Benzocycloheptane compound and preparation method thereof

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a benzocycloheptane compound and a preparation method thereof. According to the preparation method, copper salt / tert-butyl hydroperoxide is taken as an oxidizing agent, a complex formed by metal salt scandium trifluoromethanesulfonate and a chiral dinitrogen oxygen ligand is taken as a Lewis acid catalyst, oxidation dearomatization / asymmetric ring expansion reaction of non-functionalized naphthol is realized, and the benzocycloheptane compound shown in the formula I is prepared; the optimal preparation method of the benzocycloheptane compound is obtained by optimizing reaction conditions; the preparation method has the advantages of simplicity, high efficiency, good substrate universality, excellent enantioselectivity and the like. The benzocycloheptane compound provided by the invention has various biological activities such as antifungal activity, anticancer activity, anti-tumor activity and anti-malaria activity, can be used as a candidate compound of anticancer and anti-tumor drugs, and has a good application prospect. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a benzocycloheptane compound and a preparation method thereof. Background Art

[0002] The benzocycloheptane skeleton is widely present in a series of natural products, synthetic molecules and multifunctional intermediates with important biological activities. For example, Allocolchicine is a natural microscopic protein binder that can be used to treat familial Mediterranean fever and acute gout; Hamigeran G and Dihyisosubamol have multiple biological activities such as anticancer and antitumor. In addition, the substituent groups and stereochemistry in benzocycloheptane have a great influence on its biological activity. Himachalene is a male-specific aggregation pheromone component and an important scientific tool for monitoring and managing insects of great economic significance. Among them, only (R)-ar-himachalen exhibits the target pheromone activity, which essentially requires that the compound must be used in an enantiomerically pure form (structural formula as follows). Therefore, it is very meaningful and necessary to establish an asymmetric synthesis method for benzocycloheptane.

[0003]

[0004] In the past 20 years, chemists have made significant progress in the field of synthetic methodology of benzocycloheptane compounds, and have developed a variety of efficient construction strategies, including rearrangement ring expansion reaction of 1-vinylcycloalkanol derivatives, intramolecular C(sp 3 )-H bond functionalization cyclization reaction, transition metal-catalyzed cross-coupling reaction and Morita-Baylis-Hillman cyclization reaction. However, the synthetic methods reported so far still generally have two key limitations: first, most synthetic methods can only obtain racemic products; second, the existing asymmetric synthetic methods have obvious application bottlenecks, which are specifically manifested in the narrow scope of substrate applicability and low enantiomeric selectivity. In order to solve the above problems existing in the existing technology, it is urgent to develop a method for synthesizing benzocycloheptane compounds that is simple, efficient, has good substrate universality and excellent enantioselectivity. Summary of the Invention

[0005] In view of the problems of the prior art, the present invention provides a benzocycloheptane compound and a preparation method thereof.

[0006] The present invention provides a compound represented by Formula I, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotope-labeled substance thereof, or a crystalline form thereof, or a prodrug thereof:

[0007]

[0008] R 1 selected from hydrogen, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C2-C 10 Alkenyl, unsubstituted or at least one R 4 Substituted C6-C 10 Aryl, wherein the substituent is selected from C1-C 10 Alkyl, C6-C 10 aryl;

[0009] R 2 Selected from C1-C 10 Alkyl, C3-C 10 Cycloalkyl, -CH2R 5 ;

[0010] R 3 Selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C2-C 10 Alkenyl, C1-C 10 Ester group, substituted or unsubstituted C6-C 20 Aryl, wherein the substituent is selected from halogen, C6-C 10 aryl;

[0011] R 4 Selected from halogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C1-C 10 Alkylthio, cyano, nitro, substituted or unsubstituted C6-C 20 Aryl, substituted or unsubstituted C1-C 10 Ester group, wherein the substituent is selected from halogen; or, two adjacent R 4 connected to form a ring, wherein the ring is a benzene ring or a 5-6 membered saturated oxygen heterocycle;

[0012] R 5 Selected from C3-C 10 Cycloalkyl;

[0013] m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.

[0014] Preferably, R 1 is selected from hydrogen, substituted or unsubstituted 5-membered heteroaryl, substituted or unsubstituted C2-C8 alkenyl, unsubstituted or at least one R 4Substituted phenyl, wherein the substituent is selected from phenyl;

[0015] R 2 Selected from C1-C6 alkyl, C5 cycloalkyl, -CH2R 5 ;

[0016] R 3 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C2 alkyl, substituted or unsubstituted methoxy, substituted or unsubstituted C2 alkenyl, C1 ester, substituted or unsubstituted phenyl, wherein the substituent is selected from phenyl;

[0017] R 4 is selected from halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted methoxy, substituted or unsubstituted methylthio, cyano, nitro, phenyl, C1 ester, wherein the substituent is selected from halogen; or, two adjacent R 4 Connect to form a benzene ring;

[0018] R 5 Selected from C3-C6 cycloalkyl;

[0019] m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18.

[0020] Preferably, the compound represented by formula I is one of the following structures:

[0021]

[0022] The present invention also provides a method for preparing the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotope-labeled substance thereof, or a crystal form thereof, or a prodrug thereof, comprising the following steps:

[0023]

[0024] Step 1: reacting compound A with an oxidant to obtain an intermediate product D; the reaction is carried out in the presence of a catalyst, the catalyst being selected from copper or a copper salt, the copper salt being selected from at least one of cuprous bromide, cuprous chloride, cuprous iodide, cupric dibromide, cupric chloride, cuprous oxide, copper trifluoromethanesulfonate, cuprous thiocyanate, and copper acetate;

[0025] Step 2: reacting the intermediate product D with compound B to obtain compound E; the reaction is carried out under the action of a chiral catalyst; the chiral catalyst is obtained by coordination reaction of a metal salt and a chiral difluoromethanesulfonate ligand; the metal salt is selected from at least one of magnesium difluoromethanesulfonate, aluminum trifluoromethanesulfonate, nickel difluoromethanesulfonate, copper difluoromethanesulfonate, zinc difluoromethanesulfonate, yttrium trifluoromethanesulfonate, bismuth trifluoromethanesulfonate, lanthanum trifluoromethanesulfonate, indium trifluoromethanesulfonate, and scandium trifluoromethanesulfonate; the chiral difluoromethanesulfonate ligand is selected from L3-PrPr2 , at least one of L3-PiPr2, L3-TqPr2, L2-RaPr2, L2-RaPr2Ad, L3-RaPr2, L3-RaPr3, L3-RaAd, and L4-RaPr2; the structural formulas of L3-PrPr2, L3-PiPr2, L3-TqPr2, L2-RaPr2, L2-RaPr2Ad, L3-RaPr2, L3-RaPr3, L3-RaAd, and L4-RaPr2 are respectively:

[0026]

[0027] Step 3, reacting compound E with a reducing agent to obtain a compound represented by formula I;

[0028] The selection of R1, R2, R3, and m is as described above.

[0029] Preferably, the molar ratio of compound A to copper salt is 100:(5-10);

[0030] and / or, the molar ratio of the compound A to the oxidant is 100:(100-400);

[0031] and / or, the molar ratio of compound A to compound B is 100:(100-120);

[0032] and / or, the molar ratio of compound A to the chiral catalyst is 100:(1-100);

[0033] And / or, the molar ratio of the compound A to the reducing agent is 100:(80-200).

[0034] Preferably, in step 1, the reaction solvent is selected from at least one of ethyl acetate, dichloroethane, 1,1,2,2-tetrachloroethane, dichloromethane, tetrahydrofuran, and chloroform; and the oxidant is selected from tert-butyl peroxide;

[0035] And / or, in step 1, the reaction temperature is 0-50° C., and the reaction time is 0.5-10 h;

[0036] and / or, in step 2, the solvent for the coordination reaction is at least one of dichloroethane, 1,1,2,2-tetrachloroethane, dichloromethane, chlorobenzene, ethyl acetate, tetrahydrofuran, toluene, and chloroform;

[0037] And / or, in step 2, the temperature of the coordination reaction is 10-50° C., and the reaction time is 0.5-5 h;

[0038] And / or, in step 2, the reaction temperature is 0-60°C and the reaction time is 12-48h;

[0039] And / or, in step 3, the reducing agent is selected from o-phenylenediamine;

[0040] And / or, in step 3, the reaction temperature is 0-50° C., and the reaction time is 0.5-2 h.

[0041] Preferably, in step 2, the solvent for the coordination reaction is dichloromethane.

[0042] Preferably, in step 1, the copper salt is selected from at least one of cuprous bromide, cuprous chloride, cupric dibromide, cupric chloride, and cuprous oxide.

[0043] Preferably, the copper salt is selected from cuprous chloride.

[0044] Preferably, in step 1, the metal salt is selected from scandium trifluoromethanesulfonate.

[0045] Preferably, in step 1, the chiral dinitrogen oxide ligand is selected from at least one of L2-RaPr2, L2-RaPr2Ad, L3-RaPr2, and L3-RaPr3.

[0046] Preferably, the chiral dinitrogen oxide ligand is selected from L2-RaPr2 or its enantiomer ent-L2-RaPr2, and the structural formula of L2-RaPr2 is:

[0047]

[0048] The present invention also provides the use of the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotope-labeled substance thereof, or a crystal form thereof, or a prodrug thereof in the preparation of a drug for treating tumors.

[0049] The compounds and derivatives provided herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0050] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0051] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0052] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a -C b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C1-C6 alkyl" refers to an alkyl group containing from 1 to 6 carbon atoms.

[0053] "Alkyl" refers to a saturated hydrocarbon chain with a specified number of member atoms. For example, C1-C6 alkyl refers to an alkyl group with 1 to 6 member atoms, such as 1 to 4 member atoms. The alkyl group can be straight or branched. Representative branched alkyl groups have one, two or three branches. The alkyl group may optionally be substituted with one or more substituents as defined herein. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. The alkyl group may also be part of other groups, such as C1-C6 alkoxy.

[0054] "Cycloalkyl" refers to a saturated or partially saturated cyclic group having from 3 to 14 carbon atoms and no ring heteroatoms, and having a single ring or multiple rings (including fused, bridged, and spiro ring systems).

[0055] "Halogen" is fluorine, chlorine, bromine or iodine.

[0056] "Haloalkyl" refers to an alkyl group in which the hydrogen atoms are replaced by one or more halogen atoms. For example, a C1-C6 haloalkyl group refers to an alkyl group containing 1 to 6 carbon atoms in which the hydrogen atoms are replaced by one or more halogen atoms.

[0057] "Aromatic heterocycle" refers to an aromatic unsaturated ring containing at least one heteroatom and having a single ring or multiple rings; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom;

[0058] "Alkoxy" refers to an alkyl group attached to the site of attachment through an oxygen atom, for example, methoxy refers to -OCH3.

[0059] "Alkylthio" refers to an alkyl group attached to the site of attachment through a sulfur atom, for example, methylthio refers to -SCH3.

[0060] An "ester group" refers to a group that is attached to a linking site through a carbon chain and that contains at least one ester bond (ie, -COO-).

[0061] "Cyano" refers to a group consisting of a carbon atom (C) and a nitrogen atom (N), with the carbon atom and the nitrogen atom connected by a triple bond (C≡N).

[0062] "Nitro" (-NO2) is composed of a nitrogen atom (N) and two oxygen atoms (O), and the nitrogen atom and the two oxygen atoms are connected by a double bond and a single bond (O=NO).

[0063] “R a 、R b "Connected into a ring" refers to R a and R b There is at least one atom connected by a chemical bond in each of them, so that R a 、R b and the molecular skeleton structure in which they are located together constitute a ring structure.

[0064] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form and physiologically compatible with the receptor.

[0065] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final isolation and purification of the compound. They can also be obtained by mixing the above-mentioned compound, or its stereoisomer, with a certain amount of acid or base appropriately (e.g., equivalent amounts). These salts may form a precipitate in the solution and be collected by filtration, or be recovered after evaporation of the solvent, or be obtained by freeze-drying after reaction in an aqueous medium. The salts described in the present invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluorides, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates or trifluoroacetates of the compound.

[0066] In certain embodiments, one or more compounds of the present invention may be used in combination with one another. Compounds of the present invention may also be used in combination with any other active agent to prepare a drug or pharmaceutical composition for regulating cell function or treating a disease. If a group of compounds is used, these compounds may be administered to a subject simultaneously, separately, or sequentially.

[0067] This invention utilizes a tandem oxidative dearomatization / asymmetric ring expansion reaction of nonfunctional naphthols to synthesize benzocycloheptane compounds. By optimizing the reaction conditions, an optimal method for preparing benzocycloheptane compounds is obtained. This method has the advantages of simplicity, high efficiency, good substrate compatibility, and excellent enantioselectivity. Experimental testing has shown that the benzocycloheptane compounds provided by this invention exhibit anticancer and antitumor biological activities, making them promising candidates for anticancer and antitumor drugs, with promising applications in the medical field.

[0068] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0069] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. DETAILED DESCRIPTION

[0070] In the following examples and experimental examples, reagents and raw materials not specifically described are all commercially available.

[0071] Example 1: Preparation of Benzocycloheptane Compounds

[0072] Synthesis route:

[0073]

[0074] The specific preparation method is:

[0075] Compound A (0.1 mol) and 10.0 mg, 0.01 mol of cuprous chloride (CuCl) were weighed into a dry test tube, followed by the addition of ethyl acetate (1.0 mL) and 0.4 mol of tert-butyl peroxide (TBHP). The mixture was reacted at 30°C for 2 hours, and then the reaction system was pumped dry with an oil pump to obtain compound D. Meanwhile, chiral dinitrogen oxide ligand L2-RaPr2 (6.9 mg, 0.01 mol), 4.9 mg, 0.01 mol of metal salt scandium trifluoromethanesulfonate (Sc(OTf)3) and dichloromethane (1.0 mL) were weighed into a dry penicillin vial, activated at 30°C for 1 hour, and then added to compound D. Diazo compound B (0.12 mol) was added, and the mixed system was reacted at 30°C for 12 hours to obtain compound E. O-phenylenediamine (0.15 mol) was then added and the reaction continued for 1 hour. After the reaction was completed, the mixture was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 20 to 1 / 10 elution) to obtain compound C (Formula I). 1is selected from hydrogen, thienyl, substituted or unsubstituted C2-C8 alkenyl, unsubstituted or at least one R 4 Substituted phenyl, wherein the substituent is selected from phenyl; R 2 Selected from methyl, hexyl, C5 cycloalkyl, -CH2R 5 ; R 3 is selected from hydrogen, halogen, cyano, C1-C2 alkyl, methoxy, substituted or unsubstituted C2 alkenyl, C1 ester, phenyl, wherein the substituent is selected from phenyl; R 4 is selected from halogen, C1-C4 alkyl, substituted or unsubstituted methoxy, substituted or unsubstituted methylthio, cyano, nitro, phenyl, C1 ester, wherein the substituent is selected from halogen; or, two adjacent R 4 Connect to form a benzene ring; R 5 is selected from C3-C6 cycloalkyl; and m is selected from 1 to 18. The enantiomeric excess (ee value) is determined by HPLC analysis using a chiral stationary phase.

[0076] The structural formula of the L2-RaPr2 is:

[0077]

[0078] Compounds C1-C39 were prepared according to the above preparation method, except that R 3 The selection of R in diazoester compound B 1 、R 2 The selection was adaptively adjusted according to the structures of compounds C1-C39.

[0079] The yields, enantioselectivities, structural formulas, and NMR data of the benzocycloheptane compounds C1-C39 prepared by the present invention are as follows:

[0080] Compound C1: 57% yield, 95% ee

[0081]

[0082] 1 H NMR(400MHz,Chloroform-d)δ8.37–8.00(m,3H),7.79(m,2H),7.53–7.45(m,2H),7.39–7.33(m,1H),7.30(m,2H),7.2 2(m,3H),6.82(d,J=10.6Hz,1H),6.35(d,J=10.6Hz,1H),4.03(d,J=13.7Hz,1H),3.71(d,J=13.7Hz,1H),3.11(s,3H).

[0083] 13C NMR(101MHz,Chloroform-d)δ172.2,154.5,150.9,141.1,140.2,137.1,136.1,135.3,133. 2,130.7,130.5,129.7,129.7,129.2,128.9,128.3,128.0,127.7,126.8,58.6,51.7,40.2.

[0084] Compound C2: 56% yield, 94% ee

[0085]

[0086] 1 H NMR(400MHz,Chloroform-d)δ8.45–8.01(m,3H),7.79(m,2H),7.52–7.45(m,2H),7.38–7.32(m,1H),7.19(d,J=7.9Hz,2H),7.07(d,J= 7.8Hz,2H),6.82(d,J=10.6Hz,1H),6.35(d,J=10.6Hz,1H),3.97(d,J=13.7Hz,1H),3.71(d,J=13.7Hz,1H),3.14(s,3H),2.30(s,3H).

[0087] 13 C NMR(101MHz,Chloroform-d)δ172.2,154.6,150.9,141.1,140.3,136.3,136.1,135.4,133.9,133 .2,130.7,130.6,130.4,129.7,129.6,129.2,128.9,128.8,128.3,127.7,58.6,51.8,39.9,21.1.

[0088] Compound C3: 55% yield, 95% ee

[0089]

[0090] 11H NMR (400 MHz, Chloroform-d) δ 8.49–7.97 (m, 3H), 7.78 (m, 2H), 7.52–7.45 (m, 2H), 7.40–7.34 (m, 1H), 7.28–7.22 (m, 4H), 6.82 (d, J = 10.6 Hz, 1H), 6.36 (d, J = 10.6 Hz, 1H), 3.99 (d, J = 13.7 Hz, 1H), 3.68 (d, J = 13.6 Hz, 1H), 3.12 (s, 3H), 1.27 (s, 9H).

[0091] 13 13C NMR (101 MHz, Chloroform-d) δ 172.2, 154.5, 150.9, 149.4, 141.1, 140.3, 136.2, 135.4, 133.9, 133.5, 130.7, 130.5, 130.2, 129.7, 129.7, 129.7, 129.2, 128.9, 128.3, 127.7, 124.9, 58.7, 51.7, 39.7, 34.4, 31.3.

[0092] Compound C4: 46% yield, 96% ee

[0093]

[0094] 1 1H NMR (400 MHz, Chloroform-d) δ 8.46–8.04 (m, 3H), 7.81 (m, 2H), 7.59–7.55 (m, 2H), 7.50 (m, 4H), 7.40 (m, 5H), 7.32 (m, 1H), 6.86 (d, J = 10.6 Hz, 1H), 6.39 (d, J = 10.6 Hz, 1H), 4.08 (d, J = 13.6 Hz, 1H), 3.77 (d, J = 13.6 Hz, 1H), 3.16 (s, 3H).

[0095] 13 13C NMR (101 MHz, Chloroform-d) δ 172.2, 154.4, 150.9, 141.1, 140.9, 140.2, 139.6, 136.2, 136.1, 135.3, 133.2, 131.0, 130.7, 130.6, 129.8, 129.7, 129.3, 128.9, 128.7, 128.3, 127.7, 127.1, 127.0, 126.7, 58.7, 51.8, 39.9.

[0096] Compound C5: 52% yield, 96% ee

[0097]

[0098] 1 H NMR(400MHz,Chloroform-d)δ8.35–8.05(m,3H),7.79(m,2H),7.52–7.45(m,2H),7.39–7.33(m,1H),7.23(d,J=8.7Hz,2 H),6.85–6.77(m,3H),6.33(d,J=10.6Hz,1H),3.99(d,J=13.8Hz,1H),3.76(s,3H),3.66(d,J=13.8Hz,1H),3.13(s,3H).

[0099] 13 C NMR(101MHz,Chloroform-d)δ172.3,158.4,154.5,150.9,141.1,140.2,136.2,135.4,133.4,131 .5,130.7,130.5,129.7,129.7,129.2,129.0,128.9,128.3,127.7,113.4,58.7,55.1,51.8,39.4.

[0100] Compound C6: 42% yield, 96% ee

[0101]

[0102] 1 H NMR(400MHz,Chloroform-d)δ8.40–8.04(m,3H),7.79(m,2H),7.53–7.46(m,2H),7.39–7.34(m,1H),7.24(d,J=8.2Hz,2H),7.14(d,J= 7.9Hz,2H),6.82(d,J=10.6Hz,1H),6.32(d,J=10.6Hz,1H),3.99(d,J=13.7Hz,1H),3.66(d,J=13.7Hz,1H),3.14(s,3H),2.44(s,3H).

[0103] 13C NMR(101MHz,Chloroform-d)δ172.2,154.4,150.9,141.1,140.2,136.7,136.1,135.3,133.9,133 .2,131.0,130.7,130.6,129.8,129.7,129.2,128.8,128.3,127.7,126.3,58.6,51.8,39.7,15.8.

[0104] Compound C7: 46% yield, 96% ee

[0105]

[0106] 1 H NMR(600MHz,Chloroform-d)δ8.23(m,1H),8.22–8.15(m,2H),7.80(m,2H),7.50(m,2H),7.37(m,1H),7.29(m,2H),6.93(t, J=8.5Hz,2H),6.83(d,J=10.6Hz,1H),6.30(d,J=10.5Hz,1H),4.05(d,J=13.7Hz,1H),3.64(d,J=13.9Hz,1H),3.12(s,3H).

[0107] 13 C NMR(151MHz,Chloroform-d)δ172.1,161.9(d,J=245.2Hz),154.3,150.9,141.1,140.2,136.2,135.2,133.2,132.8(d,J=3. 9Hz), 132.1, 132.0, 130.7 (d, J = 10.9Hz), 129.8, 129.8, 129.3, 128.8, 128.3, 127.8, 114.8 (d, J = 20.7Hz), 58.8, 51.8, 39.3.

[0108] Compound C8: 47% yield, 96% ee

[0109]

[0110] 1H NMR(600MHz,Chloroform-d)δ8.35–8.06(m,3H),7.82–7.78(m,2H),7.49(m,2H),7.38–7.35(m,1H),7.25(d,J=7.9Hz,2H),7.2 0(d,J=8.4Hz,2H),6.82(d,J=10.6Hz,1H),6.29(d,J=10.6Hz,1H),4.03(d,J=13.7Hz,1H),3.63(d,J=13.7Hz,1H),3.12(s,3H).

[0111] 13 C NMR(151MHz,Chloroform-d)δ172.1,154.2,150.8,141.1,140.2,136.1,135.6,135.2,133.0,1 32.7,131.9,130.7,130.7,129.8,129.8,129.3,128.8,128.3,128.1,127.8,58.6,51.9,39.5.

[0112] Compound C9: 50% yield, 96% ee

[0113]

[0114] 1 H NMR(600MHz,Chloroform-d)δ8.46–7.99(m,3H),7.81–7.77(m,2H),7.53–7.48(m,2H),7.36(m,3H),7.20(d,J=8.0H z,2H),6.83(d,J=10.6Hz,1H),6.29(d,J=10.6Hz,1H),4.01(d,J=13.7Hz,1H),3.62(d,J=13.7Hz,1H),3.13(s,3H).

[0115] 13 C NMR(151MHz,Chloroform-d)δ172.0,154.1,150.8,141.1,140.2,136.1,135.2,133.0,1 32.3,131.1,130.7,129.8,129.8,129.3,128.8,128.3,127.8,120.9,58.6,51.9,39.5.

[0116] Compound C10: 32% yield, 93% ee

[0117]

[0118] 1 1H NMR (600 MHz, Chloroform-d) δ 8.27–8.21 (m, 1H), 8.18 (m, 2H), 7.81–7.78 (m, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.52–7.48 (m, 2H), 7.36 (m, 1H), 7.06 (d, J = 7.9 Hz, 2H), 6.82 (d, J = 10.6 Hz, 1H), 6.28 (d, J = 10.6 Hz, 1H), 3.99 (d, J = 13.6 Hz, 1H), 3.61 (d, J = 13.7 Hz, 1H), 3.13 (s, 3H).

[0119] 13 13C NMR (151 MHz, Chloroform-d) δ 172.0, 154.2, 150.8, 141.1, 140.2, 137.1, 136.8, 136.1, 135.2, 133.0, 132.6, 130.7, 129.8, 129.3, 128.8, 128.3, 127.8, 92.5, 58.6, 51.9, 39.6.

[0120] Compound C11: 52% yield, 96% ee

[0121]

[0122] 1 1H NMR (600 MHz, Chloroform-d) δ 8.26–8.21 (m, 1H), 8.19 (m, 2H), 7.92 (d, J = 8.1 Hz, 2H), 7.80 (m, 2H), 7.52–7.48 (m, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.37–7.35 (m, 1H), 6.82 (d, J = 10.6 Hz, 1H), 6.31 (d, J = 10.6 Hz, 1H), 4.10 (d, J = 13.5 Hz, 1H), 3.88 (s, 3H), 3.72 (d, J = 13.6 Hz, 1H), 3.12 (s, 3H).

[0123] 13C NMR(151MHz,Chloroform-d)δ172.0,167.0,154.1,150.8,142.7,141.1,140.2,136.1,135.2,132 .9,130.7,130.6,129.8,129.8,129.3,129.2,128.8,128.7,128.3,127.8,58.6,52.0,51.8,40.1.

[0124] Compound C12: 45% yield, 96% ee

[0125]

[0126] 1 H NMR(400MHz,Chloroform-d)δ8.42–8.04(m,3H),7.80(m,2H),7.54–7.47(m,2H),7.42–7.33(m,3H),7.08(d,J=8.2H z,2H),6.84(d,J=10.6Hz,1H),6.30(d,J=10.6Hz,1H),4.11(d,J=13.7Hz,1H),3.64(d,J=13.7Hz,1H),3.11(s,3H).

[0127] 13 C NMR(101MHz,Chloroform-d)δ172.0,154.1,150.9,148.1,141.1,140.1,136.1,135.9,135.1,1 33.2,131.9,130.7,130.7,129.8,129.8,129.3,128.8,128.3,127.9,120.4,58.7,51.8,39.3.

[0128] Compound C13: 30% yield, 94% ee

[0129]

[0130] 1 H NMR(400MHz,Chloroform-d)δ8.39–8.08(m,3H),7.81(m,2H),7.55–7.48(m,4H),7.43–7.35(m,3H),6.8 4(d,J=10.5Hz,1H), 6.30(d,J=10.5Hz,1H), 4.16(d,J=13.5Hz,1H), 3.65(d,J=13.5Hz,1H), 3.07(s,3H).

[0131] 13 C NMR(101MHz,Chloroform-d)δ171.9,153.9,150.8,141.1,140.6,140.1,136.1,135.9,135.1,133. 1,131.7,131.1,130.7,130.7,129.9,129.9,129.3,128.8,128.3,127.9,122.5,58.8,51.8,39.7.

[0132] Compound C14: 50% yield, 95% ee

[0133]

[0134] 1 H NMR(400MHz,Chloroform-d)δ8.46–7.98(m,3H),7.79(m,2H),7.52–7.45(m,2H),7.40–7.33(m,1H),7.12(m,3H),7.03(m,1H ),6.82(d,J=10.6Hz,1H),6.35(d,J=10.6Hz,1H),3.97(d,J=13.6Hz,1H),3.72(d,J=13.7Hz,1H),3.13(s,3H),2.31(s,3H).

[0135] 13 C NMR(101MHz,Chloroform-d)δ172.3,154.6,150.9,141.1,140.3,137.4,136.9,136.1,135.4,133.2,131 .4,130.7,130.6,129.7,129.7,129.2,128.9,128.2,127.9,127.7,127.6,127.5,58.5,51.7,40.3,21.4.

[0136] Compound C15: 29% yield, 95% ee

[0137]

[0138] 11H NMR (400 MHz, Chloroform-d) δ 8.42–8.04 (m, 3H), 7.86–7.77 (m, 2H), 7.54–7.46 (m, 2H), 7.38–7.30 (m, 2H), 7.18–7.08 (m, 3H), 6.80 (d, J = 10.6 Hz, 1H), 6.41 (d, J = 10.6 Hz, 1H), 4.05 (d, J = 14.8 Hz, 1H), 3.92 (d, J = 14.8 Hz, 1H), 3.10 (s, 3H), 2.31 (s, 3H).

[0139] 13 13C NMR (101 MHz, Chloroform-d) δ 172.6, 154.8, 151.0, 141.1, 140.2, 137.4, 136.1, 135.6, 135.4, 133.2, 130.6, 130.6, 130.5, 130.4, 129.7, 129.7, 129.7, 129.2, 129.0, 128.2, 127.7, 126.7, 125.6, 57.7, 51.9, 36.2, 20.0.

[0140] Compound C16: 53% yield, 96% ee

[0141]

[0142] 1 1H NMR (600 MHz, Chloroform-d) δ 8.36–8.16 (m, 3H), 8.10–8.07 (m, 1H), 7.84–7.79 (m, 3H), 7.76 (d, J = 8.3 Hz, 1H), 7.62 (d, J = 7.1 Hz, 1H), 7.43 (m, 5H), 7.24 (d, J = 6.4 Hz, 1H), 6.74 (d, J = 10.6 Hz, 1H), 6.48 (d, J = 10.6 Hz, 1H), 4.54 (d, J = 14.7 Hz, 1H), 4.41 (d, J = 14.7 Hz, 1H), 2.79 (s, 3H).

[0143] 13C NMR(151MHz,Chloroform-d)δ172.5,154.9,151.2,141.1,140.3,136.1,135.3,133.9,133.5,133.2,132.9,130.7,130. 7,129.7,129.7,129.6,129.3,129.0,128.8,128.7,128.1,127.7,127.6,125.7,125.3,125.2,124.0,57.6,51.8,36.2.

[0144] Compound C17: 52% yield, 96% ee

[0145]

[0146] 1 H NMR(600MHz,Chloroform-d)δ8.36–8.09(m,3H),7.80(m,5H),7.73(d,J=8.4Hz,1H),7.52–7.48(m,2H),7.43(m,3H),7.37 –7.34(m,1H),6.83(d,J=10.5Hz,1H),6.42(d,J=10.5Hz,1H),4.20(d,J=13.7Hz,1H),3.90(d,J=13.7Hz,1H),3.10(s,3H).

[0147] 13 C NMR(151MHz,Chloroform-d)δ172.3,154.5,150.9,141.1,140.3,136.1,135.4,134.7,133.3,133.2,132.4,130. 7,130.6,129.7,129.4,129.3,128.9,128.7,128.3,127.7,127.7,127.5,127.4,125.8,125.5,58.7,51.8,40.5.

[0148] Compound C18: 58% yield, 94% ee

[0149]

[0150] 11H NMR (400 MHz, Chloroform-d) δ 8.25–8.14 (m, 3H), 7.80 (m, 2H), 7.53–7.47 (m, 2H), 7.40–7.35 (m, 1H), 7.25–7.08 (m, 2H), 7.05 (m, J 1H), 6.83 (d, J = 10.6 Hz, 1H), 6.29 (d, J = 10.6 Hz, 1H), 4.08 (d, J = 14.0 Hz, 1H), 3.70 (d, J = 14.0 Hz, 1H), 3.15 (s, 3H).

[0151] 13 13C NMR (101 MHz, Chloroform-d) δ 172.3, 154.2, 151.0, 141.1, 140.2, 137.2, 136.2, 135.1, 133.6, 130.7, 130.5, 129.8, 129.7, 129.3, 128.8, 128.3, 127.8, 124.6, 123.9, 58.5, 51.9, 34.8.

[0152] Compound C19: 58% yield, 95% ee

[0153]

[0154] 1 1H NMR (600 MHz, Chloroform-d) δ 8.26–8.21 (m, 1H), 8.21–8.16 (m, 1H), 8.16–8.09 (m, 1H), 7.77 (m, 2H), 7.54–7.50 (m, 2H), 7.40 (m, 1H), 7.34 (m, 4H), 7.25–7.22 (m, 1H), 6.84 (d, J = 10.4 Hz, 1H), 6.19 (d, J = 10.4 Hz, 1H), 3.26 (s, 3H), 3.00–3.05 (m, 1H), 2.96–2.85 (m,

[0155] 1H), 2.68–2.63 (m, 2H).

[0156] 13 13C NMR (151 MHz, Chloroform-d) δ 172.7, 154.3, 151.3, 142.2, 141.0, 140.5, 136.4, 135.0, 134.2, 130.7, 130.6, 129.7, 129.6, 129.6, 129.2, 129.0, 128.6, 128.4, 128.3, 127.8, 126.0, 56.6, 52.1, 37.4, 31.5.

[0157] Compound C20: 50% yield, 91% ee

[0158]

[0159] 1 H NMR(400MHz,Chloroform-d)δ8.48–7.90(m,3H),7.85–7.70(m,2H),7.56–7.44(m,2H),7.39–7.14(m,6H), 6.79(d,J=10.4Hz,1H),6.11(d,J=10.4Hz,1H),3.19(s,3H),2.75(m,3H),2.42(m,1H),2.00–1.70(m,2H).

[0160] 13 C NMR(101MHz,Chloroform-d)δ172.8,154.5,151.2,142.1,141.0,140.4,136.3,135.0,134.3,130.6, 130.4,129.6,129.6,129.5,129.2,128.9,128.5,128.3,127.7,125.8,56.6,52.0,36.2,35.0,26.6.

[0161] Compound C21: 52% yield, 95% ee

[0162]

[0163] 1 H NMR(400MHz,Chloroform-d)δ8.38–8.01(m,3H),7.82–7.76(m,2H),7.53–7.47(m,2H),7.43–7.37(m,1H),7.33(m,2H),7.28–7.24(m,2H),7.18(m ,1H),6.84(d,J=10.5Hz,1H),6.59–6.47(m,2H),6.22(d,J=10.5Hz,1H), 3.55(dd,J=13.9,5.6Hz,1H), 3.37(dd,J=13.9,7.1Hz,1H), 3.16(s,3H).

[0164] 13C NMR(101MHz,Chloroform-d)δ172.4,154.3,151.2,141.1,140.5,137.4,136.2,135.1,133.5,130.8,1 30.7,129.7,129.7,129.6,129.2,129.0,128.4,128.3,127.7,127.2,126.2,125.8,57.1,52.0,39.3.

[0165] Compound C22: 49% yield, 92% ee,

[0166]

[0167] 1 H NMR(600MHz,Chloroform-d)δ8.46–7.98(m,3H),7.78–7.74(m,2H),7.49(m,2H),7.39–7.36(m,1H),6.84(d,J=10.4Hz,1H),6.17(d,J= 10.5Hz,1H),5.42(t,J=7.6Hz,1H),3.30(dd,J=14.5,7.9Hz,1H),3.22(dd,J=14.5,7.9Hz,1H),3.19(s,3H),1.73(s,3H),1.70(s,3H).

[0168] 13 C NMR(151MHz,Chloroform-d)δ172.6,154.7,151.2,141.0,140.5,136.2,135.3,135.3,133.8,130 .7,130.7,129.7,129.6,129.5,129.2,129.0,128.3,127.6,119.2,57.0,52.0,33.9,26.1,18.0.

[0169] Compound C23: 57% yield, 83% ee

[0170]

[0171] 11H NMR (600 MHz, Chloroform-d) δ 8.32–8.03 (m, 3H), 7.79–7.75 (m, 2H), 7.52–7.47 (m, 2H), 7.38 (m, 1H), 6.83 (d, J = 10.4 Hz, 1H), 6.18 (d, J = 10.4 Hz, 1H), 5.43 (t, J = 7.5 Hz, 1H), 5.07 (t, J = 6.7 Hz, 1H), 3.27 (m, 2H), 3.20 (s, 3H), 2.04 (m, 4H), 1.69 (s, 3H), 1.66 (s, 3H), 1.58 (s, 3H).

[0172] 13 13C NMR (151 MHz, Chloroform-d) δ 172.7, 154.7, 151.2, 141.0, 140.5, 138.7, 136.2, 135.3, 133.9, 131.3, 130.7, 130.6, 129.6, 129.5, 129.5, 129.2, 129.0, 128.3, 127.6, 124.2, 119.3, 57.0, 51.9, 40.0, 33.8, 26.7, 25.7, 17.7, 16.3.

[0173] Compound C24: 53% yield, 90% ee

[0174]

[0175] 1 1H NMR (600 MHz, Chloroform-d) δ 8.22 (m, 1H), 8.20–8.15 (m, 1H), 8.14–8.10 (m, 1H), 7.75 (m, 2H), 7.50 (m, 2H), 7.39–7.37 (m, 1H), 6.82 (d, J = 10.4 Hz, 1H), 6.14 (d, J = 10.4 Hz, 1H), 3.22 (s, 3H), 2.66–2.61 (m, 1H), 2.41–2.36 (m, 1H), 1.26 (m, 32H), 0.88 (t, J = 6.9 Hz, 3H).

[0176] 13C NMR(151MHz,Chloroform-d)δ172.9,154.8,151.3,141.0,140.5,136.3,135.2,134.5,130.7,130.4,129.6,129.5,1 29.4,129.2,129.0,128.3,127.6,56.7,51.9,35.4,31.9,30.1,29.7,29.7,29.7,29.6,29.4,29.4,24.8,22.7,14.1.

[0177] Compound C25: 45% yield, 93% ee

[0178]

[0179] 1 H NMR(400MHz,Chloroform-d)δ8.28(m,1H),8.18(m,2H),7.78(m,2H),7.48(m,2H),7.33(m,3H),7.26–7.16(m,3H),6.79(d,J=10.6Hz,1H) ,6.36(d,J=10.6Hz,1H),4.58(s,1H),4.04(d,J=13.7Hz,1H),3.70(d,J=13.7Hz,1H),1.39–1.21(m,6H),1.10–0.99(m,1H),0.67(m,1H).

[0180] 13 C NMR(101MHz,Chloroform-d)δ171.6,154.6,150.8,141.0,140.3,137.3,136.3,135.3,133.5,130.9,130.7 ,130.3,129.7,129.6,129.2,128.8,128.5,127.9,127.6,126.7,78.0,58.3,40.7,31.8,31.6,23.7,23.7.

[0181] Compound C26: 42% yield, 93% ee

[0182]

[0183] 11H NMR (400 MHz, Chloroform-d) δ 8.35–8.28 (m, 1H), 8.26–8.05 (m, 2H), 7.80–7.73 (m, 2H), 7.50 (m, 2H), 7.39–7.34 (m, 1H), 7.33–7.27 (m, 2H), 7.25–7.17 (m, 3H), 6.80 (d, J = 10.9 Hz, 1H), 6.39 (d, J = 10.9 Hz, 1H), 4.41 (p, J = 5.9 Hz, 1H), 3.86 (d, J = 13.9 Hz, 1H), 3.70 (d, J = 13.9 Hz, 1H), 1.16 (m, 4H), 0.60 (dt, J = 21.1, 7.4 Hz, 6H).

[0184] 13 13C NMR (101 MHz, Chloroform-d) δ 171.3, 154.7, 150.4, 141.0, 140.2, 137.4, 136.3, 135.4, 133.1, 131.2, 130.7, 130.3, 129.8, 129.7, 129.6, 129.2, 128.8, 128.7, 127.9, 127.7, 126.6, 78.1, 59.0, 39.6, 24.8, 24.7, 9.3, 9.1.

[0185] Compound C27: 45% yield, 94% ee

[0186]

[0187] 1 1H NMR (400 MHz, Chloroform-d) δ 8.43–8.33 (m, 1H), 8.29 (m, 2H), 7.88 (m, 2H), 7.57 (m, 2H), 7.47–7.40 (m, 3H), 7.36–7.28 (m, 3H), 6.92 (d, J = 10.6 Hz, 1H), 6.47 (d, J = 10.6 Hz, 1H), 4.14 (d, J = 13.7 Hz, 1H), 3.82 (d, J = 13.6 Hz, 1H), 3.41 (m, 2H), 0.72–0.60 (m, 1H), 0.40–0.32 (m, 2H), 0.01 (m, 2H).

[0188] 13C NMR(101MHz,Chloroform-d)δ171.9,154.5,150.9,141.1,140.3,137.2,136.3,135.4,133.3,130.8,130. 6,130.5,129.7,129.7,129.6,129.2,128.9,128.4,128.0,127.6,126.7,70.0,58.6,40.4,9.1,3.3,3.1.

[0189] Compound C28: 45% yield, 93% ee

[0190]

[0191] 1 H NMR(400MHz,Chloroform-d)δ8.27(m,1H),8.24–8.08(m,2H),7.79(m,2H),7. 48(m,2H),7.37–7.33(m,1H),7.33–7.28(m,2H),7.26–7.17(m,3H),6.81(d,J =10.7Hz,1H),6.36(d,J=10.7Hz,1H),4.02(d,J=13.7Hz,1H),3.70(d,J=13.7 Hz,1H),3.37(m,2H),1.70–1.60(m,1H),1.39–1.29(m,6H),0.90–0.79(m,2H).

[0192] 13 C NMR(101MHz,Chloroform-d)δ171.8,154.5,150.8,141.0,140.2,137.3,136.2,135.4,133.3,130.8,130.6,1 30.4,129.7,129.6,129.2,128.8,128.5,128.0,127.6,126.7,69.1,58.7,40.3,37.8,29.1,29.0,25.0,25.0.

[0193] Compound C29: 52% yield, 92% ee

[0194]

[0195] 11H NMR (400 MHz, Chloroform-d) δ 8.30–8.25 (m, 1H), 8.23–8.07 (m, 2H), 7.79 (m, 2H), 7.52–7.46 (m, 2H), 7.37–7.32 (m, 1H), 7.29 (m, 2H), 7.25–7.17 (m, 3H), 6.80 (d, J = 10.7 Hz, 1H), 6.37 (d, J = 10.7 Hz, 1H), 4.01 (d, J = 13.7 Hz, 1H), 3.69 (d, J = 13.6 Hz, 1H), 3.32 (m, 2H), 1.54 (m, 3H), 1.39–1.16 (m, 3H), 1.12–0.98 (m, 4H), 0.68–0.50 (m, 2H).

[0196] 13 13C NMR (101 MHz, Chloroform-d) δ 171.8, 154.5, 150.8, 141.0, 140.2, 137.3, 136.2, 135.3, 133.3, 130.8, 130.6, 130.4, 129.7, 129.6, 129.6, 129.2, 128.9, 128.5, 128.0, 127.6, 126.7, 70.4, 58.8, 40.2, 36.4, 29.4, 29.4, 26.2, 25.5.

[0197] Compound C30: 54% yield, 97% ee

[0198]

[0199] 1 1H NMR (600 MHz, Chloroform-d) δ 8.24–8.07 (m, 3H), 7.80–7.76 (m, 2H), 7.34–7.29 (m, 3H), 7.25 (t, J = 6.5 Hz, 2H), 7.22–7.17 (m, 2H), 6.80 (d, J = 10.6 Hz, 1H), 6.33 (d, J = 10.6 Hz, 1H), 4.00 (d, J = 13.6 Hz, 1H), 3.72 (d, J = 13.7 Hz, 1H), 3.13 (s, 3H), 2.73 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H).

[0200] 13C NMR(151MHz,Chloroform-d)δ172.3,154.4,151.0,146.2,141.1,140.2,137.2,135.4,133.7,132.8,130 .8,130.7,130.5,129.6,129.5,129.2,128.9,128.0,127.7,127.4,126.8,58.7,51.7,40.2,28.7,15.5.

[0201] Compound C31: 46% yield, 98% ee

[0202]

[0203] 1 H NMR(400MHz,Chloroform-d)δ8.32(d,J=8.2Hz,1H),8.27–8.12(m,2H),7.83–7 .77(m,2H),7.73(m,1H),7.69–7.64(m,2H),7.59(d,J=1.9Hz,1H),7.47(m,2H), 7.39(m,1H),7.35–7.29(m,2H),7.27–7.19(m,3H),6.88(d,J=10.7Hz,1H),6.40 (d,J=10.6Hz,1H),4.03(d,J=13.6Hz,1H),3.74(d,J=13.7Hz,1H),3.17(s,3H).

[0204] 13 C NMR(101MHz,Chloroform-d)δ172.2,154.4,150.6,142.5,141.1,140.3,140.0,137.1,135.7,135.0,133.4,1 31.2,130.6,130.6,129.8,129.7,129.2,128.9,128.0,127.9,127.2,126.8,126.8,126.5,58.8,51.8,40.2.

[0205] Compound C32: 50% yield, 93% ee

[0206]

[0207] 1H NMR(400MHz,Chloroform-d)δ8.27–8.07(m,3H),7.80–7.72(m,2H),7.32–7.20(m,5H),7.05(m,1H),6.83(d,J=2.6Hz,1H) ,6.77(d,J=10.6Hz,1H),6.34(d,J=10.6Hz,1H),4.00(d,J=13.7Hz,1H),3.87(s,3H),3.73(d,J=13.7Hz,1H),3.16(s,3H).

[0208] 13 C NMR(101MHz,Chloroform-d)δ172.1,160.7,154.1,150.7,141.1,140.1,137.1,136.9,133.2,132 .4,130.7,130.7,129.6,129.3,129.1,128.9,128.0,126.8,114.9,111.7,58.7,55.4,51.8,40.3.

[0209] Compound C33: 45% yield, 98% ee

[0210]

[0211] 1 H NMR(400MHz,Chloroform-d)δ8.31–8.03(m,3H),7.83–7.76(m,2H),7.64–7.57(m,1H),7.51(d,J=2.1Hz,1H),7.31–7. 17(m,5H),6.73(d,J=10.7Hz,1H),6.39(d,J=10.7Hz,1H),4.03(d,J=13.7Hz,1H),3.71(d,J=13.8Hz,1H),3.16(s,3H).

[0212] 13 C NMR(101MHz,Chloroform-d)δ171.9,154.0,149.9,141.0,140.4,136.9,136.8,135.0,134.7,1 32.3,130.8,130.8,130.5,130.0,129.4,129.2,128.9,128.1,126.9,123.9,58.6,51.9,40.3.

[0213] Compound C34: 47% yield, 96% ee

[0214]

[0215] 1 1H NMR (600 MHz, Chloroform-d) δ 8.33 (d, J = 8.2 Hz, 1H), 8.28–8.15 (m, 2H), 8.12 (d, J = 8.2 Hz, 1H), 8.07 (s, 1H), 7.84–7.80 (m, 2H), 7.30 (d, J = 7.4 Hz, 2H), 7.27–7.24 (m, 2H), 7.22–7.18 (m, 1H), 6.86 (d, J = 10.5 Hz, 1H), 6.42 (d, J = 10.6 Hz, 1H), 4.06 (d, J = 14.1 Hz, 1H), 3.96 (s, 3H), 3.69 (d, J = 14.4 Hz, 1H), 3.11 (s, 3H).

[0216] 13 13C NMR (151 MHz, Chloroform-d) δ 171.9, 166.4, 154.3, 150.0, 141.0, 140.5, 140.0, 136.8, 135.3, 134.5, 131.0, 131.0, 130.5, 130.2, 130.0, 129.9, 129.9, 129.3, 128.9, 128.1, 128.0, 126.9, 58.7, 52.4, 51.9, 40.3.

[0217] Compound C35: 28% yield, 92% ee

[0218]

[0219] 1 1H NMR (600 MHz, Chloroform-d) δ 8.38 (d, J = 8.1 Hz, 1H), 8.21 (dd, J = 20.2, 7.9 Hz, 2H), 7.85 (m, 2H), 7.74 (d, J = 8.2 Hz, 1H), 7.67 (s, 1H), 7.30–7.22 (m, 5H), 6.79 (d, J = 10.6 Hz, 1H), 6.48 (d, J = 10.6 Hz, 1H), 4.08 (d, J = 13.7 Hz, 1H), 3.71 (d, J = 13.6 Hz, 1H), 3.13 (s, 3H).

[0220] 13C NMR(151MHz,Chloroform-d)δ171.6,154.0,149.1,140.9,140.6,140.1,136.6,136.0,132.2,131. 6,130.6,130.4,130.3,130.2,129.4,129.0,128.7,128.1,127.1,118.2,113.2,58.6,52.0,40.4.

[0221] Compound C36: 38% yield, 96% ee

[0222]

[0223] 1 H NMR(600MHz,Chloroform-d)δ8.25(d,J=8.2Hz,1H),8.21–8.12(m,2H),7.81–7.77 (m,2H),7.65(d,J=8.2Hz,1H),7.55(d,J=7.6Hz,2H),7.47(s,1H),7.38(m,2H),7.3 0(m,3H),7.24(d,J=7.9Hz,2H),7.20(m,2H),7.16(m,1H),6.84(d,J=10.6Hz,1H),6 .38(d,J=10.6Hz,1H),4.02(d,J=13.7Hz,1H),3.73(d,J=13.6Hz,1H),3.16(s,3H).

[0224] 13 C NMR(151MHz,Chloroform-d)δ172.2,154.3,150.6,141.1,140.3,138.8,137.1,136.9,135.7,135.2,133.4,131.1,130. 6,130.5,130.3,129.8,129.6,129.2,128.9,128.8,128.0,128.0,127.7,126.8,126.7,126.4,125.5,58.8,51.8,40.3.

[0225] Compound C37: 59% yield, 97% ee

[0226]

[0227] 11H NMR (600 MHz, Chloroform-d) δ 8.48 (s, 1H), 8.24–8.15 (m, 2H), 7.79 (m, 2H), 7.74 (m, 3H), 7.47 (t, J = 7.6 Hz, 2H), 7.43 (d, J = 8.1 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.31 (d, J = 7.5 Hz, 2H), 7.24 (d, J = 7.2 Hz, 2H), 7.21 (d, J = 7.4 Hz, 1H), 6.85 (d, J = 10.6 Hz, 1H), 6.37 (d, J = 10.6 Hz, 1H), 4.03 (d, J = 13.6 Hz, 1H), 3.73 (d, J = 13.7 Hz, 1H), 3.15 (s, 3H).

[0228] 13 13C NMR (151 MHz, Chloroform-d) δ 172.2, 154.4, 150.8, 141.1, 140.3, 140.2, 137.1, 136.5, 134.4, 133.3, 130.6, 130.3, 129.8, 129.3, 129.2, 128.9, 128.8, 128.4, 128.0, 127.7, 127.2, 126.8, 58.8, 51.8, 40.1.

[0229] Compound C38: 50% yield, 94% ee

[0230]

[0231] 1 1H NMR (400 MHz, Chloroform-d) δ 8.19 (m, 2H), 7.79 (m, 2H), 7.74 (d, J = 2.7 Hz, 1H), 7.31–7.18 (m, 6H), 7.07 (dd, J = 8.5, 2.8 Hz, 1H), 6.75 (d, J = 10.6 Hz, 1H), 6.24 (d, J = 10.5 Hz, 1H), 4.02 (d, J = 13.6 Hz, 1H), 3.94 (s, 3H), 3.69 (d, J = 13.6 Hz, 1H), 3.17 (s, 3H).

[0232] 13C NMR(101MHz,Chloroform-d)δ172.4,158.8,154.3,150.6,141.0,140.4,137.5,137.2,131.2,130.6, 130.1,130.0,129.7,129.7,129.2,128.9,128.6,128.0,126.8,117.1,114.3,58.7,55.5,51.8,40.1.

[0233] Compound C39: 54% yield, 94% ee

[0234]

[0235] 1 H NMR(400MHz,Chloroform-d)δ8.40(d,J=2.2Hz,1H),8.31–8.08(m,2H),7.81(m,2H),7.61(dd,J=8.3,2.2Hz,1H),7.30–7 .20(m,6H),6.74(d,J=10.6Hz,1H),6.37(d,J=10.7Hz,1H),4.01(d,J=13.7Hz,1H),3.70(d,J=13.7Hz,1H),3.18(s,3H).

[0236] 13 C NMR(101MHz,Chloroform-d)δ172.0,154.0,149.4,141.0,140.5,137.8,136.9,134.3,133.9,133. 3,132.8,130.5,130.2,130.0,129.9,129.7,129.3,128.9,128.1,126.9,121.7,58.7,51.9,40.3.

[0237] The technical solution of the present invention is further illustrated by experiments below.

[0238] Experimental Example 1 Conversion of Compound C1 under different reaction conditions

[0239] 1. Conversion of compound C1 under palladium carbon / H2 conditions

[0240]

[0241] In a dry catalytic test tube, C1 (0.1 mmol), palladium carbon (10% w, 11.0 mg) and dry methanol (1.0 mL) were added in sequence, the system was sealed and the hydrogen gas was replaced; a hydrogen atmosphere in the reaction system was maintained with a hydrogen balloon, and the reaction was carried out at 60°C for 12 hours. After the reaction was completed, the reaction was filtered and concentrated, and the crude product was purified by 300-400 mesh silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 10 elution) to obtain compound F1 with a yield of 99% and an ee value of 93%.

[0242] 2. Conversion of compound C1 under DIBAL-H conditions

[0243]

[0244] C1 (0.1 mmol) was weighed into a dry catalytic test tube, the system was sealed, and the atmosphere was replaced with nitrogen. 0.15 mmol of diisobutylaluminum hydride (DIBAL-H) ​​and toluene (1.0 mL) were then added, and the mixture was allowed to react at 50°C for 48 hours. After completion, the reaction was quenched with water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by 300-400 mesh silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 10 elution) to obtain compound F2 in an 82% yield and 95% ee.

[0245] The results showed that compound C1 could undergo selective functional group transformation under different reaction conditions to generate chiral products with different functional groups, indicating that compound C1 has synthetic application value.

[0246] Experimental Example 2: Synthesis of Hemiacetal Compounds F3 and F4

[0247]

[0248] 2-Naphthol A1 (0.1 mol) and CuCl (0.01 mol) were weighed into a dry test tube, followed by the addition of ethyl acetate (1.0 mL) and TBHP (0.4 mol). The mixture was reacted at 30°C for 2 hours, and then the reaction system was pumped dry with an oil pump to obtain 1,2-naphthoquinone D1. Meanwhile, chiral dinitrogen oxide ligand L2-RaPr2 (0.01 mol), metal salt Sc(OTf)3 (0.01 mol), and dichloromethane (1.0 mL) were weighed into a dry penicillin vial, activated at 30°C for 1 hour, and then added to 1,2-naphthoquinone D1. Benzyldiazoester B1 (0.12 mol) was added, and the mixed system was reacted at 30°C for 12 hours. Alkyl alcohol (0.5 mol, methanol or benzyl alcohol) and potassium carbonate (0.5 mol) were then added, and the reaction was continued at 30°C for 3 hours. After the reaction was completed, the mixture was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 4 elution) to obtain hemiacetal compounds F3 and F4 in yields of 45% and 42%, respectively.

[0249] The results showed that the oxidative dearomatization / asymmetric ring expansion reaction of non-functionalized naphthol was achieved using copper salt / tert-butyl peroxide as oxidant and chiral N,N'-dioxide / Sc(OTf)3 complex as Lewis acid catalyst. Two high enantiomeric purity hemiacetal compounds F3 and F4 were efficiently synthesized through different post-treatment methods.

[0250] Experimental Example 3: Screening test of different copper salts

[0251] 1. Experimental Methods

[0252] 2-Naphthol A1 (0.1 mol) and 0.01 mol of copper or copper salt (CuBr, CuCl, CuI, CuBr2, CuCl2, Cu2O) were weighed into a dry test tube, followed by the addition of 1.0 mL of ethyl acetate and TBHP (0.4 mol). The mixture was reacted at 30°C for 2 hours, and then the reaction system was pumped dry with an oil pump to obtain 1,2-naphthoquinone D1. Meanwhile, chiral dinitrogen oxide ligand L3-TqPr2 (0.01 mol), metal salt Sc(OTf)3 (0.01 mol) and dichloromethane (1.0 mL) were weighed into a dry penicillin vial, activated at 30°C for 1 hour, and then added to 1,2-naphthoquinone D1. Benzyldiazoester B1 (0.12 mol) was added, and the mixed system was reacted at 30°C for 12 hours. O-phenylenediamine (0.15 mol) was then added and the reaction continued for 1 hour. After the reaction was completed, the mixture was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 4 elution) to obtain compound C1. The enantiomeric excess of the product was determined by high performance liquid chromatography. The reaction formula is as follows:

[0253]

[0254] 2. Experimental Results

[0255] As shown in Table 1, the results show that when CuCl is used as the copper salt, the comprehensive effect of product yield and ee value is the best.

[0256] Table 1. Product yield and ee value under different copper salts

[0257]

[0258]

[0259] Experimental Example 4: Screening test of different metal salts

[0260] 1. Experimental Methods

[0261] 2-Naphthol A1 (0.1 mol) and CuCl (0.01 mol) were weighed into a dry test tube, and then 1.0 mL of ethyl acetate and TBHP (0.4 mol) were added. The mixture was reacted at 30°C for 2 hours, and then the reaction system was pumped dry with an oil pump to obtain 1,2-naphthoquinone D1. At the same time, chiral dinitrogen oxide ligand L3-TqPr2 (0.01 mol), 0.01 mol of metal salts (Mg(OTf)2, Al(OTf)3, Ni(OTf)2, Cu(OTf)2, Zn(OTf)2, Y(OTf)3, Bi(OTf)3, La(OTf)3, In(OTf)3, Sc(OTf)3) and dichloromethane (1.0 mL) were activated at 30°C for 1 hour and then added to 1,2-naphthoquinone D1. Benzyldiazoester B1 (0.12 mol) was added, and the mixture was reacted at 30°C for 12 hours. O-phenylenediamine (0.15 mol) was then added and the reaction continued for 1 hour. After completion of the reaction, the mixture was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 4 elution) to obtain compound C1. The enantiomeric excess of the product was determined by high-performance liquid chromatography. The reaction formula is as follows:

[0262]

[0263] 2. Experimental Results

[0264] As shown in Table 2, the results show that when Sc(OTf)3 is used as the metal salt, the comprehensive effect of product yield and ee value is the best.

[0265] Table 2. Product yield and ee value under different metal salts

[0266]

[0267] Experimental Example 5: Screening test of different ligands

[0268] 1. Experimental Methods

[0269] 2-Naphthol A1 (0.1 mol) and CuCl (0.01 mol) were weighed into a dry test tube, and then 1.0 mL of ethyl acetate and TBHP (0.4 mol) were added. The mixture was reacted at 30°C for 2 hours, and then the reaction system was pumped dry with an oil pump to obtain 1,2-naphthoquinone D1. At the same time, 0.01 mol of chiral dinitrogen oxide ligands (L3-TqPr2, L3-RaPr2, L3-PrPr2, L3-PiPr2, L3-RaPr3, L4-RaPr2, L2-RaPr2, L2-RaPr2Ad, L3-RaAd), metal salt Sc(OTf)3 (0.01 mol), and dichloromethane (1.0 mL) were activated at 30°C for 1 hour before being added to 1,2-naphthoquinone D1. Benzyldiazoester B1 (0.12 mol) was added, and the mixture was reacted at 30°C for 12 hours. O-phenylenediamine (0.15 mol) was then added and the reaction continued for 1 hour. After completion of the reaction, the mixture was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 4 elution) to obtain compound C1. The enantiomeric excess of the product was determined by high-performance liquid chromatography. The reaction formula is as follows:

[0270]

[0271] 2. Experimental Results

[0272] As shown in Table 3, the results show that when L2-RaPr2 is used, the comprehensive effect of product yield and ee value is the best.

[0273] Table 3. Product yields and ee values ​​under different ligands

[0274]

[0275]

[0276] Experimental Example 6: Screening test of different solvents

[0277] 1. Experimental Methods

[0278] 2-Naphthol A1 (0.1 mol) and CuCl (0.01 mol) were weighed into a dry test tube, followed by the addition of 1.0 mL of ethyl acetate and TBHP (0.4 mol). The mixture was reacted at 30°C for 2 hours, and then the reaction system was pumped dry with an oil pump to obtain 1,2-naphthoquinone D1. Meanwhile, chiral dinitrogen oxide ligand L2-RaPr2 (0.01 mol), metal salt Sc(OTf)3 (0.01 mol), and 1.0 mL of solvent (dichloroethane, 1,1,2,2-tetrachloroethane, dichloromethane, chlorobenzene, ethyl acetate, tetrahydrofuran, toluene, chloroform) were weighed into a dry penicillin vial, activated at 30°C for 1 hour, and then added to 1,2-naphthoquinone D1. Benzyldiazoester B1 (0.12 mol) was added, and the mixture was reacted at 30°C for 12 hours. O-phenylenediamine (0.15 mol) was then added and the reaction continued for 1 hour. After the reaction was completed, the mixture was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 4 elution) to obtain compound C1. The enantiomeric excess of the product was determined by high performance liquid chromatography. The reaction formula is as follows:

[0279]

[0280] 2. Experimental Results

[0281] As shown in Table 4, the results show that when dichloromethane is used as the solvent, the comprehensive effect of product yield and ee value is the best.

[0282] Table 4. Product yields and ee values ​​under different solvents

[0283]

[0284]

[0285] Experimental Example 7 Determination of biological activity

[0286] 1. Experimental Methods

[0287] Test cells:

[0288] Hepatocellular carcinoma cell lines HCCLM3 and MHCC97, mouse macrophage J774A.1, tumor cell line DU145, lung cancer cell line NCI-H460, cytochrome P450, etc.

[0289] Cell test method:

[0290] Cells were cultured in 96-well plates at a density of 2*10 4Cells were treated with 1% DMSO (negative control) and test compounds C1-C39 at various concentrations for 24 hours. FBSDMEM containing 10% (v / v) CCK-8 (Selleck, Houston) was added to each well and incubated at 37°C for 1 hour. Absorbance was measured at 450 nm to calculate cell viability (%).

[0291] This invention utilizes a tandem oxidative dearomatization / asymmetric ring expansion reaction of nonfunctional naphthols to synthesize benzocycloheptane compounds. Experimental screening of the copper salt, metal salt, ligand, and solvent conditions used in the preparation method demonstrates that optimal yield and optical purity are achieved under optimized conditions. This preparation method offers advantages such as simplicity, high efficiency, good substrate compatibility, and excellent enantioselectivity. Experimental testing has shown that the benzocycloheptane compounds provided by this invention exhibit multiple biological activities, including anticancer, antitumor, and antiproliferative activities. They are promising candidates for anticancer and antitumor drugs, and have promising applications in the pharmaceutical field.

Claims

1. A compound represented by Formula I, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotope-labeled substance thereof, or a crystalline form thereof, or a prodrug thereof: R 1 selected from hydrogen, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C2-C 10 Alkenyl, unsubstituted or at least one R 4 Substituted C6-C 10 Aryl, wherein The substituent is selected from C1-C 10 Alkyl, C6-C 10 aryl; R 2 Selected from C1-C 10 Alkyl, C3-C 10 Cycloalkyl, -CH2R 5 ; R 3 Selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C2-C 10 Alkenyl, substituted or unsubstituted C1-C 10 Ester group, substituted or unsubstituted C6-C 20 Aryl, wherein the substituent is selected from halogen, C6-C 10 aryl; R 4 Selected from halogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C1-C 10 Alkylthio, cyano, nitro, substituted or unsubstituted C6-C 20 Aryl, C1-C 10 Ester group, wherein the substituent is selected from halogen; or, two adjacent R 4 connected to form a ring, wherein the ring is a benzene ring or a 5-6 membered saturated oxygen heterocycle; R 5 Selected from C3-C 10 Cycloalkyl; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotope-labeled substance thereof, or a crystal form thereof, or a prodrug thereof, characterized in that: R 1 is selected from hydrogen, substituted or unsubstituted 5-membered heteroaryl, substituted or unsubstituted C2-C8 alkenyl, unsubstituted or at least one R 4 Substituted phenyl, wherein the substituent is selected from phenyl; R 2 Selected from C1-C6 alkyl, C5 cycloalkyl, -CH2R 5 ; R 3 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C2 alkyl, substituted or unsubstituted methoxy, substituted or unsubstituted C2 alkenyl, C1 ester, substituted or unsubstituted phenyl, wherein the substituent is selected from phenyl; R 4 is selected from halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted methoxy, substituted or unsubstituted methylthio, cyano, nitro, phenyl, C1 ester, wherein the substituent is selected from halogen; or, two adjacent R 4 Connect to form a benzene ring; R 5 Selected from C3-C6 cycloalkyl; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotope-labeled substance thereof, or a crystalline form thereof, or a prodrug thereof, characterized in that: The compound shown in Formula I is one of the following structures:

4. A method for preparing the compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotope-labeled substance thereof, or a crystal form thereof, or a prodrug thereof, characterized in that: The steps include: Step 1: reacting compound A with an oxidant to obtain an intermediate product D; the reaction is carried out in the presence of a catalyst, the catalyst being selected from copper or a copper salt, the copper salt being selected from at least one of cuprous bromide, cuprous chloride, cuprous iodide, cupric dibromide, cupric chloride, cuprous oxide, copper trifluoromethanesulfonate, cuprous thiocyanate, and copper acetate; Step 2: reacting the intermediate product D with compound B to obtain compound E; the reaction is carried out under the action of a chiral catalyst; the chiral catalyst is obtained by coordination reaction of a metal salt and a chiral difluoromethanesulfonate ligand; the metal salt is selected from at least one of magnesium difluoromethanesulfonate, aluminum trifluoromethanesulfonate, nickel difluoromethanesulfonate, copper difluoromethanesulfonate, zinc difluoromethanesulfonate, yttrium trifluoromethanesulfonate, bismuth trifluoromethanesulfonate, lanthanum trifluoromethanesulfonate, indium trifluoromethanesulfonate, and scandium trifluoromethanesulfonate; the chiral difluoromethanesulfonate ligand is selected from L3-PrPr2 , at least one of L3-PiPr2, L3-TqPr2, L2-RaPr2, L2-RaPr2Ad, L3-RaPr2, L3-RaPr3, L3-RaAd, and L4-RaPr2; the structural formulas of L3-PrPr2, L3-PiPr2, L3-TqPr2, L2-RaPr2, L2-RaPr2Ad, L3-RaPr2, L3-RaPr3, L3-RaAd, and L4-RaPr2 are respectively: Step 3, reacting compound E with a reducing agent to obtain a compound represented by formula I; The selection of R1, R2, R3, and m is as described in any one of claims 1-3.

5. The preparation method according to claim 4, characterized in that: The molar ratio of compound A to copper salt is 100:(5-10); and / or, the molar ratio of the compound A to the oxidant is 100:(100-400); and / or, the molar ratio of compound A to compound B is 100:(100-120); and / or, the molar ratio of compound A to the chiral catalyst is 100:(1-100); And / or, the molar ratio of the compound A to the reducing agent is 100:(80-200).

6. The preparation method according to claim 4, characterized in that: In step 1, the reaction solvent is selected from at least one of ethyl acetate, dichloroethane, 1,1,2,2-tetrachloroethane, dichloromethane, tetrahydrofuran, and chloroform; and the oxidant is selected from tert-butyl peroxide; And / or, in step 1, the reaction temperature is 0-50° C., and the reaction time is 0.5-10 h; and / or, in step 2, the solvent for the coordination reaction is at least one of dichloroethane, 1,1,2,2-tetrachloroethane, dichloromethane, chlorobenzene, ethyl acetate, tetrahydrofuran, toluene, and chloroform; And / or, in step 2, the temperature of the coordination reaction is 10-50° C., and the reaction time is 0.5-5 h; And / or, in step 2, the reaction temperature is 0-60°C and the reaction time is 12-48h; And / or, in step 3, the reducing agent is selected from o-phenylenediamine; And / or, in step 3, the reaction temperature is 0-50° C., and the reaction time is 0.5-2 h. The solvent for the coordination reaction is dichloromethane.

7. The preparation method according to claim 4, characterized in that: In step 1, the copper salt is selected from at least one of cuprous bromide, cuprous chloride, cupric dibromide, cupric chloride, and cuprous oxide.

8. The preparation method according to claim 4, characterized in that: In step 1, the metal salt is selected from scandium trifluoromethanesulfonate.

9. The preparation method according to claim 4, characterized in that: In step 1, the chiral dinitrogen oxide ligand is selected from at least one of L2-RaPr2, L2-RaPr2Ad, L3-RaPr2, and L3-RaPr3.

10. Use of the compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotope-labeled substance thereof, or a crystal form thereof, or a prodrug thereof in the preparation of a medicament for treating tumors.

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