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WO2025140637A1 - Tdg inhibitor compound and use thereof - Google Patents

Tdg inhibitor compound and use thereof Download PDF

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Publication number
WO2025140637A1
WO2025140637A1 PCT/CN2024/143412 CN2024143412W WO2025140637A1 WO 2025140637 A1 WO2025140637 A1 WO 2025140637A1 CN 2024143412 W CN2024143412 W CN 2024143412W WO 2025140637 A1 WO2025140637 A1 WO 2025140637A1
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French (fr)
Chinese (zh)
Inventor
吴海平
米沅
王猛
郭剑南
富兴年
王龙
刘依林
石慧
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Cytosinlab Therapeutics Co Ltd
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Cytosinlab Therapeutics Co Ltd
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Definitions

  • the invention belongs to the field of pharmaceutical chemistry, and in particular relates to a compound for inhibiting TDG activity and a preparation method and application thereof.
  • TDG Human thymine DNA glycosylase
  • BER DNA base-excision repair
  • TDG can recognize the mismatched bases and hydrolyze the N-glycosidic bond of U or T to form an apurinic/apyrimidinic site (AP site).
  • AP site apurinic/apyrimidinic site
  • TDG can also promote apurinic/apyrimidinic endonuclease 1 (APE1) to bind to the AP site, cut the phosphodiester bond at the 5' end of the abasic deoxynucleic acid, and other proteins and bases involved in the repair are added to finally repair the DNA.
  • APE1 apurinic/apyrimidinic endonuclease 1
  • TDG is a key enzyme in the active DNA demethylation pathway mediated by oxidation and the BER pathway.
  • 5-methylcytosine (5mC) is oxidized to 5-carboxycytosine (5caC) by a class of TET (ten-eleven-translocation protein) dioxygenases.
  • TET ten-eleven-translocation protein
  • the TDG enzyme specifically recognizes and removes 5caC, and then activates the BER pathway to replace the original 5mC with cytosine, thereby achieving DNA demethylation.
  • DNA methylation is an important epigenetic modification.
  • TDG participates in epigenetic regulation by mediating active DNA demethylation, and plays an important role in gene expression regulation, embryonic growth and development, and hematopoietic stem cell differentiation.
  • TDG can promote tumorigenesis and may be a potential target for cancer therapy. Studies have shown that TDG is overexpressed in some human colorectal carcinoma (CRC) patients. TDG acts as a positive regulator of WNT signaling by acting as an adaptor protein for the transcription factor TCF4 and recruiting CBP/p300. Stable transfection of TDG shRNA into several CRC cell lines inhibited cell growth. Importantly, stable knockdown of TDG expression reduced the ability of CRC cells to form tumors in xenograft experiments, indicating that TDG is essential for CRC cell proliferation in vivo. In addition, knockdown of TDG can inhibit tumor formation in melanoma cell lines in xenograft models, indicating that TDG activity is essential for tumor induction and/or progression. Therefore, it is very necessary and meaningful to develop specific small molecule inhibitors targeting TDG.
  • CRC human colorectal carcinoma
  • the purpose of the present invention is to provide a highly efficient small molecule inhibitor targeting TDG.
  • R 2 is each independently selected from the group consisting of H, halogen, substituted or unsubstituted C 1 -C 6 alkyl;
  • n are each independently 0, 1, 2 or 3;
  • R4 is selected from the following group: H, halogen, cyano, substituted or unsubstituted C1 - C6 alkoxy, substituted or unsubstituted C1 - C6 amine, substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted C3- C8 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic ring, substituted or unsubstituted 5-12 membered heteroaromatic ring, substituted or unsubstituted -O-5-12 membered heteroaromatic ring,
  • R3 and R4 and the carbon atoms to which they are attached together form a structure selected from the group consisting of a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C3-C8 carbocycle, or a substituted or unsubstituted 3-10 membered heterocycle;
  • X is selected from O or S
  • Z is selected from O, S or NR 14 ; wherein R 14 is H or C 1 -C 4 alkyl;
  • the compound of formula I has a structure shown in the following formula II:
  • the compound has a structure shown in the following formula IV:
  • the B ring is a substituted or unsubstituted C3-C8 carbocycle, or a substituted or unsubstituted 3-10 membered heterocycle; preferably, the B ring is a substituted or unsubstituted C3-C6 carbocycle, or a substituted or unsubstituted 3-8 membered heterocycle; wherein, the carbocycle or heterocycle may be saturated or partially unsaturated.
  • the compound has a structure as shown in the following formula IX-A or IX-B:
  • the third aspect of the present invention provides a use of the compound as described in the first aspect, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt, or the pharmaceutical composition as described in the second aspect, for preparing a drug for treating and/or preventing diseases associated with abnormal TDG expression.
  • the disease associated with abnormal TDG expression is a tumor.
  • the tumor is selected from the following group: melanoma, acute myeloid leukemia, small cell lung cancer, non-small cell lung cancer.
  • the fourth aspect of the present invention provides a method for inhibiting TDG activity, the method comprising the steps of:
  • a fifth aspect of the present invention provides a method for treating and/or preventing a disease associated with overexpression of TDG, the method comprising the steps of:
  • the present inventors through extensive and in-depth research, unexpectedly discovered for the first time a class of compounds having TDG inhibitory activity, on the basis of which the present invention was completed.
  • the halogen is F, Cl, Br or I.
  • C1-C6 alkyl refers to a straight or branched alkyl group having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc.; preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
  • C1-C6 alkoxy refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.
  • C2-C6 alkynyl refers to a straight or branched alkynyl group having 2 to 6 carbon atoms and containing one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.
  • C1-C12 alkylaminocarbonyl refers to an alkylaminocarbonyl group having 1 to 12 carbon atoms in the alkyl chain, including but not limited to methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, dimethylaminocarbonyl and the like.
  • aromatic ring or “aryl” has the same meaning, preferably "aryl” is “C6-C12 aryl” or “C6-C10 aryl”.
  • aryl is “C6-C12 aryl” or “C6-C10 aryl”.
  • C6-C12 aryl refers to an aromatic ring group having 6 to 12 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl, etc.
  • C6-C10 aryl has a similar meaning.
  • 3-12 membered heterocyclic group refers to a saturated or unsaturated 3-12 membered ring group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen in the ring, such as dioxolanyl, etc.
  • the term “3-7 membered heterocyclic group” has a similar meaning.
  • substituted refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent.
  • the specific substituent is a substituent described above, or a substituent appearing in the embodiments.
  • a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position.
  • a cyclic substituent, such as a heterocycloalkyl may be connected to another ring, such as a cycloalkyl, to form a spiro bicyclic system, for example, two rings having a common carbon atom.
  • substituents contemplated by the present invention are those that are stable or chemically feasible.
  • the substituents include, but are not limited to, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3- to 12-membered heterocyclic groups, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C1-8 aldehyde, C2-10 acyl, C2-10 ester, C1-C12 alkoxycarbonyl, amino, alkoxy, C1-10 sulfonyl, etc.
  • the present invention provides a class of compounds having TDG inhibitory activity:
  • Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.
  • Triethylamine trihydrofluoride (59.4 mg, 368.68 umol, 60.09 uL, 0.8 eq) was added to a THF (5 mL) solution of compound (14-e) (180 mg, 460.84 umol, 1 eq) and reacted at 25 °C for 3 hours. After the reaction was completed, saturated NaHCO 3 aqueous solution (5 mL) was added to quench, and extracted with EtOAc (5 mL*3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • step 2 and step 3 in Example 2 Referring to the method of step 2 and step 3 in Example 2, (14-c-1) is replaced with the following starting material, and a two-step reaction is carried out with (14-f) to obtain the corresponding final product compound.
  • 44-B 600 mg, 2.40 mmol was used as the starting material to react and obtain colorless oil 44-A (540 mg, yield 84.59%).
  • 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.63-7.85 (m, 2H), 7.38-7.61 (m, 3H), 4.10-4.37 (m, 2H), 2.38-2.55 (m, 1H), 1.90-2.15 (m, 1H), 1.52-1.71 (m, 3H), 1.22-1.42 (m, 4H), 1.13 (s, 2H).
  • Step 1 Under microwave conditions, a mixture of compound 2-methoxy-4-(prop-2-enyloxy)benzene-1-carboxaldehyde (200 mg, 1.04 mmol, 1 eq) in N,N-dimethylaniline (2 mL) was stirred at 180 ° C for 4 hours. Cool to room temperature, dilute the reaction with EtOAc (15 mL), wash with 1M HCl (3 mL*3), and the organic phase is subjected to conventional post-treatment operation 2 to obtain a crude product.
  • the crude product was purified by silica gel column chromatography (EA/PE, EA from 7 to 15%) to obtain an off-white solid compound 284-B (50 mg, yield 25%) and a yellow solid compound 285-B (82.5 mg, yield 41.3%).
  • Step 1 A mixture of compound 14-f (1.0 g, 4.85 mmol, 1 eq) in N,N-dimethylaniline (8 mL) was stirred at 180 ° C for 8 hours. TLC showed that only a small amount of raw materials were not reacted. Cool to room temperature, dilute the reaction with EtOAc (10 mL), wash with 1M HCl (10 mL*3), and the organic phase is subjected to conventional post-treatment operations to obtain a crude product. The crude product was purified by silica gel column chromatography (EA/PE, EA from 0 to 7%) to obtain an off-white solid compound 281-B (640 mg, 3.10 mmol, yield 64%). LC-MS: (ESI) m/z[M+H] + 207.0.
  • Step 2 Dissolve compound 281-B (300 mg, 1.45 mmol) in EtOAc (30 mL), add palladium/carbon (5% content, 60 mg), and fully replace hydrogen with the reaction mixture. Stir and react at 25°C for 2 hours under a 15 Psi hydrogen atmosphere. Filter through diatomaceous earth and concentrate under reduced pressure to obtain an off-white solid compound 281-A (290 mg). The crude product is directly used in the next step.
  • Step 2 Add m-CPBA (2.79 g, 13.7 mmol, 85% purity) in batches to a solution of compound 64-C (1.0 g, 5.49 mmol) in DCM (20 mL) at 0°C and react at 25°C for 2 hours. Filter and vacuum dry to obtain a white solid compound 64-A (3.2 g, 35% purity), which is used directly in the next step.
  • step 2 and step 3 in Example 2 a two-step reaction was carried out with the following starting materials to obtain the corresponding final product compound.
  • Step 1 Dissolve compound 14-c (500 mg, 3.01 mmol, 1 eq) in an aqueous solution of hydrogen bromide (3 mL, 40% content), add paraformaldehyde (130 mg) and a catalytic amount of concentrated sulfuric acid (92 mg, 938 ⁇ mol, 50 ⁇ L), and stir at 70 ° C for 16 hours. Cool to room temperature, dilute the reaction with water (10 mL), extract with DCM (10 mL*3), and the organic phase is subjected to conventional post-treatment operations to obtain a crude product.
  • Step 3 Add 3-bromo-1-propylene (371 mg, 3.07 mmol) to a DMF (5 mL) solution of compound 283-D (430 mg) and K 2 CO 3 (707 mg, 5.11 mmol), and react at 25°C for 16 hours. After the reaction, add saturated brine (5 mL), extract with EtOAc (3 mL*3), and obtain a crude product after conventional post-treatment. The crude product is purified by silica gel column chromatography (EA:PE, EA from 0 to 5.5%) to obtain a brown oil compound 283-A (482 mg, three-step yield 64%).
  • EA:PE silica gel column chromatography
  • Step 1 Add 3-bromopropylene (2.2 g, 18 mmol) and Na 2 CO 3 (3.8 g, 36 mmol) to a mixture of 42-B (3 g, 18 mmol) in ACN (30 mL). The mixture was reacted at 70°C for 16 hours. After the reaction, the solvent was dried, water (30 mL) was added, and the mixture was extracted with EA (30 mL x 3). After conventional post-treatment operation 2, a crude product was obtained, which was purified by silica gel thin layer chromatography (THF:PE, THF from 0 to 20%) to obtain a yellow solid 42-C (1.3 g, yield 35%).
  • THF silica gel thin layer chromatography
  • Step 2 A mixture of 47-B (1 g, 5.15 mmol), 47-C (1.94 g, 10.3 mmol) and DIEA (2.00 g, 15.5 mmol) in dioxane (12 mL) was reacted at 120 °C for 16 hours.
  • LC-MS showed that ⁇ 32.3% of the starting material remained and ⁇ 48.0% of the target product was generated.
  • the solvent was evaporated to obtain a crude product, which was purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 30%) to obtain a brown oil 47-A (900 mg, yield 48.2%).
  • LCMS: (ESI) m/z 363.5 (M+1) + .
  • Step 1 Referring to the method of step 2 in the synthesis of 47-A, 46-B (1.55 g, 15.45 mmol) and 47-B (1 g, 5.15 mmol) were reacted completely, and post-treatment was performed to obtain a yellow solid 46-A (528 mg, yield 35.1%).
  • LCMS: (ESI) m/z 275.1 (M+1) + .
  • Step 2 and 3 Referring to the method of step 2 and step 3 in Example 2, a two-step reaction was carried out starting from 46-A to obtain a white solid compound 46. The two-step yield was about 4.9%.
  • Example 2-a Referring to the synthesis method of Example 2-a, the following starting materials and compound 47-B were used to carry out three-step reactions to obtain the corresponding final product compounds.
  • Step 1 Referring to the synthesis method of 31-A, 55-B (1.13 g, 15.45 mmol) was reacted with 47-B (1 g, 5.15 mmol) to obtain 55-A (250 mg, yield 19.63%).
  • Step 2 and Step 3 Referring to the method of Step 2 and Step 3 in Example 2, a two-step reaction was carried out starting from 55-A to obtain yellow solid compound 55, with a two-step yield of about 5.3%.
  • Example 2-b Referring to the synthesis method of Example 2-b, the following starting materials and compound 47-B were used to carry out three-step reactions to obtain the corresponding final product compounds.
  • the four compounds P1, P2, P3 and P4 obtained by chiral separation in the synthetic route correspond to one of the following four structures respectively, and the absolute configuration has not yet been assigned.
  • the analysis conditions of the SFC RT results indicated in the identification analysis data of the compounds obtained by the chiral separation of compound 14-g are: column: (S,S) Whelk-01 100 ⁇ 4.6mm ID, 5.0um; mobile phase: A: CO 2 B: Ethanol (0.05% DEA); gradient: from 5% to 40% of B in 4.5min and hold 40% for 2min, then 5% of B for 1.5min; flow rate: 2.5mL/min; column temperature: 40°C; ABPR: 100bar.
  • the analysis conditions of the SFC RT results indicated in the identification analysis data of the compounds obtained by the chiral separation of compound 14-g are: column: (S,S) Whelk-01 100 ⁇ 4.6mm ID, 5.0um; mobile phase: A: CO 2 B: Ethanol (0.05% DEA); gradient: from 5% to 40% of B in 4.5min and hold 40% for 2min, then 5% of B for 1.5min; flow rate: 2.5mL/min; column temperature: 40°C; ABPR: 100bar.
  • Step 1 Add n-butyllithium in THF (0.71 mL, 2.4 mol/L, 0.85 mmol) to a solution of compound 2-A (250 mg) in THF (10 mL) at -78 °C, and stir the mixture under nitrogen for 0.5 hours. Then add compound 2-B (172 mg, 1.48 mmol) and continue stirring the mixture at -78 °C for 3 hours. After the reaction, quench the reaction with water (20 mL) and extract with EA (25 mL ⁇ 3). After conventional post-treatment, a yellow oily crude product 2-C (90 mg) was obtained.
  • Step 1 Referring to the method of step 1 in Example 4, compound 1-A (400 mg, 1.7 mmol) was reacted to obtain compound 1-B (160 mg, yield 36%).
  • Step 2 A solution of compound 1-B (180 mg, 0.68 mmol) in TFA (1.02 mL) and DCM (15 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA:PE, EA from 0 to 25%) to obtain a white solid compound 1-C (122 mg, yield 73%). LC-MS: (ESI) m/z [M+H] + 244.1.
  • Step 3 Add boron tribromide (2M DCM solution, 1.25 mL) to a DCM (10 mL) solution of compound 1-C (122 mg, 0.5 mmol) at -10°C. React at -10°C for 2 hours. After the reaction, dilute with EA (30 mL) and wash with saturated NaHCO 3 solution (15 mL x 2). After conventional post-treatment operation 2, purify by prep HPLC (column: YMC-Actus Triart C18 20*250mm, 5um, phase A: H 2 O (0.1% FA), phase B: ACN, 10% ⁇ 95%) to obtain yellow solid compound 1 (51.4 mg, yield 44%).
  • Step 1 At -78°C, add n-butyllithium THF solution (1.6M n-hexane solution, 1.53mL, 2.45mmol) to a THF (5mL) solution of compound 287-A (400mg, 1.63mmol), and stir the reaction under nitrogen protection for 0.5 hours. Then add compound 2-B (1.96mmol) and continue to stir the reaction at -78°C for 3 hours. After the reaction, quench the reaction with saturated ammonium chloride solution (10mL) and extract with EA (15mL ⁇ 3).
  • Step 2 Referring to the method of step 3 in Example 4-a, compound 287-B (160 mg) was reacted to obtain yellow solid compound 1 (7.1 mg, yield 4.7%).
  • Step 1 At 20°C, aluminum chloride (6.98g, 52.32mmol) was added to a solution of compound 3-A (5.0g, 23.78mmol) in DCM (125mL), stirred for 10 minutes, and then compound 3-B (3.57g, 35.68mmol) was added at once, and the reaction was stirred at 20°C for 30 minutes.
  • the solvent was removed by distillation under reduced pressure, the residue was diluted with water (100mL), the pH was adjusted to 1-2 with 1M HCl, and extracted with EA (100mL ⁇ 3).
  • Step 2 (representative operation for constructing a five-membered lactone ring): NaOH (309.38 mg, 7.73 mmol) and NaBH 4 (292.60 mg, 7.73 mmol) were added to a mixture of compound 3-C (800 mg, 2.58 mmol) in water (30 mL). The reaction was stirred at 20°C for 60 hours. The pH was adjusted to 1-2 with 2M HCl, a white solid was precipitated, and the mixture was extracted with EA (100 mL ⁇ 3).
  • Example 5-a Referring to the synthesis method of Example 5-a, the following starting materials were reacted with compound 112 to obtain the corresponding final product compound.
  • Example 5-a Referring to the synthesis method of Example 5-a, the following starting materials were used to react to obtain the corresponding final product compound.
  • Step 1 Compound 130-A (3.70 g, 23.1 mmol) was added to a solution of compound 130-B (1.57 g, 7.69 mmol) in NaHCO 3 (646 mg, 7.69 mmol) (16 mL), and NaHCO 3 (2.26 g, 26.9 mmol, 1.05 mL of aqueous solution) was added periodically to maintain the pH at 7.5, and stirred at 20°C for 16 hours. Phosphoric acid (5 mL) was added to adjust the pH to 4-5, and extracted with EtOAc (15 mL*3). The organic phase was cooled to 0°C to precipitate a solid, which was filtered.
  • Step 2 Add cyclohexylamine (43.5 mg, 438 ⁇ mol), DIEA (142 mg, 1.10 mmol) and HATU (166 mg, 438 ⁇ mol) to a DMF (2 mL) solution of compound 130-C (120 mg, 365 ⁇ mol) and stir at 20 ° C for 2 hours. Dilute with water (20 mL) and extract with EtOAc (10 mL*3). After conventional post-treatment operation 2, a crude product was obtained. The crude product was crushed and slurried with EtOAc at 20 ° C for 3 hours. Filter to obtain a white solid compound 130-D (100 mg, yield 66.82%).
  • Step 3 Add HCl in dioxane (2M, 1 mL) to a mixture of compound 130-D (100 mg, 244 umol) in dioxane (1 mL). Stir at 20°C for 3 hours. Concentrate under reduced pressure to obtain white solid compound 130-E (90.0 mg, HCl salt), which is used directly in the next step.
  • Step 4 TEA (40.8 mg, 0.4 mmol) and 112 (35.3 mg, 0.134 mmol) were added to a solution of compound 130-E (50 mg, 0.134 mmol, HCl salt) in DMF (1 mL), and the mixture was stirred at 40°C for 16 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by prep HPLC (FA method-B; B%: 35%-55%, 10 min) to obtain white solid compound 130 (25 mg, yield 29.32%).
  • Triphenylphosphine (93.58 mg, 356.80 ⁇ mol) and di-tert-butyl azodicarboxylate (DBAD, 61.62 mg, 0.27 mmol) were added to a solution of compound 3 (50 mg, 0.18 mmol) and isopropanol (10.72 mg, 0.18 mmol) in THF (2 mL) at 20°C. The reaction was stirred at 20°C for 16 hours.
  • DBAD di-tert-butyl azodicarboxylate
  • Step 2 A yellow mixture of compound 6-B (2 g, crude product) and (1-methoxy-2-methyl-prop-1-enyloxy)-trimethylsilane (5.75 g, 33 mmol) and tetrabutylammonium fluoride trihydrate (1.04 g, 3.30 mmol) was stirred at 60°C for 12 hours.
  • the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (EA:PE, EA from 0 to 3%) to obtain a yellow gum product compound 6-C (920 mg, 2.46 mmol, two-step yield of about 32%).
  • Step 3 Dissolve compound 6-C (760 mg, 2.04 mmol) and methyl prop-2-enoate (438 mg, 5.09 mmol) in 5 ml of anhydrous toluene, add cesium carbonate (995 mg, 3.05 mmol), triphenylphosphine (427 mg, 1.63 mmol) and palladium acetate (183 mg, 814 mmol), deoxygenate the mixture under reduced pressure, replace nitrogen, and stir at 80 ° C for 12 hours under nitrogen atmosphere.
  • the reaction solution was cooled to room temperature and diluted with 30 ml of water, and the mixture was extracted with EA (30 mL ⁇ 2).
  • Step 4 Referring to the representative operation method of catalytic hydrogenation, compound 6-D (528 ⁇ mol) was used as the raw material to obtain yellow gum 6-E (342 ⁇ mol, 64.66% yield), which was purified by silica gel column chromatography (EA:PE, EA from 0 to 15%).
  • Step 5 Stir the reaction solution of 6-E (130 mg, 342 ⁇ mol) in DCM (1.5 mL) and TFA (0.1 mL) at 20°C for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to obtain a pink gel product compound 6-F (130 mg, crude product), which was directly used in the next reaction.
  • Step 6 Dissolve 6-F (130 mg) in MeOH (1 mL), add NaOH aqueous solution (238 mg, 895 ⁇ mol), and stir the reaction solution at 25 ° C for 30 minutes.
  • the reaction solution was adjusted to pH 3 with 1M HCl solution and stirred at 25 ° C for 30 minutes.
  • the reaction solution was concentrated under reduced pressure, the residue was diluted with 10 ml of water, and the mixture was extracted with EA (10 mL ⁇ 2). After conventional post-treatment operations, the residue was obtained, and the residue was purified by silica gel column chromatography to obtain white solid compound 5 (60 mg, 186 ⁇ mol, two-step yield 54.4%).
  • LC-MS (ESI) m/z. [M+H] + 323.1.
  • Step 7 Dissolve 5 (18 mg) in MeOH (10 mL), add NaOH aqueous solution (1 M, 111 uL), and stir the reaction solution at 40 ° C for 60 hours.
  • LCMS shows that 18% of the raw material remains and 30% of the target product is generated.
  • the reaction solution is concentrated under reduced pressure, EA and water (5 mL) are added, and the pH is adjusted to 3 with 1M HCl solution.
  • the mixture is extracted with EA (5 mL ⁇ 2).
  • Step 1 and step 2 Referring to the method of step 1 and step 2 of Example 5, compound 7-A was used as the starting material to obtain a white solid compound 7 through two-step reaction, and the two-step yield was about 2.4%.
  • Step 3 Add K 2 CO 3 (317.72 mg, 2.30 mmol) to a solution of compound 7 (220 mg, 766.27 umol) and chloromethyl ether (86.93 mg, 919.52 umol) in acetone (8 mL), and stir at 20°C for 16 hours.
  • the reaction solution was filtered, the filtrate was concentrated to dryness, and the residue was purified by silica gel column chromatography (EA:PE, EA from 0 to 35%) to obtain a colorless oil 8-A (250 mg, 706.14 umol).
  • EA:PE silica gel column chromatography
  • Step 4 (Suzuki coupling reaction representative operation): Add K 3 PO 4 (129 mg, 608.37 umol) and XPhos Pd G3 (17.17 mg, 20.28 umol) to a mixture of compound 8-A (70 mg, 202.79 umol) and phenylboronic acid (74.18 mg, 608.37 umol) in THF/water (3 mL, 4/1), degas and refill with nitrogen twice. Heat it to 60 ° C for 1 hour. The reaction solution is concentrated to dryness and diluted with ethyl acetate (3 mL).
  • Step 1 Add potassium ferrocyanide (53.35 mg, 144.85 umol), potassium acetate (3.55 mg, 36.21 umol), t-Bu Xphos (2.46 mg, 5.79 umol, 0.02 eq) and t-Bu Xphos Pd G3 (2.30 mg, 2.90 umol) to a mixture of compound 8-A (100 mg, 0.29 mmol) in dioxane/water (4 mL, 1/1), degas and fill with nitrogen. Heat it to 80 ° C for 2 hours. LCMS shows that a small amount of raw materials remain, but the target product has been generated. The reaction solution is cooled to room temperature and extracted with EA (5 mL*3).
  • Step 1 Add NaHCO 3 (3.91 g, 46.50 mmol) and benzyl bromide (3.98 g, 23.25 mmol) to a mixture of compound 12-A (5.76 g, 21.1 mmol) in acetonitrile (60 mL). Heat to 82°C and react for 16 hours. The reaction solution is cooled to room temperature, water (80 mL) is added, and extracted with EA (100 mL). After conventional post-treatment operation 2, a crude product is obtained, which is purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 29%) to obtain a yellow solid compound 12-B (4.6 g, yield 60.73%).
  • EA:PE silica gel thin layer chromatography
  • Step 2 Add 12-C (811 mg, 2.72 mmol) and cesium fluoride (826 mg, 5.44 mmol) to a mixture of compound 12-B (650 mg, 1.81 mmol) in acetonitrile (26 mL). React at 20 ° C for 16 hours. Add saturated brine (20 mL) and extract with EA (20 mL). After conventional post-treatment operation 2, a crude product is obtained, which is purified by silica gel thin layer chromatography (EA: PE, EA from 0 to 20%) to obtain a yellow oil 12-D (238 mg, yield 30.22%).
  • EA silica gel thin layer chromatography
  • Step 3 Referring to the representative operation method of catalytic hydrogenation, compound 12-D (235 mg, 541 ⁇ mol) was reacted to obtain yellow gum product 12-E (120 mg, 349 ⁇ mol).
  • Step 4 (representative operation of ester hydrolysis): lithium hydroxide monohydrate (36.7 mg, 0.87 mmol, about 2.5 equivalents) was added to a mixture of compound 12-E (120 mg, 0.35 mmol) in THF (1 mL) and MeOH (1 mL). The reaction was carried out at 65 ° C for 16 hours (LCMS showed that the reaction was complete). The reaction solution was cooled to room temperature, the pH was adjusted to 1-2 with 2M HCl, and extracted with EA (4 mL * 3).
  • Step 5 Referring to the representative operation of constructing a five-membered lactone ring, compound 12-F (65 mg, 205 ⁇ mol) was reacted to obtain white solid compound 12 (10 mg, yield 16.2%).
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ ppm1.54-1.60 (m, 2H)2.06-2.11 (m, 2H)2.41-2.46 (m, 2H)3.65-3.72 (m, 6H)5.98-6.07 (m, 2H)9.21-9.30 (m, 1H)11.78-11.91 (m, 1H).
  • Step 1 At 0°C and nitrogen protection, add potassium tert-butoxide (1M, 25.93mL) in THF solution to a mixture of methyltriphenylphosphine bromide (Ph 3 PMeBr, 10.65g, 29.82mmol) in THF (80mL) dropwise, and stir at 0°C for 1 hour. At 0°C, add a solution of compound 13-A (4g, 12.97mmol) in THF (60mL) to the above reaction mixture. Warm to room temperature (20°C) and react for 16 hours. At 0-10°C, quench the reaction with saturated NH 4 Cl solution (5mL), add water (8mL), and extract with MTBE (4mL*3).
  • Ph 3 PMeBr methyltriphenylphosphine bromide
  • Step 2 Add 13-C (584 mg, 2.72 mmol), H 2 O (97.9 mg, 5.44 mmol) and nonacarbonyl diiron (cas: 15321-51-4, 49.4 mg, 135.94 umol) to a mixture of 13-B (1 g, 3.26 mmol, 1.2 eq) in DMF (10 mL). React at 80°C for 16 hours. Cool to room temperature, add water (4 mL), and extract with EA (12 mL). After conventional post-treatment operation 2, a crude product is obtained.
  • Step 3 Add TEA(HF) 3 (14.6 mg, 90.78 umol) to a mixture of 13-D (50 mg, 113.47 umol) in THF (1 mL), and react at 20°C for 2 hours. After the reaction, add saturated NaHCO 3 aqueous solution to adjust the pH to 7-8, and extract with EA (2 mL ⁇ 3). After conventional post-treatment operation 2, a crude product was obtained, which was purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 62%) to obtain yellow solid compound 13 (9 mg, yield 27.9%).
  • EA:PE silica gel thin layer chromatography
  • Step 2 Add 16-C (655 mg, 3.76 mmol) and ZnI 2 (360 mg, 1.13 mmol) to a solution of 16-B (170 mg, 0.63 mmol) in DCM (4 mL). React at 25 °C for 16 hours. Add water (5 mL) and extract with DCM (3 mL x 3). After conventional post-treatment, a brown oil 16-D (280 mg) was obtained, which was used directly in the next step.
  • Step 1 A mixture of 47-B (3.6 g, 18.5 mmol), N-(2-methoxyethyl)methylamine (3.30 g, 37.1 mmol) and K 2 CO 3 (5.12 g, 37.1 mmol, 2 eq) in dioxane (80 mL) was reacted at 120°C for 40 hours. LC-MS showed ⁇ 32% of the starting material remained and ⁇ 65% of the target product was produced. The reaction was diluted with EA (100 mL), filtered, and the solvent was removed under reduced pressure.
  • Step 2 and Step 3 Referring to the method of Step 2 and Step 3 in Example 12, 65-A was subjected to two-step reaction to obtain compound 65-B as an orange oil, with a two-step yield of about 20%.
  • Step 4 Referring to the method of step 3 of Example 2, 65-A was used to react to obtain yellow oil 65, with a yield of 63%.
  • Step 1 At -78°C, add cyclopropylmagnesium bromide solution (0.5M, 205mL) to a solution of compound 66-A (5g, 29.4mmol) in THF (50mL), naturally warm to room temperature 25°C, and react for 16 hours. After the reaction, add saturated NH 4 Cl aqueous solution (200mL) to quench, and extract with EtOAc (200mL*3). After conventional post-treatment operation 2, the crude product 66-B (7.6g) was obtained as a yellow solid. LC-MS: (ESI) m/z. [M-OH] + 205.1.
  • Step 2 At -30°C, add Et 3 SiH (5.23 g, 45 mmol) and TFA (10.2 g, 90.0 mmol) to a solution of 66-B (5 g) in DCM (100 mL), maintain -30°C to -20°C, and react for 2 hours. After the reaction, add water (100 mL), adjust the pH to 8-9 with saturated sodium carbonate solution, and extract with DCM (50 mL*3). After conventional post-treatment operation 2, the crude product was obtained, which was purified by silica gel column chromatography (EA:PE, EA from 0 to 3%) to obtain a colorless oil 66-C (5.14 g, two-step yield of about 83%).
  • Et 3 SiH 5.23 g, 45 mmol
  • TFA 10.2 g, 90.0 mmol
  • Step 3 Add triethylamine trihydrofluoride (5.17 g, 32.1 mmol) to a solution of compound 66-C (5.14 g, 16 mmol) in ACN (60 mL), and react at 25°C for 16 hours. After the reaction, concentrate under reduced pressure to remove the solvent, dissolve in EtOAc (100 mL), and obtain a crude product after conventional post-treatment operation 2. Purify by silica gel column chromatography (EA:PE, EA from 0 to 3.5%) to obtain a colorless oil 66-D (3.2 g, yield 88%).
  • EA:PE silica gel column chromatography
  • Step 4 Add NBS (949 mg, 5.33 mmol) to a DCM (30 mL) solution of compound 66-D (1 g, 4.85 mmol) and react at 25°C for 16 hours. After the reaction, concentrate under reduced pressure to remove the solvent, and purify by silica gel column chromatography (EA:PE, EA from 0 to 3%) to obtain a colorless oil 66-E (610 mg, yield 44%).
  • Step 5 and Step 6 Referring to the method of Step 2 and Step 3 in Example 21, 66-E was used as the raw material for two-step reaction to obtain a yellow oil 66-G (two-step yield is about 46.74%).
  • Step 7 Referring to the method of step 1 in Example 12-a, 66-G (210 mg) was used as a raw material to obtain a yellow oil 66-H (200 mg, yield 76.07%).
  • Step 8 and Step 9 Referring to the method of Step 2 and Step 3 in Example 2, two steps of reaction were carried out starting from 66-H to obtain an off-white solid compound 66, with a two-step yield of about 51%.
  • Step 1 refers to the method of step 1 in Example 2
  • step 2 refers to the method of step 2 in Example 2
  • step 3 refers to the method of step 4 in Example 12.
  • Three steps of reaction are carried out using the starting materials in the following table to obtain compound 17.
  • step 2 and step 3 in Example 13 a two-step reaction was carried out using the starting materials in the following table to obtain the final compound.
  • Step 1 Referring to the method of step 4 in Example 8-b, 15-A (2.0 g, 9.30 mmol) was reacted with 18-A (2.90 g, 13.95 mmol) to obtain an off-white solid compound 18-B (1.96 g, yield 84.17%).
  • LCMS: (ESI) m/z 217.0 (M+1) + .
  • Step 2 to Step 4 Referring to the method in Example 13, three steps of reaction were carried out using the starting materials in the following table to obtain the final compound.
  • starting material 82-A Referring to the method of starting material 82-A, the starting materials in the following table are used instead of 18-A to react with compound 67-A to obtain the intermediate compound.
  • Step 1 Referring to the method of step 1 in Example 2, 19-A (5.1 g, 33.52 mmol) was used to prepare yellow oil 19-B (1.6 g, 24.83% yield).
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ ppm 2.10 (s, 3H)
  • Step 3 and Step 4 Referring to the method of Step 2 and Step 3 in Example 2, 19-C (573 mg, 2.41 mmol) was used for two-step reaction to obtain yellow solid compound 19 (45 mg, two-step yield of about 15.8%).
  • Example 16 Referring to the method in Example 16, the starting materials in the following table were used instead of benzyl bromide to carry out three-step reaction to obtain the final compound.
  • Step 1 Add compound 19-B (1 g, 5.20 mmol) to a solution of potassium tert-butoxide (1M THF solution, 7.80 mL) in THF (20 mL) under ice bath conditions, and stir at 0°C for 6 minutes before adding 20-A (CAS: 66003-76-7, 2.91 g, 6.76 mmol, 1.3 eq). Naturally warm to room temperature (25°C) and react for 2 hours. Add the reaction solution to ice water (20 mL) and extract with EtOAc (15 mL x 3).
  • Step 2 and step 3 Referring to the method of step 3 and step 4 in Example 2, 20-B was used for two-step reaction to obtain white solid compound 20 (6 mg, two-step yield of about 3.5%).
  • Step 1 Add compound 23-A (664 mg, 2.86 mmol) and cesium carbonate (1.70 g, 5.20 mmol) to a solution of 19-B (500 mg, 2.60 mmol) in MeCN (10 mL). React at 80°C for 16 hours. Dilute the reaction solution with water (10 mL) and extract with EtOAc (10 mL x 3). After conventional post-treatment operations, a crude product was obtained, which was purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 30%) to obtain a yellow solid 23-B (300 mg, yield 42%).
  • EA:PE silica gel thin layer chromatography
  • Step 2 and Step 3 Referring to the method of Step 3 and Step 4 in Example 2, 23-B was used for two-step reaction to obtain white solid compound 23 (10 mg, two-step yield of about 2.5%).
  • LCMS: (ESI) m/z 303.1[M+H] + , 1 HNMR (DMSO-d 6 , 400MHz) ⁇ ppm 9.29-10.19 (m, 1H) 6.83-7.09 (m, 1H) 6.48-6.61 (m, 1H) 5.30-5.80 (m, 1H) 4.61-4.82 (m, 2H) 2.15-2.28 (m, 2H) 2.02-2.11 (m, 3H) 1.03-1.36 (m, 1H) 0.66-1.01 (m, 1H).
  • Step 1 Add K 2 CO 3 (1.08 g, 7.8 mmol) to a DMF (10 mL) solution of compound 19-B (500 mg, 2.60 mmol) and compound 33-A (562 mg, 3.12 mmol), and react at 90°C for 15 hours. Cool to room temperature, dilute the reaction solution with saturated brine (50 mL), and extract with EtOAc (50 mL x 2). After conventional post-treatment operations, the crude product was obtained, which was purified by silica gel column chromatography (EA:PE, EA from 0 to 10%) to obtain a yellow solid compound 33-B (580 mg, yield 80.7%).
  • EA:PE silica gel column chromatography
  • Step 2 and Step 3 Referring to the method of Step 2 and Step 3 in Example 2, a two-step reaction was performed to obtain a white solid 33 (the two-step yield was about 46%).
  • Tetrabutylammonium fluoride (122.37 mg, 468.04 ⁇ mol) was added to a solution of compound 37 (120 mg, 312.03 ⁇ mol) in THF (2 mL) at 20°C (room temperature). The reaction was stirred at 20°C for 3 hours. After the reaction, the reaction was quenched with water (3 mL) and extracted with EA (3 mL ⁇ 3). After conventional post-treatment operation 2, the product was purified by prep HPLC (FA method, B: 20%-50% 8 min) to obtain a white solid compound 2 (15 mg, yield 19.6%).
  • Step 1 Compound 59-A (6 g, 29 mmol) was reacted in tert-butyl alcohol (60 mL) and concentrated sulfuric acid (7.5 mL) at 40 °C for 16 hours. After cooling to room temperature, the reaction was quenched with water and extracted with EtOAc (50 mL x 3). After conventional post-treatment operation 2, the crude product was obtained, which was purified by silica gel column chromatography (EA:PE, EA from 0 to 10%) to obtain a white solid compound 59-B (2.2 g, yield 28.73%).
  • EA:PE silica gel column chromatography
  • Step 2 Referring to the method of step 1 in Example 12, compound 59-B (2.2 g) was reacted to obtain white solid 59-C (2.2 g, yield 86%).
  • LCMS: (ESI) m/z 273.0 (M + 1) + .
  • Step 4 and Step 5 Referring to the method of Step 2 and Step 3 in Example 2, 59-D (585 mg, 2.5 mmol) was used to carry out two-step reaction to obtain white solid compound 59, with a two-step yield of about 4.5%.
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ (ppm) 9.48-9.66 (m, 1H), 6.90-7.03 (m, 1H), 6.43-6.56 (m, 1H), 5.33-5.80 (m, 1H), 3.69-3.78 (m, 3H), 2.13-2.26 (m, 2H), 1.07-1.37 (m, 10H), 0.66-0.98 (m, 1H).
  • Step 2 and Step 3 Referring to the method of Step 2 and Step 3 in Example 12 (representative operation-B for constructing a five-membered lactone ring), 67-B was reacted in two steps to obtain a white solid compound 67, with a two-step yield of about 17.2%.
  • Example 22 Referring to the method in Example 22 (representative operation C for constructing a five-membered lactone ring), a three-step reaction was carried out using the starting materials in the following table to obtain the final compound.
  • step 2 and step 3 in Example 22 representative operation for constructing a five-membered lactone ring-B
  • the starting materials in the following table were reacted to obtain the final compound.
  • the conditions for chiral separation are: column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: 0.1% NH 3 H 2 O IPA; B%: 15%-15%, flow rate: 100 mL/min.
  • Chiral analysis conditions are: Column: ChiralPak AS-3 150 ⁇ 4.6mm I.D., 3um; Mobile phase: A:CO2 B:Ethanol (0.05% DEA); Gradient: from 5% to 40% of B in 4.5min, then 5% of B for 1.5min; Flow rate:2.5mL/min Column temp.:40°C; Back pressure:100bar
  • Step 2 Referring to the method of step 3 in Example 12, 68-A (50 mg) was reacted to obtain a white solid compound 68 (12 mg, yield 29.2%).
  • Step 1 Add 3-bromopropylene (1.95 g, 16.13 mmol) and K 2 CO 3 (4.46 g, 32.26 mmol) to a DMF (54 mL) solution of 67-A (2.7 g, 10.75 mmol). React at 25°C for 16 hours. Filter and concentrate under reduced pressure. Add water (60 mL) and extract with EA (60 mL x 3). After conventional post-treatment operation 2, a crude product is obtained, which is purified by silica gel column chromatography (EA:PE, EA from 0 to 4%) to obtain an off-white solid 73-A (yield 98%).
  • EA:PE silica gel column chromatography
  • Step 2 to Step 3 Referring to the method of Step 2 to Step 3 in Example 12, 73-A was reacted in two steps to obtain yellow oily compound 73 (two-step yield is about 69%).
  • Example 26 Referring to the method of Example 26, the starting materials in the following table were used instead of 80-A to carry out the reaction to obtain the corresponding final product compound.
  • starting material 98-A Referring to the method of starting material 98-A, the starting materials in the following table are substituted for 98-B to carry out the reaction to obtain the corresponding borate ester starting materials.
  • Step 1 Referring to the method of step 4 in Example 8-b, 67-B (100 mg) and 18-A (74 mg) were reacted to obtain brown solid compound 69-A (50 mg, yield 47%).
  • LCMS: ES19974-299-P1B1, (ESI) m/z 367.5 [M+1] +
  • Step 2 Referring to the method of step 3 in Example 12, compound 69-A (50 mg) was reacted to obtain white solid compound 69 (1.4 mg, yield 3.28%).
  • K 3 PO 4 (93.3 mg, 439 ⁇ mol) and Pd 2 (dba) 3 (26.8 mg, 29.30 ⁇ mol) were added to a mixture of compound 67 (90 mg, 293 ⁇ mol) and 84 - A (100 mg, 352 ⁇ mol) in THF/water (2.4 mL, 5/1).
  • the mixture was heated to 60°C for 16 hours.
  • the reaction was diluted with water (5 mL) and extracted with EA (5 mL*3). After conventional post-treatment, a crude product was obtained.
  • Step 1 Under nitrogen protection, sodium methanesulfinate (29.3 mg, 287.50 ⁇ mol), K 3 PO 4 (81.4 mg, 383.33 ⁇ mol), CuI (1.83 mg, 9.58 ⁇ mol) and (2S, 4R)-N-(2,6-dimethylphenyl)-4-hydroxypyrrolidine-2-carboxamide (2.25 mg, 9.58 ⁇ mol) were added to a DMSO (1.4 mL) solution of compound 67-B (70 mg, 0.19 mmol). The mixture was heated to 90°C and reacted for 16 hours. The reaction solution was cooled to room temperature, EA was added to dilute the reaction, water (5 mL) was added, and the mixture was extracted with EA (10 mL*3).
  • Step 2 Referring to the method of Step 3 in Example 12, compound 74-A (30 mg) was reacted to obtain white solid compound 74 (10 mg, yield 40%).
  • step 1 to step 3 in Example 12 75-A was used as the starting material to react to obtain yellow solid compound 75-B, with a three-step yield of about 66.6%.
  • Step 4 Under nitrogen protection, a mixture of compound 75-B (300 mg, 0.8 mmol), Pd(PPh 3 ) 4 (92.2 mg, 79.8 ⁇ mol) and morpholine (139.0 mg, 1.60 mmol) in THF (16 mL) was reacted at 20° C. for 16 hours. Water (40 mL) was added, and the mixture was extracted with EA (30 mL*3). After conventional post-treatment, a crude product was obtained. The crude product was purified by silica gel column chromatography (EA:PE, EA from 0 to 30%) to obtain white solid compound 75 (125 mg, yield 47%).
  • EA:PE silica gel column chromatography
  • Step 1 Add 77-E (65.6 mg, 223.16 ⁇ mol) to a DMSO/ACN (100 mL, 1:1) solution of compound 77-A (1 g, 4.46 mmol) and NIS (1.14 g, 5.07 mmol) and react at 25°C for 15 hours. Add water (50 mL) and extract with EA (50 mL*2). After conventional post-treatment, 1 g of gray solid was obtained, which was directly used in the next step.
  • LCMS: (ESI) m/z 351.8 (M+1) +
  • Step 2 Referring to the method of step 1 in Example 22, 77-B (1 g crude product) was reacted to obtain yellow solid compound 77-C (1.1 g, purity 58.65%).
  • LCMS: (ESI) m/z 409.9 (M+1) +
  • Step 3 At -70°C, add a THF solution (1.3M, 1.27mL) of isopropylmagnesium chloride lithium chloride complex to a THF solution (560mg) of compound 77-C (30mL), warm to 25°C, and stir to react for 1 hour. Add a THF solution (1mL) of DMF (120mg, 1.65mmol) at -70°C, warm to 25°C, and continue to stir to react for 0.5 hours. Add water (10mL) at 0°C to quench the reaction, and extract the mixture with EA (10mL ⁇ 2).
  • Step 4 and Step 5 Referring to the method of Step 2 and Step 3 in Example 12, 77-D was used for two-step reaction to obtain yellow solid compound 77, with a five-step yield of 8.8%.
  • Step 1 Referring to the method of step 4 in Example 8-b, 77-D (200 mg, 644.86 ⁇ mol) and 18-A (147 mg, 709.35 ⁇ mol) were reacted to obtain yellow solid 86-A (130 mg, yield 64.75%).
  • Step 2 and step 3 Referring to the method of step 2 and step 3 in Example 12, 86-A (130 mg, 417.56 umol) was used for two-step reaction to obtain yellow solid compound 86 (4 mg). The two-step yield was about 2.7%.
  • LCMS: (ESI)m/z 309.9[M+H] + .
  • Step 1 Under nitrogen protection, add Pd(OAc) 2 (26.8 mg, 119.68 ⁇ mol), hexacarbonyl molybdenum (Mo(CO) 6 , 173 mg, 658.25 ⁇ mol) and tri-tert-butylphosphine tetrafluoroborate (34.7 mg, 119.68 ⁇ mol) to a solution of compound 67-B (370 mg, 1.20 mmol) and DBU (273 mg, 1.80 mmol) in EtOH (10 mL). React at 90°C for 16 hours under nitrogen protection.
  • Pd(OAc) 2 26.8 mg, 119.68 ⁇ mol
  • Mo(CO) 6 hexacarbonyl molybdenum
  • Me(CO) 6 173 mg, 658.25 ⁇ mol
  • tri-tert-butylphosphine tetrafluoroborate 34.7 mg, 119.68 ⁇ mol
  • Step 2 and step 3 Referring to the method of step 2 and step 3 in Example 12, 92-A (260 mg, 860 ⁇ mol) was used for two-step reaction to obtain white solid compound 92 (40 mg). The two-step yield was about 15.5%.
  • LCMS: (ESI) m/z 301.3(M+1) + .
  • Step 4 Compound 92 (20 mg) was dissolved in THF (0.3 mL), and NaOH (10.7 mg, 266 ⁇ mol) aqueous solution (0.3 mL) was added and stirred at 25 °C for 2 hours. The reaction solution was adjusted to pH 2 with 1 M HCl solution, and the mixture was extracted with EA (1 mL ⁇ 3). The crude product was concentrated under reduced pressure. The crude product was ground and slurried with DCM (3 mL) for 10 minutes, and filtered to obtain a white solid compound 93 (15 mg, yield 82.48%).
  • Step 5 Add DIEA (56.96 mg, 440.77 umol) and HATU (139.66 mg, 367.31 ⁇ mol) to a solution of compound 93 (40 mg, 146.92 ⁇ mol) and HOBT ammonium salt (CAS: 63307-62-0, 111.77 mg, 734.61 ⁇ mol) in DMF (1 mL), stir at 25 °C for 2 hours, dilute with water (2 mL) and acetonitrile (1 mL), and filter.
  • Lithium hydroxide monohydrate (20.5 mg, 0.49 mmol, about 1.5 equivalents) was added to a mixture of compound 116 (100 mg, 0.33 mmol) in THF (1.5 mL) and water (1.5 mL). The mixture was reacted at 25°C for 16 hours. THF was removed by distillation under reduced pressure, and the pH was adjusted to 6-7 with AcOH. A white solid (25 mg, yield 25.68%) was obtained by prep HPLC separation (FA method, B: 18%-38%, 10 min).
  • Step 1 Referring to the method of step 6 of Example 1, (14-c-1) (1.5 g, 6.29 mmol) and compound 25-A (860 mg, 2.67 mmol) were reacted to obtain white solid compound 25-B (70 mg, yield 2.9%).
  • (ESI) m/z 377.1 (M+1) + .
  • Example 37 Referring to the method in Example 37, the starting materials shown in the following table were used instead of 134-A to carry out the reaction to obtain the corresponding final compounds.
  • Example 37 Referring to the method in Example 37, the starting materials in the following table were used to react to obtain the corresponding final compounds.
  • Example 38 Referring to the method of Example 38, the starting materials shown in the following table were used to replace benzoyl chloride and react with compound 67 to obtain the corresponding final product compound.
  • Step 1 Add EDCI (40.5 mg, 211.63 ⁇ mol, 1.3 eq) and DMAP (1.99 mg, 16.28 ⁇ mol, 0.1 eq) to a DCM (2 mL) solution of compound 67 (50 mg, 163 ⁇ mol) and compound 141-A (38.5 mg, 179 ⁇ mol, 1.1 eq). Stir at 25 °C for 3 hours and concentrate under reduced pressure. The crude product was purified by silica gel column chromatography (EA/PE, EA from 0 to 30%) to obtain white solid compound 141 (70 mg, yield 82%).
  • EA/PE silica gel column chromatography
  • Step 2 (representative method for removing the Boc protecting group): A solution of compound 141 (20 mg, 0.397 mmol) in DCM (2 mL) and TFA (0.4 mL) was stirred at 25°C for 2 hours, concentrated under reduced pressure, and the residue was purified by prep HPLC (FA method; B%: 5%-35%, 8 min) to give white solid compound 140 (2 mg, yield 12%).
  • step 1 in Example 39 the starting materials shown in the following table were substituted for 141-A and reacted with compound 67 to obtain the corresponding final compound.
  • Step 1 Referring to the method of Example 38, compound 76 (60 mg) and compound 161-A (5 eq) were used as starting materials to react to obtain yellow solid compound 161-B (100 mg). The crude product was directly used for the next step.
  • Step 2 Referring to the method of Step 2 in Example 39, compound 161-B (100 mg) was reacted to obtain white solid compound 161 (25 mg, two-step yield of about 29%).
  • Step 3 Referring to the method of Step 2 of Example 5, compound 163-C (45 mg, 150.4 ⁇ mol) was reacted to obtain white solid compound 163 (12 mg, yield 28.2%).
  • Step 1 To a solution of compound 164-A (2.01 g, 16.22 mmol) in DCM (50 mL) was added aluminum chloride (3.24 g, 24.32 mmol), stirred at 10°C for 10 minutes, and then a solution of 164-B (2.5 g, 16.22 mmol) in DCM (5 mL) was added dropwise, stirred at 10°C for 10 minutes, and then refluxed for 3 hours. The mixture was concentrated under reduced pressure, water (100 mL) was added, the pH was adjusted to 1-2 with concentrated hydrochloric acid, and extracted with DCM (100 mL*3).
  • Step 2 Referring to the method of Step 2 of Example 5, compound 164-C (100 mg, 359.3 ⁇ mol) was reacted (NaOH was 5 eq, NaBH 4 was 40 eq) to obtain white solid compound 164 (18 mg, yield 19.1%) and white solid compound 165 (8 mg, yield 8.5%).
  • Synthesis of Compound 167 Referring to the synthesis method of Example 5-a, methylamine (33% ethanol solution) was reacted with Compound 166 (reaction time 2 hours, 44% of the raw material remained) to obtain white solid Compound 167, yield 28.4%.
  • Step 1 Referring to the method of step 1 in Example 45, 164-A (9.5 g, 76.53 mmol) was reacted with 171-B (1 eq) to obtain yellow solid 171-A (130 mg, yield 0.68%) and yellow oil 267-A (14 g, 55.9 mmol, yield 73.1%).
  • Step 1 Compound 174-A (100 mg, 485 ⁇ mol), morpholine (123 mg, 1.45 mmol, 3 eq) and glyoxylic acid (179 mg, 1.21 mmol, 135 ⁇ L, 2.5 eq) were stirred at 60°C for 16 hours. The mixture was cooled to room temperature, diluted with 5ACN (1 mL), and directly purified by prep HPLC (FA method, B: 15%-35% B over 38 min) to obtain brown solid compound 174-B (38 mg, yield 22.4%).
  • Step 2 Referring to the method of Step 2 in Example 5 (representative operation for constructing a five-membered lactone ring), compound 174-B (310 mg, 887 ⁇ mol, 1 eq) was reacted to obtain yellow oil 174-C (77 mg, 230 ⁇ mol, yield 26%).
  • Step 3 Referring to the method of step 3 of Example 2, compound 174-C (77 mg, 230 ⁇ mol) was reacted to obtain a white solid compound (15 mg, 51 ⁇ mol, yield 22.1%).
  • LC-MS (ESI)m/z.[M+
  • Step 1 Add 271-B (500 mg, 3.94 mmol) to a mixture of compound 271-A (500 mg, 3.49 mmol) and Na 2 CO 3 (740 mg, 6.98 mmol) in THF/water (10 mL, 1:1) at 0°C, and react the mixture at 0°C for 10 minutes.
  • the solvent was removed under reduced pressure, and the crude product was separated and purified by Prep HPLC (column: C18 150 ⁇ 40 mm; mobile phase: [water(FA)-ACN]; gradient: 1%-41% B over 9 min) to obtain a colorless oil 271-C (520 mg, yield 64%).
  • LCMS: (ESI) m/z 234.0 (M+1) + .
  • Step 3 Referring to the method of Step 2 (representative method for removing the Boc protecting group) in Example 39, compound 271-E (110 mg) was reacted to obtain white solid compound 271-F (80 mg, 184 ⁇ mol, yield 70.40%, TFA salt).
  • Step 4 Add DIEA (104 mg, 806 ⁇ mol, 5 eq) and compound 112 (42.3 mg, 161 ⁇ mol, 1.0 eq) to a DMF (1 mL) solution of compound 271-F (70 mg, 161.36 ⁇ mol, 1 eq, TFA) and stir at 50 °C for 16 hours.
  • the reaction solution was directly purified by prep HPLC (FA method, B: 18%-38% over 11 min) to obtain white solid compound 271 (15 mg, 26.4 ⁇ mol, yield 16.36%) and white solid compound 272 (45 mg, 74.2 ⁇ mol, yield 46.00%).
  • step 3 and step 4 in the synthesis method of compound 271 the starting materials in the following table were used to carry out two-step reactions to obtain the corresponding final compounds.
  • 292-B 500 mg, 2.54 mmol was used as a raw material to react with 271-D (517.7 mg, 2.54 mmol) to obtain a white solid compound 292-A (70 mg, yield 7.2%).
  • Step 1 Add 274-B (6.04 g, 32.4 mmol) and paraformaldehyde (1.95 g, 64.8 mmol, 2 eq) to a solution of compound 274-A (5 g, 32.4 mmol) in toluene (50 mL), and stir at 50°C for 16 hours. Concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (EA:PE, EA from 0 to 30%) to obtain a white solid compound 274-C (9 g, yield 79%).
  • Step 2 Add MnO 2 (16 g, 184 mmol, 10 eq) to a DCM (60 mL) solution of compound 274-C (6.5 g, 18.4 mmol), and stir at 25°C for 5 hours. Filter and concentrate under reduced pressure to obtain a white solid compound 274-D (2 g). The crude product was directly used in the next step.
  • Step 3 Referring to the method of step 1 of Example 2, compound 274-D (2 g) was reacted to obtain yellow oil compound 274-E (2 g, two-step yield about 28%).
  • Step 4 Referring to the method of Step 2 in Example 39 (representative method for removing the Boc protecting group), compound 274-E (2.5 g) was reacted to obtain yellow oil compound 274-F (1.8 g), and the crude product was directly used in the next step.
  • Step 5 Referring to the method of step 1 in Example 51, 274-E (500 mg, 1.24 mmol, TFA salt) was reacted to obtain yellow oil compound 274-G (230 mg, two-step yield about 34%).
  • Step 6 and Step 7 Referring to the method of Step 2 and Step 3 in Example 2, 274-G (143 mg, 603 ⁇ mol) was used for two-step reaction to obtain white solid compound 274 (1 mg, two-step yield of about 1.4%).
  • LC-MS (ESI)m/z[M+
  • Step 1 Add cesium carbonate (2.7 g, 8.3 mmol) to a mixture of compound 14-a (800 mg, 2.77 mmol) and 277-B (900 mg, 3.58 mmol) in toluene (15 mL) and H 2 O (5 mL), add RuPhos Pd G3 catalyst (CAS: 1445085-77-7, 231 mg, 276 ⁇ mol) after fully replacing nitrogen, and stir at 100 ° C for 16 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, and the mixture was extracted with EA (10 mL ⁇ 3).
  • Step 2 Compound 277-C (870 mg, 2.46 mmol) was dissolved in HCl in dioxane (2M, 10 mL) and stirred at 20°C for 2 hours. The mixture was concentrated under reduced pressure to obtain a green solid compound 277-D (570 mg, HCl salt). The crude product was directly used in the next step.
  • Step 3 Referring to the method of step 2 in Example 5-b, 277-D (570 mg, HCl salt) was used as a raw material to react with 1-adamantaneacetic acid (956 mg, 2 eq) to obtain a white solid compound 277-E (1.0 g, two-step yield of about 74%).
  • Step 4 Referring to the method of Example 34, 277-E (1.0 g) was used as the raw material for the reaction. After the reaction was completed, the mixture was concentrated under reduced pressure and the pH was adjusted to 1 with 1M HCl. The solid was precipitated and filtered to obtain a white solid compound 277-F (700 mg). The crude product was directly used in the next step.
  • Step 5 to Step 7 Referring to the method of Example 2, 277-F (645 mg) was used as the starting material for three-step reaction to obtain white solid compound 277 (17 mg, four-step yield 12.6%).
  • Step 1 Add chloromethyl ether (1.96 g, 20.74 mmol) and K 2 CO 3 (8.60 g, 62.21 mmol) to a solution of 5-bromo-2,4-dihydroxybenzene-1-carboxaldehyde (4.5 g, 20.74 mmol) in acetone (100 mL). React at 20°C for 16 hours. Add saturated NH 4 Cl aqueous solution (50 mL) and extract with EA (50 mL x 3). After conventional post-treatment operation 2, a crude product is obtained.
  • the crude product is purified by silica gel column chromatography (EA:PE, EA from 0 to 9%) to obtain a white solid 5-bromo-4-[(ethoxymethyl)oxy]-2-hydroxybenzene-1-carboxaldehyde (3.22 g, yield 56%).
  • Step 2 Add iodomethane (2.23 g, 15.70 mmol) and K 2 CO 3 (3.62 g, 26.17 mmol) to a mixture of 5-bromo-4-[(ethoxymethyl)oxy]-2-hydroxybenzene-1-carboxaldehyde (3.6 g, 13.09 mmol) in DMF (2 mL). React at 20°C for 16 hours. Add water (50 mL) and extract with EA (50 mL x 2). After conventional post-treatment operation 2, a crude product was obtained, which was purified by silica gel thin layer chromatography (EA:PE, EA from 6 to 9%) to obtain a white solid 14-a (3.58 g, yield 94%).
  • EA:PE silica gel thin layer chromatography
  • Step 1 Wang Resin (400 mg, 0.544 mmol) was placed in a 40 mL reaction bottle and suspended in 10 mL DCM/DMF (1:9).
  • Compound 129-A (440 mg, 1.07 mmol) and HOBt (146 mg, 1.08 mmol) in DMF (1 mL) were dissolved in a separate vial and the solution was added to the resin.
  • DMAP (8 mg, 65.5 umol) was added to the reaction bottle, followed by DIC (145 mg, 1.15 mmol), and the reaction mixture was shaken at 25 °C for 6 hours.
  • Acetic anhydride 120 mg, 1.17 mmol
  • pyridine 108 mg, 1.36 mmol
  • the filtered resin was washed twice with 20 mL of DMF and five times with 20 mL of DCM to obtain wet resin 129-B for the next step.
  • Step 2 Place resin 129-B (0.544 mmol) in a solid phase synthesis reactor and add 15 mL DMF, stir for 30 seconds to dissolve and then remove the solvent by vacuum filtration. Add 15 ml 20% piperidine/DMF, stir for 15 minutes, and then remove the solvent by vacuum filtration. Add 15 ml 20% piperidine/DMF again, stir for 15 minutes, then remove the solvent by vacuum filtration and wash the resin four times with 15 mL DMF. Dissolve 2-cyclohexylacetic acid (315 mg, 2.22 mmol), HATU (833 mg, 2.19 mmol) and HOAt (301 mg, 2.21 mmol) in DMF (15 mL) and add the solution to the resin and stir for 30 seconds.
  • Step 3 Resin 129-C (544 ⁇ mol) was placed in a reaction bottle, DCM (10 ml) and phenylsilane (482 mg, 4.46 mmol) were added, stirred gently for 1 minute, and allowed to stand for 15 minutes to allow the resin to swell. The reaction suspension was vacuum degassed and purged with nitrogen five times. Pd(PPh 3 ) 4 (150 mg, 130 ⁇ mol) was added to the reaction suspension, vacuum degassed and purged with nitrogen five times, and then the reaction suspension was shaken at 25° C. under a nitrogen atmosphere for 1.5 hours. The resin was filtered and washed with 15 mL DMF five times.
  • Step 4 Place resin 129-D (544 ⁇ mol) in a reaction bottle, add 5% TFA/DCM solution (15 mL) to the resin, and shake at 25°C for 4 hours. Filter the reaction suspension and wash the resin three times with 15 mL DCM. Combine the filtrates and concentrate under reduced pressure. Add 5 mL of deionized water to the crude product to dissolve and filter to remove insoluble matter. Repeat 3 times and freeze-dry the combined filtrate to obtain a colorless syrupy product 129-E (156 mg, yield 83.77%, TFA salt), which is used directly in the next step.
  • Step 5 TEA (51 mg, 503 ⁇ mol) was added to a DMF (1.5 mL) solution of 129-E (62 mg, 181 ⁇ mol, 1.2 eq., TFA salt), and then compound 112 (40 mg, 153 ⁇ mol, 1.0 eq). The reaction mixture was stirred at 55 °C for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by prep HPLC (FA method-A; B%: 25%-45%, 10 min) to give an off-white solid compound 129 (32 mg, 41.5% yield).
  • Example 55 Referring to the method of Example 55, the starting materials in the following table were used in place of compound 129-A in the first step to carry out five steps of reaction to obtain the corresponding final compound.
  • Step 1 Dissolve compound 125-A (780 mg, 1.95 mmol) in DCM (15 mL), and add DIPEA (964.57 mg, 7.46 mmol) to the molten solution.
  • CTC resin 2-chlorotrityl chloride resin
  • Step 2 Place resin 125-B (1.54 g, 1.0 mmol) in a solid phase synthesis reactor, add 20 mL DCM and soak for 15 minutes to swell the resin, then remove the solvent by vacuum filtration and wash once with 20 mL DMF. Add 20 ml 20% piperidine/DMF, stir for 30 minutes, and then remove the solvent by vacuum filtration. Add 20 ml 20% piperidine/DMF again, stir for 30 minutes, then remove the solvent by vacuum filtration and wash the resin five times with 20 mL DMF.
  • Step 3 Place resin 125-C (0.75 g, ⁇ 0.5 mmol) in a solid phase synthesis reactor, add 15 mL DCM and soak for 15 minutes to swell the resin, then remove the solvent by vacuum filtration and wash once with 20 mL DMF. Add 10 ml 20% piperidine/DMF, stir for 15 minutes, and then remove the solvent by vacuum filtration. Add 20 ml 20% piperidine/DMF again, stir for 15 minutes, then remove the solvent by vacuum filtration and wash the resin five times with 15 mL DMF.
  • Step 4 Referring to the method of step 3 of Example 55, resin 125-D (0.5 mmol, 1.0 eq.) was reacted to obtain yellow resin 125-E for the next reaction.
  • Step 5 Referring to the method of step 4 of Example 55, the resin 125-E (0.5 mmol, 1.0 eq.) was reacted to obtain an off-white solid 125-F (232 mg, 92.52% yield, TFA salt).
  • Step 6 Referring to the method of step 5 of Example 55 (reaction temperature is 25°C), 125-F (71 mg, 183 ⁇ mol, TFA salt) was reacted to obtain white solid compound 125 (72 mg, 69.07% yield).
  • Example 56 Referring to the method of Example 56, the starting materials in the following table were used to replace compounds 129-A and 125-B in the second step to carry out five steps of reaction to obtain the corresponding final compounds.
  • Step 1 Resin 129-B (0.544 mmol,) was placed in a reaction bottle, DCM (10 ml) and phenylsilane (482 mg, 4.46 mmol) were added, stirred gently for 1 minute, and allowed to stand for 15 minutes to allow the resin to swell.
  • the reaction suspension was vacuum degassed and purged with nitrogen five times.
  • Pd(PPh 3 ) 4 140 mg, 121 umol was added to the reaction suspension, vacuum degassed and purged with nitrogen five times, and the reaction suspension was shaken under a nitrogen atmosphere for 1.5 hours.
  • the resin was filtered and washed with 15 mL DCM five times, and then washed with 15 mL DMF 3 times to obtain yellow resin 128-A for the next step.
  • Step 2 Resin 128-A (0.544 mmol) was placed in a solid phase synthesis reactor and washed once with 20 mL DMF. 2-Cyclohexylacetic acid (315 mg, 2.22 mmol) and HATU (834 mg, 2.19 mmol) and HOAt (302 mg, 2.22 mmol) were dissolved in DMF (10 mL) and the solution was added to the resin and stirred for 30 seconds. DIPEA (649 mg, 5.02 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours, then the solvent was removed by vacuum filtration and the resin was washed twice with 15 mL DMF.
  • a DMF solution of 0.5% PIX and 0.5% DIPEA (10 mL) was added, stirred for 5 minutes, then the solvent was removed by vacuum filtration, and the resin was washed three times with 15 mL DMF after repeated 2 times.
  • 15 ml 20% piperidine/DMF was added, stirred for 30 minutes, and then the solvent was removed by vacuum filtration.
  • Add another 15 ml of 20% piperidine/DMF stir for 30 min, then remove the solvent by vacuum filtration and wash the resin four times with 15 mL of DMF.
  • Step 3 and step 4 Referring to the method of step 4 and step 5 of Example 55, 128-B was used for two-step reaction to obtain white solid compound 128, with a two-step yield of 36%.
  • LCMS: (ESI) m/z 491.5 (M+1) + ; 1 H NMR (400 MHz, CDCl 3 ) ⁇ 7.51-7.68 (m, 1H), 6.88-7.11 (m, 1H), 6.96 (s, 1H), 6.46 (s, 1H), 5.61-5.72 (m, 1H), 4.50 (br s,1H),3.74(s,3H),3.42-3.68(m,2H),2.69-2.96(m,2H),2.41-2.69(m,5H),2.07-2. 24(m,1H),1.92-2.07(m,2H),1.53-1.76(m,6H),1.00-1.28(m,3H),0.77-0.97(m,2H).
  • Example 57 Referring to the method of Example 57, the starting materials in the following table were used in place of compound 129-A in the first step to carry out five steps of reaction to obtain the corresponding final compound.
  • Step 1 Resin 125-C (0.75 g, 0.5 mmol) was placed in a reaction bottle, DCM (15 mL) and phenylsilane (438 mg, 4.05 mmol) were added, gently stirred for 1 minute, and allowed to stand for 15 minutes to allow the resin to swell.
  • the reaction suspension was vacuum degassed and purged with nitrogen five times.
  • Pd(PPh 3 ) 4 150 mg, 130 umol was added to the reaction suspension, vacuum degassed and purged with nitrogen five times, and then the reaction suspension was shaken under a nitrogen atmosphere for 1.5 hours.
  • the resin was filtered and washed with 15 mL of DMF five times. The obtained resin was placed in a solid phase synthesis reactor.
  • Step 2 and step 3 Referring to the method of step 4 and step 5 of Example 55 (the reaction temperature in step 5 is 25°C), 126-A was used for two-step reaction to obtain white solid compound 126, with a two-step yield of 31%.
  • Step 1 Referring to the method of step 2 in Example 56, 122-B was used to replace compound 129-A and react with 125-B to obtain 122-A. Referring to the method of Example 58, 122-A was used as the raw material to carry out three steps of reaction to obtain white solid compound 122.
  • Step 1 Add acetic anhydride (2.03 g, 19.91 mmol) to a pyridine (10 mL) solution of compound 67-A (500 mg, 1.99 mmol). React at 25 °C for 16 hours. Concentrate under reduced pressure, add water (10 mL), and extract with EA (5 mL x 3). After conventional post-treatment operations, the crude product is obtained, and the crude product is purified by silica gel column chromatography (EA:PE, EA from 0 to 50%) to obtain a yellow solid (560 mg, yield 95.94%).
  • EA:PE silica gel column chromatography
  • Step 2 and step 3 Referring to the method of step 2 and step 3 in Example 12, the product of the above step (510 mg, 1.74 mmol) was used as a raw material to carry out two-step reaction to obtain yellow solid compound 286, with a two-step yield of 73.6%.
  • Compound 172 (30 mg) was chirally separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 ⁇ m); mobile phase: [CO 2 -EtOH (0.1% NH 3 H 2 O)]; B%: 15%, isocratic elution mode) to give compounds 293, 294, 295 and 296.
  • Compound 295: (8 mg), white solid, SFC: Rt 1.703 min.
  • HTRF homogeneous time-resolved fluorescence
  • Microplate reader (manufacturer: Perkin Elmer, model: Envision multi-function microplate reader, equipped with HTRF function module) and Echo 550 (manufacturer: Labcyte, model: Echo 550)
  • Preparation of compound concentration gradient The starting concentration of the test compound is 250 ⁇ M, 3-fold dilution, 10 concentrations, and duplicate well detection. Gradient dilution is performed in a 384-well plate to form 10 solutions with different concentrations of 40 times the final concentration. Then 500nl is transferred to the 384 reaction plate using Echo550 for later use. 500nl of 100% DMSO or dsDNA substrate without Biotin labeling is added to the negative control well and the positive control well, respectively.
  • the biological test results are recorded in the table below.
  • the results show that the exemplary compounds of the present invention have a strong inhibitory effect on the binding of TDG to double-stranded DNA substrates.
  • Compound 14 has an inhibitory IC 50 on the proliferation of TP53 mutant and wild-type tumor cells.
  • the TP53 mutant and wild-type tumor cells used in this example are both human tumor cells.
  • Tumor cells were plated in 384-well plates and treated with DMSO or the indicated concentrations of compound 14 (0.04–30 ⁇ M). After 6 days of incubation, the chemiluminescence intensity was measured using the CellTiter-Glo Luminescence Assay Kit (Promega). The curves were fitted using GraphPad Prism software and the IC 50 values were calculated.
  • compound 14 had a certain inhibitory effect on various tumor cell lines including lung cancer, liver cancer, skin cancer, bladder cancer, breast cancer, colon cancer and esophageal cancer, especially on p53 mutant tumor cell lines (including NCI-H446, Calu-1, NCI-H1299, RERF-LC-AI, NCI-H211, NCI-H2009, NCI-H23, VMRC-LCP, NCI-H441, PC9, NCI-H520, EBC-1, NCI-H1975, NCI-H2342, NCI-H647, HCC95, SK-LU-1, SW-900, SNU423, SNU449, HuCCT1, PLC/PRF/5, SNU387, Hep3B, JHH-2, JHH7, S The in vitro proliferation of NU761, Huh7, CHL-1, RPMI-7951, SK-MEL-2, SK-MEL-28, MeWo, SK-MEL-3, 5637, UMUC3,

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Abstract

Provided in the present invention is a compound which inhibits TDG activity. Specifically, provided in the present invention is a compound having a novel structure, as shown in formula I. A small molecule inhibitor of the present invention has an excellent inhibitory effect on TDG.

Description

一种TDG抑制剂化合物及其用途A TDG inhibitor compound and its use 技术领域Technical Field

本发明属于医药化学领域，具体涉及抑制TDG活性的化合物及其制法和应用。The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a compound for inhibiting TDG activity and a preparation method and application thereof.

背景技术Background Art

人胸腺嘧啶DNA糖基化酶(thymine DNA glycosylase,TDG)作为一种DNA糖基化酶，可以通过DNA碱基切除修复(DNA base-excision repair,BER)途径介导DNA修复。当DNA双链发生G·T或者G·U错配时，TDG能识别错配的碱基，水解U或者T的N-糖苷键，形成无嘧啶位点(apurinic/apyrimidinic site,AP位点)。TDG还能促使脱嘌呤/脱嘧啶核酸内切酶1(apurinic/apyrimidinic endonuclease 1,APE1)结合到AP位点，切断无碱基脱氧核酸5’端的磷酸二酯键，其他参与修复的蛋白和碱基加入后最终修复DNA。Human thymine DNA glycosylase (TDG) is a DNA glycosylase that can mediate DNA repair through the DNA base-excision repair (BER) pathway. When a G·T or G·U mismatch occurs in the DNA double helix, TDG can recognize the mismatched bases and hydrolyze the N-glycosidic bond of U or T to form an apurinic/apyrimidinic site (AP site). TDG can also promote apurinic/apyrimidinic endonuclease 1 (APE1) to bind to the AP site, cut the phosphodiester bond at the 5' end of the abasic deoxynucleic acid, and other proteins and bases involved in the repair are added to finally repair the DNA.

TDG是氧化作用与BER途径协同介导的DNA主动去甲基化途径中一个关键的酶。在TET-TDG介导的DNA主动去甲基化机制中，5-甲基胞嘧啶(5mC)在一类TET(ten-eleven-translocation protein)双加氧酶的作用下被氧化成为5-羧基胞嘧啶(5caC)，TDG酶特异性识别并切除5caC，进而启动BER途径将原来的5mC替换成胞嘧啶，从而实现DNA去甲基化。DNA甲基化是一种重要的表观遗传修饰方式，TDG通过介导DNA主动去甲基化参与表观遗传调控，在基因表达调控、胚胎生长发育、造血干细胞分化等方面起到重要作用。TDG is a key enzyme in the active DNA demethylation pathway mediated by oxidation and the BER pathway. In the TET-TDG-mediated active DNA demethylation mechanism, 5-methylcytosine (5mC) is oxidized to 5-carboxycytosine (5caC) by a class of TET (ten-eleven-translocation protein) dioxygenases. The TDG enzyme specifically recognizes and removes 5caC, and then activates the BER pathway to replace the original 5mC with cytosine, thereby achieving DNA demethylation. DNA methylation is an important epigenetic modification. TDG participates in epigenetic regulation by mediating active DNA demethylation, and plays an important role in gene expression regulation, embryonic growth and development, and hematopoietic stem cell differentiation.

TDG可以促进肿瘤发生，并可能成为癌症治疗的潜在靶点。研究显示，TDG在部分人类结直肠癌(colorectal carcinoma,CRC)者中过表达。TDG通过作为转录因子TCF4的适配蛋白并招募CBP/p300，充当WNT信号的正调节器。将TDG shRNA稳定转染到几个CRC细胞系中抑制了细胞生长。重要的是，稳定敲低TDG表达减少了CRC细胞在异种移植试验中成瘤的能力，表明TDG对体内CRC细胞增殖是必需的。此外，TDG的敲低可以抑制黑色素瘤细胞系在异种移植模型中的肿瘤形成，表明TDG活性对肿瘤诱发和/或进展至关重要。因此，开发以TDG为靶点的特异小分子抑制剂非常必要和有意义。TDG can promote tumorigenesis and may be a potential target for cancer therapy. Studies have shown that TDG is overexpressed in some human colorectal carcinoma (CRC) patients. TDG acts as a positive regulator of WNT signaling by acting as an adaptor protein for the transcription factor TCF4 and recruiting CBP/p300. Stable transfection of TDG shRNA into several CRC cell lines inhibited cell growth. Importantly, stable knockdown of TDG expression reduced the ability of CRC cells to form tumors in xenograft experiments, indicating that TDG is essential for CRC cell proliferation in vivo. In addition, knockdown of TDG can inhibit tumor formation in melanoma cell lines in xenograft models, indicating that TDG activity is essential for tumor induction and/or progression. Therefore, it is very necessary and meaningful to develop specific small molecule inhibitors targeting TDG.

发明内容Summary of the invention

本发明的目的就是提供一种以TDG为靶点的高效的小分子抑制剂。The purpose of the present invention is to provide a highly efficient small molecule inhibitor targeting TDG.

本发明的第一方面，提供了一种如下式1所示的化合物，或其氘代产物、立体异构体、互变异构体，或其药学上可接受的盐：
In a first aspect of the present invention, there is provided a compound as shown in the following formula 1, or a deuterated product, stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof:

R1选自下组：OH、H、卤素、氰基、取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C6烷氧基、取代或未取代的C6-C10芳基、取代或未取代的3-12元的杂环、取代或未取代的5-12元的杂芳环、取代或未取代的-O-3-12元的杂环、取代或未取代的-C1-C6烷基-苯基、取代或未取代的-O-苯基、取代或未取代的C1-C4烷基-C(O)-、取代或未取代的C1-C4烷基-S(O)2-、取代或未取代的C1-C6烷基-NH-、(取代或未取代的C1-C6烷基)2-N-，-O(CH2)sR10，或-S(CH2)sR10；s为0、1、2或3；R10选自下组：H、取代或未取代的C3-8碳环、取代或未取代的3-8元的杂环、取代或未取代的C6-C10芳基、取代或未取代的5-12元的杂芳环； R1 is selected from the following group: OH, H, halogen, cyano, substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C2 - C6 alkenyl, substituted or unsubstituted C2 - C6 alkynyl, substituted or unsubstituted C1 - C6 alkoxy, substituted or unsubstituted C6- C10 aryl, substituted or unsubstituted 3-12 membered heterocycle, substituted or unsubstituted 5-12 membered heteroaromatic ring, substituted or unsubstituted -O-3-12 membered heterocycle, substituted or unsubstituted -C1 - C6 alkyl-phenyl, substituted or unsubstituted -O-phenyl, substituted or unsubstituted C1-C4 alkyl -C(O)-, substituted or unsubstituted C1 - C4 alkyl-S(O) 2- , substituted or unsubstituted C1 - C6 alkyl-NH-, (substituted or unsubstituted C1 - C6 alkyl) 2 -N-, -O(CH 2 ) s R 10 , or -S(CH 2 ) s R 10 ; s is 0, 1, 2 or 3; R 10 is selected from the group consisting of H, substituted or unsubstituted C 3-8 carbocyclic ring, substituted or unsubstituted 3-8 membered heterocyclic ring, substituted or unsubstituted C 6 -C 10 aryl group, substituted or unsubstituted 5-12 membered heteroaromatic ring;

R2各自独立地选自下组：H、卤素、取代或未取代的C1-C6烷基；R 2 is each independently selected from the group consisting of H, halogen, substituted or unsubstituted C 1 -C 6 alkyl;

R3选自下组：H、卤素、氰基、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C12环烷基，或(C1-C6烷基)C(O)R8、(C1-C6烷基)C(O)NHR8、(C1-C6烷基)C(O)N(取代或未取代的C1-C6烷基)R8、(C1-C6烷基)C(O)OR8；所述的R8选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C6-C10芳基、-(OCH2CH2)m-取代或未取代的C1-C6烷基、或取代或未取代的选自下组的基团：-(CH2)mNHC(O)(CH2)nR13、-(CH2)CHR9NHC(O)(CH2)nR13、CHR9(CH2)NHC(O)(CH2)nR13；所述的R9选自下组：H、-COOH、-CONHR12、-CONHCH2R12、-CONH(CH2CH2O)m(CH2)nCOOH、取代或未取代的C1-C6烷氧基、取代或未取代的C6-C10芳基、取代或未取代的C3-C10的碳环、取代或未取代的3-12元的杂环、取代或未取代的5-12元的杂芳环；R12选自下组：取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C6-C10芳基、取代或未取代的5-12元的杂芳环；所述的R13选自下组：取代或未取代的C3-C10的碳环； R3 is selected from the group consisting of H, halogen, cyano, substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C1 - C6 alkoxy, substituted or unsubstituted C3 - C12 cycloalkyl, or ( C1 - C6 alkyl)C(O) R8 , ( C1 - C6 alkyl)C(O) NHR8 , ( C1 - C6 alkyl)C(O)N(substituted or unsubstituted C1 - C6 alkyl) R8 , ( C1 - C6 alkyl)C(O) OR8 ; said R8 is selected from the group consisting of H, substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C6 - C10 aryl, -( OCH2CH2 ) m -substituted or unsubstituted C1 - C6 alkyl, or a substituted or unsubstituted group selected from the group consisting of - ( CH2 ) mNHC (O)(CH wherein R 9 is selected from the group consisting of H , -COOH , -CONHR 12 , -CONHCH 2 R 12 , -CONH(CH 2 CH 2 O) m (CH 2 ) n COOH , substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted C 3 -C 10 carbocyclic ring, substituted or unsubstituted 3-12 membered heterocyclic ring, substituted or unsubstituted 5-12 membered heteroaromatic ring; and R 12 is selected from the group consisting of substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl , substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 5-12 membered heteroaromatic ring; said R 13 is selected from the following group: substituted or unsubstituted C 3 -C 10 carbocyclic ring;

m和n各自独立地为0、1、2或3；m and n are each independently 0, 1, 2 or 3;

R4选自下组：H、卤素、氰基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6胺基、取代或未取代的C6-C10芳基、取代或未取代的C3-C8的环烷基、取代或未取代的3-12元的杂环、取代或未取代的5-12元的杂芳环、取代或未取代的-O-5-12元的杂芳环、 R4 is selected from the following group: H, halogen, cyano, substituted or unsubstituted C1 - C6 alkoxy, substituted or unsubstituted C1 - C6 amine, substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted C3- C8 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic ring, substituted or unsubstituted 5-12 membered heteroaromatic ring, substituted or unsubstituted -O-5-12 membered heteroaromatic ring,

或者，R3和R4以及与其相连的碳原子共同形成选自下组的结构：取代或未取代的C6-C10芳环，取代或未取代的5-10元芳杂环、取代或未取代的C3-C8碳环，或取代或未取代的3-10元杂环；Alternatively, R3 and R4 and the carbon atoms to which they are attached together form a structure selected from the group consisting of a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C3-C8 carbocycle, or a substituted or unsubstituted 3-10 membered heterocycle;

R5和R6各自独立地选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C6-C10芳环，取代或未取代的5-10元芳杂环、取代或未取代的C3-C8碳环，或取代或未取代的3-10元杂环；或所述的R5和R6以及与其相连的碳原子共同形成取代或未取代的3-12元的碳环； R5 and R6 are each independently selected from the following group: H, substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C6-C10 aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C3-C8 carbocycle, or substituted or unsubstituted 3-10 membered heterocycle; or said R5 and R6 and the carbon atoms connected thereto together form a substituted or unsubstituted 3-12 membered carbocycle;

R6'选自下组：H、取代或未取代的C1-C6烷基；或R6和R6'共同构成＝CH2 R 6 'is selected from the group consisting of H, substituted or unsubstituted C 1 -C 6 alkyl; or R 6 and R 6 'together form ＝CH 2

X选自O或S；X is selected from O or S;

Z选自O、S或NR14；其中，R14为H或C1-C4烷基；Z is selected from O, S or NR 14 ; wherein R 14 is H or C 1 -C 4 alkyl;

R7选自下组：H、取代或未取代的C1-C12烷基、或C(O)R11、C(O)OR11、-CH2OC(O)OR11、-S(O)2NHR11；R 7 is selected from the group consisting of H, substituted or unsubstituted C 1 -C 12 alkyl, or C(O)R 11 , C(O)OR 11 , -CH 2 OC(O)OR 11 , -S(O) 2 NHR 11 ;

所述的R11选自下组：H、取代或未取代的C1-C16烷基、取代或未取代的C6-C10芳基、-(OCH2CH2)m-取代或未取代的C1-C6烷基、取代或未取代的5-8元杂环基；The R 11 is selected from the following group: H, substituted or unsubstituted C 1 -C 16 alkyl, substituted or unsubstituted C 6 -C 10 aryl, -(OCH 2 CH 2 ) m -substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted 5-8 membered heterocyclic group;

除非特别说明，上述各式中，所述的杂芳环、杂芳基、杂环或杂环基含有1个、2个或3个选自N、S或O的杂原子；所述的芳环、芳基、杂芳环或杂芳基可以为单环或稠合环；所述的碳环、环烷基、杂环或杂环基可以为单环、并环、桥环或螺环；所述的碳环、杂环或杂环基可以是饱和或部分不饱和的，但不具有芳香性。Unless otherwise specified, in the above formulas, the heteroaromatic ring, heteroaryl group, heterocycle or heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, S or O; the aromatic ring, aryl group, heteroaromatic ring or heteroaryl group may be a monocyclic ring or a condensed ring; the carbocyclic ring, cycloalkyl group, heterocyclic ring or heterocyclic group may be a monocyclic ring, a fused ring, a bridged ring or a spirocyclic ring; the carbocyclic ring, heterocyclic ring or heterocyclic group may be saturated or partially unsaturated, but not aromatic.

所述的取代指对应基团上的氢原子被一个或多个选自下组的取代基所取代：氘、卤素、羟基、羧基、巯基、苄基、C2-C12烷氧基羰基、C1-C6醛基、(C1-C6烷基)3Si、氨基、C1-C6酰胺基、硝基、氰基、未取代或卤代的C1-C6烷基、C2-C10烯基、C1-C6烷氧基、C3-C6环烷基、C1-C6烷基-胺基、C1-C12烷氨基羰基、未取代或卤代的C2-C10酰基、未取代或卤代的C1-C4烷基-S(O)2-、未取代或被C1-C4烷基取代的C1-C4烷基-OC(O)NH-、未取代或卤代C1-C4烷基-SO-、未取代或被C1-C4烷基取代的5-7元杂环，或苯基(其可以具有1-5个选自卤素、C1-C4烷基、C1-C4烷氧基的取代基)。The substitution refers to that the hydrogen atoms on the corresponding group are replaced by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, carboxyl, mercapto, benzyl, C2 - C12 alkoxycarbonyl, C1 - C6 aldehyde, ( C1 - C6 alkyl) 3Si , amino, C1 - C6 amide, nitro, cyano, unsubstituted or halogenated C1 - C6 alkyl, C2 - C10 alkenyl, C1 - C6 alkoxy, C3 - C6 cycloalkyl, C1 - C6 alkyl-amino, C1 - C12 alkylaminocarbonyl, unsubstituted or halogenated C2 - C10 acyl, unsubstituted or halogenated C1 - C4 alkyl-S(O) 2- , unsubstituted or substituted C1 - C4 alkyl-OC(O ) NH-, unsubstituted or halogenated C1 - C 4 -alkyl-SO-, a 5- to 7-membered heterocyclic ring which is unsubstituted or substituted by a C 1 -C 4 alkyl group, or a phenyl group (which may have 1 to 5 substituents selected from halogen, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group).

在另一优选例中，所述的R1选自下组：卤素、取代或未取代的C1-C6烷氧基、取代或未取代的C6-C10芳基、取代或未取代的3-12元的杂环、取代或未取代的5-12元的杂芳环、取代或未取代的-O-3-12元的杂环、取代或未取代的C1-C4烷基-S(O)2-、取代或未取代的C1-C6烷基-NH-、(取代或未取代的C1-C6烷基)2-N-，或-O(CH2)sR10。In another preferred embodiment, R 1 is selected from the following group: halogen, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 3-12 membered heterocycle, substituted or unsubstituted 5-12 membered heteroaromatic ring, substituted or unsubstituted -O-3-12 membered heterocycle, substituted or unsubstituted C 1 -C 4 alkyl-S(O) 2 -, substituted or unsubstituted C 1 -C 6 alkyl-NH-, (substituted or unsubstituted C 1 -C 6 alkyl) 2 -N-, or -O(CH 2 ) s R 10 .

在另一优选例中，所述的式I化合物具有如下式II所示的结构：
In another preferred embodiment, the compound of formula I has a structure shown in the following formula II:

其中，所述的A环为取代或未取代的C6-C10芳环，取代或未取代的5-10元芳杂环、取代或未取代的C3-C8碳环，或取代或未取代的3-10元杂环；较佳地，所述的A环为取代或未取代的苯环，或取代或未取代的5-7元芳杂环。Wherein, the A ring is a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C3-C8 carbocycle, or a substituted or unsubstituted 3-10 membered heterocycle; preferably, the A ring is a substituted or unsubstituted benzene ring, or a substituted or unsubstituted 5-7 membered aromatic heterocycle.

在另一优选例中，所述的化合物具有如下式IV所示的结构：
In another preferred embodiment, the compound has a structure shown in the following formula IV:

其中，所述的B环为取代或未取代的C3-C8碳环，或取代或未取代的3-10元杂环；较佳地，所述的B环为取代或未取代的C3-C6碳环，或取代或未取代的3-8元杂环；其中，所述的碳环或杂环可以为饱和或部分不饱和的。Wherein, the B ring is a substituted or unsubstituted C3-C8 carbocycle, or a substituted or unsubstituted 3-10 membered heterocycle; preferably, the B ring is a substituted or unsubstituted C3-C6 carbocycle, or a substituted or unsubstituted 3-8 membered heterocycle; wherein, the carbocycle or heterocycle may be saturated or partially unsaturated.

在另一优选例中，所述的化合物具有如下式V所示的结构：

In another preferred embodiment, the compound has a structure shown in the following formula V:

其中，所述的D环为取代或未取代的C6-C10芳环，取代或未取代的5-10元芳杂环、取代或未取代的C3-C8碳环，或取代或未取代的3-10元杂环。Wherein, the D ring is a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C3-C8 carbon ring, or a substituted or unsubstituted 3-10 membered heterocycle.

在另一优选例中，所述的化合物具有如下式VI或VII所示的结构：
In another preferred embodiment, the compound has a structure shown in the following formula VI or VII:

其中，所述的Y为N或CH；Y1和Y2各自独立地选自下组：CHR15、NR15、O或S；t为1或2；其中所述的R15选自下组：氘、卤素、羟基、羧基、巯基、氨基、硝基、氰基、未取代或卤代的C1-C6烷基、C1-C6烷氧基。Wherein, Y is N or CH; Y1 and Y2 are each independently selected from the following group: CHR15 , NR15 , O or S; t is 1 or 2; wherein R15 is selected from the following group: deuterium, halogen, hydroxyl, carboxyl, thiol, amino, nitro, cyano, unsubstituted or halogenated C1 - C6 alkyl, C1 - C6 alkoxy.

在另一优选例中，R3选自下组：H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的苯基。In another preferred embodiment, R 3 is selected from the following group: H, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted phenyl.

在另一优选例中，R5和R6各自独立地选自下组：H、取代或未取代的C1-C6烷基；或所述的R5和R6以及与其相连的碳原子共同形成取代或未取代的3-6元的碳环。In another preferred embodiment, R 5 and R 6 are each independently selected from the following group: H, substituted or unsubstituted C 1 -C 6 alkyl; or said R 5 and R 6 and the carbon atoms connected thereto together form a substituted or unsubstituted 3-6 membered carbocyclic ring.

在另一优选例中，R3选自下组：H、卤素、氰基、取代或未取代的C1-C6烷基、取代或未取代的C3-C12环烷基，或(C1-C6烷基)C(O)R8、(C1-C6烷基)C(O)NHR8、(C1-C6烷基)C(O)N(取代或未取代的C1-C6烷基)R8、(C1-C6烷基)C(O)OR8；所述的R8选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C6-C10芳基、-(OCH2CH2)m-取代或未取代的C1-C6烷基、或取代或未取代的选自下组的基团：-(CH2)mNHC(O)(CH2)nR13、-(CH2)CHR9NHC(O)(CH2)nR13、CHR9(CH2)NHC(O)(CH2)nR13；所述的R9选自下组：H、-COOH、-CONHR12、-CONHCH2R12、-CONH(CH2CH2O)m(CH2)nCOOH、取代或未取代的C1-C6烷氧基、取代或未取代的C6-C10芳基、取代或未取代的C3-C10的碳环、取代或未取代的3-12元的杂环、取代或未取代的5-12元的杂芳环；R12选自下组：取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C6-C10芳基、取代或未取代的5-12元的杂芳环；所述的R13选自下组：取代或未取代的C3-C10的碳环；In another preferred embodiment, R 3 is selected from the following group: H, halogen, cyano, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 12 cycloalkyl, or (C 1 -C 6 alkyl)C(O)R 8 , (C 1 -C 6 alkyl)C(O)NHR 8 , (C 1 -C 6 alkyl)C(O)N(substituted or unsubstituted C 1 -C 6 alkyl)R 8 , (C 1 -C 6 alkyl)C(O)OR 8 ; said R 8 is selected from the following group: H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 6 -C 10 aryl, -(OCH 2 CH 2 ) m -substituted or unsubstituted C 1 -C 6 alkyl, or a substituted or unsubstituted group selected from the following group: -(CH 2 ) m NHC(O)(CH 2 ) n R 13 wherein R 9 is selected from the group consisting of H, -COOH, -CONHR 12 , -CONHCH 2 R 12 , -CONH(CH 2 CH 2 O) m (CH 2 ) n COOH, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted C 3 -C 10 carbocyclic ring , substituted or unsubstituted 3-12 membered heterocyclic ring, substituted or unsubstituted 5-12 membered heteroaromatic ring ; R 12 is selected from the group consisting of substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl , substituted or unsubstituted C 6 -C 10 10 aryl, substituted or unsubstituted 5-12 membered heteroaromatic ring; said R 13 is selected from the following group: substituted or unsubstituted C 3 -C 10 carbocyclic ring;

m和n各自独立地为0、1、2或3；m and n are each independently 0, 1, 2 or 3;

R4选自下组：H、卤素、取代或未取代的C1-C6烷氧基、取代或未取代的-O-5-12元的杂芳环；R 4 is selected from the group consisting of H, halogen, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted -O-5-12 membered heteroaromatic ring;

或者，R3和R4以及与其相连的碳原子共同形成取代或未取代的C6-C10芳环，或取代或未取代的5-10元芳杂环。Alternatively, R3 and R4 and the carbon atom to which they are attached together form a substituted or unsubstituted C6-C10 aromatic ring, or a substituted or unsubstituted 5-10 membered aromatic heterocyclic ring.

在另一优选例中，所述的化合物具有如下式III所示的结构：
In another preferred embodiment, the compound has a structure shown in the following formula III:

较佳地，所述的化合物具有如下式III-A或III-B所示的结构：
Preferably, the compound has a structure as shown in the following formula III-A or III-B:

较佳地，所述的化合物具有选自下组的任一结构：
Preferably, the compound has any structure selected from the following group:

在另一优选例中，所述的化合物具有如下式IX所示的结构：
In another preferred embodiment, the compound has a structure shown in the following formula IX:

较佳地，所述的化合物具有如下式IX-A或IX-B所示的结构：
Preferably, the compound has a structure as shown in the following formula IX-A or IX-B:

较佳地，所述的化合物具有选自下组的任一结构：
Preferably, the compound has any structure selected from the following group:

在另一优选例中，所述的化合物具有如下式X所示的结构：
In another preferred embodiment, the compound has a structure shown in the following formula X:

较佳地，所述的化合物具有如下式X-A或X-B所示的结构：
Preferably, the compound has a structure as shown in the following formula XA or XB:

较佳地，所述的化合物具有选自下组的任一结构：
Preferably, the compound has any structure selected from the following group:

本发明的第二方面提供了一种药物组合物，包括(i)如第一方面所述的化合物和(ii)药学上可接受的载体。The second aspect of the present invention provides a pharmaceutical composition comprising (i) the compound as described in the first aspect and (ii) a pharmaceutically acceptable carrier.

本发明的第三方面提供了一种如第一方面所述的化合物，或其氘代产物、立体异构体、互变异构体，或其药学上可接受的盐，或者如第二方面所述的药物组合物的用途，其用于制备治疗和/或预防与TDG表达异常相关的疾病的药物。The third aspect of the present invention provides a use of the compound as described in the first aspect, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt, or the pharmaceutical composition as described in the second aspect, for preparing a drug for treating and/or preventing diseases associated with abnormal TDG expression.

在另一优选例中，所述与TDG表达异常的相关疾病为肿瘤。In another preferred embodiment, the disease associated with abnormal TDG expression is a tumor.

在另一优选例中，所述肿瘤选自下组：肺癌、急性白血病、慢性白血病、结直肠癌、乳腺癌、甲状腺瘤、淋巴瘤、胆管癌、肝癌、胰腺癌、支气管癌、食管癌、皮肤癌、口腔癌、胃癌、泌尿生殖道肿瘤、中枢和外周神经系统肿瘤，或其组合。In another preferred embodiment, the tumor is selected from the following groups: lung cancer, acute leukemia, chronic leukemia, colorectal cancer, breast cancer, thyroid tumor, lymphoma, bile duct cancer, liver cancer, pancreatic cancer, bronchial cancer, esophageal cancer, skin cancer, oral cancer, gastric cancer, genitourinary tract tumors, central and peripheral nervous system tumors, or a combination thereof.

在另一优选例中，所述肿瘤选自下组：黑色素瘤、急性髓系白血病、小细胞肺癌、非小细胞肺癌。In another preferred embodiment, the tumor is selected from the following group: melanoma, acute myeloid leukemia, small cell lung cancer, non-small cell lung cancer.

本发明的第四方面提供了一种抑制TDG活性的方法，所述方法包括步骤：The fourth aspect of the present invention provides a method for inhibiting TDG activity, the method comprising the steps of:

使对象与有效量的如第一方面所述的化合物，或其立体异构体或互变异构体、或其药学上可接受的盐、或其水合物、或其晶型、或其溶剂化物，或者如第二方面所述的药物组合物接触，从而抑制TDG活性。The subject is contacted with an effective amount of the compound as described in the first aspect, or its stereoisomer or tautomer, or its pharmaceutically acceptable salt, or its hydrate, or its crystal form, or its solvate, or the pharmaceutical composition as described in the second aspect, thereby inhibiting TDG activity.

在另一优选例中，所述的方法是体外非治疗性的和非诊断性的。In another preferred embodiment, the method is in vitro non-therapeutic and non-diagnostic.

本发明的第五方面提供了一种治疗和/或预防与TDG过度表达相关的疾病的方法，所述方法包括步骤：A fifth aspect of the present invention provides a method for treating and/or preventing a disease associated with overexpression of TDG, the method comprising the steps of:

向对象施用有效量的如第一方面所述的化合物，或其盐，或其异构体，或者如第二方面所述的药物组合物。An effective amount of the compound according to the first aspect, or a salt thereof, or an isomer thereof, or the pharmaceutical composition according to the second aspect is administered to a subject.

应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here.

附图说明BRIEF DESCRIPTION OF THE DRAWINGS

图1显示了化合物14对p53突变型和野生型肿瘤细胞系体外增殖的抑制IC50。FIG1 shows the IC 50 of compound 14 on the proliferation of p53 mutant and wild-type tumor cell lines in vitro.

具体实施方式DETAILED DESCRIPTION

本发明人通过广泛而深入的研究，首次意外地发现一类具有TDG抑制活性的化合物。在此基础上完成了本发明。The present inventors, through extensive and in-depth research, unexpectedly discovered for the first time a class of compounds having TDG inhibitory activity, on the basis of which the present invention was completed.

术语the term

在本发明中，所述卤素为F、Cl、Br或I。In the present invention, the halogen is F, Cl, Br or I.

在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。本发明中，如果没有特别指明，所有化学式意在涵盖可能的任何光学或几何异构体(例如R型、S型或外消旋体，或者烯烃的顺反异构体等)。In the present invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art. In the present invention, if not otherwise specified, all chemical formulae are intended to cover any possible optical or geometric isomers (e.g., R-type, S-type or racemate, or cis-trans isomers of olefins, etc.).

在本发明中，术语“C1-C6烷基”是指具有1至6个碳原子的直链或支链烷基，非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基和已基等；优选乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基。In the present invention, the term "C1-C6 alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc.; preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

在本发明中，术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。In the present invention, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.

在本发明中，术语C1-C6胺基指“C1-C6烷基-NH-”和“(C1-C6烷基)2N-”，或其类似结构。In the present invention, the term C 1 -C 6 amine refers to "C 1 -C 6 alkyl-NH-" and "(C 1 -C 6 alkyl) 2 N-", or the like.

在本发明中，术语“C2-C6烯基”是指具有2至6个碳原子的含有一个双键的直链或支链烯基，非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。In the present invention, the term "C2-C6 alkenyl" refers to a straight or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including but not limited to ethenyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl.

在本发明中，术语“C2-C6炔基”是指具有2至6个碳原子的含有一个三键的直链或支链炔基，非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。In the present invention, the term "C2-C6 alkynyl" refers to a straight or branched alkynyl group having 2 to 6 carbon atoms and containing one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.

在本发明中，术语“C3-C10环烷基”是指在环上具有3至10个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基和环癸基等。术语“C3-C8环烷基”、“C3-C7环烷基”、和“C3-C6环烷基”具有类似的含义。In the present invention, the term "C3-C10 cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl, etc. The terms "C3-C8 cycloalkyl", "C3-C7 cycloalkyl", and "C3-C6 cycloalkyl" have similar meanings.

在本发明中，术语“C1-C12烷氧羰基”是指在烷基链上具有1至12个碳原子的烷氧羰基，非限制性地包括甲氧羰基、乙氧羰基、丙氧羰基、异丙氧羰基、叔丁氧羰基、苄氧羰基等。In the present invention, the term "C1-C12 alkoxycarbonyl" refers to an alkoxycarbonyl group having 1 to 12 carbon atoms in the alkyl chain, including but not limited to methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like.

在本发明中，术语“C1-C12烷氨基羰基”是指在烷基链上具有1至12个碳原子的烷氨基羰基，非限制性地包括甲氨基羰基、乙氨基羰基、丙氨基羰基、异丙氨基羰基、叔丁氨基羰基、苄氨基羰基、二甲氨基羰基等。In the present invention, the term "C1-C12 alkylaminocarbonyl" refers to an alkylaminocarbonyl group having 1 to 12 carbon atoms in the alkyl chain, including but not limited to methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, dimethylaminocarbonyl and the like.

在本发明中，术语“芳环”或“芳基”具有相同的含义，优选地“芳基”为“C6-C12芳基”或“C6-C10芳基”。术语“C6-C12芳基”是指在环上不含杂原子的具有6至12个碳原子的芳香族环基，如苯基、萘基等。术语“C6-C10芳基”具有类似的含义。In the present invention, the term "aromatic ring" or "aryl" has the same meaning, preferably "aryl" is "C6-C12 aryl" or "C6-C10 aryl". The term "C6-C12 aryl" refers to an aromatic ring group having 6 to 12 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl, etc. The term "C6-C10 aryl" has a similar meaning.

在本发明中，术语“芳香杂环”、“杂芳环”或“杂芳基”具有相同的含义，指包含一个到多个杂原子的杂芳族基团。这里所指的杂原子包括氧、硫和氮。例如呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。In the present invention, the terms "aromatic heterocycle", "heteroaromatic ring" or "heteroaryl" have the same meaning and refer to heteroaromatic groups containing one to multiple heteroatoms. The heteroatoms referred to here include oxygen, sulfur and nitrogen. For example, furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted.

在本发明中，术语“3-12元杂环基”是指在环上含有1～3个选自氧、硫和氮中的杂原子的饱和或不饱和的3-12元环基，例如二氧杂环戊基等。术语“3-7元杂环基”具有类似的含义。In the present invention, the term "3-12 membered heterocyclic group" refers to a saturated or unsaturated 3-12 membered ring group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen in the ring, such as dioxolanyl, etc. The term "3-7 membered heterocyclic group" has a similar meaning.

在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。环状取代基，例如杂环烷基，可以与另一个环相连，例如环烷基，从而形成螺二环系，例如，两个环具有一个共用碳原子。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基、3-至12-元杂环基，芳基、杂芳基、卤素、羟基、羧基(-COOH)、C1-8醛基、C2-10酰基、C2-10酯基、C1-C12烷氧羰基、氨基、烷氧基、C1-10磺酰基等。In the present invention, the term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is a substituent described above, or a substituent appearing in the embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. A cyclic substituent, such as a heterocycloalkyl, may be connected to another ring, such as a cycloalkyl, to form a spiro bicyclic system, for example, two rings having a common carbon atom. It will be appreciated by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. The substituents include, but are not limited to, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3- to 12-membered heterocyclic groups, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C1-8 aldehyde, C2-10 acyl, C2-10 ester, C1-C12 alkoxycarbonyl, amino, alkoxy, C1-10 sulfonyl, etc.

作为TDG抑制剂的式(I)化合物Compounds of formula (I) as TDG inhibitors

本发明中提供了一类具有TDG抑制活性的化合物：

The present invention provides a class of compounds having TDG inhibitory activity:

其中各基团具有如上文中所述的定义。wherein each group has the same meaning as described above.

药物组合物和施用方法Pharmaceutical compositions and methods of administration

由于本发明化合物具有优异的生物学活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由于TDG的活性或表达量异常引起的相关疾病。Since the compounds of the present invention have excellent biological activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate related diseases caused by abnormal activity or expression of TDG.

本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 5-200 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。"Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。在一些优选的实施方式中，本发明的化合物可以与其他小分子化合物一同形成PROTAC，或者与其他大分子化合物例如单抗共同形成ADC施用。The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. In some preferred embodiments, the compounds of the present invention can be administered together with other small molecule compounds to form PROTAC, or together with other macromolecular compounds such as monoclonal antibodies to form ADC.

使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选5～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 5 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill range of a skilled physician.

下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

缩写：

abbreviation:

原料可以通过商业途径获得或者通过本领域已经已知或者公开的方法制备获得。The raw materials can be obtained from commercial sources or prepared by methods known or disclosed in the art.

中间体和化合物的纯化采用正相或反向色谱法或者重结晶等常规的化学实验操作进行。正相色谱法为预装填硅胶色谱柱或者制备薄层色谱。硅胶色谱柱主要为玻璃柱或者快速柱色谱仪，快速柱色谱仪的型号有或者其它品牌。正相色谱法的流动相从石油醚/乙酸乙酯，二氯甲烷/甲醇或者其它合适的溶剂中选择及配比进行洗脱。反相制备液相色谱采用C18柱，用制备型液相色谱仪或者快速柱色谱仪进行，214nM和254nM或者制备型液相色谱-质谱联用仪器检测，以含0.1％盐酸的水/乙腈、水/乙腈、含0.1％碳酸氢铵的水/乙腈、含0.1％甲酸的水/乙腈、含0.1％氨水/乙腈、含0.1％三氟乙酸的水/乙腈或者其它合适的溶剂体系作为流动相进行梯度洗脱。The purification of intermediates and compounds is carried out by normal phase or reverse phase chromatography or recrystallization and other conventional chemical experimental operations. Normal phase chromatography is pre-packed silica gel chromatography column or preparative thin layer chromatography. Silica gel chromatography column is mainly glass column or flash column chromatography. The models of flash column chromatography are Or other brands. The mobile phase of normal phase chromatography is selected from petroleum ether/ethyl acetate, dichloromethane/methanol or other suitable solvents and proportioned for elution. Reverse phase preparative liquid chromatography uses a C18 column, and is performed using a preparative liquid chromatograph or a flash column chromatograph, 214nM and 254nM or preparative liquid chromatography-mass spectrometry instrument detection, with water/acetonitrile containing 0.1% hydrochloric acid, water/acetonitrile, water/acetonitrile containing 0.1% ammonium bicarbonate, water/acetonitrile containing 0.1% formic acid, water/acetonitrile containing 0.1% ammonia water/acetonitrile, water/acetonitrile containing 0.1% trifluoroacetic acid or other suitable solvent systems as mobile phase for gradient elution.

Prep HPLC在Gilson制备HPLC系统(GX-281)上进行，代表性的prep HPLC条件有：①FA方法:Column:Boston Prime C18 150*30mm*5um；mobile phase:[water(0.225％FA)-ACN]；②FA方法-A：Phenomenex Gemini C18 250*50mm*10um；mobile phase:[water(0.225％FA)-ACN]；③FA方法-B：Phenomenex C18 80*30mm*5um；mobile phase:[water(0.225FA)-ACN]。Prep HPLC was carried out on a Gilson preparative HPLC system (GX-281). Representative prep HPLC conditions were: ①FA method: Column: Boston Prime C18 150*30mm*5um; mobile phase: [water(0.225％FA)-ACN]; ②FA method-A: Phenomenex Gemini C18 250*50mm*10um; mobile phase: [water(0.225％FA)-ACN]; ③FA method-B: Phenomenex C18 80*30mm*5um; mobile phase: [water(0.225FA)-ACN].

文中所述的常规的后处理操作为：合并有机相，有机相用无水硫酸或者无水硫酸钠干燥，过滤，滤液减压浓缩除掉溶剂。文中所述的常规的后处理操作二为：合并有机相，有机相用饱和食盐水洗涤(极少数情况下用30％的氯化锂溶液洗涤)，用无水硫酸或者无水硫酸钠干燥，过滤，滤液减压浓缩除掉溶剂或者。除非特别指出，化学反应在所标示的反应时间是通过LCMS检测或者TLC检测或者其它合适的检测方法显示该反应均已反应完全或者原料完全消失的时间。The conventional post-processing operation described in the text is: combine the organic phases, dry the organic phases with anhydrous sulfuric acid or anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the solvent. The conventional post-processing operation 2 described in the text is: combine the organic phases, wash the organic phases with saturated brine (in rare cases, wash with 30% lithium chloride solution), dry with anhydrous sulfuric acid or anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the solvent or. Unless otherwise specified, the reaction time indicated for a chemical reaction is the time when the reaction is complete or the raw material disappears completely as shown by LCMS detection or TLC detection or other appropriate detection methods.

中间体和化合物结构表征采用核磁共振(NMR)和质谱(LCMS)的方法。核磁共振所用到的核磁共振波谱仪为Bruker Ascend TM-400MHz或者Bruker Ultrashileld Plus 400MHz或者其它型号。所用溶剂为氘代二甲亚砜、氘代氯仿、氘代甲醇或者其它标注的氘代溶剂。光谱数据以模式报告：化学位移δ(峰裂数，耦合常数J(Hz)，氢数目)。四甲基硅烷作为化学位移的内标，并把它的化学位移定为零(δ，0ppm)。一些缩写的含义为:s(单峰),d(双重峰),t(三重峰),q(四重峰),m(多重峰),br(宽峰)。The structures of intermediates and compounds were characterized by nuclear magnetic resonance (NMR) and mass spectrometry (LCMS). The NMR spectrometer used for NMR was Bruker Ascend TM-400MHz or Bruker Ultrashield Plus 400MHz or other models. The solvents used were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol or other deuterated solvents as noted. Spectral data were reported in the mode: chemical shift δ (peak splitting number, coupling constant J (Hz), number of hydrogens). Tetramethylsilane was used as an internal standard for chemical shift, and its chemical shift was set to zero (δ, 0ppm). The meanings of some abbreviations are: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak).

中间体和化合物结构表征中液相色谱-质谱联用(LCMS)代表性的方法如下：Representative methods for liquid chromatography-mass spectrometry (LCMS) in the structural characterization of intermediates and compounds are as follows:

LCMS在连接到Agilent 1260系统的Agilent MSD质谱仪上进行,以紫外(UV,254 or 220nm)和质谱(MS,ESI+)进行检测。LCMS was performed on an Agilent MSD mass spectrometer connected to an Agilent 1260 system with ultraviolet (UV, 254 or 220 nm) and mass spectrometry (MS, ESI + ) detection.

方法一：5-95AB,柱:Agilent Pursult 5 C18 20*2.0mm，溶剂A:0.0375％TFA水溶液，溶剂B:0.1125％TFA乙腈溶液,历时0.7分钟5％溶剂B到95％溶剂B，保持0.4分钟，共1.5分钟；流速:1.5mL/min；柱温50℃。Method 1: 5-95AB, column: Agilent Pursult 5 C18 20*2.0mm, solvent A: 0.0375% TFA aqueous solution, solvent B: 0.1125% TFA acetonitrile solution, from 5% solvent B to 95% solvent B in 0.7 minutes, hold for 0.4 minutes, for a total of 1.5 minutes; flow rate: 1.5mL/min; column temperature 50°C.

方法二：5-95AB_3min_220&254_Agilent，柱:Agilent Poroshell 120 EC-C18 2.7um3.0*30mm，溶剂A:0.0375％TFA水溶液，溶剂B:0.1125％TFA乙腈溶液,历时1.2分钟5％溶剂B到80％溶剂B，历时1.3分钟80％溶剂B到95％溶剂B,保持0.5分钟，共3分钟；流速:1.5mL/min；柱温50℃。Method 2: 5-95AB_3min_220&254_Agilent, column: Agilent Poroshell 120 EC-C18 2.7um3.0*30mm, solvent A: 0.0375% TFA aqueous solution, solvent B: 0.1125% TFA acetonitrile solution, from 5% solvent B to 80% solvent B in 1.2 minutes, from 80% solvent B to 95% solvent B in 1.3 minutes, hold for 0.5 minutes, for a total of 3 minutes; flow rate: 1.5mL/min; column temperature 50°C.

方法三：0-100AB_QC_220&254柱:ACQUITY UPLC BEH C18 50*2.1mm,1.7um，溶剂A:0.1％TFA水溶液，溶剂B:0.1％TFA乙腈溶液,历时1分钟0％溶剂B到100％溶剂B，保持0.2分钟，共1.5分钟；流速:1.0mL/min；柱温40℃。Method three: 0-100AB_QC_220&254 column: ACQUITY UPLC BEH C18 50*2.1mm, 1.7um, solvent A: 0.1% TFA aqueous solution, solvent B: 0.1% TFA acetonitrile solution, from 0% solvent B to 100% solvent B in 1 minute, hold for 0.2 minutes, a total of 1.5 minutes; flow rate: 1.0mL/min; column temperature 40°C.

方法四:10-80AB_4min_220&254_Shimadzu,柱:Nano Chrom 120 C18 3.0*30mm,3um，溶剂A:0.0375％ TFA水溶液，溶剂B:0.1125％TFA乙腈溶液,历时3分钟10％溶剂B到80％溶剂B，保持0.5分钟，共4分钟；流速:0.8mL/min；柱温50℃。Method 4: 10-80AB_4min_220&254_Shimadzu, column: Nano Chrom 120 C18 3.0*30mm, 3um, solvent A: 0.0375% TFA aqueous solution, solvent B: 0.1125% TFA acetonitrile solution, from 10% solvent B to 80% solvent B in 3 minutes, hold for 0.5 minutes, a total of 4 minutes; flow rate: 0.8mL/min; column temperature 50°C.

方法五：5-95AB_1min_220&254_Agilent，柱:Agilent Poroshell 120EC-C18 2.7um 3.0*30mm，溶剂A:0.0375％TFA水溶液，溶剂B:0.1125％TFA乙腈溶液，历时0.4分钟5％溶剂B到95％溶剂B，保持0.3分钟，共1分钟；流速:2mL/min；柱温50℃。Method 5: 5-95AB_1min_220&254_Agilent, column: Agilent Poroshell 120EC-C18 2.7um 3.0*30mm, solvent A: 0.0375% TFA aqueous solution, solvent B: 0.1125% TFA acetonitrile solution, from 5% solvent B to 95% solvent B in 0.4 minutes, hold for 0.3 minutes, for a total of 1 minute; flow rate: 2mL/min; column temperature 50°C.

方法六：0-95AB_1.5min_220&254_Agilent，柱:Waters,Xbridge C18 30*2.1mm,3.5um，溶剂A:0.0375％TFA水溶液，溶剂B:0.1125％TFA乙腈溶液,历时0.6分钟0％溶剂B到95％溶剂B，保持0.8分钟，共1.5分钟；流速:1.2mL/min；柱温40℃。Method six: 0-95AB_1.5min_220&254_Agilent, column: Waters, Xbridge C18 30*2.1mm, 3.5um, solvent A: 0.0375% TFA aqueous solution, solvent B: 0.1125% TFA acetonitrile solution, from 0% solvent B to 95% solvent B in 0.6 minutes, maintained for 0.8 minutes, for a total of 1.5 minutes; flow rate: 1.2mL/min; column temperature 40°C.

方法七：10-80CD_3MIN_220&254_Shimadzu，柱:XBridge C18 3.5um 2.1*30mm，溶剂A:0.025％氨水水溶液，溶剂B:乙腈，历时2分钟10％溶剂B到80％溶剂B，保持0.48分钟，共3分钟；流速:1mL/min；柱温50℃。Method seven: 10-80CD_3MIN_220&254_Shimadzu, column: XBridge C18 3.5um 2.1*30mm, solvent A: 0.025% ammonia aqueous solution, solvent B: acetonitrile, 10% solvent B to 80% solvent B in 2 minutes, hold for 0.48 minutes, a total of 3 minutes; flow rate: 1mL/min; column temperature 50℃.

方法八：10-80AB_7min_220&254_Shimadzu柱:Xtimate C18 2.1*30mm,3um，溶剂A:0.0375％TFA水溶液，溶剂B:0.1125％TFA乙腈溶液，历时6分钟10％溶剂B到80％溶剂B，保持0.5分钟，共7分钟；流速:0.8mL/min；柱温50℃。Method 8: 10-80AB_7min_220&254_Shimadzu column: Xtimate C18 2.1*30mm, 3um, solvent A: 0.0375% TFA aqueous solution, solvent B: 0.1125% TFA acetonitrile solution, from 10% solvent B to 80% solvent B in 6 minutes, hold for 0.5 minutes, a total of 7 minutes; flow rate: 0.8mL/min; column temperature 50℃.

催化氢化代表性操作：将化合物溶解在相应的溶剂中，比如EA、THF中，加入钯碳(10％含量，约0.1当量)或者氢氧化钯/碳(20％含量，约0.1当量)，反应混合物充分置换氢气。15Psi氢气氛围下，25℃搅拌至LCMS显示反应完全。反应液抽滤，减压浓缩至干，纯化得产物。Representative operation of catalytic hydrogenation: dissolve the compound in a corresponding solvent, such as EA, THF, add palladium carbon (10% content, about 0.1 equivalent) or palladium hydroxide/carbon (20% content, about 0.1 equivalent), and fully replace the hydrogen in the reaction mixture. Stir at 25°C under a 15Psi hydrogen atmosphere until LCMS shows that the reaction is complete. Filter the reaction solution, concentrate to dryness under reduced pressure, and purify the product.

实施例1化合物14的合成方法一
Example 1 Synthesis Method 1 of Compound 14

步骤1：
Step 1:

向经过脱气处理并充氮气的(S,S)-(+)-N,N’-双(3,5-二叔丁基邻羟亚苄基)-1,2-二氨基钴(CAS:188264-84-8,370mg,613.48umol,0.025eq)和(R,R)-(-)-N,N’-双(3,5-二叔丁基邻羟亚苄基)-1,2-环己烷二氨基钴(CAS:176763-62-5,370mg,613.48umol,0.025eq)混合物中加入H2O(25mL)、重氮乙酸乙酯(14-a-1)(3.50g,24.54mmol,80％purity,1eq)和苯基乙烯基硫醚(5.01g,36.81mmol,1.5eq)，并在40℃反应24小时.TLC显示反应毕，生成两个产物(PE:EA＝8:1,Rf＝0.4,0.5).降至25℃,脱气并冲氧气几次，然后在25℃反应1小时.硅藻土过滤并用DCM冲洗(20mL*2),水相用DCM萃取(50mL*2)。合并有机相，有机相用无水硫酸镁干燥，过滤，滤液减压浓缩。所得剩余物通过硅胶色谱柱(120gSilica Flash Column,0～0.1,2,3％EA/PE,80mL/min)纯化得红色油状物14-b-1(顺式结构，3.08g,13.85mmol,56.46％yield).1H NMR(400MHz,CDCl3)Shift 7.35-7.42(m,2H),7.26-7.30(m,2H),7.13-7.21(m,1H),4.07(q,J＝7.11Hz,2H),2.72(q,J＝7.78Hz,1H),2.22-2.35(m,1H),1.45-1.53(m,2H),1.12(t,J＝7.03Hz,3H)。To a degassed and nitrogen-filled mixture of (S,S)-(+)-N,N'-bis(3,5-di-tert-butyl-2-hydroxybenzylidene)-1,2-cobalt diamine (CAS: 188264-84-8, 370 mg, 613.48 umol, 0.025 eq) and (R,R)-(-)-N,N'-bis(3,5-di-tert-butyl-2-hydroxybenzylidene)-1,2-cyclohexanediaminocobalt (CAS: 176763-62-5, 370 mg, 613.48 umol, 0.025 eq) was added H2 O (25mL), ethyl diazoacetate (14-a-1) (3.50g, 24.54mmol, 80% purity, 1eq) and phenyl vinyl sulfide (5.01g, 36.81mmol, 1.5eq), and react at 40°C for 24 hours. TLC shows that the reaction is complete and two products are generated (PE:EA=8:1, Rf=0.4, 0.5). Reduce to 25°C, degas and flush with oxygen several times, and then react at 25°C for 1 hour. Filter with celite and rinse with DCM (20mL*2), and extract the aqueous phase with DCM (50mL*2). Combine the organic phases, dry the organic phases with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel chromatography ( 120g Silica Flash Column, 0～0.1, 2, 3% EA/PE, 80mL/min) to obtain red oil 14-b-1 (cis structure, 3.08g, 13.85mmol, 56.46% yield). 1H NMR (400MHz,CDCl 3 )Shift 7.35-7.42(m,2H),7.26-7.30(m,2H),7.13-7.21(m,1H),4.07(q,J＝7.11Hz,2H),2.72(q,J＝7.78Hz,1H),2.22-2.35(m,1H),1.45-1.53(m,2H),1.12(t,J＝7.03Hz,3H).

步骤2：
Step 2:

一小时内，在0℃条件下向化合物(14-b-1)(15.3g,68.83mmol,1eq)的DCM(400mL)溶液中分批加入m-CPBA(21.9g,101.96mmol,80％purity,1.48eq)，25℃反应16小时。反应毕加入KOH(3M,500mL)水溶液。水相用DCM萃取(300mL*2)。合并有机相，有机相用饱和食盐水洗涤(100mL)、无水硫酸镁干燥，过滤，滤液减压浓缩。所得剩余物通过硅胶色谱柱(220gSilica Flash Column,50-80％EA/PE,100mL/min)纯化得棕色油状物14-c-1(9.8g,41.12mmol,59.75％yield)。(ESI)m/z＝238.9[M+H]+。1H NMR(400MHz,CDCl3)δδ7.62-7.72(m,2H),7.50-7.55(m,3H),4.16-4.28(m,2H),2.62(dt,J＝6.60,8.36Hz,1H),2.14(dt,J＝6.49,8.20Hz,1H),2.03-2.11(m,1H),1.64(dt,J＝5.72,8.25Hz,1H),1.31(t,J＝7.15Hz,3H).Within one hour, m-CPBA (21.9 g, 101.96 mmol, 80% purity, 1.48 eq) was added in batches to a DCM (400 mL) solution of compound (14-b-1) (15.3 g, 68.83 mmol, 1 eq) at 0°C, and the mixture was reacted at 25°C for 16 hours. After the reaction, KOH (3M, 500 mL) aqueous solution was added. The aqueous phase was extracted with DCM (300 mL*2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography ( 220g Silica Flash Column, 50-80% EA/PE, 100 mL/min) was used to obtain brown oil 14-c-1 (9.8 g, 41.12 mmol, 59.75% yield). (ESI) m/z = 238.9 [M+H] + . 1 H NMR (400MHz, CDCl 3 )δδ7.62-7.72(m,2H),7.50-7.55(m,3H),4.16-4.28(m,2H),2.62(dt,J＝6.60,8.36Hz,1H),2.14( dt,J＝6.49,8.20Hz,1H),2.03-2.11(m,1H),1.64(dt,J＝5.72,8.25Hz,1H),1.31(t,J＝7.15Hz,3H).

步骤3：
Step 3:

向化合物(14-a)(1.60g,5.53mmol,1eq)和三甲基硼氧六环(4.17g,16.60mmol,4.64mL,50％purity,3.0eq)的DMF(40mL)溶液中加入K2CO3(2.29g,16.60mmol,3.0eq)，充氮气几次。加入Pd(dppf)Cl2(202mg,276.70umol,0.05eq)，氮气保护下100℃反应16小时。反应毕加入水(50mL)，用EtOAc萃取(50mL*3)。合并有机相，有机相用无水硫酸镁干燥，过滤，滤液减压浓缩。所得剩余物通过硅胶色谱柱(24gSilica Flash Column,0～25％ EA/PE,35mL/min)纯化得黄色固体(14-b)(850mg,3.79mmol,收率68.49％).(ESI)m/z＝225.1(M+1)+.To a DMF (40 mL) solution of compound (14-a) (1.60 g, 5.53 mmol, 1 eq) and trimethylboroxane (4.17 g, 16.60 mmol, 4.64 mL, 50% purity, 3.0 eq) was added K 2 CO 3 (2.29 g, 16.60 mmol, 3.0 eq), and nitrogen was filled several times. Pd(dppf)Cl 2 (202 mg, 276.70 umol, 0.05 eq) was added, and the mixture was reacted at 100°C for 16 hours under nitrogen protection. After the reaction, water (50 mL) was added, and the mixture was extracted with EtOAc (50 mL*3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography ( 24g Silica Flash Column, 0～25％ EA/PE, 35mL/min) was used to purify the yellow solid (14-b) (850mg, 3.79mmol, yield 68.49%). (ESI) m/z＝225.1(M+1) + .

步骤4：
Step 4:

化合物(14-b)(950mg,4.24mmol,1eq)的DCM(10mL)和TFA(2mL)溶液在25℃反应2小时。反应毕减压浓缩得红色油状物化合物(14-c)(3.21g,13.47mmol,97.22％yield)直接用于下步反应。A solution of compound (14-b) (950 mg, 4.24 mmol, 1 eq) in DCM (10 mL) and TFA (2 mL) was reacted at 25°C for 2 hours. After the reaction, the mixture was concentrated under reduced pressure to obtain a red oil compound (14-c) (3.21 g, 13.47 mmol, 97.22% yield) which was directly used in the next step.

步骤5：
Step 5:

向化合物(14-c)(722mg,4.34mmol,1eq)和三异丙基氯硅烷(1.26g,6.52mmol,1.39mL,1.5eq)的THF(10mL)溶液中加入咪唑(591mg,8.69mmol,2.0eq)和DIEA(1.12g,8.69mmol,1.51mL,2.0eq)，25℃反应2小时。反应毕加入水(20mL)，用EtOAc萃取(30mL*3)。合并有机相，有机相用无水硫酸镁干燥，过滤，滤液减压浓缩。所得剩余物通过硅胶色谱柱(24gSilica Flash Column,0～10％EA/PE,35mL/min)纯化得无色油状物(14-d)(1.23g,3.81mmol,87.78％yield).1H NMR(400MHz,CDCl3)Shift 10.29(s,1H),7.65(s,1H),6.40(s,1H),3.86(s,3H),2.19(s,3H),1.31-1.39(m,3H),1.08(s,18H).(ESI)m/z＝323.3(M+1)+.Imidazole (591 mg, 8.69 mmol, 2.0 eq) and DIEA (1.12 g, 8.69 mmol, 1.51 mL, 2.0 eq) were added to a solution of compound (14-c) (722 mg, 4.34 mmol, 1 eq) and triisopropylsilyl chloride (1.26 g, 6.52 mmol, 1.39 mL, 1.5 eq) in THF (10 mL), and the mixture was reacted at 25 °C for 2 hours. After the reaction, water (20 mL) was added and the mixture was extracted with EtOAc (30 mL*3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography ( 24g Silica Flash Column, 0～10％EA/PE, 35mL/min) was purified to give a colorless oil (14-d) (1.23g, 3.81mmol, 87.78％yield). 1 H NMR (400MHz,CDCl 3 )Shift 10.29(s,1H),7.65(s,1H),6.40(s,1H),3.86(s,3H),2.19(s,3H),1.31-1.39(m,3H),1.08(s,18H).(ESI)m/z＝323.3(M+1) + .

步骤6：
Step 6:

在-78℃，向化合物(14-c-1)(635mg,2.67mmol,1eq)的THF(25mL)溶液中加入异丙基氯化镁溶液(2M,2.00mL,1.5eq)，维持-78℃搅拌15分钟。加入化合物(14-d)(860mg,2.67mmol,1.0eq)的toluene(3mL)溶液，0℃反应3小时。反应毕加入饱和NH4Cl水溶液(20mL)淬灭，用EtOAc萃取(20mL*3)。合并有机相，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。所得剩余物通过硅胶色谱柱(24gSilica Flash Column,0～10％ EA/PE,35mL/min)纯化得无色油状物化合物(14-e)(220mg,563.25umol,21.12％yield)。1H NMR(400MHz,CDCl3)6.95-7.05(m,1H),6.37-6.45(m,1H),5.83(d,J＝4.77Hz,0.3H),5.49(s,0.5H),4.60(s,0.3H),3.79-3.81(m,3H),2.63-2.68(m,0.3H),2.18-2.26(m,4.4H),1.25-1.38(m,4H),1.01-1.17(m,19H).(ESI)m/z＝391.2(M+1)+.At -78°C, add isopropylmagnesium chloride solution (2M, 2.00mL, 1.5eq) to a solution of compound (14-c-1) (635mg, 2.67mmol, 1eq) in THF (25mL), and stir at -78°C for 15 minutes. Add a solution of compound (14-d) (860mg, 2.67mmol, 1.0eq) in toluene (3mL), and react at 0°C for 3 hours. After the reaction, add saturated NH 4 Cl aqueous solution (20mL) to quench, and extract with EtOAc (20mL*3). Combine the organic phases, dry them over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel chromatography ( 24g Silica Flash Column, 0-10% EA/PE, 35 mL/min) was used to obtain a colorless oily compound (14-e) (220 mg, 563.25 umol, 21.12% yield). 1 H NMR (400MHz, CDCl 3 )6.95-7.05(m,1H),6.37-6.45(m,1H),5.83(d,J＝4.77Hz,0.3H),5.49(s,0.5H),4.60(s,0.3H),3.79-3.81(m ,3H),2.63-2.68(m,0.3H),2.18-2.26(m,4.4H),1.25-1.38(m,4H),1.01-1.17(m,19H).(ESI)m/z＝391.2(M+1) + .

步骤7：
Step 7:

向化合物(14-e)(180mg,460.84umol,1eq)的THF(5mL)溶液中加入三乙胺三氢氟酸盐(59.4mg,368.68umol,60.09uL,0.8eq)，25℃反应3小时。反应毕加入饱和NaHCO3水溶液(5mL)淬灭，用EtOAc萃取(5mL*3)。合并有机相，有机相用无水硫酸镁干燥，过滤，滤液减压浓缩。所得剩余物通过硅胶色谱柱(12gSilica Flash Column,0～30％ EA/PE,35mL/min)纯化得粉色固体化合物14(70mg,283.89umol,61.60％yield,95％purity).(ESI)m/z＝235.0(M+1)+.Triethylamine trihydrofluoride (59.4 mg, 368.68 umol, 60.09 uL, 0.8 eq) was added to a THF (5 mL) solution of compound (14-e) (180 mg, 460.84 umol, 1 eq) and reacted at 25 °C for 3 hours. After the reaction was completed, saturated NaHCO 3 aqueous solution (5 mL) was added to quench, and extracted with EtOAc (5 mL*3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography ( 12g Silica Flash Column, 0-30% EA/PE, 35 mL/min) was used to purify the pink solid compound 14 (70 mg, 283.89 umol, 61.60% yield, 95% purity). (ESI) m/z = 235.0 (M+1) + .

参照上述化合物14的合成方法中步骤5到步骤7的方法，用如下表格中的起始原料进行反应得到相应的终产化合物。
Referring to the method of steps 5 to 7 in the synthesis method of compound 14, the starting materials in the following table were used to react to obtain the corresponding final compounds.

实施例2化合物14的合成方法二
Example 2 Synthesis Method 2 of Compound 14

步骤1：
Step 1:

向化合物(14-c)(5.0g,30.09mmol,1eq)的DMF(75mL)溶液中加入K2CO3(12.5g,90.27mmol,3.0eq)和3-溴-1-丙烯(4.73g,39.12mmol,1.3eq)，25℃反应3小时。反应毕过滤，减压浓缩，所得剩余物通过硅胶色谱柱(80gSilica Flash Column,0～10％ EA/PE,65mL/min)纯化得白色固体化合物(14-f)(5.3g,25.70mmol,85.41％yield).1H NMR(400MHz,CDCl3)Shift 10.30(s,1H),7.64(d,J＝0.61Hz,1H),6.40(s,1H),6.09m,1H),5.48(m,1H),5.36(m,1H),4.65(td,J＝1.53,5.01Hz,2H),3.91(s,3H),2.19(s,3H).K 2 CO 3 (12.5 g, 90.27 mmol, 3.0 eq) and 3-bromo-1-propene (4.73 g, 39.12 mmol, 1.3 eq) were added to a DMF (75 mL) solution of compound (14-c) (5.0 g, 30.09 mmol, 1 eq) and reacted at 25° C. for 3 hours. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography ( 80g Silica Flash Column, 0～10％ EA/PE, 65mL/min) to obtain a white solid compound (14-f) (5.3g, 25.70mmol, 85.41％yield). 1H NMR (400MHz,CDCl 3 )Shift 10.30(s,1H),7.64(d,J＝0.61Hz,1H),6.40(s,1H),6.09m,1H),5.48(m,1H),5.36(m,1H),4.65(td,J＝1.53,5.01Hz,2H),3.91(s,3H),2.19(s,3H).

步骤2：
Step 2:

在-78℃，向化合物(14-c-1)(8.09g,33.94mmol,1eq)的THF(210mL)溶液中加入异丙基氯化镁溶液(2M,25.46mL,1.5eq)，维持-78℃搅拌60分钟。加入化合物(14-f)(7.0g,33.94mmol,1.0eq)的toluene(20mL)溶液，0℃反应3小时。反应毕加入饱和NH4Cl水溶液(200mL)淬灭，用EtOAc萃取(200mL*3)。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩。所得剩余物通过硅胶色谱柱(220gSilica Flash Column,0～15％ EA/PE,30mL/min)纯化得无色油状物化合物(14-g)(4.8g,16.8mmol,49.49％yield).1H NMR(400MHz,CDCl3)Shift 6.96-7.08(m,1H),6.47(s,1H),6.00-6.18(m,1H),5.84(d,J＝4.62Hz,0.24H),5.51(s,0.7H),5.46(qd,J＝1.65,17.28Hz,1H),5.27-5.36(m,1H),4.59(td,J＝1.68,5.01Hz,2H),3.82-3.90(m,3H),2.61-2.72(m,0.2H),2.12-2.30(m,4.8H),1.20-1.40(m,1H),0.96-1.10(m,1H),0.80-0.90(m,0.28H).(ESI)m/z＝275.2(M+1)+ At -78°C, add isopropylmagnesium chloride solution (2M, 25.46mL, 1.5eq) to a solution of compound (14-c-1) (8.09g, 33.94mmol, 1eq) in THF (210mL), and stir at -78°C for 60 minutes. Add a solution of compound (14-f) (7.0g, 33.94mmol, 1.0eq) in toluene (20mL), and react at 0°C for 3 hours. After the reaction, add saturated NH 4 Cl aqueous solution (200mL) to quench, and extract with EtOAc (200mL*3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel chromatography ( 220g Silica Flash Column, 0～15％ EA/PE, 30mL/min) was purified to obtain a colorless oil compound (14-g) (4.8 g, 16.8mmol, 49.49％yield). 1 H NMR (400MHz,CDCl 3 )Shift 6.96-7.08(m,1H),6.47(s,1H),6.00-6.18(m,1H),5.84(d,J＝4.62Hz,0.24H),5.51(s,0.7H),5.46(qd,J＝1.65,17.28Hz,1H),5.27-5.36(m,1H),4.59(td,J＝1.6 8,5.01Hz,2H),3.82-3.90(m,3H),2.61-2.72(m,0.2H),2.12-2.30(m,4.8H),1. 20-1.40(m,1H),0.96-1.10(m,1H),0.80-0.90(m,0.28H).(ESI)m/z＝275.2(M+1) +

步骤3：
Step 3:

向化合物(14-g)(4.53g,16.53mmol,1eq)的THF(100mL)溶液中加入Pd(OAc)2(1.11g,4.96mmol,0.3eq)和PPh3(5.2g,19.84mmol,1.2eq)，25℃反应20小时。反应毕减压浓缩，所得剩余物通过硅胶色谱柱(120gSilica Flash Column,0～30％ EA/PE,60mL/min)纯化然后用MTBE:PE(1:1,10mL)打浆后得类白色固体化合物(14)(990mg,4.23mmol,25.64％yield).(ESI)m/z＝235.1(M+1)+.1HNMR(400MHz,DMSO-d6)Shift 9.19-9.67(m,1H),6.82-6.98(m,1H),6.44-6.54(m,1H),5.73(d,J＝4.65Hz,0.2H),5.39(s,0.8H),3.64-3.79(m,3H),2.12-2.28(m,2H),1.98-2.11(m,3H),1.29(dt,J＝4.46,8.16Hz,0.8H),1.00-1.10(m,0.2H),0.96(q,J＝4.28Hz,0.8H),0.71(br d,J＝3.30Hz,0.2H)Pd(OAc) 2 (1.11 g, 4.96 mmol, 0.3 eq) and PPh 3 (5.2 g, 19.84 mmol, 1.2 eq) were added to a THF (100 mL) solution of compound (14-g) (4.53 g, 16.53 mmol, 1 eq) and reacted at 25°C for 20 hours. After the reaction, the mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography ( 120g Silica Flash Column, 0～30％ EA/PE, 60mL/min) was used for purification and then slurried with MTBE:PE (1:1, 10mL) to obtain an off-white solid compound (14) (990mg, 4.23mmol, 25.64％yield). (ESI) m/z＝235.1(M+1) + . 1 HNMR(400MHz,DMSO-d6)Shift 9.19-9.67(m,1H),6.82-6.98(m,1H),6.44-6.54(m,1H),5.73(d,J＝4.65Hz,0.2H),5.39(s,0.8H),3.64-3.79(m,3H),2.12 -2.28(m,2H),1.98-2.11(m,3H),1.29(dt,J＝4.46,8.16Hz,0.8H),1.00-1.10(m,0.2H),0.96(q,J＝4.28Hz,0.8H),0.71(br d,J＝3.30Hz,0.2H)

参照实施例2中步骤2和步骤3的方法，以如下起始原料替换(14-c-1)，与(14-f)进行两步反应得相应的终产化合物。
Referring to the method of step 2 and step 3 in Example 2, (14-c-1) is replaced with the following starting material, and a two-step reaction is carried out with (14-f) to obtain the corresponding final product compound.

上述表格中涉及到的起始原料44-A的合成方法为：
The synthesis method of the starting material 44-A involved in the above table is:

参照实施例1中步骤2的方法，以44-B(600mg,2.40mmol)为起始原料进行反应得无色油状物44-A(540mg,收率84.59％).1H NMR(400MHz,CDCl3)δ7.63-7.85(m,2H),7.38-7.61(m,3H),4.10-4.37(m,2H),2.38-2.55(m,1H),1.90-2.15(m,1H),1.52-1.71(m,3H),1.22-1.42(m,4H),1.13(s,2H).Referring to the method of step 2 in Example 1, 44-B (600 mg, 2.40 mmol) was used as the starting material to react and obtain colorless oil 44-A (540 mg, yield 84.59%). 1 H NMR (400 MHz, CDCl 3 ) δ7.63-7.85 (m, 2H), 7.38-7.61 (m, 3H), 4.10-4.37 (m, 2H), 2.38-2.55 (m, 1H), 1.90-2.15 (m, 1H), 1.52-1.71 (m, 3H), 1.22-1.42 (m, 4H), 1.13 (s, 2H).

参照实施例2的方法，以如下起始原料开始进行三步反应得相应的终产化合物。




Referring to the method of Example 2, a three-step reaction was carried out with the following starting materials to obtain the corresponding final product compound.




上述表格中涉及到的起始原料284-A和285-A的合成方法为：
The synthesis methods of the starting materials 284-A and 285-A mentioned in the above table are:

步骤一：在微波条件下，将化合物2-甲氧基-4-(丙-2-烯基氧基)苯-1-甲醛(200mg,1.04mmol,1eq)在N,N-二甲基苯胺(2mL)中的混合物在180℃搅拌反应4小时。降至室温，用EtOAc(15mL)稀释反应，用1M HCl(3mL*3)洗涤，有机相经过常规的后处理操作二后得粗产品。粗产品通过硅胶柱色谱(EA/PE,EA从7到15％)纯化得灰白色固体化合物284-B(50mg,收率25％)和黄色固体化合物285-B(82.5mg,收率41.3％)。Step 1: Under microwave conditions, a mixture of compound 2-methoxy-4-(prop-2-enyloxy)benzene-1-carboxaldehyde (200 mg, 1.04 mmol, 1 eq) in N,N-dimethylaniline (2 mL) was stirred at 180 ° C for 4 hours. Cool to room temperature, dilute the reaction with EtOAc (15 mL), wash with 1M HCl (3 mL*3), and the organic phase is subjected to conventional post-treatment operation 2 to obtain a crude product. The crude product was purified by silica gel column chromatography (EA/PE, EA from 7 to 15%) to obtain an off-white solid compound 284-B (50 mg, yield 25%) and a yellow solid compound 285-B (82.5 mg, yield 41.3%).

化合物284-B:1H NMR(400MHz,CDCl3)δ(ppm)10.22(s,1H),7.74(d,J＝8.6Hz,1H),6.77(d,J＝8.6Hz,1H),6.39(br s,1H),6.06(ddt,J＝5.9,10.5,16.8Hz,1H),5.09-5.25(m,2H),3.91(s,3H),3.47-3.60(m,2H).Compound 284-B: 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 10.22 (s, 1H), 7.74 (d, J = 8.6 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 6.39 (br s, 1H), 6.06 (ddt, J = 5.9, 10.5, 16.8 Hz, 1H), 5.09-5.25 (m, 2H), 3.91 (s, 3H), 3.47-3.60 (m, 2H).

化合物285-B:1H NMR(400MHz,CDCl3)δ(ppm)10.28(s,1H),7.64(s,1H),6.46(s,1H),6.06-6.11(m,1H),5.92-6.06(m,1H),5.16-5.26(m,2H),3.88(s,3H),3.39(d,J＝6.4Hz,2H)Compound 285-B: 1 H NMR (400 MHz, CDCl 3 )δ(ppm)10.28(s,1H),7.64(s,1H),6.46(s,1H),6.06-6.11(m,1H),5.92-6.06(m,1H),5.16-5.26(m,2H),3.88(s,3H),3.39(d,J＝6.4Hz,2H)

化合物284-A：参照从化合物281-B合成化合物281-A的方法，用284-B(200mg)进行反应得黄色油状物化合物284-A(200mg)，粗产品直接用于下一步反应。LC-MS:(ESI)m/z[M+H]+195.2。1H NMR(400MHz,CDCl3)δ(ppm)10.20(s,1H),7.67(d,J＝8.4Hz,1H),6.70(d,J＝8.6Hz,1H),6.11(br s,1H),3.92(s,3H),2.55-2.74(m,2H),1.52-1.65(m,2H),0.96-1.16(m,3H)。Compound 284-A: Referring to the method for synthesizing compound 281-A from compound 281-B, 284-B (200 mg) was used for reaction to obtain yellow oily compound 284-A (200 mg), and the crude product was directly used for the next step. LC-MS: (ESI) m/z [M+H] + 195.2. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 10.20 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.6 Hz, 1H), 6.11 (br s, 1H), 3.92 (s, 3H), 2.55-2.74 (m, 2H), 1.52-1.65 (m, 2H), 0.96-1.16 (m, 3H).

化合物285-A：参照从化合物281-B合成化合物281-A的方法，用285-B(330mg)进行反应得灰白色固体化合物285-A(330mg)，粗产品直接用于下一步反应。LC-MS:(ESI)m/z[M+H]+195.2。1H NMR(400MHz,CDCl3)δ(ppm)10.27(s,1H),7.64(s,1H),6.43(s,1H),6.06(s,1H),3.87(s,3H),2.44-2.64(m,2H),1.53-1.64(m,2H),0.96(t,J＝7.3Hz,3H)。Compound 285-A: Referring to the method for synthesizing compound 281-A from compound 281-B, 285-B (330 mg) was used for reaction to obtain off-white solid compound 285-A (330 mg), and the crude product was directly used for the next step. LC-MS: (ESI) m/z [M+H] + 195.2. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 10.27 (s, 1H), 7.64 (s, 1H), 6.43 (s, 1H), 6.06 (s, 1H), 3.87 (s, 3H), 2.44-2.64 (m, 2H), 1.53-1.64 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H).

上述表格中涉及到的起始原料281-A和281-B的合成方法为：
The synthesis methods of the starting materials 281-A and 281-B mentioned in the above table are:

步骤一：将化合物14-f(1.0g,4.85mmol,1eq)在N,N-二甲基苯胺(8mL)的混合物在180℃搅拌反应8小时。TLC显示仅少量原料未反应。降至室温，用EtOAc(10mL)稀释反应，用1M HCl(10mL*3)洗涤，有机相经过常规的后处理操作后得粗产品。粗产品通过硅胶柱色谱(EA/PE,EA从0到7％)纯化得灰白色固体化合物281-B(640mg,3.10mmol,收率64％)。LC-MS:(ESI)m/z[M+H]+207.0。Step 1: A mixture of compound 14-f (1.0 g, 4.85 mmol, 1 eq) in N,N-dimethylaniline (8 mL) was stirred at 180 ° C for 8 hours. TLC showed that only a small amount of raw materials were not reacted. Cool to room temperature, dilute the reaction with EtOAc (10 mL), wash with 1M HCl (10 mL*3), and the organic phase is subjected to conventional post-treatment operations to obtain a crude product. The crude product was purified by silica gel column chromatography (EA/PE, EA from 0 to 7%) to obtain an off-white solid compound 281-B (640 mg, 3.10 mmol, yield 64%). LC-MS: (ESI) m/z[M+H] + 207.0.

步骤二：将化合物281-B(300mg,1.45mmol)溶解在EtOAc(30mL)中，加入钯/碳(5％含量，60mg)，反应混合物充分置换氢气。15Psi氢气氛围下，25℃搅拌反应2小时。经过硅藻土过滤，减压浓缩得灰白色固体化合物281-A(290mg)，粗产品直接用于下一步反应。LC-MS:(ESI)m/z[M+H]+209.1。Step 2: Dissolve compound 281-B (300 mg, 1.45 mmol) in EtOAc (30 mL), add palladium/carbon (5% content, 60 mg), and fully replace hydrogen with the reaction mixture. Stir and react at 25°C for 2 hours under a 15 Psi hydrogen atmosphere. Filter through diatomaceous earth and concentrate under reduced pressure to obtain an off-white solid compound 281-A (290 mg). The crude product is directly used in the next step. LC-MS: (ESI) m/z [M+H] + 209.1.

上述表格中涉及到的起始原料40-A的合成方法为：
The synthesis method of the starting material 40-A involved in the above table is:

在-78℃,向化合物40-B(500mg,2.97mmol)的DCM(10mL)溶液中加入二氯甲基甲醚(410mg,3.57mmol)和四氯化钛(1.41g,7.43mmol)的DCM(5mL)溶液。自然升温至25℃后搅拌反应16小时，加入水(50mL)，混合物用EtOAc(50mL x 3)萃取。经过常规的后处理操作二后通过硅胶柱色谱(EA:PE，EA从0到7％)纯化得到白色固体化合物40-A(440mg,收率75.44％).1H NMR(400MHz,CDCl3)δ10.20(s,1H),7.42(s,1H),6.42(s,1H),3.97(s,3H),3.97(s,3H),2.24(d,J＝0.72Hz,3H).To a solution of compound 40-B (500 mg, 2.97 mmol) in DCM (10 mL) was added dichloromethyl methyl ether (410 mg, 3.57 mmol) and titanium tetrachloride (1.41 g, 7.43 mmol) in DCM (5 mL) at -78°C. The mixture was stirred and reacted for 16 hours after the temperature was naturally raised to 25°C, water (50 mL) was added, and the mixture was extracted with EtOAc (50 mL x 3). After conventional post-treatment, the product was purified by silica gel column chromatography (EA:PE, EA from 0 to 7%) to obtain a white solid compound 40-A (440 mg, yield 75.44%). 1 H NMR (400 MHz, CDCl 3 ) δ 10.20 (s, 1H), 7.42 (s, 1H), 6.42 (s, 1H), 3.97 (s, 3H), 3.97 (s, 3H), 2.24 (d, J = 0.72 Hz, 3H).

上述表格中涉及到的起始原料116-A的合成方法为：
The synthesis method of the starting material 116-A involved in the above table is:

参照40-A的合成方法，用116-B(3.0g,14.27mmol)进行反应得紫色固体116-A(2.2g,收率64.7％)。1H NMR(400MHz,DMSO-d6)Shift 10.80(s,1H),10.11(s,1H),7.45(s,1H),6.54(s,1H),3.82(s,3H),3.57(s,3H),2.71-2.78(m,2H),2.53-2.60(m,2H).Referring to the synthesis method of 40-A, 116-B (3.0 g, 14.27 mmol) was used to react to obtain purple solid 116-A (2.2 g, yield 64.7%). 1 H NMR (400 MHz, DMSO-d6) Shift 10.80 (s, 1H), 10.11 (s, 1H), 7.45 (s, 1H), 6.54 (s, 1H), 3.82 (s, 3H), 3.57 (s, 3H), 2.71-2.78 (m, 2H), 2.53-2.60 (m, 2H).

上述表格中涉及到的起始原料48-A的合成方法为：
The synthesis method of the starting material 48-A involved in the above table is:

参照40-A的合成方法，用48-B(870mg,6.39mmol)进行反应得白色固体48-A(720mg,收率68.64％)。1H NMR(400MHz,DMSO-d6)δ10.41(br s,1H),9.97(s,1H),7.56(s,1H),6.71(s,1H),2.90(q,J＝7.46Hz,2H),2.12(s,3H),1.13(t,J＝7.46Hz,3H).Referring to the synthesis method of 40-A, 48-B (870 mg, 6.39 mmol) was used to react to obtain white solid 48-A (720 mg, yield 68.64%). 1 H NMR (400 MHz, DMSO-d6) δ 10.41 (br s, 1H), 9.97 (s, 1H), 7.56 (s, 1H), 6.71 (s, 1H), 2.90 (q, J = 7.46 Hz, 2H), 2.12 (s, 3H), 1.13 (t, J = 7.46 Hz, 3H).

上述表格中涉及到的起始原料62-A的合成方法为：
The synthesis method of the starting material 62-A involved in the above table is:

参照40-A的合成方法，用62-B(1.06g,5.14mmol)进行反应得棕色固体62-A(432mg,收率19.3％，纯度73.3％)。LCMS:(ESI)m/z＝235.0(M+1)+ Referring to the synthesis method of 40-A, 62-B (1.06 g, 5.14 mmol) was used to react to obtain brown solid 62-A (432 mg, yield 19.3%, purity 73.3%). LCMS: (ESI) m/z = 235.0 (M+1) +

上述表格中涉及到的起始原料31-A的合成方法为：
The synthesis method of the starting material 31-A involved in the above table is:

向化合物30-A(1.9g,12.33mmol)和二甲胺盐酸盐(3.02g,36.98mmol)的DMF(50mL)溶液中加入K2CO3(5.11g,36.98mmol)。110℃后搅拌反应16小时，降至室温，加入水(30mL)，用EtOAc和THF(1:1，50mL x 3)萃取。经过常规的后处理操作后通过硅胶柱色谱(EA:PE，EA从0到20％)纯化得到黄色固体化合物31-A(820mg,收率37.12％).1H NMR(400MHz,CDCl3)δ10.00(s,1H),7.59(s,1H),6.50(s,1H),2.85(s,6H),2.22(s,3H)K 2 CO 3 (5.11 g, 36.98 mmol) was added to a DMF (50 mL) solution of compound 30-A (1.9 g, 12.33 mmol) and dimethylamine hydrochloride (3.02 g, 36.98 mmol). The mixture was stirred at 110°C for 16 hours, cooled to room temperature, and water (30 mL) was added. The mixture was extracted with EtOAc and THF (1:1, 50 mL x 3). After conventional post-treatment, the mixture was purified by silica gel column chromatography (EA:PE, EA from 0 to 20%) to obtain yellow solid compound 31-A (820 mg, yield 37.12%). 1 H NMR (400 MHz, CDCl 3 )δ10.00(s,1H),7.59(s,1H),6.50(s,1H),2.85(s,6H),2.22(s,3H)

上述表格中涉及到的起始原料162-A的合成方法为：
The synthesis method of the starting material 162-A involved in the above table is:

步骤一：参照起始原料30-A的合成方法，以162-C(1g,4.30mmol)进行反应得黄色油状物162-B(0.95g,收率85.7％).LC-MS:(ESI)m/z.[M+H]+258.1.Step 1: Referring to the synthesis method of the starting material 30-A, 162-C (1 g, 4.30 mmol) was reacted to obtain a yellow oil 162-B (0.95 g, yield 85.7%). LC-MS: (ESI) m/z. [M+H] + 258.1.

步骤二:参照实施例1中步骤4的方法，以162-B(0.80g)进行反应得黄色油状物162-A(0.62g)，粗产品直接用于下一步反应。LC-MS:(ESI)m/z.[M+H]+200.1.Step 2: Referring to the method of step 4 in Example 1, 162-B (0.80 g) was reacted to obtain a yellow oil 162-A (0.62 g), and the crude product was directly used for the next reaction. LC-MS: (ESI) m/z. [M+H] + 200.1.

上述表格中涉及到的起始原料32-A的合成方法为：
The synthesis method of the starting material 32-A involved in the above table is:

参照实施例8-b中步骤四的方法，用15-A(500mg,2.33mmol)与乙烯三氟硼酸钾(934mg,6.98mmol)反应得类白色固体化合物32-A(250mg,收率66.3％).1H NMR(CDCl3,400MHz)δ10.13(s,1H),7.66(s,1H),7.52(dd,J＝11.00,17.36Hz,1H),6.97(s,1H),6.69(s,1H),5.65(d,J＝17.36Hz,1H),5.46(d,J＝11.00Hz,1H),2.31(s,3H).Referring to the method of step 4 in Example 8-b, 15-A (500 mg, 2.33 mmol) was reacted with potassium ethylene trifluoroborate (934 mg, 6.98 mmol) to obtain an off-white solid compound 32-A (250 mg, yield 66.3%). 1 H NMR (CDCl 3 , 400 MHz) δ 10.13 (s, 1H), 7.66 (s, 1H), 7.52 (dd, J = 11.00, 17.36 Hz, 1H), 6.97 (s, 1H), 6.69 (s, 1H), 5.65 (d, J = 17.36 Hz, 1H), 5.46 (d, J = 11.00 Hz, 1H), 2.31 (s, 3H).

上述表格中涉及到的起始原料35-A的合成方法为：
The synthesis method of the starting material 35-A involved in the above table is:

向化合物15-A(1g,4.65mmol)在dioxane/水(20mL,9/1)的混合物中加入35-B(691mg,5.58mmol)、K3PO4(2.96g,13.95mmol)，脱气并重新填充氮气三次后，加入Pd(dppf)Cl2(170mg,232.51μmol)。将其加热至100℃反应16小时。降至室温，用饱和食盐水(50mL)稀释反应，用EtOAc(20mL*3)和THF(15mL*3)萃取。经过常规的后处理操作后得到粗产物，粗产物在DCM(10mL)中碾碎，用DCM(2mL*3)洗涤，得到白色固体化合物35-A(767mg,收率77％)。1H NMR(400MHz,DMSO-d6)δppm 2.23-2.28(m,3H)6.77-6.84(m,1H)7.72-7.86(m,1H)8.80-8.90(m,2H)9.19-9.28(m,1H)9.66-9.75(m,1H)10.82-10.94(m,1H).35-B (691 mg, 5.58 mmol) and K 3 PO 4 (2.96 g, 13.95 mmol) were added to a mixture of compound 15-A (1 g, 4.65 mmol) in dioxane/water (20 mL, 9/1). After degassing and refilling with nitrogen three times, Pd(dppf)Cl 2 (170 mg, 232.51 μmol) was added. The mixture was heated to 100°C for 16 hours. The mixture was cooled to room temperature, diluted with saturated brine (50 mL), and extracted with EtOAc (20 mL*3) and THF (15 mL*3). After conventional post-treatment operations, a crude product was obtained. The crude product was crushed in DCM (10 mL) and washed with DCM (2 mL*3) to obtain a white solid compound 35-A (767 mg, yield 77%). 1H NMR(400MHz,DMSO-d6)δppm 2.23-2.28(m,3H)6.77-6.84(m,1H)7.72-7.86(m,1H)8.80-8.90(m,2H)9.19-9.28(m,1H)9.66-9.75(m,1H)10.82-10.94(m,1H).

上述表格中涉及到的起始原料41-A的合成方法为：
The synthesis method of the starting material 41-A involved in the above table is:

参照化合物35-A的合成方法，用15-A(1g,4.65mmol)与(E)-苯乙烯硼酸(413mg,2.79mmol,1.2eq)反应得棕色固体41-A(302mg,收率54.51％)。1H NMR(400MHz,DMSO-d6)δppm 2.13-2.25(m,3H)7.14-7.21(m,1H)7.29-7.35(m,1H)7.37-7.47(m,2H)7.57-7.71(m,3H)8.03-8.20(m,1H)10.09-10.19(m,1H).Referring to the synthesis method of compound 35-A, 15-A (1 g, 4.65 mmol) was reacted with (E)-phenylene boronic acid (413 mg, 2.79 mmol, 1.2 eq) to obtain brown solid 41-A (302 mg, yield 54.51%). 1 H NMR (400 MHz, DMSO-d6) δppm 2.13-2.25 (m, 3H) 7.14-7.21 (m, 1H) 7.29-7.35 (m, 1H) 7.37-7.47 (m, 2H) 7.57-7.71 (m, 3H) 8.03-8.20 (m, 1H) 10.09-10.19 (m, 1H).

上述表格中涉及到的起始原料37-A的合成方法为：
The synthesis method of the starting material 37-A involved in the above table is:

向化合物15-A(500mg,2.33mmol)在THF(10mL)的混合物中加入Pd(dppf)Cl2(326mg,465μmol)，脱气并重新填充氮气三次后，加入TEA(1.18g,11.63mmol)、CuI(44.2mg,232.51μmol)和37-B(551mg,3.02mmol)。将其加热至70℃反应16小时。降至室温，用水(5mL)稀释反应，分出有机相。经过常规的后处理操作后得到粗产物，通过硅胶柱色谱(EA:PE，EA从0到30％)纯化得到黄色固体化合物37-A(450mg,收率61.15％)。1H NMR(CDCl3,400MHz)δppm 10.44(s,1H)7.76(s,1H)6.98(s,1H)5.77(s,1H)2.30(s,3H)1.09-1.23(m,22H).Pd(dppf)Cl 2 (326 mg, 465 μmol) was added to a mixture of compound 15-A (500 mg, 2.33 mmol) in THF (10 mL). After degassing and refilling with nitrogen three times, TEA (1.18 g, 11.63 mmol), CuI (44.2 mg, 232.51 μmol) and 37-B (551 mg, 3.02 mmol) were added. The mixture was heated to 70°C for 16 hours. The mixture was cooled to room temperature, diluted with water (5 mL), and the organic phase was separated. The crude product was obtained after conventional post-treatment operations, and purified by silica gel column chromatography (EA:PE, EA from 0 to 30%) to obtain yellow solid compound 37-A (450 mg, yield 61.15%). 1 H NMR (CDCl 3 , 400MHz) δ ppm 10.44 (s, 1H) 7.76 (s, 1H) 6.98 (s, 1H) 5.77 (s, 1H) 2.30 (s, 3H) 1.09-1.23 (m, 22H).

上述表格中涉及到的起始原料61-A的合成方法为：
The synthesis method of the starting material 61-A involved in the above table is:

向化合物61-B(980mg,4.24mmol)在甲苯(50mL)/水(5mL)的混合物中加入环丙基硼酸(473mg,5.51mmol)、K3PO4(2.70g,12.7mmol)，混合物置换氮气三次，加入Pd(OAc)2(50mg,223μmol)和三环己基膦(490mg,1.75mmol)，氮气氛围下100℃搅拌16小时。反应液冷却至室温，加2毫升饱和食盐水稀释，混合物用EA(5mL×2)萃取。经过常规的后处理操作得残余物，残留物经硅胶柱色谱纯化(THF:PE，THF从0到15％)得黄色固体化合物61-A(330mg,产率40.48％)。1H NMR(400MHz,CDCl3)δ(ppm)10.26(s,1H),7.64(d,J＝0.7Hz,1H),6.50(s,1H),3.89(s,3H),1.61-1.75(m,1H),0.92-1.03(m,2H),0.61-0.67(m,2H).Cyclopropylboric acid (473 mg, 5.51 mmol) and K 3 PO 4 (2.70 g, 12.7 mmol) were added to a mixture of compound 61-B (980 mg, 4.24 mmol) in toluene (50 mL)/water (5 mL), the mixture was purged with nitrogen three times, Pd(OAc) 2 (50 mg, 223 μmol) and tricyclohexylphosphine (490 mg, 1.75 mmol) were added, and the mixture was stirred at 100°C for 16 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, diluted with 2 ml of saturated brine, and the mixture was extracted with EA (5 mL×2). After conventional post-treatment operations, a residue was obtained, which was purified by silica gel column chromatography (THF:PE, THF from 0 to 15%) to obtain yellow solid compound 61-A (330 mg, yield 40.48%). 1 H NMR (400MHz, CDCl 3 )δ(ppm)10.26(s,1H),7.64(d,J＝0.7Hz,1H),6.50(s,1H),3.89(s,3H),1.61-1.75(m,1H),0.92-1.03(m,2H),0.61-0.67(m,2H).

上述表格中涉及到的起始原料64-A的合成方法为：
The synthesis method of the starting material 64-A involved in the above table is:

步骤一：向30-A(2.50g,16.2mmol)的DMF(50mL)溶液中加入NaSCH3(4.16g,59.4mmol)。混合物在120℃反应至LC-MS显示原料反应完全。降至室温，将反应液倒入到水中(50mL),用50％的醋酸调pH为5，用EA萃取(3*50mL)。经过常规的后处理操作二得残余物，粗产物通过硅胶薄层层析色谱分离(EA:PE，EA从0到25％)纯化得到黄色油状物47-A(1.5g,收率50.7％)。1H NMR(400MHz,DMSO-d6)δ(ppm)9.87(s,1H),7.62(s,1H),6.80(s,1H),2.38(s,3H),2.13(s,3H)Step 1: Add NaSCH 3 (4.16 g, 59.4 mmol) to a DMF (50 mL) solution of 30-A (2.50 g, 16.2 mmol). The mixture was reacted at 120°C until LC-MS showed that the raw material was completely reacted. Cool to room temperature, pour the reaction solution into water (50 mL), adjust the pH to 5 with 50% acetic acid, and extract with EA (3*50 mL). After conventional post-treatment operations, the residue was obtained. The crude product was purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 25%) to obtain a yellow oil 47-A (1.5 g, yield 50.7%). 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)9.87(s,1H),7.62(s,1H),6.80(s,1H),2.38(s,3H),2.13(s,3H)

步骤二：在0℃向化合物64-C(1.0g,5.49mmol)的DCM(20mL)溶液中分批加入m-CPBA(2.79g,13.7mmol,85％purity)，25℃反应2小时。过滤，真空干燥得白色固体化合物64-A(3.2g，35％纯度)，粗产品直接用于下一步反应。Step 2: Add m-CPBA (2.79 g, 13.7 mmol, 85% purity) in batches to a solution of compound 64-C (1.0 g, 5.49 mmol) in DCM (20 mL) at 0°C and react at 25°C for 2 hours. Filter and vacuum dry to obtain a white solid compound 64-A (3.2 g, 35% purity), which is used directly in the next step.

上述表格中涉及到的起始原料278-A的合成方法为：
The synthesis method of the starting material 278-A involved in the above table is:

步骤一：向170-A(5.0g,32.9mmol)的DMF(50mL)溶液中加入K2CO3(5.0g,36.2mmol,1.1eq)和化合物278-B(4.24g,39.4mmol,1.2eq)。混合物在40℃反应3小时。降至室温，加入EA(100mL)，过滤，滤液减压浓缩，粗产物通过硅胶柱色谱分离(EA:PE，EA从0到25％)纯化得白色固体化合物278-C(7g,收率95％)。LC-MS:(ESI)m/z.[M+H]+224.21.Step 1: Add K 2 CO 3 (5.0 g, 36.2 mmol, 1.1 eq) and compound 278-B (4.24 g, 39.4 mmol, 1.2 eq) to a DMF (50 mL) solution of 170-A (5.0 g, 32.9 mmol). The mixture was reacted at 40°C for 3 hours. The temperature was cooled to room temperature, EA (100 mL) was added, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE, EA from 0 to 25%) to obtain a white solid compound 278-C (7 g, yield 95%). LC-MS: (ESI) m/z. [M+H] + 224.21.

步骤二：向化合物278-C(2g,8.96mmol)和化合物278-D(695mg,4.48mmol)在1,2-二氯乙烷(40mL)的溶液中，加入Pd(OAc)2(201mg,896μmol),三氟乙酸银(AgTFA)(198mg,896μmol)和TFA(10.2g,89.6mmol)，25℃搅拌0.5小时后加入NCS(1.80g,13.5mmol)。在60℃搅拌反应64.5小时(LCMS检测原料剩余15％)。反应液冷却至室温，加入饱和NaHCO3(50mL)溶液，混合物用DCM(100mL*3)萃取。经过常规的后处理操作二得残余物，残留物经硅胶柱色谱纯化(EA:PE，EA从0到21.5％)得白色固体化合物278-E(1.2g,4.66mmol,产率52％)。LC-MS:(ESI)m/z[M+H]+258.1.Step 2: Pd(OAc) 2 (201 mg, 896 μmol), silver trifluoroacetate (AgTFA) (198 mg, 896 μmol) and TFA (10.2 g, 89.6 mmol) were added to a solution of compound 278-C (2 g, 8.96 mmol) and compound 278-D (695 mg, 4.48 mmol) in 1,2-dichloroethane (40 mL). After stirring at 25°C for 0.5 hours, NCS (1.80 g, 13.5 mmol) was added. The reaction was stirred at 60°C for 64.5 hours (LCMS detected that the remaining raw material was 15%). The reaction solution was cooled to room temperature, saturated NaHCO 3 (50 mL) solution was added, and the mixture was extracted with DCM (100 mL*3). After conventional post-treatment, the residue was obtained, which was purified by silica gel column chromatography (EA:PE, EA from 0 to 21.5%) to obtain a white solid compound 278-E (1.2 g, 4.66 mmol, yield 52%). LC-MS: (ESI) m/z [M+H] + 258.1.

步骤三：向278-E(300mg)的MeOH(5mL)溶液中加入NaOH(70mg)的水溶液(2.5mL)，反应液50℃搅拌2小时。反应液减压浓缩，加入水(5mL)，用MTBE(3mL*2)洗涤，调pH到2～3，析出固体，过滤，滤饼用水(5mL*2)洗涤，真空干燥得黄色固体化合物278-A(200mg,产率90％)。LCMS:(ESI)m/z.[M+H]+187.1.Step 3: Add NaOH (70 mg) in water (2.5 mL) to a solution of 278-E (300 mg) in MeOH (5 mL), and stir the reaction solution at 50°C for 2 hours. The reaction solution was concentrated under reduced pressure, water (5 mL) was added, washed with MTBE (3 mL*2), the pH was adjusted to 2-3, solids were precipitated, filtered, the filter cake was washed with water (5 mL*2), and vacuum dried to obtain yellow solid compound 278-A (200 mg, yield 90%). LCMS: (ESI) m/z. [M+H] + 187.1.

参照实施例2中步骤2和步骤3的方法，以如下起始原料开始进行两步反应得相应的终产化合物。
Referring to the method of step 2 and step 3 in Example 2, a two-step reaction was carried out with the following starting materials to obtain the corresponding final product compound.

上述表格中涉及到的起始原料283-A的合成方法为：
The synthesis method of the starting material 283-A involved in the above table is:

步骤一：将化合物14-c(500mg,3.01mmol,1eq)溶解在溴化氢的水溶液中(3mL,40％含量)，加入多聚甲醛(130mg)和催化量的浓硫酸(92mg,938μmol,50μL)，在70℃搅拌反应16小时。降至室温，用水(10mL)稀释反应，用DCM(10mL*3)萃取，有机相经过常规的后处理操作后得粗产品。粗产品碾碎，在25℃在PE和DCM的混合物溶剂中(5/1)打浆得棕色固体(560mg),为化合物283-B和283-C的混合物，直接用于下一步反应。LC-MS:(ESI)m/z[M+H]+197.1。Step 1: Dissolve compound 14-c (500 mg, 3.01 mmol, 1 eq) in an aqueous solution of hydrogen bromide (3 mL, 40% content), add paraformaldehyde (130 mg) and a catalytic amount of concentrated sulfuric acid (92 mg, 938 μmol, 50 μL), and stir at 70 ° C for 16 hours. Cool to room temperature, dilute the reaction with water (10 mL), extract with DCM (10 mL*3), and the organic phase is subjected to conventional post-treatment operations to obtain a crude product. The crude product is crushed and slurried in a mixture of PE and DCM (5/1) at 25 ° C to obtain a brown solid (560 mg), which is a mixture of compounds 283-B and 283-C, which is directly used in the next step. LC-MS: (ESI) m/z[M+H] + 197.1.

步骤二：将化合物283-B和283-C的混合物(560mg)溶解于MeOH(10mL)中，加入甲醇钠的甲醇溶液(5.4M,2.00mL)，在25℃搅拌反应16小时。减压浓缩，用1M的盐酸调pH至4，用DCM(5mL*3)萃取，有机相用饱和NaHCO3溶液(5mL)洗涤，经常规的后处理操作二后得棕色油状物283-D(430mg)，粗产品直接用于下一步反应。LC-MS:(ESI)m/z[M+H]+211.2。Step 2: Dissolve the mixture of compounds 283-B and 283-C (560 mg) in MeOH (10 mL), add a methanol solution of sodium methoxide (5.4 M, 2.00 mL), and stir at 25°C for 16 hours. Concentrate under reduced pressure, adjust the pH to 4 with 1 M hydrochloric acid, extract with DCM (5 mL*3), wash the organic phase with saturated NaHCO 3 solution (5 mL), and obtain a brown oil 283-D (430 mg) after conventional post-treatment operation 2. The crude product is directly used in the next step. LC-MS: (ESI) m/z [M+H] + 211.2.

步骤三：向化合物283-D(430mg)和K2CO3(707mg,5.11mmol)的DMF(5mL)溶液中加入3-溴-1-丙烯(371mg,3.07mmol)，25℃反应16小时。反应毕，加入饱和食盐水(5mL),用EtOAc(3mL*3)萃取，经过常规的后处理操作后得粗产物，粗产物通过硅胶柱色谱分离(EA:PE，EA从0到5.5％)纯化得棕色油状物化合物283-A(482mg,三步收率64％).1H NMR(400MHz,CDCl3)δ(ppm)10.29(s,1H),7.71(s,1H),6.12(ddt,J＝5.3,10.9,16.7Hz,1H),5.46(dd,J＝0.7,17.2Hz,1H),5.31(d,J＝10.4Hz,1H),4.50(s,2H),4.48(d,J＝5.7Hz,2H),3.98(s,3H),3.47(s,3H),2.30(s,3H)。Step 3: Add 3-bromo-1-propylene (371 mg, 3.07 mmol) to a DMF (5 mL) solution of compound 283-D (430 mg) and K 2 CO 3 (707 mg, 5.11 mmol), and react at 25°C for 16 hours. After the reaction, add saturated brine (5 mL), extract with EtOAc (3 mL*3), and obtain a crude product after conventional post-treatment. The crude product is purified by silica gel column chromatography (EA:PE, EA from 0 to 5.5%) to obtain a brown oil compound 283-A (482 mg, three-step yield 64%). 1 H NMR (400 MHz, CDCl 3 )δ(ppm)10.29(s,1H),7.71(s,1H),6.12(ddt,J＝5.3,10.9,16.7Hz,1H),5.46(dd,J＝0.7,17.2Hz,1H ), 5.31 (d, J = 10.4Hz, 1H), 4.50 (s, 2H), 4.48 (d, J = 5.7Hz, 2H), 3.98 (s, 3H), 3.47 (s, 3H), 2.30 (s, 3H).

上述表格中涉及到的起始原料42-A的合成方法为：
The synthesis method of the starting material 42-A involved in the above table is:

步骤一：向42-B(3g,18mmol)的ACN(30mL)混合物中加入3-溴丙烯(2.2g,18mmol)和Na2CO3(3.8g,36mmol)。在70℃反应16小时。反应毕旋干溶剂，加入水(30mL)，用EA(30mL x 3)萃取。经过常规的后处理操作二后得到粗产物，粗产物通过硅胶薄层层析色谱分离(THF:PE，THF从0到20％)纯化得到黄色固体42-C(1.3g,收率35％)。1H NMR(400MHz,DMSO-d6)δ(ppm)10.92(br s,1H),9.98(s,1H),7.41-7.51(m,1H),6.50(s,1H),6.06(m,1H),5.27-5.48(m,2H),4.59-4.74(m,2H),2.51-2.55(m,2H),1.12(t,J＝7.5Hz,3H).Step 1: Add 3-bromopropylene (2.2 g, 18 mmol) and Na 2 CO 3 (3.8 g, 36 mmol) to a mixture of 42-B (3 g, 18 mmol) in ACN (30 mL). The mixture was reacted at 70°C for 16 hours. After the reaction, the solvent was dried, water (30 mL) was added, and the mixture was extracted with EA (30 mL x 3). After conventional post-treatment operation 2, a crude product was obtained, which was purified by silica gel thin layer chromatography (THF:PE, THF from 0 to 20%) to obtain a yellow solid 42-C (1.3 g, yield 35%). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm) 10.92 (br s,1H),9.98(s,1H),7.41-7.51(m,1H),6.50(s,1H),6.06(m,1H),5.27-5 .48(m,2H),4.59-4.74(m,2H),2.51-2.55(m,2H),1.12(t,J＝7.5Hz,3H).

步骤二：向42-C(1.1g,5mmol)的DMF(10mL)混合物中加入碘甲烷(1.1g,8.00mmol)和K2CO3(1.5g,10.6mmol)。在20℃反应16小时。加入水(10mL)，用EA(15mL x 3)萃取。经过常规的后处理操作二后得到粗产物，粗产物通过硅胶薄层层析色谱分离(THF:PE，THF从0到12％)纯化得到白色固体42-A(990mg,收率84％)。LCMS:(ESI)m/z＝221.2(M+1)+.Step 2: Add iodomethane (1.1 g, 8.00 mmol) and K 2 CO 3 (1.5 g, 10.6 mmol) to a mixture of 42-C (1.1 g, 5 mmol) in DMF (10 mL). React at 20°C for 16 hours. Add water (10 mL) and extract with EA (15 mL x 3). After conventional post-treatment operation 2, a crude product was obtained. The crude product was purified by silica gel thin layer chromatography (THF:PE, THF from 0 to 12%) to obtain a white solid 42-A (990 mg, yield 84%). LCMS: (ESI) m/z=221.2 (M+1) + .

上述表格中涉及到的起始原料47-A的合成方法为：
The synthesis method of the starting material 47-A involved in the above table is:

步骤一：参照实施例2中步骤1的方法，以30-A(268mg,1.74mmol)为原料反应得白色固体47-B(260mg,收率77.00％).LCMS:(ESI)m/z＝195.1(M+1)+.Step 1: Referring to the method of step 1 in Example 2, 30-A (268 mg, 1.74 mmol) was used as a raw material to obtain a white solid 47-B (260 mg, yield 77.00%). LCMS: (ESI) m/z = 195.1 (M+1) + .

步骤二：将47-B(1g,5.15mmol)、47-C(1.94g,10.3mmol)和DIEA(2.00g,15.5mmol)的dioxane(12mL)混合物在120℃反应16小时。LC-MS显示～32.3％的原料剩余并且～48.0％目标产物生成。蒸除溶剂得到粗产物，粗产物通过硅胶薄层层析色谱分离(EA:PE，EA从0到30％)纯化得到棕色油状物47-A(900mg,收率48.2％)。LCMS:(ESI)m/z＝363.5(M+1)+.Step 2: A mixture of 47-B (1 g, 5.15 mmol), 47-C (1.94 g, 10.3 mmol) and DIEA (2.00 g, 15.5 mmol) in dioxane (12 mL) was reacted at 120 °C for 16 hours. LC-MS showed that ~32.3% of the starting material remained and ~48.0% of the target product was generated. The solvent was evaporated to obtain a crude product, which was purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 30%) to obtain a brown oil 47-A (900 mg, yield 48.2%). LCMS: (ESI) m/z = 363.5 (M+1) + .

实施例2-a化合物46的合成
Example 2-a Synthesis of Compound 46

步骤一：参照47-A合成中步骤二的方法，用46-B(1.55g,15.45mmol)与47-B(1g,5.15mmol)反应完全，后处理得黄色固体46-A(528mg,收率35.1％)。LCMS:(ESI)m/z＝275.1(M+1)+。Step 1: Referring to the method of step 2 in the synthesis of 47-A, 46-B (1.55 g, 15.45 mmol) and 47-B (1 g, 5.15 mmol) were reacted completely, and post-treatment was performed to obtain a yellow solid 46-A (528 mg, yield 35.1%). LCMS: (ESI) m/z = 275.1 (M+1) + .

步骤二和三：参照实施例2中步骤2和步骤3的方法，以46-A开始进行两步反应得白色固体化合物46，两步收率约4.9％。LCMS:(ESI)m/z＝303.0(M+1)+；1H NMR(400MHz,DMSO-d6)δppm 0.75-0.88(m,1H)1.07(br s,1H)1.24-1.35(m,1H)2.04-2.11(m,3H)2.15-2.37(m,6H)2.55(br s,3H)2.70-2.80(m,2H)2.83-2.91(m,2H)5.58(s,1H)5.92(d,J＝4.62Hz,1H)6.62-6.78(m,1H)7.06(s,1H)8.14(s,1H).Step 2 and 3: Referring to the method of step 2 and step 3 in Example 2, a two-step reaction was carried out starting from 46-A to obtain a white solid compound 46. The two-step yield was about 4.9%. LCMS: (ESI)m/z＝303.0(M+1) + ; 1H NMR (400MHz, DMSO-d6) δppm 0.75-0.88(m,1H)1.07(br s,1H)1.24-1.35(m,1H)2.04-2.11(m,3H)2.15-2.37(m,6H)2.55(br s,3H)2.70-2.80(m,2H)2.83-2.91(m,2H)5.58(s,1H)5.92(d,J＝4.62Hz,1H)6.62-6.78(m,1H)7.06(s,1H)8.14(s,1H).

参照实施例2-a的合成方法，以如下起始原料与化合物47-B开始进行三步反应得相应的终产化合物。

Referring to the synthesis method of Example 2-a, the following starting materials and compound 47-B were used to carry out three-step reactions to obtain the corresponding final product compounds.

实施例2-b化合物55的合成
Example 2-b Synthesis of Compound 55

步骤一：参照31-A的合成方法，用55-B(1.13g,15.45mmol)与47-B(1g,5.15mmol)反应得55-A(250mg,收率19.63％)。1H NMR(CDCl3,400MHz)δppm 10.27(s,1H)7.63-7.75(m,1H)6.51-6.60(m,1H)6.01-6.18(m,1H)5.41-5.58(m,1H)5.35(dd,J＝10.64,1.47Hz,1H)4.60-4.70(m,3H)3.17(q,J＝7.09Hz,4H)2.23(s,3H)1.07(t,J＝7.09Hz,6H).Step 1: Referring to the synthesis method of 31-A, 55-B (1.13 g, 15.45 mmol) was reacted with 47-B (1 g, 5.15 mmol) to obtain 55-A (250 mg, yield 19.63%). 1 H NMR (CDCl 3 , 400 MHz) δppm 10.27 (s, 1H) 7.63-7.75 (m, 1H) 6.51-6.60 (m, 1H) 6.01-6.18 (m, 1H) 5.41-5.58 (m, 1H) 5.35 (dd, J＝10.64, 1.47 Hz, 1H) 4.60-4.70 (m, 3H) 3.17 (q, J＝7.09 Hz, 4H) 2.23 (s, 3H) 1.07 (t, J＝7.09 Hz, 6H).

步骤二和步骤三：参照实施例2中步骤2和步骤3的方法，以55-A开始进行两步反应得黄色固体化合物55，两步收率约5.3％。LCMS:(ESI)m/z＝276.2[M+H]+,1H NMR(400MHz,DMSO-d6)δppm 9.21-9.54(m,1H)6.83-7.04(m,1H)6.64-6.76(m,1H)5.95(d,J＝4.84Hz,0.201H)5.76(s,0.790H)2.80-2.97(m,4H)2.28-2.36(m,1H)2.14-2.21(m,1H)2.04-2.13(m,3H)1.23-1.34(m,1H)0.98-1.07(m,1H)0.86-0.97(m,6H)Step 2 and Step 3: Referring to the method of Step 2 and Step 3 in Example 2, a two-step reaction was carried out starting from 55-A to obtain yellow solid compound 55, with a two-step yield of about 5.3%. LCMS: (ESI)m/z＝276.2[M+H] + , 1 H NMR (400MHz, DMSO-d6)δppm 9.21-9.54(m,1H)6.83-7.04(m,1H)6.64-6.76(m,1H)5.95(d,J＝4.84Hz,0.201H)5.76(s,0.790H)2.80-2.97(m ,4H)2.28-2.36(m,1H)2.14-2.21(m,1H)2.04-2.13(m,3H)1.23-1.34(m,1H)0.98-1.07(m,1H)0.86-0.97(m,6H)

参照实施例2-b的合成方法，以如下起始原料与化合物47-B开始进行三步反应得相应的终产化合物。

Referring to the synthesis method of Example 2-b, the following starting materials and compound 47-B were used to carry out three-step reactions to obtain the corresponding final product compounds.

实施例3-a化合物26、27、28和29的合成
Example 3-a Synthesis of Compounds 26, 27, 28 and 29

说明:合成路线中手性拆分得到的P1、P2、P3和P4四个化合物分别对应如下四个结构之一，绝对构型尚未归属。
Note: The four compounds P1, P2, P3 and P4 obtained by chiral separation in the synthetic route correspond to one of the following four structures respectively, and the absolute configuration has not yet been assigned.

化合物14-g的手性拆分Chiral separation of compound 14-g

500mg化合物14-g使用SFC(柱:DAICEL CHIRALPAK AD(250mm*30mm,10um)流动相:[0.1％NH3H2O ETOH]；B％:10％-10％)拆分得包含四个化合物的无色油状的混合物(130mg,473.91μmol,26.00％yield)以及包含P3P4的混合物。P3P4的混合物再次使用SFC(柱:REGIS(S,S)WHELK-O1(250mm*25mm,10um)；流动相:[0.1％NH3H2O ETOH]；B％:30％-30％,45min)拆分得化合物P3和化合物P4.500mg of compound 14-g was separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um) mobile phase: [0.1% NH3H2O ETOH]; B%: 10%-10%) to obtain a colorless oily mixture containing four compounds (130mg, 473.91μmol, 26.00% yield) and a mixture containing P3P4. The mixture of P3P4 was separated again by SFC (column: REGIS (S, S) WHELK-O1 (250mm*25mm, 10um); mobile phase: [0.1% NH3H2O ETOH]; B%: 30%-30%, 45min) to obtain compound P3 and compound P4.

白色固体化合物(P3)(100mg,364.55μmol,20.00％yield).1H NMR(400MHz,CHLOROFORM-d)Shift 6.97-7.09(m,1H),6.47(s,1H),6.02-6.17(m,1H),5.84(d,J＝4.77Hz,0.1H),5.41-5.58(m,1.9H),5.32(dd,J＝1.41,10.58Hz,1H),4.59(td,J＝1.50,4.95Hz,2H),3.82-3.93(m,3H),2.63-2.72(m,0.1H),2.15-2.29(m,5H),1.23-1.40(m,1.1H),0.98-1.11(m,1H),0.80-0.89(m,0.1H).(ESI)m/z＝275.3(M+1)+,RT＝0.94min.SFC:RT＝3.227min.White solid compound (P3) (100 mg, 364.55 μmol, 20.00% yield). 1 H NMR (400 MHz, CHLOROFORM-d) Shift 6.97-7.09 (m, 1H), 6.47 (s, 1H), 6.02-6.17 (m, 1H), 5.84 (d, J = 4.77 Hz, 0.1H), 5.41-5.58 (m, 1.9H), 5.32 (dd, J = 1.41, 10.58 Hz, 1H), 4.59 (td, J = 1.50, 4.95 Hz, 2H), 3.82-3. 93(m,3H),2.63-2.72(m,0.1H),2.15-2.29(m,5H),1.23-1.40(m,1.1H),0.98-1.11( m,1H),0.80-0.89(m,0.1H).(ESI)m/z＝275.3(M+1)+,RT＝0.94min.SFC:RT＝3.227min.

白色固体化合物(P4)(100mg,364.55μmol,20.00％yield).1H NMR(400MHz,CHLOROFORM-d)Shift 7.05(s,1H),6.47(s,1H),5.98-6.20(m,1H),，lq 5.84(d,J＝4.65Hz,0.07H),5.51(s,0.93H),5.46(qd,J＝1.61,17.29Hz,1H),5.27-5.38(m,1H),4.59(td,J＝1.54,4.98Hz,2H),3.85(s,3H),2.11-2.30(m,5H),1.22-1.40(m,1H),0.97-1.13(m,1H),0.78-0.91(m,0.11H).LCMS:(ESI)m/z＝275.3(M+1)+,RT＝0.94min.SFC:RT＝3.751min.White solid compound (P4) (100 mg, 364.55 μmol, 20.00% yield). 1 H NMR (400 MHz, CHLOROFORM-d) Shift 7.05 (s, 1H), 6.47 (s, 1H), 5.98-6.20 (m, 1H), 1q 5.84(d,J＝4.65Hz,0.07H),5.51(s,0.93H),5.46(qd,J＝1.61,17.29Hz,1H),5.27-5.38(m,1H),4.59(td,J＝1.54,4.98Hz,2H ),3.85(s,3H),2.11-2.30(m,5H),1.22-1.40(m,1H),0.97-1.13(m,1H),0.78-0.91(m,0.11H).LCMS:(ESI)m/z＝275.3(M+1) + ,RT＝0.94min.SFC:RT＝3.751min.

130mg包含四个化合物的无色油状的混合物再次使用SFC进行再次拆分，条件为(柱:DAICEL CHIRALPAK IG(250mm*30mm,10um)；流动相:[CO2-i-PrOH(0.1％NH3H2O)]；B％:30％-30％,min)得到化合物P1和包含P2P3P4三个化合物的混合物100mg.130 mg of the colorless oily mixture containing four compounds was re-separated by SFC under the following conditions (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: [CO 2 -i-PrOH (0.1% NH 3 H 2 O)]; B%: 30%-30%, min) to obtain 100 mg of compound P1 and a mixture containing three compounds P2P3P4.

白色固体化合物(P1)(20mg,72.91μmol,4.0％收率).LCMS:(ESI)m/z＝275.3(M+1)+,RT＝0.85min.SFC:RT＝3.28min.White solid compound (P1) (20 mg, 72.91 μmol, 4.0% yield). LCMS: (ESI) m/z = 275.3 (M+1) + , RT = 0.85 min. SFC: RT = 3.28 min.

100mg包含P2P3P4三个化合物的混合物使用第三次SFC拆分，条件为(柱:REGIS(S,S)WHELK-O1(250mm*25mm,10um)；流动相:[CO2-EtOH(0.1％NH3H2O)]；B％:25％-25％,45min)得到化合物P2。100 mg of a mixture containing three compounds P2P3P4 was separated by the third SFC under the following conditions (column: REGIS (S, S) WHELK-O1 (250 mm*25 mm, 10 um); mobile phase: [CO 2 -EtOH (0.1% NH 3 H 2 O)]; B%: 25%-25%, 45 min) to obtain compound P2.

白色固体化合物(P2)(18mg,65.62μmol,3.6％收率).LCMS:(ESI)m/z＝275.3(M+1)+,RT＝1.06min.SFC:RT＝3.56min.White solid compound (P2) (18 mg, 65.62 μmol, 3.6% yield). LCMS: (ESI) m/z = 275.3 (M+1) + , RT = 1.06 min. SFC: RT = 3.56 min.

备注,化合物14-g的手性拆分所得化合物的鉴定分析数据中所标识的SFC RT结果的分析条件为:柱:(S,S)Whelk-01 100×4.6mm I.D.,5.0um；流动相:A:CO2B:Ethanol(0.05％ DEA)；梯度:from 5％to 40％of B in 4.5min and hold 40％for 2min,then 5％of B for 1.5min；流速:2.5mL/min；柱温:40℃；ABPR:100bar。Note: The analysis conditions of the SFC RT results indicated in the identification analysis data of the compounds obtained by the chiral separation of compound 14-g are: column: (S,S) Whelk-01 100×4.6mm ID, 5.0um; mobile phase: A: CO 2 B: Ethanol (0.05% DEA); gradient: from 5% to 40% of B in 4.5min and hold 40% for 2min, then 5% of B for 1.5min; flow rate: 2.5mL/min; column temperature: 40°C; ABPR: 100bar.

化合物28的合成Synthesis of compound 28

参考化合物14的合成方法二的最后一步，用化合物P3(90mg,328.09μmol)反应得淡黄色固体28(50mg,209.18μmol,63.76％yield).1H NMR(400MHz,DMSO-d6)Shift 9.28-9.63(m,1H),6.79-6.98(m,1H),6.45-6.55(m,1H),5.73(d,J＝4.52Hz,0.2H),5.39(s,0.8H),3.66-3.80(m,3H),2.12-2.29(m,1.8H),2.05(s,3H),1.21-1.36(m,1H),1.07(td,J＝4.39,7.61Hz,0.2H),0.96(q,J＝4.28Hz,0.8H),0.71(br d,J＝3.42Hz,0.2H).LCMS:(ESI)m/z＝235.2(M+1)+,RT＝0.76min.Referring to the last step of the second synthesis method of compound 14, compound P3 (90 mg, 328.09 μmol) was used to obtain a light yellow solid 28 (50 mg, 209.18 μmol, 63.76% yield). 1 H NMR (400 MHz, DMSO-d6) Shift 9.28-9.63(m,1H),6.79-6.98(m,1H),6.45-6.55(m,1H),5.73(d,J＝4.52Hz,0.2H),5.39(s,0.8H),3.66-3.80(m,3H),2 .12-2.29(m,1.8H),2.05(s,3H),1.21-1.36(m,1H),1.07(td,J＝4.39,7.61Hz,0.2H),0.96(q,J＝4.28Hz,0.8H),0.71(br d, J＝3.42Hz, 0.2H). LCMS: (ESI) m/z＝235.2(M+1) + , RT＝0.76min.

化合物29的合成Synthesis of compound 29

参考化合物14的合成方法二的最后一步，用化合物P4(90mg,328.09μmol)反应得淡黄色固体29(60mg,251.02μmol,76.51％yield).LCMS:(ESI)m/z＝235.2(M+1)+,RT＝0.76min.1H NMR(400MHz,DMSO-d6)Shift 9.26-9.66(m,1H),6.77-7.03(m,1H),6.45-6.62(m,1H),5.73(d,J＝4.65Hz,0.2H),5.39(s,0.8H),3.62-3.83(m,3H),2.10-2.28(m,1.8H),2.05(s,3H),1.14-1.34(m,0.2H),0.96(q,J＝4.24Hz,0.8H),0.65-0.76(m,0.2H).Referring to the last step of the second synthesis method of compound 14, compound P4 (90 mg, 328.09 μmol) was used to obtain a light yellow solid 29 (60 mg, 251.02 μmol, 76.51% yield). LCMS: (ESI) m/z = 235.2 (M+1) + , RT = 0.76 min. 1 H NMR (400 MHz, DMSO-d6) Shift 9.26-9.66(m,1H),6.77-7.03(m,1H),6.45-6.62(m,1H),5.73(d,J＝4.65Hz,0.2H),5.39(s,0.8H),3.62-3.83( m,3H),2.10-2.28(m,1.8H),2.05(s,3H),1.14-1.34(m,0.2H),0.96(q,J＝4.24Hz,0.8H),0.65-0.76(m,0.2H).

化合物26的合成Synthesis of compound 26

参考化合物14的合成方法二的最后一步，用化合物P1(18mg,65.62μmol)反应然后经制备高效液相分离(preparative HPLC)(柱:Boston Prime C18 150*30mm*5um；流动相:[water(FA)-ACN]；B％:23％-43％,16min)得白色固体26(8mg,34.15μmol,52.05％yield).LCMS:(ESI)m/z＝235.2(M+1)+,RT＝0.890min.1H NMR(400MHz,DMSO-d6)Shift 9.23-9.72(m,1H),6.74-7.07(m,1H),6.40-6.63(m,1H),5.73(d,J＝4.65Hz,1H),5.39(s,1H),3.60-3.80(m,3H),2.13-2.28(m,2H),2.05(s,3H),1.02-1.36(m,1H),0.66-1.00(m,1H).Referring to the last step of the second synthesis method of compound 14, compound P1 (18 mg, 65.62 μmol) was reacted and then separated by preparative HPLC (column: Boston Prime C18 150*30 mm*5 um; mobile phase: [water(FA)-ACN]; B%: 23%-43%, 16 min) to obtain a white solid 26 (8 mg, 34.15 μmol, 52.05% yield). LCMS: (ESI) m/z=235.2 (M+1)+, RT=0.890 min. 1 H NMR (400 MHz, DMSO-d6) Shift 9.23-9.72(m,1H),6.74-7.07(m,1H),6.40-6.63(m,1H),5.73(d,J＝4.65Hz,1H),5.39(s,1H ),3.60-3.80(m,3H),2.13-2.28(m,2H),2.05(s,3H),1.02-1.36(m,1H),0.66-1.00(m,1H).

化合物27的合成Synthesis of compound 27

参考化合物14的合成方法二的最后一步，用化合物P2(18mg,65.62μmol)反应然后经制备高效液相分离(preparative HPLC)(柱:Boston Prime C18 150*30mm*5um；流动相:[water(HCl)-ACN]；B％:25％-45％,16min)得淡黄色固体27(5mg,19.64μmol,29.93％yield).LCMS:(ESI)m/z＝235.2(M+1)+,RT＝0.838min.1H NMR(400MHz,DMSO-d6)Shift 9.29-9.64(s,1H),6.78-7.00(s,1H),6.40-6.57(s,1H),5.73(d,J＝4.52Hz,0.2H),5.39(s,0.8H),3.70-3.77(s,3H),2.11-2.26(m,1.8H),2.05(s,3H),1.23-1.34(m,1.2H),1.07(dt,J＝4.46,8.28Hz,0.2H),0.96(q,J＝4.28Hz,0.8H),0.88(br d,J＝5.14Hz,0.2H),0.68-0.74(m,0.2H).Referring to the last step of the second synthesis method of compound 14, compound P2 (18 mg, 65.62 μmol) was reacted and then separated by preparative HPLC (column: Boston Prime C18 150*30 mm*5 um; mobile phase: [water(HCl)-ACN]; B%: 25%-45%, 16 min) to obtain a light yellow solid 27 (5 mg, 19.64 μmol, 29.93% yield). LCMS: (ESI) m/z=235.2 (M+1) + , RT=0.838 min. 1 H NMR (400 MHz, DMSO-d6) Shift 9.29-9.64(s,1H),6.78-7.00(s,1H),6.40-6.57(s,1H),5.73(d,J＝4.52Hz,0.2H),5.39(s,0.8H),3.70-3.77(s,3H),2. 11-2.26(m,1.8H),2.05(s,3H),1.23-1.34(m,1.2H),1.07(dt,J＝4.46,8.28Hz,0.2H),0.96(q,J＝4.28Hz,0.8H),0.88(br d,J＝5.14Hz,0.2H),0.68-0.74(m,0.2H).

实施例3-b化合物268和269的合成
Example 3-b Synthesis of Compounds 268 and 269

说明:合成路线中手性拆分得到的d1、d2两个化合物分别对应如下两个结构之一，绝对构型尚未归属。
Note: The two compounds d1 and d2 obtained by chiral separation in the synthetic route correspond to one of the following two structures respectively, and the absolute configuration has not yet been assigned.

化合物14-g的手性拆分Chiral separation of compound 14-g

10g化合物14-g使用SFC(柱:REGIS(s,s)WHELK-O1(250mm×50mm,10um)流动相:[CO2-EtOH(0.1％ NH3H2O)]；B％:25％,isocratic elution mode；柱温:35℃；流速:200mL/min)拆分得类白色固体化合物d3(0.9g,3.28mmol,9.00％yield)和类白色固体化合物d2(1.1g,4.01mmol,11.00％yield)。10 g of compound 14-g was separated using SFC (column: REGIS (s, s) WHELK-O1 (250 mm×50 mm, 10 um); mobile phase: [CO 2 -EtOH (0.1% NH 3 H 2 O)]; B%: 25%, isocratic elution mode; column temperature: 35°C; flow rate: 200 mL/min) to give an off-white solid compound d3 (0.9 g, 3.28 mmol, 9.00% yield) and an off-white solid compound d2 (1.1 g, 4.01 mmol, 11.00% yield).

化合物d3,(ESI)m/z＝275.1(M+1)+,RT＝1.426min.SFC:RT＝3.217min,～19.1％和RT＝3.547min,～80.9％.1H NMR(400MHz,DMSO-d6)δ6.91(s,1H),6.66-6.73(m,1H),5.98-6.17(m,1H),5.77(d,J＝4.65Hz,1H),5.37-5.55(m,1H),5.28(dd,J＝1.41,10.58Hz,1H),4.56-4.70(m,2H),3.79-3.89(m,3H),2.57(qd,J＝4.92,7.50Hz,1H),2.14-2.30(m,1H),2.10(s,3H),1.02-1.10(m,1H),0.65-1.01(m,1H).Compound d3, (ESI) m/z = 275.1 (M+1) + , RT = 1.426 min. SFC: RT = 3.217 min, ～19.1% and RT = 3.547 min, ～80.9%. 1 H NMR(400MHz, DMSO-d6)δ6.91(s,1H),6.66-6.73(m,1H),5.98-6.17(m,1H),5.77(d,J＝4.65Hz,1H),5.37-5.55(m,1H),5.28(dd,J＝1.41,10.58Hz ,1H),4.56-4.70(m,2H),3.79-3.89(m,3H),2.57(qd,J＝4.92,7.50Hz,1H ),2.14-2.30(m,1H),2.10(s,3H),1.02-1.10(m,1H),0.65-1.01(m,1H).

化合物d2,(ESI)m/z＝275.1(M+1)+,RT＝1.423min.SFC:RT＝3.264min,～63.3％and RT＝3.745min,～36.7％.1H NMR(400MHz,DMSO-d6)δ6.87-7.04(m,1H),6.68(d,J＝4.28Hz,1H),6.01-6.17(m,1H),5.76(d,J＝4.52Hz,1H),5.37-5.52(m,2H),5.27(td,J＝1.50,10.58Hz,1H),4.48-4.77(m,2H),3.82(d,J＝8.80Hz,3H),2.57(qd,J＝4.89,7.60Hz,1H),2.14-2.27(m,2H),2.10(d,J＝2.20Hz,3H),1.03-1.31(m,1H),0.66-1.01(m,1H)。Compound d2, (ESI) m/z = 275.1 (M + 1) + , RT = 1.423 min. SFC: RT = 3.264 min, ～63.3% and RT = 3.745 min, ～36.7%. 1 H NMR(400MHz, DMSO-d6)δ6.87-7.04(m,1H),6.68(d,J=4.28Hz,1H),6.01-6.17( m,1H),5.76(d,J＝4.52Hz,1H),5.37-5.52(m,2H),5.27(td,J＝1.50,10.58Hz,1 H),4.48-4.77(m,2H),3.82(d,J＝8.80Hz,3H),2.57(qd,J＝4.89,7.60Hz,1H),2 .14-2.27(m,2H),2.10(d,J=2.20Hz,3H),1.03-1.31(m,1H),0.66-1.01(m,1H).

备注,化合物14-g的手性拆分所得化合物的鉴定分析数据中所标识的SFC RT结果的分析条件为:柱:(S,S)Whelk-01 100×4.6mm I.D.,5.0um；流动相:A:CO2B:Ethanol(0.05％ DEA)；梯度:from 5％to 40％of B in 4.5min and hold 40％for 2min,then 5％of B for 1.5min；流速:2.5mL/min；柱温:40℃；ABPR:100bar。Note: The analysis conditions of the SFC RT results indicated in the identification analysis data of the compounds obtained by the chiral separation of compound 14-g are: column: (S,S) Whelk-01 100×4.6mm ID, 5.0um; mobile phase: A: CO 2 B: Ethanol (0.05% DEA); gradient: from 5% to 40% of B in 4.5min and hold 40% for 2min, then 5% of B for 1.5min; flow rate: 2.5mL/min; column temperature: 40°C; ABPR: 100bar.

化合物268的合成Synthesis of compound 268

参考化合物14的合成方法二的最后一步，用化合物d3(850mg,3.10mmol)反应得白色固体268(315mg,1.34mmol,43.4％yield).LCMS:(ESI)m/z＝235.0(M+1)+,RT＝1.062min.SFC:RT＝3.790min,74.64％和RT＝4.125min,25.28％.1H NMR(400MHz,DMSO-d6)δ9.25-9.73(m,1H),6.75-7.04(m,1H),6.33-6.61(m,1H),5.29-5.81(m,1H),3.64-3.79(m,3H),2.12-2.26(m,2H),2.04(s,3H),1.28(dt,J＝4.52,8.07Hz,1H),0.95(q,J＝3.95Hz,1H).Referring to the last step of the second synthesis method of compound 14, compound d3 (850 mg, 3.10 mmol) was used to obtain a white solid 268 (315 mg, 1.34 mmol, 43.4% yield). LCMS: (ESI) m/z = 235.0 (M+1) + , RT = 1.062 min. SFC: RT = 3.790 min, 74.64% and RT = 4.125 min, 25.28%. 1 H NMR (400MHz, DMSO-d6) δ9.25-9.73(m,1H),6.75-7.04(m,1H),6.33-6.61(m,1H),5.29-5.81(m,1H),3. 64-3.79(m,3H),2.12-2.26(m,2H),2.04(s,3H),1.28(dt,J＝4.52,8.07Hz,1H),0.95(q,J＝3.95Hz,1H).

化合物269的合成Synthesis of compound 269

参考化合物14的合成方法二的最后一步，用化合物d2(18mg,52.5μmol)反应得白色固体269(8mg,34.15μmol,52.05％yield).LCMS:(ESI)m/z＝235.2(M+1)+,RT＝0.890min.1H NMR(400MHz,DMSO-d6)9.23-9.72(m,1H),6.74-7.07(m,1H),6.40-6.63(m,1H),5.73(d,J＝4.65Hz,1H),5.39(s,1H),3.60-3.80(m,3H),2.13-2.28(m,2H),2.05(s,3H),1.02-1.36(m,1H),0.66-1.00(m,1H).SFC:RT＝3.966min,20.82％和RT＝4.278min,79.98％.Referring to the last step of the second synthesis method of compound 14, compound d2 (18 mg, 52.5 μmol) was used to obtain a white solid 269 (8 mg, 34.15 μmol, 52.05% yield). LCMS: (ESI) m/z = 235.2 (M + 1) + , RT = 0.890 min. 1 H NMR(400MHz, DMSO-d6)9.23-9.72(m,1H),6.74-7.07(m,1H),6.40-6.63(m,1H),5.73(d,J＝4.65Hz,1H),5.39(s,1H),3.60-3.80 (m,3H),2.13-2.28(m,2H),2.05(s,3H),1.02-1.36(m,1H),0.66-1.00(m,1H).SFC: RT=3.966min, 20.82% and RT=4.278min, 79.98%.

备注,化合物268和269的合成中所标识的RT结果的SFC分析条件为:柱:Chiralpak AD-3 150*4.6mm I.D.,3um；流动相:A:CO2,B:iso-propanol(0.05％ DEA)；梯度:from 5％to 40％of B in 4min and hold 40％for 2min,then 5％of B for 2min；流速:2.5mL/min；柱温:35℃；ABPR:1500PsiNote: The SFC analysis conditions for the RT results indicated in the synthesis of compounds 268 and 269 were: column: Chiralpak AD-3 150*4.6mm ID, 3um; mobile phase: A: CO 2 , B: iso-propanol (0.05% DEA); gradient: from 5% to 40% of B in 4min and hold 40% for 2min, then 5% of B for 2min; flow rate: 2.5mL/min; column temperature: 35°C; ABPR: 1500Psi

实施例4化合物2的合成
Example 4 Synthesis of Compound 2

步骤一：在-78℃，向化合物2-A(250mg)的THF(10mL)溶液中加入正丁基锂的THF溶液(0.71mL,2.4mol/L,0.85mmol)，并在氮气保护下搅拌反应0.5小时。随后加入化合物2-B(172mg,1.48mmol)，继续在-78℃搅拌反应3小时。反应毕用水(20mL)淬灭反应，用EA(25mL×3)萃取。经过常规的后处理操作后得黄色油状物2-C粗产品(90mg)。LC-MS:(ESI)m/z[M+H]+343.1.Step 1: Add n-butyllithium in THF (0.71 mL, 2.4 mol/L, 0.85 mmol) to a solution of compound 2-A (250 mg) in THF (10 mL) at -78 °C, and stir the mixture under nitrogen for 0.5 hours. Then add compound 2-B (172 mg, 1.48 mmol) and continue stirring the mixture at -78 °C for 3 hours. After the reaction, quench the reaction with water (20 mL) and extract with EA (25 mL × 3). After conventional post-treatment, a yellow oily crude product 2-C (90 mg) was obtained. LC-MS: (ESI) m/z [M+H] + 343.1.

步骤二：在-78℃，向化合物2-C(90mg，粗产品)的THF(10mL)溶液中加入四丁基氟化铵(244mg,0.93mmol)。在25℃搅拌反应1小时。反应毕用水(10mL)淬灭反应，用EA(20mL×3)萃取。经过常规的后处理操作后通过硅胶柱色谱(EA:PE＝0到10％:90％)纯化得到黄色固体化合物2(60mg)。1HNMR(400MHz,DMSO-d6)δ8.19–8.06(m,2H),7.56–7.43(m,3H),7.22–7.18(m,1H),6.89–6.87(m,1H),6.16–6.11(m,1H),3.30–3.27(m,4H).LC-MS:(ESI)m/z[M+H]+229.7.Step 2: Add tetrabutylammonium fluoride (244 mg, 0.93 mmol) to a solution of compound 2-C (90 mg, crude product) in THF (10 mL) at -78 °C. Stir the reaction at 25 °C for 1 hour. After the reaction, quench the reaction with water (10 mL) and extract with EA (20 mL × 3). After conventional post-treatment, purify by silica gel column chromatography (EA: PE = 0 to 10%: 90%) to obtain yellow solid compound 2 (60 mg). 1 HNMR (400MHz, DMSO-d 6 )δ8.19–8.06(m,2H),7.56–7.43(m,3H),7.22–7.18(m,1H),6.89–6.87(m,1H),6.16–6.11(m,1H),3.30–3.27(m,4H).LC-MS: (ESI)m/z[M+H] + 229.7.

实施例4-a化合物1的合成
Example 4-a Synthesis of Compound 1

步骤一：参照实施例4步骤一的方法，以化合物1-A(400mg,1.7mmol)进行反应得化合物1-B(160mg,收率36％)。LC-MS:(ESI)m/z[M+H]+262.Step 1: Referring to the method of step 1 in Example 4, compound 1-A (400 mg, 1.7 mmol) was reacted to obtain compound 1-B (160 mg, yield 36%). LC-MS: (ESI) m/z [M+H] + 262.

步骤二：将化合物1-B(180mg,0.68mmol)在TFA(1.02mL)和DCM(15mL)的溶液在室温搅拌反应2小时。减压浓缩，经硅胶柱色谱(EA:PE，EA从0到25％)纯化得白色固体化合物1-C(122mg,收率73％)。LC-MS:(ESI)m/z[M+H]+244.1。Step 2: A solution of compound 1-B (180 mg, 0.68 mmol) in TFA (1.02 mL) and DCM (15 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA:PE, EA from 0 to 25%) to obtain a white solid compound 1-C (122 mg, yield 73%). LC-MS: (ESI) m/z [M+H] + 244.1.

步骤三：在-10℃，向化合物1-C(122mg,0.5mmol)的DCM(10mL)溶液中加入三溴化硼(2M的DCM溶液,1.25mL)。在-10℃反应2小时。反应毕用EA(30mL)稀释，用饱和NaHCO3溶液(15mL x 2)洗涤。经过常规的后处理操作二后通过prep HPLC(column:YMC-Actus Triart C18 20*250mm,5um,phase A:H2O(0.1％FA),phase B:ACN,10％～95％)纯化得到黄色固体化合物1(51.4mg，收率44％)。LC-MS(ESI)m/z:230.1(M+H)+；1H NMR(DMSO-d6,400MHz):δ(ppm)10.66(s,1H),8.90(dd,J＝4.2,1.8Hz,1H),8.55(dd,J＝8.4,1.8Hz,1H),8.15(s,1H),7.58(d,J＝8.0Hz,1H),7.55-7.49(m,1H),6.96(d,J＝8.0Hz,1H),6.42(t,J＝7.2Hz,1H),2.81-2.58(m,3H),2.26-2.14(m,1H).Step 3: Add boron tribromide (2M DCM solution, 1.25 mL) to a DCM (10 mL) solution of compound 1-C (122 mg, 0.5 mmol) at -10°C. React at -10°C for 2 hours. After the reaction, dilute with EA (30 mL) and wash with saturated NaHCO 3 solution (15 mL x 2). After conventional post-treatment operation 2, purify by prep HPLC (column: YMC-Actus Triart C18 20*250mm, 5um, phase A: H 2 O (0.1% FA), phase B: ACN, 10%~95%) to obtain yellow solid compound 1 (51.4 mg, yield 44%). LC-MS(ESI)m/z:230.1(M+H) + ; 1 H NMR(DMSO-d 6 ,400MHz): δ(ppm)10.66(s,1H),8.90(dd,J＝4.2,1.8Hz,1H),8.55(dd,J＝8.4,1.8Hz,1H),8.15(s,1H),7.58(d,J＝ 8.0Hz,1H),7.55-7.49(m,1H),6.96(d,J＝8.0Hz,1H),6.42(t,J＝7.2Hz,1H),2.81-2.58(m,3H),2.26-2.14(m,1H).

实施例4-b化合物287的合成
Example 4-b Synthesis of Compound 287

步骤一：在-78℃，向化合物287-A(400mg,1.63mmol)的THF(5mL)溶液中加入正丁基锂的THF溶液(1.6M的正己烷溶液,1.53mL,2.45mmol)，并在氮气保护下搅拌反应0.5小时。随后加入化合物2-B(1.96mmol)，继续在-78℃搅拌反应3小时。反应毕用饱和氯化铵溶液(10mL)淬灭反应，用EA(15mL×3)萃取。经过常规的后处理操作二后再经过硅胶柱色谱(EA:PE，EA从0到16％)纯化得黄色固体化合物287-B(165mg,收率40.4％)。LC-MS:(ESI)m/z[M+H]+251.1.Step 1: At -78°C, add n-butyllithium THF solution (1.6M n-hexane solution, 1.53mL, 2.45mmol) to a THF (5mL) solution of compound 287-A (400mg, 1.63mmol), and stir the reaction under nitrogen protection for 0.5 hours. Then add compound 2-B (1.96mmol) and continue to stir the reaction at -78°C for 3 hours. After the reaction, quench the reaction with saturated ammonium chloride solution (10mL) and extract with EA (15mL×3). After conventional post-treatment operation 2, it is purified by silica gel column chromatography (EA:PE, EA from 0 to 16%) to obtain yellow solid compound 287-B (165mg, yield 40.4%). LC-MS: (ESI) m/z[M+H] + 251.1.

步骤二：参照实施例4-a中步骤三的方法，以化合物287-B(160mg)进行反应得到黄色固体化合物1(7.1mg，收率4.7％)。LC-MS:(ESI)m/z:237(M+H)+；1H NMR(DMSO-d6,400MHz):δ(ppm)9.28(s,1H),6.67(d,J＝8.4Hz,1H),6.40(d,J＝8.4Hz,1H),5.57(t,J＝7.5Hz,1H),4.29-4.20(m,4H),2.70-2.52(m,2H),2.48-2.41(m,1H),2.20-2.08(m,1H).Step 2: Referring to the method of step 3 in Example 4-a, compound 287-B (160 mg) was reacted to obtain yellow solid compound 1 (7.1 mg, yield 4.7%). LC-MS: (ESI) m/z: 237 (M+H) + ; 1 H NMR (DMSO-d 6 , 400 MHz): δ (ppm) 9.28 (s, 1H), 6.67 (d, J = 8.4 Hz, 1H), 6.40 (d, J = 8.4 Hz, 1H), 5.57 (t, J = 7.5 Hz, 1H), 4.29-4.20 (m, 4H), 2.70-2.52 (m, 2H), 2.48-2.41 (m, 1H), 2.20-2.08 (m, 1H).

实施例5化合物3、112、107的合成
Example 5 Synthesis of Compounds 3, 112, and 107

步骤一：在20℃，向化合物3-A(5.0g,23.78mmol)的DCM(125mL)溶液中加入三氯化铝(6.98g,52.32mmol)，搅拌10分钟后一次性加入化合物3-B(3.57g,35.68mmol)，在20℃搅拌反应30分钟。减压蒸馏除掉溶剂，用水(100mL)稀释残余物，用1M的HCl调pH到1-2，用EA(100mL×3)萃取。经过常规的后处理操作二后通过硅胶柱色谱(EA:PE＝0到70％:30％)纯化得到黄色固体化合物3-C(1.5g,4.59mmol,收率19.31％)。LCMS:(ESI)m/z＝310.9(M+1)+1.1H NMR(400MHz,DMSO-d6)Shift 12.02(br s,1H),10.42(s,1H),7.50(s,1H),6.54(s,1H),3.83(s,3H),3.57(s,3H),3.08(t,J＝6.40Hz,2H),2.70-2.79(m,2H),2.52-2.55(m,2H),2.45-2.49(m,2H).Step 1: At 20°C, aluminum chloride (6.98g, 52.32mmol) was added to a solution of compound 3-A (5.0g, 23.78mmol) in DCM (125mL), stirred for 10 minutes, and then compound 3-B (3.57g, 35.68mmol) was added at once, and the reaction was stirred at 20°C for 30 minutes. The solvent was removed by distillation under reduced pressure, the residue was diluted with water (100mL), the pH was adjusted to 1-2 with 1M HCl, and extracted with EA (100mL×3). After conventional post-treatment operation 2, it was purified by silica gel column chromatography (EA:PE=0 to 70%:30%) to obtain a yellow solid compound 3-C (1.5g, 4.59mmol, yield 19.31%). LCMS: (ESI) m/z＝310.9(M+1) +1.1 H NMR(400MHz, DMSO-d6)Shift 12.02(br s,1H),10.42(s,1H),7.50(s,1H),6.54(s,1H),3.83(s,3H),3.57(s,3H),3.0 8(t,J＝6.40Hz,2H),2.70-2.79(m,2H),2.52-2.55(m,2H),2.45-2.49(m,2H).

步骤二(构建五元内酯环代表性操作)：向化合物3-C(800mg,2.58mmol)在水(30mL)的混合物中加入NaOH(309.38mg,7.73mmol)和NaBH4(292.60mg,7.73mmol)。在20℃搅拌反应60小时。用2M的HCl调pH到1-2，析出白色固体，混合物用EA(100mL×3)萃取。经过常规的后处理操作后所得残余物用EA(10mL)打浆，过滤，用EA(3mL×2)洗涤，得到白色固体化合物3(520mg,1.76mmol，收率68.37％)。LCMS:(ESI)m/z＝280.9(M+1)+；1HNMR(400MHz,DMSO-d6)Shift 12.04(br s,1H),9.61(br s,1H),7.00(s,1H),6.48(s,1H),5.59(t,J＝7.53Hz,1H),3.72(s,3H),2.66-2.72(m,2H),2.62(t,J＝9.41Hz,1H),2.53-2.59(m,1H),2.40-2.46(m,3H),2.03-2.15(m,1H).Step 2 (representative operation for constructing a five-membered lactone ring): NaOH (309.38 mg, 7.73 mmol) and NaBH 4 (292.60 mg, 7.73 mmol) were added to a mixture of compound 3-C (800 mg, 2.58 mmol) in water (30 mL). The reaction was stirred at 20°C for 60 hours. The pH was adjusted to 1-2 with 2M HCl, a white solid was precipitated, and the mixture was extracted with EA (100 mL×3). After conventional post-treatment operations, the residue was slurried with EA (10 mL), filtered, and washed with EA (3 mL×2) to obtain a white solid compound 3 (520 mg, 1.76 mmol, yield 68.37%). LCMS: (ESI) m/z＝280.9(M+1) + ； 1 HNMR(400MHz, DMSO-d6)Shift 12.04(br s,1H),9.61(br s,1H),7.00(s,1H),6.48(s,1H),5.59(t,J＝7.53Hz,1H),3.72(s,3H),2.66-2.72(m, 2H), 2.62 (t, J = 9.41Hz, 1H), 2.53-2.59 (m, 1H), 2.40-2.46 (m, 3H), 2.03-2.15 (m, 1H).

步骤三：将化合物3(100mg,0.36mmol)在DCM(3.0mL)和TFA(0.5mL)的溶液在20℃搅拌反应16小时。减压浓缩除掉溶剂，所得残余物用硅胶柱色谱(EA:PE＝0到5％:95％)纯化得白色固体化合物112(77mg,0.28mmol，收率78.17％)。LCMS:(ESI)m/z＝263.1(M+1)+,285.1(M+Na)+；1H NMR(400MHz,CHLOROFORM-d)Shift 7.17(s,1H),6.63(s,1H),5.73(t,J＝7.03Hz,1H),3.85(s,3H),2.92-3.03(m,2H),2.78-2.85(m,2H),2.68-2.77(m,1H),2.61-2.67(m,2H),2.04-2.17(m,1H).Step 3: A solution of compound 3 (100 mg, 0.36 mmol) in DCM (3.0 mL) and TFA (0.5 mL) was stirred at 20°C for 16 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (EA:PE = 0 to 5%: 95%) to obtain a white solid compound 112 (77 mg, 0.28 mmol, yield 78.17%). LCMS: (ESI)m/z＝263.1(M+1) + ,285.1(M+Na) + ; 1 H NMR (400MHz, CHLOROFORM-d)Shift 7.17(s,1H),6.63(s,1H),5.73(t,J＝7.03Hz,1H),3.85(s,3H),2.92-3.03(m,2 H),2.78-2.85(m,2H),2.68-2.77(m,1H),2.61-2.67(m,2H),2.04-2.17(m,1H).

步骤四：化合物112(70mg,0.27mmol)的MeOH(2mL)的溶液在50℃搅拌反应16小时。减压浓缩除掉溶剂，所得残余物用硅胶柱色谱(EA:PE＝0到35％:65％)纯化得白色固体化合物107(35mg,0.11mmol，收率42.33％)。LCMS:(ESI)m/z＝294.9(M+1)+；1HNMR(400MHz,CHLOROFORM-d)Shift 7.90(s,1H),7.01(s,1H),6.52(s,1H),5.63-5.74(m,1H),3.80(s,3H),3.72(s,3H),2.78-2.91(m,2H),2.70-2.77(m,2H),2.59-2.69(m,3H),2.06-2.19(m,1H).
Step 4: A solution of compound 112 (70 mg, 0.27 mmol) in MeOH (2 mL) was stirred at 50°C for 16 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (EA:PE = 0 to 35%: 65%) to obtain white solid compound 107 (35 mg, 0.11 mmol, yield 42.33%). LCMS: (ESI)m/z＝294.9(M+1) + ； 1 HNMR(400MHz,CHLOROFORM-d)Shift 7.90(s,1H),7.01(s,1H),6.52(s,1H),5.63-5.74(m,1H),3.80(s,3H),3.72(s, 3H),2.78-2.91(m,2H),2.70-2.77(m,2H),2.59-2.69(m,3H),2.06-2.19(m,1H).

化合物112(70mg,0.27mmol)的EtOH(2mL)的溶液在50℃搅拌反应16小时。减压浓缩除掉溶剂，所得残余物用硅胶柱色谱(EA:PE＝0到35％:65％)纯化得白色固体化合物108(25mg,0.077mmol，收率28.86％)。LCMS:(ESI)m/z＝308.9(M+1)+,330.9(M+Na)+；1H NMR(400MHz,CHLOROFORM-d)Shift 8.04(s,1H),7.01(s,1H),6.52(s,1H),5.65-5.72(m,1H),4.17(q,J＝7.03Hz,2H),3.80(s,3H),2.79-2.87(m,2H),2.69-2.74(m,2H),2.59-2.68(m,3H),2.06-2.19(m,1H),1.27(t,J＝7.15Hz,3H).A solution of compound 112 (70 mg, 0.27 mmol) in EtOH (2 mL) was stirred at 50° C. for 16 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (EA:PE=0 to 35%:65%) to obtain white solid compound 108 (25 mg, 0.077 mmol, yield 28.86%). LCMS: (ESI)m/z＝308.9(M+1) + ,330.9(M+Na) + ; 1 H NMR (400MHz, CHLOROFORM-d)Shift 8.04(s,1H),7.01(s,1H),6.52(s,1H),5.65-5.72(m,1H),4.17(q,J＝7.03Hz,2H),3.80(s,3H),2. 79-2.87(m,2H),2.69-2.74(m,2H),2.59-2.68(m,3H),2.06-2.19(m,1H),1.27(t,J＝7.15Hz,3H).

实施例5-a化合物109的合成
Example 5-a Synthesis of Compound 109

向化合物112(60mg,0.23mmol)的DMF(2mL)的溶液中加入二甲胺THF溶液(2M,114.39uL)，在20℃搅拌反应16小时。LCMS显示仅少量原料(3％)未反应。减压浓缩除掉溶剂，所得残余物用硅胶柱色谱(EA:PE，EA从0到60％)纯化得白色固体化合物109(30mg,收率41％)。LCMS:(ESI)m/z＝308.2(M+1)+,1H NMR(400MHz,DMSO-d6)Shift 9.72(s,1H),7.00(s,1H),6.47(s,1H),5.59(t,J＝7.65Hz,1H),3.72(s,3H),2.93(s,3H),2.81(s,3H),2.60-2.72(m,3H),2.52-2.59(m,2H),2.39-2.50(m,2H),2.02-2.19(m,1H)To a solution of compound 112 (60 mg, 0.23 mmol) in DMF (2 mL) was added dimethylamine THF solution (2M, 114.39 uL), and the mixture was stirred at 20°C for 16 hours. LCMS showed that only a small amount of starting material (3%) was unreacted. The solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (EA:PE, EA from 0 to 60%) to give white solid compound 109 (30 mg, yield 41%). LCMS:(ESI)m/z＝308.2(M+1) + , 1 H NMR(400MHz,DMSO-d6)Shift 9.72(s,1H),7.00(s,1H),6.47(s,1H),5.59(t,J＝7.65Hz,1H),3.72(s,3H),2.93(s,3H) ,2.81(s,3H),2.60-2.72(m,3H),2.52-2.59(m,2H),2.39-2.50(m,2H),2.02-2.19(m,1H)

参照实施例5-a的合成方法，以如下起始原料与化合物112进行反应得相应的终产化合物。

Referring to the synthesis method of Example 5-a, the following starting materials were reacted with compound 112 to obtain the corresponding final product compound.

参照实施例5-a的合成方法，用如下起始原料进行反应得相应的终产化合物。

Referring to the synthesis method of Example 5-a, the following starting materials were used to react to obtain the corresponding final product compound.

实施例5-b化合物130的合成
Example 5-b Synthesis of Compound 130

步骤一：向化合物130-B(1.57g,7.69mmol)在NaHCO3(646mg,7.69mmol)的水溶液(16mL)中加入化合物130-A(3.70g,23.1mmol),定期地加入NaHCO3(2.26g,26.9mmol,1.05mL的水溶液)维持pH在7.5，在20℃搅拌16小时。加入磷酸(5mL)调pH至4-5，用EtOAc(15mL*3)萃取。有机相降至0℃析出固体，过滤。粗产物用EtOAc(4mL)重结晶得白色固体化合物130-C(2.1g,收率83％)。1H NMR(400MHz,DMSO-d6)Shift＝12.50(br s,1H),7.88(br t,J＝5.4Hz,1H),6.91(br d,J＝8.0Hz,1H),4.08-3.94(m,1H),3.45-3.24(m,2H),2.00-1.86(m,2H),1.62(br d,J＝10.0Hz,6H),1.38(s,8H),1.34(br s,1H),1.26-1.09(m,3H),0.97-0.77(m,2H).Step 1: Compound 130-A (3.70 g, 23.1 mmol) was added to a solution of compound 130-B (1.57 g, 7.69 mmol) in NaHCO 3 (646 mg, 7.69 mmol) (16 mL), and NaHCO 3 (2.26 g, 26.9 mmol, 1.05 mL of aqueous solution) was added periodically to maintain the pH at 7.5, and stirred at 20°C for 16 hours. Phosphoric acid (5 mL) was added to adjust the pH to 4-5, and extracted with EtOAc (15 mL*3). The organic phase was cooled to 0°C to precipitate a solid, which was filtered. The crude product was recrystallized with EtOAc (4 mL) to obtain a white solid compound 130-C (2.1 g, yield 83%). 1 H NMR (400MHz, DMSO-d6)Shift＝12.50(br s,1H),7.88(br t,J＝5.4Hz,1H),6.91(br d,J＝8.0Hz,1H),4.08-3.94(m,1H),3.45-3.24(m,2H),2.00-1.86(m,2H),1.62(br d,J＝10.0Hz,6H),1.38(s,8H),1.34(br s,1H),1.26-1.09(m,3H),0.97-0.77(m,2H).

步骤二：向化合物130-C(120mg,365μmol)的DMF(2mL)溶液中加入环己胺(43.5mg,438μmol)、DIEA(142mg,1.10mmol)和HATU(166mg,438μmol),在20℃搅拌2小。用水(20mL)稀释,用EtOAc(10mL*3)萃取。经常规的后处理操作二后得粗产物。将粗产物碾碎，在20℃用EtOAc打浆3小时。过滤得白色固体化合物130-D(100mg,收率66.82％)。1H NMR(400MHz,DMSO-d6)Shift＝7.84-7.71(m,1H),7.61(br d,J＝7.8Hz,1H),6.65(br d,J＝8.0Hz,1H),4.02-3.89(m,1H),3.49(br d,J＝7.3Hz,1H),3.33-3.26(m,1H),3.24-3.13(m,1H),1.92(br d,J＝6.8Hz,2H),1.63(br d,J＝10.8Hz,10H),1.38(s,9H),1.30-1.03(m,9H),0.95-0.76(m,2H).Step 2: Add cyclohexylamine (43.5 mg, 438 μmol), DIEA (142 mg, 1.10 mmol) and HATU (166 mg, 438 μmol) to a DMF (2 mL) solution of compound 130-C (120 mg, 365 μmol) and stir at 20 ° C for 2 hours. Dilute with water (20 mL) and extract with EtOAc (10 mL*3). After conventional post-treatment operation 2, a crude product was obtained. The crude product was crushed and slurried with EtOAc at 20 ° C for 3 hours. Filter to obtain a white solid compound 130-D (100 mg, yield 66.82%). 1 H NMR (400MHz, DMSO-d6)Shift＝7.84-7.71(m,1H),7.61(br d,J＝7.8Hz,1H),6.65(br d,J＝8.0Hz,1H),4.02-3.89(m,1H),3.49(br d,J＝7.3Hz,1H),3.33-3.26(m,1H),3.24-3.13(m,1H),1.92(br d,J＝6.8Hz,2H),1.63(br d,J＝10.8Hz,10H),1.38(s,9H),1.30-1.03(m,9H),0.95-0.76(m,2H).

步骤三：向化合物130-D(100mg,244umol)在dioxane(1mL)的混合物中加入HCl的dioxane溶液(2M，1mL)。在20℃搅拌3小时。减压浓缩得白色固体化合物130-E(90.0mg，HCl盐)，粗产品直接用于下一步反应。Step 3: Add HCl in dioxane (2M, 1 mL) to a mixture of compound 130-D (100 mg, 244 umol) in dioxane (1 mL). Stir at 20°C for 3 hours. Concentrate under reduced pressure to obtain white solid compound 130-E (90.0 mg, HCl salt), which is used directly in the next step.

步骤四：向化合物130-E(50mg,0.134mmol，HCl盐)的DMF(1mL)的溶液中加入TEA(40.8mg,0.4mmol)和112(35.3mg,0.134mmol)，在40℃搅拌反应16小时。减压浓缩除掉溶剂，所得残余物prep HPLC(FA方法-B；B％:35％-55％,10min)纯化得白色固体化合物130(25mg,收率29.32％)。LCMS:(ESI)m/z＝572.3[M+1]+；1H NMR(400MHz,DMSO-d6)Shift＝9.61(br s,1H),7.85(dd,J＝2.4,8.2Hz,1H),7.68(br d,J＝6.8Hz,2H),6.99(d,J＝2.5Hz,1H),6.48(s,1H),5.59(t,J＝7.5Hz,1H),4.30(q,J＝7.1Hz,1H),3.72(s,3H),3.55-3.44(m,1H),3.29-3.17(m,2H),2.71-2.62(m,3H),2.38-2.31(m,2H),2.17-2.02(m,1H),1.91(br d,J＝5.3Hz,2H),1.78-1.45(m,12H),1.32-0.99(m,9H),0.85(br d,J＝10.0Hz,2H)Step 4: TEA (40.8 mg, 0.4 mmol) and 112 (35.3 mg, 0.134 mmol) were added to a solution of compound 130-E (50 mg, 0.134 mmol, HCl salt) in DMF (1 mL), and the mixture was stirred at 40°C for 16 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by prep HPLC (FA method-B; B%: 35%-55%, 10 min) to obtain white solid compound 130 (25 mg, yield 29.32%). LCMS: (ESI) m/z = 572.3 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) Shift = 9.61 (br s, 1H), 7.85 (dd, J = 2.4, 8.2 Hz, 1H), 7.68 (br d,J＝6.8Hz,2H),6.99(d,J＝2.5Hz,1H),6.48(s,1H),5.59(t,J＝7.5Hz,1H),4.30(q,J＝7.1Hz,1H),3.72(s,3 H),3.55-3.44(m,1H),3.29-3.17(m,2H),2.71-2.62(m,3H),2.38-2.31(m,2H),2.17-2.02(m,1H),1.91(br d,J＝5.3Hz,2H),1.78-1.45(m,12H),1.32-0.99(m,9H),0.85(br d,J＝10.0Hz,2H)

参照实施例5-b的合成方法中步骤二、三、四的方法，在步骤二中用如下起始原料替代环己胺，进行三步反应得相应的终产化合物。
Referring to the methods of steps 2, 3 and 4 in the synthesis method of Example 5-b, the following starting materials are used in place of cyclohexylamine in step 2 to carry out three-step reactions to obtain the corresponding final compound.

实施例6化合物111的合成
Example 6 Synthesis of Compound 111

在20℃，向化合物3(50mg,0.18mmol)和异丙醇(10.72mg,0.18mmol)的THF(2mL)溶液中加入三苯基膦(93.58mg,356.80μmol)和偶氮二甲酸二叔丁酯(DBAD，61.62mg,0.27mmol)。在20℃搅拌反应16小时。减压蒸馏除掉溶剂，残余物先通过硅胶柱色谱(EA:PE＝0到40％:60％)纯化，然后通过preparative HPLC(FA方法-A,B％:33％-53％,10min)纯化得到白色固体化合物111(20mg,0.06mmol,收率33.74％)LCMS:(ESI)m/z＝322.9(M+1)+；1HNMR(400MHz,CHLOROFORM-d)Shift 8.17(s,1H),7.00(s,1H),6.52(s,1H),5.64-5.74(m,1H),5.04(quin,J＝6.21Hz,1H),3.80(s,3H),2.75-2.89(m,2H),2.59-2.72(m,5H),2.09-2.20(m,1H),1.24(dd,J＝2.26,6.27Hz,6H).Triphenylphosphine (93.58 mg, 356.80 μmol) and di-tert-butyl azodicarboxylate (DBAD, 61.62 mg, 0.27 mmol) were added to a solution of compound 3 (50 mg, 0.18 mmol) and isopropanol (10.72 mg, 0.18 mmol) in THF (2 mL) at 20°C. The reaction was stirred at 20°C for 16 hours. The solvent was removed by distillation under reduced pressure, and the residue was first purified by silica gel column chromatography (EA:PE=0 to 40%:60%) and then purified by preparative HPLC (FA method-A, B%:33%-53%, 10 min) to obtain a white solid compound 111 (20 mg, 0.06 mmol, yield 33.74%) LCMS: (ESI) m/z=322.9 (M+1) + ; 1 HNMR (400 MHz, CHLOROFORM-d) Shift 8.17(s,1H),7.00(s,1H),6.52(s,1H),5.64-5.74(m,1H),5.04(quin,J＝6.21Hz,1H),3.80(s ,3H),2.75-2.89(m,2H),2.59-2.72(m,5H),2.09-2.20(m,1H),1.24(dd,J＝2.26,6.27Hz,6H).

参照化合物111的合成方法，用如下表格中的起始原料与化合物3进行反应得到相应的终产化合物。
Referring to the synthesis method of compound 111, the starting materials in the following table were reacted with compound 3 to obtain the corresponding final product compound.

实施例7化合物4的合成
Example 7 Synthesis of Compound 4

步骤一：在0℃，向化合物4-A(3.00g,11.8mmol)的THF(60mL)溶液中加入氢化铝锂(360mg,9.49mmol)。在0℃搅拌反应1小时。用1M的盐酸溶液淬灭反应，加入水(30mL)。混合物用EA萃取。经过常规的后处理操作后得到紫色固体化合物4-B(2.55g,9.57mmol,收率82％).1HNMR(400MHz,CDCl3)δ7.24(s,1H),6.51(s,1H),3.86(s,3H),3.68-3.66(t,J＝4,2H),2.73-2.70(t,J＝4,2H),1.89-1.83(m,2H).Step 1: Add lithium aluminum hydride (360 mg, 9.49 mmol) to a solution of compound 4-A (3.00 g, 11.8 mmol) in THF (60 mL) at 0°C. Stir the reaction at 0°C for 1 hour. Quench the reaction with 1M hydrochloric acid solution and add water (30 mL). Extract the mixture with EA. After conventional post-treatment, a purple solid compound 4-B (2.55 g, 9.57 mmol, yield 82%) was obtained. 1 HNMR (400 MHz, CDCl 3 ) δ7.24 (s, 1H), 6.51 (s, 1H), 3.86 (s, 3H), 3.68-3.66 (t, J＝4, 2H), 2.73-2.70 (t, J＝4, 2H), 1.89-1.83 (m, 2H).

步骤二：向化合物4-B(2.55g,9.77mmol)的DCM(50mL)溶液中加入DHP(2.05g,24.4mmol)和吡啶对甲苯磺酸盐(PPTS,245mg,976umol)。在室温搅拌反应16小时，加入水，混合物用DCM(20mL×3)萃取。经过常规的后处理操作二后通过硅胶柱色谱(EA:PE，EA从0到11.5％)纯化得到黄色油状物4-C(3.3g,6.15mmol,纯度80％).LCMS:(ESI)m/z＝453.1(M+Na)+.Step 2: Add DHP (2.05 g, 24.4 mmol) and pyridine p-toluenesulfonate (PPTS, 245 mg, 976 umol) to a solution of compound 4-B (2.55 g, 9.77 mmol) in DCM (50 mL). Stir the reaction at room temperature for 16 hours, add water, and extract the mixture with DCM (20 mL × 3). After conventional post-treatment operation 2, the yellow oil 4-C (3.3 g, 6.15 mmol, purity 80%) was obtained by silica gel column chromatography (EA:PE, EA from 0 to 11.5%). LCMS: (ESI) m/z = 453.1 (M + Na) + .

步骤三：确保本操作所用玻璃仪器干燥无水。在-78℃,向化合物4-C(2.00g,纯度80％)的THF(50mL)溶液中加入正丁基锂的THF溶液(2.5M,2.5mL)，搅拌1小时后加入丁二酸酐(932mg,9.32mmol)，继续搅拌反应2小时。加入10％的柠檬酸溶液(30mL)淬灭反应，混合物用EA(30mL×3)萃取。经过常规的后处理操作二后通过硅胶柱色谱(THF:PE，THF从0到40％)纯化得到无色油状物4-C(0.65g,1.3mmol,LCMS纯度89.9％).LCMS:(ESI)m/z＝473.2(M+Na)+.1HNMR显示有2分子丁二酸酐残留。Step 3: Ensure that the glassware used in this operation is dry and anhydrous. At -78°C, add n-butyllithium THF solution (2.5M, 2.5mL) to a solution of compound 4-C (2.00g, purity 80%) in THF (50mL), stir for 1 hour, add succinic anhydride (932mg, 9.32mmol), and continue stirring for 2 hours. Add 10% citric acid solution (30mL) to quench the reaction, and the mixture is extracted with EA (30mL×3). After conventional post-treatment operation 2, it is purified by silica gel column chromatography (THF:PE, THF from 0 to 40%) to obtain a colorless oil 4-C (0.65g, 1.3mmol, LCMS purity 89.9%). LCMS: (ESI) m/z＝473.2(M+Na) + . 1 HNMR shows that 2 molecules of succinic anhydride remain.

步骤四：向化合物4-D(601mg，纯度89.9％)在NaOH(190mg,4.75mmol)水溶液(5.5mL)的混合物中加入NaBH4(75.70mg,2.00mmol)。在25℃搅拌反应16小时，小心地加入10％的柠檬酸溶液(30mL)调pH到2，混合物用EA(20mL×3)萃取。经过常规的后处理操作二后得到508mg淡黄色胶状物，LCMS显示产物为20.3％的化合物4-F[(ESI)m/z＝457.4(M+Na)+]和54.8％的化合物4-E[(ESI)m/z＝475.1(M+Na)+]的混合物。Step 4: Add NaBH 4 (75.70 mg, 2.00 mmol) to a mixture of compound 4-D (601 mg, purity 89.9%) in aqueous NaOH (190 mg, 4.75 mmol) (5.5 mL). Stir the reaction at 25°C for 16 hours, carefully add 10% citric acid solution (30 mL) to adjust the pH to 2, and extract the mixture with EA (20 mL×3). After conventional post-treatment operation 2, 508 mg of light yellow jelly was obtained. LCMS showed that the product was a mixture of 20.3% of compound 4-F [(ESI) m/z=457.4 (M+Na) + ] and 54.8% of compound 4-E [(ESI) m/z=475.1 (M+Na) + ].

步骤五：向化合物4-E和4-F的混合物(190mg)的THF(2mL)和水(1mL)溶液中加入对甲苯磺酸一水合物(40mg,210.28μmol)。在25℃搅拌反应16小时。通过Prep HPLC(FA方法-A,B％:15％-35％,10min)分离得类白色固体化合物4(35mg,122.24μmol).LCMS:(ESI)m/z＝267.1(M+1)+；1HNMR(400MHz,CHLOROFORM-d)Shift＝7.02(s,1H),6.49(s,1H),5.74-5.67(m,1H),3.81(s,3H),3.74-3.63(m,2H),2.81-2.70(m,2H),2.69-2.59(m,3H),2.22-2.11(m,1H),1.91-1.83(m,2H).Step 5: Add p-toluenesulfonic acid monohydrate (40 mg, 210.28 μmol) to a solution of a mixture of compounds 4-E and 4-F (190 mg) in THF (2 mL) and water (1 mL), and stir the reaction at 25° C. for 16 hours. Prep HPLC (FA method-A, B%: 15%-35%, 10 min) was used to separate the off-white solid compound 4 (35 mg, 122.24 μmol). LCMS: (ESI) m/z=267.1 (M+1) + ; 1 HNMR (400 MHz, CHLOROFORM-d) Shift=7.02 (s, 1H), 6.49 (s, 1H), 5.74-5.67 (m, 1H), 3.81 (s, 3H), 3.74-3.63 (m, 2H), 2.81-2.70 (m, 2H), 2.69-2.59 (m, 3H), 2.22-2.11 (m, 1H), 1.91-1.83 (m, 2H).

实施例8-a化合物5、6的合成
Example 8-a Synthesis of Compounds 5 and 6

步骤一：氮气保护下，将氢化钠(304mg,7.61mmol,纯度60％)的DMSO(20mL)悬浊液在65℃加热一小时。冷却至室温，加THF(20mL)到澄清反应液中。反应液冷却至-15℃，滴加三甲基碘化锍(1.41g,6.92mmol)的DMSO(20mL)溶液，3分钟后，滴加化合物6-A(2g,6.92mmol)的THF(20mL)溶液。在25℃搅拌反应2小时。0-10℃条件下，反应液用饱和NH4Cl(50mL)溶液淬灭,用100毫升水稀释，混合物用EA(100mL×2)萃取。经过常规的后处理操作二后得到黄色胶状产品化合物6-B(2克,粗产品)，粗产品直接用于下一步反应。Step 1: Under nitrogen protection, heat a suspension of sodium hydride (304 mg, 7.61 mmol, purity 60%) in DMSO (20 mL) at 65°C for one hour. Cool to room temperature and add THF (20 mL) to the clarified reaction solution. The reaction solution was cooled to -15°C, and a solution of trimethylsulfonium iodide (1.41 g, 6.92 mmol) in DMSO (20 mL) was added dropwise. After 3 minutes, a solution of compound 6-A (2 g, 6.92 mmol) in THF (20 mL) was added dropwise. Stir the reaction at 25°C for 2 hours. At 0-10°C, the reaction solution was quenched with a saturated NH 4 Cl (50 mL) solution, diluted with 100 ml of water, and the mixture was extracted with EA (100 mL×2). After conventional post-treatment operation 2, a yellow colloid product compound 6-B (2 g, crude product) was obtained, and the crude product was directly used in the next step reaction.

步骤二：将化合物6-B(2g，粗产品)和(1-甲氧基-2-甲基-丙-1-烯氧基)-三甲基硅烷(5.75g,33mmol)和三水合四丁基氟化铵(1.04g,3.30mmol)的黄色混合物在60℃搅拌12小时。反应液减压浓缩至干，残留物经硅胶柱色谱纯化(EA:PE，EA从0到3％)得黄色胶状产品化合物6-C(920mg,2.46mmol,两步收率约32％)。1H NMR(400MHz,CDCl3)δ(ppm)7.53(s,1H),6.82(s,1H),5.61(dd,J＝6.5,9.5Hz,1H),5.29-5.34(m,2H),3.85(s,3H),3.78-3.83(m,2H),2.52(dd,J＝6.4,12.9Hz,1H),1.99(dd,J＝9.8,12.8Hz,1H),1.38(s,3H),1.32(s,3H),1.26(t,J＝7.03Hz,3H).Step 2: A yellow mixture of compound 6-B (2 g, crude product) and (1-methoxy-2-methyl-prop-1-enyloxy)-trimethylsilane (5.75 g, 33 mmol) and tetrabutylammonium fluoride trihydrate (1.04 g, 3.30 mmol) was stirred at 60°C for 12 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (EA:PE, EA from 0 to 3%) to obtain a yellow gum product compound 6-C (920 mg, 2.46 mmol, two-step yield of about 32%). 1 H NMR (400MHz, CDCl 3 )δ(ppm)7.53(s,1H),6.82(s,1H),5.61(dd,J＝6.5,9.5Hz,1H),5.29-5.34(m,2H),3.85(s,3H),3.78-3.83(m,2H ),2.52(dd,J＝6.4,12.9Hz,1H),1.99(dd,J＝9.8,12.8Hz,1H),1.38(s,3H),1.32(s,3H),1.26(t,J＝7.03Hz,3H).

步骤三：将化合物6-C(760mg,2.04mmol)和丙-2-烯酸甲酯(438mg,5.09mmol)溶解在5毫升无水甲苯中，加碳酸铯(995mg,3.05mmol)，三苯基磷(427mg,1.63mmol)和醋酸钯(183mg,814mmol)，混合物减压除氧，置换氮气，氮气氛围下80℃搅拌12小时。反应液冷却至室温加30毫升水稀释，混合物用EA(30mL×2)萃取。经过常规的后处理操作得残余物，残留物经硅胶柱色谱纯化(EA:PE，EA从0到15％)得白色胶状产品化合物6-D(560mg,1.48mmol,产率72.68％)。1H NMR(400MHz,CDCl3)δ(ppm)7.95-8.01(m,1H),7.55(s,1H),6.81(s,1H),6.39-6.47(m,1H),5.63(dd,J＝6.5,9.5Hz,1H),5.33(s,2H),3.89(s,3H),3.81(s,3H),3.78(d,J＝7.03Hz,2H),2.53(dd,J＝6.5,12.8Hz,1H),2.02(dd,J＝9.8,12.8Hz,1H),1.39(s,3H),1.33(s,3H),1.23-1.27(m,3H).Step 3: Dissolve compound 6-C (760 mg, 2.04 mmol) and methyl prop-2-enoate (438 mg, 5.09 mmol) in 5 ml of anhydrous toluene, add cesium carbonate (995 mg, 3.05 mmol), triphenylphosphine (427 mg, 1.63 mmol) and palladium acetate (183 mg, 814 mmol), deoxygenate the mixture under reduced pressure, replace nitrogen, and stir at 80 ° C for 12 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature and diluted with 30 ml of water, and the mixture was extracted with EA (30 mL × 2). After conventional post-treatment operations, the residue was obtained, and the residue was purified by silica gel column chromatography (EA: PE, EA from 0 to 15%) to obtain a white colloidal product compound 6-D (560 mg, 1.48 mmol, yield 72.68%). 1 H NMR (400MHz, CDCl 3 )δ(ppm)7.95-8.01(m,1H),7.55(s,1H),6.81(s,1H),6.39-6.47(m,1H),5.63(dd,J＝6.5,9.5Hz,1H),5.33(s,2H),3.89(s,3H),3.81(s ,3H),3.78(d,J＝7.03Hz,2H),2.53(dd,J＝6.5,12.8Hz,1H),2.02(dd,J＝9.8,12.8Hz,1H),1.39(s,3H),1.33(s,3H),1.23-1.27(m,3H).

步骤四：参照催化氢化代表性操作的方法，以化合物6-D(528μmol)为原料反应得黄色胶状物6-E(342μmol,64.66％产率)。硅胶柱色谱纯化(EA:PE，EA从0到15％)。1H NMR(400MHz,CDCl3)δ(ppm)7.13(s,1H),6.77(s,1H),5.64(dd,J＝6.4,9.6Hz,1H),5.27(s,2H),3.83(s,3H),3.72-3.81(m,2H),3.69(s,3H),2.86-2.94(m,2H),2.55-2.62(m,2H),2.48(dd,J＝6.5,12.8Hz,1H),1.99-2.05(m,1H),1.37(s,3H),1.32(s,3H),1.23-1.28(m,3H).Step 4: Referring to the representative operation method of catalytic hydrogenation, compound 6-D (528 μmol) was used as the raw material to obtain yellow gum 6-E (342 μmol, 64.66% yield), which was purified by silica gel column chromatography (EA:PE, EA from 0 to 15%). 1 H NMR (400MHz, CDCl 3 )δ(ppm)7.13(s,1H),6.77(s,1H),5.64(dd,J＝6.4,9.6Hz,1H),5.27(s,2H),3.83(s,3H),3.72-3.81(m,2H),3.69(s,3H),2.86 -2.94(m,2H),2.55-2.62(m,2H),2.48(dd,J＝6.5,12.8Hz,1H),1.99-2.05(m,1H),1.37(s,3H),1.32(s,3H),1.23-1.28(m,3H).

步骤五：将6-E(130mg,342μmol)在DCM(1.5mL)和TFA(0.1mL)的反应液20℃搅拌1小时。反应液减压浓缩至干得粉色胶状产品化合物6-F(130mg，粗产品)，直接用于下一步反应。LC-MS:(ESI)m/z.[M+H]+290.9.Step 5: Stir the reaction solution of 6-E (130 mg, 342 μmol) in DCM (1.5 mL) and TFA (0.1 mL) at 20°C for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to obtain a pink gel product compound 6-F (130 mg, crude product), which was directly used in the next reaction. LC-MS: (ESI) m/z. [M+H] + 290.9.

步骤六：将6-F(130mg)溶解在MeOH(1mL)中，加NaOH水溶液(238mg,895μmol)，反应液25℃搅拌30分钟。反应液用1M HCl溶液调pH到3，25℃搅拌30分钟。反应液减压浓缩，残留物用10毫升水稀释，混合物用EA(10mL×2)萃取。经过常规的后处理操作后得残余物，残留物经硅胶柱色谱纯化得白色固体化合物5(60mg,186μmol,两步产率54.4％)。LC-MS:(ESI)m/z.[M+H]+323.1。1H NMR(400MHz,DMSO-d6)δ(ppm)9.65(s,1H),7.02(s,1H),6.48(s,1H),5.58(dd,J＝6.5,9.8Hz,1H),3.72(s,3H),3.57(s,3H),3.34(s,2H),2.67-2.75(m,2H),2.30-2.37(m,1H),2.08(dd,J＝10.0,12.5Hz,1H),1.25(s,3H),1.21(s,3H).Step 6: Dissolve 6-F (130 mg) in MeOH (1 mL), add NaOH aqueous solution (238 mg, 895 μmol), and stir the reaction solution at 25 ° C for 30 minutes. The reaction solution was adjusted to pH 3 with 1M HCl solution and stirred at 25 ° C for 30 minutes. The reaction solution was concentrated under reduced pressure, the residue was diluted with 10 ml of water, and the mixture was extracted with EA (10 mL×2). After conventional post-treatment operations, the residue was obtained, and the residue was purified by silica gel column chromatography to obtain white solid compound 5 (60 mg, 186 μmol, two-step yield 54.4%). LC-MS: (ESI) m/z. [M+H] + 323.1. 1 H NMR (400MHz, DMSO-d 6 )δ(ppm)9.65(s,1H),7.02(s,1H),6.48(s,1H),5.58(dd,J＝6.5,9.8Hz,1H),3.72(s,3H),3.57(s,3H),3. 34(s,2H),2.67-2.75(m,2H),2.30-2.37(m,1H),2.08(dd,J＝10.0,12.5Hz,1H),1.25(s,3H),1.21(s,3H).

步骤七：将5(18mg)溶解在MeOH(10mL)中，加NaOH水溶液(1M,111uL)，反应液40℃搅拌60小时。LCMS显示18％的原料剩余，生成30％的目标产物。反应液减压浓缩，加入EA和水(5mL)，用1M HCl溶液调pH到3，混合物用EA(5mL×2)萃取。经过常规的后处理操作后得残余物，残留物经prep-HPLC(column:YMC Triart C18150*25mm*5um；mobile phase:[water(0.225％FA)-ACN]；B％:30％-50％,10min)纯化得白色固体化合物6(2mg,6.16μmol,产率11％)。LCMS:ESI)m/z＝309.2(M+H)+；1HNMR(400MHz,DMSO-d6)Shift＝12.03(br s,1H),9.62(br s,1H),7.03(s,1H),6.47(s,1H),5.57(dd,J＝6.5,10.0Hz,1H),3.71(s,3H),2.68(t,J＝7.7Hz,2H),2.42(t,J＝7.7Hz,2H),2.31(dd,J＝6.4,12.7Hz,1H),2.12-2.05(m,1H),1.24(s,3H),1.20(s,3H)。Step 7: Dissolve 5 (18 mg) in MeOH (10 mL), add NaOH aqueous solution (1 M, 111 uL), and stir the reaction solution at 40 ° C for 60 hours. LCMS shows that 18% of the raw material remains and 30% of the target product is generated. The reaction solution is concentrated under reduced pressure, EA and water (5 mL) are added, and the pH is adjusted to 3 with 1M HCl solution. The mixture is extracted with EA (5 mL×2). After conventional post-treatment operations, the residue is obtained, and the residue is purified by prep-HPLC (column: YMC Triart C18150*25mm*5um; mobile phase: [water (0.225% FA)-ACN]; B%: 30%-50%, 10min) to obtain a white solid compound 6 (2 mg, 6.16μmol, yield 11%). LCMS:ESI)m/z＝309.2(M+H) + ; 1HNMR(400MHz, DMSO-d6)Shift＝12.03(br s,1H),9.62(br s,1H),7.03(s,1H),6.47(s,1H),5.57(dd,J＝6.5,10.0Hz,1H),3.71(s,3H),2.68(t,J＝7.7Hz,2H) ,2.42(t,J＝7.7Hz,2H),2.31(dd,J＝6.4,12.7Hz,1H),2.12-2.05(m,1H),1.24(s,3H),1.20(s,3H).

实施例8-b化合物7、8的合成
Example 8-b Synthesis of Compounds 7 and 8

步骤一和步骤二：参照实施例5步骤一和步骤二的方法，以化合物7-A为起始原料经两步反应得白色固体化合物7，两步收率约2.4％。LCMS:(ESI)m/z＝288.6(M+1)+；1HNMR(400MHz,DMSO-d6)Shift 10.44(s,1H),7.36(s,1H),6.63(s,1H),5.59(t,J＝7.65Hz,1H),3.76(s,3H),2.53-2.70(m,2H),2.41-2.50(m,1H),1.98-2.18(m,1H).Step 1 and step 2: Referring to the method of step 1 and step 2 of Example 5, compound 7-A was used as the starting material to obtain a white solid compound 7 through two-step reaction, and the two-step yield was about 2.4%. LCMS: (ESI) m/z = 288.6 (M+1) + ; 1 HNMR (400MHz, DMSO-d6) Shift 10.44 (s, 1H), 7.36 (s, 1H), 6.63 (s, 1H), 5.59 (t, J = 7.65Hz, 1H), 3.76 (s, 3H), 2.53-2.70 (m, 2H), 2.41-2.50 (m, 1H), 1.98-2.18 (m, 1H).

步骤三：向化合物7(220mg,766.27umol)和氯甲基乙醚(86.93mg,919.52umol)的acetone(8mL)溶液中加入K2CO3(317.72mg,2.30mmol)，20℃搅拌16小时。反应液抽滤，滤液浓缩至干，残留物经硅胶柱色谱纯化(EA:PE，EA从0到35％)得无色油状物8-A(250mg,706.14umol).(ESI)m/z＝346.9(M+1)+。1H NMR(400MHz,CDCl3)Shift 7.48(s,1H),6.83(s,1H),5.61-5.77(m,1H),5.32(s,2H),3.86(s,3H),3.81(q,J＝7.09Hz,2H),2.53-2.81(m,3H),2.02-2.28(m,1H),1.26(t,J＝7.03Hz,3H)Step 3: Add K 2 CO 3 (317.72 mg, 2.30 mmol) to a solution of compound 7 (220 mg, 766.27 umol) and chloromethyl ether (86.93 mg, 919.52 umol) in acetone (8 mL), and stir at 20°C for 16 hours. The reaction solution was filtered, the filtrate was concentrated to dryness, and the residue was purified by silica gel column chromatography (EA:PE, EA from 0 to 35%) to obtain a colorless oil 8-A (250 mg, 706.14 umol). (ESI) m/z = 346.9 (M+1) + . 1H NMR (400MHz, CDCl 3 )Shift 7.48(s,1H),6.83(s,1H),5.61-5.77(m,1H),5.32(s,2H),3.86(s,3H),3.81( q,J＝7.09Hz,2H),2.53-2.81(m,3H),2.02-2.28(m,1H),1.26(t,J＝7.03Hz,3H)

步骤四(Suzuki偶联反应代表性操作)：向化合物8-A(70mg，202.79umol)、苯硼酸(74.18mg,608.37umol)在THF/水(3mL,4/1)的混合物中加入和K3PO4(129mg,608.37umol)和XPhos Pd G3(17.17mg,20.28umol)，脱气并重新填充氮气两次。将其加热至60℃反应1小时。反应液浓缩至干，用乙酸乙酯(3mL)稀释反应。经过常规的后处理操作后得到粗产物，粗产物通过硅胶薄层层析色谱分离(PE：EA＝1：1)纯化，得到黄色油状物化合物8-B(60mg,收率82.09％)。LCMS:(ESI)m/z＝343.2(M+1)+；1HNMR(400MHz,CHLOROFORM-d)Shift 7.44-7.52(m,2H),7.35-7.43(m,2H),7.27-7.33(m,2H),6.89(s,1H),5.67-5.82(m,1H),5.18(s,2H),3.89(s,3H),3.66(dq,J＝1.16,7.07Hz,2H),2.56-2.74(m,3H),2.13-2.28(m,1H),1.20(t,J＝7.09Hz,3H).Step 4 (Suzuki coupling reaction representative operation): Add K 3 PO 4 (129 mg, 608.37 umol) and XPhos Pd G3 (17.17 mg, 20.28 umol) to a mixture of compound 8-A (70 mg, 202.79 umol) and phenylboronic acid (74.18 mg, 608.37 umol) in THF/water (3 mL, 4/1), degas and refill with nitrogen twice. Heat it to 60 ° C for 1 hour. The reaction solution is concentrated to dryness and diluted with ethyl acetate (3 mL). After conventional post-treatment operations, a crude product is obtained, which is purified by silica gel thin layer chromatography (PE: EA = 1: 1) to obtain a yellow oil compound 8-B (60 mg, yield 82.09%). LCMS: (ESI)m/z＝343.2(M+1) + ； 1 HNMR(400MHz,CHLOROFORM-d)Shift 7.44-7.52(m,2H),7.35-7.43(m,2H),7.27-7.33(m,2H),6.89(s,1H),5.67-5.82(m,1H),5.18(s,2H),3 .89(s,3H),3.66(dq,J＝1.16,7.07Hz,2H),2.56-2.74(m,3H),2.13-2.28(m,1H),1.20(t,J＝7.09Hz,3H).

步骤五：将化合物8-B(80mg,0.23mmol)在DCM(3.5mL)和TFA(0.35mL)的溶液在20℃搅拌反应2小时。用饱和NaHCO3溶液(2mL)淬灭反应，混合物用DCM(3mL×3)萃取。经过常规的后处理操作二后得残余物，残留物经硅胶柱色(EA:PE，EA从0到30％)纯化得白色固体化合物8(35mg,收率50％)。LCMS:(ESI)m/z＝284.9(M+1)+.1H NMR(400MHz,DMSO-d6)Shift 9.81(s,1H),7.51(d,J＝7.03Hz,2H),7.38(t,J＝7.65Hz,2H),7.22-7.30(m,1H),7.19(s,1H),6.63(s,1H),5.67(t,J＝7.53Hz,1H),3.80(s,3H),2.54-2.73(m,2H),2.43-2.50(m,1H),2.12-2.25(m,1H).Step 5: A solution of compound 8-B (80 mg, 0.23 mmol) in DCM (3.5 mL) and TFA (0.35 mL) was stirred at 20 ° C for 2 hours. The reaction was quenched with saturated NaHCO 3 solution (2 mL), and the mixture was extracted with DCM (3 mL×3). After conventional post-treatment operation 2, the residue was obtained, and the residue was purified by silica gel column chromatography (EA:PE, EA from 0 to 30%) to obtain white solid compound 8 (35 mg, yield 50%). LCMS: (ESI)m/z＝284.9(M+1) + . 1 H NMR(400MHz, DMSO-d6)Shift 9.81(s,1H),7.51(d,J＝7.03Hz,2H),7.38(t,J＝7.65Hz,2H),7.22-7.30(m,1H),7.19(s,1H),6.63(s ,1H),5.67(t,J=7.53Hz,1H),3.80(s,3H),2.54-2.73(m,2H),2.43-2.50(m,1H),2.12-2.25(m,1H).

参照化合物8的合成方法，用如下表格中的起始原料与化合物8-A进行反应得到相应的终产化合物。

Referring to the synthesis method of compound 8, the starting materials in the following table were reacted with compound 8-A to obtain the corresponding final compound.

实施例9化合物11的合成
Example 9 Synthesis of Compound 11

步骤一：向化合物8-A(100mg，0.29mmol)在dioxane/水(4mL,1/1)的混合物中加入亚铁氰化钾(53.35mg,144.85umol)、醋酸钾(3.55mg,36.21umol)、t-Bu Xphos(2.46mg,5.79umol,0.02eq)和t-Bu Xphos Pd G3(2.30mg,2.90umol)，脱气并填充氮气。将其加热至80℃反应2小时。LCMS显示少量原料剩余，但目标产物已经生成.反应液降至室温，用EA(5mL*3)萃取。经过常规的后处理操作二后得到粗产物，粗产物通过硅胶薄层层析色谱分离(EA:PE，EA从0到30％)纯化，得到无色油状物化合物11-A(60mg,收率35.5％)。LCMS:(ESI)m/z＝292.2(M+1)+.Step 1: Add potassium ferrocyanide (53.35 mg, 144.85 umol), potassium acetate (3.55 mg, 36.21 umol), t-Bu Xphos (2.46 mg, 5.79 umol, 0.02 eq) and t-Bu Xphos Pd G3 (2.30 mg, 2.90 umol) to a mixture of compound 8-A (100 mg, 0.29 mmol) in dioxane/water (4 mL, 1/1), degas and fill with nitrogen. Heat it to 80 ° C for 2 hours. LCMS shows that a small amount of raw materials remain, but the target product has been generated. The reaction solution is cooled to room temperature and extracted with EA (5 mL*3). After conventional post-treatment operation 2, a crude product is obtained, which is purified by silica gel thin layer chromatography (EA: PE, EA from 0 to 30%) to obtain a colorless oil compound 11-A (60 mg, yield 35.5%). LCMS: (ESI)m/z=292.2(M+1) + .

步骤二：将化合物11-A(50mg,0.17mmol)在DCM(1mL)和TFA(0.5mL)的溶液在25℃搅拌反应1小时。用饱和NaHCO3溶液(1mL)淬灭反应，混合物用EA(3mL×3)萃取，水相用1M HCl调pH到3-4，用EA(5mL×3)再次萃取。经过常规的后处理操作二后得残余物，残留物经DCM(1mL)洗涤得白色固体化合物11(35mg,收率50％)。LCMS:(ESI)m/z＝234.1(M+1)+.1H NMR(400MHz,DMSO-d6)Shift 7.44(s,1H),6.54(s,1H),4.74(dd,J＝4.39,7.40Hz,1H),3.80(s,3H),2.16-2.25(m,2H),1.77-1.90(m,1H),1.62-1.75(m,1H).Step 2: A solution of compound 11-A (50 mg, 0.17 mmol) in DCM (1 mL) and TFA (0.5 mL) was stirred at 25 ° C for 1 hour. The reaction was quenched with saturated NaHCO 3 solution (1 mL), the mixture was extracted with EA (3 mL × 3), the aqueous phase was adjusted to pH 3-4 with 1M HCl, and extracted again with EA (5 mL × 3). After conventional post-treatment operation 2, a residue was obtained, and the residue was washed with DCM (1 mL) to obtain a white solid compound 11 (35 mg, yield 50%). LCMS: (ESI)m/z＝234.1(M+1) + . 1 H NMR(400MHz, DMSO-d6)Shift 7.44(s,1H),6.54(s,1H),4.74(dd,J＝4.39,7.40Hz,1H),3.80(s,3H),2.16-2.25(m,2H),1.77-1.90(m,1H),1.62-1.75(m,1H).

实施例10化合物12的合成
Example 10 Synthesis of Compound 12

步骤一：向化合物12-A(5.76g，21.1mmol)在乙腈(60mL)的混合物中加入NaHCO3(3.91g,46.50mmol)、溴化苄(3.98g,23.25mmol)。将其加热至82℃反应16小时。反应液降至室温，加入水(80mL)，用EA(100mL)萃取。经过常规的后处理操作二后得到粗产物，粗产物通过硅胶薄层层析色谱分离(EA:PE，EA从0到29％)纯化，得到黄色固体化合物12-B(4.6g,收率60.73％)。Step 1: Add NaHCO 3 (3.91 g, 46.50 mmol) and benzyl bromide (3.98 g, 23.25 mmol) to a mixture of compound 12-A (5.76 g, 21.1 mmol) in acetonitrile (60 mL). Heat to 82°C and react for 16 hours. The reaction solution is cooled to room temperature, water (80 mL) is added, and extracted with EA (100 mL). After conventional post-treatment operation 2, a crude product is obtained, which is purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 29%) to obtain a yellow solid compound 12-B (4.6 g, yield 60.73%).

步骤二：向化合物12-B(650mg，1.81mmol)在乙腈(26mL)的混合物中加入12-C(811mg,2.72mmol)、氟化铯(826mg,5.44mmol)。在20℃反应16小时。加入饱和食盐水(20mL)，用EA(20mL)萃取。经过常规的后处理操作二后得到粗产物，粗产物通过硅胶薄层层析色谱分离(EA:PE，EA从0到20％)纯化，得到黄色油状物12-D(238mg,收率30.22％)。1H NMR(400MHz,DMSO-d6)δppm 1.10-1.14(m,3H)2.44-2.47(m,2H)2.95-3.02(m,2H)3.77-3.82(m,3H)3.97-4.01(m,2H)5.02-5.09(m,2H)6.07-6.12(m,1H)6.54-6.59(m,1H)7.11-7.38(m,10H)Step 2: Add 12-C (811 mg, 2.72 mmol) and cesium fluoride (826 mg, 5.44 mmol) to a mixture of compound 12-B (650 mg, 1.81 mmol) in acetonitrile (26 mL). React at 20 ° C for 16 hours. Add saturated brine (20 mL) and extract with EA (20 mL). After conventional post-treatment operation 2, a crude product is obtained, which is purified by silica gel thin layer chromatography (EA: PE, EA from 0 to 20%) to obtain a yellow oil 12-D (238 mg, yield 30.22%). 1 H NMR (400MHz, DMSO-d 6 ) δppm 1.10-1.14(m,3H)2.44-2.47(m,2H)2.95-3.02(m,2H)3.77-3.82(m,3H)3.97-4.0 1(m,2H)5.02-5.09(m,2H)6.07-6.12(m,1H)6.54-6.59(m,1H)7.11-7.38(m,10H)

步骤三：参照催化氢化代表性操作的方法，用化合物12-D(235mg,541μmol)反应得黄色胶状产品12-E(120mg,349μmol)。纯化方法：硅胶柱色谱纯化(EA:PE，EA从0到15％)1H NMR(CDCl3,400MHz)δ7.95(d,J＝8.53Hz,1H),7.76(s,1H),7.29-7.57(m,9H),6.96(d,J＝8.53Hz,1H),6.23(br t,J＝5.52Hz,1H),4.75(d,J＝5.52Hz,2H),4.17-4.30(m,2H),3.89(s,3H),3.68(s,3H),2.76(t,J＝7.53Hz,2H),2.41(t,J＝7.53Hz,2H),2.01(t,J＝7.40Hz,2H),1.77-1.88(m,4H),1.63-1.77(m,3H),1.32-1.44(m,1H),1.15-1.29(m,3H),0.94-1.09(m,2H).Step 3: Referring to the representative operation method of catalytic hydrogenation, compound 12-D (235 mg, 541 μmol) was reacted to obtain yellow gum product 12-E (120 mg, 349 μmol). Purification method: silica gel column chromatography (EA:PE, EA from 0 to 15%) 1 H NMR (CDCl 3 , 400 MHz) δ7.95 (d, J＝8.53 Hz, 1H), 7.76 (s, 1H), 7.29-7.57 (m, 9H), 6.96 (d, J＝8.53 Hz, 1H), 6.23 (br t,J＝5.52Hz,1H),4.75(d,J＝5.52Hz,2H),4.17-4.30(m,2H),3.89(s,3H),3.68(s,3H),2.76(t,J＝7.53Hz,2H),2.41(t,J＝7.53 Hz,2H),2.01(t,J=7.40Hz,2H),1.77-1.88(m,4H),1.63-1.77(m,3H),1.32-1.44(m,1H),1.15-1.29(m,3H),0.94-1.09(m,2H).

步骤四(酯水解代表性操作)：向化合物12-E(120mg，0.35mmol)在THF(1mL)和MeOH(1mL)的混合物中加入氢氧化锂一水合物(36.7mg,0.87mmol，约2.5当量)。在65℃反应16小时(LCMS显示反应完全)。反应液降至室温，用2M HCl调pH至1-2，用EA(4mL*3)萃取。经过常规的后处理操作后得到粗产物，粗产物通过硅胶薄层层析色谱分离(EA:PE，EA从0到24％-73％)纯化，得到黄色油状物12-F(65mg,收率58.82％)。1H NMR(400MHz,DMSO-d6)δppm 2.46-2.48(m,2H)2.95-3.03(m,2H)3.53-3.53(m,1H)3.71-3.78(m,3H)5.78-5.87(m,1H)6.20-6.26(m,1H)6.97-7.03(m,2H)7.12-7.19(m,1H)7.34-7.44(m,2H)9.95-10.01(m,1H)Step 4 (representative operation of ester hydrolysis): lithium hydroxide monohydrate (36.7 mg, 0.87 mmol, about 2.5 equivalents) was added to a mixture of compound 12-E (120 mg, 0.35 mmol) in THF (1 mL) and MeOH (1 mL). The reaction was carried out at 65 ° C for 16 hours (LCMS showed that the reaction was complete). The reaction solution was cooled to room temperature, the pH was adjusted to 1-2 with 2M HCl, and extracted with EA (4 mL * 3). After conventional post-treatment operations, the crude product was obtained, and the crude product was purified by silica gel thin layer chromatography (EA: PE, EA from 0 to 24%-73%) to obtain a yellow oil 12-F (65 mg, yield 58.82%). 1 H NMR (400MHz, DMSO-d 6 ) δppm 2.46-2.48(m,2H)2.95-3.03(m,2H)3.53-3.53(m,1H)3.71-3.78(m,3H)5.78-5.87(m,1H) 6.20-6.26(m,1H)6.97-7.03(m,2H)7.12-7.19(m,1H)7.34-7.44(m,2H)9.95-10.01(m,1H)

步骤五：参照构建五元内酯环代表性操作，以化合物12-F(65mg,205μmol)反应得到白色固体化合物12(10mg,收率16.2％)。1H NMR(400MHz,DMSO-d6)δppm1.54-1.60(m,2H)2.06-2.11(m,2H)2.41-2.46(m,2H)3.65-3.72(m,6H)5.98-6.07(m,2H)9.21-9.30(m,1H)11.78-11.91(m,1H).LCMS:(ESI)m/z＝301.0(M+1)+.Step 5: Referring to the representative operation of constructing a five-membered lactone ring, compound 12-F (65 mg, 205 μmol) was reacted to obtain white solid compound 12 (10 mg, yield 16.2%). 1 H NMR (400 MHz, DMSO-d 6 )δppm1.54-1.60 (m, 2H)2.06-2.11 (m, 2H)2.41-2.46 (m, 2H)3.65-3.72 (m, 6H)5.98-6.07 (m, 2H)9.21-9.30 (m, 1H)11.78-11.91 (m, 1H).LCMS: (ESI)m/z＝301.0 (M+1) + .

实施例11化合物13的合成
Example 11 Synthesis of Compound 13

步骤一：在0℃和氮气保护条件下，向甲基三苯基溴化膦(Ph3PMeBr,10.65g,29.82mmol)在THF(80mL)的混合物中滴加叔丁醇钾(1M,25.93mL)的THF溶液，并保持0℃搅拌1小时。在0℃，将化合物13-A(4g,12.97mmol)在THF(60mL)的溶液加入上述反应混合物中。升至室温(20℃)并反应16小时。在0～10℃，用饱和NH4Cl溶液(5mL)淬灭反应，加入水(8mL)，用MTBE(4mL*3)萃取。经过常规的后处理操作二后得到粗产物，粗产物通过硅胶薄层层析色谱分离(EA:PE，EA从0到4％)纯化，得到黄色固体化合物13-B(2.03g,收率51％)。1H NMR(400MHz,DMSO-d6)δppm1.02-1.12(m,18H)1.21-1.30(m,3H)3.72-3.77(m,3H)5.07-5.14(m,1H)5.59-5.66(m,1H)6.39-6.48(m,2H)6.77-6.90(m,1H)7.34-7.39(m,1H).Step 1: At 0°C and nitrogen protection, add potassium tert-butoxide (1M, 25.93mL) in THF solution to a mixture of methyltriphenylphosphine bromide (Ph 3 PMeBr, 10.65g, 29.82mmol) in THF (80mL) dropwise, and stir at 0°C for 1 hour. At 0°C, add a solution of compound 13-A (4g, 12.97mmol) in THF (60mL) to the above reaction mixture. Warm to room temperature (20°C) and react for 16 hours. At 0-10°C, quench the reaction with saturated NH 4 Cl solution (5mL), add water (8mL), and extract with MTBE (4mL*3). After conventional post-treatment operation 2, a crude product is obtained, which is purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 4%) to obtain a yellow solid compound 13-B (2.03g, yield 51%). 1 H NMR (400MHz, DMSO-d 6 )δppm1.02-1.12(m,18H)1.21-1.30(m,3H)3.72-3.77(m,3H)5.07-5.14(m, 1H)5.59-5.66(m,1H)6.39-6.48(m,2H)6.77-6.90(m,1H)7.34-7.39(m,1H).

步骤二：向13-B(1g,3.26mmol,1.2eq)的DMF(10mL)混合物中加入13-C(584mg,2.72mmol)、H2O(97.9mg,5.44mmol)和九羰基合二铁(cas:15321-51-4,49.4mg,135.94umol)。在80℃反应16小时。降至室温，加入水(4mL)，用EA(12mL)萃取。经过常规的后处理操作二后得到粗产物，粗产物通过硅胶薄层层析色谱分离(EA:PE，EA从0到7％至11.5％)纯化得到白色固体化合物13-D(157mg,收率13.11％)，其结构可能为顺式结构或者反式结构，未进一步鉴定。1H NMR(400MHz,CHLOROFORM-d)δppm 1.11-1.14(m,18H)1.25-1.32(m,3H)2.66-2.85(m,2H)3.79-3.83(m,3H)3.91-3.98(m,1H)5.78-5.87(m,1H)6.44-6.54(m,2H)7.12-7.22(m,1H)7.30-7.41(m,5H).Step 2: Add 13-C (584 mg, 2.72 mmol), H 2 O (97.9 mg, 5.44 mmol) and nonacarbonyl diiron (cas: 15321-51-4, 49.4 mg, 135.94 umol) to a mixture of 13-B (1 g, 3.26 mmol, 1.2 eq) in DMF (10 mL). React at 80°C for 16 hours. Cool to room temperature, add water (4 mL), and extract with EA (12 mL). After conventional post-treatment operation 2, a crude product is obtained. The crude product is purified by silica gel thin layer chromatography (EA: PE, EA from 0 to 7% to 11.5%) to obtain a white solid compound 13-D (157 mg, yield 13.11%), which may be a cis structure or a trans structure, and is not further identified. 1H NMR(400MHz,CHLOROFORM-d)δppm 1.11-1.14(m,18H)1.25-1.32(m,3H)2.66-2.85(m,2H)3.79-3.83(m,3H)3.91-3. 98(m,1H)5.78-5.87(m,1H)6.44-6.54(m,2H)7.12-7.22(m,1H)7.30-7.41(m,5H).

步骤三：向13-D(50mg,113.47umol)的THF(1mL)混合物中加入TEA(HF)3(14.6mg,90.78umol)。在20℃反应2小时。反应毕加入饱和NaHCO3水溶液调pH至7-8，用EA(2mL×3)萃取。经过常规的后处理操作二后得到粗产物，粗产物通过硅胶薄层层析色谱分离(EA:PE，EA从0到62％)纯化得到黄色固体化合物13(9mg,收率27.9％).1H NMR(400MHz,CHLOROFORM-d)δppm 2.40(m,0.6H),2.66-2.75(m,0.4H),2.76-2.87(m,0.4H),3.09(m,0.6H),3.95(m,0.4H),4.04(m,0.6H),5.00(br s,1H)5.73(dd,J＝10.5,5.8Hz,0.6H),5.85(dd,J＝7.8,4.8Hz,0.4H),6.38-6.57(m,2H),7.09-7.25(m,1H),7.31-7.60(m,5H)Step 3: Add TEA(HF) 3 (14.6 mg, 90.78 umol) to a mixture of 13-D (50 mg, 113.47 umol) in THF (1 mL), and react at 20°C for 2 hours. After the reaction, add saturated NaHCO 3 aqueous solution to adjust the pH to 7-8, and extract with EA (2 mL×3). After conventional post-treatment operation 2, a crude product was obtained, which was purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 62%) to obtain yellow solid compound 13 (9 mg, yield 27.9%). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.40 (m, 0.6H), 2.66-2.75 (m, 0.4H), 2.76-2.87 (m, 0.4H), 3.09 (m, 0.6H), 3.95 (m, 0.4H), 4.04 (m, 0.6H), 5.00 (br s,1H)5.73(dd,J＝10.5,5.8Hz,0.6H),5.85(dd,J＝7.8,4.8Hz,0.4H),6.38-6.57(m,2H),7.09-7.25(m,1H),7.31-7.60(m,5H)

实施例12化合物16的合成
Example 12 Synthesis of Compound 16

步骤一：向16-A(300mg,1.3mmol)的DMF(6mL)混合物中加入3-溴丙烯(235mg,1.95mmol)和K2CO3(358mg,2.60mmol)。在25℃反应2小时。加入水(6mL)，用EA(8mL x 3)萃取。经过常规的后处理操作后得到粗产物，粗产物通过硅胶薄层层析色谱分离(EA:PE，EA从0到30％)纯化得到黄色油状物16-B(220mg,收率62.5％)。LCMS:(ESI)m/z＝273.0(M+1)+.Step 1: Add 3-bromopropylene (235 mg, 1.95 mmol) and K 2 CO 3 (358 mg, 2.60 mmol) to a mixture of 16-A (300 mg, 1.3 mmol) in DMF (6 mL). React at 25°C for 2 hours. Add water (6 mL) and extract with EA (8 mL x 3). After conventional post-treatment, a crude product is obtained. The crude product is purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 30%) to obtain a yellow oil 16-B (220 mg, yield 62.5%). LCMS: (ESI) m/z=273.0 (M+1) + .

步骤二：向16-B(170mg,0.63mmol)的DCM(4mL)溶液中加入16-C(655mg,3.76mmol)和ZnI2(360mg,1.13mmol)。在25℃反应16小时。加入水(5mL)，用DCM(3mL x 3)萃取。经过常规的后处理操作后得到棕色油状物16-D(280mg)，直接用于下一步反应。Step 2: Add 16-C (655 mg, 3.76 mmol) and ZnI 2 (360 mg, 1.13 mmol) to a solution of 16-B (170 mg, 0.63 mmol) in DCM (4 mL). React at 25 °C for 16 hours. Add water (5 mL) and extract with DCM (3 mL x 3). After conventional post-treatment, a brown oil 16-D (280 mg) was obtained, which was used directly in the next step.

步骤三：向化合物16-D(280mg)的DCM(4mL)和TFA(0.4mL)溶液中加入水(33.9mg,1.89mmol)，在25℃反应16小时。反应毕在5℃～10℃条件下，加入饱和NaHCO3水溶液调pH至7-8，用DCM(2mL x 3)萃取。经过常规的后处理操作后得粗产物。粗产物通过硅胶薄层层析色谱分离(EA:PE，EA从0到50％)纯化得到黄色油状物16-E(17mg,纯度74％).LCMS:(ESI)m/z＝327.0[M+H]+.Step 3: Add water (33.9 mg, 1.89 mmol) to a solution of compound 16-D (280 mg) in DCM (4 mL) and TFA (0.4 mL), and react at 25°C for 16 hours. After the reaction, add saturated NaHCO 3 aqueous solution to adjust the pH to 7-8 at 5°C to 10°C, and extract with DCM (2 mL x 3). After conventional post-treatment operations, the crude product was obtained. The crude product was purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 50%) to obtain a yellow oil 16-E (17 mg, purity 74%). LCMS: (ESI) m/z = 327.0 [M + H] + .

步骤四：氮气保护条件下，向化合物16-E(17mg)的THF(0.5mL)溶液中加入Pd(PPh3)4(6mg,5.2μmol)和PPh3(14.99mg,57.16μmol)，25℃反应16小时。反应毕减压浓缩，所得剩余物通过prep-HPLC(FA方法；B％:23％-53％,8min)纯化得白色固体化合物16(1mg,3.36umol,三步收率约5.3％).(ESI)m/z＝286.9[M+H]+).1H NMR(400MHz,CHLOROFORM-d)δppm 6.70(d,J＝2.32Hz,1H)6.43(d,J＝2.32Hz,1H)6.12(dd,J＝8.86,6.91Hz,1H)5.90(br s,1H)3.75(s,3H)2.65-2.82(m,2H)2.51-2.64(m,1H)2.35-2.46(m,1H).Step 4: Under nitrogen protection, Pd(PPh 3 ) 4 (6 mg, 5.2 μmol) and PPh 3 (14.99 mg, 57.16 μmol) were added to a solution of compound 16-E (17 mg) in THF (0.5 mL) and reacted at 25° C. for 16 hours. After the reaction, the product was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA method; B%: 23%-53%, 8 min) to give a white solid compound 16 (1 mg, 3.36 umol, three-step yield of about 5.3%). (ESI) m/z = 286.9 [M+H] + ). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.70 (d, J = 2.32 Hz, 1H) 6.43 (d, J = 2.32 Hz, 1H) 6.12 (dd, J = 8.86, 6.91 Hz, 1H) 5.90 (br s, 1H) 3.75 (s, 3H) 2.65-2.82 (m, 2H) 2.51-2.64 (m, 1H) 2.35-2.46 (m, 1H).

参照实施例12中步骤二到步骤四方法(构建五元内酯环代表性操作-A)，用如下表格中的起始原料进行三步反应得到相应的终产化合物。
Referring to the method of steps 2 to 4 in Example 12 (representative operation A for constructing a five-membered lactone ring), three steps of reaction were carried out using the starting materials in the following table to obtain the corresponding final compounds.

上述表格中涉及到的起始原料87-A的合成方法为：
The synthesis method of the starting material 87-A involved in the above table is:

向化合物73-A(300mg,1.03mmol)的DMF(5mL)溶液中加入化合物87-B(395mg,2.06mmol),氟化钾(59.8mg,1.03mmol),CuI(196mg,1.03mmol)。在避光的条件下将其加热至80℃反应16小时。降至室温，过滤，用EA洗涤。滤液经过常规的后处理操作二后得到粗产物，通过硅胶柱色谱(EA:PE，EA从0到10％)纯化得到灰色固体化合物87-A(280mg,收率97％)。LCMS：(ESI)m/z＝280.9(M+1)+ Compound 87-B (395 mg, 2.06 mmol), potassium fluoride (59.8 mg, 1.03 mmol), and CuI (196 mg, 1.03 mmol) were added to a DMF (5 mL) solution of compound 73-A (300 mg, 1.03 mmol). The mixture was heated to 80 °C for 16 hours under light-shielding conditions. The mixture was cooled to room temperature, filtered, and washed with EA. The filtrate was subjected to conventional post-treatment operation 2 to obtain a crude product, which was purified by silica gel column chromatography (EA:PE, EA from 0 to 10%) to obtain a gray solid compound 87-A (280 mg, yield 97%). LCMS: (ESI) m/z = 280.9 (M+1) +

实施例12-a化合物65的合成
Example 12-a Synthesis of Compound 65

步骤一：将47-B(3.6g,18.5mmol)、N-(2-甲氧基乙基)甲基胺(3.30g,37.1mmol)和K2CO3(5.12g,37.1mmol,2eq)的dioxane(80mL)混合物在120℃反应40小时。LC-MS显示～32％的原料剩余并且～65％目标产物生成。用EA(100mL)稀释反应，过滤，减压除去溶剂。粗产物通过硅胶薄层层析色谱分离(EA:PE，EA从0到15％)纯化得到黄色油状物65-A(3.7g,收率75.8％)。LCMS:(ESI)m/z＝264.3(M+1)+.Step 1: A mixture of 47-B (3.6 g, 18.5 mmol), N-(2-methoxyethyl)methylamine (3.30 g, 37.1 mmol) and K 2 CO 3 (5.12 g, 37.1 mmol, 2 eq) in dioxane (80 mL) was reacted at 120°C for 40 hours. LC-MS showed ~32% of the starting material remained and ~65% of the target product was produced. The reaction was diluted with EA (100 mL), filtered, and the solvent was removed under reduced pressure. The crude product was purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 15%) to give 65-A (3.7 g, yield 75.8%) as a yellow oil. LCMS: (ESI) m/z = 264.3 (M+1) + .

步骤二和步骤三：参照实施例12中步骤二和步骤三的方法，以65-A进行两步反应得化合物橙色油状物65-B，两步收率约20％。LC-MS:(ESI)m/z.[M+H]+320.3Step 2 and Step 3: Referring to the method of Step 2 and Step 3 in Example 12, 65-A was subjected to two-step reaction to obtain compound 65-B as an orange oil, with a two-step yield of about 20%. LC-MS: (ESI) m/z. [M+H] + 320.3

步骤四：参照实施例2步骤3的方法，以65-A进行反应得黄色油状物65，收率63％。LC-MS:(ESI)m/z.[M+H]+280.3；1H NMR(400MHz,DMSO-d6)δ(ppm)9.39(s,1H),7.05(s,1H),6.66(s,1H),5.87(dd,J＝6.8,9.0Hz,1H),3.37(t,J＝5.9Hz,2H),3.22(s,3H),2.84-2.98(m,2H),2.63-2.75(m,1H),2.53-2.62(m,4H),2.44(m,1H),2.08-2.16(m,1H),2.07(s,3H).Step 4: Referring to the method of step 3 of Example 2, 65-A was used to react to obtain yellow oil 65, with a yield of 63%. LC-MS: (ESI) m/z. [M+H] + 280.3; 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm) 9.39 (s, 1H), 7.05 (s, 1H), 6.66 (s, 1H), 5.87 (dd, J = 6.8, 9.0 Hz, 1H), 3.37 (t, J = 5.9 Hz, 2H), 3.22 (s, 3H), 2.84-2.98 (m, 2H), 2.63-2.75 (m, 1H), 2.53-2.62 (m, 4H), 2.44 (m, 1H), 2.08-2.16 (m, 1H), 2.07 (s, 3H).

实施例12-b化合物66的合成
Example 12-b Synthesis of Compound 66

步骤一：在-78℃，向化合物66-A(5g,29.4mmol)的THF(50mL)溶液中滴加环丙基溴化镁溶液(0.5M,205mL)，自然升至室温25℃，反应16小时。反应毕加入饱和NH4Cl水溶液(200mL)淬灭，用EtOAc萃取(200mL*3)。经过常规的后处理操作二后得粗产品黄色固体66-B(7.6g)。LC-MS:(ESI)m/z.[M-OH]+205.1.Step 1: At -78°C, add cyclopropylmagnesium bromide solution (0.5M, 205mL) to a solution of compound 66-A (5g, 29.4mmol) in THF (50mL), naturally warm to room temperature 25°C, and react for 16 hours. After the reaction, add saturated NH 4 Cl aqueous solution (200mL) to quench, and extract with EtOAc (200mL*3). After conventional post-treatment operation 2, the crude product 66-B (7.6g) was obtained as a yellow solid. LC-MS: (ESI) m/z. [M-OH] + 205.1.

步骤二：在-30℃，向66-B(5g)的DCM(100mL)溶液中滴加Et3SiH(5.23g,45mmol)以及TFA(10.2g,90.0mmol)，维持-30℃到-20℃，反应2小时。反应毕加入水(100mL)，用饱和碳酸钠溶液调pH至8-9，用DCM萃取(50mL*3)。经过常规的后处理操作二后得粗产品，通过硅胶柱色谱(EA:PE，EA从0到3％)纯化得无色油状物66-C(5.14g，两步收率约83％)。1H NMR(400MHz,CDCl3)δ(ppm)7.23(dd,J＝7.3,8.4Hz,1H),6.64(dt,J＝2.6,8.4Hz,1H),6.49(dd,J＝2.5,10.6Hz,1H),1.95(t,J＝8.6Hz,1H),1.03-1.12(m,2H),0.95-1.03(m,9H),0.73-0.82(m,6H),0.48-0.58(m,2H),0.22-0.34(m,4H),0.04-0.12(m,2H).Step 2: At -30°C, add Et 3 SiH (5.23 g, 45 mmol) and TFA (10.2 g, 90.0 mmol) to a solution of 66-B (5 g) in DCM (100 mL), maintain -30°C to -20°C, and react for 2 hours. After the reaction, add water (100 mL), adjust the pH to 8-9 with saturated sodium carbonate solution, and extract with DCM (50 mL*3). After conventional post-treatment operation 2, the crude product was obtained, which was purified by silica gel column chromatography (EA:PE, EA from 0 to 3%) to obtain a colorless oil 66-C (5.14 g, two-step yield of about 83%). 1 H NMR (400MHz, CDCl 3 )δ(ppm)7.23(dd,J＝7.3,8.4Hz,1H),6.64(dt,J＝2.6,8.4Hz,1H),6.49(dd,J＝2.5,10.6Hz,1H),1.95(t,J＝8.6Hz,1H ),1.03-1.12(m,2H),0.95-1.03(m,9H),0.73-0.82(m,6H),0.48-0.58(m,2H),0.22-0.34(m,4H),0.04-0.12(m,2H).

步骤三：向化合物66-C(5.14g,16mmol)的ACN(60mL)溶液中加入三乙胺三氢氟酸盐(5.17g,32.1mmol)，25℃反应16小时。反应毕减压浓缩除去溶剂，用EtOAc(100mL)溶解，经过常规的后处理操作二后得粗产品，通过硅胶柱色谱(EA:PE，EA从0到3.5％)纯化得无色油状物66-D(3.2g，收率88％)。1H NMR(400MHz,CDCl3)δ(ppm)7.19(dd,J＝6.7,8.50Hz,1H),6.63(dt,J＝2.5,8.4Hz,1H),6.53(dd,J＝2.5,10.0Hz,1H),5.22(s,1H),1.97(t,J＝8.0Hz,1H),1.12(tq,J＝5.1,8.0Hz,2H),0.53-0.65(m,2H),0.36-0.46(m,2H),0.31(qd,J＝4.8,9.4Hz,2H),0.06-0.19(m,2H).Step 3: Add triethylamine trihydrofluoride (5.17 g, 32.1 mmol) to a solution of compound 66-C (5.14 g, 16 mmol) in ACN (60 mL), and react at 25°C for 16 hours. After the reaction, concentrate under reduced pressure to remove the solvent, dissolve in EtOAc (100 mL), and obtain a crude product after conventional post-treatment operation 2. Purify by silica gel column chromatography (EA:PE, EA from 0 to 3.5%) to obtain a colorless oil 66-D (3.2 g, yield 88%). 1 H NMR (400MHz, CDCl 3 )δ(ppm)7.19(dd,J＝6.7,8.50Hz,1H),6.63(dt,J＝2.5,8.4Hz,1H),6.53(dd,J＝2.5,10.0Hz,1H),5.22(s,1H),1.97(t,J＝8. 0Hz,1H),1.12(tq,J＝5.1,8.0Hz,2H),0.53-0.65(m,2H),0.36-0.46(m,2H),0.31(qd,J＝4.8,9.4Hz,2H),0.06-0.19(m,2H).

步骤四：向化合物66-D(1g,4.85mmol)的DCM(30mL)溶液中加入NBS(949mg,5.33mmol)，25℃反应16小时。反应毕减压浓缩除去溶剂，通过硅胶柱色谱(EA:PE，EA从0到3％)纯化得无色油状物66-E(610mg，收率44％)。1H NMR(400MHz,CDCl3)δ(ppm)7.38(d,J＝7.8Hz,1H),6.61(d,J＝9.4Hz,1H),5.24(s,1H),1.92(t,J＝8.1Hz,1H),1.09(tq,J＝5.1,8.1Hz,2H),0.54-0.68(m,2H),0.38-0.50(m,2H),0.32(qd,J＝4.8,9.57Hz,2H),0.08-0.19(m,2H).Step 4: Add NBS (949 mg, 5.33 mmol) to a DCM (30 mL) solution of compound 66-D (1 g, 4.85 mmol) and react at 25°C for 16 hours. After the reaction, concentrate under reduced pressure to remove the solvent, and purify by silica gel column chromatography (EA:PE, EA from 0 to 3%) to obtain a colorless oil 66-E (610 mg, yield 44%). 1 H NMR (400MHz, CDCl 3 )δ(ppm)7.38(d,J＝7.8Hz,1H),6.61(d,J＝9.4Hz,1H),5.24(s,1H),1.92(t,J＝8.1Hz,1H),1.09(tq,J＝5 .1,8.1Hz,2H),0.54-0.68(m,2H),0.38-0.50(m,2H),0.32(qd,J＝4.8,9.57Hz,2H),0.08-0.19(m,2H).

步骤五和步骤六：参照实施例21中步骤二和步骤三的方法，以66-E为原料进行两步反应得黄色油状物66-G(两步收率约46.74％)。1H NMR(400MHz,CDCl3)δ(ppm)10.25(s,1H),7.82(d,J＝8.2Hz,1H),6.60(d,J＝12.5Hz,1H),6.04(tdd,J＝5.1,10.5,17.3Hz,1H),5.43(qd,J＝1.5,17.3Hz,1H),5.35(qd,J＝1.3,10.6Hz,1H),4.61(td,J＝1.5,5.1Hz,2H),1.90(t,J＝8.9Hz,1H),1.06-1.23(m,2H),0.53-0.64(m,2H),0.26-0.37(m,4H),0.01-0.11(m,2H).Step 5 and Step 6: Referring to the method of Step 2 and Step 3 in Example 21, 66-E was used as the raw material for two-step reaction to obtain a yellow oil 66-G (two-step yield is about 46.74%). 1 H NMR (400MHz, CDCl 3 )δ(ppm)10.25(s,1H),7.82(d,J＝8.2Hz,1H),6.60(d,J＝12.5Hz,1H),6.0 4(tdd,J＝5.1,10.5,17.3Hz,1H),5.43(qd,J＝1.5,17.3Hz,1H),5.35(qd,J ＝1.3,10.6Hz,1H),4.61(td,J＝1.5,5.1Hz,2H),1.90(t,J＝8.9Hz,1H),1. 06-1.23(m,2H),0.53-0.64(m,2H),0.26-0.37(m,4H),0.01-0.11(m,2H).

步骤七：参照实施例12-a中步骤一的方法，以66-G(210mg)为原料反应得黄色油状物66-H(200mg,收率76.07％)。LC-MS:(ESI)m/z.[M+H]+344.2Step 7: Referring to the method of step 1 in Example 12-a, 66-G (210 mg) was used as a raw material to obtain a yellow oil 66-H (200 mg, yield 76.07%). LC-MS: (ESI) m/z. [M+H] + 344.2

步骤八和步骤九：参照实施例2中步骤2和步骤3的方法，以66-H开始进行两步反应得米白色固体化合物66，两步收率约51％。1H NMR(400MHz,DMSO-d6)δ(ppm)9.15-9.43(m,1H),6.94-7.20(m,1H),6.60-6.80(m,1H),5.63-6.02(m,1H),3.42-3.45(m,2H),3.19-3.29(m,3H),2.89-3.04(m,2H),2.57-2.69(m,3H),2.28-2.36(m,1H),2.11-2.27(m,1H),1.67-1.79(m,1H),1.28(dt,J＝4.7,8.35Hz,1H),1.03-1.15(m,2H),0.74-0.99(m,1H),0.41-0.54(m,2H),0.17-0.30(m,4H),-0.09-0.03(m,2H).LC-MS:(ESI)m/z.[M+H]+372.4Step 8 and Step 9: Referring to the method of Step 2 and Step 3 in Example 2, two steps of reaction were carried out starting from 66-H to obtain an off-white solid compound 66, with a two-step yield of about 51%. 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm) 9.15-9.43 (m, 1H), 6.94-7.20 (m, 1H), 6.60-6.80 (m, 1H), 5.63-6.02 (m, 1H), 3.42-3.45 (m, 2H), 3.19-3.29 (m, 3H), 2.89-3.04 (m, 2H), 2.57-2.69 (m, 3H), 2.28-2.36 (m, 1H), 2.1 1-2.27(m,1H),1.67-1.79(m,1H),1.28(dt,J＝4.7,8.35Hz,1H),1.03-1.15(m,2H),0.74-0. 99(m,1H),0.41-0.54(m,2H),0.17-0.30(m,4H),-0.09-0.03(m,2H).LC-MS:(ESI)m/z.[M+H] +372.4

实施例13化合物17的合成
Example 13 Synthesis of Compound 17

步骤一参照实施例2中步骤1的方法，步骤二参照实施例2中步骤2的方法，步骤三参照实施例12中步骤四的方法，用如下表格中的起始原料进行三步反应得到化合物17。

Step 1 refers to the method of step 1 in Example 2, step 2 refers to the method of step 2 in Example 2, and step 3 refers to the method of step 4 in Example 12. Three steps of reaction are carried out using the starting materials in the following table to obtain compound 17.

参照实施例13中步骤二和步骤三的方法，用如下表格中的起始原料进行两步反应得到终产化合物。
Referring to the method of step 2 and step 3 in Example 13, a two-step reaction was carried out using the starting materials in the following table to obtain the final compound.

实施例14化合物18的合成
Example 14 Synthesis of Compound 18

步骤一：参照实施例8-b中步骤四的方法，用15-A(2.0g,9.30mmol)与18-A(2.90g,13.95mmol)反应得米白色固体化合物18-B(1.96g,收率84.17％).LCMS:(ESI)m/z＝217.0(M+1)+。Step 1: Referring to the method of step 4 in Example 8-b, 15-A (2.0 g, 9.30 mmol) was reacted with 18-A (2.90 g, 13.95 mmol) to obtain an off-white solid compound 18-B (1.96 g, yield 84.17%). LCMS: (ESI) m/z=217.0 (M+1) + .

步骤二到步骤四：参照实施例13中的方法，用如下表格中的起始原料进行三步反应得到终产化合物。

Step 2 to Step 4: Referring to the method in Example 13, three steps of reaction were carried out using the starting materials in the following table to obtain the final compound.

上述表格中涉及到的起始原料82-A的合成方法为：
The synthesis method of the starting material 82-A involved in the above table is:

参照实施例8-b中步骤四的方法，以化合物67-A(750mg,2.99mmol)与18-A(932mg，1.5eq)进行反应得到黄色固体化合物82-A(750mg，收率99％).LCMS:(ESI)m/z＝253.0(M+1)+ Referring to the method of step 4 in Example 8-b, compound 67-A (750 mg, 2.99 mmol) was reacted with 18-A (932 mg, 1.5 eq) to obtain yellow solid compound 82-A (750 mg, yield 99%). LCMS: (ESI) m/z = 253.0 (M+1) +

参照起始原料82-A的方法，用如下表格中的起始原料替代18-A与化合物67-A进行反应得到中间体化合物。
Referring to the method of starting material 82-A, the starting materials in the following table are used instead of 18-A to react with compound 67-A to obtain the intermediate compound.

实施例15化合物19的合成
Example 15 Synthesis of Compound 19

步骤一：参照实施例2中步骤1的方法，由19-A(5.1g,33.52mmol)制备得黄色油状物19-B(1.6g,24.83％yield)。1H NMR(400MHz,DMSO-d6)δppm 2.10(s,3H)Step 1: Referring to the method of step 1 in Example 2, 19-A (5.1 g, 33.52 mmol) was used to prepare yellow oil 19-B (1.6 g, 24.83% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.10 (s, 3H)

4.64(d,J＝5.00Hz,2H)5.30(dd,J＝10.63,1.38Hz,1H)5.42(dd,J＝17.26,1.63Hz,1H)6.00-6.11(m,1H)6.50(s,1H)7.45(s,1H)9.96(s,1H)10.89(s,1H)4.64(d,J＝5.00Hz,2H)5.30(dd,J＝10.63,1.38Hz,1H)5.42(dd,J＝17.26,1. 63Hz,1H)6.00-6.11(m,1H)6.50(s,1H)7.45(s,1H)9.96(s,1H)10.89(s,1H)

步骤二：向化合物19-B(400mg,2.08mmol)的乙腈(8mL)溶液中加入K2CO3(575mg,4.16mmol)和碘乙烷(486mg,3.12mmol)，25℃搅拌反应16小时。减压浓缩除去溶剂，所得剩余物通过硅胶柱色谱(EA:PE，EA从0到10％)纯化得白色固体19-C(210mg,45.81％).(ESI)m/z＝245.2(M+Na)+.Step 2: Add K 2 CO 3 (575 mg, 4.16 mmol) and iodoethane (486 mg, 3.12 mmol) to a solution of compound 19-B (400 mg, 2.08 mmol) in acetonitrile (8 mL), and stir at 25°C for 16 hours. Concentrate under reduced pressure to remove the solvent, and purify the residue by silica gel column chromatography (EA:PE, EA from 0 to 10%) to obtain a white solid 19-C (210 mg, 45.81%). (ESI) m/z = 245.2 (M+Na) + .

步骤三和步骤四：参照实施例2中步骤2和步骤3的方法，用19-C(573mg,2.41mmol)进行两步反应得到黄色固体化合物19(45mg,两步收率约15.8％)。1H NMR(400MHz,CHLOROFORM-d)δppm 0.78-0.86(m,1H)0.95-1.07(m,1H)1.28-1.36(m,1H)1.38-1.44(m,3H)2.10-2.20(m,4H)2.21-2.28(m,1H)2.64-2.72(m,1H)3.90-4.13(m,2H)4.75-5.10(m,1H)5.35-5.54(m,1H)5.83(d,J＝4.63Hz,1H)6.33-6.46(m,1H)6.87-7.02(m,1H).LCMS:(ESI)m/z＝249.1(M+1)+ Step 3 and Step 4: Referring to the method of Step 2 and Step 3 in Example 2, 19-C (573 mg, 2.41 mmol) was used for two-step reaction to obtain yellow solid compound 19 (45 mg, two-step yield of about 15.8%). 1H NMR(400MHz,CHLOROFORM-d)δppm 0.78-0.86(m,1H)0.95-1.07(m,1H)1.28-1.36(m,1H)1.38-1.44(m,3H)2.10-2.20(m,4H)2.21-2.28(m,1H)2.64-2.72(m,1H)3.90-4. 13(m,2H)4.75-5.10(m,1H)5.35-5.54(m,1H)5.83(d,J＝4.63Hz,1H)6.33-6.46(m,1H)6.87-7.02(m,1H).LCMS:(ESI)m/z＝249.1(M+1) +

实施例16化合物21的合成
Example 16 Synthesis of Compound 21

参照实施例2的方法，以19-B和溴化苄开始进行三步反应得白色固体化合物21(45mg,三步收率约1.4％)。LCMS:(ESI)m/z＝311.1[M+H]+,1H NMR(400MHz,CHLOROFORM-d)δppm 7.32-7.48(m,5H)6.94-7.09(m,1H)6.46-6.56(m,1H)5.52-5.91(m,1H)5.02-5.16(m,2H)4.71-4.87(m,1H)2.23-2.70(m,1H)2.20(s,3H)2.00-2.17(m,1H)1.30(m,1H)0.97-1.07(m,1H)。Referring to the method of Example 2, three steps of reaction were carried out starting from 19-B and benzyl bromide to obtain white solid compound 21 (45 mg, three-step yield of about 1.4%). LCMS: (ESI) m/z=311.1 [M+H] + , 1 H NMR (400 MHz, CHLOROFORM-d) δppm 7.32-7.48 (m, 5H) 6.94-7.09 (m, 1H) 6.46-6.56 (m, 1H) 5.52-5.91 (m, 1H) 5.02-5.16 (m, 2H) 4.71-4.87 (m, 1H) 2.23-2.70 (m, 1H) 2.20 (s, 3H) 2.00-2.17 (m, 1H) 1.30 (m, 1H) 0.97-1.07 (m, 1H).

参照实施例16中的方法，用如下表格中的起始原料替代溴化苄进行三步反应得到终产化合物。

Referring to the method in Example 16, the starting materials in the following table were used instead of benzyl bromide to carry out three-step reaction to obtain the final compound.

实施例17化合物20的合成
Example 17 Synthesis of Compound 20

步骤一：在冰浴条件下，向叔丁醇钾(1M的THF溶液,7.80mL)的THF(20mL)溶液中加入化合物19-B(1g,5.20mmol)，并保持0℃搅拌6分钟后加入20-A(CAS：66003-76-7，2.91g,6.76mmol,1.3eq)。自然升温至室温(25℃)并反应2小时。将反应液加入到冰水(20mL)中，EtOAc(15mL x 3)萃取。经过常规的后处理操作后得到粗产物，粗产物通过硅胶薄层层析色谱分离(EA:PE，EA从0到3％)纯化，得到黄色油状物20-B(290mg,收率21％)。1H NMR(CDCl3,400MHz)δppm 10.31(s,1H)7.75(s,1H)7.35-7.48(m,2H)7.13-7.21(m,1H)7.00-7.10(m,2H)6.34(s,1H)Step 1: Add compound 19-B (1 g, 5.20 mmol) to a solution of potassium tert-butoxide (1M THF solution, 7.80 mL) in THF (20 mL) under ice bath conditions, and stir at 0°C for 6 minutes before adding 20-A (CAS: 66003-76-7, 2.91 g, 6.76 mmol, 1.3 eq). Naturally warm to room temperature (25°C) and react for 2 hours. Add the reaction solution to ice water (20 mL) and extract with EtOAc (15 mL x 3). After conventional post-treatment operations, the crude product was obtained, and the crude product was purified by silica gel thin layer chromatography (EA: PE, EA from 0 to 3%) to obtain a yellow oil 20-B (290 mg, yield 21%). 1 H NMR (CDCl 3 ,400MHz) δppm 10.31 (s, 1H) 7.75 (s, 1H) 7.35-7.48 (m, 2H) 7.13-7.21 (m, 1H) 7.00-7.10 (m, 2H) 6.34 (s, 1H)

5.91-6.03(m,1H)5.23-5.39(m,2H)4.41-4.53(m,2H)2.25(s,3H)。5.91-6.03(m,1H)5.23-5.39(m,2H)4.41-4.53(m,2H)2.25(s,3H).

步骤二和步骤三：参照实施例2中步骤3和步骤4的方法，用20-B进行两步反应得白色固体化合物20(6mg,两步收率约3.5％)。LCMS:(ESI)m/z＝297.1[M+H]+,1H NMR(CDCl3,400MHz)δppm 8.25-8.31(m,1H)8.09(d,J＝8.56Hz,1H)7.58-7.67(m,1H)7.49-7.57(m,1H)6.88-6.93(m,1H)6.34(s,1H)2.51-2.61(m,1H)2.38-2.47(m,1H)1.63(br s,1H)1.32-1.37(m,1H).Step 2 and step 3: Referring to the method of step 3 and step 4 in Example 2, 20-B was used for two-step reaction to obtain white solid compound 20 (6 mg, two-step yield of about 3.5%). LCMS: (ESI) m/z=297.1[M+H] + , 1 H NMR (CDCl 3 ,400MHz)δppm 8.25-8.31(m,1H)8.09(d,J=8.56Hz,1H)7.58-7.67(m,1H)7.49-7.57(m,1H)6.88-6.93(m,1H)6.34(s,1H)2.51-2.61(m,1H)2.38-2.47(m,1H)1.63(br s,1H)1.32-1.37(m,1H).

实施例18化合物23的合成
Example 18 Synthesis of Compound 23

步骤一：向19-B(500mg,2.60mmol)的MeCN(10mL)溶液中加入化合物23-A(664mg,2.86mmol)以及碳酸铯(1.70g,5.20mmol)。80℃反应16小时。将反应液用水(10mL)稀释，EtOAc(10mL x 3)萃取。经过常规的后处理操作后得到粗产物，粗产物通过硅胶薄层层析色谱分离(EA:PE，EA从0到30％)纯化，得到黄色固体23-B(300mg,收率42％)。1H NMR(CDCl3,400MHz)δppm 10.32(s,1H)7.70(s,1H)Step 1: Add compound 23-A (664 mg, 2.86 mmol) and cesium carbonate (1.70 g, 5.20 mmol) to a solution of 19-B (500 mg, 2.60 mmol) in MeCN (10 mL). React at 80°C for 16 hours. Dilute the reaction solution with water (10 mL) and extract with EtOAc (10 mL x 3). After conventional post-treatment operations, a crude product was obtained, which was purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 30%) to obtain a yellow solid 23-B (300 mg, yield 42%). 1 H NMR (CDCl 3 , 400 MHz) δppm 10.32 (s, 1H) 7.70 (s, 1H)

6.37(s,1H)6.00-6.18(m,1H)5.48(dd,J＝17.17,1.32Hz,1H)5.38(dd,J＝10.56,1.32Hz,1H)4.62-4.68(m,2H)4.47(q,J＝8.00Hz,2H)2.23(s,3H)6.37(s,1H)6.00-6.18(m,1H)5.48(dd,J＝17.17,1.32Hz,1H)5.38(dd,J＝10.56,1.32Hz,1H)4.62-4.68(m,2H)4.47(q,J＝8.00Hz,2H)2.23(s,3H)

步骤二和步骤三：参照实施例2中步骤3和步骤4的方法，用23-B进行两步反应得白色固体化合物23(10mg,两步收率约2.5％)。LCMS:(ESI)m/z＝303.1[M+H]+,1HNMR(DMSO-d6,400MHz)δppm 9.29-10.19(m,1H)6.83-7.09(m,1H)6.48-6.61(m,1H)5.30-5.80(m,1H)4.61-4.82(m,2H)2.15-2.28(m,2H)2.02-2.11(m,3H)1.03-1.36(m,1H)0.66-1.01(m,1H).Step 2 and Step 3: Referring to the method of Step 3 and Step 4 in Example 2, 23-B was used for two-step reaction to obtain white solid compound 23 (10 mg, two-step yield of about 2.5%). LCMS: (ESI) m/z=303.1[M+H] + , 1 HNMR (DMSO-d 6 , 400MHz) δppm 9.29-10.19 (m, 1H) 6.83-7.09 (m, 1H) 6.48-6.61 (m, 1H) 5.30-5.80 (m, 1H) 4.61-4.82 (m, 2H) 2.15-2.28 (m, 2H) 2.02-2.11 (m, 3H) 1.03-1.36 (m, 1H) 0.66-1.01 (m, 1H).

实施例19化合物33的合成
Example 19 Synthesis of Compound 33

步骤一：向化合物19-B(500mg,2.60mmol)和化合物33-A(562mg,3.12mmol)的DMF(10mL)溶液中加入K2CO3(1.08g,7.8mmol，90℃反应15小时。降至室温，将反应液用饱和食盐水(50mL)稀释，EtOAc(50mL x 2)萃取。经过常规的后处理操作后得到粗产物，通过硅胶色柱色谱(EA:PE，EA从0到10％)纯化得黄色固体化合物33-B(580mg,收率80.7％).Step 1: Add K 2 CO 3 (1.08 g, 7.8 mmol) to a DMF (10 mL) solution of compound 19-B (500 mg, 2.60 mmol) and compound 33-A (562 mg, 3.12 mmol), and react at 90°C for 15 hours. Cool to room temperature, dilute the reaction solution with saturated brine (50 mL), and extract with EtOAc (50 mL x 2). After conventional post-treatment operations, the crude product was obtained, which was purified by silica gel column chromatography (EA:PE, EA from 0 to 10%) to obtain a yellow solid compound 33-B (580 mg, yield 80.7%).

步骤二和步骤三：参照实施例2中步骤2和步骤3的方法，进行两步反应得到白色固体33(两步收率约46％)。LCMS:(ESI)m/z＝305.1(M+H)+；1H NMR(400MHz,DMSO-d6)Shift 9.48(s,1H),6.94(s,1H),6.51-6.57(m,1H),5.36(s,1H),4.37-4.51(m,1H),3.86(td,J＝4.22,11.32Hz,2H),3.39-3.55(m,2H),2.13-2.33(m,2H),2.04(s,3H),1.92-2.00(m,2H),1.50-1.71(m,2H),1.30(dt,J＝4.38,8.13Hz,1H),0.90(br s,1H)Step 2 and Step 3: Referring to the method of Step 2 and Step 3 in Example 2, a two-step reaction was performed to obtain a white solid 33 (the two-step yield was about 46%). LCMS: (ESI)m/z＝305.1(M+H) + ； 1 H NMR (400MHz, DMSO-d6)Shift 9.48(s,1H),6.94(s,1H),6.51-6.57(m,1H),5.36(s,1H),4.37-4.51(m,1H),3.86(td,J＝4.22,11.32Hz,2H),3.39-3.5 5(m,2H),2.13-2.33(m,2H),2.04(s,3H),1.92-2.00(m,2H),1.50-1.71(m,2H),1.30(dt,J＝4.38,8.13Hz,1H),0.90(br s,1H)

参照实施例19中的方法，用如下表格中的起始原料替代33-A进行三步反应得到终产化合物。

Referring to the method in Example 19, the starting materials in the following table were used instead of 33-A to carry out three steps of reaction to obtain the final compound.

实施例20化合物38的合成
Example 20 Synthesis of Compound 38

在20℃(室温)，向化合物37(120mg,312.03μmol)的THF(2mL)溶液中加入四丁基氟化铵(122.37mg,468.04μmol)。在20℃搅拌反应3小时。反应毕用水(3mL)淬灭反应，用EA(3mL×3)萃取。经过常规的后处理操作二后通过prep HPLC(FA方法，B:20％-50％8min)纯化得到白色固体化合物2(15mg，收率19.6％)。1HNMR(400MHz,DMSO-d6)δ9.65-10.02(m,1H)6.96-7.10(m,1H)6.89-6.94(m,1H)5.86(d,J＝4.84Hz,0.28H)5.53(s,0.81H)4.38-4.48(m,1H)2.28(dd,J＝8.36,3.74Hz,2H)2.10-2.18(m,3H)1.34(td,J＝8.36,4.62Hz,1H)1.03-1.17(m,1H).LC-MS:(ESI)m/z＝229.0[M+H]+.Tetrabutylammonium fluoride (122.37 mg, 468.04 μmol) was added to a solution of compound 37 (120 mg, 312.03 μmol) in THF (2 mL) at 20°C (room temperature). The reaction was stirred at 20°C for 3 hours. After the reaction, the reaction was quenched with water (3 mL) and extracted with EA (3 mL×3). After conventional post-treatment operation 2, the product was purified by prep HPLC (FA method, B: 20%-50% 8 min) to obtain a white solid compound 2 (15 mg, yield 19.6%). 1 HNMR (400MHz, DMSO-d 6 )δ9.65-10.02(m,1H)6.96-7.10(m,1H)6.89-6.94(m,1H)5.86(d,J＝4.84Hz,0.28H)5.53(s,0.81H)4.38-4.48(m,1H)2.28 (dd,J＝8.36,3.74Hz,2H)2.10-2.18(m,3H)1.34(td,J＝8.36,4.62Hz,1H)1.03-1.17(m,1H).LC-MS: (ESI)m/z＝229.0[M+H] + .

实施例21化合物59的合成
Example 21 Synthesis of Compound 59

步骤一：化合物59-A(6g,29mmol)在叔丁醇(60mL)和浓硫酸(7.5mL)溶液在40℃反应16小时。降至室温，将反应用水淬灭，EtOAc(50mL x 3)萃取。经过常规的后处理操作二后得到粗产物，通过硅胶色柱色谱(EA:PE，EA从0到10％)纯化得白色固体化合物59-B(2.2g,收率28.73％).1H NMR(400MHz,DMSO-d6)δ(ppm)9.70(s,1H),7.16(s,1H),6.48-6.56(m,1H),3.74(s,3H),1.29(s,9H).Step 1: Compound 59-A (6 g, 29 mmol) was reacted in tert-butyl alcohol (60 mL) and concentrated sulfuric acid (7.5 mL) at 40 °C for 16 hours. After cooling to room temperature, the reaction was quenched with water and extracted with EtOAc (50 mL x 3). After conventional post-treatment operation 2, the crude product was obtained, which was purified by silica gel column chromatography (EA:PE, EA from 0 to 10%) to obtain a white solid compound 59-B (2.2 g, yield 28.73%). 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)9.70(s,1H),7.16(s,1H),6.48-6.56(m,1H),3.74(s,3H),1.29(s,9H).

步骤二：参照实施例12中步骤一的方法，以化合物59-B(2.2g)进行反应得白色固体59-C(2.2g,收率86％)。LCMS:(ESI)m/z＝273.0(M+1)+.1H NMR(400MHz,DMSO-d6)δ(ppm)7.25(s,1H),6.74(s,1H),6.04-6.18(m,1H),5.46(dd,J＝1.8,17.39Hz,1H),5.30(dd,J＝1.7,10.7Hz,1H),4.67(d,J＝5.1Hz,2H),3.83(s,3H),1.28-1.34(m,9H).Step 2: Referring to the method of step 1 in Example 12, compound 59-B (2.2 g) was reacted to obtain white solid 59-C (2.2 g, yield 86%). LCMS: (ESI) m/z = 273.0 (M + 1) + . 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm) 7.25 (s, 1H), 6.74 (s, 1H), 6.04-6.18 (m, 1H), 5.46 (dd, J = 1.8, 17.39 Hz, 1H), 5.30 (dd, J = 1.7, 10.7 Hz, 1H), 4.67 (d, J = 5.1 Hz, 2H), 3.83 (s, 3H), 1.28-1.34 (m, 9H).

步骤三：在-60℃,向化合物59-C(2.00g,6.7mmol)的THF(20mL)溶液中加入正丁基锂的THF溶液(2.5M,3.2mL)，搅拌0.5小时后加入DMF(977mg,13mmol)，升至25℃，继续搅拌反应3小时。加入NH4Cl溶液(20mL)淬灭反应，混合物用EA(30mL×3)萃取。经过常规的后处理操作二后通过硅胶柱色谱(THF:PE，THF从0到30％)纯化得到白色固体59-D(0.61g,收率37％).LCMS:(ESI)m/z＝249.2(M+H)+.Step 3: At -60°C, add n-butyllithium THF solution (2.5M, 3.2mL) to a THF (20mL) solution of compound 59-C (2.00g, 6.7mmol), stir for 0.5 hours, add DMF (977mg, 13mmol), warm to 25°C, and continue stirring for 3 hours. Add NH 4 Cl solution (20mL) to quench the reaction, and extract the mixture with EA (30mL×3). After conventional post-treatment operation II, the product was purified by silica gel column chromatography (THF:PE, THF from 0 to 30%) to obtain a white solid 59-D (0.61g, yield 37%). LCMS: (ESI) m/z＝249.2(M+H) + .

步骤四和步骤五：参照实施例2中步骤2和步骤3的方法，以59-D(585mg,2.5mmol)开始进行两步反应得白色固体化合物59，两步收率约4.5％。1H NMR(400MHz,DMSO-d6)δ(ppm)9.48-9.66(m,1H),6.90-7.03(m,1H),6.43-6.56(m,1H),5.33-5.80(m,1H),3.69-3.78(m,3H),2.13-2.26(m,2H),1.07-1.37(m,10H),0.66-0.98(m,1H).LC-MS:(ESI)m/z.[M+H]+277.3Step 4 and Step 5: Referring to the method of Step 2 and Step 3 in Example 2, 59-D (585 mg, 2.5 mmol) was used to carry out two-step reaction to obtain white solid compound 59, with a two-step yield of about 4.5%. 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm) 9.48-9.66 (m, 1H), 6.90-7.03 (m, 1H), 6.43-6.56 (m, 1H), 5.33-5.80 (m, 1H), 3.69-3.78 (m, 3H), 2.13-2.26 (m, 2H), 1.07-1.37 (m, 10H), 0.66-0.98 (m, 1H). LC-MS: (ESI) m/z. [M+H] + 277.3

实施例22化合物67的合成
Example 22 Synthesis of Compound 67

步骤一：向16-A(2.1g,8.36mmol)的DMF(40mL)溶液中加入氯甲基乙醚(1.58g,16.73mmol)和K2CO3(3.47g,25.09mmol)。在25℃反应5小时。加入水(50mL)，用EA(50mL x 3)萃取。经过常规的后处理操作二后得到粗产物，粗产物通过硅胶柱色谱分离(EA:PE，EA从0到3％)纯化得到白色固体67-B(2.3g,收率89％)。LCMS:(ESI)m/z＝308.9(M+1)+.Step 1: Add chloromethyl ether (1.58 g, 16.73 mmol) and K 2 CO 3 (3.47 g, 25.09 mmol) to a DMF (40 mL) solution of 16-A (2.1 g, 8.36 mmol). React at 25°C for 5 hours. Add water (50 mL) and extract with EA (50 mL x 3). After conventional post-treatment operation 2, a crude product was obtained. The crude product was purified by silica gel column chromatography (EA:PE, EA from 0 to 3%) to obtain a white solid 67-B (2.3 g, yield 89%). LCMS: (ESI) m/z=308.9 (M+1) + .

步骤二和步骤三：参照实施例12中步骤二和步骤三的方法(构建五元内酯环代表性操作-B)，以67-B进行两步反应得白色固体化合物67，两步收率约17.2％。LCMS:(ESI)m/z＝306.9[M+H]+，1H NMR(400MHz,CDCl3)8.32(d,J＝7.19Hz,1H),7.98(d,J＝7.43Hz,1H),7.51-7.60(m,2H),7.32(s,1H),6.50(t,J＝8.50Hz,1H),5.43-5.50(m,2H),3.82(q,J＝7.00Hz,2H),2.83-2.94(m,2H),2.61-2.71(m,2H),1.28(t,J＝7.07Hz,3H)。Step 2 and Step 3: Referring to the method of Step 2 and Step 3 in Example 12 (representative operation-B for constructing a five-membered lactone ring), 67-B was reacted in two steps to obtain a white solid compound 67, with a two-step yield of about 17.2%. LCMS: (ESI) m/z=306.9[M+H] + , 1 H NMR (400MHz, CDCl 3 )8.32(d,J＝7.19Hz,1H),7.98(d,J＝7.43Hz,1H),7.51-7.60(m,2H),7.32(s,1H),6.50(t,J＝8.50Hz,1H), 5.43-5.50(m,2H),3.82(q,J＝7.00Hz,2H),2.83-2.94(m,2H),2.61-2.71(m,2H),1.28(t,J＝7.07Hz,3H).

参照实施例22中的方法(构建五元内酯环代表性操作-C)，用如下表格中的起始原料进行三步反应得到终产化合物。
Referring to the method in Example 22 (representative operation C for constructing a five-membered lactone ring), a three-step reaction was carried out using the starting materials in the following table to obtain the final compound.

上述表格中涉及到的起始原料78-A的合成方法为：
The synthesis method of the starting material 78-A involved in the above table is:

参照中间体40-A的合成方法，以化合物78-B(440mg,2.46mmol)进行反应得到黄色固体化合物78-A(400mg，收率78％).LCMS:(ESI)m/z＝207.0(M+1)+ Referring to the synthesis method of intermediate 40-A, compound 78-B (440 mg, 2.46 mmol) was reacted to obtain yellow solid compound 78-A (400 mg, yield 78%). LCMS: (ESI) m/z = 207.0 (M+1) +

参照实施例22中步骤二和步骤三的方法(构建五元内酯环代表性操作-B)，用如下表格中的起始原料进行反应得到终产化合物。
Referring to the method of step 2 and step 3 in Example 22 (representative operation for constructing a five-membered lactone ring-B), the starting materials in the following table were reacted to obtain the final compound.

上述表格中涉及到的起始原料78-A的合成方法为：
The synthesis method of the starting material 78-A involved in the above table is:

参照实施例37的方法，以78-A(60mg)为原料得黄色固体化合物144-A(50mg,收率69％)。LCMS:(ESI)m/z＝248.9[M+H]+。Referring to the method of Example 37, 78-A (60 mg) was used as a raw material to obtain a yellow solid compound 144-A (50 mg, yield 69%). LCMS: (ESI) m/z = 248.9 [M+H] + .

实施例23化合物71和72的合成
Example 23 Synthesis of Compounds 71 and 72

向化合物67(45mg,146.51μmol)的吡啶(1mL)溶液中加入醋酐(22.4mg,219.77μmol)。在25℃反应16小时。加入水(3mL)，用EA(2mL x 3)萃取。经过常规的后处理操作后得到粗产品，粗产物通过硅胶柱色谱分离(EA:PE，EA从0到50％)纯化后再通过SFC手性拆分得到白色固体化合物71(5mg)和72(5mg)。To a solution of compound 67 (45 mg, 146.51 μmol) in pyridine (1 mL) was added acetic anhydride (22.4 mg, 219.77 μmol). The mixture was reacted at 25 °C for 16 hours. Water (3 mL) was added and extracted with EA (2 mL x 3). After conventional post-treatment, the crude product was obtained. The crude product was purified by silica gel column chromatography (EA:PE, EA from 0 to 50%) and then chiral separation by SFC to obtain white solid compounds 71 (5 mg) and 72 (5 mg).

手性分离的条件为column:DAICEL CHIRALPAK AD(250mm*30mm,10um)；mobile phase:0.1％ NH3H2O IPA；B％:15％-15％,flowrate:100mL/min.The conditions for chiral separation are: column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: 0.1% NH 3 H 2 O IPA; B%: 15%-15%, flow rate: 100 mL/min.

第一个化合物LCMS:(ESI)m/z＝349.0[M+H]+,1H NMR(400MHz,DMSO-d6)δppm 8.13-8.19(m,1H)8.02-8.08(m,1H)7.66-7.76(m,3H)6.54(dd,J＝10.38,7.38Hz,1H)2.90-3.03(m,1H)2.78-2.88(m,1H)2.62-2.68(m,1H)2.54(br d,J＝2.00Hz,1H)2.48(s,3H)。SFC手性分析:RT＝2.703minLCMS of the first compound: (ESI) m/z=349.0 [M+H] + , 1 H NMR (400 MHz, DMSO-d 6 ) δppm 8.13-8.19 (m, 1H) 8.02-8.08 (m, 1H) 7.66-7.76 (m, 3H) 6.54 (dd, J=10.38, 7.38 Hz, 1H) 2.90-3.03 (m, 1H) 2.78-2.88 (m, 1H) 2.62-2.68 (m, 1H) 2.54 (br d, J=2.00 Hz, 1H) 2.48 (s, 3H). SFC chiral analysis: RT=2.703 min

第二个化合物LCMS:(ESI)m/z＝349.0[M+H]+,1H NMR(400MHz,DMSO-d6)δppm 8.13-8.19(m,1H)8.01-8.09(m,1H)7.64-7.75(m,3H)6.54(dd,J＝10.32,7.44Hz,1H)2.90-3.03(m,1H)2.78-2.89(m,1H)2.62-2.68(m,1H)2.54(br s,1H)2.48(s,3H)。SFC手性分析:RT＝2.974minLCMS of the second compound: (ESI) m/z=349.0 [M+H] + , 1 H NMR (400 MHz, DMSO-d 6 ) δppm 8.13-8.19 (m, 1H) 8.01-8.09 (m, 1H) 7.64-7.75 (m, 3H) 6.54 (dd, J=10.32, 7.44 Hz, 1H) 2.90-3.03 (m, 1H) 2.78-2.89 (m, 1H) 2.62-2.68 (m, 1H) 2.54 (br s, 1H) 2.48 (s, 3H). SFC chiral analysis: RT=2.974 min

手性分析条件为：Column:ChiralPak AS-3 150×4.6mm I.D.,3um；Mobile phase:A:CO2 B:Ethanol(0.05％ DEA)；Gradient:from 5％to 40％of B in 4.5min,then 5％of B for 1.5min；Flow rate:2.5mL/min Column temp.:40℃；Back pressure:100barChiral analysis conditions are: Column: ChiralPak AS-3 150×4.6mm I.D., 3um; Mobile phase: A:CO2 B:Ethanol (0.05% DEA); Gradient: from 5% to 40% of B in 4.5min, then 5% of B for 1.5min; Flow rate:2.5mL/min Column temp.:40℃; Back pressure:100bar

实施例24化合物68的合成
Example 24 Synthesis of Compound 68

步骤一：在氮气保护的条件下，向化合物67-B(60mg，0.17mmol)的NMP(1.2mL)溶液中加入Zn(CN)2(68.8mg,0.59mmol)和Pd(PPh3)4(22.5mg,0.2mmol)。将其加热至120℃反应16小时。反应液降至室温，加入水(5mL)，用EA(5mL*3)萃取。经过常规的后处理操作二后得到粗产物，粗产物通过prep-HPLC(FA方法；B％:28％-48％,13min)纯化，得黄色固体68-A(17mg,收率33％)。LCMS:(ESI)m/z＝312.1(M+1)+.Step 1: Under nitrogen protection, Zn(CN) 2 (68.8 mg, 0.59 mmol) and Pd(PPh 3 ) 4 (22.5 mg, 0.2 mmol) were added to a solution of compound 67-B (60 mg, 0.17 mmol) in NMP (1.2 mL). The mixture was heated to 120°C for 16 hours. The reaction solution was cooled to room temperature, water (5 mL) was added, and extracted with EA (5 mL*3). After conventional post-treatment operation 2, a crude product was obtained, which was purified by prep-HPLC (FA method; B%: 28%-48%, 13 min) to obtain a yellow solid 68-A (17 mg, yield 33%). LCMS: (ESI) m/z=312.1 (M+1) + .

步骤二：参照实施例12中步骤三的方法，以68-A(50mg)进行反应得白色固体化合物68(12mg，收率29.2％)。LCMS:(ESI)m/z＝253.9[M+1]+；1H NMR(400MHz,DMSO-d6)11.24(br s,1H),8.25-8.34(m,1H),8.18(br d,J＝8.28Hz,1H),7.67-7.80(m,2H),7.06(s,1H),6.43-6.52(m,1H),2.83-2.98(m,1H),2.70-2.82(m,2H),2.28-2.42(m,1H)Step 2: Referring to the method of step 3 in Example 12, 68-A (50 mg) was reacted to obtain a white solid compound 68 (12 mg, yield 29.2%). LCMS: (ESI) m/z = 253.9 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) 11.24 (br s, 1H), 8.25-8.34 (m, 1H), 8.18 (br d, J = 8.28 Hz, 1H), 7.67-7.80 (m, 2H), 7.06 (s, 1H), 6.43-6.52 (m, 1H), 2.83-2.98 (m, 1H), 2.70-2.82 (m, 2H), 2.28-2.42 (m, 1H)

实施例25化合物73的合成
Example 25 Synthesis of Compound 73

步骤一：向67-A(2.7g,10.75mmol)的DMF(54mL)溶液中加入3-溴丙烯(1.95g,16.13mmol)和K2CO3(4.46g,32.26mmol)。在25℃反应16小时。过滤后减压浓缩。加入水(60mL)，用EA(60mL x 3)萃取。经过常规的后处理操作二后得到粗产物，粗产物通过硅胶柱色谱(EA:PE，EA从0到4％)纯化得米白色固体73-A(收率98％)。1H NMR(400MHz,CDCl3)10.68(s,1H),9.32(d,J＝8.78Hz,1H),8.33(d,J＝8.52Hz,1H),7.68-7.74(m,1H),7.58(t,J＝7.64Hz,1H),7.06(s,1H),6.19(ddt,1H),5.54-5.61(m,1H),5.45(dd,J＝1.25,10.54Hz,1H),4.80-4.86(m,2H)。Step 1: Add 3-bromopropylene (1.95 g, 16.13 mmol) and K 2 CO 3 (4.46 g, 32.26 mmol) to a DMF (54 mL) solution of 67-A (2.7 g, 10.75 mmol). React at 25°C for 16 hours. Filter and concentrate under reduced pressure. Add water (60 mL) and extract with EA (60 mL x 3). After conventional post-treatment operation 2, a crude product is obtained, which is purified by silica gel column chromatography (EA:PE, EA from 0 to 4%) to obtain an off-white solid 73-A (yield 98%). 1 H NMR (400MHz, CDCl 3 )10.68(s,1H),9.32(d,J＝8.78Hz,1H),8.33(d,J＝8.52Hz,1H),7.68-7.74(m,1H),7.58(t,J＝7.64Hz,1 H),7.06(s,1H),6.19(ddt,1H),5.54-5.61(m,1H),5.45(dd,J＝1.25,10.54Hz,1H),4.80-4.86(m,2H).

步骤二到步骤三：参照实施例12中步骤二到步骤三的方法，以73-A进行两步反应得黄色油状物化合物73(两步收率约69％)。1H NMR(400MHz,CDCl3)8.37(d,J＝7.53Hz,1H),7.97(d,J＝7.62Hz,1H),7.51-7.60(m,2H),6.99(s,1H),6.48(t,J＝8.91Hz,1H),6.13-6.23(m,1H),5.55(dd,J＝1.25,17.32Hz,1H),5.41(dd,J＝1.25,10.54Hz,1H),4.74(d,J＝5.27Hz,2H),2.86-2.93(m,2H),2.64-2.70(m,2H)。Step 2 to Step 3: Referring to the method of Step 2 to Step 3 in Example 12, 73-A was reacted in two steps to obtain yellow oily compound 73 (two-step yield is about 69%). 1 H NMR (400MHz, CDCl 3 )8.37(d,J＝7.53Hz,1H),7.97(d,J＝7.62Hz,1H),7.51-7.60(m,2H),6.99(s,1H),6.48(t,J＝8.91Hz,1H),6.13-6.23(m,1H),5 .55(dd,J＝1.25,17.32Hz,1H),5.41(dd,J＝1.25,10.54Hz,1H),4.74(d,J＝5.27Hz,2H),2.86-2.93(m,2H),2.64-2.70(m,2H).

实施例26化合物80的合成
Example 26 Synthesis of Compound 80

参照实施例8-b中步骤四的方法，以67(70mg,227.91μmol)与80-A(1.2eq)进行反应得白色固体化合物80(25mg,收率27％)。LCMS:(ESI)m/z＝371.0[M+1]+；1H NMR(400MHz,DMSO-d6)10.57(s,1H),8.67(s,1H),8.27(d,J＝8.03Hz,1H),7.89-7.98(m,4H),7.49-7.59(m,4H),7.34-7.39(m,1H),6.85(s,1H),6.14(t,J＝8.78Hz,1H),2.85-2.98(m,1H),2.72-2.80(m,1H),2.63-2.70(m,2H)Referring to the method of step 4 in Example 8-b, 67 (70 mg, 227.91 μmol) was reacted with 80-A (1.2 eq) to obtain white solid compound 80 (25 mg, yield 27%). LCMS: (ESI)m/z＝371.0[M+1] + ; 1 H NMR (400MHz, DMSO-d6)10.57(s,1H),8.67(s,1H),8.27(d,J＝8.03Hz,1H),7.89-7.98(m,4H),7.49-7.59(m,4H), 7.34-7.39(m,1H),6.85(s,1H),6.14(t,J＝8.78Hz,1H),2.85-2.98(m,1H),2.72-2.80(m,1H),2.63-2.70(m,2H)

参照实施例26的方法，用如下表格中的起始原料替代80-A进行反应得到相应的终产化合物。



Referring to the method of Example 26, the starting materials in the following table were used instead of 80-A to carry out the reaction to obtain the corresponding final product compound.



上述表格中涉及到的起始原料103-A的合成方法为：
The synthesis method of the starting material 103-A involved in the above table is:

步骤一：向103-B(0.7g,3.57mmol)的MeCN(14mL)溶液中加入4-四氢吡喃基甲磺酸酯(4eq)以及碳酸铯(6eq)。80℃反应24小时,LCMS显示未反应完全，但目标产物生成。过滤，减压浓缩，粗产物通过硅胶柱色谱分离(EA:PE，EA从0到5％)纯化，得到黄色油状物103-C(560mg,收率39％)。LCMS:(ESI)m/z＝281.9[M+1]+ Step 1: Add 4-tetrahydropyranyl methanesulfonate (4 eq) and cesium carbonate (6 eq) to a solution of 103-B (0.7 g, 3.57 mmol) in MeCN (14 mL). React at 80°C for 24 hours. LCMS shows that the reaction is not complete, but the target product is generated. Filter and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (EA:PE, EA from 0 to 5%) to obtain a yellow oil 103-C (560 mg, yield 39%). LCMS: (ESI) m/z = 281.9 [M + 1] +

步骤二：在氮气保护的条件下，向化合物103-C(400mg,1.43mmol)和双(频哪醇合)二硼(2eq)、醋酸钾(3eq)的dioxane(8mL)混合物中加入Pd(dppf)Cl2(104mg,0.1eq)。氮气保护下100℃反应16小时。反应毕，降至室温，加入水(10mL)，用EtOAc萃取(10mL*3)。经过常规的后处理操作二后得粗产品，然后通过硅胶柱色谱(EA:PE，EA从0到14％)纯化得黄色固体103-A(420mg,84％收率).(ESI)m/z＝328.1(M+1)+.Step 2: Under nitrogen protection, add Pd(dppf)Cl 2 (104 mg, 0.1 eq) to a mixture of compound 103-C (400 mg, 1.43 mmol), bis(pinacolato)diboron (2 eq), potassium acetate ( 3 eq) in dioxane (8 mL). React at 100°C for 16 hours under nitrogen protection. After the reaction, cool to room temperature, add water (10 mL), and extract with EtOAc (10 mL*3). After conventional post-treatment operation 2, the crude product is obtained, and then purified by silica gel column chromatography (EA:PE, EA from 0 to 14%) to obtain a yellow solid 103-A (420 mg, 84% yield). (ESI) m/z=328.1(M+1) + .

上述表格中涉及到的起始原料101-A的合成方法为：
The synthesis method of the starting material 101-A involved in the above table is:

在0℃,向化合物101-B(1g,2.89mmol)的THF(20mL)溶液中滴加异丙基氯化镁氯化锂络合物的THF溶液(1.3M,4.44mL)，搅拌反应1小时后滴加化合物98-C(1.07g,5.78mmol)的THF(1.18mL)溶液，升温至25℃，继续搅拌反应15小时。加入饱和氯化铵溶液(20mL)淬灭反应，混合物用EA(20mL×2)萃取。经过常规的后处理操作二后通过硅胶柱色谱(EA:PE，EA从0到5％)纯化得到米白色固体101-A(600mg,收率56％).LCMS:(ESI)m/z＝347.1(M+H)+.At 0°C, add a THF solution (1.3M, 4.44mL) of isopropylmagnesium chloride lithium chloride complex to a THF solution (101-B, 2.89mmol) of compound 101-B (1g, 2.89mmol) and stir for 1 hour, then add a THF solution (1.18mL) of compound 98-C (1.07g, 5.78mmol), warm to 25°C, and continue stirring for 15 hours. Add saturated ammonium chloride solution (20mL) to quench the reaction, and extract the mixture with EA (20mL×2). After conventional post-treatment operation II, the off-white solid 101-A (600mg, yield 56%) was purified by silica gel column chromatography (EA:PE, EA from 0 to 5%). LCMS: (ESI) m/z＝347.1(M+H) + .

上述表格中涉及到的起始原料98-A的合成方法为：
The synthesis method of the starting material 98-A involved in the above table is:

在-70℃，向化合物98-B(500mg,2.14mmol)的THF(20mL)溶液中滴加正丁基锂的THF溶液(2.5M,1.71mL)，在氮气保护下搅拌反应1小时。随后滴加化合物98-C(794mg,4.27mmol)，升温至0℃搅拌反应3小时。反应毕，用饱和NH4Cl溶液淬灭反应，减压浓缩，加入EtOAc(20mL)。过滤，滤液再次减压浓缩后通过硅胶柱色谱分离(EA:PE，EA从0到30％)得黄色胶状物(220mg,收率51.76％)。1H NMR(400MHz,DMSO-d6)Shift 8.72(s,1H),8.67(d,J＝5.06Hz,1H),7.39-7.51(m,6H),1.17-1.25(m,12H).At -70°C, a solution of compound 98-B (500 mg, 2.14 mmol) in THF (20 mL) was added dropwise with a solution of n-butyl lithium in THF (2.5 M, 1.71 mL), and the mixture was stirred under nitrogen protection for 1 hour. Compound 98-C (794 mg, 4.27 mmol) was then added dropwise, and the mixture was heated to 0°C and stirred for 3 hours. After the reaction was completed, the reaction was quenched with a saturated NH 4 Cl solution, concentrated under reduced pressure, and EtOAc (20 mL) was added. After filtration, the filtrate was concentrated under reduced pressure again and separated by silica gel column chromatography (EA:PE, EA from 0 to 30%) to obtain a yellow jelly (220 mg, yield 51.76%). 1 H NMR (400MHz, DMSO-d6) Shift 8.72 (s, 1H), 8.67 (d, J = 5.06Hz, 1H), 7.39-7.51 (m, 6H), 1.17-1.25 (m, 12H).

参照起始原料98-A的方法，用如下表格中的起始原料替代98-B进行反应得到相应的硼酸酯起始原料。
Referring to the method of starting material 98-A, the starting materials in the following table are substituted for 98-B to carry out the reaction to obtain the corresponding borate ester starting materials.

实施例27化合物69的合成
Example 27 Synthesis of Compound 69

步骤一：参照实施例8-b中步骤四的方法，以67-B(100mg)与18-A(74mg)进行反应得棕色固体化合物69-A(50mg,收率47％).LCMS:ES19974-299-P1B1,(ESI)m/z＝367.5[M+1]+ Step 1: Referring to the method of step 4 in Example 8-b, 67-B (100 mg) and 18-A (74 mg) were reacted to obtain brown solid compound 69-A (50 mg, yield 47%). LCMS: ES19974-299-P1B1, (ESI) m/z = 367.5 [M+1] +

步骤二：参照实施例12中步骤三的方法，以化合物69-A(50mg)进行反应得白色固体化合物69(1.4mg,收率3.28％)。LCMS:(ESI)m/z＝309.0[M+1]+,1H NMR(400MHz,DMSO-d6)Shift＝10.50(br s,1H),8.23(d,J＝8.0Hz,1H),7.91-7.84(m,2H),7.58-7.51(m,2H),7.51-7.45(m,1H),6.76(s,1H),6.09(dd,J＝7.8,10.0Hz,1H),3.93(s,3H),2.95-2.73(m,2H),2.70-2.57(m,2H)Step 2: Referring to the method of step 3 in Example 12, compound 69-A (50 mg) was reacted to obtain white solid compound 69 (1.4 mg, yield 3.28%). LCMS: (ESI) m/z = 309.0 [M+1] + , 1 H NMR (400 MHz, DMSO-d6) Shift = 10.50 (br s, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.91-7.84 (m, 2H), 7.58-7.51 (m, 2H), 7.51-7.45 (m, 1H), 6.76 (s, 1H), 6.09 (dd, J = 7.8, 10.0 Hz, 1H), 3.93 (s, 3H), 2.95-2.73 (m, 2H), 2.70-2.57 (m, 2H)

参照实施例27中的方法，用如下表格中的起始原料替代18-A进行反应得到相应的终产化合物。
Referring to the method in Example 27, the starting materials in the following table were used instead of 18-A to carry out the reaction to obtain the corresponding final product compound.

实施例28化合物84的合成
Example 28 Synthesis of Compound 84

在氮气保护的条件下，向化合物67(90mg，293μmol)、84-A(100mg,352μmol)在THF/水(2.4mL,5/1)的混合物中加入和K3PO4(93.3mg,439μmol)和Pd2(dba)3(26.8mg,29.30μmol)。将其加热至60℃反应16小时。用水(5mL)稀释反应，用EA萃取(5mL*3),经过常规的后处理操作后得到粗产物，粗产物通过硅胶薄层层析色谱分离(PE：EA,EA从0到15％)纯化，再经过prep HPLC(FA方法；B％:35％-55％,9min)纯化得白色固体化合物84(18mg,收率16％)。LCMS:(ESI)m/z＝385.1[M+1]+ Under nitrogen protection, K 3 PO 4 (93.3 mg, 439 μmol) and Pd 2 (dba) 3 (26.8 mg, 29.30 μmol) were added to a mixture of compound 67 (90 mg, 293 μmol) and 84 - A (100 mg, 352 μmol) in THF/water (2.4 mL, 5/1). The mixture was heated to 60°C for 16 hours. The reaction was diluted with water (5 mL) and extracted with EA (5 mL*3). After conventional post-treatment, a crude product was obtained. The crude product was purified by silica gel thin layer chromatography (PE: EA, EA from 0 to 15%) and then purified by prep HPLC (FA method; B%: 35%-55%, 9 min) to obtain a white solid compound 84 (18 mg, yield 16%). LCMS: (ESI) m/z=385.1[M+1] +

实施例28-a化合物85的合成
Example 28-a Synthesis of Compound 85

在氮气保护的条件下，向化合物67(80mg，0.26mmol)、85-A(80mg,312μmol)、3-(叔丁基)-4-(2,6-二甲氧基苯基)-2,3-二氢苯并[d][1,3]氧磷杂环戊二烯(CAS:1246888-90-3,17.2mg,52.09umol)和CsF(59.3mg,390.70umol,14.41uL,1.5eq)在异丙醇(2mL)的混合物中加入Pd2(dba)3(23.8mg,26μmol)。将其加热至50℃反应16小时。降至室温，用水(5mL)稀释反应，用EA萃取(5mL*3),经过常规的后处理操作二后得到粗产物，粗产物通过硅胶薄层层析色谱分离(PE：EA,EA从0到25％)纯化，再经过prep HPLC(FA方法，B％:30％-50％,9min)纯化得白色固体化合物85(10mg,收率10.6％)。LCMS:(ESI)m/z＝356.0[M+1]+.1H NMR(400MHz,DMSO-d6)10.77(br s,1H),8.89(s,1H),8.39(s,1H),8.32(d,J＝7.48Hz,1H),8.11(dd,J＝4.73,7.81Hz,2H),7.95(d,J＝8.36Hz,1H),7.85(t,J＝7.59Hz,1H),7.68-7.74(m,1H),7.55-7.66(m,2H),6.80(s,1H),5.80(br t,J＝8.47Hz,1H),2.58-2.81(m,4H)Under nitrogen protection, Pd 2 (dba) 3 (23.8 mg, 26 μmol) was added to a mixture of compound 67 (80 mg, 0.26 mmol), 85-A (80 mg, 312 μmol), 3-(tert-butyl) -4- (2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole (CAS: 1246888-90-3, 17.2 mg, 52.09 μmol) and CsF (59.3 mg, 390.70 μmol , 14.41 μL, 1.5 eq) in isopropanol (2 mL), and the mixture was heated to 50° C. for 16 hours. The mixture was cooled to room temperature, diluted with water (5 mL), extracted with EA (5 mL*3), and subjected to conventional post-treatment operation 2 to obtain a crude product. The crude product was purified by silica gel thin layer chromatography (PE:EA, EA from 0 to 25%), and then purified by prep HPLC (FA method, B%:30%-50%, 9 min) to obtain white solid compound 85 (10 mg, yield 10.6%). LCMS: (ESI) m/z＝356.0[M+1] + . 1 H NMR (400MHz, DMSO-d6) 10.77(br s,1H),8.89(s,1H),8.39(s,1H),8.32(d,J＝7.48Hz,1H),8.11(dd,J＝4.73,7.81Hz,2H),7.95(d,J ＝8.36Hz,1H),7.85(t,J＝7.59Hz,1H),7.68-7.74(m,1H),7.55-7.66(m,2H),6.80(s,1H),5.80(br t,J＝8.47Hz,1H),2.58-2.81(m,4H)

实施例29化合物74的合成
Example 29 Synthesis of Compound 74

步骤一：在氮气保护的条件下，向化合物67-B(70mg，0.19mmol)的DMSO(1.4mL)溶液中加入甲烷亚磺酸钠(29.3mg,287.50μmol)，K3PO4(81.4mg,383.33μmol),CuI(1.83mg,9.58μmol)和(2S,4R)-N-(2,6-二甲基苯基)-4-羟基吡咯烷-2-甲酰胺(2.25mg,9.58μmol)。将其加热至90℃反应16小时。反应液降至室温，加入EA稀释反应，加入水(5mL)，用EA(10mL*3)萃取。经过常规的后处理操作后得到粗产物，粗产物通过硅胶柱色谱(EA:PE，EA从0到20％)纯化，得黄色胶状物74-A(35mg,收率25％)。LCMS:(ESI)m/z＝365.0(M+1)+.Step 1: Under nitrogen protection, sodium methanesulfinate (29.3 mg, 287.50 μmol), K 3 PO 4 (81.4 mg, 383.33 μmol), CuI (1.83 mg, 9.58 μmol) and (2S, 4R)-N-(2,6-dimethylphenyl)-4-hydroxypyrrolidine-2-carboxamide (2.25 mg, 9.58 μmol) were added to a DMSO (1.4 mL) solution of compound 67-B (70 mg, 0.19 mmol). The mixture was heated to 90°C and reacted for 16 hours. The reaction solution was cooled to room temperature, EA was added to dilute the reaction, water (5 mL) was added, and the mixture was extracted with EA (10 mL*3). After conventional post-treatment operations, a crude product was obtained, which was purified by silica gel column chromatography (EA:PE, EA from 0 to 20%) to obtain a yellow jelly 74-A (35 mg, yield 25%). LCMS: (ESI)m/z=365.0(M+1) + .

步骤二：参照实施例12中步骤三的方法，以化合物74-A(30mg)进行反应得白色固体化合物74(10mg,收率40％)。LCMS:(ESI)m/z＝307.0[M+1]+,1H NMR(400MHz,DMSO-d6)11.23(br s,1H),8.29-8.35(m,1H),8.05-8.12(m,1H),7.67-7.73(m,2H),7.51(s,1H),6.74(dd,J＝7.53,10.04Hz,1H),3.44(br s,3H),2.95(td,J＝10.48,17.69Hz,1H),2.81(br dd,J＝8.28,17.82Hz,1H),2.61(br d,J＝10.54Hz,2H)Step 2: Referring to the method of Step 3 in Example 12, compound 74-A (30 mg) was reacted to obtain white solid compound 74 (10 mg, yield 40%). LCMS: (ESI)m/z＝307.0[M+1] + , 1 H NMR (400MHz, DMSO-d6)11.23(br s,1H),8.29-8.35(m,1H),8.05-8.12(m,1H),7.67-7.73(m,2H),7.51(s,1H),6.74(dd,J＝7.53,10.04Hz,1H),3.44(br s,3H),2.95(td,J＝10.48,17.69Hz,1H),2.81(br dd,J＝8.28,17.82Hz,1H),2.61(br d,J＝10.54Hz,2H)

实施例30化合物75的合成
Example 30 Synthesis of Compound 75

参照实施例12中步骤一到步骤三的方法：以75-A为起始原料进行反应得黄色固体化合物75-B，三步收率约66.6％。1H NMR(400MHz,CHLOROFORM-d)Shift＝7.21-7.12(m,2H),6.19(t,J＝8.8Hz,1H),6.07-5.91(m,1H),5.47-5.30(m,2H),4.54-4.52(m,2H),2.78-2.71(m,2H),2.59-2.54(m,2H).Referring to the method of step 1 to step 3 in Example 12: 75-A was used as the starting material to react to obtain yellow solid compound 75-B, with a three-step yield of about 66.6%. 1 H NMR (400MHz, CHLOROFORM-d) Shift＝7.21-7.12(m,2H),6.19(t,J＝8.8Hz,1H),6.07-5.91(m,1H),5.47-5.30(m,2H),4.54-4.52(m,2H),2.78-2.71(m,2H),2.59-2.54(m,2H).

步骤四：氮气保护条件下，将化合物75-B(300mg,0.8mmol)、Pd(PPh3)4(92.2mg,79.8μmol)和吗啉(139.0mg,1.60mmol)的THF(16mL)混合物在20℃反应16小时。加入水(40mL)，用EA(30mL*3)萃取，经过常规的后处理操作二后得粗产物，粗产物通过硅胶柱色谱(EA:PE，EA从0到30％)纯化得白色固体化合物75(125mg,收率47％).LCMS:(ESI)m/z＝336.8[M+1]+；1H NMR(400MHz,DMSO-d6)Shift＝10.58(s,1H),7.20-7.03(m,2H),6.09(t,J＝8.8Hz,1H),2.90-2.74(m,1H),2.70-2.59(m,1H),2.49-2.43(m,1H),2.42-2.25(m,1H).Step 4: Under nitrogen protection, a mixture of compound 75-B (300 mg, 0.8 mmol), Pd(PPh 3 ) 4 (92.2 mg, 79.8 μmol) and morpholine (139.0 mg, 1.60 mmol) in THF (16 mL) was reacted at 20° C. for 16 hours. Water (40 mL) was added, and the mixture was extracted with EA (30 mL*3). After conventional post-treatment, a crude product was obtained. The crude product was purified by silica gel column chromatography (EA:PE, EA from 0 to 30%) to obtain white solid compound 75 (125 mg, yield 47%). LCMS: (ESI) m/z = 336.8 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) Shift = 10.58 (s, 1H), 7.20-7.03 (m, 2H), 6.09 (t, J = 8.8 Hz, 1H), 2.90-2.74 (m, 1H), 2.70-2.59 (m, 1H), 2.49-2.43 (m, 1H), 2.42-2.25 (m, 1H).

实施例31化合物77的合成
Example 31 Synthesis of Compound 77

步骤一：向化合物77-A(1g,4.46mmol)和NIS(1.14g,5.07mmol)的DMSO/ACN(100mL，1:1)溶液中加入77-E(65.6mg,223.16μmol)，25℃反应15小时。加入水(50mL)，用EA(50mL*2)萃取，经过常规的后处理操作后得灰色固体1g，直接用于下一步反应。LCMS:(ESI)m/z＝351.8(M+1)+ Step 1: Add 77-E (65.6 mg, 223.16 μmol) to a DMSO/ACN (100 mL, 1:1) solution of compound 77-A (1 g, 4.46 mmol) and NIS (1.14 g, 5.07 mmol) and react at 25°C for 15 hours. Add water (50 mL) and extract with EA (50 mL*2). After conventional post-treatment, 1 g of gray solid was obtained, which was directly used in the next step. LCMS: (ESI) m/z = 351.8 (M+1) +

步骤二：参照实施例22中步骤一的方法，以77-B(1g粗产品)进行反应得黄色固体化合物77-C(1.1g,纯度58.65％)。LCMS:(ESI)m/z＝409.9(M+1)+ Step 2: Referring to the method of step 1 in Example 22, 77-B (1 g crude product) was reacted to obtain yellow solid compound 77-C (1.1 g, purity 58.65%). LCMS: (ESI) m/z = 409.9 (M+1) +

步骤三：在-70℃,向化合物77-C(560mg)的THF(30mL)溶液中滴加异丙基氯化镁氯化锂络合物的THF溶液(1.3M,1.27mL)，升至25℃，搅拌反应1小时。在-70℃加入DMF(120mg,1.65mmol)的THF(1mL)溶液，升至25℃，继续搅拌反应0.5小时。在0℃加入水(10mL)淬灭反应，混合物用EA(10mL×2)萃取。经过常规的后处理操作后通过硅胶柱色谱(EA:PE，EA从0到5％)纯化得到黄色固体77-D(240mg,纯度80.4％).LCMS:(ESI)m/z＝311.9(M+H)+.Step 3: At -70°C, add a THF solution (1.3M, 1.27mL) of isopropylmagnesium chloride lithium chloride complex to a THF solution (560mg) of compound 77-C (30mL), warm to 25°C, and stir to react for 1 hour. Add a THF solution (1mL) of DMF (120mg, 1.65mmol) at -70°C, warm to 25°C, and continue to stir to react for 0.5 hours. Add water (10mL) at 0°C to quench the reaction, and extract the mixture with EA (10mL×2). After conventional post-treatment operations, 77-D (240mg, purity 80.4%) was purified by silica gel column chromatography (EA:PE, EA from 0 to 5%) to obtain a yellow solid. LCMS: (ESI) m/z＝311.9(M+H) + .

步骤四和步骤五：参照实施例12中步骤二和步骤三的方法，以77-D进行两步反应得黄色固体化合物77，五步收率8.8％。LCMS:(ESI)m/z＝310.0(M+H)+；1H NMR(400MHz,DMSO-d6)Shift 11.25(s,1H),8.91(d,J＝4.49Hz,1H),8.54(d,J＝8.56Hz,1H),7.56(dd,J＝4.14,8.41Hz,1H),7.11-7.14(m,1H),6.58(dd,J＝7.53,8.78Hz,1H),2.71-2.91(m,2H),2.57-2.68(m,2H).Step 4 and Step 5: Referring to the method of Step 2 and Step 3 in Example 12, 77-D was used for two-step reaction to obtain yellow solid compound 77, with a five-step yield of 8.8%. LCMS: (ESI) m/z=310.0 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) Shift 11.25 (s, 1H), 8.91 (d, J=4.49 Hz, 1H), 8.54 (d, J=8.56 Hz, 1H), 7.56 (dd, J=4.14, 8.41 Hz, 1H), 7.11-7.14 (m, 1H), 6.58 (dd, J=7.53, 8.78 Hz, 1H), 2.71-2.91 (m, 2H), 2.57-2.68 (m, 2H).

实施例32化合物86的合成
Example 32 Synthesis of Compound 86

步骤一：参照实施例8-b中步骤四的方法，以77-D(200mg,644.86μmol)与18-A(147mg,709.35μmol)进行反应得黄色固体86-A(130mg,收率64.75％)。1H NMR(400MHz,CHLOROFORM-d)δ11.03(s,1H),9.02(dd,J＝1.83,4.28Hz,1H),8.58(dd,J＝1.83,8.44Hz,1H),7.87(s,1H),7.76(s,1H),7.44(dd,J＝4.16,8.44Hz,1H),7.23(s,1H),5.52(s,2H),3.99(s,3H),3.82(q,J＝7.09Hz,2H),1.26(t,J＝7.09Hz,3H).Step 1: Referring to the method of step 4 in Example 8-b, 77-D (200 mg, 644.86 μmol) and 18-A (147 mg, 709.35 μmol) were reacted to obtain yellow solid 86-A (130 mg, yield 64.75%). 1 H NMR (400MHz, CHLOROFORM-d) δ11.03(s,1H),9.02(dd,J＝1.83,4.28Hz,1H),8.58(dd,J＝1.83,8.44Hz,1H),7.87(s,1H),7.76( s,1H),7.44(dd,J＝4.16,8.44Hz,1H),7.23(s,1H),5.52(s,2H),3.99(s,3H),3.82(q,J＝7.09Hz,2H),1.26(t,J＝7.09Hz,3H).

步骤二和步骤三：参照实施例12中步骤二和步骤三的方法，以86-A(130mg,417.56umol)进行两步反应得黄色固体化合物86(4mg)，两步收率约2.7％。LCMS:(ESI)m/z＝309.9[M+H]+.1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),8.85(dd,J＝1.76,4.02Hz,1H),8.52(dd,J＝1.76,8.28Hz,1H),7.92(s,1H),7.59(s,1H),7.47(dd,J＝4.27,8.28Hz,1H),6.84(s,1H),6.10(t,J＝7.53Hz,1H),3.94(s,3H),2.85-2.98(m,1H),2.61-2.76(m,3H).Step 2 and step 3: Referring to the method of step 2 and step 3 in Example 12, 86-A (130 mg, 417.56 umol) was used for two-step reaction to obtain yellow solid compound 86 (4 mg). The two-step yield was about 2.7%. LCMS: (ESI)m/z＝309.9[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.79(s,1H),8.85(dd,J＝1.76,4.02Hz,1H),8.52(dd,J＝1.76,8.28Hz,1H),7.92(s,1H),7.59(s,1 H),7.47(dd,J＝4.27,8.28Hz,1H),6.84(s,1H),6.10(t,J＝7.53Hz,1H),3.94(s,3H),2.85-2.98(m,1H),2.61-2.76(m,3H).

实施例33化合物92、93、94的合成
Example 33 Synthesis of Compounds 92, 93, and 94

步骤一：在氮气保护的条件下，向化合物67-B(370mg,1.20mmol)和DBU(273mg,1.80mmol)的EtOH(10mL)溶液中加入Pd(OAc)2(26.8mg,119.68μmol),六羰基钼(Mo(CO)6，173mg,658.25μmol)和四氟硼酸三叔丁基膦(34.7mg,119.68μmol)。氮气保护的条件在90℃反应16小时。过滤、减压蒸馏除去溶剂，通过硅胶柱色谱(EA:PE，EA从0到2％)纯化得黄色油状物化合物92-A(170mg,收率47％)。LCMS:(ESI)m/z＝303.0(M+1)+.Step 1: Under nitrogen protection, add Pd(OAc) 2 (26.8 mg, 119.68 μmol), hexacarbonyl molybdenum (Mo(CO) 6 , 173 mg, 658.25 μmol) and tri-tert-butylphosphine tetrafluoroborate (34.7 mg, 119.68 μmol) to a solution of compound 67-B (370 mg, 1.20 mmol) and DBU (273 mg, 1.80 mmol) in EtOH (10 mL). React at 90°C for 16 hours under nitrogen protection. Filter and remove the solvent by reduced pressure distillation, and purify by silica gel column chromatography (EA:PE, EA from 0 to 2%) to obtain a yellow oil compound 92-A (170 mg, yield 47%). LCMS: (ESI) m/z=303.0 (M+1) + .

步骤二和步骤三：参照实施例12中步骤二和步骤三的方法，以92-A(260mg,860μmol)进行两步反应得白色固体化合物92(40mg)，两步收率约15.5％。LCMS:(ESI)m/z＝301.3(M+1)+.1H NMR(400MHz,CDCl3)δ8.35-8.50(m,1H),7.90-8.06(m,1H),7.59-7.77(m,2H),7.36(br s,1H),7.30(s,1H),5.90(dd,J＝2.31,8.47Hz,1H),3.91-4.26(m,2H),2.77-2.93(m,1H),2.59-2.73(m,1H),2.46(td,J＝6.27,16.95Hz,1H),2.03(dt,J＝6.71,14.36Hz,1H),1.25(t,J＝7.15Hz,3H).Step 2 and step 3: Referring to the method of step 2 and step 3 in Example 12, 92-A (260 mg, 860 μmol) was used for two-step reaction to obtain white solid compound 92 (40 mg). The two-step yield was about 15.5%. LCMS: (ESI) m/z＝301.3(M+1) + . 1 H NMR (400MHz, CDCl 3 ) δ8.35-8.50(m,1H),7.90-8.06(m,1H),7.59-7.77(m,2H),7.36(br s,1H),7.30(s,1H),5.90(dd,J＝2.31,8.47Hz,1H),3.91-4.26(m,2H),2.77-2.93(m,1H),2.59-2. 73(m,1H),2.46(td,J＝6.27,16.95Hz,1H),2.03(dt,J＝6.71,14.36Hz,1H),1.25(t,J＝7.15Hz,3H).

步骤四：将化合物92(20mg)溶解在THF(0.3mL)中，加入NaOH(10.7mg,266μmol)水溶液(0.3mL)，25℃搅拌2小时。反应液用1M HCl溶液调pH到2，混合物用EA(1mL×3)萃取。减压浓缩得粗产物。粗产物研碎，用DCM(3mL)打浆10分钟，过滤得白色固体化合物93(15mg,收率82.48％)。1H NMR(400MHz,DMSO-d6)δ12.25(br s,1H),10.95(br s,1H),8.22-8.42(m,1H),7.99-8.16(m,1H),7.54-7.88(m,2H),7.04(s,1H),5.97(dd,J＝2.53,8.25Hz,1H),2.55-2.71(m,1H),2.33-2.47(m,1H),2.14-2.29(m,1H),1.83-1.98(m,1H).LCMS:(ESI)m/z＝273.2(M+1)+.Step 4: Compound 92 (20 mg) was dissolved in THF (0.3 mL), and NaOH (10.7 mg, 266 μmol) aqueous solution (0.3 mL) was added and stirred at 25 °C for 2 hours. The reaction solution was adjusted to pH 2 with 1 M HCl solution, and the mixture was extracted with EA (1 mL × 3). The crude product was concentrated under reduced pressure. The crude product was ground and slurried with DCM (3 mL) for 10 minutes, and filtered to obtain a white solid compound 93 (15 mg, yield 82.48%). 1H NMR(400MHz,DMSO-d6)δ12.25(br s,1H),10.95(br s,1H),8.22-8.42(m,1H),7.99-8.16(m,1H),7.54-7.88(m,2H),7.04(s,1H),5.97(dd,J＝2.53,8.25Hz,1H ),2.55-2.71(m,1H),2.33-2.47(m,1H),2.14-2.29(m,1H),1.83-1.98(m,1H).LCMS:(ESI)m/z＝273.2(M+1) + .

步骤五：向化合物93(40mg,146.92μmol)和HOBT铵盐(CAS:63307-62-0,111.77mg,734.61μmol)的DMF(1mL)溶液中加入DIEA(56.96mg,440.77umol)和HATU(139.66mg,367.31μmol),在25℃搅拌2小。用水(2mL)和乙腈(1mL)稀释,过滤。滤液浓缩后通过prep HPLC纯化(column:C18-1 150*30mm*5um；mobile phase:[water(FA)-ACN]；B％:5％-45％,9min)得白色固体化合物94(20mg,收率50.18％).1H NMR(400MHz,DMSO-d6)δ10.95(s,1H),8.25-8.40(m,1H),8.04-8.17(m,1H),7.64-7.83(m,2H),7.35(br s,1H),7.03(s,1H),6.82(br s,1H),5.95(dd,J＝2.64,7.92Hz,1H),2.55-2.72(m,1H),2.18-2.33(m,1H),1.95-2.06(m,1H),1.80-1.95(m,1H).LCMS:(ESI)m/z＝272.0(M+1)+.Step 5: Add DIEA (56.96 mg, 440.77 umol) and HATU (139.66 mg, 367.31 μmol) to a solution of compound 93 (40 mg, 146.92 μmol) and HOBT ammonium salt (CAS: 63307-62-0, 111.77 mg, 734.61 μmol) in DMF (1 mL), stir at 25 °C for 2 hours, dilute with water (2 mL) and acetonitrile (1 mL), and filter. The filtrate was concentrated and purified by prep HPLC (column: C18-1 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 5%-45%, 9min) to give white solid compound 94 (20 mg, yield 50.18%). 1 H NMR (400MHz, DMSO-d6) δ10.95 (s, 1H), 8.25-8.40 (m, 1H), 8.04-8.17 (m, 1H), 7.64-7.83 (m, 2H), 7.35 (br s, 1H), 7.03 (s, 1H), 6.82 (br s,1H),5.95(dd,J＝2.64,7.92Hz,1H),2.55-2.72(m,1H),2.18-2.33(m,1H),1.95-2.06(m,1H),1.80-1.95(m,1H).LCMS:(ESI)m/z＝272.0(M+1) + .

实施例34化合物117的合成
Example 34 Synthesis of Compound 117

向化合物116(100mg，0.33mmol)在THF(1.5mL)和水(1.5mL)的混合物中加入氢氧化锂一水合物(20.5mg,0.49mmol，约1.5当量)。在25℃反应16小时。减压蒸馏除去THF，用AcOH调pH至6-7。通过prep HPLC分离(FA方法,B:18％-38％,10min)得白色固体(25mg,收率25.68％).1H NMR(400MHz,DMSO-d6)Shift 10.84(m,1H),9.38-12.31(m,1H),6.82-7.05(m,1H),6.42-6.56(m,1H),5.73(d,J＝4.65Hz,0.24H),5.37(s,0.76H),3.67-3.82(m,3H),2.64-2.75(m,2H),2.38-2.43(m,2H),2.21(dt,J＝2.45,5.69Hz,2H),1.29(dt,J＝4.46,8.16Hz,1H),1.05(br d,J＝4.52Hz,1H),0.68-0.99(m,1H)。LCMS:(ESI)m/z＝293.3(M+1)+ Lithium hydroxide monohydrate (20.5 mg, 0.49 mmol, about 1.5 equivalents) was added to a mixture of compound 116 (100 mg, 0.33 mmol) in THF (1.5 mL) and water (1.5 mL). The mixture was reacted at 25°C for 16 hours. THF was removed by distillation under reduced pressure, and the pH was adjusted to 6-7 with AcOH. A white solid (25 mg, yield 25.68%) was obtained by prep HPLC separation (FA method, B: 18%-38%, 10 min). 1 H NMR (400 MHz, DMSO-d6) Shift 10.84(m,1H),9.38-12.31(m,1H),6.82-7.05(m,1H),6.42-6.56(m,1H),5.73(d,J＝4.65Hz,0.24H),5.37(s,0.76H),3.67 -3.82(m,3H),2.64-2.75(m,2H),2.38-2.43(m,2H),2.21(dt,J＝2.45,5.69Hz,2H),1.29(dt,J＝4.46,8.16Hz,1H),1.05(br d,J＝4.52Hz,1H),0.68-0.99(m,1H). LCMS: (ESI)m/z＝293.3(M+1) +

实施例35化合物118和119的合成
Example 35 Synthesis of Compounds 118 and 119

将化合物117(90mg,307.92μmol)在TFA(0.2mL)和DCM(2mL)的溶液在25℃搅拌反应1小时。用饱和NaHCO3溶液(5mL)淬灭反应,用DCM(5mL*3)萃取，经过常规的后处理操作后得黄色油状物117-A(60mg,收率71.05％).LCMS:(ESI)m/z＝275.3(M+1)+ A solution of compound 117 (90 mg, 307.92 μmol) in TFA (0.2 mL) and DCM (2 mL) was stirred at 25°C for 1 hour. The reaction was quenched with saturated NaHCO 3 solution (5 mL), extracted with DCM (5 mL*3), and after conventional post-treatment, a yellow oil 117-A (60 mg, yield 71.05%) was obtained. LCMS: (ESI) m/z=275.3 (M+1) +

化合物117-A(15mg)通过prep HPLC(column:Boston Prime C18 150*30mm*5um；mobile phase:[water(ammonia hydroxide v/v)-ACN]；gradient:33％-53％ B over 10min)纯化得白色固体化合物118(8mg,纯度80％)和白色固体化合物119(5mg,纯度90％)。Compound 117-A (15 mg) was purified by prep HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water(ammonia hydroxide v/v)-ACN]; gradient: 33%-53% B over 10 min) to obtain white solid compound 118 (8 mg, purity 80%) and white solid compound 119 (5 mg, purity 90%).

化合物118:1H NMR(400MHz,DMSO-d6)Shift 7.15(s,1H),6.86(s,1H),5.48(s,1H),3.83(s,3H),2.89-2.98(m,2H),2.75-2.83(m,2H),2.16-2.38(m,3H),1.30-1.37(m,1H),1.00-1.06(m,1H)。LCMS:(ESI)m/z＝275.3(M+1)+ Compound 118: 1 H NMR (400 MHz, DMSO-d6) Shift 7.15 (s, 1H), 6.86 (s, 1H), 5.48 (s, 1H), 3.83 (s, 3H), 2.89-2.98 (m, 2H), 2.75-2.83 (m, 2H), 2.16-2.38 (m, 3H), 1.30-1.37 (m, 1H), 1.00-1.06 (m, 1H). LCMS: (ESI) m/z＝275.3 (M+1) +

化合物119:1H NMR(400MHz,DMSO-d6)Shift 7.06(s,1H),6.77-6.86(m,1H),6.83(s,1H),5.80(d,J＝4.52Hz,1H),3.84(s,3H),2.89-2.95(m,2H),2.73-2.81(m,2H),2.58-2.66(m,1H),2.21(ddd,J＝3.14,5.58,8.85Hz,1H),1.06(dt,J＝4.89,8.22Hz,1H),0.70(q,J＝4.27Hz,1H)。LCMS:(ESI)m/z＝275.3(M+1)+ Compound 119: 1 H NMR (400 MHz, DMSO-d6) Shift 7.06 (s, 1H), 6.77-6.86 (m, 1H), 6.83 (s, 1H), 5.80 (d, J = 4.52 Hz, 1H), 3.84 (s, 3H), 2.89-2.95 (m, 2H), 2.73-2.81 (m, 2H), 2.58-2.66 (m, 1H), 2.21 (ddd, J = 3.14, 5.58, 8.85 Hz, 1H), 1.06 (dt, J = 4.89, 8.22 Hz, 1H), 0.70 (q, J = 4.27 Hz, 1H). LCMS: (ESI) m/z = 275.3 (M+1) +

实施例36化合物25的合成
Example 36 Synthesis of Compound 25

步骤一：参照实施例1的步骤6的方法以(14-c-1)(1.5g,6.29mmol)和化合物25-A(860mg,2.67mmol)进行反应得白色固体化合物25-B(70mg,收率2.9％)。(ESI)m/z＝377.1(M+1)+.Step 1: Referring to the method of step 6 of Example 1, (14-c-1) (1.5 g, 6.29 mmol) and compound 25-A (860 mg, 2.67 mmol) were reacted to obtain white solid compound 25-B (70 mg, yield 2.9%). (ESI) m/z = 377.1 (M+1) + .

步骤二：向化合物25-B(60mg,159μmol)的MeOH(2mL)溶液中加入氟化铵(11.8mg,318.67umol,2eq)，25℃反应2小时。反应毕减压浓缩，加入EtOAc(20mL)，经过常规的后处理操作二后通过硅胶柱色谱(EA/PE,EA从0到50％)纯化得白色固体化合物25(5mg,收率14.25％).(ESI)m/z＝221.0(M+1)+.1H NMR(400MHz,CDCl3)δ7.11(d,J＝8.03Hz,1H),6.46(d,J＝2.26Hz,1H),6.39-6.44(m,1H),5.50(s,1H),3.82(s,3H),2.25(m,1H),2.14-2.21(m,1H),1.33(m,1H),1.02-1.10(m,1H)。Step 2: Add ammonium fluoride (11.8 mg, 318.67 umol, 2 eq) to a solution of compound 25-B (60 mg, 159 μmol) in MeOH (2 mL) and react at 25° C. for 2 hours. After the reaction, the mixture was concentrated under reduced pressure and EtOAc (20 mL) was added. After conventional post-treatment, the mixture was purified by silica gel column chromatography (EA/PE, EA from 0 to 50%) to give a white solid compound 25 (5 mg, yield 14.25%). (ESI) m/z = 221.0 (M+1) + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.11 (d, J = 8.03 Hz, 1H), 6.46 (d, J = 2.26 Hz, 1H), 6.39-6.44 (m, 1H), 5.50 (s, 1H), 3.82 (s, 3H), 2.25 (m, 1H), 2.14-2.21 (m, 1H), 1.33 (m, 1H), 1.02-1.10 (m, 1H).

实施例37化合物134的合成
Example 37 Synthesis of Compound 134

向化合物134-A(20mg,96μmol)的吡啶(0.5mL)溶液中加入醋酐(14.7mg,144.09μmol)。在室温(15℃)反应16小时。减压浓缩，加入水(2mL)，用EA(1mL x 2)萃取。经过常规的后处理操作后得到粗产品，粗产物通过硅胶柱色谱分离(EA:PE，EA从0到30％)纯化得黄色油状物134(15mg，收率60.28％)。LCMS:ESI m/z＝251.0[M+H]+。1H NMR(400MHz,CDCl3)δppm 7.34(d,J＝8.44Hz,1H)6.73(dd,J＝8.31,2.08Hz,1H)6.68(d,J＝2.08Hz,1H)5.74(t,J＝7.03Hz,1H)3.85(s,3H)2.67-2.76(m,1H)2.60-2.66(m,2H)2.33(s,3H)2.09-2.20(m,1H)。To a solution of compound 134-A (20 mg, 96 μmol) in pyridine (0.5 mL) was added acetic anhydride (14.7 mg, 144.09 μmol). The mixture was reacted at room temperature (15°C) for 16 hours. The mixture was concentrated under reduced pressure, water (2 mL) was added, and the mixture was extracted with EA (1 mL x 2). After conventional post-treatment, the crude product was obtained, and the crude product was purified by silica gel column chromatography (EA:PE, EA from 0 to 30%) to obtain a yellow oil 134 (15 mg, yield 60.28%). LCMS: ESI m/z = 251.0 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δppm 7.34(d,J＝8.44Hz,1H)6.73(dd,J＝8.31,2.08Hz,1H)6.68(d,J＝2.08Hz,1H)5.74(t,J＝7. 03Hz,1H)3.85(s,3H)2.67-2.76(m,1H)2.60-2.66(m,2H)2.33(s,3H)2.09-2.20(m,1H).

参照实施例37中的方法，用如下表格中的起始原料替代134-A进行反应得到相应的终产化合物。

Referring to the method in Example 37, the starting materials shown in the following table were used instead of 134-A to carry out the reaction to obtain the corresponding final compounds.

参照实施例37中的方法，用如下表格中的起始原料进行反应得到相应的终产化合物。
Referring to the method in Example 37, the starting materials in the following table were used to react to obtain the corresponding final compounds.

实施例38化合物138的合成
Example 38 Synthesis of Compound 138

向化合物67(50mg,163μmol)的DCM(2mL)溶液中加入TEA(24.7mg,212μmol)和苯甲酰氯(29.7mg,212μmol)，25℃反应4小时。反应毕减压浓缩，通过硅胶柱色谱(EA/PE,EA从0到30％)纯化得白色固体化合物138(20mg,收率28.6％).LCMS:(ESI)m/z＝411.0[M+H]+；1H NMR(400MHz,DMSO-d6)δ8.28(d,J＝7.28Hz,2H),8.20(d,J＝8.53Hz,1H),8.00(d,J＝8.03Hz,1H),7.91(s,1H),7.81-7.87(m,1H),7.66-7.77(m,4H),6.58(dd,J＝7.53,10.29Hz,1H),2.80-3.06(m,2H),2.64-2.75(m,1H),2.55-2.62(m,1H).TEA (24.7 mg, 212 μmol) and benzoyl chloride (29.7 mg, 212 μmol) were added to a DCM (2 mL) solution of compound 67 (50 mg, 163 μmol) and reacted at 25°C for 4 hours. After the reaction, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA/PE, EA from 0 to 30%) to obtain a white solid compound 138 (20 mg, yield 28.6%). LCMS: (ESI) m/z = 411.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.28(d,J＝7.28Hz,2H),8.20(d,J＝8.53Hz,1H),8.00(d,J＝8.03Hz,1H),7.91(s,1H),7.81-7.8 7(m,1H),7.66-7.77(m,4H),6.58(dd,J＝7.53,10.29Hz,1H),2.80-3.06(m,2H),2.64-2.75(m,1H),2.55-2.62(m,1H).

参照实施例38的方法，用如下表格中的起始原料替换苯甲酰氯与化合物67进行反应得到相应的终产化合物。
Referring to the method of Example 38, the starting materials shown in the following table were used to replace benzoyl chloride and react with compound 67 to obtain the corresponding final product compound.

实施例39化合物140和化合物141的合成
Example 39 Synthesis of Compound 140 and Compound 141

步骤一：向化合物67(50mg,163μmol)和化合物141-A(38.5mg,179μmol,1.1eq)的DCM(2mL)溶液中加入EDCI(40.5mg,211.63μmol,1.3eq)和DMAP(1.99mg,16.28μmol,0.1eq)。在25℃搅拌3小时，减压浓缩。粗产品通过硅胶柱色谱(EA/PE,EA从0到30％)纯化得白色固体化合物141(70mg,收率82％)。1H NMR(400MHz,DMSO-d6)δ8.09-7.95(m,2H),7.60-7.81(m,3H),6.54(br dd,J＝7.64,9.96Hz,1H),4.52-4.77(m,1H),3.46-3.56(m,2H),2.62-3.06(m,3H),2.44(br d,J＝5.14Hz,3H),1.90-2.16(m,2H),1.44(d,J＝18.46Hz,9H).(ESI)m/z＝403.9[M-Boc+H]+ Step 1: Add EDCI (40.5 mg, 211.63 μmol, 1.3 eq) and DMAP (1.99 mg, 16.28 μmol, 0.1 eq) to a DCM (2 mL) solution of compound 67 (50 mg, 163 μmol) and compound 141-A (38.5 mg, 179 μmol, 1.1 eq). Stir at 25 °C for 3 hours and concentrate under reduced pressure. The crude product was purified by silica gel column chromatography (EA/PE, EA from 0 to 30%) to obtain white solid compound 141 (70 mg, yield 82%). 1H NMR(400MHz,DMSO-d6)δ8.09-7.95(m,2H),7.60-7.81(m,3H),6.54(br dd,J＝7.64,9.96Hz,1H),4.52-4.77(m,1H),3.46-3.56(m,2H),2.62-3.06(m,3H),2.44(br d,J＝5.14Hz,3H),1.90-2.16(m,2H),1.44(d,J＝18.46Hz,9H).(ESI)m/z＝403.9[M-Boc+H] +

步骤二(脱Boc保护基的代表性方法)：化合物141(20mg,0.397mmol)在DCM(2mL)和TFA(0.4mL)的溶液在25℃搅拌反应2小时,减压浓缩，所得残余物prep HPLC(FA方法；B％:5％-35％,8min)纯化得白色固体化合物140(2mg,收率12％)。LCMS:(ESI)m/z＝404.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.22(d,J＝7.78Hz,1H),7.96(d,J＝8.53Hz,1H),7.50-7.69(m,2H),7.11(s,1H),6.43(dd,J＝7.53,10.29Hz,1H),3.67(br dd,J＝6.02,8.53Hz,1H),2.74-3.07(m,4H),1.65-2.13(m,4H).Step 2 (representative method for removing the Boc protecting group): A solution of compound 141 (20 mg, 0.397 mmol) in DCM (2 mL) and TFA (0.4 mL) was stirred at 25°C for 2 hours, concentrated under reduced pressure, and the residue was purified by prep HPLC (FA method; B%: 5%-35%, 8 min) to give white solid compound 140 (2 mg, yield 12%). LCMS: (ESI)m/z＝404.1[M+H] + .1H NMR (400MHz, DMSO-d6) δ8.22(d,J＝7.78Hz,1H),7.96(d,J＝8.53Hz,1H),7.50-7.69(m,2H),7.11(s,1H),6.43(dd,J＝7.53,10.29Hz,1H),3.67(br dd,J＝6.02,8.53Hz,1H),2.74-3.07(m,4H),1.65-2.13(m,4H).

参照实施例39中步骤一的方法，用如下表格中的起始原料替换141-A与化合物67进行反应得到相应的终产化合物。

Referring to the method of step 1 in Example 39, the starting materials shown in the following table were substituted for 141-A and reacted with compound 67 to obtain the corresponding final compound.

参照实施例39中步骤一的方法，用如下表格中的起始原料进行反应得到相应的终产化合物。

Referring to the method of step 1 in Example 39, the starting materials in the following table were used to react to obtain the corresponding final compounds.

实施例40化合物161的合成
Example 40 Synthesis of Compound 161

步骤一：参照实施例38的方法，以化合物76(60mg)和化合物161-A(5eq)为起始原料进行反应得黄色固体化合物161-B(100mg)。粗产品直接用于下一步反应。Step 1: Referring to the method of Example 38, compound 76 (60 mg) and compound 161-A (5 eq) were used as starting materials to react to obtain yellow solid compound 161-B (100 mg). The crude product was directly used for the next step.

步骤二：参照实施例39中步骤二的方法，以化合物161-B(100mg)进行反应得白色固体化合物161(25mg,两步收率约29％)。LCMS:(ESI)m/z＝398.1(M+1)+,1H NMR(400MHz,DMSO-d6)Shift 8.46(br s,2H),8.30-8.36(m,1H),8.24(dd,J＝2.87,7.03Hz,1H),8.16(d,J＝8.44Hz,1H),7.52-7.83(m,4H),6.41(s,0.86H),6.28(s,0.12H),2.54-2.70(m,2H),1.39-1.68(m,2H).Step 2: Referring to the method of Step 2 in Example 39, compound 161-B (100 mg) was reacted to obtain white solid compound 161 (25 mg, two-step yield of about 29%). LCMS: (ESI) m/z = 398.1 (M+1) + , 1 H NMR (400 MHz, DMSO-d6) Shift 8.46 (br s, 2H), 8.30-8.36 (m, 1H), 8.24 (dd, J = 2.87, 7.03 Hz, 1H), 8.16 (d, J = 8.44 Hz, 1H), 7.52-7.83 (m, 4H), 6.41 (s, 0.86H), 6.28 (s, 0.12H), 2.54-2.70 (m, 2H), 1.39-1.68 (m, 2H).

实施例41化合物143的合成
Example 41 Synthesis of Compound 143

将化合物142(100mg,0.22mmol)在DCM(2mL)的溶液中加入DIEA(84.9mg,657μmol)和三氯硅烷(89.0mg,657μmol)。在25℃搅拌反应2小时。用饱和NaHCO3溶液(10mL)淬灭反应，混合物用DCM(15mL×3)萃取。经过常规的后处理操作二后得残余物，残留物经硅胶柱色(EA:PE，EA从0到40％)纯化得白色固体化合物143(30mg,收率28％)。LCMS:(ESI)m/z＝427.9[M+H]+；1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝8.53Hz,1H),8.09-8.15(m,1H),7.93-7.97(m,1H),7.81(s,1H),7.65-7.75(m,2H),7.39-7.45(m,1H),6.90(d,J＝8.53Hz,1H),6.78-6.84(m,2H),6.69(t,J＝7.53Hz,1H),6.57(dd,J＝7.28,10.29Hz,1H),2.79-3.06(m,2H),2.65-2.74(m,1H),2.57-2.61(m,1H).DIEA (84.9 mg, 657 μmol) and trichlorosilane (89.0 mg, 657 μmol) were added to a solution of compound 142 (100 mg, 0.22 mmol) in DCM (2 mL). The reaction was stirred at 25 °C for 2 hours. The reaction was quenched with saturated NaHCO 3 solution (10 mL), and the mixture was extracted with DCM (15 mL×3). After conventional post-treatment operation 2, the residue was obtained, and the residue was purified by silica gel column chromatography (EA:PE, EA from 0 to 40%) to obtain white solid compound 143 (30 mg, yield 28%). LCMS: (ESI) m/z=427.9[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ8.19(d,J＝8.53Hz,1H),8.09-8.15(m,1H),7.93- 7.97(m,1H),7.81(s,1H),7.65-7.75(m,2H),7.39-7.45(m,1H),6.90(d,J ＝8.53Hz,1H),6.78-6.84(m,2H),6.69(t,J＝7.53Hz,1H),6.57(dd,J＝7.2 8,10.29Hz,1H),2.79-3.06(m,2H),2.65-2.74(m,1H),2.57-2.61(m,1H).

实施例42化合物149的合成
Example 42 Synthesis of Compound 149

向化合物149-A(36.7mg,146μmol)和氯化亚砜(20.9mg,176μmol)的DCM(0.2mL)溶液中加入1滴DMF，在40℃搅拌40分钟。降至25℃，用氮气吹干溶剂，将化合物67(30mg,97.68μmol)的吡啶(2mL)溶液加入其中，在60℃搅拌1小时。加入EtOAc(4mL)，经过常规的后处理操作二后得粗产品，粗产品通过硅胶柱色谱(EA/PE,EA从8％到30％)纯化得白色固体化合物149(25mg,收率47％)。1H NMR(400MHz,DMSO-d6)δppm 2.54-2.59(m,1H)2.68-2.74(m,1H)2.83-2.89(m,1H)2.92-3.00(m,1H)4.03(s,6H)6.57(dd,J＝10.27,7.46Hz,1H)7.15(s,1H)7.68(s,1H)7.74-7.81(m,2H)8.15-8.19(m,1H)8.20-8.26(m,1H).LCMS:(ESI)m/z＝541.0(M+1)+.To a solution of compound 149-A (36.7 mg, 146 μmol) and thionyl chloride (20.9 mg, 176 μmol) in DCM (0.2 mL) was added 1 drop of DMF and stirred at 40°C for 40 minutes. The temperature was lowered to 25°C, the solvent was blown dry with nitrogen, a solution of compound 67 (30 mg, 97.68 μmol) in pyridine (2 mL) was added thereto, and stirred at 60°C for 1 hour. EtOAc (4 mL) was added, and a crude product was obtained after conventional post-treatment operation 2. The crude product was purified by silica gel column chromatography (EA/PE, EA from 8% to 30%) to obtain white solid compound 149 (25 mg, yield 47%). 1 H NMR (400MHz, DMSO-d 6 ) δppm 2.54-2.59(m,1H)2.68-2.74(m,1H)2.83-2.89(m,1H)2.92-3.00(m,1H)4.03(s,6H)6.57(dd,J＝10.27,7.46Hz, 1H)7.15(s,1H)7.68(s,1H)7.74-7.81(m,2H)8.15-8.19(m,1H)8.20-8.26(m,1H).LCMS:(ESI)m/z＝541.0(M+1) + .

实施例43化合物160的合成
Example 43 Synthesis of Compound 160

向化合物76(65mg,204μmol)和碳酸铯(99.5mg,305.50μmol)的DMF(2mL)溶液中加入化合物160-A(38mg,306μmol)，25℃反应16小时。反应毕加入饱和食盐水(10mL)，用EtOAc萃取(5mL*3)。合并有机相，有机相用无水硫酸镁干燥，过滤，滤液减压浓缩。所得剩余物通过硅胶柱色谱(EA/PE,EA从0到20％)纯化，然后再通过prep HPLC(FA方法；B％:43％-63％,16min)纯化得白色固体化合物160(10mg,收率12％).(ESI)m/z＝407.2(M+1)+.1H NMR(400MHz,CDCl3),δ8.22-8.40(m,1H),8.09(d,J＝8.58Hz,1H),7.48-7.69(m,2H),7.33(s,1H),6.33(s,1H),5.99(s,2H),3.87(s,3H),2.50-2.67(m,1H),2.42(dt,J＝4.62,6.05Hz,1H),1.62-1.66(m,1H),1.37(q,J＝4.03Hz,1H).Compound 160-A (38 mg, 306 μmol) was added to a DMF (2 mL) solution of compound 76 (65 mg, 204 μmol) and cesium carbonate (99.5 mg, 305.50 μmol), and the mixture was reacted at 25°C for 16 hours. After the reaction, saturated brine (10 mL) was added and extracted with EtOAc (5 mL*3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA/PE, EA from 0 to 20%), and then purified by prep HPLC (FA method; B%: 43%-63%, 16 min) to obtain a white solid compound 160 (10 mg, yield 12%). (ESI) m/z = 407.2 (M+1) + . 1 H NMR (400 MHz, CDCl 3 ), δ8.22-8.40(m,1H),8.09(d,J＝8.58Hz,1H),7.48-7.69(m,2H),7.33(s,1H),6.33(s,1H),5.99(s,2H), 3.87(s,3H),2.50-2.67(m,1H),2.42(dt,J＝4.62,6.05Hz,1H),1.62-1.66(m,1H),1.37(q,J＝4.03Hz,1H).

实施例44化合物163的合成
Example 44 Synthesis of Compound 163

步骤一：Step 1:

LDA溶液的制备：在-78℃，向二异丙胺(402mg,3.98mmol)的THF(8mL)溶液中滴加正丁基锂的THF溶液(2.5M,1.46mL)，在20℃搅拌0.5小时。Preparation of LDA solution: To a solution of diisopropylamine (402 mg, 3.98 mmol) in THF (8 mL) was added dropwise a solution of n-butyllithium in THF (2.5 M, 1.46 mL) at -78°C and the mixture was stirred at 20°C for 0.5 h.

在-20℃，将化合物163-A(400mg,1.66mmol)的THF(2mL)加入到上述LDA溶液中，在0℃搅拌1小时。随后加入溴乙酸叔丁酯(356mg,1.83mmol)和1,3-二甲基-2-咪唑啉酮(189mg,1.66mmol)，在0℃搅拌5小时，用饱和NH4Cl溶液(6mL)淬灭反应。在20℃搅拌0.5小时hou1用EtOAc(8mL x 3)萃取，经常规的后处理操作二后得粗产品，再通过硅胶柱色谱(EA/PE,EA从8到32％)纯化得黄色油状物163-B(161mg,收率27.32％)。1H NMR(400MHz,DMSO-d6)δppm 1.36-1.40(m,9H)1.75-1.85(m,1H)2.00-2.06(m,1H)2.34-2.43(m,1H)2.54-2.57(m,1H)2.81-2.92(m,2H)2.96-3.04(m,1H)6.66-6.70(m,1H)6.94-7.00(m,1H)10.63-10.70(m,1H)。Compound 163-A (400 mg, 1.66 mmol) in THF (2 mL) was added to the above LDA solution at -20°C and stirred at 0°C for 1 hour. Tert-butyl bromoacetate (356 mg, 1.83 mmol) and 1,3-dimethyl-2-imidazolidinone (189 mg, 1.66 mmol) were then added and stirred at 0°C for 5 hours. The reaction was quenched with saturated NH 4 Cl solution (6 mL). The mixture was stirred at 20°C for 0.5 hours and then extracted with EtOAc (8 mL x 3). After conventional post-treatment, the crude product was obtained, which was then purified by silica gel column chromatography (EA/PE, EA from 8 to 32%) to obtain a yellow oil 163-B (161 mg, yield 27.32%). 1 H NMR (400MHz, DMSO-d 6 ) δppm 1.36-1.40(m,9H)1.75-1.85(m,1H)2.00-2.06(m,1H)2.34-2.43(m,1H)2.54-2.57(m,1H)2 .81-2.92(m,2H)2.96-3.04(m,1H)6.66-6.70(m,1H)6.94-7.00(m,1H)10.63-10.70(m,1H).

步骤二：化合物163-B(140mg,394.12μmol)的DCM(2mL)和TFA(224mg,1.97mmol,150uL,5eq)溶液在40℃反应1小时。减压浓缩，粗产物通过硅胶柱色谱(EA/PE,EA从0到57％)纯化得黄色油状物163-C(51mg,收率43％).LCMS:(ESI)m/z＝300.9[M+H]+.Step 2: Compound 163-B (140 mg, 394.12 μmol) in DCM (2 mL) and TFA (224 mg, 1.97 mmol, 150 uL, 5 eq) was reacted at 40°C for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA/PE, EA from 0 to 57%) to obtain a yellow oil 163-C (51 mg, yield 43%). LCMS: (ESI) m/z = 300.9 [M+H] + .

步骤三：参照实施例5步骤二的方法，以化合物163-C(45mg,150.4μmol)进行反应得白色固体化合物163(12mg,收率28.2％)。1H NMR(400MHz,CDCl3)δppm 1.86(br dd,J＝13.27,3.97Hz,1H)2.43(d,J＝17.36Hz,1H)2.65-2.85(m,4H)2.97(dd,J＝17.18,7.52Hz,1H)5.03-5.22(m,1H)5.54(d,J＝5.26Hz,1H)6.61(d,J＝2.45Hz,1H)7.04(d,J＝2.45Hz,1H)。LCMS:(ESI)m/z＝284.9(M+1)+.Step 3: Referring to the method of Step 2 of Example 5, compound 163-C (45 mg, 150.4 μmol) was reacted to obtain white solid compound 163 (12 mg, yield 28.2%). 1 H NMR (400 MHz, CDCl 3 ) δppm 1.86 (br dd, J＝13.27, 3.97 Hz, 1H) 2.43 (d, J＝17.36 Hz, 1H) 2.65-2.85 (m, 4H) 2.97 (dd, J＝17.18, 7.52 Hz, 1H) 5.03-5.22 (m, 1H) 5.54 (d, J＝5.26 Hz, 1H) 6.61 (d, J＝2.45 Hz, 1H) 7.04 (d, J＝2.45 Hz, 1H). LCMS: (ESI)m/z=284.9(M+1) + .

实施例45化合物164和165的合成
Example 45 Synthesis of Compounds 164 and 165

步骤一：向化合物164-A(2.01g,16.22mmol)的DCM(50mL)溶液中加入三氯化铝(3.24g,24.32mmol)，在10℃搅拌10分钟后滴加164-B(2.5g,16.22mmol)的DCM(5mL)溶液，在10℃搅拌10分钟后回流反应3小时。减压浓缩，加入水(100mL)，用浓盐酸调pH到1-2，用DCM萃取(100mL*3)，经过常规的后处理操作后得粗产物，再通过硅胶柱色谱(EA/PE,EA从16到53％)纯化得黄色固体164-C(180mg,收率4％).1H NMR(400MHz,DMSO-d6)11.95(br s,1H),10.18(s,1H),7.36(d,J＝7.96Hz,1H),6.44(s,1H),6.40(dd,J＝2.26,8.53Hz,1H),3.82(s,3H),3.67(br d,J＝4.02Hz,1H),2.68(br s,1H),1.62-1.93(m,6H),1.49(br s,1H),1.34(br d,J＝15.06Hz,4H)Step 1: To a solution of compound 164-A (2.01 g, 16.22 mmol) in DCM (50 mL) was added aluminum chloride (3.24 g, 24.32 mmol), stirred at 10°C for 10 minutes, and then a solution of 164-B (2.5 g, 16.22 mmol) in DCM (5 mL) was added dropwise, stirred at 10°C for 10 minutes, and then refluxed for 3 hours. The mixture was concentrated under reduced pressure, water (100 mL) was added, the pH was adjusted to 1-2 with concentrated hydrochloric acid, and extracted with DCM (100 mL*3). After conventional post-treatment, the crude product was obtained, which was then purified by silica gel column chromatography (EA/PE, EA from 16 to 53%) to give a yellow solid 164-C (180 mg, yield 4%). 1 H NMR (400 MHz, DMSO-d6) 11.95 (br s, 1H), 10.18 (s, 1H), 7.36 (d, J = 7.96 Hz, 1H), 6.44 (s, 1H), 6.40 (dd, J = 2.26, 8.53 Hz, 1H), 3.82 (s, 3H), 3.67 (br d, J = 4.02 Hz, 1H), 2.68 (br s, 1H), 1.62-1.93 (m, 6H), 1.49 (br s,1H),1.34(br d,J＝15.06Hz,4H)

步骤二：参照实施例5步骤二的方法，以化合物164-C(100mg,359.3μmol)进行反应(NaOH为5eq，NaBH4为40eq)得白色固体化合物164(18mg,收率19.1％)和白色固体化合物165(8mg,收率8.5％)。Step 2: Referring to the method of Step 2 of Example 5, compound 164-C (100 mg, 359.3 μmol) was reacted (NaOH was 5 eq, NaBH 4 was 40 eq) to obtain white solid compound 164 (18 mg, yield 19.1%) and white solid compound 165 (8 mg, yield 8.5%).

化合物164：LCMS:(ESI)m/z＝263.0[M+1]+；1H NMR(400MHz,DMSO-d6)9.56(s,0.6H),9.47(s,0.3H),7.02(d,J＝8.0Hz,0.3H),6.93(d,J＝8.3Hz,0.6H),6.45(d,J＝2.0Hz,0.6H),6.42(d,J＝2.0Hz,0.3H),6.36(dd,J＝8.3,2.0Hz,1H),5.53(d,J＝4.5Hz,0.3H),5.29(d,J＝3.5Hz,0.6H),3.77(s,2H),3.75(s,1H),3.10(br t,J＝5.6Hz,0.3H),2.65-2.72(m,1.2H),2.35-2.43(m,0.6H),1.98(br d,J＝14.1Hz,0.4H),1.77-1.88(m,1.3H),1.42-1.63(m,3.2H),1.16-1.30(m,2H),0.83-1.05(m,1.2H),0.58-0.69(m,0.3H)Compound 164: LCMS: (ESI) m/z=263.0[M+1] + ; 1 H NMR(400MHz, DMSO-d6)9.56(s,0.6H),9.47(s,0.3H),7.02(d,J＝8.0Hz,0.3H),6.93(d,J＝8.3Hz,0.6H),6.45(d,J＝2.0Hz,0.6H),6.42 (d,J＝2.0Hz,0.3H),6.36(dd,J＝8.3,2.0Hz,1H),5.53(d,J＝4.5Hz,0.3H),5.29(d,J＝3.5Hz,0.6H),3.77(s,2H),3.75(s,1H),3.10(br t,J＝5.6Hz,0.3H),2.65-2.72(m,1.2H),2.35-2.43(m,0.6H),1.98(br d,J＝14.1Hz,0.4H),1.77-1.88(m,1.3H),1.42-1.63(m,3.2H),1.16-1.30(m,2H),0.83-1.05(m,1.2H),0.58-0.69(m,0.3H)

化合物165：LCMS:(ESI)m/z＝263.0[M+1]+；1H NMR(400MHz,DMSO-d6)9.65(s,1H),7.15(d,J＝8.5Hz,1H),6.44(s,1H),6.39(br d,J＝8.3Hz,1H),5.33(d,J＝10.3Hz,1H),3.74(s,3H),2.31-2.39(m,1H),1.92-2.04(m,2H),1.66-1.82(m,2H),1.61(br d,J＝12.0Hz,1H),1.14-1.30(m,4H)Compound 165: LCMS: (ESI) m/z=263.0 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) 9.65 (s, 1H), 7.15 (d, J=8.5 Hz, 1H), 6.44 (s, 1H), 6.39 (br d, J=8.3 Hz, 1H), 5.33 (d, J=10.3 Hz, 1H), 3.74 (s, 3H), 2.31-2.39 (m, 1H), 1.92-2.04 (m, 2H), 1.66-1.82 (m, 2H), 1.61 (br d, J=12.0 Hz, 1H), 1.14-1.30 (m, 4H)

实施例46化合物166的合成
Example 46 Synthesis of Compound 166

步骤一：参照催化氢化代表性操作的方法，以化合物166-A(35mg)为原料反应得白色固体化合物166(28mg,产率39％)。硅胶柱色谱纯化(EA:PE，EA从0到25％)。LCMS:(ESI)m/z＝291.1[M+1]+；1H NMR(400MHz,CDCl3)6.99(s,1H),6.58(s,1H),5.40(s,1H),3.92(s,1H),3.77(s,3H),2.84-2.93(m,2H),2.67-2.80(m,2H),1.60(s,3H).Step 1: Referring to the representative operation method of catalytic hydrogenation, compound 166-A (35 mg) was used as the raw material to obtain white solid compound 166 (28 mg, yield 39%). Purification by silica gel column chromatography (EA:PE, EA from 0 to 25%). LCMS: (ESI) m/z = 291.1 [M + 1] + ; 1 H NMR (400MHz, CDCl 3 ) 6.99 (s, 1H), 6.58 (s, 1H), 5.40 (s, 1H), 3.92 (s, 1H), 3.77 (s, 3H), 2.84-2.93 (m, 2H), 2.67-2.80 (m, 2H), 1.60 (s, 3H).

化合物168的合成：向化合物166的DMF(0.5mL)溶液中加入NaOH(0.5M,1.5eq)。在25℃搅拌反应2小时，LCMS显示20％原料剩余并有35％目标产物生成。用甲酸调pH至6，直接通过prep HPLC(FA方法-B；B％:23％-43％,10min)纯化得白色固体化合物168(收率54％)。LCMS:(ESI)m/z＝309.0[M+1]+；1H NMR(400MHz,DMSO-d6)9.67-11.99(m,1H),7.06(br s,1H),6.50(br s,1H),5.37(br s,1H),4.29(br s,1H),3.76(br s,1H),3.69(br s,3H),2.61-2.79(m,2H),2.44(br d,J＝7.03Hz,2H),1.49-1.63(m,3H).Synthesis of Compound 168: NaOH (0.5 M, 1.5 eq) was added to a DMF (0.5 mL) solution of Compound 166. The reaction was stirred at 25°C for 2 hours. LCMS showed that 20% of the starting material remained and 35% of the target product was generated. The pH was adjusted to 6 with formic acid and purified directly by prep HPLC (FA method-B; B%: 23%-43%, 10 min) to obtain a white solid Compound 168 (yield 54%). LCMS: (ESI) m/z＝309.0[M+1] + ; 1 H NMR (400MHz, DMSO-d6) 9.67-11.99 (m, 1H), 7.06 (br s, 1H), 6.50 (br s, 1H), 5.37 (br s, 1H), 4.29 (br s, 1H), 3.76 (br s,1H),3.69(br s,3H),2.61-2.79(m,2H),2.44(br d,J＝7.03Hz,2H),1.49-1.63(m,3H).

化合物167的合成：参照实施例5-a的合成方法，用甲胺(33％的乙醇溶液)与化合物166进行反应(反应时间2小时，44％的原料剩余)得白色固体化合物167，收率28.4％。LCMS:(ESI)m/z＝322.0[M+1]+；1H NMR(400MHz,DMSO-d6)9.84(br s,1H),7.75(br s,1H),7.02(s,1H),6.49(s,1H),5.37(s,1H),4.29(s,1H),3.70(s,3H),2.63-2.71(m,2H),2.56(br d,J＝4.28Hz,3H),2.24-2.32(m,2H),1.58(s,3H)。Synthesis of Compound 167: Referring to the synthesis method of Example 5-a, methylamine (33% ethanol solution) was reacted with Compound 166 (reaction time 2 hours, 44% of the raw material remained) to obtain white solid Compound 167, yield 28.4%. LCMS: (ESI) m/z = 322.0 [M + 1] + ; 1 H NMR (400MHz, DMSO-d6) 9.84 (br s, 1H), 7.75 (br s, 1H), 7.02 (s, 1H), 6.49 (s, 1H), 5.37 (s, 1H), 4.29 (s, 1H), 3.70 (s, 3H), 2.63-2.71 (m, 2H), 2.56 (br d, J = 4.28 Hz, 3H), 2.24-2.32 (m, 2H), 1.58 (s, 3H).

实施例47化合物169的合成
Example 47 Synthesis of Compound 169

向化合物169-A(100mg,416μmol)在THF(2mL)和水(5mL)的混合物中加入NaOH(49.9mg,1.25mmol)和NaBH4(94.5mg,2.5mmol)。在20℃搅拌反应3小时。在10℃加入1M的HCl(5mL)和EtOAc(5mL)，混合物用EA(5mL×2)萃取。合并的有机相用氮气吹干(注意：不要减压浓缩)得粗产品，粗产品通过硅胶柱色谱(EA/PE,EA从0到50％)纯化得白色化合物169(20mg,收率21％)。LCMS:(ESI)m/z＝224.9[M+H]+,1H NMR(400MHz,DMSO-d6)δ7.23(d,J＝7.78Hz,1H),6.88(d,J＝1.51Hz,1H),6.85(dd,J＝1.51,7.78Hz,1H),5.03(br s,1H),4.79(dd,J＝4.64,7.15Hz,1H),3.74(s,3H),2.15-2.23(m,2H),1.64-1.85(m,2H).To a mixture of compound 169-A (100 mg, 416 μmol) in THF (2 mL) and water (5 mL) were added NaOH (49.9 mg, 1.25 mmol) and NaBH 4 (94.5 mg, 2.5 mmol). The reaction was stirred at 20°C for 3 hours. 1M HCl (5 mL) and EtOAc (5 mL) were added at 10°C, and the mixture was extracted with EA (5 mL×2). The combined organic phase was dried with nitrogen (note: do not concentrate under reduced pressure) to obtain a crude product, which was purified by silica gel column chromatography (EA/PE, EA from 0 to 50%) to obtain white compound 169 (20 mg, yield 21%). LCMS: (ESI) m/z＝224.9[M+H] + , 1 H NMR (400MHz, DMSO-d6) δ7.23 (d, J＝7.78Hz, 1H), 6.88 (d, J＝1.51Hz, 1H), 6.85 (dd, J＝1.51, 7.78Hz, 1H), 5.03 (br s,1H),4.79(dd,J＝4.64,7.15Hz,1H),3.74(s,3H),2.15-2.23(m,2H),1.64-1.85(m,2H).

实施例48化合物171和化合物267的合成
Example 48 Synthesis of Compound 171 and Compound 267

步骤一：参照实施例45中步骤一的方法，以164-A(9.5g,76.53mmol)与171-B(1eq)反应得黄色固体171-A(130mg,收率0.68％)和黄色油状物267-A(14g,55.9mmol,收率73.1％)。Step 1: Referring to the method of step 1 in Example 45, 164-A (9.5 g, 76.53 mmol) was reacted with 171-B (1 eq) to obtain yellow solid 171-A (130 mg, yield 0.68%) and yellow oil 267-A (14 g, 55.9 mmol, yield 73.1%).

化合物171-A:1H NMR(400MHz,DMSO-d6)δ(ppm)9.63(s,1H),7.46(s,1H),7.43-7.45(m,1H),6.32-6.39(m,2H),3.5(s,3H),1.75(s,3H),1.58(s,3H).Compound 171-A: 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)9.63(s,1H),7.46(s,1H),7.43-7.45(m,1H),6.32-6.39(m,2H),3.5(s,3H),1.75(s,3H),1.58(s,3H).

化合物171的合成：将化合物171-A(50mg,199μmol)溶解在THF(5mL)中，加入氢氧化钯/碳(20％含量，100mg)，反应混合物充分置换氢气。15Psi氢气氛围下，25℃搅拌反应16小时。反应液抽滤，减压浓缩至干，通过硅胶柱色谱(EA/PE,EA从0到35％)纯化得黄色固体化合物171(15mg,收率32％)。1H NMR(400HMz,DMSO-d6)δ(ppm)9.59(s,1H),6.96-7.01(m,1H),6.35-6.44(m,2H),5.22-5.39(m,1H),3.75(s,3H),2.68-2.85(m,1H),2.49-2.55(m,1H),1.05-1.18(m,3H),0.94-1.03(m,2H),0.36-0.38(m,0.5H).LC-MS:(ESI)m/z.[M+H]+237.0.Synthesis of compound 171: Compound 171-A (50 mg, 199 μmol) was dissolved in THF (5 mL), palladium hydroxide/carbon (20% content, 100 mg) was added, and the reaction mixture was fully replaced with hydrogen. The reaction was stirred at 25°C for 16 hours under a 15 Psi hydrogen atmosphere. The reaction solution was filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (EA/PE, EA from 0 to 35%) to obtain a yellow solid compound 171 (15 mg, yield 32%). 1 H NMR (400HMz, DMSO-d 6 )δ(ppm)9.59(s,1H),6.96-7.01(m,1H),6.35-6.44(m,2H),5.22-5.39(m,1H),3.75(s,3H),2.68-2.85(m, 1H),2.49-2.55(m,1H),1.05-1.18(m,3H),0.94-1.03(m,2H),0.36-0.38(m,0.5H).LC-MS:(ESI)m/z.[M+H] + 237.0.

化合物267的合成：参照化合物171的合成方法，以化合物267-A(100mg,399μmol,1eq)进行反应得白色固体化合物267(30mg,收率30.5％)。1H NMR(400HMz,DMSO-d6)δ(ppm)9.72-9.92(m,1H),6.97-7.13(m,1H),6.42(dt,J＝2.2,4.7Hz,2H),5.20-5.69(m,1H),3.70(s,3H),2.82-3.20(m,1H),2.56-2.80(m,1H),1.07(dd,J＝7.4,15.7Hz,3H),0.36-0.98(m,3H)。LC-MS:(ESI)m/z.[M+H]+237.0。Synthesis of compound 267: Referring to the synthesis method of compound 171, compound 267-A (100 mg, 399 μmol, 1 eq) was reacted to obtain white solid compound 267 (30 mg, yield 30.5%). 1 H NMR (400HMz, DMSO-d 6 )δ(ppm)9.72-9.92(m, 1H),6.97-7.13(m, 1H),6.42(dt, J＝2.2,4.7 Hz, 2H),5.20-5.69(m, 1H),3.70(s, 3H),2.82-3.20(m, 1H),2.56-2.80(m, 1H),1.07(dd, J＝7.4,15.7 Hz, 3H),0.36-0.98(m, 3H). LC-MS: (ESI)m/z. [M+H] + 237.0.

实施例50化合物174的合成
Example 50 Synthesis of Compound 174

步骤一：将化合物174-A的(100mg,485μmol)、吗啉(123mg,1.45mmol,3eq)和乙醛酸(179mg,1.21mmol,135μL,2.5eq)的混合在60℃搅拌反应16小时。降至室温，加5ACN(1mL)稀释，直接通过prep HPLC(FA方法，B:15％-35％ B over 38min)纯化得棕色固体化合物174-B(38mg,产率22.4％)。1H NMR(400MHz,CDCl3)δ(ppm)7.87(d,J＝8.6Hz,1H),6.58(dd,J＝2.4,8.8Hz,1H),6.48(d,J＝2.2Hz,1H),6.03-6.20(m,1H),5.47(dd,J＝1.3,17.4Hz,1H),5.38(dd,J＝0.9,10.6Hz,1H),4.66(d,J＝5.7Hz,2H),4.21(t,J＝6.2Hz,1H),3.88(s,3H),3.80-3.85(m,4H),3.65-3.74(m,1H),3.47-3.57(m,1H),2.81-2.88(m,4H)。Step 1: Compound 174-A (100 mg, 485 μmol), morpholine (123 mg, 1.45 mmol, 3 eq) and glyoxylic acid (179 mg, 1.21 mmol, 135 μL, 2.5 eq) were stirred at 60°C for 16 hours. The mixture was cooled to room temperature, diluted with 5ACN (1 mL), and directly purified by prep HPLC (FA method, B: 15%-35% B over 38 min) to obtain brown solid compound 174-B (38 mg, yield 22.4%). 1 H NMR (400MHz, CDCl 3 )δ(ppm)7.87(d,J＝8.6Hz,1H),6.58(dd,J＝2.4,8.8Hz,1H),6.48(d,J＝2.2Hz,1H),6.03-6.20(m,1H),5.47(dd,J＝1.3,17.4Hz,1H),5.38(dd,J＝0.9, 10.6Hz,1H),4.66(d,J＝5.7Hz,2H),4.21(t,J＝6.2Hz,1H),3.88(s,3H),3. 80-3.85(m,4H),3.65-3.74(m,1H),3.47-3.57(m,1H),2.81-2.88(m,4H).

步骤二：参照实施例5中步骤二(构建五元内酯环代表性操作)的方法，以化合物174-B(310mg,887μmol,1eq)进行反应得到黄色油状物174-C(77mg,230μmol,收率26％)。LC-MS:(ESI)m/z.[M+H]+334.1。Step 2: Referring to the method of Step 2 in Example 5 (representative operation for constructing a five-membered lactone ring), compound 174-B (310 mg, 887 μmol, 1 eq) was reacted to obtain yellow oil 174-C (77 mg, 230 μmol, yield 26%). LC-MS: (ESI) m/z. [M+H] + 334.1.

步骤三：参照实施例2步骤3的方法，以化合物174-C(77mg,230μmo)进行反应得白色固体化合物(15mg,51μmol,收率22.1％)。1H NMR(400MHz,DMSO-d6)δ(ppm)9.68-10.17(m,1H),7.05-7.22(m,1H),6.42(dd,J＝2.1,4.5Hz,2H),5.61(dd,J＝5.0,8.5Hz,0.3H),5.51(dd,J＝5.7,10.8Hz,0.7H),3.91(dd,J＝8.4,12.1Hz,0.7H),3.69-3.76(s,3H),3.67(dd,J＝2.3,4.7Hz,0.3H),3.59(t,J＝4.5Hz,4H),2.76-2.91(m,2H),2.42-2.50(m,3H),2.18-2.39(m,1H).LC-MS:(ESI)m/z.[M+H]+294.1.Step 3: Referring to the method of step 3 of Example 2, compound 174-C (77 mg, 230 μmol) was reacted to obtain a white solid compound (15 mg, 51 μmol, yield 22.1%). 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)9.68-10.17(m,1H),7.05-7.22(m,1H),6.42(dd,J＝2.1,4.5Hz,2H),5.61 (dd,J＝5.0,8.5Hz,0.3H),5.51(dd,J＝5.7,10.8Hz,0.7H),3.91(dd,J＝8.4,12.1H z,0.7H),3.69-3.76(s,3H),3.67(dd,J＝2.3,4.7Hz,0.3H),3.59(t,J＝4.5Hz,4H) ,2.76-2.91(m,2H),2.42-2.50(m,3H),2.18-2.39(m,1H).LC-MS:(ESI)m/z.[M+H] + 294.1.

实施例51化合物271和化合物272的合成
Example 51 Synthesis of Compound 271 and Compound 272

步骤一：在0℃，向化合物271-A(500mg,3.49mmol)和Na2CO3(740mg,6.98mmol)在THF/水(10mL,1:1)的混合物中加入271-B(500mg,3.94mmol)，混合物在0℃反应10分钟。减压除去溶剂，粗产物通过Prep HPLC(column:C18 150×40mm；mobile phase:[water(FA)-ACN]；gradient:1％-41％ B over 9min)分离纯化得到无色油状物271-C(520mg,收率64％)。LCMS:(ESI)m/z＝234.0(M+1)+.Step 1: Add 271-B (500 mg, 3.94 mmol) to a mixture of compound 271-A (500 mg, 3.49 mmol) and Na 2 CO 3 (740 mg, 6.98 mmol) in THF/water (10 mL, 1:1) at 0°C, and react the mixture at 0°C for 10 minutes. The solvent was removed under reduced pressure, and the crude product was separated and purified by Prep HPLC (column: C18 150×40 mm; mobile phase: [water(FA)-ACN]; gradient: 1%-41% B over 9 min) to obtain a colorless oil 271-C (520 mg, yield 64%). LCMS: (ESI) m/z=234.0 (M+1) + .

步骤二：Step 2:

酰氯的制备：向化合物271-C(320mg,1.37mmol)的DCM(5mL)溶液中加入氯化亚砜(349mg,2.01eq)和DMF(1.00mg,0.01eq)，在25℃搅拌2小时后减压浓缩，用THF(2mL)溶解备用。Preparation of acid chloride: To a solution of compound 271-C (320 mg, 1.37 mmol) in DCM (5 mL) were added thionyl chloride (349 mg, 2.01 eq) and DMF (1.00 mg, 0.01 eq), stirred at 25 °C for 2 hours, concentrated under reduced pressure, and dissolved in THF (2 mL) for later use.

向化合物271-D(140mg,687μmol)在THF/水(10mL,1:1)混合物中加入Na2CO3(218mg,2.06mmol)并降至0℃，将上述制备的酰氯溶液加入到其中，在0℃搅拌10分钟。减压浓缩，粗产品直接通过prep HPLC(column:Boston Prime C18 150*30mm*5um；mobile phase:[Water(NH3H2O-NH4HCO3)-MeCN]；gradient:10％-30％ B over 10min)纯化得黄色固体化合物271-E(110mg,收率38.29％)。LC-MS:(ESI)m/z.[M+H]+420.3。Na 2 CO 3 (218 mg, 2.06 mmol) was added to a mixture of compound 271-D (140 mg, 687 μmol) in THF/water (10 mL, 1:1) and the temperature was lowered to 0°C. The above-prepared acyl chloride solution was added thereto and stirred at 0°C for 10 minutes. The mixture was concentrated under reduced pressure and the crude product was directly purified by prep HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [Water(NH 3 H 2 O-NH 4 HCO 3 )-MeCN]; gradient: 10%-30% B over 10min) to obtain yellow solid compound 271-E (110 mg, yield 38.29%). LC-MS: (ESI) m/z. [M+H] + 420.3.

步骤三：参照实施例39中步骤二(脱Boc保护基的代表性方法)的方法，以化合物271-E(110mg)反应得白色固体化合物271-F(80mg,184μmol,收率70.40％,TFA盐)。LC-MS:(ESI)m/z.[M+H]+320.0。Step 3: Referring to the method of Step 2 (representative method for removing the Boc protecting group) in Example 39, compound 271-E (110 mg) was reacted to obtain white solid compound 271-F (80 mg, 184 μmol, yield 70.40%, TFA salt). LC-MS: (ESI) m/z. [M+H] + 320.0.

步骤四：向化合物271-F(70mg,161.36μmol,1eq,TFA)的DMF(1mL)溶液中加入DIEA(104mg,806μmol,5eq)和化合物112(42.3mg,161μmol,1.0eq)，在50℃搅拌反应16小时。反应液直接通过prep HPLC(FA方法，B:18％-38％over 11min)纯化得白色固体化合物271(15mg,26.4μmol,收率16.36％)和白色固体化合物272(45mg,74.2μmol,收率46.00％)。Step 4: Add DIEA (104 mg, 806 μmol, 5 eq) and compound 112 (42.3 mg, 161 μmol, 1.0 eq) to a DMF (1 mL) solution of compound 271-F (70 mg, 161.36 μmol, 1 eq, TFA) and stir at 50 °C for 16 hours. The reaction solution was directly purified by prep HPLC (FA method, B: 18%-38% over 11 min) to obtain white solid compound 271 (15 mg, 26.4 μmol, yield 16.36%) and white solid compound 272 (45 mg, 74.2 μmol, yield 46.00%).

化合物271：1H NMR(400MHz,DMSO-d6)δ(ppm)9.45-9.78(m,1H),7.74-8.05(m,2H),6.99(d,J＝3.9Hz,1H),6.77(br dd,J＝10.7,16.3Hz,1H),6.48(s,1H),6.06(dd,J＝2.3,16.8Hz,1H),5.48-5.73(m,2H),3.78-4.50(m,4H),3.72(s,3H),2.78-3.13(m,3H),2.63-2.75(m,3H),2.40-2.46(m,1H),2.31-2.39(m,2H),1.89-2.24(m,4H),1.42-1.89(m,4H),1.04-1.38(m,2H)。LC-MS:(ESI)m/z.[M+H]+546.3Compound 271: 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm) 9.45-9.78 (m, 1H), 7.74-8.05 (m, 2H), 6.99 (d, J=3.9 Hz, 1H), 6.77 (br dd,J＝10.7,16.3Hz,1H),6.48(s,1H),6.06(dd,J＝2.3,16.8Hz,1H),5.48-5.73(m,2H),3.78-4.50(m,4H),3.72(s,3H),2.78-3 .13(m,3H),2.63-2.75(m,3H),2.40-2.46(m,1H),2.31-2.39(m,2H),1.89-2.24(m,4H),1.42-1.89(m,4H),1.04-1.38(m,2H). LC-MS:(ESI)m/z.[M+H] + 546.3

化合物272：1H NMR(400MHz,DMSO-d6)δ(ppm)9.35-9.86(m,1H),7.97-8.11(m,1H),7.80-7.96(m,1H),6.99(d,J＝4.0Hz,1H),6.49(s,1H),5.59(t,J＝7.5Hz,1H),4.72-4.81(m,1H),4.00-4.39(m,2H),3.64-3.86(m,6H),2.61-3.06(m,8H),2.29-2.48(m,4H),1.88-2.28(m,4H),1.42-1.87(m,4H),1.08-1.41(m,2H).LC-MS:(ESI)m/z.[M+H]+582.5Compound 272: 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)9.35-9.86(m,1H),7.97-8.11(m,1H),7.80-7.96(m,1H),6.99(d,J ＝4.0Hz,1H),6.49(s,1H),5.59(t,J＝7.5Hz,1H),4.72-4.81(m,1H),4.00-4 .39(m,2H),3.64-3.86(m,6H),2.61-3.06(m,8H),2.29-2.48(m,4H),1.88- 2.28(m,4H),1.42-1.87(m,4H),1.08-1.41(m,2H).LC-MS:(ESI)m/z.[M+H] +582.5

参照化合物271的合成方法，用如下表格中的起始原料进行四步反应得到相应的终产化合物。
Referring to the synthesis method of compound 271, four steps of reaction were carried out using the starting materials in the following table to obtain the corresponding final compounds.

参照化合物271的合成方法中步骤三和步骤四的方法，用如下表格中的起始原料进行两步反应得到相应的终产化合物。
Referring to the method of step 3 and step 4 in the synthesis method of compound 271, the starting materials in the following table were used to carry out two-step reactions to obtain the corresponding final compounds.

上述表格中涉及的292-A的合成方法为
The synthesis method of 292-A mentioned in the above table is

参照实施例5-b中步骤二的方法，以292-B(500mg,2.54mmol)为原料与271-D(517.7mg,2.54mmol)进行反应得白色固体化合物292-A(70mg,收率7.2％)。LC-MS(ESI)m/z:384.4(M+H)+。Referring to the method of step 2 in Example 5-b, 292-B (500 mg, 2.54 mmol) was used as a raw material to react with 271-D (517.7 mg, 2.54 mmol) to obtain a white solid compound 292-A (70 mg, yield 7.2%). LC-MS (ESI) m/z: 384.4 (M+H) + .

实施例52化合物274的合成
Example 52 Synthesis of Compound 274

步骤一：向化合物274-A的(5g,32.4mmol)在toluene(50mL)的溶液中加入274-B(6.04g,32.4mmol)和多聚甲醛(1.95g,64.8mmol,2eq)，在50℃搅拌反应16小时。减压浓缩，粗产物经硅胶柱色谱纯化(EA:PE，EA从0到30％)得白色固体化合物274-C(9g,产率79％)。LC-MS:(ESI)m/z[M+H]+353.2。Step 1: Add 274-B (6.04 g, 32.4 mmol) and paraformaldehyde (1.95 g, 64.8 mmol, 2 eq) to a solution of compound 274-A (5 g, 32.4 mmol) in toluene (50 mL), and stir at 50°C for 16 hours. Concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (EA:PE, EA from 0 to 30%) to obtain a white solid compound 274-C (9 g, yield 79%). LC-MS: (ESI) m/z [M+H] + 353.2.

步骤二：向化合物274-C(6.5g,18.4mmol)的DCM(60mL)溶液中加入MnO2(16g,184mmol,10eq)，在25℃搅拌反应5小时。过滤，减压浓缩得白色固体化合物274-D(2g)，粗产品直接用于下一步反应。LC-MS:(ESI)m/z[M+H]+351.1。Step 2: Add MnO 2 (16 g, 184 mmol, 10 eq) to a DCM (60 mL) solution of compound 274-C (6.5 g, 18.4 mmol), and stir at 25°C for 5 hours. Filter and concentrate under reduced pressure to obtain a white solid compound 274-D (2 g). The crude product was directly used in the next step. LC-MS: (ESI) m/z [M+H] + 351.1.

步骤三：参照实施例2步骤1的方法，以化合物274-D(2g)进行反应得黄色油状物化合物274-E(2g,两步收率约28％)。LC-MS:(ESI)m/z[M+H]+391.2。Step 3: Referring to the method of step 1 of Example 2, compound 274-D (2 g) was reacted to obtain yellow oil compound 274-E (2 g, two-step yield about 28%). LC-MS: (ESI) m/z [M+H] + 391.2.

步骤四：参照实施例39中步骤二(脱Boc保护基的代表性方法)的方法，以化合物274-E(2.5g)进行反应得黄色油状物化合物274-F(1.8g)，粗产品直接用于下一步反应。LC-MS:(ESI)m/z[M+H]+291.1。Step 4: Referring to the method of Step 2 in Example 39 (representative method for removing the Boc protecting group), compound 274-E (2.5 g) was reacted to obtain yellow oil compound 274-F (1.8 g), and the crude product was directly used in the next step. LC-MS: (ESI) m/z [M+H] + 291.1.

步骤五：参照实施例51中步骤一的方法，以274-E(500mg,1.24mmol,TFA盐)进行反应得黄色油状物化合物274-G(230mg,两步收率约34％)。LC-MS:(ESI)m/z[M+H]+381.1。Step 5: Referring to the method of step 1 in Example 51, 274-E (500 mg, 1.24 mmol, TFA salt) was reacted to obtain yellow oil compound 274-G (230 mg, two-step yield about 34%). LC-MS: (ESI) m/z [M+H] + 381.1.

步骤六和步骤七：参照实施例2中步骤2和步骤3的方法，以274-G(143mg,603μmol)进行两步反应得白色固体化合物274(1mg，两步收率约1.4％)。1H NMR(400MHz,DMSO-d6)δ(ppm)6.89(s,1H),6.73-6.85(m,1H),6.46-6.53(m,1H),6.05-6.15(m,1H),5.73-5.78(m,1H),5.63-5.71(m,1H),5.36-5.43(m,1H),3.73-3.80(m,3H),3.48-3.61(m,6H),2.41(br s,4H),2.12-2.26(m,2H),1.29(td,J＝4.4,8.3Hz,1H),0.93-1.12(m,1H),0.63-0.70(m,1H).LC-MS:(ESI)m/z[M+H]+373.3。Step 6 and Step 7: Referring to the method of Step 2 and Step 3 in Example 2, 274-G (143 mg, 603 μmol) was used for two-step reaction to obtain white solid compound 274 (1 mg, two-step yield of about 1.4%). 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm) 6.89 (s, 1H), 6.73-6.85 (m, 1H), 6.46-6.53 (m, 1H), 6.05-6.15 (m, 1H), 5.73-5.78 (m, 1H), 5.63-5.71 (m, 1H), 5.36-5.43 (m, 1H), 3.73-3.80 (m, 3H), 3.48-3.61 (m, 6H), 2.41 (br s,4H),2.12-2.26(m,2H),1.29(td,J＝4.4,8.3Hz,1H),0.93-1.12(m,1H),0.63-0.70(m,1H).LC-MS: (ESI)m/z[M+H] + 373.3.

实施例53化合物276的合成
Example 53 Synthesis of Compound 276

向化合物14(100mg,427μmol)的DCM(5mL)溶液中加入，m-CPBA(4.33mg,21.3μmol,85％purity,0.05eq)，25℃搅拌15分钟后加入NBS(76mg,427μmol)，40℃反应16小时。反应毕减压浓缩除去溶剂，通过硅胶柱色谱(EA:PE，EA从0到6％)纯化得白色固体化合物276(100mg，收率75％)。1H NMR(400MHz,DMSO-d6)δ(ppm)9.13-9.45(m,1H),6.94-7.12(m,1H),5.84(d,J＝4.8Hz,0.22H),5.47(s,0.75H),3.69-3.85(m,3H),2.56-2.63(m,0.27H),2.26-2.37(m,1.61H),2.17-2.21(m,3H),1.07-1.37(m,1H),0.78-1.06(m,1H).LC-MS:(ESI)m/z.[M+H]+313.0.To a DCM (5 mL) solution of compound 14 (100 mg, 427 μmol) was added m-CPBA (4.33 mg, 21.3 μmol, 85% purity, 0.05 eq), stirred at 25°C for 15 minutes, and then NBS (76 mg, 427 μmol) was added, and the mixture was reacted at 40°C for 16 hours. After the reaction, the solvent was removed by concentration under reduced pressure, and the mixture was purified by silica gel column chromatography (EA:PE, EA from 0 to 6%) to obtain a white solid compound 276 (100 mg, yield 75%). 1 H NMR (400MHz, DMSO-d 6 )δ(ppm)9.13-9.45(m,1H),6.94-7.12(m,1H),5.84(d,J＝4.8Hz,0.22H),5.47(s,0.75H),3.69-3.85(m,3H),2.56-2. 63(m,0.27H),2.26-2.37(m,1.61H),2.17-2.21(m,3H),1.07-1.37(m,1H),0.78-1.06(m,1H).LC-MS:(ESI)m/z.[M+H] +313.0 .

实施例54化合物277的合成
Example 54 Synthesis of Compound 277

步骤一：向化合物14-a(800mg,2.77mmol)和277-B(900mg,3.58mmol)在甲苯(15mL)和H2O(5mL)的混合物中加入碳酸铯(2.7g,8.3mmol)，充分置换氮气后加入RuPhos Pd G3催化剂(CAS：1445085-77-7，231mg,276μmol)，氮气氛围下100℃搅拌16小时。反应液冷却至室温，混合物用EA(10mL×3)萃取。经过常规的后处理操作得残余物，残留物经硅胶柱色谱纯化(EA:PE，EA从0到20％)得白色固体化合物277-C(960mg,产率98％)。LC-MS:Rt＝0.983min,(ESI)m/z[M+H]+354.2Step 1: Add cesium carbonate (2.7 g, 8.3 mmol) to a mixture of compound 14-a (800 mg, 2.77 mmol) and 277-B (900 mg, 3.58 mmol) in toluene (15 mL) and H 2 O (5 mL), add RuPhos Pd G3 catalyst (CAS: 1445085-77-7, 231 mg, 276 μmol) after fully replacing nitrogen, and stir at 100 ° C for 16 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, and the mixture was extracted with EA (10 mL×3). After conventional post-treatment operations, the residue was purified by silica gel column chromatography (EA:PE, EA from 0 to 20%) to obtain a white solid compound 277-C (960 mg, yield 98%). LC-MS: Rt＝0.983 min, (ESI) m/z[M+H] + 354.2

步骤二：化合物277-C(870mg,2.46mmol)在HCl的dioxane溶液(2M,10mL)溶液在20℃搅拌2小时。减压浓缩得绿色固体化合物277-D(570mg，HCl盐)，粗产品直接用于下一步反应。LC-MS:(ESI)m/z[M+H]+196.1。Step 2: Compound 277-C (870 mg, 2.46 mmol) was dissolved in HCl in dioxane (2M, 10 mL) and stirred at 20°C for 2 hours. The mixture was concentrated under reduced pressure to obtain a green solid compound 277-D (570 mg, HCl salt). The crude product was directly used in the next step. LC-MS: (ESI) m/z [M+H] + 196.1.

步骤三：参照实施例5-b中步骤二的方法，以277-D(570mg，HCl盐)为原料与1-金刚烷乙酸(956mg,2eq)反应得白色固体化合物277-E(1.0g,两步收率约74％)。LC-MS:(ESI)m/z[M+H]+548.4。Step 3: Referring to the method of step 2 in Example 5-b, 277-D (570 mg, HCl salt) was used as a raw material to react with 1-adamantaneacetic acid (956 mg, 2 eq) to obtain a white solid compound 277-E (1.0 g, two-step yield of about 74%). LC-MS: (ESI) m/z [M+H] + 548.4.

步骤四：参照实施例34的方法，以277-E(1.0g)为原料进行反应，反应完毕减压浓缩，用1M HCl调pH至1，析出固体后过滤得白色固体化合物277-F(700mg)，粗产品直接用于下步反应。LC-MS:(ESI)m/z[M+H]+372.2。Step 4: Referring to the method of Example 34, 277-E (1.0 g) was used as the raw material for the reaction. After the reaction was completed, the mixture was concentrated under reduced pressure and the pH was adjusted to 1 with 1M HCl. The solid was precipitated and filtered to obtain a white solid compound 277-F (700 mg). The crude product was directly used in the next step. LC-MS: (ESI) m/z [M+H] + 372.2.

步骤五到步骤七：参照实施例2的方法，以277-F(645mg)为原料进行三步反应得白色固体化合物277(17mg,四步收率12.6％).LC-MS:(ESI)m/z[M+H]+440.2。1HNMR(400MHz,DMSO-d6)δ(ppm)9.48-9.88(m,1H),7.60-7.79(m,1H),6.78-6.98(m,1H),6.45-6.56(m,1H),5.72(d,J＝4.6Hz,0.2H),5.37(s,0.8H),3.64-3.81(m,3H),3.10-3.23(m,2H),2.58(br t,J＝7.4Hz,2H),2.21(m,1.8H),1.89(br s,3H),1.73-1.83(m,2H),1.44-1.71(m,13H),1.24-1.35(m,1H),0.92-1.09(m,1H),0.71-0.78(m,0.2H)Step 5 to Step 7: Referring to the method of Example 2, 277-F (645 mg) was used as the starting material for three-step reaction to obtain white solid compound 277 (17 mg, four-step yield 12.6%). LC-MS: (ESI) m/z [M+H] + 440.2. 1 HNMR (400MHz, DMSO-d 6 )δ(ppm)9.48-9.88(m,1H),7.60-7.79(m,1H),6.78-6.98(m,1H),6.45-6.56(m,1H),5 .72(d,J＝4.6Hz,0.2H),5.37(s,0.8H),3.64-3.81(m,3H),3.10-3.23(m,2H),2.58(br t,J＝7.4Hz,2H),2.21(m,1.8H),1.89(br s,3H),1.73-1.83(m,2H),1.44-1.71(m,13H),1.24-1.35(m,1H),0.92-1.09(m,1H),0.71-0.78(m,0.2H)

化合物14-a的合成方法为：
The synthesis method of compound 14-a is:

步骤一：向5-溴-2,4-二羟基苯-1-甲醛(4.5g,20.74mmol)的丙酮(100mL)溶液中加入氯甲基乙醚(1.96g,20.74mmol)和K2CO3(8.60g,62.21mmol)。在20℃反应16小时。加入饱和NH4Cl水溶液(50mL)，用EA(50mL x 3)萃取。经过常规的后处理操作二后得到粗产物，粗产物通过硅胶柱色谱分离(EA:PE，EA从0到9％)纯化得到白色固体5-溴-4-[(乙氧基甲基)氧基]-2-羟基苯-1-甲醛(3.22g,收率56％)。Step 1: Add chloromethyl ether (1.96 g, 20.74 mmol) and K 2 CO 3 (8.60 g, 62.21 mmol) to a solution of 5-bromo-2,4-dihydroxybenzene-1-carboxaldehyde (4.5 g, 20.74 mmol) in acetone (100 mL). React at 20°C for 16 hours. Add saturated NH 4 Cl aqueous solution (50 mL) and extract with EA (50 mL x 3). After conventional post-treatment operation 2, a crude product is obtained. The crude product is purified by silica gel column chromatography (EA:PE, EA from 0 to 9%) to obtain a white solid 5-bromo-4-[(ethoxymethyl)oxy]-2-hydroxybenzene-1-carboxaldehyde (3.22 g, yield 56%).

步骤二：向5-溴-4-[(乙氧基甲基)氧基]-2-羟基苯-1-甲醛(3.6g,13.09mmol)的DMF(2mL)混合物中加入碘甲烷(2.23g,15.70mmol)和K2CO3(3.62g,26.17mmol)。在20℃反应16小时。加入水(50mL)，用EA(50mL x 2)萃取。经过常规的后处理操作二后得到粗产物，粗产物通过硅胶薄层层析色谱分离(EA:PE，EA从6到9％)纯化得到白色固体14-a(3.58g,收率94％)。Step 2: Add iodomethane (2.23 g, 15.70 mmol) and K 2 CO 3 (3.62 g, 26.17 mmol) to a mixture of 5-bromo-4-[(ethoxymethyl)oxy]-2-hydroxybenzene-1-carboxaldehyde (3.6 g, 13.09 mmol) in DMF (2 mL). React at 20°C for 16 hours. Add water (50 mL) and extract with EA (50 mL x 2). After conventional post-treatment operation 2, a crude product was obtained, which was purified by silica gel thin layer chromatography (EA:PE, EA from 6 to 9%) to obtain a white solid 14-a (3.58 g, yield 94%).

实施例55化合物129的合成
Example 55 Synthesis of Compound 129

步骤一:将Wang树脂(Wang Resin,400mg，0.544mmol)置于40mL反应瓶，并悬浮在10mL DCM/DMF(1:9)中。在单独的小瓶中溶解化合物129-A(440mg，1.07mmol)和HOBt(146mg,1.08mmol)的DMF(1mL)溶液，并将溶液添加到树脂中。将DMAP(8mg,65.5umol)添加到反应瓶中，然后添加DIC(145mg,1.15mmol)，并将反应混合物在25℃震荡6小时。将醋酸酐(120mg，1.17mmol)和吡啶(108mg，1.36mmol)加入到反应瓶中，并在25℃下再震荡30分钟将树脂上未反应的羟基封端。过滤树脂用并20mL DMF洗涤两次，20mLDCM洗涤5次，得到湿树脂129-B用于下一步。Step 1: Wang Resin (400 mg, 0.544 mmol) was placed in a 40 mL reaction bottle and suspended in 10 mL DCM/DMF (1:9). Compound 129-A (440 mg, 1.07 mmol) and HOBt (146 mg, 1.08 mmol) in DMF (1 mL) were dissolved in a separate vial and the solution was added to the resin. DMAP (8 mg, 65.5 umol) was added to the reaction bottle, followed by DIC (145 mg, 1.15 mmol), and the reaction mixture was shaken at 25 °C for 6 hours. Acetic anhydride (120 mg, 1.17 mmol) and pyridine (108 mg, 1.36 mmol) were added to the reaction bottle and shaken at 25 °C for another 30 minutes to cap the unreacted hydroxyl groups on the resin. The filtered resin was washed twice with 20 mL of DMF and five times with 20 mL of DCM to obtain wet resin 129-B for the next step.

步骤二:将树脂129-B(0.544mmol)置于固相合成反应器中并添加15mL DMF,搅拌30秒溶涨后真空过滤去除溶剂。加入15ml 20％哌啶/DMF，搅拌15分钟，然后通过真空过滤去除溶剂。再次加入15ml 20％哌啶/DMF，搅拌15分钟，然后通过真空过滤去除溶剂并用15mL DMF洗涤树脂四次。将2-环己基乙酸(315mg,2.22mmol),HATU(833mg,2.19mmol)和HOAt(301mg,2.21mmol)溶解在DMF(15mL)中并将溶液添加到树脂中，搅拌30秒。添加DIPEA(643mg,4.98mmol)。反应混合物在25℃下搅拌2小时，然后通过真空过滤除去溶剂并用15mL DMF洗涤树脂四次。将得到的树脂129-C用15mLDCM洗涤四次后收集到反应瓶中用于下一步反应。Step 2: Place resin 129-B (0.544 mmol) in a solid phase synthesis reactor and add 15 mL DMF, stir for 30 seconds to dissolve and then remove the solvent by vacuum filtration. Add 15 ml 20% piperidine/DMF, stir for 15 minutes, and then remove the solvent by vacuum filtration. Add 15 ml 20% piperidine/DMF again, stir for 15 minutes, then remove the solvent by vacuum filtration and wash the resin four times with 15 mL DMF. Dissolve 2-cyclohexylacetic acid (315 mg, 2.22 mmol), HATU (833 mg, 2.19 mmol) and HOAt (301 mg, 2.21 mmol) in DMF (15 mL) and add the solution to the resin and stir for 30 seconds. Add DIPEA (643 mg, 4.98 mmol). The reaction mixture is stirred at 25 ° C for 2 hours, then remove the solvent by vacuum filtration and wash the resin four times with 15 mL DMF. The obtained resin 129-C was washed four times with 15 mL DCM and then collected into a reaction bottle for the next reaction.

将一些树脂珠转移到小玻璃管中，加入1mL 5％ TFA的DCM溶液并等待3小时。除去溶剂并用ACN/水(1:1，1mL)稀释，过滤并通过LCMS监测反应得到目标化合物。LC-MS:(ESI)m/z.[M+H]+313.1。Transfer some resin beads to a small glass tube, add 1 mL of 5% TFA in DCM and wait for 3 hours. Remove the solvent and dilute with ACN/water (1:1, 1 mL), filter and monitor the reaction by LCMS to obtain the target compound. LC-MS: (ESI) m/z. [M+H] + 313.1.

步骤三:将树脂129-C(544μmol)置于反应瓶中，加入DCM(10毫升)和苯硅烷(482mg,4.46mmol)，轻微搅拌1分钟，放置15分钟使树脂溶胀。将反应悬浮液真空脱气并用氮气吹扫五次。将Pd(PPh3)4(150mg,130μmol)添加到反应悬浮液中，真空脱气并用氮气吹扫五次后将反应悬浮液在氮气氛下，25℃震荡1.5小时。过滤得到树脂并用15mL DMF洗涤树脂五次。添加0.5％ PIX(异丙基黄酸钾盐)和0.5％ DIEA的DMF溶液(10mL)，轻轻搅拌5分钟，然后通过真空过滤除去溶剂，重复2次后用15mL DMF洗涤树脂五次。再用15mL DCM洗涤树脂五次得到类白色树脂129-D用于下一步反应。Step 3: Resin 129-C (544 μmol) was placed in a reaction bottle, DCM (10 ml) and phenylsilane (482 mg, 4.46 mmol) were added, stirred gently for 1 minute, and allowed to stand for 15 minutes to allow the resin to swell. The reaction suspension was vacuum degassed and purged with nitrogen five times. Pd(PPh 3 ) 4 (150 mg, 130 μmol) was added to the reaction suspension, vacuum degassed and purged with nitrogen five times, and then the reaction suspension was shaken at 25° C. under a nitrogen atmosphere for 1.5 hours. The resin was filtered and washed with 15 mL DMF five times. A DMF solution (10 mL) of 0.5% PIX (isopropyl xanthate potassium salt) and 0.5% DIEA was added, stirred gently for 5 minutes, and then the solvent was removed by vacuum filtration. After repeating twice, the resin was washed five times with 15 mL DMF. The resin was washed five times with 15 mL DCM to obtain an off-white resin 129-D for the next step reaction.

步骤四:将树脂129-D(544μmol)置于反应瓶中，将5％TFA/DCM溶液(15mL)添加到树脂中，并在25℃下震荡4小时。将反应悬浮液过滤并用15mLDCM洗涤树脂三次，合并滤液后减压浓缩。所得粗品中加入5mL去离子水溶解并过滤除去不溶物质，重复3次将合并滤液冷冻干燥后得无色糖浆状产品129-E(156mg,收率83.77％,TFA盐)，并用直接用于下一步。LC-MS:(ESI)m/z.[M+H]+229.1；Step 4: Place resin 129-D (544 μmol) in a reaction bottle, add 5% TFA/DCM solution (15 mL) to the resin, and shake at 25°C for 4 hours. Filter the reaction suspension and wash the resin three times with 15 mL DCM. Combine the filtrates and concentrate under reduced pressure. Add 5 mL of deionized water to the crude product to dissolve and filter to remove insoluble matter. Repeat 3 times and freeze-dry the combined filtrate to obtain a colorless syrupy product 129-E (156 mg, yield 83.77%, TFA salt), which is used directly in the next step. LC-MS: (ESI) m/z. [M+H] + 229.1;

步骤五:向129-E(62mg，181μmol，1.2eq.，TFA盐)的DMF(1.5mL)溶液中加入TEA(51mg,503μmol)，然后加入化合物112(40mg,153μmol,1.0eq)。将反应混合物在55℃搅拌12小时。将反应混合物减压浓缩后用prep HPLC纯化(FA方法-A；B％:25％-45％,10min)得到类白色固体化合物129(32mg,41.5％收率)。LC-MS:(ESI)m/z.[M+H]+491.4；1H NMR(400MHz,CDCl3)δ(ppm)7.36-7.55(m,2H),6.93(s,1H),6.46(s,1H),5.61-5.69(m,1H),4.42(br s,1H),3.74(s,3H),3.43-3.70(m,2H),2.66-2.90(m,2H),2.38-2.66(m,5H),1.97-2.22(m,3H),1.53-1.76(m,6H),0.99-1.28(m,3H),0.82-0.99(m,2H)。Step 5: TEA (51 mg, 503 μmol) was added to a DMF (1.5 mL) solution of 129-E (62 mg, 181 μmol, 1.2 eq., TFA salt), and then compound 112 (40 mg, 153 μmol, 1.0 eq). The reaction mixture was stirred at 55 °C for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by prep HPLC (FA method-A; B%: 25%-45%, 10 min) to give an off-white solid compound 129 (32 mg, 41.5% yield). LC-MS: (ESI) m/z.[M+H]+491.4; 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.36-7.55 (m, 2H), 6.93 (s, 1H), 6.46 (s, 1H), 5.61-5.69 (m, 1H), 4.42 (br s,1H),3.74(s,3H),3.43-3.70(m,2H),2.66-2.90(m,2H),2.38-2.66(m,5H) ,1.97-2.22(m,3H),1.53-1.76(m,6H),0.99-1.28(m,3H),0.82-0.99(m,2H).

参照实施例55的方法，用如下表格中的起始原料在第一步替代化合物129-A进行五步反应得到相应的终产化合物。
Referring to the method of Example 55, the starting materials in the following table were used in place of compound 129-A in the first step to carry out five steps of reaction to obtain the corresponding final compound.

实施例56化合物125的合成
Example 56 Synthesis of Compound 125

步骤一:将化合物125-A(780mg，1.95mmol)溶解在DCM(15mL)中，并将DIPEA(964.57mg,7.46mmol)添加到融溶液中。将2-氯三苯甲基氯树脂(CTC树脂)(1.3g，1.0mmol/g，1.30mmol)加入到溶液中，并将混合物在25℃下震荡2小时。将2mL甲醇添加到溶液中，并将混合物在25℃下震荡30分钟。过滤混合物，用20mL DCM洗涤树脂五次，真空干燥，得到所需黄色固体树脂125-B(1.78g)。Step 1: Dissolve compound 125-A (780 mg, 1.95 mmol) in DCM (15 mL), and add DIPEA (964.57 mg, 7.46 mmol) to the molten solution. Add 2-chlorotrityl chloride resin (CTC resin) (1.3 g, 1.0 mmol/g, 1.30 mmol) to the solution, and shake the mixture at 25 °C for 2 hours. Add 2 mL of methanol to the solution, and shake the mixture at 25 °C for 30 minutes. Filter the mixture, wash the resin five times with 20 mL of DCM, and vacuum dry to obtain the desired yellow solid resin 125-B (1.78 g).

步骤二:将树脂125-B(1.54g,1.0mmol)置于固相合成反应器中,加入20mL DCM浸泡15分钟使树脂溶胀后真空过滤除去溶剂，并用20mL DMF洗涤一次。加入20ml20％哌啶/DMF，搅拌30分钟，然后通过真空过滤去除溶剂。再次加入20ml 20％哌啶/DMF，搅拌30分钟，然后通过真空过滤去除溶剂并用20mL DMF洗涤树脂五次。将化合物129-A(827mg,2.02mmol)，HATU(768mg,2.02mmol)和HOAt(275mg,2.02mmol)溶解在DMF(10mL)中并将溶液添加到树脂中，搅拌30秒。添加DIPEA(890mg,6.89mmol)。反应混合物在25℃下搅拌2小时，然后通过真空过滤除去溶剂并用15mL DMF洗涤树脂五次。将得到的树脂125-C用15mL DCM洗涤五次用于下一步。Step 2: Place resin 125-B (1.54 g, 1.0 mmol) in a solid phase synthesis reactor, add 20 mL DCM and soak for 15 minutes to swell the resin, then remove the solvent by vacuum filtration and wash once with 20 mL DMF. Add 20 ml 20% piperidine/DMF, stir for 30 minutes, and then remove the solvent by vacuum filtration. Add 20 ml 20% piperidine/DMF again, stir for 30 minutes, then remove the solvent by vacuum filtration and wash the resin five times with 20 mL DMF. Dissolve compound 129-A (827 mg, 2.02 mmol), HATU (768 mg, 2.02 mmol) and HOAt (275 mg, 2.02 mmol) in DMF (10 mL) and add the solution to the resin and stir for 30 seconds. Add DIPEA (890 mg, 6.89 mmol). The reaction mixture is stirred at 25 ° C for 2 hours, then remove the solvent by vacuum filtration and wash the resin five times with 15 mL DMF. The obtained resin 125-C was washed five times with 15 mL of DCM for the next step.

步骤三:将树脂125-C(0.75g,～0.5mmol)置于固相合成反应器中,加入15mLDCM浸泡15分钟使树脂溶胀后真空过滤除去溶剂，并用20mL DMF洗涤一次。加入10ml 20％哌啶/DMF，搅拌15分钟，然后通过真空过滤去除溶剂。再次加入20ml 20％哌啶/DMF，搅拌15分钟，然后通过真空过滤去除溶剂并用15mL DMF洗涤树脂五次。将2-环己基乙酸(285mg,2.00mmol)和HATU(760mg,2.00mmol)和HOAt(273mg,2.01mmol)溶解在DMF(10mL)中并将溶液添加到树脂中，搅拌30秒。添加DIPEA(649mg,5.02mmol)。反应混合物在25℃下搅拌2小时，然后通过真空过滤除去溶剂并用15mL DMF洗涤树脂五次。将得到的树脂125-D用15mL DCM洗涤五次后收集到反应瓶中用于下一步。Step 3: Place resin 125-C (0.75 g, ~0.5 mmol) in a solid phase synthesis reactor, add 15 mL DCM and soak for 15 minutes to swell the resin, then remove the solvent by vacuum filtration and wash once with 20 mL DMF. Add 10 ml 20% piperidine/DMF, stir for 15 minutes, and then remove the solvent by vacuum filtration. Add 20 ml 20% piperidine/DMF again, stir for 15 minutes, then remove the solvent by vacuum filtration and wash the resin five times with 15 mL DMF. Dissolve 2-cyclohexylacetic acid (285 mg, 2.00 mmol) and HATU (760 mg, 2.00 mmol) and HOAt (273 mg, 2.01 mmol) in DMF (10 mL) and add the solution to the resin and stir for 30 seconds. Add DIPEA (649 mg, 5.02 mmol). The reaction mixture is stirred at 25 ° C for 2 hours, then the solvent is removed by vacuum filtration and the resin is washed five times with 15 mL DMF. The obtained resin 125-D was washed five times with 15 mL of DCM and collected in a reaction bottle for the next step.

步骤四:参照实施例55步骤三的方法，以树脂125-D(0.5mmol,1.0eq.)进行反应得黄色树脂125-E用于下一步反应。Step 4: Referring to the method of step 3 of Example 55, resin 125-D (0.5 mmol, 1.0 eq.) was reacted to obtain yellow resin 125-E for the next reaction.

将一些树脂珠转移到小玻璃管中，加入1mL 2％ TFA的DCM溶液并等待15分钟。除去溶剂并用乙腈/水(1:1，1mL)稀释，过滤并通过LCMS监测反应得到目标化合物。LC-MS:(ESI)m/z.[M+H]+388.2；Transfer some resin beads to a small glass tube, add 1 mL of 2% TFA in DCM and wait for 15 minutes. Remove the solvent and dilute with acetonitrile/water (1:1, 1 mL), filter and monitor the reaction by LCMS to obtain the target compound. LC-MS: (ESI) m/z. [M+H] + 388.2;

步骤五:参照实施例55步骤四的方法，以树脂125-E(0.5mmol,1.0eq.)进行反应得类白色固体125-F(232mg,92.52％收率,TFA盐)。LC-MS:(ESI)m/z[M+H]+388.3；Step 5: Referring to the method of step 4 of Example 55, the resin 125-E (0.5 mmol, 1.0 eq.) was reacted to obtain an off-white solid 125-F (232 mg, 92.52% yield, TFA salt). LC-MS: (ESI) m/z [M+H] + 388.3;

步骤六:参照实施例55步骤五的方法(反应温度为25℃)，以125-F(71mg,183μmol,TFA盐)进行反应得到白色固体化合物125(72mg,69.07％收率)。LC-MS:(ESI)m/z.[M+H]+650.6；1H NMR(400MHz,CDCl3)δ(ppm)7.03-7.21(m,3H),6.89-7.01(m,1H),6.47(s,1H),5.62-5.69(m,1H),4.59-4.74(m,1H),3.77(s,3H),3.70-3.86(m,2H),3.41-3.67(m,9H),3.23-3.39(m,1H),2.73-2.94(m,2H),2.48-2.70(m,7H),1.98-2.22(m,3H),1.55-1.83(m,6H),1.05-1.33(m,3H),0.77-1.02(m,2H).Step 6: Referring to the method of step 5 of Example 55 (reaction temperature is 25°C), 125-F (71 mg, 183 μmol, TFA salt) was reacted to obtain white solid compound 125 (72 mg, 69.07% yield). LC-MS: (ESI) m/z. [M+H] + 650.6; 1 H NMR (400 MHz, CDCl 3 )δ(ppm)7.03-7.21(m,3H),6.89-7.01(m,1H),6.47(s,1H),5.62-5.69 (m,1H),4.59-4.74(m,1H),3.77(s,3H),3.70-3.86(m,2H),3.41-3.67 (m,9H),3.23-3.39(m,1H),2.73-2.94(m,2H),2.48-2.70(m,7H),1.98 -2.22(m,3H),1.55-1.83(m,6H),1.05-1.33(m,3H),0.77-1.02(m,2H).

参照实施例56的方法，用如下表格中的起始原料在第二步替代化合物129-A与125-B进行五步反应得到相应的终产化合物。
Referring to the method of Example 56, the starting materials in the following table were used to replace compounds 129-A and 125-B in the second step to carry out five steps of reaction to obtain the corresponding final compounds.

实施例57化合物128的合成
Example 57 Synthesis of Compound 128

步骤一:将树脂129-B(0.544mmol,)置于反应瓶中，加入DCM(10毫升)和苯硅烷(482mg,4.46mmol)，轻微搅拌1分钟，放置15分钟使树脂溶胀。将反应悬浮液真空脱气并用氮气吹扫五次。将Pd(PPh3)4(140mg,121umol)添加到反应悬浮液中，真空脱气并用氮气吹扫五次后将反应悬浮液在氮气氛下震荡1.5小时。过滤得到树脂并用15mLDCM洗涤树脂五次，再用15mL DMF洗涤树脂3次，得到黄色树脂128-A用于下一步。Step 1: Resin 129-B (0.544 mmol,) was placed in a reaction bottle, DCM (10 ml) and phenylsilane (482 mg, 4.46 mmol) were added, stirred gently for 1 minute, and allowed to stand for 15 minutes to allow the resin to swell. The reaction suspension was vacuum degassed and purged with nitrogen five times. Pd(PPh 3 ) 4 (140 mg, 121 umol) was added to the reaction suspension, vacuum degassed and purged with nitrogen five times, and the reaction suspension was shaken under a nitrogen atmosphere for 1.5 hours. The resin was filtered and washed with 15 mL DCM five times, and then washed with 15 mL DMF 3 times to obtain yellow resin 128-A for the next step.

步骤二：将树脂128-A(0.544mmol)置于固相合成反应器中并用20mL DMF洗涤一次。将2-环己基乙酸(315mg,2.22mmol)和HATU(834mg,2.19mmol)和HOAt(302mg,2.22mmol)溶解在DMF(10mL)中并将溶液添加到树脂中，搅拌30秒。添加DIPEA(649mg,5.02mmol)。反应混合物在25℃下搅拌2小时，然后通过真空过滤除去溶剂并用15mL DMF洗涤树脂两次。添加0.5％ PIX和0.5％ DIPEA的DMF溶液(10mL)，搅拌5分钟，然后通过真空过滤除去溶剂，重复2次后用15mL DMF洗涤树脂三次。加入15ml 20％哌啶/DMF，搅拌30分钟，然后通过真空过滤去除溶剂。再次加入15ml 20％哌啶/DMF，搅拌30分钟，然后通过真空过滤去除溶剂并用15mL DMF洗涤树脂四次。Step 2: Resin 128-A (0.544 mmol) was placed in a solid phase synthesis reactor and washed once with 20 mL DMF. 2-Cyclohexylacetic acid (315 mg, 2.22 mmol) and HATU (834 mg, 2.19 mmol) and HOAt (302 mg, 2.22 mmol) were dissolved in DMF (10 mL) and the solution was added to the resin and stirred for 30 seconds. DIPEA (649 mg, 5.02 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours, then the solvent was removed by vacuum filtration and the resin was washed twice with 15 mL DMF. A DMF solution of 0.5% PIX and 0.5% DIPEA (10 mL) was added, stirred for 5 minutes, then the solvent was removed by vacuum filtration, and the resin was washed three times with 15 mL DMF after repeated 2 times. 15 ml 20% piperidine/DMF was added, stirred for 30 minutes, and then the solvent was removed by vacuum filtration. Add another 15 ml of 20% piperidine/DMF, stir for 30 min, then remove the solvent by vacuum filtration and wash the resin four times with 15 mL of DMF.

步骤三和步骤四：参照实施例55步骤四和步骤五的方法，以128-B进行两步反应得白色固体化合物128，两步收率36％。LCMS:(ESI)m/z＝491.5(M+1)+；1H NMR(400MHz,CDCl3)δ7.51-7.68(m,1H),6.88-7.11(m,1H),6.96(s,1H),6.46(s,1H),5.61-5.72(m,1H),4.50(br s,1H),3.74(s,3H),3.42-3.68(m,2H),2.69-2.96(m,2H),2.41-2.69(m,5H),2.07-2.24(m,1H),1.92-2.07(m,2H),1.53-1.76(m,6H),1.00-1.28(m,3H),0.77-0.97(m,2H).Step 3 and step 4: Referring to the method of step 4 and step 5 of Example 55, 128-B was used for two-step reaction to obtain white solid compound 128, with a two-step yield of 36%. LCMS: (ESI) m/z=491.5 (M+1) + ; 1 H NMR (400 MHz, CDCl 3 ) δ7.51-7.68 (m, 1H), 6.88-7.11 (m, 1H), 6.96 (s, 1H), 6.46 (s, 1H), 5.61-5.72 (m, 1H), 4.50 (br s,1H),3.74(s,3H),3.42-3.68(m,2H),2.69-2.96(m,2H),2.41-2.69(m,5H),2.07-2. 24(m,1H),1.92-2.07(m,2H),1.53-1.76(m,6H),1.00-1.28(m,3H),0.77-0.97(m,2H).

参照实施例57的方法，用如下表格中的起始原料在第一步替代化合物129-A进行五步反应得到相应的终产化合物。
Referring to the method of Example 57, the starting materials in the following table were used in place of compound 129-A in the first step to carry out five steps of reaction to obtain the corresponding final compound.

实施例58化合物126的合成
Example 58 Synthesis of Compound 126

步骤一：树脂125-C(0.75g,0.5mmol)置于反应瓶中，加入DCM(15mL)和苯硅烷(438mg,4.05mmol)，轻微搅拌1分钟，放置15分钟使树脂溶胀。将反应悬浮液真空脱气并用氮气吹扫五次。将Pd(PPh3)4(150mg,130umol)添加到反应悬浮液中，真空脱气并用氮气吹扫五次后将反应悬浮液在氮气氛下震荡1.5小时。过滤得到树脂并用15mL DMF洗涤树脂五次。将所得树脂置于固相合成反应器中。将2-环己基乙酸(285mg,2.00mmol)和HATU(761mg,2.00mmol)和HOAt(273mg,2.01mmol)溶解在DMF(15mL)中并将溶液添加到树脂中，搅拌30秒。添加DIPEA(742mg,5.74mmol)。反应混合物在25℃下搅拌2小时，然后通过真空过滤除去溶剂并用15mL DMF洗涤树脂四次。加入15mL 20％哌啶/DMF，搅拌15分钟，然后通过真空过滤去除溶剂。再次加入15mL20％哌啶/DMF，搅拌15分钟，然后通过真空过滤去除溶剂并用15mL DMF洗涤树脂四次。Step 1: Resin 125-C (0.75 g, 0.5 mmol) was placed in a reaction bottle, DCM (15 mL) and phenylsilane (438 mg, 4.05 mmol) were added, gently stirred for 1 minute, and allowed to stand for 15 minutes to allow the resin to swell. The reaction suspension was vacuum degassed and purged with nitrogen five times. Pd(PPh 3 ) 4 (150 mg, 130 umol) was added to the reaction suspension, vacuum degassed and purged with nitrogen five times, and then the reaction suspension was shaken under a nitrogen atmosphere for 1.5 hours. The resin was filtered and washed with 15 mL of DMF five times. The obtained resin was placed in a solid phase synthesis reactor. 2-Cyclohexylacetic acid (285 mg, 2.00 mmol), HATU (761 mg, 2.00 mmol) and HOAt (273 mg, 2.01 mmol) were dissolved in DMF (15 mL) and the solution was added to the resin and stirred for 30 seconds. DIPEA (742 mg, 5.74 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours, then the solvent was removed by vacuum filtration and the resin was washed four times with 15 mL of DMF. 15 mL of 20% piperidine/DMF was added, stirred for 15 minutes, and then the solvent was removed by vacuum filtration. 15 mL of 20% piperidine/DMF was added again, stirred for 15 minutes, then the solvent was removed by vacuum filtration and the resin was washed four times with 15 mL of DMF.

步骤二和步骤三：参照实施例55步骤四和步骤五(在步骤五中的反应温度为25℃)的方法，以126-A进行两步反应得白色固体化合物126，两步收率31％。LC-MS:(ESI)m/z[M+H]+650.6；1H NMR(400MHz,CDCl3)δ(ppm)7.64-7.78(m,1H),7.13-7.27(m,1H),6.97(s,1H),6.70-6.88(m,1H),6.47(s,1H),5.57-5.79(m,1H),4.60-4.72(m,1H),3.76(s,3H),3.70-3.84(m,2H),3.43-3.67(m,10H),3.23-3.37(m,1H),3.23-3.37(m,1H),2.47-2.93(m,9H),2.09-2.22(m,1H),1.90-2.09(m,2H),1.55-1.79(m,6H),1.04-1.31(m,3H),0.78-0.99(m,2H).Step 2 and step 3: Referring to the method of step 4 and step 5 of Example 55 (the reaction temperature in step 5 is 25°C), 126-A was used for two-step reaction to obtain white solid compound 126, with a two-step yield of 31%. LC-MS: (ESI) m/z [M+H] + 650.6; 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.64-7.78 (m, 1H), 7.13-7.27 (m, 1H), 6.97 (s, 1H), 6.70-6.88 (m, 1H), 6.47 (s, 1H), 5.57-5.79 (m, 1H), 4.60-4.72 (m, 1H), 3.76 (s, 3H), 3.70-3.84 (m, 2H), 3.43 -3.67(m,10H),3.23-3.37(m,1H),3.23-3.37(m,1H),2.47-2.93(m,9H),2.09-2.22 (m,1H),1.90-2.09(m,2H),1.55-1.79(m,6H),1.04-1.31(m,3H),0.78-0.99(m,2H).

实施例59化合物122的合成
Example 59 Synthesis of Compound 122

步骤一参照实施例56中步骤二的方法，用122-B替代化合物129-A与125-B进行反应得到122-A。再参照实施例58的方法以122-A为原料进行三步反应得白色固体化合物122。LC-MS:(ESI)m/z.[M+H]+650.4；1H NMR(400MHz,CDCl3)δ(ppm)7.57-7.79(m,1H),7.10-7.27(m,1H),6.97(s,1H),6.60-6.78(m,1H),6.47(s,1H),5.55-5.75(m,1H),4.62-4.73(m,1H),3.77(s,3H),3.69-3.87(m,2H),3.38-3.69(m,9H),3.19-3.37(m,1H),2.72-2.97(m,2H),2.35-2.72(m,7H),2.08-2.22(m,1H),1.88-2.08(m,2H),1.47-1.80(m,6H),1.04-1.33(m,3H),0.80-0.98(m,2H)Step 1: Referring to the method of step 2 in Example 56, 122-B was used to replace compound 129-A and react with 125-B to obtain 122-A. Referring to the method of Example 58, 122-A was used as the raw material to carry out three steps of reaction to obtain white solid compound 122. LC-MS: (ESI) m/z.[M+H] + 650.4; 1 H NMR (400MHz,CDCl 3 )δ(ppm)7.57-7.79(m,1H),7.10-7.27(m,1H),6.97(s,1H),6.60-6.78(m,1H),6.47(s,1H),5.55-5.75(m,1H),4.62-4.73(m,1H),3.77(s,3H),3.69-3.87(m,2H),3.3 8-3.69(m,9H),3.19-3.37(m,1H),2.72-2.97(m,2H),2.35-2.72(m,7H),2.08-2.22 (m,1H),1.88-2.08(m,2H),1.47-1.80(m,6H),1.04-1.33(m,3H),0.80-0.98(m,2H)

实施例60化合物286的合成
Example 60 Synthesis of Compound 286

步骤一：向化合物67-A(500mg,1.99mmol)的吡啶(10mL)溶液中加入醋酐(2.03g,19.91mmol)。在25℃反应16小时。减压浓缩，加入水(10mL)，用EA(5mL x 3)萃取。经过常规的后处理操作后得到粗产品，粗产物通过硅胶柱色谱分离(EA:PE，EA从0到50％)纯化得黄色固体(560mg,收率95.94％)。1H NMR(400MHz,DMSO-d6)δppm 10.60(s,1H)8.97(d,J＝8.53Hz,1H)8.10(d,J＝8.03Hz,1H)7.86(s,1H)7.79-7.84(m,1H)7.71-7.76(m,1H)2.49-2.50(m,3H).Step 1: Add acetic anhydride (2.03 g, 19.91 mmol) to a pyridine (10 mL) solution of compound 67-A (500 mg, 1.99 mmol). React at 25 °C for 16 hours. Concentrate under reduced pressure, add water (10 mL), and extract with EA (5 mL x 3). After conventional post-treatment operations, the crude product is obtained, and the crude product is purified by silica gel column chromatography (EA:PE, EA from 0 to 50%) to obtain a yellow solid (560 mg, yield 95.94%). 1H NMR(400MHz,DMSO-d6)δppm 10.60(s,1H)8.97(d,J＝8.53Hz,1H)8.10(d,J＝8.03Hz,1H)7.86(s,1H)7.79-7.84(m,1H)7.71-7.76(m,1H)2.49-2.50(m,3H).

步骤二和步骤三：参照实施例12中步骤二和步骤三的方法，以上步产品(510mg,1.74mmol)为原料进行两步反应得黄色固体化合物286，两步收率73.6％。LCMS:m/z＝349.0[M+H]+；1H NMR(400MHz,CDCl3)δppm 8.03-8.12(m,1H)7.90-7.98(m,1H)7.56-7.63(m,2H)7.52(s,1H)6.51(dd,J＝10.57,7.19Hz,1H)2.87-2.94(m,2H)2.67-2.77(m,1H)2.59-2.67(m,1H)2.47-2.51(m,3H)。Step 2 and step 3: Referring to the method of step 2 and step 3 in Example 12, the product of the above step (510 mg, 1.74 mmol) was used as a raw material to carry out two-step reaction to obtain yellow solid compound 286, with a two-step yield of 73.6%. LCMS: m/z=349.0 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δppm 8.03-8.12 (m, 1H) 7.90-7.98 (m, 1H) 7.56-7.63 (m, 2H) 7.52 (s, 1H) 6.51 (dd, J=10.57, 7.19 Hz, 1H) 2.87-2.94 (m, 2H) 2.67-2.77 (m, 1H) 2.59-2.67 (m, 1H) 2.47-2.51 (m, 3H).

实施例61化合物172的手性拆分Example 61 Chiral separation of compound 172

化合物172(30mg)经SFC(column:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；mobile phase:[CO2-EtOH(0.1％NH3H2O)]；B％:15％,isocratic elution mode)进行手性拆分得化合物293、294、295、296。化合物293：(3mg)，白色固体，SFC:Rt＝1.343min。化合物294：(10mg)，白色固体，SFC:Rt＝1.497min。化合物295：(8mg)，白色固体，SFC:Rt＝1.703min。化合物296：(3mg)，白色固体，SFC:Rt＝1.775min。SFC分析方法为:柱:Chiralpak AD-3 100×4.6mm I.D.,3μm；流动相:A:CO2 B:ethanol(0.05％ DEA)；梯度:3分钟内B从5％到40％，40％的B保持0.5min,然后5％的B保持1.5min；流速:2.8mL/min；柱温:35℃；ABPR:1500psi。Compound 172 (30 mg) was chirally separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [CO 2 -EtOH (0.1% NH 3 H 2 O)]; B%: 15%, isocratic elution mode) to give compounds 293, 294, 295 and 296. Compound 293: (3 mg), white solid, SFC: Rt=1.343 min. Compound 294: (10 mg), white solid, SFC: Rt=1.497 min. Compound 295: (8 mg), white solid, SFC: Rt=1.703 min. Compound 296: (3 mg), white solid, SFC: Rt=1.775 min. SFC analysis method: column: Chiralpak AD-3 100×4.6mm ID, 3μm; mobile phase: A: CO 2 B: ethanol (0.05% DEA); gradient: B from 5% to 40% in 3 minutes, 40% B for 0.5min, then 5% B for 1.5min; flow rate: 2.8mL/min; column temperature: 35℃; ABPR: 1500psi.

生物活性测试例1Biological Activity Test Example 1

利用HTRF(均相时间分辨荧光)技术评估化合物对TDG和双链DNA底物结合的抑制作用。HTRF (homogeneous time-resolved fluorescence) technology was used to evaluate the inhibitory effect of compounds on the binding of TDG to double-stranded DNA substrate.

试剂耗材
Reagents and consumables

仪器instrument

酶标仪(生产厂家：Perkin Elmer，型号：Envision多功能酶标仪，配备HTRF功能模块)和Echo 550(生产厂家：Labcyte，型号：Echo 550)Microplate reader (manufacturer: Perkin Elmer, model: Envision multi-function microplate reader, equipped with HTRF function module) and Echo 550 (manufacturer: Labcyte, model: Echo 550)

实验方法Experimental methods

1.化合物浓度梯度的配制：受试化合物起始浓度250μM，3倍稀释，10个浓度，复孔检测。在384孔板中梯度稀释成40倍终浓度的10个不同浓度的溶液。然后用Echo550转移500nl到384反应板中备用。阴性对照孔和阳性对照孔中分别加500nl的100％DMSO或者无Biotin标记的dsDNA底物。1. Preparation of compound concentration gradient: The starting concentration of the test compound is 250μM, 3-fold dilution, 10 concentrations, and duplicate well detection. Gradient dilution is performed in a 384-well plate to form 10 solutions with different concentrations of 40 times the final concentration. Then 500nl is transferred to the 384 reaction plate using Echo550 for later use. 500nl of 100% DMSO or dsDNA substrate without Biotin labeling is added to the negative control well and the positive control well, respectively.

2.在384孔板中加入1.5μl/孔的Epigeneous Binding Domain diluent buffer，1000rpm离心1min。2. Add 1.5 μl/well of Epigeneous Binding Domain diluent buffer to a 384-well plate and centrifuge at 1000 rpm for 1 min.

3.在384孔板中加入4μl 5倍终浓度的His标记的TDG蛋白(终浓度40nM，使用Epigeneous Binding Domain diluent buffer稀释),1000rpm离心1min，室温抚育10min。3. Add 4 μl of 5 times the final concentration of His-tagged TDG protein (final concentration 40 nM, diluted with Epigeneous Binding Domain diluent buffer) into a 384-well plate, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 10 min.

4.在384孔板中加入4μl 5倍终浓度的Biotin标记的dsDNA底物(终浓度40nM，使用Epigeneous Binding Domain diluent buffer稀释)，1000rpm离心1min，室温抚育30min。4. Add 4 μl of 5 times the final concentration of Biotin-labeled dsDNA substrate (final concentration 40 nM, diluted with Epigeneous Binding Domain diluent buffer) into a 384-well plate, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 30 min.

5.在384孔板中加入5μl 4倍终浓度的Streptavidin-XL665(终浓度5nM，使用Epigeneous Binding Domain Detection buffer稀释)，1000rpm离心1min。5. Add 5 μl of 4 times the final concentration of Streptavidin-XL665 (final concentration 5 nM, diluted with Epigeneous Binding Domain Detection buffer) into a 384-well plate and centrifuge at 1000 rpm for 1 min.

6.在384孔板中加入5μl 4倍终浓度的MAb Anti-6HIS-Eu cryptate Gold(终浓度0.1μg/ml，使用Epigeneous Binding Domain Detection buffer稀释),1000rpm离心1min。6. Add 5 μl of 4 times the final concentration of MAb Anti-6HIS-Eu cryptate Gold (final concentration 0.1 μg/ml, diluted with Epigeneous Binding Domain Detection buffer) into a 384-well plate and centrifuge at 1000 rpm for 1 min.

4℃孵育过夜，酶标仪读HTRF。Incubate at 4°C overnight and read HTRF with a microplate reader.

数据分析Data analysis

1.每个孔的Ratio值计算1. Calculation of Ratio value for each hole

Ratio＝Signal 665nm/Signal 620nm×104Ratio＝Signal 665nm/Signal 620nm×104

2.每个孔的delta Ratio值计算2. Calculation of delta ratio value for each hole

delta Ratio＝Ratio standard or sample-Ratio standard 0(negative control)delta Ratio＝Ratio standard or sample-Ratio standard 0 (negative control)

3.利用四参数逻辑(4PL)曲线拟合IC50 3. IC50 curve fitting using four-parameter logistic (4PL)

下表中记录了生物测试结果。结果显示，本发明示例化合物对TDG和双链DNA底物的结合有很强的抑制作用。The biological test results are recorded in the table below. The results show that the exemplary compounds of the present invention have a strong inhibitory effect on the binding of TDG to double-stranded DNA substrates.

A:IC50≤500nM；A: IC 50 ≤500nM;

B:500nM<IC50≤5μM；B: 500nM<IC 50 ≤5μM;

C:5μM<IC50≤50μM；C: 5μM < IC 50 ≤ 50μM;

D:>50μMD:>50μM

采用上述测试方法，得到了以下化合物的效果：

Using the above test method, the effects of the following compounds were obtained:

生物活性测试例2化合物14对TP53突变型和野生型肿瘤细胞增殖的抑制Biological Activity Test Example 2 Inhibition of Compound 14 on Proliferation of TP53 Mutant and Wild-type Tumor Cells

化合物14对TP53突变和野生型肿瘤细胞增殖的抑制IC50，本实施例中使用的TP53突变型和野生型肿瘤细胞均为人肿瘤细胞。Compound 14 has an inhibitory IC 50 on the proliferation of TP53 mutant and wild-type tumor cells. The TP53 mutant and wild-type tumor cells used in this example are both human tumor cells.

将肿瘤细胞铺在384孔板上，并用DMSO或指定浓度的化合物14(0.04–30μM)进行处理。经过6天的孵育后，使用CellTiter-Glo发光检测试剂盒(Promega)测量化学发光强度。利用GraphPad Prism软件对曲线进行拟合，并计算出IC50值。Tumor cells were plated in 384-well plates and treated with DMSO or the indicated concentrations of compound 14 (0.04–30 μM). After 6 days of incubation, the chemiluminescence intensity was measured using the CellTiter-Glo Luminescence Assay Kit (Promega). The curves were fitted using GraphPad Prism software and the IC 50 values were calculated.

结果显示，化合物14对包括肺癌、肝癌、皮肤癌、膀胱癌、乳腺癌、结肠癌和食管癌在内的各个肿瘤细胞株均具有一定的抑制效果，特别是针对p53突变型肿瘤细胞系(包括NCI-H446、Calu-1、NCI-H1299、RERF-LC-AI、NCI-H211、NCI-H2009、NCI-H23、VMRC-LCP、NCI-H441、PC9、NCI-H520、EBC-1、NCI-H1975、NCI-H2342、NCI-H647、HCC95、SK-LU-1、SW-900、SNU423、SNU449、HuCCT1、PLC/PRF/5、SNU387、Hep3B、JHH-2、JHH7、SNU761、Huh7、CHL-1、RPMI-7951、SK-MEL-2、SK-MEL-28、MeWo、SK-MEL-3、5637、UMUC3、RT112、HT1376、BT549、MDA-MB-468、MDA-MB-231、HS578T、EFM-19、MDA-MB-436、Colo320DM、Colo205、RKO_E6、NCI-H508、TE-15、TE-8、TE-1、TE-9、TE-10、TE-4、TE-6、TE-14、T.T)体外增殖有明显抑制(图1)，表明包括化合物14在内的各个本发明化合物具有优异的抗肿瘤活性，特别是针对p53突变型肿瘤细胞的抗肿瘤活性。The results showed that compound 14 had a certain inhibitory effect on various tumor cell lines including lung cancer, liver cancer, skin cancer, bladder cancer, breast cancer, colon cancer and esophageal cancer, especially on p53 mutant tumor cell lines (including NCI-H446, Calu-1, NCI-H1299, RERF-LC-AI, NCI-H211, NCI-H2009, NCI-H23, VMRC-LCP, NCI-H441, PC9, NCI-H520, EBC-1, NCI-H1975, NCI-H2342, NCI-H647, HCC95, SK-LU-1, SW-900, SNU423, SNU449, HuCCT1, PLC/PRF/5, SNU387, Hep3B, JHH-2, JHH7, S The in vitro proliferation of NU761, Huh7, CHL-1, RPMI-7951, SK-MEL-2, SK-MEL-28, MeWo, SK-MEL-3, 5637, UMUC3, RT112, HT1376, BT549, MDA-MB-468, MDA-MB-231, HS578T, EFM-19, MDA-MB-436, Colo320DM, Colo205, RKO_E6, NCI-H508, TE-15, TE-8, TE-1, TE-9, TE-10, TE-4, TE-6, TE-14, and T.T was significantly inhibited (Figure 1), indicating that each compound of the present invention, including compound 14, has excellent anti-tumor activity, especially anti-tumor activity against p53 mutant tumor cells.

在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims (15)

一种如下式1所示的化合物，或其氘代产物、立体异构体、互变异构体，或其药学上可接受的盐：
A compound as shown in the following formula 1, or a deuterated product, stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof:
R1选自下组：OH、H、卤素、氰基、取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C6烷氧基、取代或未取代的C6-C10芳基、取代或未取代的3-12元的杂环、取代或未取代的5-12元的杂芳环、取代或未取代的-O-3-12元的杂环、取代或未取代的-C1-C6烷基-苯基、取代或未取代的-O-苯基、取代或未取代的C1-C4烷基-C(O)-、取代或未取代的C1-C4烷基-S(O)2-、取代或未取代的C1-C6烷基-NH-、(取代或未取代的C1-C6烷基)2-N-，-O(CH2)sR10，或-S(CH2)sR10；s为0、1、2或3； R1 is selected from the following group: OH, H, halogen, cyano, substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C2 - C6 alkenyl, substituted or unsubstituted C2 - C6 alkynyl, substituted or unsubstituted C1 - C6 alkoxy, substituted or unsubstituted C6- C10 aryl, substituted or unsubstituted 3-12 membered heterocycle, substituted or unsubstituted 5-12 membered heteroaromatic ring, substituted or unsubstituted -O-3-12 membered heterocycle, substituted or unsubstituted -C1 - C6 alkyl-phenyl, substituted or unsubstituted -O-phenyl, substituted or unsubstituted C1-C4 alkyl -C(O)-, substituted or unsubstituted C1 - C4 alkyl-S(O) 2- , substituted or unsubstituted C1 - C6 alkyl-NH-, (substituted or unsubstituted C1 - C6 alkyl) 2 -N-, -O(CH 2 ) s R 10 , or -S(CH 2 ) s R 10 ; s is 0, 1, 2 or 3; R10选自下组：H、取代或未取代的C3-8碳环、取代或未取代的3-8元的杂环、取代或未取代的C6-C10芳基、取代或未取代的5-12元的杂芳环；R 10 is selected from the following group: H, substituted or unsubstituted C 3-8 carbocyclic ring, substituted or unsubstituted 3-8 membered heterocyclic ring, substituted or unsubstituted C 6 -C 10 aryl group, substituted or unsubstituted 5-12 membered heteroaromatic ring; R2各自独立地选自下组：H、卤素、取代或未取代的C1-C6烷基；R 2 is each independently selected from the group consisting of H, halogen, substituted or unsubstituted C 1 -C 6 alkyl; R3选自下组：H、卤素、氰基、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C12环烷基，或(C1-C6烷基)C(O)R8、(C1-C6烷基)C(O)NHR8、(C1-C6烷基)C(O)N(取代或未取代的C1-C6烷基)R8、(C1-C6烷基)NHC(O)R8、(C1-C6烷基)C(O)OR8；R 3 is selected from the following group: H, halogen, cyano, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 12 cycloalkyl, or (C 1 -C 6 alkyl)C(O)R 8 , (C 1 -C 6 alkyl)C(O)NHR 8 , (C 1 -C 6 alkyl)C(O)N(substituted or unsubstituted C 1 -C 6 alkyl)R 8 , (C 1 -C 6 alkyl)NHC(O)R 8 , (C 1 -C 6 alkyl)C(O)OR 8 ; 所述的R8选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C6-C10芳基、-(OCH2CH2)m-取代或未取代的C1-C6烷基、金刚烷、或取代或未取代的选自下组的基团：-(CH2)mNHC(O)(CH2)nR13、-(CH2)CHR9NHC(O)(CH2)nR13、CHR9(CH2)NHC(O)(CH2)nR13；The R 8 is selected from the group consisting of H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 6 -C 10 aryl, -(OCH 2 CH 2 ) m -substituted or unsubstituted C 1 -C 6 alkyl, adamantane, or a substituted or unsubstituted group selected from the group consisting of -(CH 2 ) m NHC(O)(CH 2 ) n R 13 , -(CH 2 )CHR 9 NHC(O)(CH 2 ) n R 13 , CHR 9 (CH 2 )NHC(O)(CH 2 ) n R 13 ; 所述的R9选自下组：H、-COOH、-CONHR12、-CONHCH2R12、-CONH(CH2CH2O)m(CH2)nCOOH、取代或未取代的C1-C6烷氧基、取代或未取代的C6-C10芳基、取代或未取代的C3-C10的碳环、取代或未取代的3-12元的杂环、取代或未取代的5-12元的杂芳环；The R 9 is selected from the following group: H, -COOH, -CONHR 12 , -CONHCH 2 R 12 , -CONH(CH 2 CH 2 O) m (CH 2 ) n COOH, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted C 3 -C 10 carbocycle, substituted or unsubstituted 3-12 membered heterocycle, substituted or unsubstituted 5-12 membered heteroaromatic ring; R12选自下组：取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C6-C10芳基、取代或未取代的5-12元的杂芳环；R 12 is selected from the group consisting of a substituted or unsubstituted C 1 -C 6 alkyl group, a substituted or unsubstituted C 3 -C 8 cycloalkyl group, a substituted or unsubstituted C 6 -C 10 aryl group, and a substituted or unsubstituted 5-12 membered heteroaromatic ring; 所述的R13选自下组：取代或未取代的C3-C10的碳环、取代或未取代的5-12元的杂环；The R 13 is selected from the following group: a substituted or unsubstituted C 3 -C 10 carbocycle, a substituted or unsubstituted 5-12 membered heterocycle; m和n各自独立地为0、1、2或3；m and n are each independently 0, 1, 2 or 3; R4选自下组：H、卤素、氰基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6胺基、取代或未取代的C6-C10芳基、取代或未取代的C3-C8的环烷基、取代或未取代的3-12元的杂环、取代或未取代的5-12元的杂芳环、取代或未取代的-O-5-12元的杂芳环； R4 is selected from the following group: H, halogen, cyano, substituted or unsubstituted C1 - C6 alkoxy, substituted or unsubstituted C1 - C6 amine, substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted C3- C8 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic ring, substituted or unsubstituted 5-12 membered heteroaromatic ring, substituted or unsubstituted -O-5-12 membered heteroaromatic ring; 或者，R3和R4以及与其相连的碳原子共同形成选自下组的结构：取代或未取代的C6-C10芳环，取代或未取代的5-10元芳杂环、取代或未取代的C3-C8碳环，或取代或未取代的3-10元杂环；Alternatively, R3 and R4 and the carbon atoms to which they are attached together form a structure selected from the group consisting of a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C3-C8 carbocycle, or a substituted or unsubstituted 3-10 membered heterocycle; R5和R6各自独立地选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C6-C10芳环，取代或未取代的5-10元芳杂环、取代或未取代的C3-C8碳环，或取代或未取代的3-10元杂环；或所述的R5和R6以及与其相连的碳原子共同形成取代或未取代的3-12元的碳环； R5 and R6 are each independently selected from the following group: H, substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C6-C10 aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C3-C8 carbocycle, or substituted or unsubstituted 3-10 membered heterocycle; or said R5 and R6 and the carbon atoms connected thereto together form a substituted or unsubstituted 3-12 membered carbocycle; R6'选自下组：H、取代或未取代的C1-C6烷基；R 6 'is selected from the group consisting of H, substituted or unsubstituted C 1 -C 6 alkyl; X选自O或S；X is selected from O or S; Z选自O、S或NR14；其中，R14为H或C1-C4烷基；Z is selected from O, S or NR 14 ; wherein R 14 is H or C 1 -C 4 alkyl; R7选自下组：H、或C(O)R11、C(O)OR11、-CH2OC(O)OR11、-S(O)2NHR11；R 7 is selected from the group consisting of H, or C(O)R 11 , C(O)OR 11 , -CH 2 OC(O)OR 11 , -S(O) 2 NHR 11 ; 所述的R11选自下组：H、取代或未取代的C1-C16烷基、取代或未取代的C6-C10芳基、-(OCH2CH2)m-取代或未取代的C1-C6烷基、取代或未取代的5-8元杂环基；The R 11 is selected from the following group: H, substituted or unsubstituted C 1 -C 16 alkyl, substituted or unsubstituted C 6 -C 10 aryl, -(OCH 2 CH 2 ) m -substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted 5-8 membered heterocyclic group; 除非特别说明，上述各式中，所述的杂芳环、杂芳基、杂环或杂环基含有1个、2个或3个选自N、S或O的杂原子；所述的芳环、芳基、杂芳环或杂芳基可以为单环或稠合环；所述的碳环、环烷基、杂环或杂环基可以为单环、并环、桥环或螺环；所述的碳环、杂环或杂环基可以是饱和或部分不饱和的，但不具有芳香性。Unless otherwise specified, in the above formulas, the heteroaromatic ring, heteroaryl group, heterocycle or heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, S or O; the aromatic ring, aryl group, heteroaromatic ring or heteroaryl group may be a monocyclic ring or a condensed ring; the carbocyclic ring, cycloalkyl group, heterocyclic ring or heterocyclic group may be a monocyclic ring, a fused ring, a bridged ring or a spirocyclic ring; the carbocyclic ring, heterocyclic ring or heterocyclic group may be saturated or partially unsaturated, but not aromatic. 所述的取代指对应基团上的氢原子被一个或多个选自下组的取代基所取代：氘、卤素、羟基、羧基、巯基、苄基、C2-C12烷氧基羰基、C1-C6醛基、(C1-C6烷基)3Si、氨基、C1-C6酰胺基、硝基、氰基、未取代或卤代的C1-C6烷基、C2-C10烯基、C1-C6烷氧基、C3-C6环烷基、金刚烷、C1-C6烷基-胺基、C1-C12烷氨基羰基、未取代或卤代的C2-C10酰基、未取代或卤代的C1-C4烷基-S(O)2-、未取代或被C1-C4烷基取代的C1-C4烷基-OC(O)NH-、未取代或卤代C1-C4烷基-SO-、未取代或被C1-C4烷基取代的5-7元杂环，或苯基(其可以具有1-5个选自卤素、C1-C4烷基、C1-C4烷氧基的取代基)。The substitution refers to that the hydrogen atoms on the corresponding group are replaced by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, carboxyl, mercapto, benzyl, C2 - C12 alkoxycarbonyl, C1 - C6 aldehyde, ( C1 - C6 alkyl) 3Si , amino, C1 - C6 amide, nitro, cyano, unsubstituted or halogenated C1 - C6 alkyl, C2 - C10 alkenyl, C1 - C6 alkoxy, C3 - C6 cycloalkyl, adamantane, C1 - C6 alkyl-amino, C1 - C12 alkylaminocarbonyl, unsubstituted or halogenated C2 - C10 acyl, unsubstituted or halogenated C1 - C4 alkyl-S(O) 2- , unsubstituted or substituted C1 - C4 alkyl-OC(O)NH-, unsubstituted or halogenated C1 - C 4 -alkyl-SO-, a 5- to 7-membered heterocyclic ring which is unsubstituted or substituted by a C 1 -C 4 alkyl group, or a phenyl group (which may have 1 to 5 substituents selected from halogen, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group). 如权利要求1所述的化合物，或其氘代产物、立体异构体、互变异构体，或其药学上可接受的盐，其特征在于，所述的R1选自下组：卤素、取代或未取代的C1-C6烷氧基、取代或未取代的C6-C10芳基、取代或未取代的3-12元的杂环、取代或未取代的5-12元的杂芳环、取代或未取代的-O-3-12元的杂环、取代或未取代的C1-C4烷基-S(O)2-、取代或未取代的C1-C6烷基-NH-、(取代或未取代的C1-C6烷基)2-N-，或-O(CH2)sR10。The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that R 1 is selected from the following group: halogen, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 3-12 membered heterocycle, substituted or unsubstituted 5-12 membered heteroaromatic ring, substituted or unsubstituted -O-3-12 membered heterocycle, substituted or unsubstituted C 1 -C 4 alkyl-S(O) 2 -, substituted or unsubstituted C 1 -C 6 alkyl-NH-, (substituted or unsubstituted C 1 -C 6 alkyl) 2 -N-, or -O(CH 2 ) s R 10 . 如权利要求1所述的化合物，或其氘代产物、立体异构体、互变异构体，或其药学上可接受的盐，其特征在于，所述的式I化合物具有如下式II所示的结构：
The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that the compound of formula I has a structure shown in formula II below:
其中，所述的A环为取代或未取代的C6-C10芳环，取代或未取代的5-10元芳杂环、取代或未取代的C3-C8碳环，或取代或未取代的3-10元杂环；较佳地，所述的A环为取代或未取代的苯环，或取代或未取代的5-7元芳杂环。Wherein, the A ring is a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C3-C8 carbocycle, or a substituted or unsubstituted 3-10 membered heterocycle; preferably, the A ring is a substituted or unsubstituted benzene ring, or a substituted or unsubstituted 5-7 membered aromatic heterocycle. 如权利要求1所述的化合物，或其氘代产物、立体异构体、互变异构体，或其药学上可接受的盐，其特征在于，所述的化合物具有如下式IV所示的结构：
The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that the compound has a structure as shown in the following formula IV:
其中，所述的B环为取代或未取代的C3-C8碳环，或取代或未取代的3-10元杂环；较佳地，所述的B环为取代或未取代的C3-C6碳环，或取代或未取代的3-8元杂环；其中，所述的碳环或杂环可以为饱和或部分不饱和的。Wherein, the B ring is a substituted or unsubstituted C3-C8 carbocycle, or a substituted or unsubstituted 3-10 membered heterocycle; preferably, the B ring is a substituted or unsubstituted C3-C6 carbocycle, or a substituted or unsubstituted 3-8 membered heterocycle; wherein, the carbocycle or heterocycle may be saturated or partially unsaturated. 如权利要求1所述的化合物，或其氘代产物、立体异构体、互变异构体，或其药学上可接受的盐，其特征在于，所述的化合物具有如下式V所示的结构：
The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that the compound has a structure as shown in the following formula V:
其中，所述的D环为取代或未取代的C6-C10芳环，取代或未取代的5-10元芳杂环、取代或未取代的C3-C8碳环，或取代或未取代的3-10元杂环。Wherein, the D ring is a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C3-C8 carbon ring, or a substituted or unsubstituted 3-10 membered heterocycle. 如权利要求1所述的化合物，或其氘代产物、立体异构体、互变异构体，或其药学上可接受的盐，其特征在于，所述的化合物具有如下式VI或VII所示的结构：
The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that the compound has a structure as shown in Formula VI or VII:
其中，所述的Y为N或CH；Y1和Y2各自独立地选自下组：CHR15、NR15、O或S；t为1或2；其中所述的R15选自下组：氘、卤素、羟基、羧基、巯基、氨基、硝基、氰基、未取代或卤代的C1-C6烷基、C1-C6烷氧基。Wherein, Y is N or CH; Y1 and Y2 are each independently selected from the following group: CHR15 , NR15 , O or S; t is 1 or 2; wherein R15 is selected from the following group: deuterium, halogen, hydroxyl, carboxyl, thiol, amino, nitro, cyano, unsubstituted or halogenated C1 - C6 alkyl, C1 - C6 alkoxy. 如权利要求1所述的化合物，或其氘代产物、立体异构体、互变异构体，或其药学上可接受的盐，其特征在于，R3选自下组：H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的苯基。The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of H, halogen, substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C3 - C8 cycloalkyl, substituted or unsubstituted phenyl. 如权利要求1所述的化合物，或其氘代产物、立体异构体、互变异构体，或其药学上可接受的盐，其特征在于，R5和R6各自独立地选自下组：H、取代或未取代的C1-C6烷基；或所述的R5和R6以及与其相连的碳原子共同形成取代或未取代的3-6元的碳环。The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that R5 and R6 are each independently selected from the following group: H, substituted or unsubstituted C1 - C6 alkyl; or said R5 and R6 and the carbon atom connected thereto together form a substituted or unsubstituted 3-6-membered carbocyclic ring. 如权利要求1所述的化合物，或其氘代产物、立体异构体、互变异构体，或其药学上可接受的盐，其特征在于，R3选自下组：H、卤素、氰基、取代或未取代的C1-C6烷基、取代或未取代的C3-C12环烷基，或(C1-C6烷基)C(O)R8、(C1-C6烷基)C(O)NHR8、(C1-C6烷基)C(O)N(取代或未取代的C1-C6烷基)R8、(C1-C6烷基)C(O)OR8；所述的R8选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C6-C10芳基、-(OCH2CH2)m-取代或未取代的C1-C6烷基、或取代或未取代的选自下组的基团：-(CH2)mNHC(O)(CH2)nR13、-(CH2)CHR9NHC(O)(CH2)nR13、CHR9(CH2)NHC(O)(CH2)nR13；所述的R9选自下组：H、-COOH、-CONHR12、-CONHCH2R12、-CONH(CH2CH2O)m(CH2)nCOOH、取代或未取代的C1-C6烷氧基、取代或未取代的C6-C10芳基、取代或未取代的C3-C10的碳环、取代或未取代的3-12元的杂环、取代或未取代的5-12元的杂芳环；R12选自下组：取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C6-C10芳基、取代或未取代的5-12元的杂芳环；所述的R13选自下组：取代或未取代的C3-C10的碳环；The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that R 3 is selected from the group consisting of H, halogen, cyano, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 12 cycloalkyl, or (C 1 -C 6 alkyl)C(O)R 8 , (C 1 -C 6 alkyl)C(O)NHR 8 , (C 1 -C 6 alkyl)C(O)N(substituted or unsubstituted C 1 -C 6 alkyl)R 8 , (C 1 -C 6 alkyl)C(O)OR 8 ; wherein R 8 is selected from the group consisting of H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 6 -C 10 aryl, -(OCH 2 CH 2 ) m -substituted or unsubstituted C 1 -C 6 alkyl wherein R 9 is selected from the group consisting of H, -COOH , -CONHR 12 , -CONHCH 2 R 12 , -CONH(CH 2 CH 2 O) m (CH 2 ) n COOH, a substituted or unsubstituted C 1 -C 6 alkyl group, a substituted or unsubstituted C 6 -C 10 aryl group, a substituted or unsubstituted C 3 -C 10 carbocyclic ring, a substituted or unsubstituted 3-12 membered heterocyclic ring, or a substituted or unsubstituted 5-12 membered heteroaromatic ring; and R 12 is selected from the group consisting of a substituted or unsubstituted C 1 -C 6 alkoxy group, a substituted or unsubstituted C 6 -C 10 aryl group, a substituted or unsubstituted C 3 -C 10 carbocyclic ring, a substituted or unsubstituted 3-12 membered heterocyclic ring, or a substituted or unsubstituted 5-12 membered heteroaromatic ring . -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 5-12 membered heteroaromatic ring; said R 13 is selected from the following group: substituted or unsubstituted C 3 -C 10 carbocyclic ring; m和n各自独立地为0、1、2或3；m and n are each independently 0, 1, 2 or 3; R4选自下组：H、卤素、取代或未取代的C1-C6烷氧基、取代或未取代的-O-5-12元的杂芳环；R 4 is selected from the group consisting of H, halogen, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted -O-5-12 membered heteroaromatic ring; 或者，R3和R4以及与其相连的碳原子共同形成取代或未取代的C6-C10芳环，或取代或未取代的5-10元芳杂环。Alternatively, R3 and R4 and the carbon atom to which they are attached together form a substituted or unsubstituted C6-C10 aromatic ring, or a substituted or unsubstituted 5-10 membered aromatic heterocyclic ring. 如权利要求1所述的化合物，或其氘代产物、立体异构体、互变异构体，或其药学上可接受的盐，其特征在于，所述的化合物具有如下式III所示的结构：
The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that the compound has a structure as shown in the following formula III:
较佳地，所述的化合物具有如下式III-A或III-B所示的结构：
Preferably, the compound has a structure as shown in the following formula III-A or III-B:
较佳地，所述的化合物具有选自下组的任一结构：
Preferably, the compound has any structure selected from the following group:
如权利要求1所述的化合物，或其氘代产物、立体异构体、互变异构体，或其药学上可接受的盐，其特征在于，所述的化合物具有如下式IX所示的结构：
The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that the compound has a structure as shown in the following formula IX:
较佳地，所述的化合物具有如下式IX-A或IX-B所示的结构：
Preferably, the compound has a structure as shown in the following formula IX-A or IX-B:
较佳地，所述的化合物具有选自下组的任一结构：
Preferably, the compound has any structure selected from the following group:
如权利要求1所述的化合物，或其氘代产物、立体异构体、互变异构体，或其药学上可接受的盐，其特征在于，所述的化合物具有如下式X所示的结构：
The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that the compound has a structure shown in the following formula X:
较佳地，所述的化合物具有如下式X-A或X-B所示的结构：
Preferably, the compound has a structure as shown in the following formula XA or XB:
较佳地，所述的化合物具有选自下组的任一结构：
Preferably, the compound has any structure selected from the following group:
如权利要求1-12任一所述的化合物，或其氘代产物、立体异构体、互变异构体，或其药学上可接受的盐，其特征在于，所述的化合物选自下组：













The compound according to any one of claims 1 to 12, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that the compound is selected from the following group:













一种药物组合物，其特征在于，包括(i)如权利要求1所述的化合物，或其氘代产物、立体异构体、互变异构体，或其药学上可接受的盐；和(ii)药学上可接受的载体。A pharmaceutical composition, characterized in that it comprises (i) the compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier. 如权利要求1-13任一所述的化合物，或其氘代产物、立体异构体、互变异构体，或其药学上可接受的盐的用途，其特征在于，用于制备治疗和/或预防与TDG表达异常相关的疾病的药物；较佳地，所述的疾病选自下组：在另一优选例中，所述肿瘤选自下组：肺癌、急性白血病、慢性白血病、结直肠癌、乳腺癌、甲状腺瘤、淋巴瘤、胆管癌、肝癌、胰腺癌、支气管癌、食管癌、皮肤癌、膀胱癌、口腔癌、胃癌、泌尿生殖道肿瘤、中枢和外周神经系统肿瘤，或其组合；更佳地，所述肿瘤选自下组：黑色素瘤、急性髓系白血病、小细胞肺癌、非小细胞肺癌。The use of the compound according to any one of claims 1 to 13, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that it is used to prepare a drug for treating and/or preventing diseases associated with abnormal TDG expression; preferably, the disease is selected from the following group: in another preferred embodiment, the tumor is selected from the following group: lung cancer, acute leukemia, chronic leukemia, colorectal cancer, breast cancer, thyroid tumor, lymphoma, bile duct cancer, liver cancer, pancreatic cancer, bronchial cancer, esophageal cancer, skin cancer, bladder cancer, oral cancer, gastric cancer, urogenital tract tumors, central and peripheral nervous system tumors, or a combination thereof; more preferably, the tumor is selected from the following group: melanoma, acute myeloid leukemia, small cell lung cancer, non-small cell lung cancer.
PCT/CN2024/143412 2023-12-28 2024-12-27 Tdg inhibitor compound and use thereof Pending WO2025140637A1 (en)

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