WO2014056446A1 - Phenyl 1,2-isoxazolyl or phenyl 1,2-pyrazole compound and application thereof - Google Patents

Description

 Phenyl 1,2-isoxazole or phenyl 1,2-pyrazole compound and use thereof

 The present invention is in the field of pharmacy, and in particular, relates to a phenyl 1,2-isoxazole or phenyl 1,2-pyrazole compound and a pharmaceutical composition thereof and use thereof in the preparation of an antitumor drug. Background technique

 Heat shock protein 90 (Hsp90) is one of the most active chaperone proteins in the cell, and the normal function of many signal transduction proteins is dependent on Hsp90. It interacts with proteins that change their conformation due to environmental stimuli during cell stress, ensuring proper folding of the protein and preventing non-specific aggregation of the protein, thereby maintaining normal cell activity. In addition, Hsp90 is also an important buffer factor in cell mutations, presumably to correct the misfolding of mutant proteins. Hsp90 is also an important regulator when cells are in normal physiological conditions. It is known to regulate the spatial structure and mutation of about 40 proteins. All of these proteins are important regulatory proteins in the process of cell physiology and biochemistry.

 Human Hsp90 has four subtypes: Hsp90a and Hsp90p. These two subtypes are present in the cytoplasm, GRP94 is present in the endoplasmic reticulum, and Hsp75/TNF receptor-associated protein 1 (TRAP1) is present in the mitochondrial matrix. Inside. It is now believed that the four members work in almost the same way, but because they are located differently within the cell, they bind different proteins. For example, the tyrosine kinase ErbB2 receptor is a GLP94-specific downstream action protein, and the type I tumor necrosis factor receptor and the retinal glioma protein Rb are downstream proteins of TRAP1.

 HSP90 is one of the important members of the heat shock protein family. Most of its substrate proteins are proteins that control cell differentiation and growth, including signal transduction molecules of tumor cell metastasis, such as epidermal growth factor receptor 2, Bcr/Abl fusion gene, and protein. Kinases c-Raf, cyclin-dependent kinase 4, hypoxia-inducible factor 1, steroid hormone receptor, and the like. The function of these conformationally variable substrate proteins is dependent on HSP90 maintenance.

 Studies have shown that inhibition of HSP90 function can lead to the degradation of its substrate protein through the ubiquitin-protease complex pathway, and can also down-regulate a variety of downstream proteins to regulate a variety of cell signal transduction pathways, thereby achieving multiple points of tumor Attack "to achieve inhibition of tumor growth and metastasis (Banerji, U.; O'nell, A.; Scurr, MJ Clin. Oncol. 2005, 23, 4152).

HSP90 exists mainly in the form of homodimers in the cytoplasm, and each homodimer consists of two monomers. The HSP90 monomer includes three major domains: a conserved N-terminal domain, a C-terminal domain, and an intermediate domain (Bauer, S.; Yu, LJ Clin. Cancer Res. 2005, 11, 9111). There are very important interactions between these three domains. The N-terminal domain is Adenosine triphosphate (ATP) / adenosine diphosphate The (adenosine diphosphate, ADP) binding site is also a target for specific binding of Geldnamycin (GA). The ATP/ADP binding site is closely related to the chaperone function of HSP90. Due to the antagonism of GA and its derivatives, HSP90 also exhibits ATPase activity associated with the ATP/ADP binding site. The C-terminal domain is a self-dimerization site of HSP90, which is also a calmodulin binding site and a target protein binding site (Whitesell, L.; Mimnaugh, EG Proc. Natl. Acad. Sci. USA 1994, 91, 8324) .

 HSP90 is mainly in the activated state in tumor cells, and is mainly in the silent state in normal cells. When in the activated state, HSP90 forms a complex with the substrate protein and the chaperones HSP70, HSP40, etc., and the substrate protein is not degraded by the proteasome. The role of HSP90 depends on the presence of ATP, and the ATP/ADP binding site functions as a conformational transition region. Upon binding to ATP, the conformation of HSP90 changes to form a dimer that regulates the assembly of the multi-molecular companion complexes involved (Biamonte, M. A.; Shi, J. J. Med. Chem. 2006, 49, 817).

 HSP90 is closely related to oncogenes. In the early 1990s, Blachere (Blachere, NE; H. Udono J. Immunother. Emphasis. Tumor Immunol, 1993, 14, 353) and others confirmed that the hot body protein extracted from tumor cells can lead to strong host production. The immune response, which may be due to this thermogram, can act as a molecular chaperone for some tumor antigens. Studies have shown that the anti-tumor effect of HSP90 is mainly dependent on the inactivation of those oncoproteins and protein kinases by proteolytic pathways, rather than directly inhibiting the catalytic activity of kinases. For example, HSP90 can help Src proteins achieve proper assembly and folding. When the function of HSP90 is inhibited, the Src protein that cannot be correctly folded is recognized by ubiquitin in the body and is inactivated by proteolytic degradation. Many basic studies have shown that HSP90 plays a very important role in the survival of tumors and has also been found to be an important component of the oncogene pathway.

 HSP90 is expressed in tumor tissues. Studies have shown that HSP90 is highly expressed in tumor tissues, and the expression of HSP90 and tumor differentiation can be observed by immunohistochemistry, which is related to the degree of lymph node metastasis (Byrd, C. A.;

Bornmann, W. Proc. Natl. Acad. Sci. 1999, 96, 5645). HSP90 in tumor tissues usually forms an active multi-complex complex with other proteins, and ATPase activity is also higher than HSP90 in normal tissues. Tumor tissue-derived HSP90 has a 100-fold higher affinity for 17-AAG than normal tissue-derived HSP90 (Dymock, B. W.; Barril, X., Brough, P. A. J. Med. Chem. 2005, 48, 4212). Therefore, the inhibitor of HSP90 has a certain degree of targeting. This targeting makes many HSP90 inhibitors, including GA, promising as ideal targeted drugs, as well as for the localization of tumors and metastases. The study found that HSP90 also increased the sensitivity of tumor cells to other chemotherapeutic drugs (Ku, X. Thesis for Master's Degree Shanghai Institute of Materia Medica).

 In general, HSP90 is one of the most active molecular chaperone proteins in the cell, and plays an important role in the occurrence and progression of tumors. The anti-tumor effect of HSP90 inhibitors is extensive, making it a promising anti-tumor. New drug.

Geldanamyc i (GA) was originally a natural one isolated from the fermentation broth of Streptomyces hygroscopicus. The product, the first HSP90 N-terminal inhibitor found, belongs to the class of benzoquinone Ansa. These antibiotics are structurally linked by a phenyl ester moiety and a planar macrocyclic ansa bridge, which reverses the malignant transformation of fibroblasts transfected with the v-Src proto-oncogene, and has been confirmed in vitro and in animals. Its anti-tumor activity. The anti-tumor activity of geldanamycin alters the HSP90 conformation by competitively binding to the Hsp90 N-terminal ATP/ADP binding site, specifically inhibits the ATPase activity required for HSP90, and renders it incompatible with effector proteins and others. Small molecule proteins form a complex that inhibits its normal molecular chaperone function, ultimately leading to degradation of the client's protein and blocking the signaling pathway by which the tumor depends. The inhibitory activity of geldanamycin on HSP90 reached micromolar levels (=1.2 mol/L) in vitro, but increased by 50-100 fold in vivo. Due to the high reactivity of the 17-position methoxy group to the nucleophile and the easy conversion of the anthracene ring to the active hydroquinone form, the GA has the disadvantages of greater hepatotoxicity and poor water solubility, which limits its clinical significance. application.

 Rhodamine CRadkkol, RD) is a macrocyclic antibiotic isolated from the fungus Monosporium bonorden, which reverses the malignancy of fibroblasts transfected with v-Src and v-Ha-Ras, and its site of action is also HSP90 The N-terminal region has a higher affinity for HSP90 in vitro than GA and B17-AAG (Kd = 19 nmol/L). However, in vivo, since radicicol contains an electrophilic epoxy ring and a Michael acceptor, it is easy to lose the antitumor activity by the Meissin addition reaction with the thiol-containing nucleophile. Summary of the invention

 In order to solve the technical problems existing in the prior art, the present inventors designed and synthesized a series of phenyl 1,2-isoxazole or phenyl 1,2-pyrazole compounds and pharmaceutically acceptable salts thereof, It has HSP90 inhibitory activity and can be used to prepare antitumor drugs.

 Accordingly, it is an object of the present invention to provide a phenyl 1,2-isoxazole or phenyl 1,2-pyrazole compound represented by the following formula I, and a pharmaceutically acceptable salt thereof.

 A further object of the present invention is to provide a pharmaceutical composition comprising a compound represented by the formula I or a pharmaceutically acceptable salt thereof as an active ingredient.

 A further object of the present invention is to provide a use of a compound represented by Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the preparation of a medicament as an HSP90 inhibitor, or for use in the preparation of an antitumor medicament, Especially in the preparation of anti-lung cancer drugs.

 Specifically, the present invention provides a phenyl 1,2-isoxazole or phenyl 1,2-pyrazole compound represented by the general formula I and a pharmaceutically acceptable salt thereof:

I

I

 Its towel:

X is O or NR4, wherein 114 is 15, dC ₆ linear or branched alkyl or C ₃ -C ₆ cycloalkyl;

Is 15; halogen; dC ₆ straight or branched alkyl; phenyl dC ₆ alkyl; phenyl substituted C ₂ -C ₆ alkenyl; phenyl; dC ₆ straight or branched alkyl substituted benzene a naphthyl group; a dC ₆ linear or branched alkyl substituted naphthyl group; a substituted or unsubstituted 6-10 membered aromatic heterocyclic group having 1 to 3 hetero atoms, wherein the substituted one contains 1-3 The substituent of the 6-10 membered aromatic heterocyclic group of a hetero atom is a dC ₆ linear or branched alkyl group or a dC ₆ alkoxy group substituted with N(R ₅ ) ₂ , and R ₅ is a linear or branched dC ₆ An alkyl group or N(R ₅ ) ₂ is a 6-10 membered saturated heterocyclic group having 1 to 3 hetero atoms selected from N, 0 and S;

R ₂ is H; halogen; dC ₆ straight or branched alkyl; phenyl; substituted phenyl, wherein the substituted phenyl substituent is dC ₆ alkoxy, hydroxy dC ₆ alkylene, Substituted or unsubstituted 5-8 membered saturated heterocyclic dC ₆ alkylene group having 1 to 3 hetero atoms, substituted or unsubstituted amino dC ₆ alkylene group, C ₃ -C ₇ cycloalkylcarbonyloxy group a dC ₆ alkylene group or a tetrahydroisoquinoline dC ₆ alkylene group, wherein the substituted 5-8 membered saturated heterocyclic group dC ₆ alkylene group having 1 to 3 hetero atoms has a substituent dC ₆ a linear or branched alkyl group, a dC ₆ linear or branched alkyl substituted amino group or a 5-8 membered saturated heterocyclic group having 1 to 3 hetero atoms, the substituted amino dC ₆ alkylene group substituted The base is dC ₆ straight or branched alkyl, C ₅ -C ₇ cycloalkyl, phenyl dC ₆ alkylene, dimethylamino dC ₆ alkylene, the hetero atom is selected in g N, 0 and S ;

R ₃ is H, dC ₇ linear or branched alkylcarbonyl or C ₃ -C ₆ cycloalkylcarbonyl.

 In the compound represented by the general formula I, when X is NH, that is, when the compound is a phenyl 1,2-pyrazole compound, it is preferred that:

Is halogen, R ₂ is 4-dC ₆ alkoxyphenyl, R ₃ is H or dC ₆ linear or branched alkylcarbonyl; more preferably, R ₂ is 4-methoxyphenyl, R ₃ is H or methylcarbonyl.

 In the compound represented by the general formula I, when X is 0, that is, when the compound is a phenyl 1,2-isoxazole compound, it is preferred that:

Is 15, halogen, dC ₄ linear or branched alkyl, phenyl dC ₄ alkylene, phenyl substituted C ₂ -C ₄ alkenyl, phenyl, ^ ₄ linear or branched alkyl substituted benzene a naphthyl group, a ₄ linear or branched alkyl substituted naphthyl group, a substituted or unsubstituted 6- or 10-membered aromatic heterocyclic group containing 1 hetero atom; wherein the substituted one contains 1 hetero atom The substituent of the 6- or 10-membered aromatic heterocyclic group is a dC ₄ linear or branched alkyl group or a dC ₄ alkoxy group substituted with N(R ₅ ) ₂ , and R ₅ is a dC ₄ linear or branched alkane. Or N(R ₅ ) ₂ is a 6-membered saturated heterocyclic group containing 2 hetero atoms selected from N, 0 and S;

Is a halogen or a substituted phenyl group; the substituent of the substituted phenyl group is a dC ₄ alkoxy group, a hydroxyl group dC ₄ An alkylene group, a substituted or unsubstituted 5-7 membered saturated heterocyclic group dC ₄ alkylene group having 1 to 2 hetero atoms, a substituted or unsubstituted amino dC ₄ alkylene group, a C ₃ -C ₆ naphthenic group a carbonylcarbonyloxy dC ₄ alkylene group or a tetrahydroisoquinoline dC ₄ alkylene group, wherein the substituted 5-7 membered saturated heterocyclic group dC ₄ alkylene group having 1 to 2 hetero atoms is substituted The group is a dC ₃ linear or branched alkyl group, a dC ₄ linear or branched alkyl group substituted amino group or a 5-7 membered saturated heterocyclic group having 1-2 hetero atoms, the substituted amino dC ₄ subunit The substituent of the alkyl group is a dC ₄ linear or branched alkyl group, a C ₅ -C ₇ cycloalkyl group, a phenyl dC ₄ alkylene group, a dimethylamino dC ₄ alkylene group, and the hetero atom is selected as g N, 0 and S;

R ₃ is H, dC ₇ linear or branched alkylcarbonyl or C ₃ -C ₆ cycloalkylcarbonyl;

More preferably, it is 15, halogen, dC ₄ linear or branched alkyl, phenyl dC ₄ alkylene, C ₂ -C ₄ alkenyl substituted with phenyl, phenyl, naphthyl, substituted or not a substituted 6- or 10-membered aromatic heterocyclic group containing 1 nitrogen atom; wherein the substituted 6- or 10-membered aromatic heterocyclic group having 1 N atom is a dC ₄ straight or branched alkane Or a N(R ₅ ) ₂ -substituted dC ₄ alkoxy group, wherein R ₅ is methyl or ethyl, or N(R ₅ ) ₂ is morpholinyl;

R ₂ is H, halogen or substituted phenyl; the substituent of the substituted phenyl is selected from the group consisting of dC ₄ alkoxy, hydroxy dC ₄ alkylene, substituted or unsubstituted, containing 1-2 heteroatoms 4 of a 5-7-membered saturated heterocyclic group dC ₄ methylene group, a substituted or unsubstituted aminomethylene group, a C ₃ -C ₆ cycloalkylcarbonyloxymethylene group, and a tetrahydroisoquinoline methylene group a substituent at the position wherein the substituted 5-7 membered saturated heterocyclic group dC ₄ methylene group having 1 to 2 hetero atoms is a dC ₃ linear or branched alkyl group, dimethylamino group, Diethylamino, dipropylamino, morpholinyl or piperidinyl, the substituent of the substituted aminomethylene is dC ₄ straight or branched alkyl, C ₅ -C ₇ cycloalkyl, phenyl dC ₄ alkylene, dimethylamino dC ₄ alkylene, the hetero atom selected in g N, 0 and S;

R ₃ is H, dC ₇ linear or branched alkylcarbonyl or C ₃ -C ₆ cycloalkylcarbonyl;

 Most preferably, it is 15, Cl, Br, ethyl, isopropyl, tert-butyl, phenethyl, styryl, naphthyl, pyridyl, isoquinolinyl, quinolinyl, methyl substituted a quinolinyl, dimethylaminoethoxy substituted quinolinyl or morpholinylethoxy substituted quinolyl;

、 2-甲基哌啶基亚甲基、 3，5-二甲基哌啶基亚甲基、 3，5-二甲基吗R ₂ is H, halogen or substituted phenyl; the substituent of the substituted phenyl is selected from the group consisting of methoxy, ethoxy, hydroxymethyl, morpholinylmethylene, 4-dimethylaminopiperidine Methylidene, piperidinyl methylene, tetrahydropyrrolylmethylene,

, 2-methylpiperidinylmethylene, 3,5-dimethylpiperidinylmethylene, 3,5-dimethyl?

, s

 ■ N,

Lolinylmethylene, 4-thiomorpholinylmethylene I, tetrahydroisoquinolinylmethylene, 4-methylpiperazinylmethylene, 4- Morpholinyl piperidinyl methylene, 4-tetrahydropyrrolylpiperidinyl methylene, N-methylcyclohexylamino, N-

、 N-甲基苯基亚乙基氨基亚甲基 、二甲氨 Methyl dimethylaminoethylaminomethylene

, N-methylphenylethyleneaminomethylene, dimethylamine

a 4-position substituent in a methylidene group, a diethylaminomethylene group, a diisopropylaminomethylene group, or a cyclopropylcarbonyloxymethylene group ¹ ;

 Is 15, methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, heptylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl or ring Hexylcarbonyl.

 The compound represented by the formula I according to the invention is preferably selected from the following compounds:

S80/CT0ZN3/X3d

所述药学上可接受的盐为所述由通式 I表示的化合物与无机酸或有机酸形成的盐；其 中， 所述无机酸为盐酸、 氢溴酸、 硫酸或磷酸， 所述有机酸为柠檬酸、 乳酸、 苹果酸、 葡 糖酸、 酒石酸、 己二酸、 醋酸、 琥珀酸、 富马酸、 抗坏血酸、 衣康酸、 甲磺酸或苯磺酸。

The pharmaceutically acceptable salt is a salt of the compound represented by the formula I and an inorganic or organic acid; wherein the inorganic acid is hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, and the organic acid is Citric acid, lactic acid, malic acid, gluconic acid, tartaric acid, adipic acid, acetic acid, succinic acid, fumaric acid, ascorbic acid, itaconic acid, methanesulfonic acid or benzenesulfonic acid.

According to another object of the present invention, the present invention provides the phenyl 1,2-isoxazole or phenyl 1,2- represented by the general formula I A process for the preparation of pyrazoles which uses the following synthetic route 1, 2, 3 or 4:

 Synthetic route 1 : (corresponding to the specific compound is compound 1-2)

其中， Ri为卤素；

Wherein Ri is a halogen;

R ₂ is a phenyl group substituted with a CC ₆ alkoxy group;

Is a linear or branched alkylcarbonyl group or a C ₃ -C ₆ cycloalkylcarbonyl group of H, dC ₇ .

 The reaction steps are as follows:

 a) using 1A as a starting material, after a complex reaction to obtain a compound 1B, the catalyst used may be a boron trifluoride diethyl ether solution, the solvent may be acetic acid, the condition may be heated reflux, the time may be 4h;

 b) Compound IB is nucleophilically substituted to give 1C, the solvent used is acetonitrile;

 c) Compound 1C is reacted with bromoform to obtain 1D, the base used is sodium hydroxide, and the solvent is a mixed solution of 1,4-dioxane and water;

 d) Compound ID is obtained by nucleophilic reaction to obtain compound IE, the base used is potassium carbonate, the solvent is acetonitrile, and the reaction condition is heated reflux for 1 hour;

 e) Compound IE is subjected to nucleophilic reaction to obtain 1F, and the base used is lithium hexamethyldisilazide (LHMDS);

f) Compound 1F is closed to give compounds 1G and 1H, the solvent used is acetic acid, and the reaction conditions are refluxed overnight; g) Compound 1G or 1H is reacted with boron trichloride in dichloromethane to give compounds II and 1J; (The corresponding specific compounds are compounds 3-15, 22-25 and 34-38)

 2H 21

Wherein, halogen, dC ₆ straight or branched alkyl;

R ₂ is H, halogen, or dC ₆ alkoxy substituted phenyl;

Is a linear or branched alkylcarbonyl group of H, dC ₇ or a C ₃ -C ₆ cycloalkylcarbonyl group.

 The reaction steps are as follows:

 Synthesis of compound 1F according to synthetic route 1

 f) using 2,4-dihydroxyethylbenzene or 2,4-dihydroxyacetophenone as starting material, compound 1F synthesized by direct route or purchased directly, and compound 2G obtained by Guanhuan, the solvent used is pyridine, the reaction The condition is reflux overnight;

 g) compound 2G is reacted to obtain compound 2H, the base used is triethylamine, the solvent used is dichloromethane; h) compound 2H is reacted with boron trichloride in dichloromethane to obtain compound 21;

 -21 and 26-33)

 31

3H wherein, anthracene, phenyl dC ₆ alkylene, phenyl C ₂ -C ₆ alkenyl, phenyl, naphthyl, substituted or unsubstituted 6-10 membered aromatic containing 1-3 heteroatoms a ring group; wherein the substituted 6-10 membered aromatic heterocyclic group having 1 to 3 hetero atoms has a dC ₆ linear or branched alkyl group or a dC ₆ alkane substituted with N(R ₅ ) ₂ Oxyl, R ₅ is a dC ₆ linear or branched alkyl group or N(R ₅ ) ₂ is a 6-10 membered saturated heterocyclic group having 1 to 3 hetero atoms selected from N, 0 and S;

R ₂ is a phenyl group substituted with a CC ₆ alkoxy group;

Is a linear or branched alkylcarbonyl group or a C ₃ -C ₆ cycloalkylcarbonyl group of dC ₇ .

 The reaction steps are as follows:

 a) using 3A as a starting material, bromination to obtain compound 3B, the solvent used is acetic acid, and the reaction condition is room temperature reaction for 4 hours.

 b) esterification of compound 3B to give compound 3C, the solvent used is methanol,

 c) Compound 3C is nucleophilically substituted to give 3D, the solvent used is acetonitrile,

 d) Compound 3D is subjected to nucleophilic reaction to obtain 3E, and the base used is lithium hexamethyldisilazide (LHMDS);

e) Compound 3E is closed to compound 3F, the solvent used is pyridine, and the reaction conditions are refluxed overnight; ί) compound 3F is reacted to obtain compound 3G, the base used is triethylamine, the solvent used is dichloromethane; g) compound 3G The compound 3H is obtained by a Suzuki reaction, the catalyst used is Pd(PPh ₃ ) ₄ , and the base used is potassium carbonate;

h) Compound 3H is reacted with a solution of boron trichloride in dichloromethane to give compound 31; Scheme 4: (corresponding specific compound is compound 39-59)

其中， R₂'为羟基 d-C₆亚烷基、取代或未取代的含有 1-3个杂原子的 5-8元饱和杂环 基 d-C₆亚烷基、取代或未取代的氨基 d-C₆亚烷基、 C₃-C₇环烷基羰基氧基 d-C₆亚烷基 或者四氢异喹啉 ₆亚烷基， 其中， 所述取代的含有 1-3个杂原子的 5-8元饱和杂环基 d-C₆亚烷基的取代基为 d-C₆直链或支链烷基、 d-C₆直链或支链烷基取代的氨基或者含 有 1-3个杂原子的 5-8元饱和杂环基， 所述取代的氨基 d-C₆亚烷基的取代基为 d-C₆直 链或支链烷基、 C₅-C₇环烷基、 苯基 d-C₆亚烷基、 二甲氨基取代的 d-C₆亚烷基， 所述杂 原子选 N、 0和 S中；

Wherein R ₂ 'is a hydroxy dC ₆ alkylene group, a substituted or unsubstituted 5-8 membered saturated heterocyclic group dC ₆ alkylene group having 1 to 3 hetero atoms, a substituted or unsubstituted amino dC ₆ alkylene group; a C ₃ -C ₇ cycloalkylcarbonyloxydC ₆ alkylene group or a tetrahydroisoquinoline ₆ alkylene group, wherein the substituted 5-8 membered saturated heterocyclic ring having 1 to 3 hetero atoms The substituent of the dC ₆ alkylene group is a dC ₆ linear or branched alkyl group, a dC ₆ linear or branched alkyl substituted amino group or a 5-8 membered saturated heterocyclic group having 1 to 3 hetero atoms. The substituent of the substituted amino dC ₆ alkylene group is a dC ₆ linear or branched alkyl group, a C ₅ -C ₇ cycloalkyl group, a phenyl dC ₆ alkylene group, a dimethylamino substituted dC ₆ alkylene group. The hetero atom is selected from N, 0 and S;

The reaction steps are as follows: a) Compound 4A is nucleophilically substituted to give 4B, the solvent used is acetonitrile;

 b) Compound 4B is subjected to Witing reaction to obtain compound 4C, and the base used is butyllithium;

 c) hydrogenation of compound 4C to give compound 4D, the catalyst used is palladium;

 d) Compound 4D is subjected to a Vismeier reaction to obtain compound 4E in a solvent of N,N-dimethylformamide (DMF); e) compound 4E is subjected to nucleophilic substitution to give 4F, the solvent used is acetonitrile;

 f) Compound 4F is reacted with hydroxylamine hydrochloride to give compound 4G, the solvent used is methanol;

 g) Compound 4G is reacted with NBS to give compound 4H, the solvent used is N,N-dimethylformamide (DMF); h) compound 41 is hydrolyzed to give compound 4J, the base used is NaOH;

 i) compound 4J is reacted with hydrazine, Ν'-carbonyldiimidazole (CDI) and reduced by sodium borohydride to obtain compound 4;

 j) The hydroxyl group of the compound 4K is protected with dihydropyran (DHP) to obtain the compound 4L, the solvent used is dichloromethane; k) the compound 4H and 4K are closed to give the compound 4M, the base used is t-butyllithium;

 1) The compound 4M is reacted to obtain the compound 4N, the base used is triethylamine, the solvent used is dichloromethane; m) the compound 4N is deprotected by DHP to obtain the compound 40, the solvent used is tetrahydrofuran and methanol;

 n) The hydroxyl group of compound 40 is protected with methanesulfonyl group to give compound 4P, the solvent used is dichloromethane, and the base used is triethylamine;

 ο) Compound 4Ρ is nucleophilicly reacted with an amine to give compound 4Q, the solvent used is acetonitrile;

 p) Compound 4Q is reacted with a solution of boron trichloride in dichloromethane to give compound 4R.

 According to a further object of the present invention, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by the formula I or a pharmaceutically acceptable salt thereof as an active ingredient.

 According to a further object of the invention, the invention provides the use of the compound represented by the general formula I for the preparation of a medicament as an HSP90 inhibitor or for the preparation of an antitumor medicament.

 The phenyl 1,2-isoxazole or phenyl 1,2-pyrazole compound represented by the formula I according to the present invention has a significant activity of inhibiting HSP90, which is a further study of diseases which may be associated with HSP90 ( Tumors such as epithelial-derived cancers or interstitial-derived sarcomas provide valuable information. Specific real Ife^

 The invention is further illustrated by the following examples, which are described by way of example only. It is apparent that various modifications and alterations of the present invention are possible within the scope and spirit of the invention. It is to be understood that the invention is intended to cover such modifications and modifications

 Instruments used for experiments and sample analysis:

Nuclear Magnetic Resonance Spectroscopy (C1H NMR) by Merian's Mercury-300 or Mercury-400 Nuclear Magnetic Resonance Instrument LC-MS was determined by a Thermo Finnigan LCQDECAxP mass spectrometer.

 HRMS was determined by a Finnigan MAT 95 mass spectrometer.

 Sample purity was determined by Gilson's high performance liquid chromatograph (306 pump, uv/vis-156 Detector, 215 liquid handle).

 The silica gel used for column chromatography separation is a product of Qingdao Ocean Chemical Plant (200-300 mesh).

 The TLC silica gel plate is a HSF-254 thin layer chromatography prefabricated plate produced by Yantai Chemical.

 The UV lamp is a ZF-1 three-purpose UV analyzer from Shanghai Gucun Electro-optical Instrument Factory.

 The microwave reactor is a Biotage Initiator product.

 Preparation example

 Example 1: 3-(5-Chloro-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-5-amino-1H-imidazole

化合物 采

Compound mining

 Compound 1

 Reaction steps:

a) Under the protection of nitrogen, acetic acid (25.1mL, 0.42mol) was added dropwise to 4-chlororesorcinol (compound la, 61g _: 0.42 mol) of boron trifluoride etherate (290 mL) was suspended, and the reaction solution was reacted at 90 ° C for 3.5 hours, and then cooled to room temperature, and a large amount of yellow insoluble matter was precipitated. The reaction mixture was poured into 1 L of a 10% (w/v) aqueous sodium acetate solution, and after vigorously stirring for 2.5 hours, a large amount of a yellow solid was precipitated. After suction filtration and water washing, it was dried overnight to give 5-chloro-2,4-dihydroxyacetophenone (compound lb, 67 g, yield: 85%).

 MP= 122-125 °C

1H NMR (300 MHz, DMSO- ₆ ) δ 12.35 (s, 1H), 11.45 (s, 1H), 8.03 (s, 1H), 6.62 (s, 1H), 2.70 (s, 3H);

 MS (EI): m/z l 86;

 b) Benzyl bromide (100.5 mL, 0.84 mol) was added dropwise 5-chloro-2,4-dihydroxyacetophenone (compound lb, 67 g, 0.36 mol) and potassium carbonate (124 g, 0.9 mol) in acetonitrile (600 mL) In a suspension, reflux overnight and then cool to room temperature. After evaporating most of the solvent, 1 L of water was added, and the mixture was stirred at room temperature to precipitate a large white solid. After suction filtration and washing with water, washed with petroleum ether and dried to give 5-chloro-2,4-dibenzyloxyacetophenone ( Compound lc, 123.6 g, yield 94%).

 MP= 102-104 °C

1H NMR (300 MHz, CDC1 ₃ ) δ 7.91 (s, 1H), 7.42-7.32 (m, 10H), 6.55 (s, 1H), 5.13 (s, 2H), 5.07 (s, 2H), 2.54 (s , 3H).

 MS (EI): m/z 366;

_£ ;) 5-Chloro-2,4-dibenzyloxyacetophenone (compound lc, l. lg, 3 mmol) suspended in sodium hydroxide (1.2 g, 30 mmol) in water (10 mL) and 1, 4-di To a mixture of hexacyclohexane (10 mL), bromine (1.44 g, 9 mmol) was added dropwise and stirred at room temperature overnight. After distilling off most of the 1,4-dioxane, the pH was adjusted to 2 with 2M hydrochloric acid to precipitate a large amount of pale yellow insoluble material. After suction filtration and water washing, it was dried overnight to give 5-chloro-2,4-dihydroxybenzoic acid (compound ld, 0.9 g, yield 81%).

 MP=132-133 °C

1H NMR (300 MHz, CDC1 ₃ ) δ 10.50 (br, 1H), 8.20 (s, 1H), 7.45-7.35 (m, 10H), 6.64 (s, 1H), 5.20 (d, 4H)

 MS (EI): m/z 368;

d) Methyl iodide (0.5 mL, 7 mol) was added to a suspension of 5-chloro-2,4-dihydroxybenzoic acid (compound ld, lg, 2.7 mmol) and potassium carbonate (lg, 7 mm ₀ ) in acetonitrile (50 mL) After refluxing for 1 hour, it was cooled to room temperature. After evaporating most of the solvent, 100 mL of water was added, and the mixture was stirred at room temperature to precipitate a large white solid. After suction filtration and washing with water, it was washed with petroleum ether and dried to give ethyl 5-chloro-2,4-dibenzyloxybenzoate (compound le, 0.92 g, yield 88.6%).

 MP=90-93 °C

1H NMR (300 MHz, CDC1 ₃ ) δ 7.95 (s, 1H), 7.50-7.30 (m, 10H), 6.57 (s, 1H), 5.12 (d, 4H),

3.88 (s, 3H) LC-MS: m/z 382.8 [M+H] ⁺

e) 4-methoxyphenylacetonitrile (0.2 g, 1.36 mmol) was added dropwise to a solution of lithium hexamethyldisilazide (3.4 mL, 3.4 mmol) in 20 mL of tetrahydrofuran at -78 °C under nitrogen. After stirring for 30 minutes, a solution of methyl 5-chloro-2,4-dibenzyloxybenzoate (Compound l _e , 0.5 g, 1.36 mmol) in 10 mL of tetrahydrofuran was added dropwise. After 30 minutes of low temperature reaction, it was allowed to warm to room temperature and stirred for 2 hours. After quenching the reaction by the addition of 2M hydrochloric acid (10 mL), the mixture was evaporated and evaporated. After washing with saturated sodium chloride and dried over anhydrous sodium sulfate, evaporated.

 MP=125-126°C

1H NMR (300 MHz, CDC1 ₃ ) δ 7.74 (s, 1 Η), 7.63 (d, J = 8.8 Hz, 2H), 7.45-7.35 (m, 10H), 6.95 (d, J = 8.8 Hz, 2H), 6.65 (s, 1H), 6.59 (s, 1H), 5.15 (s, 2H), 5.09 (s, 2H), 3.84 (s, 3H)

 LC-MS: m/z 496.1 [M-H]";

 f) Compound If (0.5 g, 1 mmol) and hydrazine monohydrate (0.2 mL, 1 mmol) were dissolved in a mixture of ethanol (5 mL) and acetic acid (10 mL) and refluxed overnight. After alkalization of concentrated aqueous ammonia, the mixture was extracted with methylene chloride, evaporated to dryness, and then evaporated to silica gel to afford white solids lg (0.126 g) and lh (0.141 g), yield 24.5%, 25.3%.

 MP=79-81 °C

1H NMR (300 MHz, CDC1 ₃ ) δ 7.41-7.24 (m, 11H), 7.20-7.16 (m, 3H), 7.93 (d, J=8.6Hz, 2H), 6.57 (s, 1H), 5.05 (d , 4H), 3.85 (s, 3H)

LC-MS: m/z 512.2 [M+H] ⁺

1H NMR (300 MHz, CDC1 ₃ ) δ 7.41-7.26 (m, 12H), 7.12-7.05 (m, 3H), 6.95-6.87 (m, 2H), 6.51 (s, 1H), 5.05 (s, 2H) , 4.84 (s, 2H), 3.84 (s, 3H), 2.14 (s, 3H)

LC-MS: m/z 554.2 [M+H] ⁺

 g) Under a nitrogen atmosphere, the compound lg CO. lg, 0.2 mmol) was dissolved in anhydrous dichloromethane (20 mL). The reaction mixture was diluted with ethyl acetate. EtOAc (EtOAc m. (Compound 1), yield 37%.

 MP= 179-182 °C

1H NMR (400MHz, CD ₃ OD) δ 7.17 (d, J=8.4Hz, 2H), 6.95 (d, J=8.4Hz, 2H), 6.91 (s, 1H), 6.44 (s, 1H), 3.81 ( s, 3H).

LC-MS: m/z 332.2 [M+H] ⁺

化合物 2 采用合成路线 1 Example 2: 3-(5-Chloro-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-5-acetamido-1H-imidazole

Compound 2 uses synthetic route 1

 Reaction steps:

 The compound lh was obtained by the procedures a to f described in Example 1. The compound lh (0.1 g, 0.18 mmol) was dissolved in methylene chloride (20 mL), and then evaporated. The reaction mixture was diluted with ethyl acetate. EtOAc (EtOAc m. (Compound 2), yield 45.9%.

 MP=101-103 °C

1H NMR (400MHz, CD ₃ OD) δ 7.15 (d, J=8.3Hz, 2H), 6.90 (brs, 3H), 6.46 (s, 1H), 3.78 (s, 3H), 2.06 (s, 3H).

LC-MS: m/z 374.2 [M+H] ⁺

 Example 3: 3-(5-Chloro-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-5-aminoisoxazole

采用合成路线 2

Using synthetic route 2

反应步骤：

Reaction steps:

 Compound l f was prepared by the procedure a-e described in Example 1.

a) Compound If (0.15 g, 0.3 mmol) and hydroxylamine hydrochloride (0.042 g, 0.6 mmol) are dissolved in 5 mL of pyridine. The reaction was carried out at 100 ° C overnight. After the reaction mixture was diluted with dichloromethane, washed with saturated aqueous citric acid/water (1:1) (30 mL×2), washed with water (30 mL×1), saturated sodium hydrogen carbonate (30 mL×2), and washed with saturated brine (50 mL) The mixture was dried over sodium sulfate, filtered, and evaporated.

 MP=143-145 °C

1H NMR (300 MHz, CDC1 ₃ ) δ 7.48 (s, 1Η), 7.38-7.30 (m, 5H), 7.24-7.20 (m, 3H), 6.96 (d, J=8.6Hz, 2H), 6.89-6.84 (m, 2H), 6.78 (d, J=8.6Hz, 2H), 6.40 (s, 1H), 5.01 (s, 2H), 4.64 (s, 2H) 4.52 (s, 2H), 3.79 (s, 3H) )

 LC-MS: m/z 513.1 [M+H]+;

 b) Under a nitrogen atmosphere, compound 3a (O.lg, 0.2 mmol) was dissolved in anhydrous dichloromethane (20 mL). The reaction mixture was diluted with ethyl acetate. EtOAc (EtOAc m. (Compound 3), yield 70.9%.

 MP=179-181 °C

1H NMR (400MHz, CD ₃ OD) δ 7.13 (d, J=8.9Hz, 2H), 6.96 (s, 1H), 6.93 (d, J=8.9Hz, 2H), 6.44 (s, 1H), 3.79 ( s, 3H).

LC-MS: m/z 333.0 [M+H] ⁺

 Example 4: 3-(5-Chloro-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-5-acetylaminoisoxazole

反应步骤:

Reaction steps:

 Compound 3a (0.2 g, 0.4 mmol) and triethylamine (1 mL) were dissolved in 20 mL of anhydrous dichloromethane. After adding a catalytic amount of DMAP, acetyl chloride (0.1 mg, 1.2 mmol) was added dropwise at room temperature. hour. After the reaction mixture was diluted with dichloromethane, washed with saturated aqueous citric acid/water (1:1) (30 mL×2), washed with water (30 mL×1), saturated sodium hydrogen carbonate (30 mL×2), and brine (50 mL) Drying with sodium sulfate, filtration, concentrating, EtOAc (EtOAc) -5-(N,N-Diacetylamino)isoxazole 0.192 g, yield 88.6%.

 MP= 169-172 °C

1H NMR (300 MHz, CDC1 ₃ ) δ 7.50 (s, 1H), 7.40-7.34 (m, 5H), 7.33 (s, 1H), 7.26-7.23 (m, 3H), 6.97 (d, J=8.6Hz, 2H), 6.85-6.90 (m, 2H), 6.78 (d, J=8.6Hz, 2H), 6.43 (s, 1H), 5.04 (s, 2H) 4.63 (s, 2H), 3.81 (s, 3H), 1.60 (s, 3H),

 LC-MS: m/z 555.1 [M+H]+;

 3-(5-Chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-(N,N-diacetylamino)isoxazole under nitrogen O. lg, 0.18 mmol) was dissolved in anhydrous dichloromethane (20 mL). The reaction mixture was diluted with ethyl acetate. EtOAc (EtOAc m. 0.038 g of compound 4), yield 56.4%.

1H NMR (400MHz, CD ₃ OD) δ 7.13 (d, J=8.3Hz, 2H), 7.05 (s, 1H), 6.90 (d, J=8.3Hz, 2H), 6.45 (s, 1H), 3.77 ( s, 3H), 2.09 (s, 3H).

LC-MS: m/z 375.0 [M+H] ⁺

 Example 5: 3-(5-Chloro-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-5-cyclopropanoylaminoisoxazole

按照实施例 4 的方法， 3a 与环丙甲酰氯反应得白色固体 3-(5-氯 -2,4-二苄氧基苯 基)—4-(4-甲氧基苯基) -5-(N，N-二环丙甲酰基氨基)异噁唑 0.196g， 产率 77.5%。

According to the method of Example 4, 3a was reacted with cyclopropionyl chloride to give 3-(5-chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5- as a white solid. (N,N-Dicyclopropionylamino)isoxazole 0.196 g, yield 77.5%.

 3-(5-Chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-(N,N-bicyclopropanoylamino)isoxazole debenzylated The title compound was obtained as a white foamy solid, 0.039 g (Comp. 5), yield 63.3%.

1H NMR (400MHz, CD ₃ OD) δ 7.13 (d, J=8.4Hz, 2H), 7.04 (s, 1H), 6.90 (d, J=8.4Hz, 2H), 6.44 (s, 1H), 3.78 ( s, 3H), 1.76 (m, 1H), 0.94-0.85 (m, 4H).

LC-MS: m/z 400.9 [M+H] ⁺

 Example 6: 3-(5-Chloro-2,4-di-4-(4-methoxyphenyl)-5-pivaloylaminoisoxazole

化合物 6

Compound 6

 3a was reacted with pivaloyl chloride according to the method of Example 4 to give 3-(5-chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-CN as a white solid. , N-dipivoylamino)isoxazole 0.186 g, yield 69.9%.

3-(5-Chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-(N,N-dipivoylamino)isoxazole debenzylated The title compound was obtained as a white foamy solid, 0.051 g (Comp. 6), yield 83.6%.

1H NMR (400MHz, CD ₃ OD) δ 7.12 (d, J=8.4Hz, 2H), 7.07 (s, 1H), 6.88 (d, J=8.4Hz, 2H) 6.45 (s, 1H), 3.77 (s , 3H), 1.23 (s, 9H).

LC-MS: m/z 417.0 [M+H] ⁺

 Example 7: 3-(5-Chloro-2,4-dicyclopentanoylaminoisoxazole

 According to the method of Example 4, 3a was reacted with cyclopentanoyl chloride to give 3-(5-chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5- as a white solid. (N,N-Dicyclopentanoylamino)isoxazole 0.218 g, yield 79.6%.

 3-(5-Chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-(N,N-dicyclopentanoylamino)isoxazole debenzylated The title compound was obtained as a white foamy solid, 0.048 g (Comp. 7), yield 78.7%.

1H NMR (400MHz, CD ₃ OD) δ 7.13 (d, J=8.4Hz, 2H), 7.05 (s, 1H), 6.89 (d, J=8.4Hz, 2H), 6.45 (s, 1H), 3.77 ( s, 3H), 2.86-2.77 (m, 1H), 1.94-1.83 (m, 2H), 1.80-1.67 (m, 4H), 1.63-1.55 (m, 2H).

LC-MS: m/z 429.0 [M+H] ⁺

 Example 8: 3-(5-Chloro-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-5-butyrylaminoisoxazole

按照实施例 4的方法， 3a与丁酰氯反应得白色固体 3-(5-氯 -2,4-二苄氧基苯基 )-4-(4- 甲氧基苯基) -5-CN，N-二丁酰基氨基)异噁唑 0.169g， 产率 66.3%。

According to the method of Example 4, 3a was reacted with butyryl chloride to give 3-(5-chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-CN as a white solid. N-dibutyrylamino)isoxazole 0.169 g, yield 66.3%.

 Debenzylation protection of 3-(5-chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-(N,N-dibutyrylamino)isoxazole The title compound was obtained as a white foamy solid, 0.055 g of Compound 8), yield 88.7%.

1H NMR (400MHz, CD ₃ OD) δ 7.13 (d, J=8.4Hz, 2H), 7.05 (s, 1H), 6.88 (d, J=8.4Hz, 2H), 6.45 (s, 1H), 3.77 ( s, 3H), 2.32 (t, J=7.2Hz, 2H), 1.70-1.60 (m, 2H), 0.93 (t, J=7.2Hz, 3H).

LC-MS: m/z 403.0 [M+H] ⁺

化合物 9 按照实施例 4的方法， 3a与辛酰氯反应得白色固体 3-(5-氯 -2,4-二苄氧基苯基 )-4-(4- 甲氧基苯基) -5-CN，N-二辛酰基氨基)异噁唑 0.212g， 产率 71.1%。 Example 9: 3-(5-Chloro-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-5-octanoylaminoisoxazole

Compound 9 was reacted with octanoyl chloride according to the method of Example 4 to give 3-(5-chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5- CN,N-dioctanoylamino)isoxazole 0.212 g, yield 71.1%.

 Debenzylation protection of 3-(5-chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-(N,N-dioctanoylamino)isoxazole The target compound was obtained in an amount of 0.059 g of compound 9), yield 98.3%.

 MP=101-103 °C

1H NMR (400MHz, CD ₃ OD) δ 7.13 (d, J=8.4Hz, 2H), 7.05 (s, 1H), 6.88 (d, J=8.4Hz, 2H), 6.45 (s, 1H), 3.77 ( s, 3H), 2.34 (t, J=7.2Hz, 2H), 1.65-1.56 (m, 2H), 1.35-1.22 (m, 11H).

LC-MS: m/z 459.0 [M+H] ⁺

 Example 10: 3-(5-Chloro-2,4-dihydroxyphenyl-4-(4-methoxyphenyl)-5-isobutyrylaminoisoxazole

化合物 10 按照实施例 4的方法，3a与异丁酰氯反应得白色固体 3-(5-氯 -2,4-二苄氧基苯基 )-4-(4- 甲氧基苯基) -5-CN，N-二异丁酰基氨基)异噁唑 0.194g， 产率 76.1%。

Compound 10 was reacted with isobutyryl chloride according to the method of Example 4 to give 3-(5-chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5 as a white solid. -CN,N-diisobutyrylamino)isoxazole 0.194 g, yield 76.1%.

 3-(5-Chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-(N,N-diisobutyrylamino)isoxazole debenzylated The title compound was obtained as a white foamy solid (0.047 g, Compound 10), yield 75.8%.

1H NMR (400MHz, CD ₃ OD) δ 7.12 (d, J=8.4Hz, 2H), 7.05 (s, 1H), 6.88 (d, J=8.4Hz, 2H), 6.45 (s, 1H), 3.77 ( s, 3H), 2.66-2.58 (m, 1H), 1.14 (d, J=7.1Hz, 6H).

LC-MS: m/z 403.0 [M+H] ⁺

 Example 11: 3-(5-Chloro-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-5-propionylaminoisoxazole

化合物 11 按照实施例 4的方法， 3a与丙酰氯反应得白色固体 3-(5-氯 -2,4-二苄氧基苯基 )-4-(4- 甲氧基苯基) -5-CN，N-二丙酰基氨基)异噁唑 0.187g， 产率 84.3%。

Compound 11 3a was reacted with propionyl chloride according to the method of Example 4 to give 3-(5-chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-CN as a white solid. N-dipropionylamino)isoxazole 0.187 g, yield 84.3%.

 Debenzylation protection of 3-(5-chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-(N,N-dipropionylamino)isoxazole The title compound was obtained as a white foamy solid (0.052 g, Compound 11).

1H NMR (400MHz, CD ₃ OD) δ 7.13 (d, J=8.4Hz, 2H), 7.04 (s, 1H), 6.89 (d, J=8.4Hz, 2H), 6.44 (s, 1H), 3.77 ( s, 3H), 2.37 (t, J=7.4Hz, 2H), 1.13 (d, J=7.4Hz, 3H).

LC-MS: m/z 389.0 [M+H] ⁺

 Example 12: 3-(5-Chloro-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-5-isovalerylaminoisoxazole

化合物 12 按照实施例 4的方法，3a与异戊酰氯反应得白色固体 3-(5-氯 -2,4-二苄氧基苯基 )-4-(4- 甲氧基苯基) -5-(N，N-二异戊酰基氨基)异噁唑 0.214g， 产率 81%。

Compound 12 was reacted with isovaleryl chloride according to the method of Example 4 to give 3-(5-chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5 as a white solid. -(N,N-Diisopentanoylamino)isoxazole 0.214 g, yield 81%.

 3-(5-Chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-(N,N-diisopentanoylamino)isoxazole debenzylated The title compound was obtained as a white foamy solid, 0.053 g (Comp. 12), yield 75.9%.

1H NMR (400MHz, CD ₃ OD) δ 7.14 (d, J=8.4Hz, 2H), 7.05 (s, 1H), 6.89 (d, J=8.4Hz, 2H), 6.45 (s, 1H), 3.77 ( s, 3H), 2.22 (d, J=7.3Hz, 2H), 2.12-2.02 (m, 1H), 0.94 (d, J=6.7Hz, 6H).

LC-MS: m/z 417.0 [M+H] ⁺

 Example 13: 3-(5-Chloro-2,4-dihydroxyphenyl-4-(4-methoxyphenyl)-5-cyclobutyrylaminoisoxazole

化合物 13 按照实施例 4 的方法， 3a 与环丁甲酰氯反应得白色固体 3-(5-氯 -2,4-二苄氧基苯 基) -4-(4-甲氧基苯基) -5-(N，N-二环丁甲酰基氨基)异噁唑 0.186g， 产率 70.7%。

Compound 13 was reacted with cyclobutyryl chloride according to the method of Example 4 to give 3-(5-chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)- 5-(N,N-bicyclobutyrylamino)isoxazole 0.186 g, yield 70.7%.

 3-(5-Chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-(N,N-bicyclobutyrylamino)isoxazole debenzylated The title compound was obtained as a white foamy solid (0.03 g, Compound 13).

1H NMR (400MHz, CD ₃ OD) δ 7.12 (d, J=8.4Hz, 2H), 7.05 (s, 1H), 6.89 (d, J=8.4Hz, 2H), 6.45 (s, 1H), 3.78 (s, 3H), 2.32-2.14 (m, 5H), 2.06-1.96 (m, 1H), 1.92-1.82 (m, 1H).

LC-MS: m/z 415.0 [M+H] ⁺

 Example 14: 3-(5-Chloro-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-5-cyclohexanoylaminoisoxazole

按照实施例 4 的方法， 3a 与环己甲酰氯反应得白色固体 3-(5-氯 -2,4-二苄氧基苯 基) -4-(4-甲氧基苯基) -5-(N，N-二环己甲酰基氨基)异噁唑 0.221g， 产率 77.5%。

3a was reacted with cyclohexylcarbonyl chloride according to the method of Example 4 to give 3-(5-chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5- (N,N-Dicyclohexylamino)isoxazole 0.221 g, yield 77.5%.

 3-(5-Chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-(N,N-dicyclohexylamino)isoxazole debenzylated The target compound was obtained as a white foamy solid, 0.055 g (Comp. 14), yield 90.2%.

1H NMR (400MHz, CD ₃ OD) δ 7.12 (d, J=8.4Hz, 2H), 7.05 (s, 1H), 6.89 (d, J=8.4Hz, 2H), 6.45 (s, 1H), 3.78 ( s, 3H), 2.41-2.32 (m, 1H), 1.87-1.75 (m, 4H), 1.50-1.38 (m, 2H), 1.37-1.20 (m, 4H).

LC-MS: m/z 443.0 [M+H] ⁺

 Example 15: N-[3-(5-Chloro-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)isoxazole-5]-N,-ethylurea

按照实施例 4的方法， 3a与乙基异氰酸酯反应得白色固体 N-[3-(5-氯 -2,4-二苄氧基苯 基)—4-(4-甲氧基苯基)异噁唑 -5]-Ν'-乙基脲 0.192g， 产率 75.2%。

According to the method of Example 4, 3a was reacted with ethyl isocyanate to give a white solid N-[3-(5-chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl) Oxazole-5]-oxime-ethyl urea 0.192 g, yield 75.2%.

 Target of N-[3-(5-chloro-2,4-dibenzyloxyphenyl 4-(4-methoxyphenyl)isoxazol-5]-oxime-ethylurea debenzylation Compound 0.021 g (Compound 15), Yield 34.8%.

 MP=156-158°C

1H NMR (400MHz, CD ₃ OD) δ 7.16 (d, J=8.9Hz, 2H), 7.02 (s, 1H), 6.91 (d, J=8.9Hz, 2H), 6.45 (s, 1H), 3.78 ( s, 3H), 3.16 (t, J=7.6Hz, 2H), 1.07 (d, J=7.6Hz, 3H).

LC-MS: m/z 404.0 [M+H] ⁺

Example 16: 3-(5-Bromo-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-5-acetylaminoisoxazole

反应步骤：

Reaction steps:

 a) Bromine (1.lmL, 23.3 mmol) was dissolved in 18 mL of acetic acid, and a suspension of 2,4-dihydroxybenzoic acid (Compound 3A, 3 g, 19.6 mmol) in acetic acid (21 mL) was added dropwise. . After the reaction mixture was diluted with water, it was extracted with ethyl acetate. The mixture was washed with brine (50 mL) dry Recrystallization (acetonitrile / toluene, 1:1) gave a white solid (5-bromo-2,4-dihydroxybenzoic acid, compound 3B, 2.93 g, yield 64.6%).

 MP=193-195°C

1H NMR (300 MHz, DMSO- ₆ ) δ 11.26 (s, lH), 7.80 (s, lH), 6.46 (s, 1H)

 b) 5-Bromo-2,4-dihydroxybenzoic acid (Compound 3B, 21 g, 90 mmol) was dissolved in 150 mL of methanol, and then succinyl chloride (7.86 mL, 108 mmol) was added dropwise under ice-cooling, and refluxed overnight. After evaporating most of the solvent, 300 mL of water was added to precipitate a large white solid, which was stirred for 0.5 hour. After suction filtration and washing with water, it was dried overnight to give ethyl 5-bromo-2,4-dihydroxybenzoate (Compound 3C, 19.2 g, yield: 86.2%).

 MS (EI): m/z 232,234;

1H NMR (300 MHz, DMSO- ₆ ) δ 11.25 (s,lH), 7.81 (s,lH), 6.44 (s, 1H), 3.88 (s, 3H). c) benzyl bromide (44.8mL, 444mmoL) Methyl 5-bromo-2,4-dihydroxybenzoate (Compound 3C, 44g, 178 mmol) and potassium carbonate (61.3 g, 444 mmol) in acetonitrile (500 mL). After evaporating most of the solvent, 1 L of water was added, and the mixture was stirred at room temperature to precipitate a large white solid. After suction filtration and washing with water, it was washed with petroleum ether and dried to give ethyl 5-bromo-2,4-dibenzyloxybenzoate (compound 3D, 68.3 g, yield 89.8%).

 MP= 106-107 °C

1H NMR (300 MHz, CDC1 ₃ ) 3 8.11 (s, 1H), 7.49-7.32 (m, 10H), 6.54 (s, 1H), 5.13 (d, 4H),

3.88 (s, 3H)

 MS (EI): m/z 426,428;

d) 4-methoxyphenylacetonitrile (0.5 mL, 3.4 mmmol) was added dropwise to a solution of LHMDS (8.5 mL _: 8.5 mmol) in 40 mL of tetrahydrofuran at -78 °C under nitrogen. A solution of methyl 5-bromo-2,4-dibenzyloxybenzoate (Compound 3D, 1.45 g, 3.4 mmol) in 20 mL of THF. After 30 minutes of low temperature reaction, it was allowed to warm to room temperature and stirred for 2 hours. After quenching the reaction by the addition of 2M hydrochloric acid (20 mL), the mixture was evaporated and evaporated. After washing with saturated sodium chloride and dried over anhydrous sodium sulfate, evaporated and evaporated.

 MP= 127-128 °C

 MS (EI): m/z 541,543;

 e) Compound 16e (0.8 g, 1.5 mmol) and hydroxylamine hydrochloride (0.3 g, 4.5 mmol) were dissolved in 10 mL of pyridine and reacted at 100 ° C overnight. After the reaction mixture was diluted with dichloromethane, washed with saturated aqueous citric acid/water (1:1) (30 mL×2), washed with water (30 mL×1), saturated sodium hydrogen carbonate (30 mL×2), and brine (50 mL) The aqueous solution was dried over sodium sulfate, filtered, and evaporated.

 MP=130-132°C

1H NMR (300 MHz, CDC1 ₃ ) δ 7.67 (s, 1H), 7.40-7.35 (m, 5H), 7.26-7.21 (m, 3H), 6.98 (d, J=8.6Hz, 2H), 6.90-6.86 (m, 2H), 6.79 (d, J=8.6Hz, 2H), 6.40 (s, 1H), 5.02 (s, 2H), 4.66 (s, 2H) 4.54 (s, 2H), 3.80 (s, 3H) )

LC-MS: m/z 557.0 [M+H] ⁺

 f) Compound 16f (0.2g, 0.4mmol) and triethylamine (1.13mL, 8mmol) were dissolved in 20mL of anhydrous dichloromethane. After adding a catalytic amount of DMAP, acetyl chloride (0.15mg, 2mmol) was added dropwise. Stir at room temperature for 2 hours. After the reaction mixture was diluted with dichloromethane, washed with saturated aqueous citric acid/water (1:1) (30 mL×2), washed with water (30 mL×1), saturated sodium hydrogen carbonate (30 mL×2), and brine (50 mL) Drying with sodium sulfate, filtration, concentrating, EtOAc (EtOAc) -5-(N,N-Diacetylamino)isoxazole 16 g 0.181 g, yield 78.6%.

MP=179-181 °C NMR NMR (300 MHz, CDC1 ₃ ) δ 7.74 (s, 1H), 7.42-7.35 (m, 5H), 7.26-7.22 (m, 3H), 6.95-6.90 (m, 2H), 6.87 (d, J= 9.0Hz, 2H), 6.73 (d, J=9.0Hz, 2H), 6.46 (s, 1H), 5.09 (s, 2H), 4.65 (s, 2H), 3.78 (s, 3H), 2.26 (s, 6H),

 LC-MS: m/z 641.0 [M+H]+;

 g) 3-(5-chloro-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5 N,N-diacetylamino)isoxazole under nitrogen protection 16 g of C 0.1 g (0.16 mmol) was dissolved in anhydrous dichloromethane (20 mL). The reaction mixture was diluted with ethyl acetate. EtOAc (EtOAc m. 0.024 g (Compound 16), yield 36.7%.

1H NMR (400MHz, CD ₃ OD) δ 7.20 (s, 1H), 7.13 (d, J=8.4Hz, 2H), 6.90 (d, J=8.4Hz, 2H), 6.44 (s, 1H), 3.78 ( s, 3H), 2.08 (s, 3H).

LC-MS: m/z 420.9 [M+H] ⁺

 Example 17: 3-(5-Phenyl-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-5-acetylaminoisoxazole

反应步骤:

Reaction steps:

16g of the compound prepared in Example 16 under the protection of nitrogen: 3-(5-bromo-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-(N, N-diacetylamino)isoxazole (0.3 g, 0.47 mmol) and phenylboronic acid (0.086 g, 0,7 mmol) potassium carbonate (0.193 g, 1.4 mmol) and Pd(PPh ₃ ) ₄ (O.Olg, O .OOlmmol) was suspended in a mixed solvent of 2 mL of ethylene glycol dimethyl ether and 0.5 mL of water, and heated by microwave to 140 ° C for 1 hour. The reaction mixture was diluted with methylene chloride. EtOAc (EtOAc) Oxyphenyl)-4-(4-methoxyphenyl)-5-acetamidoisoxazole 0.153 g, yield 54.8%.

 MP=148-151 °C

1H NMR (300 MHz, CDC1 ₃ ) δ 7.55 (d, J = 7.1 Hz, 2H), 7.49-7.23 (m, 13H), 7.03 (d, J = 8.9 Hz, 2H), 6.96-6.91 (m, 2H) ), 6.81 (d, J=8.9Hz, 2H), 6.51 (s, 1H), 4.96 (s, 2H), 4.71 (s, 2H) 3.81 (s, 3H), 2.16 (s, 3H)

 MS (EI): m/z 596;

3-(5-phenyl-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-acetylaminoisoxazole (0.1 g, under nitrogen) 0.17 mmol) was dissolved in anhydrous dichloromethane (20 mL). The reaction mixture was diluted with ethyl acetate. EtOAc (EtOAc m. 0.046 g (Compound 17), yield 65.9%.

1H NMR (400MHz, CD ₃ OD) δ 7.27-7.15 (m, 7H), 6.99 (s, 1H), 6.95 (d, J=8.4Hz, 2H), 6.46 (s, 1H), 3.80 (s, 3H ), 2.08 (s, 3H).

LC-MS: m/z 417.0 [M+H] ⁺

 Example 18: 3-[5-(Pyridin-3-)-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-5-acetylaminoisoxazole

反应步骤：

Reaction steps:

 According to the method of Example 17, 16 g of pyridine-3-boronic acid was reacted to give 3-[5-(pyridine-3-)-2,4-dibenzyloxyphenyl)]-4-(4-methoxy) as a white solid. Phenylphenyl)-5-acetamidoisoxazole 0.187 g, yield 66.8%.

 MP=114-116°C

1H NMR (300 MHz, CDC1 ₃ ) δ 8.72 (s, 1H), 8.48 (d, J = 4.4 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.34- 7.20 (m, 10H), 7.03 (d, J=7.9Hz, 2H), 6.95-6.91 (m, 2H), 6.79 (d, J=7.9Hz,

2H), 6.52 (s, 1H), 4.98 (s, 2H), 4.73 (s, 2H), 3.78 (s, 3H), 2.17 (s, 3H)

 LC-MS: m/z 598.1 [M+H]+;

 Deprotection of 3-[5-(pyridine-3-)-2,4-dibenzyloxyphenyl)]-4-(4-methoxyphenyl)-5-acetylaminoisoxazole Compound 0.039 g of compound 18), yield 55.8%.

 MP=218-220 °C

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.43 (brs, 1H), 10.15 (s, 1H), 9.81 (s, 1H), 8.71 (s, 1H) _: 8.46 (d, J = 4.7 Hz, 1H ), 7.99 (d, J=7.5Hz, 1H), 7.49-7.42 (m, 1H), 7.21 (s, 1H), 7.14 (d, J=8.8Hz _: 2H), 6.89 (d, J=8.8Hz , 2H), 6.56 (s, 1H), 3.72 (s, 3H), 2.04 (s, 3H).

LC-MS: m/z 418.1 [M+H] ⁺

化合物 19 Example 19: 3-[5-(8-Methylquinolin-5-)-2,4-dihydroxyphenyl)]-4-(4-methoxyphenyl)-5-acetylamino isomer Azole

Compound 19

 Reaction steps:

 According to the method of Example 17, 16 g of reaction with 8-methylquinolin-5-boronic acid gave 3-[5-(8-methylquinolin-5-)-2,4-dibenzyloxyphenyl as a white solid. ]] 4-(4-methoxyphenyl)-5-acetamidoisoxazole 0.136 g, yield 43.9%.

 MP=98-100°C

1H NMR (300 MHz, CDC1 ₃ ) δ 8.93 (m, 1 Η), 7.94 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.39-7.35 (m, 2H), 7.34-7.26 (m, 5H), 7.22-7.16 (m, 3H), 7.07-6.91 (m, 6H), 6.85-6.80 (m, 2H), 6.57 (s, 1H), 4.87 (s, 2H), 4.78 (s, 2H), 3.83 (s, 3H), 2.86 (s, 3H), 2.16 (s, 3H)

 MS (EI): m/z 661;

 3-[5-(8-methylquinolin-5-)-2,4-dibenzyloxyphenyl)]-4-(4-methoxyphenyl)-5-acetylaminoisoxazole The benzyl group protected the title compound 0.033 g of compound 19), yield 45.4%.

 MP=205-208°C

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.46 (brs, 1H), 9.76 (d, J=4.3Hz, 2H), 8.92-8.90 (m, 1H), 7.93 (d, J=8.2Hz, 1H ), 7.61 (d, J=7.4Hz, 1H), 7.49-7.44 (m, 1H), 7.29 (d, J=6.8Hz, 1H), 7.16 (d, J=8.7Hz, 2H), 6.94-6.89 (m, 3H), 6.62 (s, 1H), 3.74 (s, 3H), 2.73 (s, 3H), 2.03 (s, 3H).

LC-MS: m/z 482.2 [M+H] ⁺

 Example 20: 3-(5-styryl-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-5-acetylaminoisoxazole

化合物 20 按照实施例 17的方法， 16g与苯乙烯硼酸反应得白色固体 3-(5-苯乙烯基 -2,4-二苄氧 基苯基 )]-4-(4-甲氧基苯基) -5-乙酰氨基异噁唑 0.262g， 产率 89.9%。

Compound 20 was reacted with styrene boronic acid to give 3-(5-styryl-2,4-dibenzyloxyphenyl)]-4-(4-methoxyphenyl) as a white solid. -5-Acetylaminoisoxazole 0.262 g, yield 89.9%.

 MP=133-135 °C

1H NMR (300 MHz, CDC1 ₃ ) δ 7.74 (s, 1H), 7.49-7.45 (m, 2H), 7.41-7.31 (m, 10H), 7.27-7.21 (m, 3H), 7.08-7.01 (m, 3H), 6.93-6.89 (m, 2H), 6.78 (d, J=8.4Hz, 2H), 6.43 (s, 1H), 5.04 (s, 2H), 4.68 (s, 2H), 3.80 (s, 3H), 2.17 (s, 3H).

 MS (EI): m/z 622;

 Deprotection of 3-(5-styryl-2,4-dibenzyloxyphenyl)]-4-(4-methoxyphenyl)-5-acetylaminoisoxazole to obtain the target compound white foam The solid was 0.049 g (Compound 20) in a yield of 69.1%.

1H NMR (400MHz, CD ₃ OD) δ 7.35-7.20 (m, 8H), 7.17-7.1 1 (m, 1H), 7.02 (d, J=8.4Hz, 2H) 6.39 (s, 1H), 3.80 (s , 3H), 2.08 (s, 3H).

LC-MS: m/z 443.0 [M+H] ⁺

 Example 21: 3-(5-Phenylethyl-2-dihydroxyphenyl)-4-(4-methoxyphenyl)-5-acetylaminoisoxazole

化合物 21

Compound 21

 Reaction steps:

 3-(5-styryl-2,4-dibenzyloxyphenyl)]-4-(4-methoxyphenyl)-5-acetylaminoisoxazole prepared in Example 20 ( 0.311 g, 0.5 mmol) was dissolved in 20 mL of THF, and 10 mg of palladium charcoal (10%) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen pressure of lamat. The reaction mixture was filtered to remove palladium charcoal, evaporated to dryness, and purified by flash silica gel column to give 3-(5-phenethyl-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl) as a white solid. -5-Acetylaminoisoxazole 0.27 g, yield 86.8%.

 MP= 126-128 °C

1H NMR (300 MHz, CDC1 ₃ ) δ 7.40-7.30 (m, 7H), 7.25-7.21 (m, 6H), 7.15-7.12 (m, 2H), 6.96 (d, J=8.9Hz, 2H), 6.93 -6.89 (m, 2H), 6.78 (d, J=8.9Hz, 2H), 6.41 (s, 1H), 4.95 (s, 2H), 4.65 (s, 2H), 3.79 (s, 3H), 2.88 ( Brs, 4H), 2.15 (s, 3H).

LC-MS: m/z 625.1 [M+H] ⁺

 3-(5-Phenylethyl-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-acetylaminoisoxazole (O. lg, 0.16) Methyl acetate (20 mL) was dissolved in methylene chloride (1 mL). The reaction mixture was diluted with ethyl acetate. EtOAc (EtOAc m. 0.045 g of compound 21), yield 69%.

1H NMR (400MHz, CD ₃ OD) δ 7.22-7.03 (m, 7H), 6.92 (d, J=8.4Hz, 2H), 6.71 (s, 1H), 6.35 (s, 1H), 3.77 (s, 3H), 2.60 (brs, 4H), 2.07 (s, 3H).

 LC-MS: m/z 445.1 [M+H]+;

 Compound 22 Reaction Steps:

 a) 4-methoxyphenylacetonitrile (1.3 mL, 8.6 mmmol) was added dropwise to a solution of LHMDS (30 mL, 30 mmol) in 80 mL of tetrahydrofuran at -78 °C under nitrogen, stirring for 30 minutes, then dropping Methyl 2,4-dibenzyloxybenzoate (synthesized from 2,4-dihydroxybenzoic acid methyl ester and benzyl bromide in acetonitrile) (2 g, 5.75 mmol) in 40 mL of THF. After 30 minutes of low temperature reaction, it was allowed to warm to room temperature and stirred for another 2 hours. After quenching the reaction by the addition of 2M hydrochloric acid (40 mL), the mixture was evaporated and evaporated. After washing with saturated sodium chloride and dried over anhydrous sodium sulfate, evaporated.

1H NMR (300MHz, CDC1 ₃ ) δ 7.81 (d, J=8.8Hz, 1H), 7.47-7.33 (m, 10H), 7.05 (d, J=8.8Hz, 2H), 6.78 (d, J=8.8Hz , 2H), 6.64-6.57 (m, 2H), 5.80 (s, 1H), 5.19-5.05 (m, 4H), 3.76 (s, 3H).

 MS (EI): m/z 463;

b) Compound 22B (2.412 g, 5.2 mmol) and hydroxylamine hydrochloride (1. lg, 15.6 mmol) were dissolved in 30 mL of pyridine and reacted at 100 ° C overnight. The reaction solution was diluted with dichloromethane and washed with saturated aqueous citric acid/water (1:1) (30 mL×2), Washed with water (30 mL×1), saturated sodium bicarbonate (30 mL×2), EtOAc (EtOAc) 17.8%.

1H NMR (300MHz, CDC1 ₃ ) δ 7.45-7.32 (m, 6H), 7.25-7.19 (m, 3H), 7.00-6.92 (m, 4H), 6.77 (d, J=8.8Hz, 2H), 6.62 ( Dd, J=1.3, 8.8Hz, 1H), 6.48 (d, J=2.0Hz, 1H), 5.01 (s, 2H), 4.72 (s, 2H), 4.52 (s, 2H), 3.78 (s, 3H) ).

LC-MS: m / z 479.0 [M + H] +;

 c) Compound 22C (0.2 g, 0.4 mmol) and triethylamine (1.13 mL, 8 mmol) were dissolved in 20 mL of anhydrous dichloromethane. After adding a catalytic amount of DMAP, acetyl chloride (0.15 mg, 2 mmol) was added dropwise. Stir at room temperature for 2 hours. After the reaction mixture was diluted with dichloromethane, washed with saturated aqueous citric acid/water (1:1) (30 mL×2), washed with water (30 mL×1), saturated sodium hydrogen carbonate (30 mL×2), and brine (50 mL) Drying with sodium sulfate, filtering, concentrating, EtOAc (EtOAc) N,N-diacetylamino)isoxazole 22D 0.174 g, yield 74%.

 MP=83-85 °C

1H NMR (300MHz, CDC1 ₃ ) δ 7.45-7.32 (m, 6Η), 7.25-7.19 (m, 3Η), 7.00-6.92 (m, 4H), 6.77 (d, J=8.8Hz, 2H), 6.62 ( Dd, J=1.3, 8.8Hz, 1H), 6.48 (d, J=2.0Hz, 1H), 5.01 (s, 2H), 4.72 (s,

2H), 3.78 (s, 3H), 2.25 (s, 6H).

 MS (EI): m/z 562;

 d) 3-(2,4-Dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-(N,N-diacetylamino)isoxazole 22D (under nitrogen) O. lg, 0.16 mmol) was dissolved in anhydrous dichloromethane (20 mL). The reaction mixture was diluted with ethyl acetate. EtOAc (EtOAc m. (Compound 22), yield 77.7%.

 MP=91-94°C

1H NMR (400MHz, CD ₃ OD) δ 7.13 (d, J=8.7Hz, 2H), 6.93 (d, J=8.9Hz, 1H), 6.87 (d, J=8.7Hz, 2H), 6.32 (d, J=2.5Hz, 1H), 6.23 (dd, J=2.5, 8.9Hz, 1H), 3.76(s, 3H), 2.08 (s, 3H).

LC-MS: m/z 341.0 [M+H] ⁺

化合物 23 采用合成路线 2 Example 23: 3-(5-Ethyl-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-5-acetylaminoisoxazole

Compound 23 using synthetic route 2

 23H Compound 23

 Reaction steps:

 a) Under nitrogen, acetic acid (5.42 g, 90.3 mmol) was added dropwise to a suspension of 4-ethyl resorcinol (6.23 g, 45.1 mmol) in boron trifluoride etherate (50 mL). After reacting at ° C for 12 hours, it was cooled to room temperature, and a large amount of yellow insoluble matter was precipitated. The reaction mixture was poured into 300 mL of a 10% (w/v) aqueous sodium acetate solution, and after vigorously stirring for 2.5 hours, a large amount of pale pink solid was precipitated. After suction filtration and washing with water, the mixture was dried overnight to give 5-ethyl-2,4-dihydroxyacetophenone 5.63 g, yield 69%.

 MP= 107-109 °C

1H NMR (400 MHz, CDC1 ₃ ) δ 12.59 (s, 1H), 7.45 (s, 1H), 6.81 (s, 1H), 6.34 (s, 1H), 2.58 (q, J = 7.8 Hz, 2H), 2.56 (s, 3H), 1.21 (t, J=7.8 Hz, 3H).

 MS (EI): m/z l80;

b) Benzyl bromide (18.6 mL, 156 mmol) was added dropwise 5-ethyl-2,4-dihydroxyacetophenone (12.8 g, 71 mmol) and potassium carbonate (21.5 g, 156 mmol) in acetonitrile (200 mL). In a solution, it was refluxed overnight and then cooled to room temperature. After evaporating most of the solvent, 0.3 L of water was added, and the mixture was stirred at room temperature to precipitate a large amount of white solid. After suction filtration and washing with water, the mixture was washed with petroleum ether and dried to give ethyl 2-ethyl-2,4-dibenzyloxyacetophenone (24.2 g, yield: 94.5%). MP=105-107°C

1H NMR (300 MHz, CDC1 ₃ ) δ Ί .12 (s, 1H), 7.43-7.32 (m, 10H), 6.51 (s, 1H), 5.11 (s, 2H), 5.09 (s, 2H), 2.64 (q, J=7.8 Hz, 2H), 2.57 (s, 3H), 1.20 (t, J=7.8 Hz, 3H).

 MS (EI): m/z 360;

 c) 5-Ethyl-2,4-dibenzyloxyacetophenone (1.87 g, 5.2 mmol) suspended in sodium hydroxide (2.08 g, 52 mmol) in water (30 mL) br. Bromine (0.8 mL, 15.6 mmol) was added dropwise to a mixture (30 mL). After distilling off most of the 1,4-dioxane, the pH was adjusted to 2 with 2M hydrochloric acid to precipitate a large amount of pale yellow insoluble material. After suction filtration and washing with water, the mixture was dried overnight to give <EMI ID=9.1>>

 MP= 104-107 °C

1H NMR (400 MHz, DMSO- ₆ ) δ 7.57-7.28 (m, 11H), 6.89 (s, 1H), 5.20 (s, 4H), 2.54 (q,

J = 7.4 Hz, 2H), 1.11 (t, J = 7.4 Hz, 3H).

 MS (EI): m/z 362;

 d) Methyl iodide (7.2 mL, 114.6 mol) was added to a suspension of 5-ethyl-2,4-dihydroxybenzoic acid (34.58 g, 95.5 mmol) and potassium carbonate (15.82 g, 114.6 mmol) in acetonitrile (200 mL) , reflux for 1 hour and then cool to room temperature. After evaporating most of the solvent, 300 mL of water was added, and the mixture was stirred at room temperature to precipitate a large white solid. After suction filtration and washing with water, the mixture was washed with petroleum ether and dried to yield ethyldiethyl 5-ethyl-bromo-diethyl benzoate (32.42 g, yield: 90.3%).

 MP=60-62°C

1H NMR (300 MHz, CDC1 ₃ ) δ 7.74 (s, 1Η), 7.51-7.29 (m, 10H), 6.53 (s, 1H), 5.13 (s, 2H), 5.06 (s, 2H), 3.88 (s , 3H), 2.64 (q, J=7.8 Hz, 2H), 1.20 (t, J=7.8 Hz, 3H).

 MS (EI): m/z 376;

e) 4-methoxyphenylacetonitrile (1.3 mL, 7.98 mmol) was added dropwise to a solution of LHMDS (30 mL, 30 mmol) in 40 mL of tetrahydrofuran at -78 ° C under nitrogen atmosphere, stirred for 30 min, then drip A solution of methyl 5-ethyl-2,4-dibenzyloxybenzoate (2 g, 5.32 mm ₀ l) in 20 mL of THF. After 30 minutes of low temperature reaction, it was allowed to warm to room temperature and stirred for 2 hours. After quenching the reaction by the addition of 2M hydrochloric acid (20 mL), the mixture was evaporated and evaporated. After washing with saturated sodium chloride and dried over anhydrous sodium sulfate, evaporated and evaporated.

 MP=78-81 °C

1H NMR (400MHz, CDC1 ₃ ) δ 7.69 (s, 1Η), 7.46-7.33 (m, 10H), 7.09 (d, J=8.7Hz, 2H), 6.79 (d, J=8.7Hz, 2H), 6.48 (s, 1H), 5.85 (s, 1H), 5.18-5.05 (m, 4H), 3.76 (s, 3H), 2.60 (q, J = 7.8 Hz, 2H), 1.17 (t, J = 7.8 Hz, 3H).

 MS (EI): m/z 491;

f) Compound 23F (2.5 g, 5.1 mmol) and hydroxylamine hydrochloride (1.06 g, 15.3 mmol) were dissolved in 30 mL of pyridine. The reaction was carried out at 100 ° C overnight. After the reaction mixture was diluted with dichloromethane, washed with saturated aqueous citric acid/water (1:1) (30 mL×2), washed with water (30 mL×1), saturated sodium hydrogen carbonate (30 mL×2), and washed with saturated brine (50 mL) The aqueous solution was dried over sodium sulfate, filtered, and evaporated.

1H NMR (300MHz, CDC1 ₃ ) δ 7.41-7.30 (m, 6H), 7.24-7.20 (m, 3H), 6.99 (d, J=8.9Hz, 2H), 6.96-6.91 (m, 2H), 6.78 ( d, J=8.9Hz, 2H), 6.39 (s, 1H), 4.95 (s, 2H), 4.67 (s, 2H), 4.50 (s, 2H), 3.78 (s, 3H), 2.63 (q, J =7.8 Hz, 2H), 1.18 (t, J=7.8 Hz, 3H).

LC-MS: m/z 507.0 [M+H] ⁺

 g) Compound 23G (0.2g, 0.4mmol) and triethylamine (1.13mL, 8mmol) were dissolved in 20mL of anhydrous dichloromethane. After adding a catalytic amount of DMAP, acetyl chloride (0.15mg, 2mmol) was added dropwise. Stir at room temperature for 2 hours. After the reaction mixture was diluted with dichloromethane, washed with saturated aqueous citric acid/water (1:1) (30 mL×2), washed with water (30 mL×1), saturated sodium hydrogen carbonate (30 mL×2), and brine (50 mL) Drying with sodium sulfate, filtration, concentrating, EtOAc (EtOAc) -5-(N,N-Diacetylamino)isoxazole 23H 0.178 g, yield 76.3%.

 MP= 142-144 °C

1H NMR (300MHz, CDC1 ₃ ) δ 7.41-7.36 (m, 5H), 7.30 (s, 1H), 7.25-7.22 (m, 3H), 7.00-6.96 (m, 2H), 6.87 (d, J=8.7 Hz, 2H), 6.72 (d, J=8.7Hz, 2H), 6.45 (s, 1H), 5.01 (s, 2H), 4.66 (s, 2H), 3.76 (s, 3H), 2.66 (q, J =7.8 Hz, 2H), 2.26 (s, 6H), 1.21 (d, J=7.8Hz, 3H).

 MS (EI): m/z 590;

 h) Under a nitrogen atmosphere, compound 23H (O. lg, 0.16 mmol) was dissolved in anhydrous dichloromethane (20 mL). The reaction mixture was diluted with ethyl acetate. EtOAc (EtOAc m. 0.044 g (Compound 23), yield 70.5%.

1H NMR (400MHz, CD ₃ OD) δ 7.16 (d, J=8.4Hz, 2H), 6.91 (d, J=8.4Hz, 2H), 6.78 (s, 1H), 6.33 (s, 1H), 3.79 ( s, 3H), 2.36 (q, J=7.3Hz, 2H), 2.08 (s, 3H), 0.94 (t, J=7.3Hz, 3H).

LC-MS: m / z 369.0 [M + H] +;

 Example 24: 3-(5-Isopropyl-2-cyclohydroxyphenyl)-4-(4-methoxyphenyl)-5-acetylaminoisoxazole

化合物 24

Compound 24

 24K Compound 24 Reaction Steps:

 a) Benzyl bromide (483 mL, 4 mol) was added dropwise to a suspension of 2,4-dihydroxyacetophenone (280 g, 1.84 mol) and potassium carbonate (560 g, 4 mol) in acetonitrile (1400 mL). Room temperature. After evaporating most of the solvent, 2 L of water was added, and the mixture was stirred at room temperature to precipitate a large amount of white solid. After suction filtration and washing with water, the mixture was washed with petroleum ether and dried to give 2,4-dibenzyloxyacetophenone 590 g, yield 96.5%.

 MP=78-80°C

1H NMR (300 MHz, CDC1 ₃ ) δ 7.85 (d, J = 9.3 Hz, 1H), 7.44-7.35 (m, 10H), 6.63-6.60 (m, 2H), 5.1 1 (s, 2H), 5.08 ( s, 2H), 2.55 (s, 3H)

 MS (EI): m/z 332;

 b) Under nitrogen protection, methyltriphenylphosphonium bromide (826 g, 2.31 mol) was suspended in anhydrous THF, cooled to -5 °C, and dropwisely added dropwise a solution of 2.5 M butyllithium in n-hexane (924 mL, 2.31) Mol). After stirring for 0.5 hour, a solution of 2,4-dibenzyloxyacetophenone (590 g, 1.78 mol) in THF was added dropwise, and the mixture was stirred for 0.5 hr. Quenched with the appropriate amount of methanol, evaporated and evaporated. It was evaporated to dryness, then purified tolululululululululululululululu

MP=44-45 °C 1H NMR (300MHz, CDC1 ₃ ) δ 7.44-7.29 (m, 10H), 7.14 (d, J=8.3Hz, 1H), 6.59 (d, J=2.5Hz, 1H), 6.54 (m, 1H), 5.07 (s, 2H), 5.05 (s, 2H), 5.03 (s, 2H), 2.12 (s, 3H)

 MS (EI): m/z 330;

 c) Compound 24C (466 g, 1.4 mol) was dissolved in a mixed solvent of dichloromethane and ethanol (1:50), and 10% palladium carbon (100 g) was added thereto, and the mixture was reacted at 60 ° C under a hydrogen pressure of 20 atm for 8 hours. After removing the catalyst by suction filtration, the mixture was evaporated to dryness.

 MP=85-86°C

1H NMR (300 MHz, CDCl ₃ ) δ 7.03 (d, J = 8.3 Hz, 1H), 6.38 (d, J = 8.3 Hz 1H), 6.29 (d, J = 2.5 Hz, 1H), 4.74 (brs, 1H) ), 4.63 (brs, 1H), 3.09 (m, lH), 1.22 (d, 6H)

 MS (EI): m/z 152;

 d) Under nitrogen, acetic acid (9 mL, 157 mmol) was added dropwise to a suspension of 4-isopropyl resorcinol (12 g, 79 mmol) in boron trifluoride etherate (60 mL), and the reaction mixture was reacted at 90 ° C. After 16 hours, it was cooled to room temperature, and a large amount of yellow insoluble matter was precipitated. The reaction mixture was poured into 500 mL of a 10% (w/v) aqueous sodium acetate solution, and after vigorously stirring for 2.5 hours, a large amount of a yellow solid was precipitated. After suction filtration and washing with water, the mixture was dried overnight to give 5-isopropyl- 2,4-dihydroxyacetophenone, 13.57 g, yield 88%.

 MP=130-132°C

1H NMR (400 MHz, CDC1 ₃ ) δ 12.56 (s, 1Η), 7.50 (s, 1H), 6.30 (s, 1H), 5.64 (s, 1H), 3.13 (m, 1H), 2.57 (s, 3H ), 1.25 (d, J=6.8Hz, 6H).

 MS (EI): m/z 194;

 e) Benzyl bromide (18.3 mL, 154 mmoL) was suspended dropwise with 5-isopropyl-2,4-dihydroxyacetophenone (13.57 g, 70 mmol) and potassium carbonate (21.27 g, 154 mmol) in acetonitrile (200 mL). In a solution, it was refluxed overnight and then cooled to room temperature. After evaporating most of the solvent, 0.3 L of water was added, and the mixture was stirred at room temperature to precipitate a large amount of white solid. After suction filtration and washing with water, the mixture was washed with petroleum ether and dried to yield white solid 23. lg, yield 88%.

 MP=134-136°C

1H NMR (300MHz, CDC1 ₃ ) δ 7.76 (s, 1Η), 7.44-7.31 (m, 10H), 6.51 (s, 1H), 5.10 (s, 2H),

5.08 (s, 2H), 3.28 (m, 1H), 2.56 (s, 3H), 1.22 (d, J= 6.9Hz, 6H).

 MS (EI): m/z 374;

f) 5-isopropyl-2,4-dibenzyloxyacetophenone (1.94 g, 5.2 mmol) suspended in sodium hydroxide (2.08 g, 52 mmol) in water (30 mL) and 1,4-dioxane Bromine (0.8 mL, 15.6 mmol) was added dropwise to a mixture (30 mL). After distilling off most of the 1,4-dioxane, the pH was adjusted to 2 with 2M hydrochloric acid to precipitate a large amount of pale yellow insoluble material. After suction filtration and washing with water, it was dried overnight to give a white solid (1.7 g, yield: 87.2%). MP=128-130°C

1H NMR (400 MHz, DMSO- ₆ ) δ 12.2 (brs, 1H), 7.60 (s, 1H), 7.54-7.29 (m, 10H), 6.90 (s, 1H), 5.21 (s, 4H), 3.18 ( m, 1H), 1.15 (d, J= 7.3Hz, 6H).

 MS (EI): m/z 376;

 g) Methyl iodide (8.2 mL, 130 mol). Add a solution of 5-isopropyl-2,4-dihydroxybenzoic acid (40.7 g, 108 mmol) and potassium carbonate (18 g, 130 mmol) in acetonitrile (200 mL). After an hour, cool to room temperature. After distilling off most of the solvent, 300 mL of water was added, and the mixture was stirred at room temperature to precipitate a large white solid. After suction filtration and washing with water, the mixture was washed with petroleum ether and dried to give a white solid (36.5 g).

 MP=75-77°C

1H NMR (300MHz, CDC1 ₃ ) δ 7.76 (s, 1H), 7.50-7.29 (m, 10H), 6.52 (s, 1H), 5.12 (s, 2H),

5.05 (s, 2H), 3.88 (s, 3H), 3.29 (m, 1H), 1.22 (d, J= 6.9Hz, 6H).

 MS (EI): m/z 390;

h) 4-methoxyphenylacetonitrile (0.52 mL, 10.2 mmol) was added dropwise to a solution of LHMDS (15 mL, 15 mmol) in 40 mL of tetrahydrofuran at -78 °C, stirred for 30 min, then drip A solution of methyl 5-isopropyl-2,4-dibenzyloxybenzoate (lg, 2.56 mm ₀ l) in 20 mL of THF. After 30 minutes of low temperature reaction, it was allowed to warm to room temperature and stirred for 2 hours. After quenching the reaction by the addition of 2M hydrochloric acid (20 mL), the mixture was evaporated and evaporated. The mixture was washed with saturated sodium chloride and dried over anhydrous sodium sulfate.

1H NMR (400MHz, CDC1 ₃ ) δ 7.76 (s, 1H), 7.46-7.33 (m, 10H), 7.10 (d, J=8.7Hz, 2H), 6.80 (d, J=8.7Hz, 2H), 6.48 (s, 1H), 5.84 (s, 1H), 5.20-5.04 (m, 4H), 3.76 (s, 3H), 3.24 (m, 1H),

1.20 (t, J = 6.5Hz, 6H).

 MS (EI): m/z 505;

 i) Compound 241 (1.14 g, 2.25 mmol) and hydroxylamine hydrochloride (0.47 g, 6.76 mmol) were dissolved in 10 mL of pyridine and reacted at 100 ° C overnight. After the reaction mixture was diluted with dichloromethane, washed with saturated aqueous citric acid/water (1:1) (30 mL×2), washed with water (30 mL×1), saturated sodium hydrogen carbonate (30 mL×2), and washed with saturated brine (50 mL) The aqueous solution was dried over sodium sulfate, filtered, and evaporated.

1H NMR (300MHz, CDC1 ₃ ) δ 7.40-7.30 (m, 5H), 7.27 (s, 1H), 7.23-7.21 (m, 3H), 6.97 (d, J=8.1Hz, 2H), 6.96-6.92 ( m, 2H), 6.78 (d, J=8.1Hz, 2H), 6.38 (s, 1H), 4.94 (s, 2H), 4.68 (s, 2H) 4.49 (s, 2H), 3.78 (s, 3H) , 3.29 (m, 1H), 1.18 (d, 6H)

LC-MS: m/z 521.0 [M+H] ⁺

j) Compound 24J (0.2 g, 0.4 mmol) and triethylamine (1.13 mL, 8 mmol) dissolved in 20 mL anhydrous dichloromethane After adding a catalytic amount of DMAP, acetyl chloride (0.15 mg, 2 mmol) was added dropwise thereto, and the mixture was stirred at room temperature for 2 hours. After the reaction mixture was diluted with dichloromethane, washed with saturated aqueous citric acid/water (1:1) (30 mL×2), washed with water (30 mL×1), saturated sodium hydrogen carbonate (30 mL×2), and brine (50 mL) Drying with sodium sulfate, filtering, concentrating, and chromatography on silica gel chromatography to give 3-(5-isopropyl-2,4-dibenzyloxyphenyl)-4-(4-methoxybenzene -5-(N,N-Diacetylamino)isoxazole 24K 0.192 g, yield 82.6%.

 MP=132-133 °C

1H NMR (300MHz, CDC1 ₃ ) δ 7.40-7.36 (m, 5Η), 7.31 (s, 1Η), 7.25-7.22 (m, 3H), 7.00-6.96 (m, 2H), 6.87 (d, J=8.7 Hz, 2H), 6.72 (d, J=8.7Hz, 2H), 6.45 (s, 1H), 5.01 (s, 2H), 4.68 (s, 2H), 3.76 (s, 3H), 3.32 (m, 1H) ), 2.27 (s, 6H), 1.21 (d, J=6.8Hz, 6H).

 MS (EI): m/z 604;

 k) 3-(5-isopropyl-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-(N,N-diacetylamino) under nitrogen protection Isoxazole 24K (0.1 g, 0.16 mmol) was dissolved in methylene chloride (20 mL). The reaction mixture was diluted with ethyl acetate. EtOAc (EtOAc m. Compound 24), yield 68.1%.

 MP= 177-179 °C

1H NMR (400MHz, CD ₃ OD) δ 7.17 (d, J=8.2Hz, 2H), 6.94 (d, J=7.8Hz, 2H), 6.81 (s, 1H), 6.33 (s, 1H), 3.79 ( s, 3H), 3.03 (m, 1H), 2.07 (s, 3H), 0.90 (d, J=8.9Hz, 6H).

LC-MS: m/z 383.0 [m+H] ⁺

 Example 25: 3-(5-tert-Butyl-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-5-acetylaminoisoxazole

化合物 25

Compound 25

Using synthetic route 2

 25H Compound 25

 Reaction steps:

 a) Sulfuric acid (4 mL, 75 mmol) was added dropwise to a suspension of 2,4-dihydroxyacetophenone (22.8 g, 150 mmol) in tert-butanol (35 g, 470 mmol) and trifluoroacetic acid (80 mL). The reaction solution was reacted at 75 ° C for 3 hours and then cooled to room temperature. The reaction mixture was poured into 350 mL of ice water to precipitate a large amount of pink solid. After suction filtration and water washing, the mixture was dried overnight to give 2-bromobutyl-2,4-dihydroxyacetophenone 28.8 g (yield: 92%).

 MP= 182-183 °C

1H NMR (400 MHz, CDC1 ₃ ) δ 12.68 (brs, 1H), 12.52 (brs, 1H), 7.59 (s, 1H), 6.27 (s, lH), 2.580, 3H), 1.390, 9H).

 MS (EI): m/z 208;

 b) Benzyl bromide (22 mL, 185 mmol) was added dropwise to a suspension of 5-tert-butyl-2,4-dihydroxyacetophenone (17.5 g, 84 mmol) and potassium carbonate (25.5 g, 185 mmol) in acetonitrile (200 mL) The mixture was refluxed overnight and then cooled to room temperature. After evaporating most of the solvent, 0.3 L of water was added, and the mixture was stirred at room temperature to precipitate a large amount of an orange solid. After suction filtration and washing with water, the mixture was washed with petroleum ether and dried to give 2-br.

 MP=114-116°C

1H NMR (300 MHz, CDC1 ₃ ) δ 7.85 (s, 1H), 7.42-7.33 (m, 10H), 6.53 (s, 1H), 5.11 (s, 2H), 5.08 (s, 2H), 2.57 (s , 3H), 1.38 (s, 9H).

 MS (EI): m/z 388;

c) 5-tert-Butyl-2,4-dibenzyloxyacetophenone (2.02 g, 5.2 mmol) suspended in sodium hydroxide (2.08 g, 52 mmol) in water (30 mL) Bromine (0.8 mL, 15.6 mmol) was added dropwise to a mixture of hexanes (30 mL). After distilling off most of the 1,4-dioxane, adjust the pH to 2 with 2M hydrochloric acid to precipitate a large amount of light yellow insoluble. Things. After suction filtration and washing with water, the mixture was dried overnight to yield white solid (yield:

1H NMR (400 MHz, DMSO- ₆ ) δ 12.18 (IH, s s), 7.69 (IH, s), 7.52 (4H, t), 7.45-7.33 (6H, m), 6.93 (IH, s), 5.24 (2H, s), 5.23 (2H, s), 1.32 (9H, s).

LC-MS: m/z 391 [M+H] ⁺

 d) methyl iodide (2.7 mL, 43 mol) was added to a suspension of 5-tert-butyl-2,4-dihydroxybenzoic acid (13.93 g, 35.7 mmol) and potassium carbonate (5.9 g, 43 mmol) in acetonitrile (200 mL). After refluxing for 1 hour, it was cooled to room temperature. After distilling off most of the solvent, 300 mL of water was added and stirred at room temperature until a large amount of white solids precipitated. After suction filtration and washing with water, the mixture was washed with petroleum ether and dried to yield 11.

 MP=97-99°C

1H NMR (300 MHz, CDC1 ₃ ) δ 7.86 (s, IH), 7.50-7.30 (m, 10H), 6.54 (s, IH), 5.1 1 (s, 2H),

5.08 (s, 2H), 3.88 (s, 3H), 1.38 (s, 9H).

 MS (EI): m/z 404;

 e) 4-methoxyphenylacetonitrile (1 mL, 6.8 mmol) was added dropwise to a solution of LHMDS (30 mL, 30 mmol) in 40 mL of tetrahydrofuran at -78 °C, stirring for 30 min, then drip dropwise A solution of methyl 5-tert-butyl-2,4-dibenzyloxybenzoate (2 g, 4.95 mmol) in 20 mL of THF. After 30 minutes of low temperature reaction, it was allowed to warm to room temperature and stirred for another 2 hours. After quenching the reaction by the addition of 2M hydrochloric acid (20 mL), the mixture was evaporated and evaporated. After washing with saturated sodium chloride and dried over anhydrous sodium sulfate, evaporated.

1H NMR (400MHz, CDC1 ₃ ) δ 7.85 (s, IH), 7.45-7.34 (m, 10H), 7.1 1 (d, J=8.7Hz, 2H), 6.80 (d, J=8.7Hz, 2H), 6.49 (s, IH), 5.83 (s, IH), 5.20-5.07 (m, 4H), 3.77 (s, 3H), 1.34 (s, 9H).

 MS (EI): m/z 519;

 f) Compound 25F (2.26 g, 4.36 mmol) and hydroxylamine hydrochloride (0.9 g, 13.07 mmol) were dissolved in 30 mL of pyridine and reacted at 100 ° C overnight. After the reaction mixture was diluted with dichloromethane, washed with saturated aqueous citric acid/water (1:1) (30 mL×2), washed with water (30 mL×1), saturated sodium hydrogen carbonate (30 mL×2), and washed with saturated brine (50 mL) The aqueous solution was dried over sodium sulfate, filtered, and evaporated.

 MP=59-61 °C

1H NMR (300MHz, CDC1 ₃ ) δ 7.39-7.36 (m, 5Η), 7.32 (s, IH), 7.24-7.21 (m, 3H), 6.99 (d, J=8.6Hz, 2H), 6.96-6.92 ( m, 2H), 6.79 (d, J=8.6Hz, 2H), 6.40 (s, 1H), 4.96 (s, 2H), 4.68 (s, 2H) 4.49 (s, 2H), 3.79 (s, 3H) , 1.33 (d, 9H).

LC-MS: m/z 535.0 [M+H] ⁺

g) Compound 25G (0.2g, 0.4mmol) and triethylamine (1.13mL, 8mmol) dissolved in 20mL anhydrous dichloromethane After adding a catalytic amount of DMAP, acetyl chloride (0.15 mg, 2 mmol) was added dropwise thereto, and the mixture was stirred at room temperature for 2 hours. After the reaction mixture was diluted with dichloromethane, washed with saturated aqueous citric acid/water (1:1) (30 mL×2), washed with water (30 mL×1), saturated sodium hydrogen carbonate (30 mL×2), and brine (50 mL) Drying with sodium sulfate, filtering, concentrating, and chromatography on silica gel chromatography to give 3-(5-tert-butyl-2,4-dibenzyloxyphenyl)-4-(4-methoxybenzene -5-(N,N-Diacetylamino)isoxazole 23H 0.186 g, yield 80.4%.

 MP=62-64°C

 MS (EI): m/z 618;

 h) Under a nitrogen atmosphere, compound 25H (0.1 g, 0.16 mmol) was dissolved in methylene chloride (20 mL). The reaction mixture was diluted with ethyl acetate. EtOAc (EtOAc m. 0.056 g (Compound 25), yield 87.4%.

1H NMR (400MHz, CD ₃ OD) δ 7.17 (d, J=8.4Hz, 2H), 6.95 (d, J=8.4Hz, 2H), 6.90 (s, 1H), 6.33 (s, 1H), 3.80 ( s, 3H), 2.07 (s, 3H), 1.09 (s, 9H).

LC-MS: m/z 397.0 [M+H] ⁺

 Example 26: 3-[5-虔-l)-2,4-dihydroxyphenyl]-4-(4-methoxyphenyl)-5-cyclopropanoylaminoisoxazole

采用合成路线 3

Using synthetic route 3

反应步骤：

Reaction steps:

 a) Compound 16f (0.2g, 0.4mmol) and triethylamine (1.13mL, 8mmol) were dissolved in 20mL of anhydrous dichloromethane. After adding a catalytic amount of DMAP, drop propylformyl chloride (0.15mg, 2mmol) ), stirred at room temperature for 2 hours. After the reaction mixture was diluted with dichloromethane, washed with saturated aqueous citric acid/water (1:1) (30 mL×2), washed with water (30 mL×1), saturated sodium hydrogen carbonate (30 mL×2), and brine (50 mL) Drying with sodium sulfate, filtration, concentrating, EtOAc (EtOAc) -5-(N,N-Dicyclopropionylamino)isoxazole 26A 0.224 g, yield 90%.

 MP=115-117°C

1H NMR (400 MHz, CDC1 ₃ ) δ 7.71 (s, 1Η), 7.41-7.33 (m, 5Η), 7.27-7.19 (m, 3Η), 7.00-6.86 (m, 4H), 6.76-6.70 (m, 2H), 6.44 (s, 1H), 5.07 (s, 2H), 4.62 (s, 2H), 3.77 (s, 3H),

2.15-1.93 (m, 2H), 1.07-0.98 (m, 4H), 0.87-0.77 (m, 4H).

 MS (EI): m/z 692,694;

b) 3-(5-Bromo-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-(N,N-bicyclopropanoylamino) under nitrogen protection Isoxazole 26A (0.3 g, 0.47 mmol) Naphthalene boronic acid (0.112 g, 0.65 mmol) Potassium carbonate (0.193 g, 1.4 mmol) 卩Pd(PPh ₃ ) ₄ (O.Olg, 0.001 mmol) suspended in 2 mL In a mixed solvent of ethylene glycol dimethyl ether and 0.5 mL of water, the mixture was heated to 140 ° C for 1 hour by microwave. The reaction mixture was diluted with methylene chloride, washed with brine (50 mL), dried over anhydrous sodium sulfate Oxyphenyl)-4-(4-methoxyphenyl)-5-cyclopropanoylaminoisoxazole 26B 0.245 g, Yield 84.3%.

 MP=67-69°C

_{1H NMR (400 MHz, CDC1 3} ) δ 7.90-7.82 (m, 2H), 7.63 (d, J = 8.2Hz, 1H), 7.52-7.44 (m,

2H), 7.42-7.35 (m, 4H), 7.29-7.26 (m, 3H), 7.18-7.14 (m, 3H), 7.06 (d, J=8.6Hz, 2H), 7.01-6.97 (m, 2H) , 6.94-6.90 (m, 2H), 6.82 (d, J=8.6Hz, 2H), 6.55 (s, 1H), 4.86 (s, 2H), 4.76 (s, 2H), 3.82 (s, 3H), 1.73-1.64 (m, 1H), 1.08-1.03 (m, 2H), 0.84-0.78 (m, 2H).

 MS (EI): m/z 672;

 c) Under the protection of nitrogen, compound 26B (O. lg, 0.15 mmol) was dissolved in anhydrous dichloromethane (20 mL),

IN boron trichloride in dichloromethane (0.5 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate. EtOAc (EtOAc m. 0.035 g (Compound 26), yield 47.8%.

1H NMR (400 MHz, CD ₃ OD) δ 7.81 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.41-7.36 (m, 1H), 7.33-7.28 (m, 1H), 7.20-7.11 (m, 4H), 6.88 (s, 1H), 6.83 (d,

J=8.4Hz, 2H), 6.56 (s, 1H), 3.69 (s, 3H), 1.74 (brs, 1H), 0.92-0.83 (m, 4H). LC-MS: m/z 493.1 [M+Hf;

 Example 27: 3-[5-(Quinolin-5)-2,4-dihydroxyphenyl]-4-(4-methoxyphenyl)-5-cyclopropanoylaminoisoxazole

 According to the method of Example 26, 26A was reacted with quinoline-5-boronic acid to give 3-[5-(quinolin-5-)-2,4-dibenzyloxyphenyl)-4-(4-methyl as a white solid. Oxyphenyl)-5-cyclopropionylaminoisoxazole 0.257 g, yield 88.4%.

 3-[5-(quinolin-5-)-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-cyclopropionylaminoisoxazole debenzylated The target compound was protected as 0.042 g of compound 27), yield 57.3%.

 MP=247-249°C

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.64 (brs, 1 Η), 9.76 (d, J = 5.3 Hz, 2H), 8.88-8.86 (m, 1H), 7.96 (d, J = 8.5 Hz, 1H ), 7.90 (d, J=8.5Hz, 1H), 7.76-7.70 (m, 1H), 7.45-7.38 (m, 2H), 7.14 (d, J=8.7Hz, 2H), 6.95-6.90 (m, 3H), 6.60 (s, 1H), 3.74 (s, 3H), 1.77 (brs, 1H), 0.87-0.76 (m, 4H).

LC-MS: m/z 494.2 [M+H] ⁺

 Example 28: 3-[5-(8-Methylquinolin-5)-2,4-dihydroxyphenyl]-4-(4-methoxyphenyl)-5-cyclopropanoylamino Oxazole

按照实施例 26的方法， 26A与 8-甲基喹啉 -5-硼酸反应得白色固体 3-[5-(8-甲基喹啉 -5-)-2，4-二苄氧基苯基 )-4-(；4-甲氧基苯基) -5-环丙甲酰氨基异噁唑 0.238g， 产率 81.9%。

According to the method of Example 26, 26A was reacted with 8-methylquinolin-5-boronic acid to give 3-[5-(8-methylquinolin-5-)-2,4-dibenzyloxyphenyl as a white solid. -4-(; 4-methoxyphenyl)-5-cyclopropionamidoisoxazole 0.238 g, yield 81.9%.

 3-[5-(8-methylquinolin-5-)-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-cyclopropanoylamino isomer The azole debenzyl group protected the target compound 0.039 g (Compound 28) in a yield of 52.8%.

 MP=234-236°C

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.64 (brs, 1H), 9.70 (d, J = 5.8 Hz, 2H), 8.90-8.88 (m, 1H), 7.88 (dd, J = 0.8, 8.9 Hz , 1H), 7.59 (d, J=7.3Hz, 1H), 7.45-7.31 (m, 1H), 7.27 (d, J=7.4Hz, 1H), 7.14 (d, J=8.6Hz, 2H), 6.95-6.90 (m, 3H), 6.58 (s, 1H), 3.74 (s, 3H), 2.73 (s, 3H), 1.77 (brs, 1H) ), 0.87-0.74 (m, 4H).

LC-MS: m/z 508.2 [M+H] ⁺

 Example 29: 3-[5-(Isoquinoline-4)-2,4-dihydroxyphenyl]-4-(4-methoxyphenyl)-5-cyclopropanoylaminoisoxazole

按照实施例 26的方法， 26A与异喹啉 -4-硼酸反应得白色固体 3-[5- (异喹啉 -4-)-2，4-二 苄氧基苯基) -4-(4-甲氧基苯基) -5-环丙甲酰氨基异噁唑 0.241g， 产率 82.9%。

According to the method of Example 26, 26A was reacted with isoquinoline-4-boronic acid to give 3-[5-(isoquinolin-4-)-2,4-dibenzyloxyphenyl)-4-(4) as a white solid. -Methoxyphenyl)-5-cyclopropionamidoisoxazole 0.241 g, yield 82.9%.

 3-[5-(isoquinolin-4-)-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-cyclopropionylaminoisoxazole debenzylated The target compound was obtained (0.032 g, Compound 29), yield 43.3%.

 MP=157-159°C

1H NMR (400 MHz, DMSO- d 6) δ 10.64 (brs, 1Η), 9.82 (s, 1H), 9.79 (s, 1H), 9.25 (s, 1H), 8.28 (s, 1H), 8.15-8.12 (m, 1H), 7.72-7,63 (m, 2H), 7.56-7,52 (m, 1H), 7.15 (d, J=8.8Hz, 2H), 6.97-6.91 (m, 3H), 6.62 (s, 1H), 3.74 (s, 3H), 1.78 (brs, 1H), 0.86-0.76 (m, 4H).

LC-MS: m/z 494.2 [M+H] ⁺

 Example 30: 3-[5-(Quinolin-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-5-cyclopropanoylaminoisoxazole

 According to the method of Example 26, 26A was reacted with quinoline-3-boronic acid to give 3-[5-(quinolin-3-)-2,4-dibenzyloxyphenyl)-4-(4-methyl as a white solid. Oxyphenyl) 5-cyclopropionamidoisoxazole 0.255 g, yield 87.7%.

 3-[5-(quinolin-3-)-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-cyclopropionylaminoisoxazole debenzylated The target compound was protected to be 0.036 g (Compound 30) in a yield of 48.7%.

 MP=215-217°C

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.66 (brs, 1H), 10.16 (s, 1H), 9.82 (s, 1H), 9.07 (d, J = 2.1 Hz, 1H), 8.33 (d, J = 1.8Hz, 1H), 8.01-7.94 (m, 2H), 7.74-7,69 (m, 1H), 7.61-7.56 (m, 1H), 7.31 (s, 1H), 7.17 (d, J = 8.3Hz, 2H), 6.93 (d, J = 8.3Hz, 2H), 6.60 (s, 1H), 3.74 (s, 3H), 1.78 (brs, 1H) ), 0.86-0.76 (m, 4H).

LC-MS: m/z 494.2 [M+H] ⁺

 Example 31: 3-[5-(Quinolin-8)-2,4-dihydroxyphenyl]-4-(4-methoxyphenyl)-5-cyclopropanoylaminoisoxazole

按照实施例 26的方法， 26A与喹啉 -8-硼酸反应得白色固体 3-[5- (喹啉 -8-)-2，4-二苄氧 基苯基 )-4-(4-甲氧基苯基) -5-环丙甲酰氨基异噁唑 0.237g， 产率 81.5%。

According to the method of Example 26, 26A was reacted with quinoline-8-boronic acid to give 3-[5-(quinolin-8-)-2,4-dibenzyloxyphenyl)-4-(4-methyl as a white solid. Oxyphenyl)-5-cyclopropionamidoisoxazole 0.237 g, yield 81.5%.

 3-[5-(Quinolin-8-)-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-cyclopropionylaminoisoxazole debenzylated The target compound was protected as 0.035 g of compound 31), yield 47.4%.

 MP=231-233 °C

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.62 (brs, 1H), 9.96 (s, 1H), 9.61 (s, 1H), 8.88-8.86 (m, 1H), 8.43-8.40 (m, 1H) , 7.96-7.93 (m, 1H), 7.65-7.52 (m, 3H), 7.19 (d, J = 9.2Hz, 2H), 7.09 (s, 1H), 6.91 (d, J = 9.2Hz, 2H), 6.51 (s, 1H), 3.73 (s, 3H), 1.77 (brs, 1H), 0.86-0.76 (m, 4H).

LC-MS: m/z 494.2 [M+H] ⁺

 Example 32: 3-[5-(8-Dimethylaminoethoxyquinolin-5)-2,4-dihydroxyphenyl]-4-(4-methoxyphenyl)-5-cyclopropane Formylaminoisoxazole

采用合成路线 3

Using synthetic route 3

 Compound 32 Reaction steps:

 a) 5-bromo-8-hydroxyquinoline (0.448 g, 2 mmol), chloroethyl dimethylamine hydrochloride (0.432 g, 3 mmol) and potassium carbonate (0.828 g, 6 mmol) dissolved in 20 mL acetonitrile and heated to reflux 2 hours. After distilling off most of the acetonitrile, it was diluted with water, extracted with methylene chloride, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated and evaporated to silica.

_{1H NMR (300 MHz, CDC1 3} ) δ 8.90-8.87 (m, 1H), 8.46-8.41 (m, 1H), 7.67 (d, J = 8.4Hz, 1H), 7.51-7.45 (m, 1H), 6.94 (d, J = 8.4 Hz, 1H), 4.38 (t, J = 6.0 Hz, 2H), 3.10 (t, J = 6.0 Hz, 2H).

LC-MS: m/z 295.0, 297.0 [M+H] ⁺

b) 5-bromo-8-dimethylamine ethoxyquinoline 32B (0.295 g, 1 mmol), bis-nonanol borate (0.508 g, 2 mmol), potassium acetate (0.294 g, 3 mmol). ) and _{Pd (dppf) Cl 2 (0.03g} , O.lmmol) was suspended in 4mLl, a mixed solvent of dioxane and 4- lmL DMF and heated to 100 ° C overnight. The reaction mixture was diluted with methylene chloride. EtOAc (EtOAc)EtOAc.

_{1H NMR (300 MHz, CDC1 3} ) δ 9.13-9.08 (m, 1H), 8.88-8.84 (m, 1H), 8.06 (d, J = 8.4Hz, 1H), 7.48-7.42 (m, 1H), 7.02 (d, J=8.4Hz, 1H), 4.32 (t, J=6.0Hz, 2H), 3.03 (t, J=6.0Hz, 2H), 1.38 (s, 12H).

LC-MS: m/z 343.1 [M+H] ⁺

c) 3-(5-Bromo-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-(N,N-bicyclopropanoylamino) under nitrogen protection Isoxazole 26A (0.3 g, 0.43 mmol) 32C (0.222 g, 0.65 mmol), potassium carbonate (0.193 g, 1.4 mmol) and Pd(PPh ₃ ) ₄ (0.0 lg, O.OOlmmol) was suspended in a mixed solvent of 2 mL of ethylene glycol dimethyl ether and 0.5 mL of water, and heated under microwave heating to 140 ° C for 1 hour. The reaction mixture was diluted with methylene chloride and washed with brine (50 mL), dried over anhydrous sodium sulfate, dried, filtered, and concentrated, and purified by silica gel chromatography to obtain brown amorphous solid 32D 0.117 g, yield 35.6% .

LC-MS: m/z 761.0 [M+H] ⁺

 d) Under a nitrogen atmosphere, compound 32D (0.1 g, 0.13 mmol) was dissolved in anhydrous dichloromethane (20 mL). After the reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate (30 mL×2), brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. g (Compound 32), yield 15.7%.

 MP= 177-179 °C

1H NMR (300 MHz, CD ₃ OD) δ 8.84 (s, 1H), 8.00 (m, 1H), 7.52-7.47 (m, 1H), 7.32-7.22 (m, 2H), 7.16 (d, J=8.7 Hz, 2H), 6.89-6.84 (m, 3H), 6.56 (s, 1H), 4.56-4.51 (m, 2H), 3.74 (s, 3H), 3.73-3.66 (m, 2H), 3.05 (s, 6H), 1.80-1.72 (m, 1H), 0.95-0.84 (m, 4H).

LC-MS: m/z 58 <RTI ID=0.0></RTI>^</RTI>^</RTI>^<RTIgt; (4-methoxyphenyl)-5-cyclopropionylaminoisoxazole

采用合成路线 3

Using synthetic route 3

反应步骤：

Reaction steps:

 a) 5-bromo-8-hydroxyquinoline (0.448 g, 2 mmol), chloroethylmorpholine hydrochloride (0.558 g, 3 mmol) and potassium carbonate (0.828 g, 6 mmol) dissolved in 20 mL acetonitrile and heated to reflux 2 hour. After distilling off most of the acetonitrile, it was diluted with water, extracted with methylene chloride, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated and evaporated to silica.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.97-8.93 (m, 1H), 8.52-8.46 (m, 1H), 8.05 (d, J=7.9Hz, 1H), 7.48-7.43 (m, 1H), 7.02 (d, J=7.9Hz, 1H), 4.33 (t, J=5.6Hz, 2H), 3.77 (t, J=4.4Hz, 4H), 3.00 (t, J=5.6Hz, 2H), 2.66-2.59 (m, 4H), 1.38 (s, 12H).

LC-MS: m/z 337.2 [M+H] ⁺

b) 5-bromo-8-morpholine ethoxyquinoline 33B (0.337 g, 1 mmol), bis-nonanol borate (0.508 g, 2 mmol), potassium acetate (0.294 g, 3 mmol) And Pd(dppf)Cl ₂ (0.03 g, 0.1 mmol) was suspended in 4 mL of a mixed solvent of 1, 4-dioxane and 1 mL of DMF, and heated to 100 ° C for overnight reaction. The reaction mixture was diluted with methylene chloride. EtOAc (EtOAc)EtOAc.

 MP=111-113 °C

1H NMR (300 MHz, CDC1 ₃ ) ^ 9.13-9.09 (m, 1H), 8.88-8.85 (m, 1H), 7.74-7.69 (m, 1H), 7.57-7.51 (m, 1H), 6.99-6.94 ( m, 1H), 4.40-4.30 (m, 2H), 3.79-3.64 (m, 4H), 3.05-2.98 (m, 2H), 2.67-2.58 (m, 4H).

LC-MS: m/z 385.2 [M+H] ⁺ c) 3-(5-Bromo-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-(N,N-bicyclopropanoylamino) under nitrogen protection Isoxazole 26A (0.3g, 0.43mmol) 33C (0.25g, 0.65mmol), potassium carbonate (0.193g, 1.4mmol) and Pd(PPh ₃ ) ₄ (0.0 lg, O.OOlmmol) suspended in 2mL of ethylene The mixture was heated in a microwave to 140 ° C for 1 hour in a mixed solvent of glyceryl ether and 0.5 mL of water. The reaction mixture was diluted with methylene chloride. EtOAc (EtOAc)EtOAc.

 MP=57-59°C

LC-MS: m/z 803.5 [M+H] ⁺

 d) Under a nitrogen atmosphere, compound 33D (O. lg, 0.13 mmol) was dissolved in anhydrous dichloromethane (20 mL). The reaction mixture was diluted with ethyl acetate and washed with EtOAc EtOAc EtOAc EtOAc. g (Compound 33), Yield 20.7%.

 MP=157-159°C

1H NMR (300 MHz, CD ₃ OD) δ 8.80-8.75 (m, 1 Η), 7.97-7.91 (m, 1H), 7.46-7.39 (m, 1H), 7.26-7.13 (m, 4H), 6.90-6.83 (m, 3H), 6.54 (s, 1H), 4.46-4.38 (m, 2H), 3.83-3.71 (m, 7H), 3.24-3.17 (m, 2H), 2.91-2.83 (m, 4H), 1.80 -1.72 (m, 1H), 0.95-0.84 (m, 4H).

LC-MS: m/z 623.3 [M+H] ⁺

 34: 3-(5-isopropyl-2,4-dihydroxyphenyl)-5-aminoisoxazole

 34B Compound 34 Reaction Steps:

a) Acetonitrile (0.53 mL, 10.2 mmol) was added dropwise to a solution of LHMDS (15 mL, 15 mmol) in 40 mL of tetrahydrofuran at -78 ° C under a nitrogen atmosphere. After stirring for 30 min, add 5-isopropyl A solution of methyl 2,4-dibenzyloxybenzoate (Compound 24) (lg, 2.56 mm ₀ l) in 20 mL of THF. After 30 minutes of low temperature reaction, it was allowed to warm to room temperature and stirred for 2 hours. After quenching the reaction by the addition of 2M hydrochloric acid (20 mL), the mixture was evaporated and evaporated. After washing with saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated and evaporated to silica. 90.9%.

 MP= 142-144 °C

1H NMR (300 MHz, CDC1 ₃ ) δ 7.82 (s, 1H), 7.47-7.34 (m, 10H), 6.52 (s, 1H), 5.11 (s, 4H), 3.92 (s, 2H), 3.28 (m , lH), 1.22 (d, J=7.1Hz, 6H).

 MS (EI): m/z 399;

 b) Compound 34A (1.026 g, 2.57 mmol) and hydroxylamine hydrochloride (0.54 g, 7.77 mmol) were dissolved in 10 mL of pyridine and reacted at 100 ° C overnight. After the reaction mixture was diluted with dichloromethane, washed with saturated aqueous citric acid/water (1:1) (30 mL×2), washed with water (30 mL×1), saturated sodium bicarbonate (30 mL×2), washed with saturated brine (50 mL), anhydrous The residue was dried over sodium sulfate, filtered, and evaporated.

 MP= 147-148 °C

1H NMR (300 MHz, CDC1 ₃ ) δ 7.80 (s, 1H), 7.43-7.34 (m, 10H), 6.58 (s, 1H), 6.19 (s, 1H), 5.11 (s, 2H), 5.08 (s , 2H), 3.90 (brs, 2H), 3.34 (m,lH), 1.25 (d, J=7.1Hz, 6H)

LC-MS: m/z 415.1 [M+H] ⁺

 c) Under a nitrogen atmosphere, 34B C 0.1 g (0.24 mmol) was dissolved in anhydrous dichloromethane (20 mL). The reaction mixture was diluted with ethyl acetate. EtOAc (EtOAc m. 0.047 g (Compound 34), yield 83.2%.

1H NMR (400MHz, CD ₃ OD) δ 7.52 (s, 1H), 6.87 (s, 1H), 3.85 (s, 1H), 3.36-3.32 (m, 1H), 1.25 (d, J=6.8Hz, 6H ).

LC-MS: m/z 235.0 [M+H] ⁺

 Example 35: 3-(5-Isopropyl-2-cyclohydroxyphenyl)-5-acetylaminoisoxazole

 Using synthetic route 2

 According to the method of Example 4, 34B was reacted with acetyl chloride to obtain a white solid 3-(5-isopropyl-2,4-dibenzyloxyphenyl)-5-(N,N-diacetylamino)iso Oxazole.

 Debenzylation of 3-(5-isopropyl-2,4-dibenzyloxyphenyl)-5-(N,N-diacetylamino)isoxazole afforded the title compound 0.029 g (Comp. The yield was 52.4%.

MP=218-220 °C NMR NMR (400MHz, CD ₃ OD) δ 7.33 (s, IH), 6.71 (s, IH), 6.38 (s, IH), 3.23-3.15 (m, IH) 2.18 (s, 3H), 1.22 (d, J=7.0Hz, 6H).

LC-MS: m/z 277.1 [M+H] ⁺

 Example 36: 3-(5-Isopropyl-2,4-dihydroxyphenyl)-5-cyclopropanmethylaminoisoxazole

按照实施例 4的方法， 34B与环丙甲酰氯反应得白色固体 3-(5-异丙基 -2,4-二苄氧基 苯基） -5-(N，N-二环丙甲酰基氨基)异噁唑。

By the method of Example 4, 34B was reacted with cyclopropionyl chloride to give 3-(5-isopropyl-2,4-dibenzyloxyphenyl)-5-(N,N-bicyclopropanoyl) as a white solid. Amino)isoxazole.

 Deprotection of 3-(5-isopropyl-2,4-dibenzyloxyphenyl)-5-(N,N-bicyclopropionylamino)isoxazole to give the target compound 0.032 g of compound 36) , the yield was 58.4%.

 MP= 196-198 °C

1H NMR (400MHz, CD ₃ OD) δ Ί .1,2 (s, IH), 6.68 (s, IH), 6.38 (s, IH), 3.24-3.16 (m, 1H), 1.91-1.83 (m, IH), 1.20 (d, J=7.1Hz, 6H), 1.05-0.95 (m, 4H).

LC-MS: m/z 303.1 [M+H] ⁺

 Example 37: 3-(5-isopropyl-2,4-dihydroxyphenyl)-4-bromo-5-cyclopropanoylaminoisoxazole

 Using synthetic route 2

反应步骤: a) 化合物 34B (1.758g，4.2mmol) 溶于 50mL三氯甲烷中，加入 NBS (0.756g， 4.2mmol) 后， 室温搅拌 1小时。 反应液经二氯甲烷稀释后， 分别用饱和食盐水洗 （50mL)， 无水硫 酸钠干燥， 过滤， 浓縮， 薄层层析硅胶板分离得黄色固体 37A 1.902g， 产率 90.8%。

Reaction steps: a) Compound 34B (1.758 g, 4.2 mmol) was dissolved in 50 mL of chloromethane, and NBS (0.756 g, 4.2 mmol). The reaction mixture was diluted with methylene chloride, and washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated.

 MP=105-107°C

1H NMR (300 MHz, CDC1 ₃ ) δ 7.42-7.30 (m, 11H), 6.59 (s, 1H), 5.10 (s, 2H), 5.03 (s, 2H), 4.63 (brs, 2H), 3.34 (m ,lH), 1.23 (d, 6H)

LC-MS: m/z 493.1 [M+H] ⁺

 b) Compound 37A (0.5 g, 1 mmol) and triethylamine (2.9 mL, 20 mmol) were dissolved in 50 mL of anhydrous dichloromethane. After adding a catalytic amount of DMAP, drop of propylformyl chloride (0.523 g, 5 mmol) was added dropwise. Stir at room temperature for 2 hours. After the reaction mixture was diluted with dichloromethane, washed with saturated aqueous citric acid/water (1:1) (30 mL×2), washed with water (30 mL×1), saturated sodium hydrogen carbonate (30 mL×2), and brine (50 mL) The aqueous solution was dried over sodium sulfate, filtered, and evaporated.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.44-7.29 (m, 11H), 6.65 (s, 1H), 5.10 (s, 2H), 5.03 (s, 2H), 3.35 (m, lH), 1.70 (m , lH), 1.61 (m, lH), 1.24 (d, 6H), 1.10-1.00 (m, 4H), 0.96-0.85 (m, 4H) LC-MS: m/z 629.1 [M+H] ⁺ ;

 c) Under a nitrogen atmosphere, compound 37B (0.5 g, 0.8 mmol) was dissolved in anhydrous dichloromethane (50 mL). The reaction mixture was diluted with ethyl acetate. EtOAc (EtOAc m. (Compound 37), Yield 97.7%.

 MP=171-174°C

1H NMR (400MHz, CD ₃ OD) δ 7.39 (s, 1Η), 6.41 (s, 1Η), 3.24-3.16 (m, 1H), 1.91-1.83 (m, 1H), 1.20 (d, J=7.1Hz , 6H), 1.05-0.95 (m, 4H).

LC-MS: m/z 381.0 [M+H] ⁺

 Example 38: 3-(5-Isopropyl-2,4-dihydroxyphenyl-4-(4-methoxyphenyl)-5-cyclopropionamidoisoxazole

 Adopting reaction route 2

According to the method of Example 4, 24J was reacted with cyclopropionyl chloride to give a white solid 3-(5-isopropyl-2,4-dibenzyloxybenzene. Base 4-(4-methoxyphenyl)-5-(N,N-bicyclopropionylamino)isoxazole 0.213 g, yield 84.6%.

 3-(5-isopropyl-2,4-dibenzyloxyphenyl)-4-(4-methoxyphenyl)-5-(N,N-bicyclopropionylamino)isoxazole Debenzylation gave the target compound 0.035 g of compound 38), yield 56.3%.

 MP=179-181 °C

1H NMR (400MHz, CD ₃ OD) δ 7.16 (d, J=8.2Hz, 2H), 6.94 (d, J=7.8Hz, 2H), 6.81 (s, 1H), 6.33 (s, 1H), 3.79 ( s, 3H), 3.03 (m, 1H), 1.75 (m, 1H), 0.90 (d, 10H).

LC-MS: m/z 409.1 [M+H] ⁺

 Example 39: 3-(5-Isopropyl-2,4-dihydroxyphenyl)-4-(4-morpholinylmethylphenyl)-5-cyclopropanoylaminoisoxazole

化合物 39

Compound 39

 Adopt

反应步骤：

Reaction steps:

 a) At -5 °C, phosphorus oxychloride (155mL, 1.64mol) was added dropwise to 350mL of anhydrous DMF, stirred for 0.5 hours, then added dropwise 4-isopropyl resorcinol (100g, 0.65 mol) of 200 mL of anhydrous DMF solution. The reaction mixture was stirred at room temperature for 1 hour, then at 50 ° C for 1 hour, and after cooling, slowly poured into a 2 L aqueous solution of 315 g of sodium hydroxide. After the mixture was reacted at 70 ° C for 15 minutes, after cooling to room temperature, concentrated hydrochloric acid was acidified to pH = 2-3, and ethyl acetate was extracted. The organic layer was washed with brine, dried over anhydrous sodium sulfate.

 MP=110-112°C

1H NMR (300MHz, CDC1 ₃ ) δ 11.29 (s, 1Η), 9.70 (s, 1H), 7.34 (s, 1H), 6.60 (s, 1H), 6.36 (s _: 1H), 3.18 (m, 1H) , 1.26 (d, 6H).

 MS (EI): m/z l80;

 b) Benzyl bromide (127 mL, 1.08 mol) was added dropwise to 5-isopropyl-2,4-dihydroxybenzaldehyde (86.6 g, 0.48 mol) and potassium carbonate (202 g, 1.46 mol) in acetonitrile (1 L). In a solution, it was refluxed overnight and then cooled to room temperature. After evaporating most of the solvent, 2 L of water was added, and the mixture was stirred at room temperature until a large amount of a yellow solid precipitated. After suction filtration and washing with water, it was washed with petroleum ether and dried to give white solid 4F 143.2 g, yield 82.7%.

 MP=132-135 °C

1H NMR (300MHz, CDC1 ₃ ) δ 10.40 (s, 1Η), 7.76 (s, 1H), 7.43-7.33 (s, 10H), 6.52 (s, 1H), 6.36 (s, 1H), 5.13 (s, 2H), 5.11 (s, 2H), 3.29 (m, 1H), 1.23 (d, 6H).

 MS (EI): m/z 360;

 c) 5-isopropyl-2,4-dibenzyloxybenzaldehyde 39B (143.2 g, 0.4 mol), hydroxylamine hydrochloride (55.5 g, 0.8 mol) and sodium hydroxide (32 g, 0.8 mol) suspended in 600 mL of ethanol The mixture was mixed with 300 mL of water, and reacted at 100 ° C for 5 hours, and then cooled to room temperature. After evaporating most of the solvent, 2 L of water was added, and the mixture was stirred at room temperature for 0.5 hour. After suction filtration and washing with water, the mixture was washed with petroleum ether and dried to give white solid 4 g 140.1 g, yield 93.9%.

 MP=121-123 °C

1H NMR (300MHz, CDC1 ₃ ) δ 8.51 (s, 1Η), 7.62 (s, 1H), 7.41-7.31 (s, 10H), 6.51 (s, 1H),

5.05 (d, 4H), 3.30 (m, 1H), 1.22 (d, 6H).

 MS (EI): m/z 375;

 d) Compound 39C (140 g, 0.37 mol) was dissolved in 500 mL of dry DMF, and NCS (60 g, 0.45 mol) was added and stirred at room temperature for 5 hours. The reaction mixture was diluted with methylene chloride. EtOAc (EtOAc)EtOAc.

e) Add 160 mL of sodium hydroxide solution to methyl cyanomethylbenzoate (25 g, 0.14 mol) in 300 mL of methanol Medium, reflux for 3 hours. After evaporating most of the solvent, 500 mL of water was added, and concentrated hydrochloric acid was acidified to pH = 2-3 to precipitate a large amount of white solid. Filtered, washed with water and dried to give 4I 21.2 g, yield 92.2%.

 MP=248-250°C

1H NMR (400 MHz, DMSO- ₆ ) δ 12.89 (brs, 1 Η), 7.87 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 3.45 (s, 2H).

 MS (EI): m/z 161;

 f) CDI (23.3 g, 0.14 mol) A solution of cyanomethylbenzoic acid (21.2 g, 0.13 mol) in 600 mL of anhydrous tetrahydrofuran was added portionwise and stirred at room temperature until no more. The reaction mixture was added dropwise to a solution of sodium borohydride (15 g, 0.39 mol) in 800 mL, and stirred at room temperature for 4 hr. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness.

1H NMR (300MHz, CDC1 ₃ ) δ 7.37 (d, J = 8.5Hz, 2H), 7.30 (d, J = 8.5Hz, 2H), 4.68 (s, 2H), 3.74 (s, 2H).

 MS (EI): m/z 147;

 g) hydroxymethyl phenylacetonitrile 4K (14.36g, 98mmol), 3,4-dihydro-2H-pyran (10.05mL, l lOmmol) and p-toluenesulfonic acid monohydrate (0.345g, 1.8mmol) The reaction was carried out for 1 hour at room temperature in 400 mL of dichloromethane. The reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate (300 mL×2) and brine (300 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The yield was 89.1%.

1H NMR (300MHz, CDC1 ₃ ) δ 7.38 (d, J=8.3Hz, 2H), 7.30 (d, J=8.3Hz, 2H), 4.78 (d, J= 11.2Hz, 1H), 4.69 (t, J =3.4Hz, 1H), 4.49 (d, J=11.2Hz, 1H), 3.93-3.87 (m, 1H), 3.74 (s, 2H), 3.58-3.51 (m, 1H), 1.90-1.80 (m, 1H), 1.78-1.70 (m, 1H), 1.68-1.51 (m, 4H).

 MS (EI): m/z 231;

 h) -78 ° C, under nitrogen, tert-butyl lithium (lmL, 1.6mmmol) was added dropwise to 4L (180mg, 0.78mmol) in 300mL anhydrous tetrahydrofuran solution, stirred for 20 minutes, then drip 4H (320 mg, 0.78 mmol) in 100 mL of tetrahydrofuran. After 30 minutes of low temperature reaction, the reaction was quenched by the addition of 50 mL of water, and the mixture was evaporated and evaporated. After washing with saturated sodium chloride and dried over anhydrous sodium sulfate, EtOAc evaporated.

 MP=86-88°C

1H NMR (300MHz, CDC1 ₃ ) δ 7.40-7.19 (m, 11H), 7.03 (d, J=8.1Hz, 2H), 6.92-6.88 (m, 2H), 6.39 (s, 1H), 4.94 (s, 2H), 4.77 (d, J=11.9Hz, 1H), 4.72 (t, J=3.4Hz, 1H), 4.65 (s, 2H), 4.58 (s, 2H), 4.46 (d, J=11.9Hz, 1H), 3.97-3.89 (m, 1H), 3.60-3.53 (m, 1H), 3.30 (m, 1H),

1.92-1.81 (m, 1H), 1.79-1.71 (m, 1H), 1.69-1.51 (m, 4H), 1.18 (d, 6H). i) Compound 4M (200 mg, 0.33 mmol) and triethylamine (1.13 mL, 8 mmol) were dissolved in 100 mL of anhydrous dichloromethane. After adding a catalytic amount of DMAP, cyclopropionyl chloride (235 mg, 2 mmol) was added dropwise. Stir at room temperature for 2 hours. After the reaction mixture was diluted with dichloromethane, washed with saturated aqueous citric acid/water (1:1) (100 mL×2), washed with water (100 mL×1), washed with saturated sodium hydrogen carbonate (100 mL×2), washed with saturated brine (100 mL), The mixture was dried over sodium sulfate, filtered and evaporated.

1H NMR (300MHz, CDC1 ₃ ) δ 7.42-7.32 (m, 6H), 7.25-7.19 (m, 5H), 7.03 (d, J = 7.8 Hz, 2H),

6.98- 6.93 (m, 2H), 6.46 (s, 1H), 5.01 (s, 2H), 4.77 (d, J=12.5Hz, 1H), 4.71 (t, J=3.6Hz, 1H), 4.65 (s , 2H), 4.47 (d, J = 12.1Hz, 1H), 3.96-3.88 (m, 1H), 3.60-3.51 (m, 1H), 3.30 (m, 1H), 1.91-1.52 (m, 8H), 1.21 (d, 6H), 0.98-0.92 (m, 4H), 0.87-0.82 (m, 4H).

LC-MS: m/z 741.3 [M+H] ⁺

 j) Compound 4N (2 g, 2.7 mmol) and p-toluenesulfonic acid monohydrate (0.05 g, 0.27 mmol) were dissolved in a mixture of 100 mL of methanol and 100 mL of tetrahydrofuran, and allowed to react at room temperature for 1 hour. The reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate solution (100 mL×2) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column to obtain 40 1.325 g, yield 74.7 %.

 MP=55-57°C

1H NMR (300MHz, CDC1 ₃ ) δ 7.42-7.33 (m, 6H), 7.26-7.18 (m, 5H), 7.03 (d, J=8.1Hz, 2H),

6.99- 6.95 (m, 2H), 6.46 (s, 1H), 5.02 (s, 2H), 4.66 (s, 4H), 3.30 (m, 1H), 2.10-2.00 (m, 2H), 1.22 (d, 6H), 1.08-1.02 (m, 4H), 0.88-0.81 (m, 4H).

 MS (EI): m/z 656;

 k) Compound 40 (200 mg, 0.3 mmol) and triethylamine (1.13 mL, EtOAc) After the reaction mixture was diluted with dichloromethane, washed with saturated aqueous citric acid/water (1:1) (100 mL×2), washed with water (100 mL×1), washed with saturated sodium hydrogen carbonate (100 mL×2), and washed with saturated brine (100 mL). The mixture was dried over sodium sulfate, filtered, and evaporated.

 MP=129-131 °C

1H NMR (400 MHz, DMSO- ₆ ) δ

 1) Compound 4P (65 mg, 1 mmol) and morpholine (0.2 mL) were dissolved in 20 mL of acetonitrile and allowed to react at room temperature overnight. After evaporating most of the solvent, 50 mL of water was added, and the mixture was diluted with methylene chloride, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 39M 50 mg.

m) Under a nitrogen atmosphere, compound 39M C 50 mg (0.076 mmol) was dissolved in methylene chloride (30 mL). After the reaction solution was diluted with ethyl acetate, The mixture was washed with saturated aqueous sodium hydrogen sulfate (30 mL?), EtOAc (EtOAc)

 MP= 174-175 °C

1H NMR (400MHz, CD ₃ OD) δ 7.39 (d, J=7.8Hz, 2H), 7.25 (d, J=7.8Hz, 2H), 6.80 (s, 1H), 6.33 (s, 1H), 3.71 ( t, J=4.5Hz, 4H), 3.67 (s, 2H), 3.03 (m, 1H), 2.60 (brs, 4H), 1.74 (m, 1H), 0.89 (m, 10H).

LC-MS: m/z 478.1 [M+H] ⁺

 Example 40: 3-(5-Isopropyl-2,4-dihydroxyphenyl)-4-(4-hydroxymethylphenyl)-5-cyclopropanoylaminoisoxazole

采用合成路线 4

Using synthetic route 4

 Reaction steps:

 Under a nitrogen atmosphere, the compound 4O C (100 mg, 0.15 mmol) was dissolved in methylene chloride (30 mL). The reaction mixture was diluted with ethyl acetate. EtOAc (EtOAc m. Compound 40), yield 62.8%.

 MP=201-204°C

1H NMR (400MHz, CD ₃ OD) δ 7.36 (d, J=8.2Hz, 2H), 7.23 (d, J=8.2Hz, 2H), 6.82 (s, 1H), 6.32 (s, 1H), 4.61 ( s, 2H), 3.03 (m, 1H), 1.75 (m, 1H), 0.94-0.84 (m, 10H).

LC-MS: m/z 409.2 [M+H] ⁺

 Example 41: 3-(5-Isopropyl-2,4-dihydroxyphenyl)-4-(4-cyclopropanoyloxymethylphenyl)-5-cyclopropanoylaminoisoxazole

反应步骤: Using synthetic route 4

Reaction steps:

 a) Compound 40 (200 mg, 0.3 mmol) and triethylamine (1.13 mL, 8 mmol) were dissolved in 100 mL of anhydrous dichloromethane. After adding a catalytic amount of DMAP, cyclopropionyl chloride (235 mg, 2 mmol) was added dropwise. Stir at room temperature for 2 hours. After the reaction mixture was diluted with dichloromethane, washed with saturated aqueous citric acid/water (1:1) (100 mL×2), washed with water (100 mL×1), washed with saturated sodium hydrogen carbonate (100 mL×2), washed with saturated brine (100 mL), anhydrous The residue was dried over sodium sulfate, filtered, and evaporated.

 b) Under a nitrogen atmosphere, compound 41A (100 mg, 0.14 mmol) was dissolved in methylene chloride (30 mL). The reaction mixture was diluted with ethyl acetate. EtOAc (EtOAc m. Compound 41), Yield 64%.

 MP=193-195°C

1H NMR (400MHz, CD ₃ OD) δ 7.44-7.36 (m, 2Η), 7.25 (d, J=7.9Hz, 2H), 6.80-6.76 (m, 1H) 6.33 (s, 1H), 5.11 (s, 2H), 3.03 (m, 1H), 1.75 (m, 1H), 1.66 (m, 1H), 0.90 (m, 14H).

LC-MS: m/z 477.1 [M+H] ⁺

 Example 42: 3-(5-Isopropyl-2,4-dihydroxyphenyl)-4-(4-dimethylaminopiperidinemethylphenyl)-5-cyclopropionylaminoisoxazole

采用合成路线 4

反应步骤:

Using synthetic route 4

Reaction steps:

 a) Compound 4P (65 mg, 1 mmol) and 4-dimethylaminopiperidine (0.2 mL) were dissolved in 20 mL of acetonitrile and allowed to react overnight at room temperature. After evaporating most of the solvent, 50 mL of water was added, and the mixture was diluted with methylene chloride, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated.

 b) Under a nitrogen atmosphere, compound 42A was dissolved in anhydrous dichloromethane (30 mL), and then 1N trichloromethane in dichloromethane (mL) was added and stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate. EtOAc (EtOAc m. Compound 42), Yield 34.7%.

 MP= 172-174 °C

1H NMR (400MHz, CD ₃ OD) δ 7.36 (d, J=8.2Hz, 2H), 7.24 (d, J=8.2Hz, 2H), 6.79 (s, 1H), 6.34 (s, 1H), 3.61 ( s, 2H), 3.20-2.99 (m, 4H), 2.82 (s, 6H), 2.18 (t, J = 12.4Hz, 2H), 2.06 (d, J=10Hz, 2H), 1.80-1.68 (m, 3H), 0.95-0.83 (m, 10H).

LC-MS: m/z 519.3 [M+H] ⁺

 Example 43: 3-(5-Isopropyl-2,4-dihydroxyphenyl)-4-(4-diethylaminomethylphenyl)-5-cyclopropanoylaminoisoxazole

采用合成路线 4

Using synthetic route 4

 After reacting the compound 4P with an aqueous dimethylamine solution according to the method of Example 42 and then debenzylation, the title compound (yield: 18 mg of Compound 43) was obtained, yield 38.8%.

MP=204-206°C NMR NMR (400MHz, CD ₃ OD) δ 7.49 (d, J=7.9Hz, 2H), 7.34 (d, J=7.9Hz, 2H), 6.84 (s, 1H), 6.33 (s, 1H), 4.24 ( s, 2H), 3.15-3.03 (m, 5H), 1.76 (m, 1H), 1.30 (t, J=7.3Hz, 6H), 0.97 (d, J=6.7Hz, 6H), 0.88 (d, J =6.0Hz, 4H).

LC-MS: m/z 464.1 [M+H] ⁺

 Example 44: 3-(5-Isopropyl-2,4-dihydroxyphenyl)-4-(4-piperidinylmethylphenyl)-5-cyclopropanoylaminoisoxazole

采用合成路线 4

Using synthetic route 4

 The compound 4P was reacted with piperidine according to the method of Example 42 and then subjected to debenzylation to give the title compound 14 mg (yield 44) in a yield of 29.4%.

 MP= 187-189 °C

1H NMR (400MHz, CD ₃ OD) δ 7.47 (d, J=8.2Hz, 2H), 7.32 (d, J=8.2Hz, 2H), 6.82 (s, 1H), 6.32 (s, 1H), 4.13 ( s, 2H), 3.10-3.01 (m, 5H), 1.83-1.73 (m, 5H), 1.63 (brs, 2H), 0.95 (m, 6H), 0.87 (m, 4H).

LC-MS: m/z 476.2 [M+H] ⁺

 Example 45: 3-(5-Isopropyl-2,4-dihydroxyphenyl)-4-(4-tetrahydropyrrolemethylphenyl)-5-cyclopropanoylaminoisoxazole

采用合成路线 4

Using synthetic route 4

 The compound 4P was reacted with tetrahydropyrrole according to the method of Example 42 and then subjected to debenzylation to give the title compound 15 mg (yield 45) in a yield of 32.5%.

MP=163-165 °C NMR NMR (400MHz, CD ₃ OD) δ 7.47 (d, J=8.2Hz, 2H), 7.32 (d, J=8.2Hz, 2H), 6.83 (s, 1H), 6.32 (s, 1H), 4.21 ( s, 2H), 3.19-3.14 (m, 4H), 3.07 (m, 1H), 2.06-2.01 (m, 4H), 1.76 (m, 1H), 0.96 (d, 6H), 0.87 (d, 4H) .

LC-MS: m/z 462.3 [M+H] ⁺

 Example 46: 3-(5-Isopropyl-2,4-dihydroxyphenyl)-4-(4-indoleridinylmethylphenyl)-5-cyclopropanoylaminoisoxazole

 Using synthetic route 4

 The compound 4P was reacted with homopiperidine according to the method of Example 42 and then subjected to debenzylation to give the title compound 19 mg of compound 46), yield 38.8%.

 MP=161-163°C

1H NMR (400MHz, CD ₃ OD) δ 7.51 (d, J=7.8Hz, 2H), 7.33 (d, J=7.8Hz, 2H), 6.83 (s, 1H), 6.32 (s, 1H), 4.27 ( s, 2H), 3.23 (t, J=5.1Hz, 4H), 3.07 (m, 1H), 1.90-1.84 (m, 4H), 1.79-1.70 (m, 5H), 0.96 (m, 6H), 0.88 (m, 4H).

LC-MS: m / z 490.3 [M + H] +;

 Example 47: 3-(5-Isopropyl-2,4-dihydroxyphenyl)-4-[4-(2-methylpiperidinyl)methylphenyl]-5-cyclopropanoylamino Oxazole

采用合成路线 4

Using synthetic route 4

 The compound 4P was reacted with 2-methylpiperidine according to the method of Example 42 and then subjected to debenzylation to give 21 mg (yield 47) of the desired compound (yield: 42%).

MP=165-167°C NMR NMR (400MHz, CD ₃ OD) δ 7.46 (d, J=8.1Hz, 2H), 7.32 (d, J=8.1Hz, 2H), 6.83 (s, 1H), 6.33 (s, 1H), 4.44 ( d, J = 12.9 Hz, 1H), 3.87 (d, J = 12.9 Hz, 1H), 3.13-3.02 (m, 3H), 2.69-2.61 (m, 1H), 1.93-1.86 (m, 1H), 1.82 -1.72 (m, 3H), 1.69-1.57 (m, 2H), 1.54-1.42 (m, 4H), 0.95 (d, 6H), 0.88 (d, 4H).

LC-MS: m/z 490.3 [M+H] ⁺

 Example 48: 3-(5-Isopropyl-2,4-dihydroxyphenyl)-4-[4-(3,5-dimethylpiperidine)methylphenyl]-5-cyclopropane Amidoisoxazole

 Using synthetic route 4

 The compound 4P was reacted with 3,5-dimethylpiperidine according to the method of Example 42 and then subjected to debenzylation to give the title compound 17 mg of compound 48), yield 33.7%.

 MP=175-177°C

1H NMR (400MHz, CD ₃ OD) δ 7.43 (d, J=8.4Hz, 2H), 7.29 (d, J=8.4Hz, 2H), 6.83 (s, 1H), 6.34 (s, 1H), 3.93 ( s, 2H), 3.12-3.03 (m, 3H), 2.08-2.01 (m, 2H), 1.86-1.74 (m, 5H), 0.95-0.86 (m, 16H).

LC-MS: m/z 502.3 [M+H] ⁺

 Example 49: 3-(5-Isopropyl-2,4-dihydroxyphenyl)-4-[4-(3,5-dimethylmorpholine)methylphenyl]-5-cyclopropane Amidoisoxazole

采用合成路线 4

Using synthetic route 4

According to the method of Example 42, after the reaction of the compound 4P with 2,6-dimethylmorpholine, the debenzylation protection was targeted. 13 mg (Compound 49), yield 25.7%.

 MP= 179-180 °C

1H NMR (400MHz, CD ₃ OD) δ 7.36 (d, J=8.3Hz, 2H), 7.23 (d, J=8.3Hz, 2H), 6.81 (s, 1H), 6.34 (s, 1H), 3.72- 3.64 (m, 2H), 3.54 (s, 2H), 3.03 (m, 1H), 2.77 (d, J = 10.7 Hz, 2H), 1.82-1.71 (m, 3H), 1.11 (d, 6H), 0.91 -0.85 (m, 10H).

 LC-MS: m/z 506.3 [M+H]+;

 Example 50: 3-(5-Isopropyl-2,4-dihydroxyphenyl)-4-(4-thiomorpholinemethylphenyl)-5-cyclopropanoylaminoisoxazole

 Using synthetic route 4

 The compound 4P was reacted with thiomorpholine according to the method of Example 42 and then subjected to debenzylation to give the title compound 18 mg (yield 50) in a yield of 36.4%.

 MP=198-200 °C

1H NMR (400MHz, CD ₃ OD) δ 7.35 (d, J=8.3Hz, 2H), 7.22 (d, J=8.3Hz, 2H), 6.80 (s, 1H), 6.34 (s, 1H), 3.56 ( s, 2H), 3.03 (m, 1H), 2.75-2.71 (m, 4H), 2.67-2.63 (m, 4H), 1.74 (m, 1H), 0.91-0.85 (m, 10H).

LC-MS: m/z 494.2 [M+H] ⁺

 Example 51: 3-(5-Isopropyl-2,4-dihydroxyphenyl)-4-(4-tetrahydroisoquinolinylmethylphenyl)-5-cyclopropanoylaminoisoxazole

 Using synthetic route 4

According to the method of Example 42, after reacting the compound 4P with tetrahydroisoquinoline, the benzyl group is protected to obtain the target compound. 15 mg (Compound 51), yield 28.6%.

 MP=185-188 °C

1H NMR (400MHz, CD ₃ OD) δ 7.44 (d, J=7.7Hz, 2H), 7.26 (d, J=7.7Hz, 2H), 7.12-7.09 (s, 3H), 7.01-6.97 (s, 1H ), 6.82 (s, 1H), 6.34 (s, 1H), 3.76 (s, 2H), 3.68 (s, 2H), 3.02 (m, 1H), 2.91 (t, J=5.8Hz, 2H), 2.81 (t, J = 5.4 Hz, 2H), 1.75 (m, 1H), 0.92-0.84 (m, 10H).

LC-MS: m/z 524.3 [M+H] ⁺

 Example 52: 3-(5-Isopropyl-2,4-dihydroxyphenyl)-4-(4-dimethylaminomethylphenyl)-5-cyclopropanoylaminoisoxazole

 Using synthetic route 4

 After reacting the compound 4P with an aqueous solution of dimethylamine in the same manner as in Example 42 and then debenzylating, the title compound 13 mg (yield of compound 52) was obtained, yield 29.8%.

 MP=171-173 °C

1H NMR (400MHz, CD ₃ OD) δ 7.42 (d, J=8.2Hz, 2H), 7.31 (d, J=8.2Hz, 2H), 6.83 (s, 1H), 6.33 (s, 1H), 4.02 ( s, 2H), 3.06 (m, 1H), 2.64 (s, 6H), 1.76 (m, 1H), 0.95 (d, 6H), 0.90-0.86 (m, 4H).

LC-MS: m/z 436.2 [M+H] ⁺

 Example 53: 3-(5-Isopropyl-2,4-dihydroxyphenyl)-4-(4-diisopropylaminomethylphenyl)-5-cyclopropanoylaminoisoxazole

 Using synthetic route 4

The compound 4P was reacted with diisopropylamine according to the method of Example 42 and then subjected to debenzylation to give the title compound 18 mg (Comp. 53) in a yield of 36.6%. MP=152-153 °C

1H NMR (400MHz, CD ₃ OD) δ 7.47 (d, J=8.1Hz, 2H), 7.30 (d, J=8.1Hz, 2H), 6.84 (s, 1H), 6.32 (s, 1H), 4.20 ( Brs, 2H), 3.58 (brs, 2H), 3.06 (m, 1H), 1.75 (m, 1H), 1.36-1.26 (m, 12H), 0.96 (d, 6H), 0.87 (d, 4H).

LC-MS: m/z 492.2 [M+H] ⁺

 Example 54: 3-(5-Isopropyl-2,4-dihydroxyphenyl)-4-(4-methylpiperazinylmethylphenyl)-5-cyclopropanoylaminoisoxazole

 Using synthetic route 4

 The compound 4P was reacted with methylpiperazine according to the method of Example 42 and then subjected to debenzylation to give the title compound 14 mg (yield 54) in a yield of 28.5%.

 MP= 180-183 °C

1H NMR (400MHz, CD ₃ OD) δ 7.37 (d, J=8.2Hz, 2H), 7.24 (d, J=8.2Hz, 2H), 6.80 (s, 1H), 6.34 (s, 1H), 3.60 ( s, 2H), 3.04 (m, 1H), 2.92 (brs, 4H), 2.64 (brs, 4H), 2.60 (s, 3H), 1.75 (m, 1H), 0.92-0.85 (m, 10H).

LC-MS: m/z 491.3 [M+H] ⁺

 Example 55: 3-(5-Isopropyl-2,4-dihydroxyphenyl)-4-[4-(N-methylcyclohexylamino)methylphenyl]-5-cyclopropanoylamino Isoxazole

采用合成路线 4

Using synthetic route 4

The compound 4P was reacted with N-methylcyclohexylamine according to the method of Example 42 and then subjected to debenzylation to give the title compound 22 mg of Compound 55), yield 43.7%. MP=171-174°C

1H NMR (400MHz, CD ₃ OD) δ 7.48 (d, J=8.3Hz, 2H), 7.35 (d, J=8.3Hz, 2H), 6.85 (s, 1H), 6.32 (s, 1H), 4.28 ( s, 2H), 3.23 (m, 1H), 3.08 (m, 1H), 2.68 (s, 3H), 2.11 (d, J=11.3Hz, 2H), 1.95 (d, J=11.3Hz, 2H), 1.80-1.69 (m, 2H), 1.64-1.52 (m, 2H), 1.43-1.31 (m, 2H), 1.30-1.21 (m, 1H), 0.99 (d, 6H), 0.90-0.85 (m, 4H) ).

LC-MS: m/z 504.3 [M+H] ⁺

 Example 56: 3-(5-Isopropyl-2,4-dihydroxyphenyl)-4-[4-(N-methyldimethylaminoethylamino)methylphenyl]-5-cyclopropane Formylaminoisoxazole

 Using synthetic route 4

 The compound 4P was reacted with hydrazine, hydrazine, hydrazine-trimethylethylenediamine according to the method of Example 42 to give the title compound 17 mg (yield compound 56) in a yield of 34.5%.

 MP= 152-154 °C

1H NMR (400MHz, CD ₃ OD) δ 7.43 (d, J=7.6Hz, 2H), 7.26 (d, J=7.6Hz, 2H), 6.84 (s, 1H), 6.33 (s, 1H), 3.74 ( Brs, 2H), 3.13-3.02 (m, 3H), 2.76 (brs, 2H), 2.67 (s, 6H), 2.34 (s, 3H), 1.76 (m, 1H), 0.94 (d, 6H), 0.91 -0.86 (m, 4H).

LC-MS: m/z 491.3 [M+H] ⁺

 Example 57: 3-(5-Isopropyl-2,4-dihydroxyphenyl)-4-[4-(N-methylphenylethylamino)methylphenyl]-5-cyclopropanoylamino Isoxazole

Using synthetic route 4 The compound 4P was reacted with N-methylphenylethylamine in the same manner as in Example 42 and then subjected to debenzylation to give the title compound 13 mg (yield 57) in a yield of 24.7%.

 MP=109-111 °C

1H NMR (400MHz, CD ₃ OD) δ 7.37 (d, J=8.2Hz, 2H), 7.29-7.24 (m, 4H), 7.21-7.16 (m, 3H) 6.82 (s, 1H), 6.33 (s, 1H), 3.81 (s, 2H), 3.02 (m, 1H), 2.93-2.80 (m, 4H), 2.45 (s, 3H), 1.74 (m, 1H), 0.92-0.86 (m, 10H).

LC-MS: m/z 526.3 [M+H] ⁺

 Example 58: 3-(5-Isopropyl-2,4-dihydroxyphenyl)-4-[4-(4-morpholinylpiperidine)methylphenyl]-5-cyclopropanoylamino Isoxazole

采用合成路线 4

Using synthetic route 4

 The compound 4P was reacted with 4-morpholinylpiperidine according to the method of Example 42 and then subjected to debenzylation to give the title compound 17 mg of compound 58), yield 30.3%.

 MP=157-159°C

1H NMR (400MHz, CD ₃ OD) δ 7.41 (d, J=8.0Hz, 2H), 7.27 (d, J=8.0Hz, 2H), 6.82 (s, 1H), 6.34 (s, 1H), 3.81 ( s, 2H), 3.71 (t, J=4.8Hz, 4H), 3.18 (d, J=12.1Hz, 2H), 3.05 (m, 1H),

2.67-2.62 (m, 4H), 2.47-2.37 (m, 3H), 2.03-1.94 (m, 2H), 1.80-1.72 (m, 1H), 1.71-1.59 (m, 2H), 0.95-0.84 (m , 10H).

 LC-MS: m/z 561.4 [M+H]+;

化合物 59 Example 59: 3-(5-Isopropyl-2,4-dihydroxyphenyl)-4-[4-(4-tetrahydropyrrolylpiperidine)methylphenyl]-5-cyclopropanoyl Aminoisoxazole

Compound 59

 Using synthetic route 4

 The compound 4P was reacted with 4-tetrahydropyrrolylpiperidine according to the method of Example 42 and then subjected to debenzylation to give the title compound 15 mg of compound 59), yield 27.5%.

 MP=216-218 °C

1H NMR (400MHz, CD ₃ OD) δ 7.37 (d, J=8.0Hz, 2H), 7.24 (d, J=8.0Hz, 2H), 6.80 (s, 1H), 6.35 (s, 1H), 3.59 ( s, 2H), 3.40-3.29 (brs, 4H), 3.16-2.99 (m, 4H), 2.20-2.02 (m, 8H), 1.80-1.68 (m, 3H), 0.93-0.84 (m, 10H).

 LC-MS: m/z 545.4 [M+H]+;

 Example 60: Determination of Enzyme Level Activity of Phenyl 1,2-isoxazole or Phenyl 1,2-pyrazole Compounds Derived from Formula I Constructing a Screening Platform for Human HSP90-alpha Inhibitors Using Fluorescence Polarization (FP) The method is based on the principle of measuring the fluorescence polarization values in the horizontal and vertical directions by detecting the change in molecular weight before and after the interaction of fluorescein-labeled small molecules with other molecules. If the equilibrium between the fluorescently labeled small molecule and the macromolecule is established, it will move slowly when excited, and the measured fluorescence polarization will increase. If the binding between the fluorescently labeled small molecule and the macromolecule is replaced by another ligand, its rotation or flipping speed will be faster in the free state, and the emitted light will be depolarized with respect to the plane of the excitation light, and the measured polarization value Decrease to calculate the polarization value of the sample (polarization value unit mP).

The fluorescently labeled small molecule to be used in the present invention is GM-BODIPY (synthesized by the synthesis method described in BMCL, 2003, 13, 3975-3978). The reaction was carried out in a 384-well blackboard using the reaction hydrophobin HFB buffer: 50 mM KCl, 5 mM MgCl ₂ , 20 mM Na ₂ Mo 0 ₄ , 0.01% NP40, 0.1 mg/ml BGG, 2 mM DTT, pH 7.3. The reaction system has a volume of 50 mL, which contains 5 nM GM-BODIPY (; geldanamycin), 30 M HSP90 and the measured small molecule compound or DMSO (dimethyl sulfoxide), and the content of DMSO is 2%. . Two wells with only HFB buffer were used as a blank control and 5 nM GM-BODIPY as a negative control. The reaction was carried out at 4 ° C for 12-16 hours, and the detection was carried out under a Biotek microplate reader with an excitation wavelength of 485 nm and an emission wavelength of 530 nm, and the mP value was measured. Calculate the inhibition rate using the following formula:

 (no compound mP-add compound mP) / (no compound mP-negative control mP)* 100%

After calculating the inhibition rates of the compounds at different concentrations, the IC _{5Q of} the compound was calculated. The IC _5Q values of the compounds are shown in

实施例 61：由通式 I表示的苯基 1,2-异噁唑或苯基 1,2-吡唑类化合物细胞水平活性测 定

Example 61: Determination of cell level activity of phenyl 1,2-isoxazole or phenyl 1,2-pyrazole compounds represented by Formula I

 Tumor cell growth inhibition was detected by sulforhodamine B (SRB) staining. The specific steps are as follows: Human lung cancer cell line A549 (purchased from American Type Culture Collection, ATCC) in logarithmic growth phase. Inoculate to a 96-well microplate at a suitable density (4000/well, 100 μL per well, overnight after culture). Add compounds of different concentrations (100, 10, 1, 0.1, Ο.ΟΙμΜ) for 72 h, set three replicate wells for each concentration, and set the corresponding concentration of vehicle control and cell-free zero-tuning. The parietal cells were removed from the culture medium, and 10% (w/v) trichloroacetic acid (100 μΙ 7 well) was added and fixed at 4 ° C for 1 h, followed by rinsing with distilled water five times. After drying at room temperature, SRB solution was added to each well (4 Mg/mL, dissolved in 1% glacial acetic acid) 100 L, incubate for 15 min at room temperature, rinse with unwashed SRB five times with 1% glacial acetic acid, and dry at room temperature, add 10 mM Tris solution to each well. The VERSMax plate reader measures the optical density (OD value) at a wavelength of 515 nm. The inhibition rate of the drug on tumor cell growth is calculated according to the following formula: inhibition rate (%) = COD control well-OD administration hole) / OD control Hole x l00%. The experiment was repeated twice.

 The inhibition rate (%) of each compound against A549 cells is shown in the following table:

i3/:ϋ O 9i8il£ 9ϊοίAV

I3/:ϋ O 9i8il£ 9ϊοίAV

Claims

The phenyl 1,2-isoxazole or phenyl 1,2-pyrazole compound represented by the general formula I or a pharmaceutically acceptable compound thereof

 I  Its towel: X is 0 or NR4, wherein 114 is 15, a dC ₆ linear or branched alkyl group or a C ₃ -C ₆ cycloalkyl group; Is 15; halogen; dC ₆ straight or branched alkyl; phenyl dC ₆ alkyl; phenyl substituted C ₂ -C ₆ alkenyl; phenyl; dC ₆ straight or branched alkyl substituted benzene a naphthyl group; a dC ₆ linear or branched alkyl substituted naphthyl group; a substituted or unsubstituted 6-10 membered aromatic heterocyclic group having 1 to 3 hetero atoms, wherein the substituted one contains 1-3 The substituent of the 6-10 membered aromatic heterocyclic group of a hetero atom is a dC ₆ linear or branched alkyl group or a dC ₆ alkoxy group substituted with N(R ₅ ) ₂ , and R ₅ is a linear or branched dC ₆ An alkyl group or N(R ₅ ) ₂ is a 6-10 membered saturated heterocyclic group having 1 to 3 hetero atoms selected from N, 0 and S; R ₂ is H; halogen; dC ₆ straight or branched alkyl; phenyl or substituted phenyl; wherein the substituted phenyl substituent is dC ₆ alkoxy, hydroxy dC ₆ alkylene, Substituted or unsubstituted 5-8 membered saturated heterocyclic dC ₆ alkylene group having 1 to 3 hetero atoms, substituted or unsubstituted amino dC ₆ alkylene group, C ₃ -C ₇ cycloalkylcarbonyloxy group a dC ₆ alkylene group or a tetrahydroisoquinoline dC ₆ alkylene group, wherein the substituted 5-8 membered saturated heterocyclic group dC ₆ alkylene group having 1 to 3 hetero atoms has a substituent dC ₆ a linear or branched alkyl group, a dC ₆ linear or branched alkyl substituted amino group or a 5-8 membered saturated heterocyclic group having 1 to 3 hetero atoms, the substituted amino dC ₆ alkylene group substituted The group is dC ₆ linear or branched alkyl, C ₅ -C ₇ cycloalkyl, phenyl dC ₆ alkylene, dimethylamino substituted dC ₆ alkylene, the hetero atom is selected as g N, 0 and S; R ₃ is H, dC ₇ linear or branched alkylcarbonyl or C ₃ -C ₆ cycloalkylcarbonyl.  2. A compound according to claim 1  Where X is NH, Is halogen, R ₂ is 4-dC ₆ alkoxyphenyl, and R ₃ is H or dC ₆ linear or branched alkylcarbonyl.  3. A compound according to claim 2, Wherein R ₂ is 4-methoxyphenyl and R ₃ is H or methylcarbonyl. 4. A compound according to claim 1 Where X is 0, Is 15, halogen, dC ₄ linear or branched alkyl, phenyl dC ₄ alkylene, phenyl substituted C ₂ -C ₄ alkenyl, phenyl, ^ ₄ linear or branched alkyl substituted benzene a naphthyl group, a ₄ linear or branched alkyl substituted naphthyl group, a substituted or unsubstituted 6- or 10-membered aromatic heterocyclic group containing 1 hetero atom; wherein the substituted one contains 1 hetero atom The substituent of the 6- or 10-membered aromatic heterocyclic group is a dC ₄ linear or branched alkyl group or a dC ₄ alkoxy group substituted with N(R ₅ ) ₂ , and R ₅ is a dC ₄ linear or branched alkane. Or N(R ₅ ) ₂ is a 6-membered saturated heterocyclic group containing 2 hetero atoms selected from N, 0 and S; Is a halogen or a substituted phenyl group; the substituent of the substituted phenyl group is a dC ₄ alkoxy group, a hydroxy dC ₄ alkylene group, a substituted or unsubstituted 5-7 member having 1-2 hetero atoms a saturated heterocyclic group dC ₄ alkylene group, a substituted or unsubstituted amino dC ₄ alkylene group, a C ₃ -C ₆ cycloalkylcarbonyloxy dC ₄ alkylene group or a tetrahydroisoquinoline dC ₄ alkylene group, Wherein the substituted substituent of the 5-7 membered saturated heterocyclic group dC ₄ alkylene having 1 to 2 hetero atoms is a dC ₃ linear or branched alkyl group, a dC ₄ linear or branched alkyl group a substituted amino group or a 5-7 membered saturated heterocyclic group having 1-2 hetero atoms, the substituent of the substituted amino dC ₄ alkylene group being a dC ₄ linear or branched alkyl group, C ₅ -C ₇ a cycloalkyl group, a phenyl dC ₄ alkylene group, a dimethylamino substituted dC ₄ alkylene group, wherein the hetero atom is selected from g N, 0 and S; R ₃ is H, dC ₇ linear or branched alkylcarbonyl or C ₃ -C ₆ cycloalkylcarbonyl.  5. A compound according to claim 4, Wherein, is halogen, dC ₄ linear or branched alkyl, phenyl dC ₄ alkylene, phenyl substituted C ₂ -C ₄ alkenyl, phenyl, naphthyl, substituted or unsubstituted containing 1 nitrogen a 6- or 10-membered aromatic heterocyclic group of an atom; wherein the substituted substituent of a 6- or 10-membered aromatic heterocyclic group having 1 N atom is a dC ₄ linear or branched alkyl group or N (R) ₅ ) a _2- substituted dC ₄ alkoxy group, wherein R ₅ is a methyl group or an ethyl group, or N(R ₅ ) ₂ is a morpholinyl group; R ₂ is H, halogen or substituted phenyl; the substituent of the substituted phenyl is selected from the group consisting of dC ₄ alkoxy, hydroxy dC ₄ alkylene, substituted or unsubstituted, containing 1-2 heteroatoms 4 of a 5-7-membered saturated heterocyclic group dC ₄ methylene group, a substituted or unsubstituted aminomethylene group, a C ₃ -C ₆ cycloalkylcarbonyloxymethylene group, and a tetrahydroisoquinoline methylene group a substituent at the position wherein the substituted 5-7 membered saturated heterocyclic group dC ₄ methylene group having 1 to 2 hetero atoms is a dC ₃ linear or branched alkyl group, dimethylamino group, Diethylamino, dipropylamino, morpholinyl or piperidinyl, the substituent of the substituted aminomethylene is dC ₄ straight or branched alkyl, C ₅ -C ₇ cycloalkyl, phenyl dC ₄ alkylene, dimethylamino substituted dC ₄ alkylene, said hetero atom selected in g N, 0 and S; R ₃ is H, dC ₇ linear or branched alkylcarbonyl or C ₃ -C ₆ cycloalkylcarbonyl.  6. A compound according to claim 5, Wherein, H, Cl, Br, ethyl, isopropyl, tert-butyl, phenethyl, styryl, naphthyl, pyridyl, isoquinolyl, quinolinyl, methyl substituted quinolyl Dimethylaminoethoxy substituted quinolinyl or morpholinyl ethoxy Substituted quinolinyl; R ₂ is H, halogen or substituted phenyl; the substituent of the substituted phenyl is selected from the group consisting of methoxy, ethoxy, hydroxymethyl, morpholinylmethylene, 4-dimethylaminopiperidine Methylidene, piperidinyl methylene, tetrahydropyrrolylmethylene, High piperidinyl methylene

, 2-methylpiperidinylmethylene, 3,5-dimethylpiperidinylmethylene, 3,5-dimethyl? Lolinylmethylene, 4-thiomorpholinylmethylene I, tetrahydroisoquinolinylmethylene, 4-methylpiperazinylmethylene, 4- Morpholinyl piperidinyl methylene, 4-tetrahydropyrrolylpiperidinyl methylene, N-methylcyclohexylamino 1 , N Methyl dimethylaminoethylaminomethylene

, N-methylphenylethyleneaminomethylene, dimethylamine a methylidene group, a diethylaminomethylene group, a diisopropylaminomethylene group, a cyclopropylcarbonyloxymethylene group, a 4-position substituent in the oxime; a methyl carbonyl group, an ethyl carbonyl group, a propyl group Carbocarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, heptylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl or cyclohexylcarbonyl.  7. A compound according to claim 1 selected from the group consisting of:  Compound compound chemical structure

LL

6L

9Z0S80/CT0ZN3/X3d

The compound according to claim 1, wherein the pharmaceutically acceptable salt is represented by the formula I a salt formed by the compound and an inorganic or organic acid; wherein the inorganic acid is hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, and the organic acid is citric acid, lactic acid, malic acid, gluconic acid, tartaric acid, and hexanic acid. Acid, acetic acid, succinic acid, fumaric acid, ascorbic acid, itaconic acid, methanesulfonic acid or benzenesulfonic acid.  A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.  10. Use of a compound according to claim 1 or a pharmaceutical composition according to claim 9 for the preparation of a medicament as an HSP90 inhibitor or for the preparation of an antitumor medicament.