.0当量)的四氢呋喃(10毫升)溶液。混合物在-60℃下搅拌反应0.5 小时。升至室温反应4小时，反应结束后，加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物(2-(喹啉-2-基)-2-氧代乙基)磷酸二甲酯(0.57毫克，收率：76.6％)为无色油状液体。LCMS(ESI):m/z 280[M+1]+。
步骤43c:1-(喹啉-2-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(quinolin-2-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)(化合物0804-133)的制备:将(2-(喹啉-2-基)-2-氧代乙基)磷酸二甲酯(0803-133)(279毫克，1.0毫摩尔，1.0当量)，2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(414毫克，1.0毫摩尔，1.0当量)和碳酸铯的(651毫克，2.0毫摩尔，2.0当量)异丙醇溶液(10毫升)在室温下搅拌反应过夜。反应结束后，用水淬灭，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到黄色油状物。所得黄色油状物通过硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1至100/5)纯化，得到目标产物1-(喹啉-2-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(200毫克，粗品)为黄色油状物。LCMS(ESI):m/z 568[M+1]+。
步骤43d:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-2-基)乙烷-1-酮(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(quinolin-2-yl)ethan-1-one)(化合物0805-133)的制备:将化合物1-(喹啉-2-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0804-133)(200毫克，0.353毫摩尔，1.0当量)和醋酸(5毫升)混合于甲醇(10毫升)中，混合物在90℃下搅拌反应过夜。反应结束后，降至室温，用饱和碳酸钠水溶液调节pH值至10，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1至100/10)纯化，得到目标产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-2-基)乙烷-1-酮(100毫克，收率：87.7％)为黄色固体。LCMS(ESI):m/z 326[M+1]+。
步骤43e:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-2-基)乙烷-1-醇(1-(quinolin-2-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物133)的制备:将化合物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-2-基)乙烷-1-酮(0805-133)(100毫克，0.308毫摩尔，1.0当量)溶解于10毫升甲醇中，再缓慢加入硼氢化钠(23毫克，0.616毫摩尔，2.0当量)。混合物在室温下搅拌反应2小时。反应结束后，加入饱和氯化铵水溶液淬灭，搅拌10分钟，减压除去甲醇，加入饱和碳酸钠水溶液(10毫升)，用二氯甲烷(50毫升)萃取，有机相用饱和食盐水洗一遍，无水硫酸钠干燥，浓缩，所得物硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1至100/8)纯化，得到目标产物2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹啉-2-基)乙烷-1-酮醇(65毫克，收率：64.6％)为淡黄色固体。LCMS(ESI):m/z 328[M+1]+。熔点：156～160℃；1H NMR(300MHz,CDCl3)δ9.00-8.44(m,1H),7.96-7.78(m,2H),7.67-7.55(m,2H),7.52-7.47(m,2H),7.44-7.20(m,5H),5.66-5.49(m,1H),5.32(m,1H),3.40-3.26(m,1H), 2.53-2.11(m,2H).
实施例44：2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹喔啉-2-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(quinoxalin-2-yl)ethan-1-ol)(化合物134)的制备(按照方案八线路制备)
步骤44a:2-喹喔啉羧酸甲酯(methyl quinoxaline-2-carboxylate)(化合物0802-134)的制备:将2-喹喔啉羧酸(0801-134)(1.0克，5.7毫摩尔，1.0当量)溶解于20毫升甲醇中，加入二氯亚砜(1.25毫升，17.2毫摩尔，3.0当量)，加热回流3小时。冷却至室温，减压浓缩至干，用乙酸乙酯萃取，水洗，分液，用无水硫酸钠干燥有机相，过滤浓缩，减压浓缩，经过硅胶柱层析分离(洗脱剂：洗脱剂：石油醚：乙酸乙酯＝5：1)，得到淡黄色固体产物2-喹喔啉羧酸甲酯(1.01克，收率：93.5％)。LCMS(ESI):m/z 189[M+1]+。
步骤44b:(2-(喹喔啉-2-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-oxo-2-(quinoxalin-2-yl)ethyl)phosphonate)(化合物0803-134)的制备:在氮气保护下，在圆底烧瓶中，加入甲基膦酸二甲酯(500毫克，4.0毫摩尔，1.5当量)和20毫升无水甲苯，于干冰-乙醇浴中冷却至-72℃，滴加2.5M正丁基锂正己烷溶液(2.6毫升，6.5毫摩尔，2.5当量)，搅拌一个小时，于-72℃滴加2-喹喔啉羧酸甲酯(500毫克，2.66毫摩尔，1.0当量)的甲苯溶液，搅拌反应2小时。加氯化铵水溶液和乙酸乙酯，分液，无水硫酸钠干燥有机相，减压浓缩，经过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝1：1)，得到微黄色油状液体产物(2-(喹喔啉-2-基)-2-氧代乙基)磷酸二甲酯(340毫克，收率：46.0％)。LCMS(ESI):m/z 281[M+1]+。
步骤44c:1-(喹喔啉-2-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(quinoxalin-2-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)(化合物0804-134)的制备:将(2-(喹喔啉-2-基)-2-氧代乙基)磷酸二甲酯(0803-134)(224毫克，0.80毫摩尔，1.1当量)、2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(300毫克，0.73毫摩尔，1.0当量)和碳酸铯(472毫克，1.45毫摩尔，2.0当量)加入到40毫升异丙醇中，在室温下搅拌反应过夜，减压浓缩，加入乙酸乙酯和水，分液，无水硫酸钠干燥，减压浓缩，得到黄色固体产物1-(喹喔啉-2-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(400毫克，粗产品)。LCMS(ESI):m/z 569[M+1]+。
步骤44d:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹喔啉-2-基)乙烷-1-酮(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(quinoxalin-2-yl)ethan-1-one)(化合物0805-134)的制备:将1-(喹喔啉-2-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0804-134)(400毫克，0.80毫摩尔，1.0当量)溶解到30毫升甲醇中，加入乙酸5毫升，加热回流过夜。冷却 到室温，减压浓缩，加入水，用2M氢氧化钠水溶液调节pH至12，加入二氯甲烷萃取，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝15：1)，得到产物黄色固体(200毫克，收率：76.7％)。LCMS(ESI):m/z 327[M+1]+。
步骤44e:2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹喔啉-2-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(quinoxalin-2-yl)ethan-1-ol)(化合物134的制备:将2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(喹喔啉-2-基)乙烷-1-酮(0805-134)(200毫克，0.61毫摩尔，1.0当量)溶解到30毫升甲醇中，冰浴中，冷却至0℃，加入硼氢化钠(35毫克，0.92毫摩尔，1.5当量)，搅拌反应半小时，加入丙酮，减压浓缩，加入二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝30:1～15:1)，得到产物黄色固体(32毫克，收率：15.9％)。LCMS(ESI):m/z 329[M+1]+。熔点：168～170℃；1H NMR(500MHz,CDCl3)δ9.12-8.52(m,2H),8.07-7.97(m,2H),7.74(m,2H),7.57(m,2H),7.40-7.20(m,3H),5.78-5.65(m,1H),5.51(m,1H),2.76-2.27(m,2H).
实施例45：1-(苯并呋喃-2-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(benzofuran-2-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物135)的制备(按照方案九线路制备)
步骤45a:苯并呋喃-2-羧酸甲酯(methyl benzofuran-2-carboxylate)(化合物0902-135)的制备:将化合物苯并呋喃-2-羧酸(0901-135)(1.0克，6.1毫摩尔，1.0当量)溶解于50毫升甲醇中。冰浴冷却，缓慢滴加氯化亚砜(1.3毫升，18.3毫摩尔，3.0当量)。混合物在40℃下搅拌反应6小时。反应结束后，减压浓缩，将残留物溶解在二氯甲烷中，加入饱和碳酸氢钠溶液，调至碱性，分液。有机相用无水硫酸钠干燥，旋干，残留物用硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝10/1)纯化，得到产物苯并呋喃-2-羧酸甲酯(900毫克，收率：82％)。LCMS(ESI):m/z 177[M+1]+。
步骤45b:(2-(苯并呋喃-2-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(benzofuran-2-yl)-2-oxoethyl)phosphonate)(化合物0903-135)的制备:在氮气保护下，将甲基磷酸二甲酯(420毫克，3.38毫摩尔，1.5当量)溶解于20毫升的干燥的四氢呋喃中，冷却到-70℃，缓慢滴加入正丁基锂(1.8毫升，2.5摩尔/升的正己烷溶液，4.5毫摩尔，2.0当量)。混合物在此温度下搅拌反应30分钟，再缓慢滴加化合物苯并呋喃-2-羧酸甲酯(0902-135)(400毫克，2.26毫摩尔，1.0当量)的1毫升四氢呋喃溶液，搅拌反应4小时。反应结束后，加水淬灭，二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，得到化合物(2-(苯并呋喃-2-基)-2-氧代乙基)磷酸二甲酯(600毫克，粗品)。LCMS(ESI):m/z 269[M+1]+。
步骤45c:1-(苯并呋喃-2-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮 (1-(benzofuran-2-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)(化合物0904-135)的制备:将2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)200毫克，0.48毫摩尔，1.0当量),化合物(2-(苯并呋喃-2-基)-2-氧代乙基)磷酸二甲酯(0903-135)(257毫克，0.96毫摩尔，2.0当量)和碳酸铯(313毫克，0.96毫摩尔，2.0当量)混合于异丙醇(30毫升)中，在室温下搅拌反应过夜。反应结束后，用水淬灭，有固体析出，过滤，干燥，得到化合物1-(苯并呋喃-2-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(290毫克，粗品)。LCMS(ESI):m/z 557[M+1]+。
步骤45d:1-(苯并呋喃-2-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(benzofuran-2-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0905-135)的制备:将化合物1-(苯并呋喃-2-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0904-135)(290毫克，0.52毫摩尔，1.0当量)和醋酸(10毫升)混合于甲醇(40毫升)中，混合物在90℃下搅拌反应过夜。反应结束后，减压浓缩，残留物溶解于二氯甲烷中，用饱和碳酸氢钠溶液中和剩余的酸，二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝50/1)纯化，得到产物1-(苯并呋喃-2-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(148毫克，收率：90％)。LCMS(ESI):m/z 315[M+1]+。
步骤45e:1-(苯并呋喃-2-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(benzofuran-2-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物135)的制备:将化合物1-(苯并呋喃-2-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0905-135)(148毫克，0.47毫摩尔，1.0当量)溶解于10毫升甲醇中，冷却至0℃，再缓慢加入硼氢化钠(70毫克，1.88毫摩尔，4.0当量)。混合物在室温下搅拌反应1小时。反应结束后，加入2毫升丙酮淬灭，减压浓缩，所得物硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝50/1-20/1)纯化，得到化合物1-(苯并呋喃-2-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(130毫克，收率：87％)，黄色固体。LCMS(ESI):m/z 317[M+1]+。熔点：119℃；1H NMR(400MHz,DMSO)δ8.22-8.19(m,1H),7.69-7.21(m,9H),6.81-6.80(m,1H),6.17-6.14(m,1H),5.62-5.54(m,1H),5.17-5.03(m,1H),2.78-1.99(m,2H).
实施例46：1-(苯并噻吩-2-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(benzo[b]thiophen-2-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)化合物137)的制备(按照方案九线路制备)
步骤46a:2-苯并噻吩羧酸甲酯(methyl benzo[b]thiophene-2-carboxylate)(化合物0902-137)的制备：将化合物2-苯并噻吩羧酸(0901-137)(1.0克，5.61毫摩尔，1.0当量)加入20毫升的甲醇中，然后加入浓硫酸(0.1克)，混合物在60℃下搅拌反应16小时。反应结束后， 加入50毫升饱和碳酸氢钠水溶液，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物2-苯并噻吩羧酸甲酯(1.05克，收率97.4％)为白色固体。LCMS(ESI):m/z 193[M+1]+。
步骤46b:(2-(苯并噻吩-2-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(benzo[b]thiophen-2-yl)-2-oxoethyl)phosphonate)(化合物0903-137)的制备:在氮气的氛围下，将甲基磷酸二甲酯(480毫克，3.9毫摩尔，1.5当量)溶解于10毫升的干燥的四氢呋喃中，用干冰/乙醇冷却到-60℃，缓慢滴加入正丁基锂(2.08毫升，2.5摩尔/升的四氢呋喃溶液，5.2毫摩尔，2.0当量)，混合物在此温度下搅拌反应30分钟，再缓慢滴加化合物2-苯并噻吩羧酸甲酯(0902-137)(500毫克，2.6毫摩尔，1.0当量)的四氢呋喃(10毫升)溶液。混合物在-60℃下搅拌反应0.5小时。升至室温反应4小时，反应结束后，加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到目标产物(2-(苯并噻吩-2-基)-2-氧代乙基)磷酸二甲酯(570毫克，收率：76.9％)为无色油状液体。LCMS(ESI):m/z 285[M+1]+。
步骤46c:1-(苯并噻吩-2-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(benzo[b]thiophen-2-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)(化合物0904-137)的制备:将(2-(苯并噻吩-2-基)-2-氧代乙基)磷酸二甲酯(0903-137)(284毫克，1.0毫摩尔，1.0当量)，2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(414毫克，1.0毫摩尔，1.0当量)和碳酸铯(651毫克，2.0毫摩尔，2.0当量)的异丙醇溶液(10毫升)在室温下搅拌反应过夜。反应结束后，用水淬灭，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到黄色油状物，所得黄色油状物通过硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝1/2)纯化，得到目标产物1-(苯并噻吩-2-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(200毫克，粗品)为黄色油状物。LCMS(ESI):m/z 573[M+1]+。
步骤46d:1-(苯并噻吩-2-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(benzo[b]thiophen-2-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0905-137)的制备。将化合物1-(苯并噻吩-2-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0904-137)(200毫克，0.349毫摩尔，1.0当量)和醋酸(5毫升)混合于甲醇(10毫升)中，混合物在90℃下搅拌反应过夜。反应结束后，降至室温，用饱和碳酸钠水溶液调节pH值至10，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得物用硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1)纯化，得到目标产物1-(苯并噻吩-2-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(100毫克，收率：86.8％)为黄色固体。LCMS(ESI):m/z 331[M+1]+。
步骤46e:1-(苯并噻吩-2-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇 (1-(benzo[b]thiophen-2-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物137)的制备:将化合物1-(苯并噻吩-2-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0905-137)(100毫克，0.303毫摩尔，1.0当量)溶解于10毫升甲醇中，再缓慢加入硼氢化钠(22毫克，0.606毫摩尔，2.0当量)。混合物在室温下搅拌反应2小时。反应结束后，加入饱和氯化铵水溶液淬灭，搅拌10分钟，减压除去甲醇，加入饱和碳酸钠水溶液(10毫升)，用二氯甲烷(50毫升)萃取，有机相用饱和食盐水洗一遍，无水硫酸钠干燥，浓缩，所得物硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1至100/10)纯化，得到目标产物1-(苯并噻吩-2-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(65毫克，收率：64.6％)为淡黄色固体。LCMS(ESI):m/z 333[M+1]+。熔点：78-80℃；1H NMR(400MHz,DMSO)δ8.23-8.19(m,1H),7.92(m,1H),7.76-7.56(m,3H),7.45-7.25(m,6H),6.41-6.35(m,1H),5.59-5.48(m,1H),5.37-5.28(m,1H),2.67-2.36(m,2H).
实施例47：1-(苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮肟甲基(O-methyl oxime 1-(benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one O-methyl oxime)(化合物146)的制备(按照方案二线路制备)
将化合物1-(苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0209-1)(50毫克，0.159毫摩尔，1.0当量)溶解于10毫升乙醇和5毫升水的混合液中，再加入碳酸钾(220毫克，1.59毫摩尔，10.0当量)，然后加入甲氧基胺盐酸盐(133毫克，1.59毫摩尔，10.0当量)。混合物在室温搅拌下滴加两滴醋酸，然后加热到70℃反应过夜。反应结束后，减压除去乙醇，加入水，用二氯甲烷(50毫升)萃取，有机相用饱和食盐水洗一遍，无水硫酸钠干燥，浓缩，所得物通过硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1至100/8)纯化，得到目标产物1-(苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮肟甲基(41毫克，收率：75.1％)为黄色固体。LCMS(ESI):m/z 344[M+1]+。熔点：107～111℃；1H NMR(300MHz,DMSO)δ8.05-7.98(m,2H),7.83-7.78(m,1H),7.67-7.58(m,3H),7.49-7.34(m,2H),7.26-7.14(m,2H),6.98(m,1H),5.60(m,1H),3.84-3.82(m,3H),3.64-3.33(m,2H).
实施例48：立体异构体的分离
所列化合物有两个手性中心，共有四个立体异构体，此四个异构体可以通过使用手性柱在高效液相(HPLC)中分离。手性柱层析方法如下：
48a:分离化合物2：手性柱层析方法如下：
色谱柱 CHIRALPAK AD-H；4.6*250mm
进样量 20μl
流动相 正己烷/异丙醇＝80/20(V/V)
流速 1.5ml/min
检测波长 UV 254nm
温度 室温
运用上述HPLC方法，对化合物2进行了分离，按出峰顺序依次为化合物3、化合物4、化合物5和化合物6。各组分用上述分析方法的保留时间如下(如图1所示)：
化合物 保留时间(分) 面积％
3 8.264 13.949
4 13.037 37.387
5 22.091 12.702
6 27.438 35.961
表征数据：
(R)-1-(苯并呋喃-5-基)-2-((R)-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇((R)-1-(benzofuran-5-yl)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物3)：LCMS(ESI):m/z 317[M+1]+；1H NMR(400MHz,DMSO)δ7.97(m,2H),7.70(s,1H),7.54(m,3H),7.36(m,2H),7.24(t,J＝7.1Hz,1H),7.17(s,1H),6.93(d,J＝1.3Hz,1H),5.84(d,J＝4.7Hz,1H),5.51(m,1H),5.10(m,1H),2.54(m,1H),1.83(m,1H)。
(S)-1-(苯并呋喃-5-基)-2-((R)-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇((S)-1-(benzofuran-5-yl)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物4)：LCMS(ESI):m/z 317[M+1]+；1H NMR(400MHz,DMSO)δ7.97(d,J＝2.2Hz,1H),7.84(s,1H),7.71(d,J＝1.2Hz,1H),7.61(dd,J＝7.0,5.2Hz,2H),7.55(d,J＝8.5Hz,1H),7.39(m,2H),7.30(t,J＝7.5Hz,1H),7.10(s,1H),6.93(d,J＝1.4Hz,1H),5.74(d,J＝4.2Hz,1H),5.37(t,J＝6.2Hz,1H),5.10(m,1H),2.34(m,1H),2.21(m,1H)。
(S)-1-(苯并呋喃-5-基)-2-((S)-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇((S)-1-(benzofuran-5-yl)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物5)：LCMS(ESI):m/z 317[M+1]+；1H NMR(400MHz,DMSO)δ7.97(m,2H),7.70(s,1H),7.54(m,3H),7.36(m,2H),7.24(t,J＝7.1Hz,1H),7.17(s,1H),6.93(d,J＝2.2Hz,1H),5.84(d,J＝4.8Hz,1H),5.50(m,1H),5.10(m,1H),2.53(m,1H),1.83(m,1H)。
(R)-1-(苯并呋喃-5-基)-2-((S)-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇((R)-1-(benzofuran-5-yl)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物6)：LCMS(ESI):m/z 317[M+1]+；1H NMR(400MHz,DMSO)δ7.97(d,J＝2.1Hz,1H),7.84(s,1H),7.71(s,1H),7.59(m,3H),7.39(dd,J＝13.2,4.8Hz,2H),7.30(t,J＝7.6Hz,1H),7.09(s,1H),6.93(d,J＝2.1Hz,1H),5.74(d,J＝4.2Hz,1H),5.36(t,J＝6.3Hz,1H),5.10(m,1H),2.34(m, 1H),2.20(m,1H)。
48b:分离化合物8：手性柱层析方法如下：
色谱柱 CHIRALPAK AD-H；4.6*250mm
进样量 20μl
流动相 正己烷/异丙醇；等梯度洗脱；异丙醇含量在50分钟由20％升至43％
流速 1.5ml/min
检测波长 UV 220nm
温度 室温
运用上述HPLC方法，对化合物8进行了分离，按出峰顺序依次为化合物9、化合物10、化合物11和化合物12。各组分用上述分析方法的保留时间如下(如图2所示)：
化合物 保留时间(分) 面积％
9 7.406 12.368
10 8.922 35.406
11 34.366 12.270
12 37.328 39.957
表征数据：
(R)-1-(6-氟苯并呋喃-5-基)-2-((R)-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇((R)-1-(6-fluorobenzofuran-5-yl)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物9)：LCMS(ESI):m/z 335[M+1]+；1H NMR(400MHz,DMSO)δ8.01(m,2H),7.88(d,J＝7.4Hz,1H),7.60(d,J＝7.5Hz,1H),7.46(t,J＝9.0Hz,2H),7.36(t,J＝7.5Hz,1H),7.24(d,J＝7.6Hz,1H),7.18(s,1H),7.00(dd,J＝2.1,0.8Hz,1H),5.95(d,J＝5.0Hz,1H),5.54(dd,J＝9.7,3.0Hz,1H),5.31(m,1H),2.51(s,1H),1.84(m,1H)。
(S)-1-(6-氟苯并呋喃-5-基)-2-((R)-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇((S)-1-(6-fluorobenzofuran-5-yl)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物10)：LCMS(ESI):m/z 335[M+1]+；1H NMR(400MHz,DMSO)δ8.01(d,J＝2.2Hz,1H),7.85(d,J＝7.3Hz,1H),7.79(s,1H),7.61(d,J＝8.3Hz,2H),7.49(d,J＝10.6Hz,1H),7.41(t,J＝7.5Hz,1H),7.31(t,J＝8.0Hz,1H),7.10(s,1H),6.99(dd,J＝2.1,0.8Hz,1H),5.86(d,J＝4.5Hz,1H),5.46(t,J＝6.2Hz,1H),5.32(m,1H),2.38(m,1H),2.18(m,1H)。
(S)-1-(6-氟苯并呋喃-5-基)-2-((S)-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇((S)-1-(6-fluorobenzofuran-5-yl)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物11)：LCMS(ESI):m/z 335[M+1]+；1H NMR(400MHz,DMSO)δ8.01(m,2H),7.88(d,J＝7.4Hz, 1H),7.60(d,J＝7.5Hz,1H),7.46(m,2H),7.36(t,J＝7.5Hz,1H),7.23(m,2H),7.01(dd,J＝2.2,0.8Hz,1H),5.95(d,J＝4.9Hz,1H),5.55(m,1H),5.32(m,1H),2.50(m,1H),1.84(m,1H).
(R)-1-(6-氟苯并呋喃-5-基)-2-((S)-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇((R)-1-(6-fluorobenzofuran-5-yl)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物12)：LCMS(ESI):m/z 335[M+1]+；1H NMR(400MHz,DMSO)δ8.00(d,J＝2.2Hz,1H),7.83(m,2H),7.61(d,J＝8.2Hz,2H),7.49(d,J＝10.6Hz,1H),7.41(t,J＝7.6Hz,1H),7.32(m,1H),7.10(s,1H),6.99(dd,J＝2.2,0.9Hz,1H),5.86(d,J＝4.5Hz,1H),5.46(t,J＝6.2Hz,1H),5.32(m,1H),2.38(m,1H),2.18(m,1H)。
实施例49：(S)-1-(6-氟苯并呋喃-5-基)-2-((S)-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇((S)-1-(6-fluorobenzofuran-5-yl)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物11)的制备(按照方案十一线路制备)
步骤49a:2-氟-4-羟基-5-碘苯甲醛(2-fluoro-4-hydroxy-5-iodobenzaldehyde)(化合物1102-11)的制备：在冰浴和搅拌的条件下，将化合物2-氟-4-羟基苯甲醛(1101-11)(20克，142.86毫摩尔，1当量)缓慢加入200毫升浓硫酸中，撤去冰浴，在室温下搅拌，待化合物溶解后，再置于冰浴中。缓慢滴加NIS(32.14克，142.86毫摩尔，1当量)的四氢呋喃(50毫升)溶液，保持内温在10℃以下。滴加完毕后，再搅拌1小时。反应结束后，缓慢加入至碎冰中，用乙酸乙酯和水萃取，有机相用10％的硫代硫酸钠水溶液洗，水洗，盐水洗，无水硫酸钠干燥，减压浓缩，得到产物2-氟-4-羟基-5-碘苯甲醛(29克，粗品)。LCMS(ESI):m/z 267[M+1]+。
步骤49b：6-氟苯并呋喃-5-甲醛(6-fluorobenzofuran-5-carbaldehyde)(化合物1104-11)的制备:在氮气保护下，将2-氟-4-羟基-5-碘苯甲醛(1102-11)(29克，109毫摩尔，1当量)，三甲基硅乙炔(16克，163.5毫摩尔，1.4当量)，碘化亚铜(311毫克，1.635毫摩尔，0.015当量)和四三苯基膦钯(2.3克，3.27毫摩尔，0.03当量)加入到150毫升四氢呋喃和75毫升氯仿中，然后加入三乙胺(33克，327毫摩尔，3当量)，混合物加热至55℃，搅拌反应4小时。LCMS监测原料2-氟-4-羟基-5-碘苯甲醛反应完全后，再加入碘化亚铜(933毫克，4.905毫摩尔，0.045当量)，混合物在55℃下搅拌过夜。反应结束后，过滤，滤液减压浓缩，冷却至室温，减压浓缩，所得浓缩液用洗脱剂(石油醚/乙酸乙酯＝5/1)冲一小段硅胶纯化，旋干，得到化合物6-氟-2-三甲基硅基苯并呋喃-5-甲醛(20克，粗品)。将得到的6-氟-2-三甲基硅基苯并呋喃-5-甲醛(20克)溶解在200毫升甲醇中，加入碳酸钾(22.7克，163.5毫摩尔，1.5当量)，混合物在55℃下搅拌反应2小时。反应结束后，用乙酸乙酯和水萃取，有机相用水洗，盐水洗，无水硫酸钠干燥，减压浓缩，所得浓缩液用硅胶柱层析分离纯化(洗脱剂：石油醚：乙 酸乙酯＝25：1)，得到黄色固体产物6-氟苯并呋喃-5-甲醛(6克，收率：33.56％)。LCMS(ESI):m/z 165[M+1]+。
步骤49c：3-(6-氟苯并呋喃-5-基)-3-羟基-1-(2-碘苯基)丙烷-1-酮(3-(6-fluorobenzofuran-5-yl)-3-hydroxy-1-(2-iodophenyl)propan-1-one)(化合物1106-11)的制备:氮气保护条件下，将二异丙胺(5.0克，49.35毫摩尔，1.5当量)溶于无水四氢呋喃(60毫升)，干冰乙醇浴降温到-20℃以下，往里滴加2.5摩尔每升正丁基锂(20毫升，49.35毫摩尔，1.5当量)，滴加完后保持-20℃以下反应半小时。降温到-70℃，往里滴加2’-碘苯乙酮(1105-11)(8.1克，32.9毫摩尔，1.0当量)溶于无水四氢呋喃(50毫升)，滴加完后保持-70℃以下反应1小时，往里滴加6-氟苯并呋喃-5-甲醛(5.4克，32.9毫摩尔，1.0当量)溶于无水四氢呋喃(50毫升)，滴加完后保持-70℃以下反应1小时。往里加入氯化铵水溶液淬灭，分液，乙酸乙酯萃取，合并有机相，旋干经过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝20:1～5:1)，得到淡黄色液体产物3-(6-氟苯并呋喃-5-基)-3-羟基-1-(2-碘苯基)丙烷-1-酮(7.1克，收率：52.6％)。LCMS(ESI):m/z 393[M+1]+。
步骤49d：3-((叔丁基二甲基硅基)氧)-3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)丙烷-1-酮(3-((tert-butyldimethylsilyl)oxy)-3-(6-fluorobenzofuran-5-yl)-1-(2-iodophenyl)propan-1-one)(化合物1107-11)的制备：氮气保护条件下，将3-(6-氟苯并呋喃-5-基)-3-羟基-1-(2-碘苯基)丙烷-1-酮(1106-11)(7.1克，17.3毫摩尔，1.0当量)和2，6-二甲基吡啶(7.4克，69.2毫摩尔，4.0当量)溶于二氯甲烷(80毫升)，冰浴条件下，往里滴加叔丁基二甲硅基三氟甲磺酸酯(9.1克，34.6毫摩尔，2.0当量)溶于二氯甲烷(50毫升)溶液。滴加完在室温下反应2小时，反应液用碳酸氢钠水溶液洗，2摩尔每升盐酸洗，饱和食盐水洗，干燥，旋干经过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝100:1～50:1)，得到淡黄色液体产物3-((叔丁基二甲基硅基)氧)-3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)丙烷-1-酮(8克，收率：87.9％)。
步骤49e：(1R,3S)-3-((叔丁基二甲基硅基)氧)-3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)丙烷-1-醇((1R,3S)-3-((tert-butyldimethylsilyl)oxy)-3-(6-fluorobenzofuran-5-yl)-1-(2-iodophenyl)propan-1-ol)(化合物1108-11)和(1R,3R)-3-((叔丁基二甲基硅基)氧)-3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)丙烷-1-醇((1R,3R)-3-((tert-butyldimethylsilyl)oxy)-3-(6-fluorobenzofuran-5-yl)-1-(2-iodophenyl)propan-1-ol)(化合物1109-11)的制备：氮气保护条件下，将S-CBS(0.42克，1.53毫摩尔，0.1当量)溶于四氢呋喃(50毫升)中，冰浴条件下，往里滴加10摩尔每升硼烷二甲硫醚(3毫升，30.6毫摩尔，2.0当量)。滴加完后保持冰浴条件下反应15分钟，往里滴加化合物1107-11(8克，15.3毫摩尔，1.0当量)溶于四氢呋喃(60毫升)，滴加完后，室温条件下反应过夜。反应液用甲醇淬灭，2摩尔每升盐酸洗，碳酸氢钠水溶液洗，饱和食盐水洗，干燥， 旋干经过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝100:1～20:1)，得到白色固体产物(1R,3S)-3-((叔丁基二甲基硅基)氧)-3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)丙烷-1-醇(1108-11)(上点，2.95克)和(1R,3R)-3-((叔丁基二甲基硅基)氧)-3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)丙烷-1-醇(下点，2.65克)，以及(1R)-3-((叔丁基二甲基硅基)氧)-3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)丙烷-1-醇(混合点，1.9克)；总收率：93.8％。
步骤49f：1-((1S,3S)-3-((叔丁基二甲基硅基)氧)-3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)丙烷)-1H-咪唑-2-羧酸乙酯(1-((1S,3S)-3-((tert-butyldimethylsilyl)oxy)-3-(6-fluorobenzofuran-5-yl)-1-(2-iodophenyl)propyl)-1H-imidazole-2-carboxylate)(化合物1111-11)的制备：将(1R,3S)-3-((叔丁基二甲基硅基)氧)-3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)丙烷-1-醇(1108-11)(2.65克，5毫摩尔，1.0当量)，三苯基膦(4.85克，18.5毫摩尔，3.7当量)和咪唑-2-羧酸乙酯(1110-11)(980毫克，7毫摩尔，1.4当量)溶于无水四氢呋喃(250毫升)中，用氮气置换体系中的空气，再缓慢滴加偶氮二甲酸叔丁酯(4.6克，20毫摩尔，4.0当量)的无水四氢呋喃(30ml)溶液。反应4h后，将溶剂减压除去，残留物经硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝30:1～5:1)，得到黄色油状产物1-((1S,3S)-3-((叔丁基二甲基硅基)氧)-3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)丙烷)-1H-咪唑-2-羧酸乙酯(2.9克)。LCMS(ESI):m/z 649[M+1]+。
步骤49g：(S)-5-((S)-2-((叔丁基二甲基硅基)氧)-2-(6-氟苯并呋喃-5-基)乙基)-5H-咪唑[5,1-a]异吲哚啉-3-羧酸乙酯(ethyl(S)-5-((S)-2-((tert-butyldimethylsilyl)oxy)-2-(6-fluorobenzofuran-5-yl)ethyl)-5H-imidazo[5,1-a]isoindole-3-carboxylate(化合物1112-11)的制备：在氮气保护下，将1-((1S,3S)-3-((叔丁基二甲基硅基)氧)-3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)丙烷)-1H-咪唑-2-羧酸乙酯(1111-11)(2.9克，4.5毫摩尔，1.0当量)，醋酸钯(150毫克，0.67毫摩尔，0.15当量)，DEPphos(574毫克，1.05毫摩尔，0.23当量)和二异丙基乙胺(1.16克，9毫摩尔，2.0当量)加入到80毫升四氢呋喃中，加热回流反应18小时。冷却至室温，减压浓缩，经过硅胶柱层析分离纯化(洗脱剂：石油醚：乙酸乙酯＝10:1～4:1)，得到黄色油状产物(S)-5-((S)-2-((叔丁基二甲基硅基)氧)-2-(6-氟苯并呋喃-5-基)乙基)-5H-咪唑(2.85克)。LCMS(ESI):m/z 521[M+1]+。
步骤49h：(S)-5-((S)-2-(6-氟苯并呋喃-5-基)-2-((叔丁基二甲基硅基)氧)乙基)-5H-咪唑[5,1-a]异吲哚啉((S)-5-((S)-2-(6-fluorobenzofuran-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)-5H-imidazo[5,1-a]isoindole)(化合物1113-11)的制备：将(S)-5-((S)-2-((叔丁基二甲基硅基)氧)-2-(6-氟苯并呋喃-5-基)乙基)-5H-咪唑[5,1-a]异吲哚啉-3-羧酸乙酯(1112-11)(2.85克，4.5毫摩尔，1.0当量)，三丁基氧化锡(5.36克，9毫摩尔，2.0当量)加入到60毫升甲苯中，加热回流反应18小时。冷却至室温，减压浓缩，经过硅胶柱层析分离纯化(洗脱剂：石油醚：乙酸乙 酯＝10:1～2:1)，得到黄色固体产物(S)-5-((S)-2-(6-氟苯并呋喃-5-基)-2-((叔丁基二甲基硅基)氧)乙基)-5H-咪唑[5,1-a]异吲哚啉(800毫克，三步总收率：35.7％)。LCMS(ESI):m/z 449[M+1]+。
步骤49i：(S)-1-(6-氟苯并呋喃-5-基)-2-((S)-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇((S)-1-(6-fluorobenzofuran-5-yl)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物11)的制备:将(S)-5-((S)-2-(6-氟苯并呋喃-5-基)-2-((叔丁基二甲基硅基)氧)乙基)-5H-咪唑[5,1-a]异吲哚啉(1113-11)(800毫克，1.79毫摩尔，1.0当量)，溶于30毫升无水乙醇中，加入2ml浓盐酸，室温反应18小时。加入二氯甲烷萃取，碳酸钾调节pH至8，所得有机相用饱和食盐水洗，干燥后减压浓缩，经过硅胶柱层析分离纯化(洗脱剂：二氯甲烷：甲醇＝100:1～30:1)，得到黄色固体产物(S)-1-(6-氟苯并呋喃-5-基)-2-((S)-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(330毫克，收率：55.0％)。LCMS(ESI):m/z 335[M+1]+。1H NMR(300MHz,DMSO)δ8.01(m,2H),7.88(d,J＝7.4Hz,1H),7.60(d,J＝7.5Hz,1H),7.46(m,2H),7.36(t,J＝7.5Hz,1H),7.23(m,2H),7.01(dd,J＝2.2,0.8Hz,1H),5.95(d,J＝4.9Hz,1H),5.55(m,1H),5.32(m,1H),2.50(m,1H),1.84(m,1H).
实施例50：(S)-1-(6-氟苯并呋喃-5-基)-2-((S)-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇((S)-1-(6-fluorobenzofuran-5-yl)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物11)的制备(按照方案十四线路制备)
步骤50a:：(1R)-3-((叔丁基二甲基硅基)氧)-3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)丙烷-1-醇((1R)-3-((tert-butyldimethylsilyl)oxy)-3-(6-fluorobenzofuran-5-yl)-1-(2-iodophenyl)propan-1-ol)(化合物1401-11)的制备:氮气保护条件下，将S-CBS(0.42克，1.53毫摩尔，0.1当量)溶于四氢呋喃(50毫升)中，冰浴条件下，往里滴加10摩尔每升的硼烷二甲硫醚(3毫升，30.6毫摩尔，2.0当量)。滴加完后保持冰浴条件下反应15分钟，往里滴加3-((叔丁基二甲基硅基)氧)-3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)丙烷-1-酮(1107-11)(8克，15.3毫摩尔，1.0当量)的四氢呋喃(60毫升)溶液，滴加完后，室温条件下反应过夜。反应液用甲醇淬灭，2摩尔每升盐酸洗，碳酸氢钠水溶液洗，饱和食盐水洗，干燥，旋干后经过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝100:1～20:1)，得到无色液体产物(1R)-3-((叔丁基二甲基硅基)氧)-3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)丙烷-1-醇(7.4克，收率：91.9％)。MS(ESI):m/z＝509[M+1-18]+。
步骤50b：1-((1S)-3-((叔丁基二甲基硅基)氧)-3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)丙烷)-1H-咪唑-2-羧酸乙酯(1-((1S)-3-((tert-butyldimethylsilyl)oxy)-3-(6-fluorobenzofuran-5-yl)-1-(2-iodophenyl)propyl)-1H-imidazole-2-carboxylate)(化合物1402-11)的制备：将(1R)-3-((叔丁基二甲基硅基)氧)-3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)丙烷-1-醇(1401-11)(5.3克，10毫 摩尔，1.0当量)和三苯基膦(9.7克，37毫摩尔，3.7当量)和咪唑-2-羧酸乙酯(1110-11)(1.96克，14毫摩尔，1.4当量)溶于无水四氢呋喃(250毫升)中，氮气置换体系中的空气，缓慢滴加偶氮二甲酸叔丁酯(9.2克，40毫摩尔，4.0当量)的无水四氢呋喃(30毫升)溶液。反应4小时后，将溶剂减压除去，残留物经硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝30:1～5:1)，得到黄色油状产物1-((1S)-3-((叔丁基二甲基硅基)氧)-3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)丙烷)-1H-咪唑-2-羧酸乙酯(2.5克，收率：38％)。LCMS(ESI):m/z 649[M+1]+。
步骤50c：1-((1S)-3-(6-氟苯并呋喃-5-基)-3-羟基-1-(2-碘苯基)丙基)-1H-咪唑-2-羧酸乙酯(ethyl 1-((1S)-3-(6-fluorobenzofuran-5-yl)-3-hydroxy-1-(2-iodophenyl)propyl)-1H-imidazole-2-carboxylate)(化合物1403-11)的制备：将1-((1S)-3-((叔丁基二甲基硅基)氧)-3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)丙烷)-1H-咪唑-2-羧酸乙酯(1402-11)(700毫克，1.08毫摩尔，1.0当量)和四丁基氟化铵三水合物(341毫升，1.08毫摩尔，1.0当量)溶于四氢呋喃(20毫升)中，升温到85℃回流反应30分钟，冷却到室温，水洗，饱和食盐水洗，旋干经过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝5:1～1:1)，得到白色固体产物1-((1S)-3-(6-氟苯并呋喃-5-基)-3-羟基-1-(2-碘苯基)丙基)-1H-咪唑-2-羧酸乙酯(500毫克，收率：86.7％)。LCMS(ESI):m/z 535[M+1]+。
步骤50d：(S)-1-(3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)-3-氧代丙基)-1H-咪唑-2-羧酸乙酯(ethyl(S)-1-(3-(6-fluorobenzofuran-5-yl)-1-(2-iodophenyl)-3-oxopropyl)-1H-imidazole-2-carboxylate(化合物1404-11)的制备:将1-((1S)-3-(6-氟苯并呋喃-5-基)-3-羟基-1-(2-碘苯基)丙基)-1H-咪唑-2-羧酸乙酯(1403-11)(500毫克，0.94毫摩尔，1.0当量)和IBX(524毫升，1.88毫摩尔，2.0当量)溶于DMSO(10毫升)，室温下反应过夜，倒入冰水中，乙酸乙酯萃取，碳酸氢钠水溶液洗，饱和食盐水洗，旋干经过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝10:1～1:1)，得到白色固体产物(S)-1-(3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)-3-氧代丙基)-1H-咪唑-2-羧酸乙酯(440毫克，收率：88.0％)。LCMS(ESI):m/z 533[M+1]+。
步骤50e：1-((1S,3S)-3-(6-氟苯并呋喃-5-基)-3-羟基-1-(2-碘苯基)丙烷)-1H-咪唑-2-羧酸乙酯(ethyl 1-((1S,3S)-3-(6-fluorobenzofuran-5-yl)-3-hydroxy-1-(2-iodophenyl)propyl)-1H-imidazole-2-carboxylate)(化合物1405-11)的制备:氮气保护条件下，将R-CBS(23毫克，0.083毫摩尔，0.1当量)溶于四氢呋喃(10毫升)，冰浴条件下，往里滴加10摩尔每升的硼烷二甲硫醚(0.17毫升，1.66毫摩尔，2.0当量)。滴加完后保持冰浴条件下反应15分钟，往里滴加(S)-1-(3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)-3-氧代丙基)-1H-咪唑-2-羧酸乙酯(1404-11)(440毫克，0.83毫摩尔，1.0当量)的四氢呋喃(10毫升)溶液，滴加完后，室温条件下反应过夜。反应液用甲醇淬灭，2摩尔每升盐酸洗，碳酸氢钠水溶液洗，饱和食盐水洗，干燥，旋干经 过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝10:1～1:1)，得到白色固体产物1-((1S,3S)-3-(6-氟苯并呋喃-5-基)-3-羟基-1-(2-碘苯基)丙烷)-1H-咪唑-2-羧酸乙酯(410克，收率：93.2％)。LCMS(ESI):m/z 535[M+1]+。
步骤50f：1-((1S,3S)-3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)-3-((三甲基硅基)氧)丙烷)-1H-咪唑-2-羧酸乙酯(ethyl 1-((1S,3S)-3-(6-fluorobenzofuran-5-yl)-1-(2-iodophenyl)-3-((trimethylsilyl)oxy)propyl)-1H-imidazole-2-carboxylate)(化合物1111-11)的制备：氮气保护条件下，将1-((1S,3S)-3-(6-氟苯并呋喃-5-基)-3-羟基-1-(2-碘苯基)丙烷)-1H-咪唑-2-羧酸乙酯(1405-11)(290毫克，0.54毫摩尔，1.0当量)和三甲基氰硅烷(0.5毫升)溶于四氢呋喃(10毫升)，回流反应4小时，冷却到室温，反应液用碳酸氢钠水溶液洗，饱和食盐水洗，干燥，旋干经过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝20:1～5:1)，得到无色液体产物1-((1S,3S)-3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)-3-((三甲基硅基)氧)丙烷)-1H-咪唑-2-羧酸乙酯(230毫克，收率：70.1％)。LCMS(ESI):m/z 607[M+1]+。
步骤50g：(S)-5-((S)-2-(6-氟苯并呋喃-5-基)-2-((三甲基硅基)氧)乙基)-5H-咪唑[5,1-a]异吲哚啉-3-羧酸乙酯(ethyl(S)-5-((S)-2-(6-fluorobenzofuran-5-yl)-2-((trimethylsilyl)oxy)ethyl)-5H-imidazo[5,1-a]isoindole-3-carboxylate)(化合物1112-11)的制备：在氮气保护下，将1-((1S,3S)-3-(6-氟苯并呋喃-5-基)-1-(2-碘苯基)-3-((三甲基硅基)氧)丙烷)-1H-咪唑-2-羧酸乙酯(1111-11)(140毫克，0.23毫摩尔，1.0当量)，醋酸钯(8毫克，0.035毫摩尔，0.15当量)，DEPphos(29毫克，0.053毫摩尔，0.23当量)和二异丙基乙胺(60毫克，0.46毫摩尔，2.0当量)加入到6毫升四氢呋喃中，加热回流反应18小时。冷却至室温，减压浓缩，经过硅胶柱层析分离纯化(洗脱剂：石油醚：乙酸乙酯＝10:1～4:1)，得到黄色固体产物(S)-5-((S)-2-(6-氟苯并呋喃-5-基)-2-((三甲基硅基)氧)乙基)-5H-咪唑[5,1-a]异吲哚啉-3-羧酸乙酯(55毫克，收率：50.0％)。LCMS(ESI):m/z 479[M+1]+。
步骤50h：(S)-5-((S)-2-(6-氟苯并呋喃-5-基)-2-((三甲基硅基)氧)乙基)-5H-咪唑[5,1-a]异吲哚啉((S)-5-((S)-2-(6-fluorobenzofuran-5-yl)-2-((trimethylsilyl))oxy)ethyl)-5H-imidazo[5,1-a]isoindole)(化合物1113-11)的制备：将(S)-5-((S)-2-((三甲基硅基)氧)-2-(6-氟苯并呋喃-5-基)乙基)-5H-咪唑[5,1-a]异吲哚啉-3-羧酸乙酯(1112-11)(55毫克，0.12毫摩尔，1.0当量)，三丁基氧化锡(68.5克，0.24毫摩尔，2.0当量)加入到10毫升甲苯中，加热回流反应18小时。冷却至室温，减压浓缩，经过硅胶柱层析分离纯化(洗脱剂：石油醚：乙酸乙酯＝10:1～2:1)，得到黄色固体产物(S)-5-((S)-2-(6-氟苯并呋喃-5-基)-2-((三甲基硅基)氧)乙基)-5H-咪唑[5,1-a]异吲哚啉(30毫克，收率：64％)。LCMS(ESI):m/z 407[M+1]+。
步骤50i：(S)-1-(6-氟苯并呋喃-5-基)-2-((S)-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇 ((S)-1-(6-fluorobenzofuran-5-yl)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物11)的制备:将(S)-5-((S)-2-(6-氟苯并呋喃-5-基)-2-((叔丁基二甲基硅基)氧)乙基)-5H-咪唑[5,1-a]异吲哚啉(1113-11)(30毫克，0.07毫摩尔，1.0当量)溶于2毫升无水乙醇中，加入0.15ml浓盐酸，室温反应18小时。加入二氯甲烷萃取，碳酸钾调节pH至8，所得有机相用饱和食盐水洗，干燥后减压浓缩，经过制备硅胶层板析分离纯化(洗脱剂：二氯甲烷：甲醇＝20:1)，得到黄色固体产物(S)-1-(6-氟苯并呋喃-5-基)-2-((S)-5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(20毫克，收率：85.7％)。LCMS(ESI):m/z 335[M+1]+。1H NMR(300MHz,DMSO)δ8.01(m,2H),7.88(d,J＝7.4Hz,1H),7.60(d,J＝7.5Hz,1H),7.46(m,2H),7.36(t,J＝7.5Hz,1H),7.23(m,2H),7.01(dd,J＝2.2,0.8Hz,1H),5.95(d,J＝4.9Hz,1H),5.55(m,1H),5.32(m,1H),2.50(m,1H),1.84(m,1H).
实施例51：1-(7-氯-6-氟苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(7-chloro-6-fluorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物19)的制备(按照方案二线路制备)
步骤51a：3-氯-2-氟-4-羟基-5-碘苯甲酸甲酯(methyl 3-chloro-2-fluoro-4-hydroxy-5-iodobenzoate)(化合物0204-19)的制备：将2-氟-4-羟基-5-碘苯甲酸甲酯(700毫克，2.36毫摩尔，1.0当量)溶解于50毫升二氯甲烷中，加入二异丙基乙胺(0.82毫升，4.72毫摩尔，2.0当量)，于室温下滴加溴甲基甲基醚(0.3毫升，3.54毫摩尔，1.5当量)。室温下搅拌反应2小时，用水和饱和食盐水洗有机相，无水硫酸钠干燥，经过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝10：1)，得到无色油状物2-氟-5-碘-4-(甲氧基甲氧基)苯甲酸甲酯(800毫克，收率：99.1％)。在氮气保护下，将四甲基哌啶(466mg，3.3毫摩尔，1.5当量)加入到30毫升四氢呋喃中，冷却至-40℃，滴加2.5M正丁基锂正己烷溶液(1.6毫升，3.96毫摩尔，1.8当量)。自然升温至室温，继续搅拌半小时。冷却至-70℃，将上述反应得到的2-氟-5-碘-4-(甲氧基甲氧基)苯甲酸甲酯(750毫克，2.2毫摩尔，1.0当量)溶解于四氢呋喃中，滴加到上述混合物中，于-70℃下搅拌1小时，加入六氯乙烷(782毫克，3.3毫摩尔，1.5当量)的四氢呋喃溶液，搅拌反应1小时。用饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，水洗，无水硫酸钠干燥。室温下搅拌反应2小时，用水和饱和食盐水洗有机相，无水硫酸钠干燥，减压浓缩，得到黄色油状物3-氯-2-氟-5-碘-4-(甲氧基甲氧基)苯甲酸甲酯(800毫克，粗产品)。将上述3-氯-2-氟-5-碘-4-(甲氧基甲氧基)苯甲酸甲酯溶解于四氢呋喃中，加入3M盐酸水溶液，在50℃下搅拌反应3小时。加入乙酸乙酯萃取，水洗，无水硫酸钠干燥，减压浓缩，得到黄色油状物产物3-氯-2-氟-4-羟基-5-碘苯甲酸甲酯(760毫克，粗产品)。
步骤51b：7-氯-6-氟苯并呋喃-5-羧酸甲酯(methyl  7-chloro-6-fluorobenzofuran-5-carboxylate)(化合物0206-19)的制备：在氮气保护下，将3-氯-2-氟-4-羟基-5-碘苯甲酸甲酯(0204-19)(760毫克，2.13毫摩尔，1.0当量)，三甲基硅基乙炔(626毫克，6.39毫摩尔，3.0当量)，三乙胺(645毫克，6.39毫摩尔，3.0当量)，碘化亚铜(8毫克，0.043毫摩尔，0.02当量)和二氯二三苯基膦钯(75毫克，0.11毫摩尔，0.05当量)溶解于50毫升四氢呋喃，在60℃下搅拌反应过夜。减压浓缩，经过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝15：1)，得到黄色固体7-氯-6-氟-2-三甲基硅基苯并呋喃-5-羧酸甲酯(168毫克，收率：26.0％)。LCMS(ESI):m/z 301[M+1]+。将上述得到的7-氯-6-氟-2-三甲基硅基苯并呋喃-5-羧酸甲酯(168毫克，0.56毫摩尔，1.0当量)溶解于四氢呋喃中，加入四正丁基氟化胺(585毫克，2.24毫摩尔，4.0当量)，室温搅拌1小时。减压浓缩，经过硅胶柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝5：1)，得到黄色固体产物7-氯-6-氟苯并呋喃-5-羧酸甲酯(128毫克，粗产品)。LCMS(ESI):m/z 229[M+1]+。
步骤51c：(2-(7-氯-6-氟苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯dimethyl(2-(7-chloro-6-fluorobenzofuran-5-yl)-2-oxoethyl)phosphonate(化合物0207-19)的制备:在氮气保护下，在圆底烧瓶中，加入甲基膦酸二甲酯(136毫克，1.1毫摩尔，2.0当量)和20毫升无水四氢呋喃，于干冰-乙醇浴中冷却至-72℃，滴加2.5M正丁基锂正己烷溶液(0.51毫升，1.3毫摩尔，2.3当量)，搅拌1小时，于-72℃滴加7-氯-6-氟苯并呋喃-5-羧酸甲酯(128毫克，0.55毫摩尔，1.0当量)的四氢呋喃溶液，搅拌反应2小时。加入氯化铵水溶液和乙酸乙酯，分液，无水硫酸钠干燥有机相，减压浓缩，得到产物微黄色固体(2-(7-氯-6-氟苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(185毫克，粗产品)。LCMS(ESI):m/z 321[M+1]+。
步骤51d：1-(7-氯-6-氟苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(7-chloro-6-fluorobenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)(化合物0208-19)的制备:将(2-(7-氯-6-氟苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(0207-19)(185毫克，0.55毫摩尔，1.0当量)、2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(228毫克，0.55毫摩尔，1.0当量)和碳酸铯(359毫克，1.1毫摩尔，2.0当量)加入到20毫升异丙醇中，在室温下搅拌反应过夜，减压浓缩，加入乙酸乙酯和水，分液，无水硫酸钠干燥，减压浓缩，得到微黄色固体产物1-(7-氯-6-氟苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(150毫克，粗品)。LCMS(ESI):m/z 596[M+1]+。
步骤51e：1-(7-氯-6-氟苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(7-chloro-6-fluorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物209-19)的制备：将1-(7-氯-6-氟苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0208-19)(150毫克，0.25毫摩尔，1.0当量)溶解到30毫升甲醇中，加入乙酸6 毫升，加热回流过夜。冷却到室温，减压浓缩，加入水，用2M氢氧化钠水溶液调节pH至12，加入二氯甲烷萃取，无水硫酸钠干燥，减压浓缩，得到微黄色固体产物1-(7-氯-6-氟苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(100毫克，粗产品)。LCMS(ESI):m/z 367[M+1]+。
步骤51f：1-(7-氯-6-氟苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(7-chloro-6-fluorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物19)的制备:将1-(7-氯-6-氟苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0209-19)(100毫克，0.28毫摩尔，1.0当量)溶解到30毫升甲醇中，冰浴中，冷却至0℃，加入硼氢化钠(21毫克，0.56毫摩尔，2.0当量)，搅拌反应半小时，加入丙酮，减压浓缩，加入二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝30:1～15:1)，得到微黄色固体产物1-(7-氯-6-氟苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(40毫克，收率：38.4％)。LCMS(ESI):m/z 369[M+1]+。熔点：198～200℃；1H NMR(400MHz,DMSO)δ8.13(d,J＝2.1Hz,1H),8.04-7.78(m,2H),7.60(m,2H),7.45-7.29(m,2H),7.23-7.08(m,2H),6.04-5.94(m,1H),5.55-5.46(m,1H),5.30-5.24(m,1H),2.53-1.90(m,2H).
实施例52：1-(6-氟-2-羟甲基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(6-fluoro-2-(hydroxymethyl)benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-o l)(化合物51)的制备(按照方案二线路制备)
步骤52a：2-(((叔丁氧羰基)氧)甲基)-6-氟苯并呋喃-5-羧酸甲酯(methyl 2-(((tert-butoxycarbonyl)oxy)methyl)-6-fluorobenzofuran-5-carboxylate)(化合物0206-51)的制备。在氮气保护下，将2-氟-5-碘-4-羟基苯甲酸甲酯(0204-51)(900毫克，3.04毫摩尔，1.0当量)，丙炔醇(340毫克，6.08毫摩尔，1.5当量)，碘化亚铜(8毫克，0.046毫摩尔，0.015当量)和四三苯基膦钯(64毫克，0.09毫摩尔，0.03当量)加入到10毫升四氢呋喃和20毫升氯仿中，然后滴加三乙胺(921毫克，9.12毫摩尔，3当量)，混合物加热至55℃，搅拌反应过夜。冷却至室温，减压浓缩，所得浓缩液经过硅胶柱层析分离纯化(洗脱剂：石油醚：乙酸乙酯＝50：1)，得到黄色固体6-氟-2-羟甲基苯并呋喃-5-羧酸甲酯(600毫克，粗品)。LCMS(ESI):m/z 225[M+1]+。将二碳酸二叔丁酯(499毫克，2.4毫摩尔，1.5当量)加入至上述得到的化合物6-氟-2-羟甲基苯并呋喃-5-羧酸甲酯(600毫克，1.6毫摩尔，1当量)与DMAP(10毫克)，三乙胺(485毫克，4.8毫摩尔，3当量)的四氢呋喃溶液中。室温下搅拌反应1小时。反应结束后，用乙酸乙酯和水萃取，有机相用水洗，饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得油状物经过硅胶柱层析分离纯化(洗脱剂：石油醚：乙酸乙酯＝50：1)，得到黄色 油状产物2-(((叔丁氧羰基)氧)甲基)-6-氟苯并呋喃-5-羧酸甲酯(600毫克，粗品)。LCMS(ESI):m/z 325[M+1]+。
步骤52b：((5-(2-(二甲氧基磷酰基)乙酰基)-6-氟苯并呋喃-2-基)甲基)碳酸叔丁酯(tert-butyl((5-(2-(dimethoxyphosphoryl)acetyl)-6-fluorobenzofuran-2-yl)methyl)carbonate)(化合物0207-51)的制备:在氮气的氛围下，将甲基膦酸二甲酯(345毫克，2.78毫摩尔，1.5当量)溶解于15毫升的干燥的四氢呋喃中。用干冰/乙醇冷却到-60℃，缓慢滴加入正丁基锂(1.2毫升，2.5摩尔/毫升的正己烷溶液，2.78毫摩尔，1.5当量)。混合物在此温度下搅拌反应30分钟，再缓慢滴加化合物2-(((叔丁氧羰基)氧)甲基)-6-氟苯并呋喃-5-羧酸甲酯(0206-51)(600毫克，1.85毫摩尔，1当量)的四氢呋喃(5毫升)溶液。混合物在此条件下搅拌反应1小时。反应结束后，加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到产物((5-(2-(二甲氧基磷酰基)乙酰基)-6-氟苯并呋喃-2-基)甲基)碳酸叔丁酯(772毫克，粗品)为黄色油状物。LCMS(ESI):m/z 417[M+1]+。
步骤52c：((6-氟-5-(3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烯酰基)苯并呋喃-2-基)甲基)碳酸叔丁酯(tert-butyl((6-fluoro-5-(3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)acryloyl)benzofuran-2-yl)methyl)carbonate)(化合物0208-51)的制备:将2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(696毫克，1.68毫摩尔，1当量),化合物((5-(2-(二甲氧基磷酰基)乙酰基)-6-氟苯并呋喃-2-基)甲基)碳酸叔丁酯(0207-51)(772毫克，1.85毫摩尔，1.1当量)和碳酸铯(1090毫克，3.36毫摩尔，2当量)混合于异丙醇(10毫升)中，混合物在室温下搅拌反应16小时。反应结束后，用水淬灭，过滤，得到产物((6-氟-5-(3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烯酰基)苯并呋喃-2-基)甲基)碳酸叔丁酯(930毫克，粗品)为黄色固体。LCMS(ESI):m/z 706[M+1]+。
步骤52d:1-(6-氟-2-羟甲基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(6-fluoro-2-(hydroxymethyl)benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0209-51)的制备。将化合物((6-氟-5-(3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烯酰基)苯并呋喃-2-基)甲基)碳酸叔丁酯(0208-51)(930毫克，1.32毫摩尔，1当量)和醋酸(5毫升)混合于甲醇(10毫升)中。混合物在90℃下搅拌反应16小时。反应结束后，用2N氢氧化钠水溶液调节pH值至12，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，所得黄色油状物用10毫升甲醇溶解，加入2毫升浓盐酸，混合物在室温下搅拌1小时。反应结束后，用2N氢氧化钠水溶液调节pH值至12，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝30:1～15:1)，得到产物1-(6-氟-2-羟甲基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(250毫 克，收率：52.21％)为黄色固体。LCMS(ESI):m/z 364[M+1]+。
步骤52e：1-(6-氟-2-羟甲基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(6-fluoro-2-(hydroxymethyl)benzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物51)的制备:将1-(6-氟-2-羟甲基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0209-51)(250毫克，0.688毫摩尔，1.0当量)溶解到10毫升甲醇中，冰浴中，冷却至0℃，加入硼氢化钠(52毫克，1.377毫摩尔，2当量)，搅拌反应半小时，加入丙酮，减压浓缩，加入二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝30:1～15:1)，得到白色固体产物1-(6-氟-2-羟甲基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(140毫克，收率：55.69％)。LCMS(ESI):m/z 366[M+1]+。熔点：194～196℃；1H NMR(300MHz,DMSO)δ8.01-7.77(m,2H),7.62-7.10(m,6H),6.78(m,1H),5.95-5.84(m,1H),5.54-5.43(m,2H),5.34-5.28(m,1H),4.54(m,2H),2.40-1.76(m,2H).
实施例53：1-(6-氟-2-甲基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇1-(6-fluoro-2-methylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol(化合物69)的制备(按照方案三线路制备)
步骤53a：6-氟-2-甲基苯并呋喃-5-甲酸甲酯(methyl 6-fluoro-2-methylbenzofuran-5-carboxylate)(化合物0303-69)的制备:在氮气保护下，将5-溴-6-氟-2-甲基苯并呋喃(0301-69)(0.7克，3.0毫摩尔，1.0当量)加入到10毫升无水四氢呋喃中，降温到-78℃，然后滴加正丁基锂(1.8毫升，4.5毫摩尔，1.5当量)，搅拌反应0.5小时。通入干燥的二氧化碳气体0.5小时，升温至室温，加入碘甲烷(0.51克，3.6毫摩尔，1.2当量)和碳酸钾(0.62克，4.5毫摩尔，1.5当量)，常温搅拌过夜，反应结束后，50毫升水，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析分离纯化得到产物6-氟-2-甲基苯并呋喃-5-甲酸甲酯(0.30克，收率48.1％)。LCMS(ESI):m/z 209[M+1]+。
步骤53b：1-(6-氟-2-甲基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(1-(6-fluoro-2-methylbenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)prop-2-en-1-one)(化合物0305-69)。在氮气的氛围下，将甲基膦酸二甲酯(402毫克，3.24毫摩尔，1.5当量)溶解于5毫升的干燥的四氢呋喃中。用干冰/乙醇冷却到-60℃，缓慢滴加入正丁基锂(1.70毫升，2.5摩尔/毫升的正己烷溶液，4.32毫摩尔，2当量)。混合物在此温度下搅拌反应30分钟，再缓慢滴加化合物6-氟-2-甲基苯并呋喃-5-甲酸甲酯(0303-69)(450毫克，2.16毫摩尔，1当量)的四氢呋喃(5毫升)溶液。混合物在此条件下搅拌反应1小时。加入异丙醇(15毫升)， 碳酸铯(1.0克，3.24毫摩尔，1.5当量)和2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(894毫克，2.16毫摩尔，1当量)在室温下搅拌反应16小时，反应结束后，加入水(50毫升)，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析分离纯化得到产物1-(6-氟-2-甲基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(530毫克，收率41.9％)。LCMS(ESI):m/z 589[M+1]+。
步骤53c.1-(6-氟-2-甲基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(6-fluoro-2-methylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)-ethan-1-one)(化合物0306-69)的制备。将化合物1-(6-氟-2-甲基苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-4-基)苯基)丙烷-2-烯-1-酮(0305-69)(530毫克，0.90毫摩尔，1当量)和醋酸(3毫升)混合于甲醇(15毫升)中。混合物在90℃下搅拌反应16小时。反应结束后，用2N氢氧化钠水溶液调节pH值至12，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到产物1-(6-氟-2-甲基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(350毫克，粗品)为黄色固体。LCMS(ESI):m/z 347[M+1]+。
步骤53d：1-(6-氟-2-甲基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(6-fluoro-2-methylbenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物69)的制备:将1-(6-氟-2-甲基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0306-69)(350毫克，1.01毫摩尔，1.0当量)溶解到30毫升甲醇中，冰浴中，冷却至0℃，加入硼氢化钠(77毫克，2.02毫摩尔，2.0当量)，搅拌反应半小时，加入丙酮，减压浓缩，加入二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝30:1～15:1)，得到产物1-(6-氟-2-甲基苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(200毫克，收率：56.8％)黄色固体。LCMS(ESI):m/z 349[M+1]+。熔点：78～80℃；1H NMR(400MHz,DMSO)δ8.24-8.08(m,1H),7.63-7.57(m,2H),7.45–6.90(m,5H),6.51(m,1H),5.81(m,1H),5.63-5.51(m,1H),5.37-5.24(m,1H),3.07-2.62(m,2H),2.44-2.38(m,3H).
实施例54：5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)苯并呋喃-2-羧酸乙酯(ethyl5-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)benzofuran-2-carboxylate)(化合物89)的制备(按照方案五线路制备)
步骤54a：5-溴苯并呋喃-2-羧酸乙酯(ethyl 5-bromobenzofuran-2-carboxylate)(化合物0505-89)的制备:将5-溴水杨醛(0504-89)(5克，25毫摩尔，1.0当量)和碳酸铯(8.2克，25毫摩尔，1.0当量)混合于80毫升DMF，往里滴加溴乙酸乙酯(8.3克，50毫摩尔，2.0当量)，滴加完后，室温下反应半小时。升温至120℃反应两小时，液质检测反应完全，冷却至室温， 将其倒入冰水中，搅拌半小时。过滤，滤饼用水洗，干燥得到黄色粉末固体产物5-溴苯并呋喃-2-羧酸乙酯(4克，59.7％)。LCMS(ESI):m/z 269[M+1]+。
步骤54b：5-乙酰基苯并呋喃-2-羧酸甲酯(ethyl 5-acetylbenzofuran-2-carboxylate)(化合物0506-89)的制备：氮气保护下，将化合物5-溴苯并呋喃-2-羧酸乙酯(0505-89)(2克，7.43毫摩尔，1.0当量)，丁基乙烯基醚(7.4克，74.3毫摩尔，10当量)，醋酸钯(33毫克，0.15毫摩尔，0.02当量)，双(2-二苯基磷苯基)醚(120毫克，0.22毫摩尔，0.03当量)和二异丙基乙胺(2.4毫克，18.6毫摩尔，2.5当量)混合于50毫升正丁醇。升温至90℃反应18小时，冷却到室温，过滤，旋干溶剂。将残留物溶于30毫升四氢呋喃，加入5毫升2摩尔每升的盐酸溶液，搅拌过夜，用乙酸乙酯萃取，分液，饱和食盐水洗，旋干，用硅胶柱层析纯化(洗脱剂为石油醚/乙酸乙酯＝20/1到7/1)，得到白色固体产物5-乙酰基苯并呋喃-2-羧酸甲酯(870毫克，收率：50.6％)。LCMS(ESI):m/z 233[M+1]+。
步骤54c：5-(2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙酰基)苯并呋喃-2-羧酸乙酯(ethyl5-(2-(5H-imidazo[5,1-a]isoindol-5-yl)acetyl)benzofuran-2-carboxylate)(化合物0507-89)的制备:将5-乙酰基苯并呋喃-2-羧酸甲酯(0506-89)(200毫克，0.86毫摩尔，1.0当量)和2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(534毫克，1.3毫摩尔，1.5当量)溶于乙醇(10毫升)中，冰浴条件下往里滴加浓硫酸5毫升，升温至90℃，搅拌反应18小时。冷却至室温，滴加到冰水中，冰浴条件下，往里加入氢氧化钠调节pH>8，乙酸乙酯萃取，分液，旋干，粗产品用硅胶柱层析纯化(洗脱剂为二氯甲烷/甲醇＝200/1到40/1)得到产物5-(2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙酰基)苯并呋喃-2-羧酸乙酯(95毫克，28.5％)。LCMS(ESI):m/z 387[M+1]+。
步骤54d：5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)苯并呋喃-2-羧酸乙酯(ethyl5-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)benzofuran-2-carboxylate)(化合物89)的制备：将5-(2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙酰基)苯并呋喃-2-羧酸乙酯(0507-89)(40毫克，0.1毫摩尔，1.0当量)溶解到5毫升乙醇中，加入硼氢化钠(19毫克，0.5毫摩尔，5.0当量)，搅拌反应半小时，液质检测反应完全，往里加入水，再加入二氯甲烷萃取，有机相用水和饱和食盐水洗，减压浓缩，用制备TLC纯化(展开剂：二氯甲烷：甲醇＝20:1+氨水+无水硫酸钠干燥)，得到白色固体产物5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)苯并呋喃-2-羧酸乙酯(27毫克，收率：67.5％)。LCMS(ESI):m/z 389[M+1]+。熔点：110～120℃；1H NMR(300MHz,DMSO)δ8.18-7.66(m,6H),7.58-7.22(m,4H),5.93(m,1H),5.56(m,1H),5.11(m,1H),4.36(q,J＝7.1Hz,2H),2.38-1.88(m,2H),1.34(t,J＝7.1Hz,3H)。
实施例55：5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)苯并呋喃-2-羧酸酰胺(5-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)benzofuran-2-carboxamide)(化合物 90)的制备(按照方案五线路制备)
步骤55a：5-(2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙酰基)苯并呋喃-2-羧酸酰胺(5-(2-(5H-imidazo[5,1-a]isoindol-5-yl)acetyl)benzofuran-2-carboxamide)(化合物0507-90)的制备。在闷罐中，将5-(2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙酰基)苯并呋喃-2-羧酸乙酯(0507-89)(60毫克，0.16毫摩尔，1.0当量)溶于6毫升THF，往里滴加氨水(4毫升)，升温至90℃反应18小时。冷却到室温，旋干溶剂，用制备TLC纯化(展开剂：二氯甲烷：甲醇＝15:1+氨水+无水硫酸钠干燥)，得到白色固体产物5-(2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙酰基)苯并呋喃-2-羧酸酰胺(30毫克，收率：54.5％)。LCMS(ESI):m/z 358[M+1]+。
步骤55b：5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)苯并呋喃-2-羧酸酰胺(5-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)benzofuran-2-carboxamide)(化合物90)的制备：将5-(2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙酰基)苯并呋喃-2-羧酸酰胺(0507-90)(25毫克，0.07毫摩尔，1.0当量)溶解到4毫升甲醇中，加入硼氢化钠(13毫克，0.35毫摩尔，5.0当量)，搅拌反应半小时，液质检测反应完全，往里加入水，再加入二氯甲烷萃取，有机相用水和饱和食盐水洗，减压浓缩，用制备TLC纯化(展开剂：二氯甲烷：甲醇＝12:1)，得到黄色固体产物5-(1-羟基-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙基)苯并呋喃-2-羧酸酰胺(10毫克，收率：40％)。LCMS(ESI):m/z 360[M+1]+。熔点：65～70℃；1H NMR(500MHz,DMSO)δ8.09-7.11(m,10H),5.90-5.80(m,1H),5.53-5.32(m,1H),5.10(m,1H),2.39-1.85(m,2H).
实施例56：1-(6-溴苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(6-bromobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物156)的制备(按照方案二线路制备)
步骤56a：2-溴-4-羟基苯甲酸(2-bromo-4-hydroxybenzoic acid)(化合物0201-156)的制备:将2-溴-4-羟基苯甲醛(1.7克，8.46毫摩尔，1.0当量)溶解于2摩尔每升的氢氧化钠水溶液(30毫升)中，冰浴条件下，分批加入高锰酸钾(2.7克，616.92毫摩尔，2.0当量)，升到室温搅拌2小时。过滤，滤液用二氯甲烷洗涤一次，往滤液中加入2摩尔每升的盐酸水溶液调节pH至1，用乙酸乙酯萃取，有机相用无水硫酸钠干燥，旋干，得到白色固体产物2-溴-4-羟基苯甲酸(1.6克，88％)。LCMS(ESI):m/z 217[M+1]+。
步骤56b：2-溴-4-羟基苯甲酸甲酯methyl 2-bromo-4-hydroxybenzoate(化合物0202-156)的制备:氮气保护条件下，将化合物2-溴-4-羟基苯甲酸(0201-156)(1.6克，7.4毫摩尔，1当量)溶解于30毫升甲醇，冰浴下缓慢滴加入氯化亚砜(4毫升)。升温到55℃反应过夜，反应结束后，减压浓缩，加入水，用乙酸乙酯萃取，干燥，旋干，得到淡黄色固体产物2-溴-4-羟基苯甲酸甲酯(1.7克，收率：100％)。LCMS(ESI):m/z 231[M+1]+。
步骤56c：2-溴-4-羟基-5-碘苯甲酸甲酯(methyl 2-bromo-4-hydroxy-5-iodobenzoate)(化合物0204-156)的制备：将2-溴-4-羟基苯甲酸甲酯(0202-156)(1.0克，4.33毫摩尔，1.0当量)和碳酸钾(1.2克，8.66毫摩尔，2.0当量)混合于四氢呋喃(50毫升)中，往里滴加碘单质(1.43克，5.63毫摩尔，1.3当量)溶于20毫升的四氢呋喃溶液，滴加完后，室温下反应18小时。反应液用亚硫酸钠水溶液洗涤，水洗，饱和食盐水洗，干燥，旋干，粗产品用二氯甲烷打浆，过滤，滤饼用二氯甲烷洗涤，干燥得到白色固体产物2-溴-4-羟基-5-碘苯甲酸甲酯(1.0克，65％)。LCMS(ESI):m/z 257[M+1]+。
步骤56d：6-溴苯并呋喃-5-羧酸甲酯(methyl 6-bromobenzofuran-5-carboxylate)(化合物0206-156)的制备：在氮气保护下，将2-溴-4-羟基-5-碘苯甲酸甲酯(0204-156)(1克，2.8毫摩尔，1.0当量)，三甲基硅乙炔(550毫克，5.6毫摩尔，2.0当量)，碘化亚铜(8.0毫克，0.042毫摩尔，0.015当量)，二三苯基膦二氯化钯(60毫克，0.084毫摩尔，0.03当量)和三乙胺(2毫升)加入到50毫升四氢呋喃中，加热至60℃，搅拌反应18小时。冷却至室温，减压浓缩，往浓缩液中甲醇(20毫升)，N，N-二异丙基乙胺(1毫升)和碘化亚铜(100毫克)，于60℃下反应2小时。旋干溶剂，往里加入四氢呋喃(30毫升)和四丁基氟化铵(1克)，加热回流反应20分钟。冷却到室温，加入石油醚20毫升和乙酸乙酯20毫升，水洗，饱和食盐水洗，旋干，经过硅胶柱层析分离纯化(洗脱剂：石油醚：乙酸乙酯＝25：1)，得到产物黄色固体6-溴苯并呋喃-5-羧酸甲酯(250毫克，收率：35.7％)。LCMS(ESI):m/z 255[M+1]+。
步骤56e：(2-(6-溴苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(dimethyl(2-(6-bromobenzofuran-5-yl)-2-oxoethyl)phosphonate)(化合物0207-156)的制备：在氮气保护条件下，将甲基膦酸二甲酯(119毫克，0.96毫摩尔，1.5当量)溶解于10毫升的干燥的四氢呋喃中。用干冰/乙醇冷却到-70℃，缓慢滴加入正丁基锂(0.4毫升，0.96毫摩尔，1.5当量)。滴加完后，在此温度下反应30分钟，再缓慢滴加化合物6-溴苯并呋喃-5-羧酸甲酯(0206-156)(100毫克，0.64毫摩尔，1.0当量)的四氢呋喃(2毫升)溶液。滴加完后，在此条件下反应1小时。反应结束后，加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到黄色油状产物(2-(6-溴苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(200毫克，收率：90.1％)。LCMS(ESI):m/z 347[M+1]+。
步骤56f：1-(6-溴苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烷-2-烯-1-酮(1-(6-bromobenzofuran-5-yl)-3-(2-(1-trityl-1H-imidazol-5-yl)phenyl)prop-2-en-1-one)(化合物0208-156)的制备：将2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(240毫克，0.58毫摩尔，1.0当量)，(2-(6-溴苯并呋喃-5-基)-2-氧代乙基)磷酸二甲酯(0207-156)(200毫克，0.58毫摩尔，1.0当量)和碳酸铯(378毫克，1.16毫摩尔，2.0当量)混合于异丙醇(10毫升)中，室温下 反应18小时。反应结束后，用水淬灭，乙酸乙酯萃取，无水硫酸钠干燥，旋干得到黄色固体产物1-(6-溴苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烷-2-烯-1-酮(350毫克，收率：94.8％)。LCMS(ESI):m/z 635[M+1]+。
步骤56g:1-(6-溴苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(6-bromobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0209-156)的制备:将化合物1-(6-溴苯并呋喃-5-基)-3-(2-(1-三苯甲基-1H-咪唑-5-基)苯基)丙烷-2-烯-1-酮(0208-156)(350毫克，0.55毫摩尔，1当量)和醋酸(8毫升)混合于甲醇(16毫升)中，加热至回流反应16小时。反应结束后，用2N氢氧化钠水溶液调节pH值至12，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝150:1～50:1)，得到产物黄色固体1-(6-溴苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(180毫克，收率：82.9％)。LCMS(ESI):m/z 393[M+1]+。
步骤56h：1-(6-溴苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(6-bromobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物156)的制备：将1-(6-溴苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(130毫克，0.33毫摩尔，1.0当量)溶解到10毫升甲醇中，冰浴中，加入硼氢化钠(25毫克，0.66毫摩尔，2.0当量)，搅拌反应半小时，往里加入水淬灭，用二氯甲烷萃取，用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，经过硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝30:1～15:1)，得到白色固体产物1-(6-溴苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(100毫克，收率：76.9％)。LCMS(ESI):m/z 335[M+1]+。熔点：85～95℃；1H NMR(300MHz,DMSO)δ8.04-8.00(m,2H),7.89-7.82(m,2H),7.67-7.61(m,2H),7.46-7.24(m,2H),7.19-7.02(m,2H),6.10-6.01(m,1H),5.55(m,1H),5.39(m,1H),2.26-2.16(m,2H).
实施例57：1-(2-氯苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(2-chlorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物157)的制备(按照方案五线路制备)
步骤57a：1-(2-氯苯并呋喃-5-基)乙烷-1-酮(1-(2-chlorobenzofuran-5-yl)ethan-1-one)(化合物0506-157)的制备:氮气保护下，将化合物5-溴苯并呋喃(0505-157)(1克，5.1毫摩尔，1.0当量)，丁基乙烯基醚(2.55克，25.5毫摩尔，5当量)，醋酸钯(114毫克，0.51毫摩尔，0.1当量)，1,3-双(二苯基磷)丙烷(210毫克，0.51毫摩尔，0.1当量)和三乙胺(1.55克，1.53毫摩尔，3.0当量)混合于30毫升乙二醇。升温至120℃反应18小时，冷却到室温，倒入水中，用乙酸乙酯萃取，分液，饱和食盐水洗，旋干，用硅胶柱层析纯化(洗脱剂为石油醚/乙酸乙酯＝50/1到40/1)，得到淡黄色油状物5-(2-甲基-1,3-二氧戊烷-2-基)苯并呋喃(950毫克，收率： 92.2％)。LCMS(ESI):m/z 205[M+1]+。在氮气保护下，将上述化合物5-(2-甲基-1,3-二氧戊烷-2-基)苯并呋喃(204毫克，1毫摩尔，1.0当量)溶于10毫升无水四氢呋喃中，降温到-70℃，往里滴加正丁基锂(0.8毫升，2毫摩尔，2.0当量)，滴加完后，保持温度搅拌半小时，再往里滴加六氯乙烷(474毫克，2毫摩尔，2.0当量)的四氢呋喃(4毫升)溶液，滴加完后，保持温度搅拌半小时。往里加入氯化铵水溶液，搅拌10分钟，分液，水相用乙酸乙酯萃取一遍，合并有机相，旋干，用硅胶柱层析纯化(洗脱剂为石油醚/乙酸乙酯＝100/1到40/1)，得到无色油状化合物2-氯-5-(2-甲基-1,3-二氧戊烷-2-基)苯并呋喃(150毫克，收率：62.8％)。LCMS(ESI):m/z 239[M+1]+。将化合物2-氯-5-(2-甲基-1,3-二氧戊烷-2-基)苯并呋喃(150毫克，0.63毫摩尔，1.0当量)溶于无水四氢呋喃于6毫升，往里加入2摩尔每升盐酸(0.5毫升)，升温回流反应半小时。冷却到室温，加水，用乙酸乙酯萃取，干燥，旋干，得到白色固体产物1-(2-氯苯并呋喃-5-基)乙烷-1-酮(120毫克，收率：98.4％)。LCMS(ESI):m/z 195[M+1]+。
步骤57b：1-(2-氯苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(1-(2-chlorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-one)(化合物0507-157)的制备:将1-(2-氯苯并呋喃-5-基)乙烷-1-酮(0506-157)(120克，0.61毫摩尔，1.0当量)和2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛(0105-1)(380毫克，0.92毫摩尔，1.5当量)溶于10毫升二氧六环中，冰浴条件下往里滴加浓硫酸1毫升，升温至90℃，搅拌反应18小时。冷却至室温，滴加到冰水中，冰浴条件下，往里加入氢氧化钠调节pH>8，乙酸乙酯萃取，分液，旋干，粗产品用硅胶柱层析纯化(洗脱剂为二氯甲烷/甲醇＝200/1到40/1)得到产物1-(2-氯苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(100毫克，46.5％)。LCMS(ESI):m/z 349[M+1]+。
步骤57c：1-(2-氯苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(1-(2-chlorobenzofuran-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol)(化合物157)的制备:将1-(2-氯苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-酮(0507-157)(30毫克，0.086毫摩尔，1.0当量)溶解到5毫升甲醇中，室温下加入硼氢化钠(16毫克，0.43毫摩尔，5.0当量)，搅拌反应半小时，液质检测反应完全，往里加入水，再加入二氯甲烷萃取，减压浓缩，用制备HPLC纯化得到黄色固体产物1-(2-氯苯并呋喃-5-基)-2-(5H-咪唑[5,1-a]异吲哚啉-5-基)乙烷-1-醇(25毫克，收率：83.3％)。LCMS(ESI):m/z 351[M+1]+。熔点：68～79℃；
1H NMR(400MHz,DMSO)δ8.04-7.00(m,10H),5.90-5.79(m,1H),5.52-5.38(m,1H),5.07(m,1H),2.37-1.84(m,2H).
实施例58生物活性试验
一、IDO1酶活性抑制实验
1、实验方法
参照Jsamu Hayaishi et al方法(J.BIO.CHEM.255:1339-1345,1980)，测定待测化合物对IDO1酶转换L-色氨酸(L-Trp)生成犬尿氨酸kynurenine(Kyn)的抑制活性。
将待测化合物或参照化合物(NLG919)用DMSO溶解和稀释成不同浓度，采用96孔板(Corning,Cat.No.3635)，每孔中加入2ul化合物和98ul 2×IDO-1(BPS,Cat#71182)酶溶液，室温下孵育15分钟。加入100ul 2×L-色氨酸(Sigma,Cat.No.93659-10G)底物溶液。上述200ul反应溶液包含50mM pH值6.5磷酸钾缓冲，0.02mM亚甲蓝(Sigma,Cat.No.M9140-100G)、20mM抗坏血酸盐(Sigma,Cat.No.11140-250G)，0.1mM L-色氨酸(Sigma,Cat.No.93659-10G)，0.2mg/ml过氧化氢酶(Sigma,Cat.No.C9322-5G)。无化合物对照孔是0.2ml含酶与底物的反应液和1％DMSO(阳性对照),无酶活性对照孔是0.2ml无酶有底物的混合液和1％DMSO(阴性对照)。
采用Spectramax读取吸光度321nm动力学吸收值并计算斜率数据。
％抑制率＝(阳性对照-化合物孔值)/(阳性对照-阴性对照)×100。
使用GraphPad Prism 5.0软件拟合曲线并计算IC50。
2、实验结果
本发明的含咪唑稠合三环类化合物能抑制IDO1酶活性。在IDO1活酶性抑制实验检测中，使用下述级别：对于IC50而言，I>3000nM,3000nM≧II>1000nM,1000nM≧III>500nM,500nM≧IV>200nM,V≦200nM。结果见表1。
表1IDO1酶活性抑制结果
Figure PCTCN2017100722-appb-000027
Figure PCTCN2017100722-appb-000028
注：表中化合物的编号同实施例1-57中的化合物编号。
二、Hela细胞实验
1、实验方法
Hela细胞购自上海复旦IBS细胞资源中心。用胰酶将细胞从细胞培养盘上消化和DPBS培养基重悬后，Scepter自动细胞计数仪(Millipore，Cat.No.PHCC00000)计数测定细胞密度。采用细胞培养液将细胞稀释成每毫升含56,000个细胞的溶液。调整密度后的细胞液以每孔180微升加入96孔板中，每孔加入20ul含10ng/ml重组人类干扰素γ(R&D,Cat.No.CAA31639)和不同浓度的待测化合物或参照化合物的细胞培养液；最大酶活性对照孔加入20ul含10ng/ml干扰素γ和10％DMSO的细胞培养液；空白对照孔加入20ul含10％DMSO和不含干扰素γ的细胞培养液。在37℃、5％CO2培养箱，培养24小时后，每孔取出140ul培养上清至新的96孔板中，加入10μl 6.1N三氯乙酸混匀。放置于50℃孵育30分钟，2500rpm离心10分钟，取100ul上清至新的96孔板中，加入100ul 2％对二甲基氨基苯甲醛(乙酸溶解)， 混匀。用酶标仪Thermo Scientific MULTISKAN MK3检测波长480nm信号。抑制率％＝(最大酶活性对照孔的信号值-化合物孔的信号值)/(最大酶活性对照孔的信号值-空白对照孔的信号值)×100％。使用GraphPad Prism 5.0软件拟合曲线并计算IC50。
2、实验结果
人宫颈癌Hela细胞可由促炎细胞活素诱导内源性IDO1表达。尽管IDO1，IDO2和TDO都可以分解代谢色氨酸生产犬尿氨酸，但是在Hela细胞中，干扰素γ刺激IDO1表达的同时，对IDO2和TDO没有影响(Blood,115:3520,2010)。在检测中，本发明的含咪唑稠合三环类化合物能抑制Hela细胞的IDO1酶活性。在这些检测中，使用下述级别：对于IC50而言，I>3000nM,3000nM≧II>1000nM,1000nM≧III>500nM,500nM≧IV>200nM,V≦200nM。结果见表2。
表2Hela细胞实验结果
Figure PCTCN2017100722-appb-000029
Figure PCTCN2017100722-appb-000030
注：表中化合物的编号同实施例1-57中的化合物编号。
三、药代动力学(PK)实验
1、实验方法
雄性SD大鼠，体重300-350克，试验前过夜禁食。待测化合物溶解在30％磺丁基-β-环糊精(SBE-β-CD)中，以20mg/kg灌胃给药。给药后15分钟、30分钟和1、2、3、4、6、8及24小时尾端断口取血，每时间点约0.3ml，置于含K2-EDTA的离心管中，离心处理(2,000g，10分钟，4℃)取血浆，储存在-80℃的超低温冰箱中。50μL的血浆样品与5微升内标(IS)混合，用乙酸乙酯萃取。真空干燥后残留物重新溶于乙腈中。对样品进行过滤，并注入到LC-MS/MS分析。
2、实验结果
本发明提供的化合物2、化合物8、化合物11、化合物36、化合物42在大鼠经口服给药后，吸收良好，血液暴露量较高。结果见图3和表3，本发明的含咪唑稠合三环类化合物Tmax为0.5-1.1小时，Cmax为930-2769ng/ml，是参照化合物NLG919Cmax的7.1-21.1倍；AUC0-24h为1538-11099ng/ml*h,是参照化合物NLG919AUC0-24h的3.6-26.3倍。Cmax是指最大血药浓度，T1/2为半衰期，AUC0-24是指0-24小时时间-浓度曲线下面积，AUC0-inf是指0-Inf时间-浓度曲线下面积。
表3.大鼠灌胃给药(20mg/kg)药代动力学
Figure PCTCN2017100722-appb-000031
四、Caco-2药物的跨膜转运实验
1、实验方法Caco-2细胞模型是一种人克隆结肠腺癌细胞，用来进行模拟体内肠转运的实验(J Mass Spectrom 35:71-76,2000)。在HBSS培养溶液中，化合物11(10uM)和Caco-2单层细胞在37℃下培养90分钟后，采用LC-/MS/MS测定化合物转运，化合物由顶端至基底外表观通透性系数(Papp A-B)和基底外侧到顶端通透系数(Papp B-A)，分别表示化合物双向转运的能力。而外排率(Efflux Rate＝Papp B-A/Papp A-B)的高低反映化合物发生主动外排作用的强弱。
2、实验结果：本试验条件下，如果药物表观通透性系数Papp A-B>10×106cm/s，表明药物通透性高。化合物11的表观通透性系数Papp A-B值和Papp B-A分别为49.8×106cm/s和26.5×106cm/s，提示该化合物通过肠道的吸收率很高。因为外排率(Papp B-A/Papp A-B)<1.0,表示化合物11的外排作用弱。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (28)

  1. 具有式(I)所示结构的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子：
    Figure PCTCN2017100722-appb-100001
    其中：
    n选自：0，1，2，3或4；
    X选自CR6或N；
    Y选自(CH2)y或CR7R8，其中，y选自0或1；
    W选自(CH2)z，CR7R8或-N(R)2，其中，z选自0或1；
    R1选自：H，卤素，C1-C6烷基，C2-C6烯基，C2-C6炔基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代的C1-C6烷基，硝基，氰基，-OR，-N(R)2，-SR，-C(O)OR，-C(O)N(R)2，-C(O)R，-S(O)R，-S(O)2R，-S(O)2N(R)2，-N(R)C(O)R；
    R2和R3分别独立选自：H，卤素，C1-C6烷基，C2-C6烯基，C2-C6炔基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代的C1-C6烷基，硝基，氰基，-OR，-N(R)2，-SR，-C(O)R,-C(O)OR,-C(O)N(R)2,-S(O)R，-S(O)2R，-S(O)2N(R)2,-N(R)C(O)R；
    R4和R5分别独立选自：H，卤素，C1-C6烷基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，-OR，-N(R)2，-SR，氰基，硝基，-C(O)OR，-C(O)N(R)2，-C(O)R，-S(O)R，-S(O)2R，-S(O)2N(R)2,-N(R)C(O)R；或R4和R5一起形成G，G选自＝O或＝N-OR；
    R6选自：H，卤素，C1-C6烷基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，-OR；
    R7和R8分别独立选自：C1-C6烷基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基， 烷氧基取代的C1-C6烷基，-OR，-N(R)2，-SR，-S(O)2R；
    R选自：H，C1-C6烷基，C2-C6烯基，C2-C6炔基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基的取代C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代的C1-C6烷基；
    环A选自8-16元取代的或未取代的双环并环或三环并环，所述双环并环或三环并环为饱和、部分不饱和或芳香的双环并环或三环并环，所述双环并环或三环并环的环上的原子选自C、O、N和S中的一种或化学上可接受的几种的组合。
  2. 根据权利要求1所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，环A选自：
    Figure PCTCN2017100722-appb-100002
    其中：
    m选自0,1或2；
    X1、X2、X3、X4、X5、X6、X7分别独立选自CR9或N；
    R9选自：H，卤素，C1-C6烷基，C2-C6烯基，C2-C6炔基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基 取代的C1-C6烷基,烷基胺基取代的C1-C6烷基，芳基，杂芳基，硝基，氰基，-OR，-N(R)2，-SR，-C(O)OR，-C(O)N(R)2，-C(O)R，-S(O)R，-S(O)2R，-S(O)2N(R)2，-N(R)C(O)R；
    R10选自：H，C1-C6烷基，C2-C6烯基，C2-C6炔基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代的C1-C6烷基；
    R选自：H，C1-C6烷基，C2-C6烯基，C2-C6炔基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代的C1-C6烷基。
  3. 根据权利要求2所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，环A选自：
    Figure PCTCN2017100722-appb-100003
  4. 根据权利要求3所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，环A选自：
    Figure PCTCN2017100722-appb-100004
  5. 根据权利要求4所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，环A选自：
    Figure PCTCN2017100722-appb-100005
  6. 根据权利要求2-5任一项所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，X1、X2、X3、X4、X5、X6、X7分别独立选自CR9。
  7. 根据权利要求2-5任一项所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，
    R9选自：H，卤素，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代C1-C6烷基，芳基，硝基，氰基，-OR，-N(R)2，-SR，-C(O)OR，-C(O)N(R)2，-C(O)R；
    R选自：H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代的C1-C6烷基。
  8. 根据权利要求7所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，
    R9选自：H，卤素，C1-C6烷基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，苯基，硝基，氰基，-OR，-N(R)2，-C(O)OR，-C(O)N(R)2，-C(O)R。
  9. 根据权利要求8所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，
    R9选自：H，卤素，C1-C6烷基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，苯基，-OR，-C(O)OR，-C(O)N(R)2；R选自：H，C1-C6烷基。
  10. 根据权利要求9所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，
    R9选自：H，卤素，甲基，三氟甲基，甲氧基，羟甲基，羟基异丙基，苯基，-C(O)OC2H5，-C(O)NH2。
  11. 根据权利要求2-5任一项所述的含咪唑稠合三环类化合物或者其药学上可接受的盐 或者其立体异构体或者其前药分子，其特征在于，
    R10选自：H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代的C1-C6烷基。
  12. 根据权利要求11所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R10选自H或C1-C6烷基。
  13. 根据权利要求1-5任一项所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，具有式II或式III所示结构：
    Figure PCTCN2017100722-appb-100006
  14. 根据权利要求1-5任一项所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，
    X为CR6；
    Y选自CH2或CR7R8；
    W为(CH2)z，z选自0或W为-N(R)2；
    R6选自H或C1-C6烷基；
    R7和R8分别独立选自：C1-C6烷基，-OR，-N(R)2，-SR；
    R选自：H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代的C1-C6烷基。
  15. 根据权利要求14所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，具有式IV所示结构：
    Figure PCTCN2017100722-appb-100007
  16. 根据权利要求1-5任一项所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，
    n选自0，1或2；
    R1选自：H，卤素，C1-C6烷基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，硝基，氰基，-OR，-N(R)2，-SR，-C(O)OR，-C(O)N(R)2，-C(O)R，-S(O)R，-S(O)2R，-S(O)2N(R)2，-N(R)C(O)R；
    R选自：H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代的C1-C6烷基。
  17. 根据权利要求16所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，
    n选自0，1或2；
    R1选自：H，卤素，-OR，R为C1-C6烷基。
  18. 根据权利要求1-5任一项所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，
    R2和R3分别独立选自：H，卤素，C1-C6烷基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，硝基，氰基，-OR，-N(R)2，-SR，-S(O)R，-S(O)2R，-S(O)2N(R)2,-N(R)C(O)R；
    R选自：H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代的C1-C6烷基。
  19. 根据权利要求18所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R2和R3分别独立选自：H，卤素。
  20. 根据权利要求1-5任一项所述的含咪唑稠合三环类化合物或者其药学上可接受的盐 或者其立体异构体或者其前药分子，其特征在于，
    R4和R5分别独立选自：H，羟基取代的C1-C6烷基，-OR，-N(R)2，-SR，氰基，硝基，-C(O)OR，-C(O)N(R)2，-C(O)R，-S(O)R，-S(O)2R，-S(O)2N(R)2,-N(R)C(O)R；或R4和R5一起形成G，G选自＝O或＝N-OR；
    R选自：H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,烷基胺基取代的C1-C6烷基。
  21. 根据权利要求20所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，
    R4和R5分别独立选自：-OR，或R4和R5一起形成G，G选自＝O或＝N-OR；
    R选自：H，C1-C6烷基。
  22. 根据权利要求21所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R4和R5中的一个选自H，另一个选自-OH。
  23. 根据权利要求1所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，选自如下化合物：
    Figure PCTCN2017100722-appb-100008
    Figure PCTCN2017100722-appb-100009
    Figure PCTCN2017100722-appb-100010
    Figure PCTCN2017100722-appb-100011
    Figure PCTCN2017100722-appb-100012
    Figure PCTCN2017100722-appb-100013
    Figure PCTCN2017100722-appb-100014
    Figure PCTCN2017100722-appb-100015
    Figure PCTCN2017100722-appb-100016
    Figure PCTCN2017100722-appb-100017
  24. 权利要求1-23任一项所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备IDO1抑制剂中的应用。
  25. 权利要求1-23任一项所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备防治肿瘤的药物中的应用。
  26. 根据权利要求25所述的应用，其特征在于，所述肿瘤为实体肿瘤或血液肿瘤；所述实体肿瘤为乳腺癌、胰腺癌、肺癌、肝癌、胃癌、结肠癌、肾癌、前列腺癌、头颈肿瘤、食道癌、卵巢癌或宫颈癌；所述血液肿瘤为淋巴瘤、白血病或骨髓瘤。
  27. 一种防治肿瘤的药物组合物，其特征在于，其活性成分包含权利要求1-23任一项所述的含咪唑稠合三环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子。
  28. 根据权利要求27所述的防治肿瘤的药物组合物，其特征在于，所述肿瘤包括：乳腺癌、胰腺癌、肺癌、肝癌、胃癌、结肠癌、肾癌、前列腺癌、头颈肿瘤、食道癌、卵巢癌、宫颈癌、淋巴瘤、白血病和骨髓瘤。
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