WO2012068702A1 - Benzo 5-membered unsaturated heterocyclic compounds and preparation methods thereof - Google Patents

Abstract

Disclosed are benzo 5-membered unsaturated heterocyclic compounds represented by formula I and their pharmaceutically acceptable salts, preparation methods and uses thereof in the preparation of the drugs for treating osteoporosis, wherein each substituent of formula (I) is defined as the description.

Description

 Benzo five-membered unsaturated heterocyclic compound and preparation method thereof

 The present invention relates to a benzo five-membered unsaturated heterocyclic compound, and discloses a process for preparing the benzo five-membered unsaturated heterocyclic compound, and to the benzo five-membered unsaturated heterocyclic compound. Use in anti-osteoporosis and pharmaceutical compositions containing such compounds as active ingredients. Background technique

 Osteoporosis is a common global disease that occurs mostly in the middle-aged and elderly population, especially in menopausal women. The main clinical feature is the reduction of systemic bone mass in the microstructural destruction of bone tissue. The risk of fractures in people with osteoporosis is significantly increased, especially in the wrist, spine and hip joints. It is estimated that 30-50% of women and 15-30% of men with osteoporosis will experience fractures during their lifetime. Patients with fractures have longer hospital stays than those with diabetes, breast cancer, or myocardial infarction. There are approximately 75 million osteoporotic patients in the United States, Europe, and Japan. In 2008, the International Osteoporosis Foundation and the China Health Promotion Foundation jointly published the White Paper on Osteoporosis Prevention and Control in China, which introduced at least 69.44 million people with osteoporosis and 210 million people with low bone mass. There is a risk of osteoporosis. The prevalence of osteoporosis in China's population over 50 years old is 15.7%, and this proportion is gradually increasing as the life expectancy of the population increases. The "White Book" pointed out that 70-80% of the fractures in middle-aged and elderly people in China are caused by osteoporosis. Among them, there are about 1.81 million new vertebral fractures and 230,000 hip fractures per year. The elderly population in China is increasing at a rate of 5.2% per year, which also means an increase in potential osteoporosis patients. Currently, it is estimated that the cost of treating thigh fractures in middle-aged and elderly patients is as high as 10.4 billion yuan per year. This figure will exceed 21.7 billion by 2020.

― During the formation of bone, osteoblasts (Osteoblast) and osteoclasts (Osteoclast) coordinate with each other to maintain a dynamic balance between bone formation and dissolution, and to maintain the continuous renewal of bone. when This coordination imbalance, when bone resorption exceeds bone formation, leads to osteoporosis.

 Adult bone has a significant bone remodeling process. The bone repair function was first discovered in 1965, and Bone Morphogenetic Protein (BMP) was found to be an active molecule in this process. Later, the BMP protein family was discovered. There is increasing evidence in modern times that Bone Morphogenetic Protein-2 (BMP-2:) plays an important role in bone formation and bone repair. Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2, INFUSE® Bone Graft) was approved by the US FDA for autologous bone transplantation and localization in 2007 for its promotion of bone deposition and repair of long bones. Alveolar ridge augmentation was approved by the US FDA for the treatment of tibiofibular fractures in 2004 and was approved by the FDA for spinal fusion in 2002. In Germany, when treating a tibial fracture, the cost of injecting a recombinant human BMP-2 protein is approximately 2,970 euros, and the drug cannot be reimbursed from a health insurance company. Therefore, the use of recombinant human BMP-2 protein will place a heavy economic burden on patients.

BMP-2 is a member of the BMPs family of osteoinductive growth factors stored in bone and belongs to the transforming growth factor (TGF2P) superfamily. BMP-2 first synthesizes a large precursor molecule, a dormant protein that, upon activation, is hydrolyzed by a protease to form a carboxy-terminal monomer containing 100-140 amino acids. The two monomers are linked by a chain disulfide bond to form a mature and active dimer with a relative molecular mass of 18,000. The BMP-2 receptor belongs to the transforming growth factor beta receptor superfamily and has a serine/threonine protein kinase structure with a signaling mechanism similar to that of the TGF-beta receptor. The ΒΜΡ-2 receptors involved in ΒΜΡ-2 signaling are classified into type I and type II. Type I receptors recruit and phosphorylate Smadl, Smad5 and Smad8 proteins in the cytoplasm and assist the Smadl-Az-HsN3 triplet complex. Into the nucleus, this plays a decisive role in the directed differentiation of osteoblasts; type II receptors do not play a key role in the directed differentiation of osteoblasts, but type II receptors bind to BMP-2 and activate I. Type receptors and greatly enhance the affinity of BMP-2 for receptors. The binding of the BMP-2 protein to the type II receptor of BMP-2 activates the protein kinase activity of the receptor, catalyzing the intracellular GS region of the type I receptor (characteristically conserved SGSGSG sequence) The second amino acid residue, glutamine, is converted to aspartic acid, and the type I receptor is activated to bind to Smadl or Smad5 and phosphorylate the serine at the carboxy terminus of Smadl or Smad5, thereby activating the Smadl or Smad5 protein. As a major component of the TGF2P-associated transduction pathway, Smads protein is a key transcriptional coping regulator that transduces the BMP-2 signaling pathway from the cell surface to the nucleus. The activated Smadl or Smad5 protein is transferred from the cell paddle to the nucleus and acts directly and indirectly on downstream target genes, such as the ALP gene, which ultimately promotes bone formation.

 Studies have shown that BMP-2 promotes bone formation in two ways: First, it promotes osteoblast differentiation. BMP-2 in the bone matrix can recruit bone marrow stem cells and induce bone marrow stem cells to differentiate into osteoblasts and chondrocytes, and then form new bone by calcium salt deposition. BMP-2 also induces osteoblast differentiation and remodeling of young bone in mesenchymal cells. BMP-2 also promotes osteoblast differentiation and inhibits apoptosis during bone regeneration and repair. The second is to promote the expression of other osteogenic factors. BMP-2 can increase the expression of osteoblast marker genes OPN, CbfaK Col I alphaK BSP, ALP, fabp4 (fatty acid coupled protein 4), etc. The corresponding proteins of these genes play a key role in osteoblast differentiation.

 Studies have shown that the osteoporosis citrus gene (one or more genes) is located in a region on the short arm of chromosome 20, and the bone morphogenetic protein-2 (BMP-2) protein gene is one of the related genes. The 3'-UTR (3'-untranslated regions of the BMP-2 protein gene bmp-2 in mammals and fish are highly conserved, indicating that the 3,-UTR of bmp-2 is evolutionarily Subject to (selective pressure. This conserved region has been shown to be an important regulator of bmp-2 gene transcription, and regulation of the 3'-UTR of bmp-2 can affect the expression of the gene bmp-2, which in turn affects the BMP-2 protein. And expression of other osteoporosis-related factors.

In order to obtain a new drug for promoting bone formation, Zhang Yueqin et al. established an anti-osteoporosis drug screening model that promotes BMP-2 up-regulation with the bmp-2 promoter as a drug target (see Chinese Patent Application: 03104750.5) And use this model to screen for microbial sources and chemically synthesized compounds. Through extensive screening work, it was found that a class of compounds with a five-membered unsaturated heterocyclic structure has a significant up-regulation of BMP-2 activity and was verified in ovarian ablation model rats. It does have the effect of improving the symptoms of osteoporosis (see Chinese patent ZL 200610008114.6). Based on the above studies, the present invention further designs, synthesizes and screens a series of benzo five-membered unsaturated heterocyclic compounds (Formula I) which can be represented by the following general formula, especially the 2-acyl benzo-5-membered compounds thereof. Unsaturated heterocyclic compounds, through structural structural modification and structure-activity relationship studies, can provide a new lead structure for osteoporosis treatment, and start from the active compounds that can up-regulate BMP-2 protein, and further develop a new type of bone-promoting Anti-osteoporosis drugs.

 Formula (I) Summary of the invention

 The present invention provides a series of benzo five-membered unsaturated heterocyclic compounds having the structure of the general formula (I) or a pharmaceutically acceptable salt thereof, which has an up-regulating BMP-2 expression activity and can be used for the treatment of osteoporosis .

 The present invention also provides a method for synthesizing the benzo five-membered unsaturated heterocyclic compound.

 The present invention also provides the use of the benzo five-membered unsaturated heterocyclic compound in the treatment of osteoporosis and related patients due to osteoporosis.

 The present invention also provides a pharmaceutical composition for treating osteoporosis, which comprises the above benzopenta-unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention mainly designs a compound of the formula I which synthesizes a benzothiophene, a benzofuran or a hydrazine having a 2-position carboxylic acid ester substituted at a different position on the benzene ring (4-, 5-, 6-, 7-). A compound having a phenylpropenyl group is introduced at the 2-position, and a compound having a methyl sulfone or methyl sulfoxide is introduced at the 2-position. It is discussed that the phenyl ring is bonded with a thiol group, a halogen, a methoxy group, an amino group, an acyl group, a carboxyl group or the like with different substituents, and a different conjugated extension of the 2-position acetyl group to up-regulate the BMP-2 activity of the compound. influences. The designed target compound structure is shown in Table 1, and the benzene ring in Formula I may have a ruthenium Substituents such as thiol, halo, halo fluorenyl; thiophene, furan ring or pyrrole moiety

1 is a fluorenyl group, an alkoxy group, a carboxyl group, a sulfone methyl group, a sulfoxide methyl group, a substituted aryl propylene structure, or the like.

 The present invention provides a benzo five-membered unsaturated heterocyclic compound having the structure of the formula I or a pharmaceutically acceptable substance,

 In the formula,

X represents 0, S or NR ₇ , wherein R ₇ represents H, a hydrocarbyl group, a halogenated hydrocarbyl group, a carbonyl hydrocarbyl group, a hydroxyhydrocarbyl group, an aminohydrocarbyl group or a hydrocarbyloxy group;

 Y represents CO or CR OH; R represents the following groups: H, OH, a hydrocarbon group having 1 to 18 carbons, a carboxyl group, an acyl group, an alkoxy group, a sulfonic acid group;

^ represents the following groups: H, OH, a hydrocarbon group having 1 to 18 carbons, a carboxyl group, an acyl group, an alkoxy group, a sulfonic acid group, a CH ₂ S(0)nR ₈ , a R ₉ -substituted phenylpropenyl group; wherein R ₈ Representative H, a hydrocarbon group having 1 to 18 carbons, a halogenated hydrocarbon group, a hydroxyalkyl group or a hydrocarbyloxy group, n=l-2; R ₉ represents H, a hydrocarbyl group, an alkoxy group, a halogen, a carboxyl group, an amino group or a substituted amino group; And ^ can be the same as or different from;

R ₂ represents the following groups: H, a hydrocarbon group having 1 to 18 carbons, a halogen, an acyl group, a carboxyl group, an amino group or a substituted amino group, a sulfonic acid group, a nitrile group or an acyl alkoxy group;

 Represents the following groups: H, hydrocarbyl, alkoxy, halogen or halodecyl, carboxy, amino or substituted amino, acyl, amide, ester or sulfonate;

 R4 represents the following groups: H, a hydrocarbyl group, a decyloxy group, a halogen or a haloalkyl group, a carboxyl group, an amino group or a substituted amino group, an amide group, an acyl group, an ester group or a sulfonic acid group;

Represents the following groups: H, hydrocarbyl, decyloxy, halogen or halodecyl, carboxy, amino Or substituted amino, acyl, amide, ester or sulfonic acid groups;

R ₆ represents the following group: H, a hydrocarbyl group, a decyloxy group, a halogen or a halogenated fluorenyl group, a carboxyl group, an amino group or a substituted amino group, an acyl group, an amide group, an ester group or a sulfonic acid group, etc.;

R4 and ^ are bonded together by carbon, oxygen or nitrogen to form a 5-7 membered ring structure or a 5-7 membered ring structure having a substituent R _1Q wherein R _1Q represents H, a hydrocarbon group, a halogenated hydrocarbon group, a carbonyl hydrocarbon group, a hydroxyl group. Hydrocarbyl, aminohydrocarbyl or hydrocarbyloxy.

 As stated in the above definition:

 "Hydrocarbyl" may mean a straight or branched alkyl or cycloalkyl group having from 1 to 18 carbon atoms, for example, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl , sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc. or their corresponding cyclodecyl groups.

 "Alkoxy" may be an alkoxy group having 1 to 18 carbon atoms, for example, methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, isobutoxy, sec. Butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy and the like.

 "Acyl" may be a hydrocarbon substituted acyl or aryl acyl group having 1 to 18 carbons, such as formyl, acetyl, isopropyl acyl, n-propyl acyl, allyl acyl, cyclopropyl acyl, n-butyl Acyl, isobutyl acyl, sec-butyl acyl, tert-butyl acyl, n-pentyl acyl, isopentyl acyl, n-hexyl acyl, isohexyl acyl, phenyl acyl, tolyl acyl and the like.

 The "ester group" may be a hydrocarbon-substituted ester group (hydrocarbyl oxy group) or an aryl ester group having 1 to 18 carbons, such as formyloxy group, acetoxy group, isopropyl acyloxy group, n-propyl acyl group. Oxyl, allyloxy, cyclopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy A group, an isopentyl acyloxy group, a n-hexyl acyloxy group, an isohexyl acyloxy group, a phenyl acyloxy group, a tolyl acyloxy group or the like.

"Acylamino" may be a hydrocarbon-substituted amide or arylamino group having 1 to 18 carbons, such as methylamido, ethylamido, isopropylamido, n-propylamido, allylacyl Amino, cyclopropylamido, n-butylamido, isobutylamido, sec-butylamido, tert-butylamido, n-pentylamino, isopentylamino, n-hexylamino, dissident Amino group, Phenylamino, tolylamino and the like.

 In the benzo five-membered unsaturated heterocyclic compound provided by the present invention or a pharmaceutically acceptable salt thereof, when it has a substituent group, it generally means a C1-C6 lower fluorenyl group, a lower decyloxy group, a halogen group, an amino group, etc., especially The substituent of the substituted amino group may be a C2-C6 fluorenyl group.

 In the substituent of the structural formula of the benzo five-membered unsaturated heterocyclic compound of the present invention or a pharmaceutically acceptable salt thereof, the hydrocarbon group in the halogenated hydrocarbon group, the carbonyl hydrocarbon group, the hydroxyalkyl group or the amino hydrocarbon group is a C1-C6 hydrocarbon group.

 The benzo five-membered unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof according to the present invention, the corresponding benzothiophene/furan, anthraquinone compound, in particular, has an effect of significantly upregulating the expression activity of bone morphogenetic protein BMP-2, in vivo The results of the anti-osteoporosis study showed that the compounds of the present invention have an effect of improving the symptoms of osteoporosis in SAMP6 mice.

 Preferably, the benzo five-membered unsaturated heterocyclic compound comprises 2-substituted phenylacryloyl-benzothiophene, 2-substituted phenylacryloyl-benzofuran, or a benzene ring partially passed, and formaldehyde is condensed to form an adjacent two A compound obtained after the structure of a phenyl ether.

 The benzo five-membered unsaturated heterocyclic compound of the present invention or a pharmaceutically acceptable salt thereof preferably comprises a benzothiophene or benzofuran compound in which the substituent at the 2-position is a 2-hydrocarbyloxyformyl group or a 2-hydrocarbylacyl group.

 The benzo five-membered unsaturated heterocyclic compound of the present invention or a pharmaceutically acceptable salt thereof preferably comprises a 2-position substituent of 2-(2,-methylsulfone or methylsulfoxideacetyl) or 2-(2, a benzothiophene, benzofuran or anthracene compound in which -methylsulfoxide or methyl sulfoxide is substituted with -Γ-hydroxy)ethyl.

 As a non-limiting example, the benzo five-membered unsaturated heterocyclic compound of the present invention may be selected from the following specific compounds:

 2-ethoxycarbonyl-benzothiophene

 2-(2,-methylsulfoxide)-acetylbenzothiophene

 2-(2,-methylsulfonyl)acetyl-benzothiophene

 2-ethoxycarbonyl-5,6-methylenedioxy-benzothiophene

2-(2,-Methylsulfoxide)acetyl-5,6-methylenedioxy-benzothiophene 2-(2,-Methylsulfonyl)acetyl-5,6-methylenedioxy-benzothiophene

 2-ethoxycarbonyl-benzofuran

 2-(2,-methylsulfoxide)-acetylbenzofuran

 2-ethoxycarbonyl-4-chloro-benzothiophene

2-(1,-hydroxy-2,-methylsulfoxide)-ethyl-benzothiophene

 2-ethoxycarbonyl 4-methoxy-benzofuran

 2-ethoxycarbonyl-5-methoxy-benzofuran

 2-ethoxycarbonyl-6-methoxy-benzofuran

 2-ethoxycarbonyl-7-methoxy-benzofuran

2-ethoxycarbonyl-5,6-dimethoxy-benzothiophene

 2-ethoxycarbonyl-7-fluoro-benzofuran

 2-ethoxycarbonyl-5,7-dichloro-benzofuran

 2-ethoxycarbonyl-5-methoxycarbonyl-benzothiophene

 2-acetyl-5-methoxycarbonyl-benzothiophene

2-ethoxycarbonyl-6-methoxycarbonyl-benzothiophene

 2-acetyl-5-carboxy-benzothiophene

 2-acetyl-6-methoxycarbonyl-benzothiophene

 2-acetyl-6-carboxy-benzothiophene

 2-(2,-Methylsulfoxide)acetyl-4-chloro-benzothiophene

2-(2,-Methylsulfoxide)acetyl-4-methoxy-benzofuran

 2-(2,-Methylsulfoxide)acetyl-5-methoxy-benzofuran

 2-(2,-Methylsulfoxide)acetyl-5,6-dimethoxy-benzothiophene

2-(2,-Methylsulfoxide)acetyl-6-methoxy-benzofuran

 2-(2,-Methylsulfoxide)acetyl-7-methoxy-benzofuran

2-ethoxycarbonyl-6-diethylamino-benzofuran

-2-[3,-(4"-methoxyphenyl)acryloyl]-6-ethoxycarbonyl-benzothiophene ( )-2-[3'-(4"-Methoxybenzene)acryloyl]-5-ethoxycarbonyl-benzothiophene 2-(anthracene-hydroxy-2,-methylsulfoxide)ethyl -5,6-methylenedioxy-benzothiophene

 2-(1 '-hydroxy)ethyl-5-methoxycarbonyl-benzothiophene

 2-(Γ-hydroxy)ethyl-6-methoxyformo-benzothiophene

 F3⁄4)-2-cinnamoyl-6-ethoxycarbonyl-benzothiophene

 (E 2-[3,-(2",3",4,,-Trimethoxyphenyl)acryloyl]-5-ethoxycarbonyl-benzothiophene

(3⁄4-2-[3,-(2",3",4"-Trimethoxyphenyl)acryloyl]-6-ethoxycarbonyl-benzothiophene f3⁄4j-2-cinnamoyl-5-ethoxylated Acyl-benzothiophene

 (3⁄4-2-[3,-(2"-Chlorophenyl)acryloyl]-5-ethoxycarbonyl-benzothiophene^-2-[3,-(2"-chlorophenyl)acryloyl] -5-methoxycarbonyl-benzothiophene

 fE 2-[3,-(2,--chlorophenyl)acryloyl]-6-ethoxycarbonyl-benzothiophene

 (3⁄4)-2-[3,-(3",4"-Dimethoxyphenyl)acryloyl]-6-ethoxycarbonyl-benzothiophene

 (3⁄4-2-[3 '-(3",4"-Dimethoxyphenyl)acryloyl]-5-ethoxycarbonyl-benzothiophene

 2-(2'-Methylsulfonyl)acetyl-5-methoxy-benzofuran

 2-(1,-hydroxy-2,-methylsulfoxide)ethyl-5-methoxy-benzofuran

 fE 2-[3,-(4,,-methoxyphenyl)acryloyl]-5,6-dimethoxy-anthracene

 Small methyl-2-[3,-(4"-methoxyphenyl)acryloyl]-5,6-dimethoxy-anthracene

 1-chloroethyl-2-[3,-(4"-methoxyphenyl)acryloyl]-5,6-dimethoxy"

 -1-acetyl-2-[3,-(4"-fluorophenyl)acryloyl]-5,6-dimethoxy-oxime

 F3⁄4M-(2,-Hydroxyethyl)-2-[3,-(4"-fluorophenyl)acryloyl]-5-acetoxy-oxime

(£ 1-( ² ,-aminoethyl)-2-[3,-(4"-fluorophenyl)acryloyl]-5-acetoxy-oxime

 (Ε 1-(2,-methoxyethyl)-2-[3,-(4,--fluorophenyl)acryloyl]-5-acetoxy" 哚 2-ethoxycarbonyl-4- Methyl-benzothiophene

 2-heptyl-5,6-dimethyl-benzothiophene

 2-pentoxycarbonyl-5,6-diaminobenzothiophene

2-keto acid-benzothiophene 2-(Γ,2'-dicarbonyl)pentylbenzothiophene

 2-(butyl sulfoxide) acetyl -5,6-diamino-benzothiophene

 2-(4'-chloroheptyloxycarbonyl)-5,6-dimethoxy-benzothiophene

 2-(4,-chlorohexylsulfoxide)acetyl-5,6-dimethoxy-benzothiophene

 2-(6'-hydroxyhexyl:)oxycarbonyl-5,6-dimethoxy-benzothiophene

 2-(6,-hydroxypentylsulfonyl)acetyl-5,6-dimethoxy-benzothiophene

 2^(6'-methoxyhexyl)oxycarbonyl-5,6-dimethoxy-benzothiophene

 2-(6,-methoxypentylsulfenyl)acetyl-5,6-dimethoxy-benzothiophene

 2-ethoxycarbonyl-5,6-ethylmethylenedioxy-benzothiophene

 2-ethoxycarbonyl-5,6-(2,-chloroethyl)methylenedioxy-benzothiophene

 2-ethoxycarbonyl-5,6-(1,-hydroxyethyl)methylenedioxy-benzothiophene

 2-ethoxycarbonyl-5,6-(1,-aminoethyl)methylenedioxy-benzothiophene

 2-ethoxycarbonyl-5,6-(1,-methoxyethyl)methylenedioxy-benzothiophene

 2-acetylbenzothiophene

 (Ε 2-(3'-(4"-methoxyphenyl)acryloyl)-benzothiophene

 2-acetyl-benzofuran

 The present invention also provides a method for synthesizing a compound of the formula (I).

Α, when X in the formula (I) is S, Y represents CO or CR OH, and is a CH ₂ S(0)nR ₈ or substituted phenylpropenyl structure, the intermediate is first obtained by the method shown in Scheme 1 or Route 2. (IV), wherein R ₂ , R ₃ , R ₅ , R ₆ , R ₈ , R ₉ , n, ' are as defined in claim 1, R „ represents H, OH, a hydrocarbon group having 1 to 18 carbons , carboxyl, acyl, alkoxy or sulfonate; Route 1:

The synthesis method comprises the following steps: using a substituted nitrobenzaldehyde (hydrazine) as a starting material, and using a mercaptoethanol to carry out an aromatic nucleophilic substitution reaction under the catalysis of an alkaline reagent, the N0 _{2 of the} raw material is taken by an ethylthio group.

.R

Generation, intermediate (III) is produced; a halogenated reagent 0 (Z represents a leaving group), which is reacted with an intermediate (ΙΠ) under the catalysis of an alkaline reagent to obtain a derivative of a 2-substituted acylbenzothiophene (IV) );

 Route 2:

 II IV

The synthesis method is as follows: using substituted o-nitrobenzaldehyde (Π) as a starting material, and catalyzing with an alkaline reagent, with a thiol reagent

Directly reacting to obtain a derivative of 2-substituted acylbenzothiophene (W);

 Further, the intermediate (W) can be separately reacted to obtain the corresponding compound of the formula I:

When one or more of R ₃ , , R ₅ , and R ₆ are ester groups, the intermediate (W) is hydrolyzed under basic conditions to obtain a carboxylic acid derivative (V) wherein R ₃ ', R , R ₅ ', R ₆ ' correspond to the groups after hydrolysis of R ₃ , R 4 , R ₅ , R ₆ , respectively

; or

b. Intermediate (IV) is reduced to give the corresponding hydroxy derivative (VI)

 IV VI ; or

c. When R „ is a methyl group, the intermediate (IV) is aldehyde-condensed with the R ₉ -substituted phenyl formaldehyde intermediate (VII) to obtain a compound of the R ₉ substituted phenyl acryloyl group (covered)

d. When „ is an oximeoxy group, the intermediate (IV) can be reacted as follows to give the corresponding compound of the formula I:

 XI

 Intermediate (IV) is reacted with a sulfinylmethyl derivative under strong base and heating to obtain a compound 2-(2,-substituted methyl sulfoxide) acylbenzothiophene derivative (K), which is subjected to oxidation and reduction. The compound 2-(2,-substituted methylsulfonylacetyl)benzothiophene derivative (X) and 2-(2,-substituted sulfone or methyl sulfoxide-hydrazine-hydroxy)ethylbenzothiophene derivative are respectively obtained. (XI);

B, when X in the formula (I) is 0, Y represents CO or CR OH, and R! is CH ₂ S(0) nR ₈ , the synthesis thereof is carried out by the method shown in Scheme 3, wherein R ₂ , R ₃ , , R ₅ , Re, R ₈ , n, R are as defined in claim 1, and R ₁₂ represents the following groups: H, OH, a hydrocarbon group having 1 to 18 carbons, a carboxyl group, an acyl group, an anthracene Oxyl, sulfonic acid group Route 3:

 The synthesis method is as follows: using substituted o-hydroxybenzaldehyde (ΧΠ) as a starting material, in alkaline reagents

R ₂

 13

And reacting with a halogenating reagent 0 (Z represents a leaving group) to form a 2-carbonyl group (XIII) compound;

Wherein, when R ₁₂ is a decyloxy group, the intermediate (ΧΠΙ) can be reacted as follows to obtain the corresponding compound of the formula I:

 XVI

 The intermediate (ΧΠΙ) is further reacted with a sulfinylmethyl derivative under strong base and heating to obtain a 2-(2,-substituted methyl sulfoxide) acylbenzofuran derivative (XIV), (XIV) continues Oxidation and reduction give the compound 2-(2,-substituted sulfone)acetobenzofuran derivative (XV) and 2-(2,-substituted sulfone or methyl sulfoxide-hydrazine-hydroxy)ethylbenzofuran, respectively. Derivative (XVI);

C. When X in the formula (I) is NR ₇ and Y represents CO, when R _{9 is} substituted for the phenylpropenyl structure, the synthesis is carried out by the method shown in Scheme 4, wherein R ₂ , R ₃ , R 4 , R ₅ , R ₆ , R ₇ , R ₉ are defined as in claim 1 ;

Route 4:

The synthesis method comprises the following steps: using substituted NR ₇ -2-acetyl oxime (XVII ) as a starting material, and performing aldol condensation with the substituted phenylformaldehyde intermediate (W) under the catalysis of an alkaline reagent to obtain 2 positions. R ₉ substituted phenylacryloyl target (XVIII ).

 The present invention finds a compound of the formula (I), 2-nonyloxycarbonyl-benzothiophene/furan derivative

(Compounds 3b, 5b, 6b, 7b, 9b, 10b, l ib, 12b, 13b, 16b, 18b, 21b, 22b, 23b, etc.), 2-acetyl/hydroxyethylbenzothiophene/furan derivative (compound G39) , lc, le, 2c, 2e, If, 2f, etc., 2-substituted phenylacryloyl-benzothiophene/furan derivative (compound S25, IdA, ldBl, ldC, 2dA, 2dB, 2dC, 2dD, G33-1 , G33-2, G33-3, G33-4, G33-5, G33-6, G33-7, etc.), 2-(2-sulfoxide/sulfone)-acetylbenzothiophene/furan derivative (compound) 3c, 3d, 4c, 7c, 9c, 10c, l id, l ie, 12c, 13c, 18c, 22c, 23c, etc.), phenyl moiety R4, R ₅ is a formaldehyde o-diphenyl ether structural derivative (compound 8b) , 8c, 8e, 24b, 25b, 26b, 27b, 28b, etc.) have significant up-regulation of BMP-2 expression activity. As a result of the anti-osteoporosis effect in vivo, the representative compounds (8b, 3c, S25, G39) of the above various compounds all have the effect of improving osteoporosis symptoms in SAMP6 mice, and the present invention provides them in the treatment of osteoporosis. Applications.

 The invention further provides a pharmaceutical composition comprising said compound, which may contain a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable carriers.

 The compounds of formula I of the invention and pharmaceutical compositions are useful in the preparation of anti-osteoporosis drugs.

The pharmaceutical composition provided by the present invention may be in various administration forms prepared according to a conventional production method in the pharmaceutical field, for example, by mixing the active ingredient with one or more carriers, and then preparing the desired dosage form. For example, the compound itself or a mixture thereof with a pharmaceutically acceptable excipient, diluent, etc. Oral administration in the form of tablets, capsules, granules, powders or syrups or parenteral administration in the form of injections. The pharmaceutical composition of the present invention preferably contains the active ingredient in a weight ratio of from 0.1% to 99.5%, and most preferably contains from 0.5% to 99.5% by weight of the active ingredient. The above formulations can be prepared by conventional pharmaceutical methods. Examples of useful pharmaceutical adjuvants include excipients (e.g., saccharide derivatives such as lactose, sucrose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, dextrin, and carboxymethyl starch; Cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose; gum arabic; dextran; silicate derivatives such as magnesium metasilicate Aluminum; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, etc., binders (eg gelatin, polyvinylpyrrolidone and polyethylene glycol), disintegration Agents (such as cellulose derivatives such as sodium carboxymethylcellulose, polyvinylpyrrolidone), lubricants (such as talc, calcium stearate, magnesium stearate, cetyl, boric acid, sodium benzoate, leucine), stable Agents (methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, etc.), flavoring agents (such as commonly used sweeteners, sour agents and perfumes), diluents and solvents for injections (eg water, ethanol and glycerol) Wait).

 Pharmacodynamic experiment

 According to the above route and method, the compound of the present invention can be synthesized stably and reproducibly.

 Experiment 1 In vitro BMP-2 up-regulation activity screening

Using the constructed up-regulated BMP-2 screening model (see the Chinese patent application: 03104750.5 for details), the plasmid PYJ was transiently transfected into MC3T3E1 cells by: 100 μ! 7 wells of appropriate concentration of MC3T3E1 cells in 96 wells. Incubate in a sterile plastic culture plate for 8 h, dilute the appropriate amount of PYJ plasmid DNA in a sterile centrifuge tube with 25 μ! 7 well serum-free, double-anti-DMEM medium, and use 25 μ! 7 well serum-free in another sterile centrifuge tube. Dilute the DMEM medium with 0.5 μ! 7-well LF2000 Reagent. Mix the above two tubes in 5 min, incubate for 20 min at room temperature, and add the mixed transfection suspension to the above 96-well plate. 50 μί per well, mix well, place 96-well plate in a 37 ° C carbon dioxide incubator, culture for a certain period of time and then add appropriate concentration of drug-acting cells before fluorescence detection; specific detection process Bottom: Discard the medium in the 96-well plate, gently rinse the cells with 200 μΙ 7-well PBS (ρΗ 7.0), completely discard the PBS, add 25 μΙ 7-well l xPLB, shake at room temperature for 15 min, and let the cells Completely lysate, completely aspirate the lysate into the corresponding well of a 96-well white plate for fluorescence analysis, and add 70 μΙ 7-well analysis reagent LAR II to the analytical whiteboard, and immediately place the analytical whiteboard on the Galaxy spectrophotometer within 5 min. The detection conditions are: no excitation light wavelength, emission light wavelength is empty, Positioning delay is 1.0, Number of intervals is 1, Interval time is 1.0s, setting the instrument reading before shaking mode, shaking diameter is 1 Millimeter, using the set of positive controls, blank controls, and related data and calculation formulas, calculate the up-regulation rate of the sample. The results are shown in Table 1.

 Up-regulation rate = (sample luminescence number - DMSO luminescence number) / DMSO luminescence number χ 100% The activity of the synthesized compound was evaluated by the above-described ΒΜΡ-2 screening model. 0.1% DMSO was used as the negative control, 0.4 M Lovastatin was used as the positive control, and the test drug concentration was 4 μΜ. The activity measurement results are shown in Table 1. Table 1 shows the structures of preferred compounds of the invention, but does not limit the invention in any way. Table 1 Structure of the compound of the present invention and up-regulation of ΒΜΡ-2 activity in vitro

Acyl]-5,6-dimethoxy-oxime

 Methyl -2-[3 '-(4"-methoxyphenyl) propylene

G33-2 C ₂₁ H ₂₁ N0 ₄ acyl] -5,6-dimethoxy-oxime 46.76

C ₂₂ H ₂₂ ClNO small chloroethyl-2-[3,-(4"-methoxybenzene)

 G33-3 4 enoyl] -5,6-dimethoxy" 哚 15.50

 (3⁄4H-acetyl-2-[3, -(4"-fluorophenyl) propylene

G33-4 C ₂₁ H ₁₈ FN0 ₄ acyl] -5,6-dimethoxy-oxime 30.2

OH

 (E)- l-( 2,-Hydroxyethyl)-2-[3,-(4"-fluorobenzene)

G33-5 C ₂₁ H ₁₈ FN0 ₄ acryloyl]-5-acetoxy-吲哚' 28.9

NH ₂

C ₂₁ H ₁₉ FN ₂ 0 (E)-\- ( 2,-aminoethyl) -2-[3,-(4,,-fluoro

 G33-6 3 phenyl)acryloyl]-5-acetoxy-purine 30.1

OMe

 (E)-\ - ( 2,-methoxyethyl) -2-[3,- (4,,-

G33-7 C ₂₂ H ₂₀ FNO ₄ fluorobenzene)acryloyl]-5-acetoxy" 哚 35.6

The results of multiple activity assays demonstrated that the compounds of the invention both upregulate bone morphogenetic protein-2. Among them, the compounds in Table 1 are 2dB, 7b, 5b, lc, 6b, le, 2c, 2e, 2f, 2dA, 8b, 10b, lib, 12b, G33-1, G33-2, G33-4, G33-5, The activity of G33-6, G33-7, and 24b is stronger than that of the reference drug. The up-regulation rate of compounds 6b, le, 2e, 2c, 12b, etc. is about 100%, and the activities of the compounds ldBl, 4c, 10c, 8e, 3c, 23c are The comparator is equivalent. Experimental example 2 in vivo activity experiment

On the basis of the in vitro activity screening results, the compounds G39, S25, 3c and 8b which were combined in this subject were selected for in vivo activity evaluation. SAMP6 (Senescence-accellerated mouse, strain P6, purchased from Peking University Medical Laboratory Animal Center) was selected as a model for in vivo activity screening, 19-week-old SAMP6 mouse, SPF grade. A total of 35, 14 females Mouse, 21 male mice. Female mice weighed 25-35 g and male mice weighed 30-38 g. The positive control drugs were lovastatin (Lovastatin, Lov, purchased from Zhejiang Ruibang Pharmaceutical Co., Ltd.) and strontium mnelate (Sr, purchased from Beijing Huafeng Lianbo Technology Co., Ltd.); 0.5% MC (methylcellulose aqueous solution).

 Reagents: Immunohistochemistry used primary antibody BMP-2 antibody purchased from American Abeam (item number abl4933), secondary antibody purchased from American Zymed (product number PV6001). Mouse bone alkaline phosphatase (BAP) kit and mouse (urine) The deoxypyridinoline (DPD) kit is a product of American ADL Company. The osteocalcin test kit is a product of Beijing Zhongtong Lanbo Clinical Laboratory. The urinary creatinine (Cr) kit is manufactured by Baiding Bioengineering (Beijing) Co., Ltd.

 After purchasing SAMP6 mice, they were placed in the laboratory animal room barrier system, and the common word feed was used for one week. Female rats are each caged, and males are each caged. At room temperature 18-23 °C, the water is sufficient, the water bottle and litter are changed twice a week, and the weight is averaged every 10 days. The bone density of the mice was measured, and the SAMP6 male and female mice were randomly divided according to the bone density value. The mice were divided into 7 groups, 2 female rats and 3 male rats in each group. Female 1 cage 2, male 1 cage 1 .

 The lanthanum strontium was dissolved in physiological saline, and the remaining drugs were all suspended in 0.5% MC.

 Preparation method of 0.5% MC (methylcellulose) solution: Add 5 g of MC to 1000 ml of distilled water and mix well.

 The dose of the experimental drug was set as follows: lovastatin and lanthanum strontium were administered at doses of 10 mg/kg-d and 625 mg/kg'd, respectively, and the remaining doses were 30 mg/kg. d, the blank group was given a 0.5% MC solution. The mode of administration is all intragastric. It was administered at 9 am every day, once a day, continuously, and administered for 3 months for 13 weeks. The experimental results are as follows:

BMP-2 expression level in mice: At the end of the administration, the left femur of the mice was frozen and sectioned, and then BMP-2 immunohistochemical staining was performed to determine the cytoplasmic staining level of BMP-2 positive cells. The specific values and statistical results are shown in Table 2. Table 2 Percentage of BMP-2 positive cells in SAMP6 mice of each administration group (mean±SD) Compound Lov ^a Sr MC G39 ^b S25 3c ^a 8b ^a area% 2.23±0.52 2.19±0.71 1.25±0.21 2.19±0.31 2.47±0.79 2.48±0.76 2.27±0.51 a p<0.05 compared with the blank control MC group (n= 5) _; ^b compared to the blank control MC group, p < 0.005 (n = 5). The results of immunohistochemical staining of mouse femur BMP-2 showed that the expression of BMP-2 in femur tissues of all the mice was significantly improved compared with the control group (MC) of the rapidly aging mouse model. Among them, the expression of BMP-2 in the Lov, G39, 3c and 8b groups was significantly improved, and no significant difference was found in the Sr and S25 groups. The expression levels of BMP-2 in the femur of mice in the G39 and 8b groups were comparable to those in the Lov group. The expression level of femur BMP-2 in the 3c-administered group was higher than that in the Lov and Sr control groups.

 Bone mineral density in mice: Bone density was measured using a digital cone beam flash bone densitometer OSTEOCORE 3 manufactured by MEDILINK, France. The bone densitometer is a dual energy X-ray absorptiometry

(dual-energy X-ray absorptiometry, DXA). Data analysis was performed using the small animal analysis software (V6.14) included in the instrument. In the software environment, the mouse bones were manually filled and the software calculated the bone density of the filled area. Analysis of bone density selected three regions of interest (ROIs: regions of interest): 1. total: whole body; 2. spine: spine; 3. left hind leg: left hind leg. Bone mineral density collection time points were 0th week of administration (19 weeks old mice), 4th week (23 weeks old mice), 8th week (27 weeks old mice), 12th week (mouse 31) Zhou Ling). The bone mineral density data at each time point is shown in Table 3.

Table 3 BMD data of 3 ROIs at each time point (mean±SD) group age/weeks 19 23 27 31

ROIs BMD (g/cm ² )

 Lov 0.067±0.002 0.069±0.003 0.069±0.003 0.070±0.003

Sr 0.068±0.003 0.065±0.003 0.069±0.002 0.070±0.007

MC 0.067±0.003 0.065±0.004 0.067±0.004 0.067±0.002

G39 total 0.066±0.005 0.066±0.004 0.074±Ό.009 0.068±0.002

S25 0.065±0.002 0.064±0.004 0.068±0.004 0.070±0.006

3c 0.067±0.004 0.067±0.006 0.069±0.005 0.072±0.005

8b 0.067±0.002 0.066±0.004 0.068±0.007 0.072±0.003 ^a

Lov 0.057±0.005 0.073±0.009 0.091±0.007 0.095±0.007 ^a Sr 0.060±0.009 0.066±0.010 0.089±0.015 0.090±0.019

MC 0.056±0.007 0.071±0.005 0.082±0.014 0.087±0.007

G39 spine 0.053±0.007 0.067±0.013 0.094±0.020 0.086±0.004

S25 0.052±0.007 0.064±0.010 0.083±0.008 0.089±0.013

3c 0.060±0.008 0.072±0.015 0.088 ± 0.011 0.090±0.013

8b 0.055±0.008 0.069±0.013 0.081±0.006 0.091±0.008

Lov 0.061±0.006 0.055±0.003 0.053±0.003 0.046±0.003

Sr 0.065±0.005 0.051±0.01 1 0.049±0.003 0.047±0.006

MC left 0.059±0.004 0.050±0.003 0.047士0.002 0.046±0.002

G39 hind leg 0.064±0.003 0.056±0.002 0.059±0.002 0.050 0.001

S25 0.061±0.007 0.051±0.003 0.048±0.003 0.050±0.007

3c 0.064±0.004 0.051±0.006 0.043±0.002 0.050士 0.004

8b 0.064±0.003 0.050±0.003 0.049±0.003 0.053±0.008 a compared with the blank control MC group, p<0.05 (n=5);

The bone mineral density measurement after 13 weeks of continuous administration showed that compared with the model control group, the bone density of the mice in the Lov, Sr, S25, 3c and 8b administration groups increased, and the increase in the 3c and 8b groups was more pronounced. The bone mineral density of the 8b group was the most obvious. The spinal bone density of the mice in the Low Sr, 3c and 8b groups was significantly increased. The bone density of the spine in the Lov group was the most obvious; S25, 3c and 8b were administered. The bone density of the left hind leg of the mice in the group was significantly increased, and the changes of the control drugs Lov and Sr were not obvious.

The trend of bone mineral density in mice can also be seen from Table 3. The spinal bone density of the mice in each test group increased during the administration period, and the increase trend of the drug-administered group was stronger than that of the model control group. The bone density of the left hind leg of the group showed a decreasing trend, and the decrease trend of the drug-administered group was slower than that of the model control. The curve of bone mineral density in the whole body of mice was complicated during the administration. After 1 month of administration, the bone mineral density of the mice decreased, and then gradually increased. The peak of bone mineral density in SAMP6 mice occurs around 4 months, and then the bone density decreases gradually. After administration for a period of time, the bone density of the whole body has been improved relative to the initial administration. The G39 group was more special. After 2 months of administration, the G89 group had the most obvious increase in bone mineral density, spinal bone density, and left hind leg bone density. However, the bone density was not more than 3 months after administration. Increase Image, the reason for further research.

 Morphometry of mouse bone tissue: After the end of the administration, the right femur of the mouse was taken into a non-decalcified bone slice to determine the histomorphometric data of the bone tissue. Morphometry of non-decalcified bone sections was performed using a Leica-Qwin image analyzer system. Trabecular volume percentage (TBV%): The percentage of trabecular bone volume to the total volume of the bone marrow cavity measured, is the main indicator of bone mass level; trabecular bone absorption surface percentage (TRS%): irregular, rugged The percentage of the trabecular surface that accounts for the surface of the trabecular bone, which determines the activity of osteoclasts; the percentage of trabecular bone formation surface (TFS%): the percentage of the osteoid surface covered by osteoblasts to the trabecular surface. It can determine the activity of osteoblasts; the average width of the inner surface of the cortex (OSW): the average width of the osteoids covered by osteoblasts on the inner surface of the cortex. The detailed data of each administration group is shown in Table 4.

Table 4 Morphometric data of bone tissue of SAMP6 mice in each drug-administered group (mean±SD)

Group TBV% TFS% TRS% OSW )

Lov 7.44±2.05 ^a 6.22±0.97 ^a 6.64±1.64 6.59±0.29 ^a

 Sr 6.72±5.47 5.25士 2.03 7.56±1.86 5.63±0.66

 MC 3.88±0.58 4.46±0.47 7.47±1.12 5.93±0.42

G39 4.95 ± 0.80 ^a 5.89 ± 0.61 ^b 7.09 ± 1.31 5.55 ± 0.82

S25 8.94士3.68 ^a 6.54±0.81 ^b 6.29 soil 1.48 5.50±0.82

3c 5.95士 1.93 5.13士 0.82 6.45士0.60 5.85士 0.64

8b 7.10±2.15 ^a 5·55±0.93 6.45±0.82 5.76±0.58

a p<0.05 (n=5) compared with the blank control MC group _; ^b < 0.005 (n=5) compared with the blank control MC group. The percentage of trabecular bone volume (TBV%^ determined), the femoral TBV% of each group was significantly higher than that of the model control group, and the TBV% of the Lov control group and the G39, S25, and 8b drug groups increased significantly. Ding 8 ¥% is the main indicator to measure the bone level, indicating that the bone mass of the mice in each drug-administered group is higher than that in the model control group (MC group).

The results of trabecular bone formation surface percentage (TFS%) showed that the femoral TFS°/03⁄4 of the mice in each treatment group was significantly higher than that of the model control group, and the TFS°/^ level of the Lov control group, G39 and S25 mice were compared. The model control group was significantly improved. TFS% is the bone-like surface covered by osteoblasts. The percentage of the surface of the beam that determines the activity of the osteoblasts. The results confirmed that the Lov group, the G39 group and the S25 group significantly improved the osteoblast activity of the mice.

 The percentage of trabecular bone absorption surface (TRS%) was determined. The TRS% of the Sr control group was comparable to that of the model group, and the TRS% of all other groups were lower than the model control group. TRS% refers to the percentage of irregular, uneven trabecular surface that occupies the surface of the trabecular bone, which determines the activity of osteoclasts. From the results, except for Sr, other drugs have a tendency to reduce the activity of mouse osteoclasts, but there is no statistically significant difference.

 As a result of the average width of the intraosseous bone-like bone (OSW), the OSW of the Lov drug control group was significantly higher than that of the model control group, and the OSW of the other administration groups was not significantly different from that of the model group. OSW is an important marker of osteoblast activity in cortical bone, so other compounds other than Lov have no effect on increasing cortical bone osteoblast activity.

 The band of blue river-like sputum in the photo of the non-decalcified bone section of the mouse is the trabecular bone. The photo is taken in part, which does not represent the whole bone, but the model control group (MC group) can be seen. There are fewer trabecular bones than in each administration group.

 The results of bone histomorphometry showed that Lov, G39, S25 and 8b could improve bone mass levels in mice; Lov, G39 and S25 improved the activity of mouse osteoblasts, but had no effect on cortical bone osteoblast activity; The effect of each drug-administered group on osteoclast activity of mice was not significant.

 Changes in body weight of the mice: During the administration, the body weight of the mice was weighed on the 0th, 5th, 12th, 21st, 37th, 51st, 66th, and 80th day of administration, and the weights of the 8th time were all non-fasting body weight. Detailed data and trends are shown in Table 5. The body weight of each group of mice increased slowly, suggesting that each group of mice had no serious toxicity. Table 5 Changes in body weight of mice during administration (non-fasting weight) Group j 0d 5d 12d 21d 37d 51d 66d 80d

Lov 35.40±1.95 35.83±1.56 36.40±1.90 36.16±2.00 37.94±1.55 39.17±1.12 38.55±1.45 38.92±1.53 Sr 33.24±4.84 34.39±5.18 35.84±4.40 34.43±5.16 35.33±4.34 37.39±5.15 37.70±3.96 36.47±5.88 MC 31.17±3.26 32.01±2.24 33.38±1.42 33.35±2.07 34.58±1.92 35.64±2.46 36.03±1.89 36.04±2.59 G39 32.62±4.47 32.51±4.55 34.54±4.01 33.33±4.52 34.52±4.75 35.91±5.70 36.06±5.63 36.04±5.92 S25 31.81±2.77 32.31±3.56 33.60±2.72 32.56±2.89 33.61i4.10 36.82±3.31 35.95±4.01 36.59±2.05 3c 33.91±4.04 34.09±4.92 35.15±4.78 35.02±5.04 36.16±4.89 37.48±4.69 37.46±4.99 37.57± 4.89 8b 34.47±2.54 35.04±2.67 36.74±4.96 36.31±4.87 37.88±6.17 40.25±5.43 40.46±5.96 39.98±3.96

The following examples are intended to provide a more complete understanding of the invention, and are not intended to limit the invention in any way. The structures of all the compounds in the present invention were determined by ¹ H NMR. Example 1: 2-ethoxycarbonyl-benzothiophene (3b)

Slowly drip in DMF (60 ml) containing o-nitrobenzaldehyde (4.5 g, 30 mmol) and anhydrous K ₂ CO ₃ (5.0 g, 36.2 mmol) cooled to 0 ° C in an ice bath. Ethyl thiol (3.29 ml, 30 mmol) ₀ dropwise addition was completed, stirred at 0 ° C for 30 min, and then reacted in a 60 ° C oil bath for 12 h. The reaction solution was poured into ice-water, the solid was collected by filtration, the solid was dissolved in chloroform, dried over anhydrous Na ₂ S0 _4, filtered, and spin dry the solvent by silica gel column chromatography to give a yellow solid 5.80 g (94%).

iHNMR ( CDC1 ₃ ) δ: 1.42 (t, J = 7.0 Hz, 3H), 4.42 (q, J = 7.0 Hz, 2H), 7.39-7.47 (m, 2H), 7.86-7.89 (m, 2H), 8.06 (s, 1H). MS (EI+) m/z: 206[M]+. HRMS (EI+): found 206.0397 [M] ⁺ , (Calcd for C „ H ₁₀ O ₂ S: 206.0397 ). Example 2: 2-(2,-Methylsulfoxide)-acetylbenzothiophene (3c)

Under nitrogen protection, 60% sodium hydride (280 mg) was placed in a three-necked flask, and petroleum ether was washed three times to wash away the oil of sodium hydride. A constant pressure dropping funnel containing DMSO (8 ml) was added, and the remaining small amount of petroleum ether was drained under reduced pressure. DMSO was added to sodium hydride, and THF (8 ml) in which 2-ethoxycarbonyl-benzothiophene (3b) (200 mg, 0.97 mmol) was dissolved was quickly added to a constant pressure dropping funnel. Drain the air quickly, add nitrogen, and repeat three times. The above reaction system was heated to 70-75 ° C, and the solution released a large amount of hydrogen. After the bubbles were allowed to cool, the mixture was cooled to room temperature and then cooled with an ice bath, and the THF solution in the dropping funnel was slowly added dropwise. After the addition, stir at room temperature for 30 min. The reaction solution was poured into 3 volumes (60 ml) of ice water. The pH was adjusted to 3 to 4 with 2N hydrochloric acid. The reaction solution was extracted with chloroform (80 ml×2), and the mixture was washed with distilled water (160 ml×3). The chloroform was dried over anhydrous Na ₂ SO ₄ . The Na ₂ SO _{4 4 was} filtered off, and the chloroform phase was evaporated to give a white solid (202 mg, 87%). ^{] HNMR (CDCI3) δ: 2.79} (s, 3H), AB system (4.33, 4.41, J = 13.2 Hz, 2H), 7.43 (t, J = 7Hz, IH), 7.51 (t, J = 7.0 Ηζ, ΙΗ ), 7.88(d, J= 7.0 Hz, IH), 7.94(d, J = 7.0 Hz, IH), 8.09(s, IH). MS (EI+) m/z: 238 [M]+. HRMS (EI+ ): found 238.0102 [M]+, (Calcd for CUHK SZ: 238.0122 ). Example ³ : 2-(2,-Methylsulfonyl)acetyl-benzothiophene (3d)

2-(2,-Methyl sulfoxide) acetyl-benzothiophene (3c) (50 mg, 0.21 mmol) dissolved in glacial acetic acid (2 ml), slowly added 30% H ₂ O ₂ (1) Ml). After the addition, the reaction was stirred at room temperature for 5-6 h. The product was extracted by the addition of dichloromethane (3 ml EtOAc). EtOAc (EtOAc)

1H NMR (CDC1 ₃ ) 5: 3.17 (s, 3H), 4.60 (s, 2H), 7.45 (t, J = 7.0 Hz, 1H), 7.53 (t,

J= 7.0 Hz, IH), 7.89 (d, J= 8.0 Hz, 1H), 7.96 (d, J 8.0 Hz, IH), 8.11(s, IH). HRMS (EI+): found 254.0074 [M]+, (Calcd for C„H ₁₀ O ₃ S ₂ : 254.0071).

 Example 4: 2-Ethoxycarbonyl-5,6-methylenedioxy-benzothiophene (8b)

Using 3,4-methylenedioxy-6-nitrobenzaldehyde and ethyl decylacetate as raw materials, the orange yellow solid 2-ethoxycarbonyl-5,6-methylene II was synthesized according to the method of Example 1. Oxy-benzothiophene (68.5%) ₀

^{] HNMR (CDCI3) δ: 1.39} (t, J = 7.2 Hz, 3H), 4.37 (q, J = 7.2 Hz, 2H), 6.04 (s, 1H), 7.19 (s, IH), 7.20 (s, IH ), 7.89(s, IH). MS (EI ⁺ ) m/z: 250 [M] ⁺ . HRMS (EI ⁺ ): found 250.0305 [M]+, (Calcd for C ₁₂ H ₁₀ O ₄ S: 282.0002 ) .

 Example 5: 2-(2,-Methylsulfoxide)acetyl-5,6-methylenedioxy-benzothiophene (8c) was synthesized as a yellow material from compound 8b. Solid powder (90%).

" ^l WM (CDCI3) δ: 2.77(s, 3H), AB system(4.26, 4.33, J= 13.2 Hz, 2H), 6.08(s, IH), 7.22(s, 1H), 7.24(s, 1H) , 7.91(s, 1H). HRMS (EI ⁺ ): found 282.0002 [M]+, (Calcd for C ₁₂ H _{1 ()} 0 ₄ S ₂ : 282.0021 ). Example 6: 2-(2,-Methanesulfone Acetyl-5,6-methylenedioxy-benzothiophene (8d) Using the compound 8c as a raw material, a pale yellow solid powder (80.0%) was obtained by the method of Example 3.

^MR ( CDC1 ₃ ) 5: 3.15 (s, 3H), 4.53 (s, 2H), 6.09 (s, 2H), 7.22 (s, 1H), 7.24 (s, 1H), 7.94 (s, 1H). MS (EI+) m/z: 298 [M]+. HRMS (EI+): found 297.9967 [M]+, (Calcd for C ₁₂ H ₁₀ O ₅ S ₂ : 297.9970 ). Example 7: 2-ethoxycarbonyl-benzofuran (9b)

 DMF (5 ml), ethyl bromoacetate (118 mg, 0.71 mmol), salicylaldehyde (146.6 mg, 1.2 mmol), anhydrous potassium carbonate (166 mg, 1.2 mmol) were added to the reaction mixture. The reaction was carried out in a 100 ° C oil bath for 4 h. After returning to room temperature, DMF was distilled off first. Dissolve in chloroform and wash the chloroform phase with water. When stratified, many insolubles appear in the chloroform phase. The insoluble material was filtered off with suction, and the filter cake was washed with chloroform several times. After drying the solvent, silica gel column chromatography afforded 57 mg of pale yellow oil (55.9%).

iHNMR CDCH 1.35 (t, J = 7.2 Hz, 3H), 4.37 (q, J = 7.2 Hz, 2H), 7.22 (t _; J = 7.6 Hz, 1H), 7.36 (t, J = 7.6 Ηζ, ΙΗ), 7.45 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H). MS (ESI+) m/z: 191.4 [M+H] ⁺ .HRMS (EI+): found 297.9967 [M]+, (Calcd for C _u H ₁₀ O ₃ : 190.0630 ). Example 8: 2-(2,-Methylsulfoxide)acetobenzofuran (9c)

 A yellow solid 2-(2,-methylsulfoxide)acetyl-benzofuran (29.6%) was obtained by the procedure of Example 2 from 9b.

^{! HNMR (CDCI3) δ: 2.85} (s, 3H), AB system (4.30, 4.39, J = 13.2 Hz, 2H), 7.35 (t, J = 7.2 Hz, 1H), 7.54 (t, J = 7.2 Hz, 1H), 7.61 (d, J = 8.0 Ηζ, ΙΗ), 7.68 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H). MS (EI+) m/z: 222 [M]+. HRMS (EI+): found 222.0350 [M]+, (Calcd for C s H ₁₀ O ₃ S: 222.0351 ). Example 9: 2-ethoxycarbonyl -4-chloro-benzothiophene (4b)

Sodium hydroxide (100 mg, 2.5 mmol) was dissolved in water (0.2 ml). Add 2-chloro-6-fluoro-benzaldehyde (200 mg, 1.26 mmol) and dioxane (2 ml), reacted in a 70 ° C oil bath for 7 h. Filter and wash the filter cake with chloroform. Chromatographic separation on a fully automated rapid preparative chromatograph gave a lightly creamy product which, after cooling, was a yellow solid.

^J HNMR ( CDC1 ₃ ) δ: 1.43 (t, J = 7.0 Hz, 3H), 4.43 (q, J = 7.0 Hz, 2H), 7.35-7.41 (m, 2H), 7.73-7.75 (m, 1H). MS (EI): 240. 'CNMR (CDC1 ₃ ) δ: 14.30 (C-2"), 61.83 (C-1 "), 121.25 (C-3), 124.81 (C-7), 127.46 (C-6 ), 128.35(C-5), 130.46(C-4), 134.76(C-4a), 137.27(C-2), 143.10(C-7a), 162.39(C-1 ').MS (EI+) m /z : 240 冈+, 242 [M+2] +· HRMS (EI+ ): found 240.0014 [M] ⁺ , (Calcd for C„H ₉ 0 ₂ SC1: 240.0012) Example 10: 2-(Γ- Hydroxy-2,-methylsulfoxide)-ethyl-benzothiophene (3e)

 2-(2,-Methylsulfoxide)-acetylbenzothiophene (3c) (100 mg, 0.42 mmol) was added to

A mixture of THF (2 ml) and distilled water (2 ml) was stirred and dissolved. Sodium borohydride (20 mg, 0.53 mmol) was added portionwise in an ice-bath and stirred at room temperature for 0.5 h. Filtration and the filtrate was extracted with chloroform. After drying the solvent, it was separated by silica gel column chromatography to give pale-yellow solid. 2-(1,-hydroxy-2,-methylsulfenyl)-ethyl-benzothiophene 46 mg (54.2%) o

 !HNMR (CDCI3) δ: 2.74 (s, 3H), 3.06-3.32 (m, 2H), 5.73-5.77 (m, 1H),

7.29 (s, 1H), 7.32-7.36 (m, 2H), 7.73-7.83 (m, 2H). MS (ESI +) m / z : 263.0 [M + Na] + .HRMS (ESI +): found 263.01885 [M + Na] +, (Calcd for C u H 12 0 2 S 2 Na: 263.01764). Example 11: 2-ethoxycarbonyl-4-methoxy-benzofuran (10b)

 Using 2-methoxy-6-hydroxybenzaldehyde and ethyl bromoacetate as starting materials, the pale yellow solid 2-ethoxycarbonyl-4-methoxy-benzofuran was obtained by the method of Example 7. %).

_{^{! HNMR (CDC1 3) 6:}} 1.42 (t, J = 7.2 Hz, 3H), 3.95 (s, 3H), 4.43 (q, 7.2 Hz, 2H), 6.68 (d, J = 8.0 Hz, lH), 7.19 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.62(s, 1H). MS (EI+) m/z: 220[M] +. HRMS (EI+ ): found 220.0732 [M] ⁺ , (Calcd for C ₁₂ H ₁₂ 0 ₄ : 220.0736). Example 12: 2-ethoxycarbonyl-5-methoxy-benzofuran (l ib) Using 3-methoxy-6-hydroxybenzaldehyde and ethyl bromoacetate as starting materials, the white solid 2-ethoxycarbonyl-5-methoxy-benzofuran was obtained by the method of Example 7. ).

 1HNMR (CDC13) 5: 1.43 (t, J = 12 Hz, 3H), 3.85 (s, 3H), 4.44 (q, J = 7.2 Hz, 2H), 7.05 (d, J = 2.4 Hz, IH), 7.06 (dxd, J = 8.2 Hz, 2.4Hz, IH), 7.46-7.49(m, 2H). MS (EI+) m/z: 220[M] +. HRMS (EI+ ): found 220.0733 [M] +, ( Calcd for C12H1204: 220.0736). Example 13: 2-ethoxycarbonyl-6-methoxy-benzofuran (12b)

 4-methoxy-2-hydroxybenzaldehyde and ethyl bromoacetate were used as starting materials, and the white solid 2-ethoxycarbonyl-6-methoxy-benzofuran was obtained by the method of Example 7. ).

!HNMR (CDC1 ₃ ) 5: 1.42 (t, J = 7.2 Hz, 3H), 3.87 (s, 3H), 4.42 (q, J = 7.2

Hz, 2H), 6.94 (dxd, J = 8.8 Hz, 2.0 Hz, lH), 7.07 (d, J = 2.0 Hz, 1H), 7.47(s, IH), 7.53(d, J = 8.8 Hz, 1H) .MS (EI ⁺ ) m/z: 220 [M] ⁺ . HRMS (EI+): found 220.0739 [M]+, (Calcd for C ₁₂ H ₁₂ 0 ₄ : 220.0736).

 Example 14: 2-ethoxycarbonyl-7-methoxy-benzofuran (13b)

 Starting from 3-methoxy-2-hydroxybenzaldehyde and ethyl bromoacetate as a starting material, the white solid 2-ethoxycarbonyl-7-methoxy-benzofuran (58%) was obtained. ).

^J HNMR (CDC1 ₃ ) 5: 1.42 (t, J = 7.2 Hz, 3H), 4.02 (s, 3H), 4.44 (q, J = 7.2 Hz, 2H), 6.92 (d, J = 7.6 Hz, lH) , 7.21 (d, J = 7.6 Hz, IH), 7.22 (dxd, J = 7.6 Hz _; 3.2 Hz, IH), 7.52(s, IH). MS (EI+) m/z: 220 [M] +.HRMS (EI+ ): found 220.0733 [M]+, (Calcd for C ₁₂ H ₁₂ 0 ₄ : 220.0736).

 Example 15: 2-ethoxycarbonyl-5,6-dimethoxy-benzothiophene (7b)

2-Nitro-4,5-dimethoxybenzaldehyde (2.0 g, 9.5 mmol) and a catalytic amount of NaOH were added to 25 ml of DMF, and the mixture was cooled to 0 ° C in an ice bath, and ethyl mercaptoacetate was slowly added dropwise. 1.25 ml, 11.4 mmol) ₀ drops were added, the reaction was stirred at 0 ° C for 30 min, then reacted in a 100 ° C oil bath for 2 h. The reaction solution was poured into ice-water, the solid was collected by filtration, the solid was dissolved in chloroform, dried over anhydrous Na ₂ S0 ₄ overnight. After drying the solvent, it was separated by silica gel column chromatography to give white crystals of 2-ethoxycarbonyl-5,6-dimethoxy-benzo. Thiophene 1.58 g (62.6 %).

¹ H NMR (CDC1 ₃ ) 5: 1.405 (t, J = 7.2 Hz, 3H), 3.95 (s, 3H), 3.98 (s, 3H), 4.38 (q, J = 7.2 Hz, 2H), 7.24 (s, 1H), 7.25(s, 1H), 7.93(s, 1H). MS (EI+) m/z: 266 [M] +. HRMS (EI+ ): found 266.0613 [M]+, (Calcd for C ₁₃ H ₁₄ 0 ₄ S: 266.0631 ).

 Example 16: 2-ethoxycarbonyl-7-fluoro-benzofuran (14b)

 Using 3-fluoro-2-hydroxybenzaldehyde and ethyl bromoacetate as a starting material, the title compound was obtained as a yellow oil (yield: 2-ethoxycarbonyl-7-fluoro-benzofuran (47%).

'HNMR (CDC1 ₃ ) 6: 1.43 (t, J = 7.2 Hz, 3H), 4.45 (q, J = 7.2 Hz, 2H), 7.14 - 7.25 (m, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 2.8 Hz, 1H). MS (EI+) m/z: 208 [M] +· HRMS (EI+ ): found 208.0531 [M]+, (Calcd for CuH C^F: 208.0536 ) o

Example 17: ² -ethoxycarbonyl-5,7-dichloro-benzofuran (15b)

 Using 3,5-dichloro-2-hydroxybenzaldehyde and ethyl bromoacetate as starting materials, the white solid solid 2-ethoxycarbonyl-5,7-dichloro-benzofuran was obtained by the procedure of Example 7. 65%).

_{^{! HNMR (CDCl 3) 5:}} 1.44 (t, J = 7.2 Hz, 3H), 4.46 (q, J = 7.2 Hz, 2H), 7.46 (d, J = 1.6 Hz, 1H), 7.48 (s, 1H) , 7.57(d, J = 1.6 Hz, 1H). MS (EI+) m/z: 258[M] ⁺ , 260 [M+2] ⁺ , 262 [M+4] +. HRMS (EI+ ): found 257.9840 [M]+, (Calcd for C _n H ₈ 0 ₃ Cl ₂ : 257.9850 ) c

 Example 18: 2-Ethoxycarbonyl-5-methoxycarbonyl-benzothiophene (5b)

 Using 2-nitro-5-methoxyformylbenzaldehyde and ethyl decylacetate as starting materials, the reaction was carried out in the same manner as in Example 1 to give a white solid 2- ethoxycarbonyl-5-methoxycarbonyl-benzothiophene ( 5b) (97%).

_{^{! HNMR (CDCl 3) 6:}} 1.43 (t, J = 7.2 Hz, 3H), 3.97 (s, 3H), 4.43 (q, J = 7.2 Hz, 2H), 7.91 (d, J = 8.4 Hz, 1H) , 8.10(d, J = 8.4 Hz, 1H), 8.12(s, 1H), 8.58(s, 1H ). HRMS (EI+ ): found 264.0452 [M]+, (Calcd for C ₁₃ H ₁₂ 0 ₄ S: 264.0456 ).

Example 19: 2-Acetyl-5-methoxycarbonyl-benzothiophene (lc) Under ice-cooling, 3-aldehyde--4-nitro-benzoic acid methyl ester (1.95 g, 9.3 mmol), anhydrous K ₂ C0 ₃ (1.55 g, 11.2 mmol) and ethanethiol were added to 60 ml of DMF. 0.70 mg, 11.3 mmol). After stirring for 10 min, it was stirred at room temperature for 1 h. The K ₂ C0 _{3 was} filtered off, the DMF was evaporated to dryness, and the crude product was dissolved in chloroform. The chloroform phase was washed with water and dried over anhydrous sodium sulfate. After the solvent was evaporated to dryness, silica gel column chromatography was afforded white crystals of 3- aldehyde 4-ethylthio-benzoic acid methyl ester (lb) 1.81 g (86.5%).

_{^{! HNM (CDC1 3) 5:}} 1.44 (t, J = 7.6 Hz, 3H), 3.05 (q, J = 7.6 Hz, 2H), 3.94 (s, 3H), 7.42 (d, J = 8.4 Hz, 1H) , 8.12 (dd, J = 8.6 Hz, 1.6 Ηζ, ΙΗ), 8.44 (d, ·/= 1.6 Hz, 1H), 10.25 (s, 1H).

3-Aldehyde 4-ethylthio-benzoic acid methyl ester (lb) (1.0 g, 4.5 mmol), calcium oxide (125 mg, 2.2 mmol), chloroacetone (825 mg, 8.9 mmol) was added to 20 ml of DMF. ). The reaction was carried out in a 90 ° C oil bath for 10 h. Filter and the filtrate was evaporated to dryness. The crude product was dissolved in chloroform, the chloroform phase was washed with water, and the chloroform phase was dried over anhydrous sodium sulfate. After rotary evaporation after silica gel column chromatography to give yellow solid of 2-acetyl-5-methoxy-formyl - benzothiophene 0.929 g (88.9%) ₀

^! ΗΝΜΚ (CDC1 ₃ )5: 2.69(s, 3H), 3.98(s, 3H), 7.93(d, J = 8.4 Hz, 1H), 8.00(s, 1H), 8.1 l(d, J = 8.4 Hz , 1H), 8.61 (s, 1H). HRMS (EI+): found 234.0339 [M]+, (Calcd for C ₁₂ H ₁₀ O ₃ S: 234.0351 ). Example 20: 2-ethoxycarbonyl-6-methoxycarbonyl-benzothiophene (6b)

 Using 2-nitro-4-methoxyformylbenzaldehyde and ethyl decylacetate as starting materials, the reaction was carried out in the same manner as in Example 1 to give a white solid 2-ethoxycarbonyl-6-methoxycarbonyl-benzothiophene ( 6b) (97%).

iHNMR (CDCl ₃ ) 5: 1.43 (t, J = 7.2 Hz, 3H), 3.97 (s, 3H), 4.43 (q, J = 7.2 Hz,

2H), 7.91 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 8.07(s, 1H), 8.58(s, 1H).

HRMS (EI+): found 264.0449 [M]+, (Calcd for C ₁₃ H ₁₂ 0 ₄ S: 264.0456 ). Example 21: 2-Acetyl-5-carboxy-benzothiophene (le)

2-Acetyl-5-methoxycarbonyl-benzothiophene ( lc) (133 mg, 0.57 mmol) was added to 5 ml of dioxane and dissolved by stirring. 2 ml of water in which NaOH (34 mg, 0.85 mmol) was dissolved was added to dioxane and stirred at room temperature for 2 h. Evaporate the reaction solution, dissolve the crude product in water, adjust the pH to 2 with 5% hydrochloric acid. A solid precipitated. Filtration, the filter cake was washed with water and dried to give 36 mg of brown solid product of 2-acetyl-5-carboxy-benzothiophene (29%).

¹ H NMR (CDC1 ₃ ) 6: 2.66 (s, 3H), 8.01 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 8.15 (d, J = 8.4 Hz, IH), 8.48 (s, 1H), 8.61 (s, IH), 13.1(s, IH). MS (ESF) m/z: 219[MH]'. HRMS (ESI" ): found 219.01148 [M- H] -, (Calcd for C _n H ₇ 0 ₃ S: 219.01159). Example 22: 2-acetyl-6-methoxycarbonyl-benzothiophene (2c) using 3-aldehyde-4-nitro-benzoic acid methyl ester and ethyl mercaptan as raw materials, The reaction of the method of Example 19 gave a yellow solid, 2-ethylthio-3- aldehyde-benzoic acid methyl ester (2-b) (101.2%).

1HNMR (CDC1 ₃ ) 5: 1.39 (t, J = 7.6 Hz, 3H), 3.06 (q, J = 7.6 Hz, 2H),

3.96(s, IH), 7.90(s, IH), 7.90(s, IH), 8.08(s, IH), 10.44(s, IH).

The compound 2-b and chloroacetone were used as a starting material to give a yellow solid (yield: 73%). _{^{] HNMR (CDC1 3) 5:}} 2.69 (s, 3H), 3.97 (s, 3H), 7.94 (d, J = 8.4 Hz, IH), 7.96 (s, 1H), 8.05 (d, J = 8.4 Hz, IH), 8.59 (s, IH). HRMS (EI+): found 234.0343 [M]+, (Calcd for C ₁₂ H ₁₀ O ₃ S: 234.0351 ). Example 23: 2-Acetyl-6-carboxy-benzothiophene (2e)

 The compound 2c was used as a starting material to give a brown solid product, 2-acetyl-6-carboxy-benzothiophene (59%).

¹ H NMR (CDCI3) δ: 2.67 (s, 3H), 7.97 (dd, J = 8.4 Hz, 1.2 Hz, IH), 8.10 (d, J = 8.4 Hz, IH), 8.40 (s, IH), 8.65 ( s, IH), 13.2 (s, IH). HRMS (ESF): found 219.01326 [MH]-, (Calcd for CnH ₇ 0 ₃ S: 219.01159). Example 24: 2-(2,-Methylsulfoxide)acetyl-4-chloro-benzothiophene (4c)

 The compound 4b was used as a starting material to give a pale-yellow solid of 2-(2'-methylsulfinyl)acetyl-4-chloro-benzothiophene (4c) (59%).

 HNMR (CDCI3) δ: 2.83 (s, 3H), AB system (4.38, 4.45, J = 13. Hz, 2H),

7.46 (d, J = 4.5 Hz, 2H), 7.79 (t, J = 4.5 Hz, 1H), 8.24 (s, IH). HRMS (EI ⁺ ): Found 271.9733 [M]+, (Calcd for C11H9O2S2CI: 271.9733 ). Example 25: 2_(2'-Methylsulfoxide)acetyl-4-methoxy-benzofuran (10c)

 The compound 10b was used as a starting material to give a yellow solid, 2-(2'-methylsulfoxide) acetyl-4-methoxy-benzofuran (10c) (76%).

 JHNMR (CDCI3) δ: 2.80 (s, 3H), 3.98 (s, 3H), AB system (4.26, 4.39, J =

13.5 Hz, 2H), 6.71 (d, J= 8.0 Hz, 1H), 7.19 (d, J= 8.0 Hz, IH), 7.47 (t, J= 8.0 Hz, IH ), 7.79 (s, IH). HRMS (EI ⁺ ): found 252.0437 [M]+, (Calcd for C ₁₂ H ₁₂ 0 ₄ S: 252.0456 Example ² 6: 2-( ² ,-Methylsulfoxide)acetyl- ⁵ -methoxy-benzene And furan (11c)

 The compound l ib was used as a starting material to give a yellow solid, 2-(2'-methylsulfinyl)acetyl-5-methoxy-benzofuran (11c) (83%).

^{! HNMR (CDCI3) δ: 2.79} (s, 3H), 3.86 (s, 3H), AB system (4.27, 4.37, J = 13.2 Hz, 2H), 7.10 (d, J = 2.0 Hz, lH), 7.15 ( Dxd, J = 8.8 Hz, 2.0 Hz, IH), 7.48 (d, J = 8.8 Hz, IH ), 7.60(s, IH). HRMS (EI+ ): found 252.0439 [M]+, (Calcd for Ci ₂ H ₁₂ 0 ₄ S: 252.0456 ) ₀ Example 27: 2-(2,-Methylsulfoxide)acetyl-5,6-dimethoxy-benzothiophene (7c) Starting from compound 7b, according to the examples The reaction of 2 gave 2-(2'-methylsulfoxide)acetyl-5,6-dimethoxy-benzothiophene (7c) (96%) as a yellow solid.

iHNMR (CDCI3) δ: 2.78 (s, 3H), 3.96 (s, 3H), 3.99 (s, 3H), AB system (4.28 _; 4.35, J = 13.6 Hz, 2H), 7.25 (s, IH), 7.28 (s, IH), 7.96(s, IH). HRMS (EI+): found 298.0306 [M]+, (Calcd for C ₁₃ H ₁₄ 0 ₄ S ₂ : 298.0334 ). Example 28: 2-(2,-Methylsulfoxide)acetyl-6-methoxy-benzofuran (12c)

 The title compound (b) was obtained as a yellow solid (yield: 2-(2'-methylsulfenyl)acetyl-6-methoxy-benzofuran (12c) (51%).

 1HNMR (CDCI3) δ: 2.79 (s, 3H), 3.89 (s, 3H), AB system (4.23, 4.33, J =

13.2 Hz, 2H), 6.97 (dxd, J = 8.8 Hz, 2.0 Hz, IH), 7.04 (s, IH), 7.60 (d, J = 8.8 Hz, IH ), 7.62 (s, IH). HRMS (EI+ ): found 252.0443 [M]+, (Calcd for

 Example 29: 2-(2,-Methylsulfoxide)acetyl-7-methoxy-benzofuran (13c)

 The compound 13b was used as a starting material to give a yellow solid, 2-(2'-methylsulfoxide)acetyl-7-methoxy-benzofuran (13c) (66%).

lHNMR (d6-DMSO) δ: 2.73 (s, 3Η), 3.97 (s, 3H), AB system (4.46, 4.57, J = 14.0 Hz, 2H), 7.17 (d, J = 7.6 Hz, IH), 7.30 (t, J = 7.6 Hz, IH), 7.41 (d, J = 7.6 Hz, IH ), 8.08 (s, IH). HRMS (EI+ ): found 252.0459 [M] ⁺ , (Calcd for C ₁₂ H ₁₂ 0 ₄ S: 252.0456 ). Example 30: 2-ethoxycarbonyl-6-diethylamino-benzofuran (16b)

4-Diethylaminosalicylaldehyde was used as a starting material to give ² -y-ethoxycarbonyl-6-diethylamino-benzofuran (16b) (36%) as a yellow oil.

^J HNMR (CDC1 ₃ ) δ: 1.20 (t, J = 6.8 Hz, 6H), 1.41. (t, J = 7.2 Hz, 3H), 3.41 (q, J = 6.8 Hz, 4H), 4.41 (q, J = 7.2 Hz, 2H), 6.73 (d, J = 8.8 Hz, IH), 6.76 (s, IH), 7.40 (s, 1H), 7.43 (d, J = 8.8 Hz, IH). MS (EI+) m /z: 261 [M] ⁺ . HRMS (EI+ ): found 261.1365 [M] ⁺ , (Calcd for C ₁₅ H ₁₉ N0 ₃ : 261.1365 ). Example 31: -2-[3,-(4"-methoxyphenyl)acryloyl]-6-ethoxycarbonyl-benzothiophene (2dC)

 2-Acetyl-6-methoxycarbonyl-benzothiophene (2c) (100 mg, 0.43 mmol) was added to 10 ml of absolute ethanol, a catalytic amount of sodium ethoxide, p-methoxybenzaldehyde (87.2 mg) , 0.64 mmol ). Stir at room temperature for 1.5 h, evaporate the ethanol, dissolve the crude product in chloroform, and filter. The chloroform phase was washed with water, and the chloroform phase was dried over anhydrous sodium sulfate. After drying the solvent, it was separated by silica gel column chromatography to give a yellow-yellow solid 78 mg (52%).

¹ H NMR (CDCI3) δ: 1.45 (t, J = 7.2 Hz, 3H), 3.88 (s, 3H), 4.44 (q, J = 7.2 Hz, 2H), 6.69 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 15.2 Hz, IH), 7.65 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 15.2 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 8.07 ( d, J= 8.4 Hz _; 1H), 8.11 (s, IH), 8.62 (s, IH). HRMS (EI+ ): found 366.0920 [M]+, (Calcd for C ₂₁ H ₁₈ 0 ₄ S: 366.0926). Example 32: (£)- ² -[3,-( ⁴ "-Methoxybenzene)acryloyl]-5-ethoxycarbonyl-benzothiophene (ldC)

 Using the compound lc and p-methoxybenzaldehyde as starting materials, the reaction was carried out in the same manner as in Example 31 to give a yellow-green solid. -2-[3,-(4"-methoxyphenyl)acryloyl]-5-ethoxymethyl Acyl-benzothiophene (ldC) (34%).

_{^{! HNMR (CDC1 3) δ:}} 1.45 (t, J = 7.2 Hz, 3H), 3.88 (s, 3H), 4.44 (q, J = 7.2 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H) , 7.42 (d, J = 15.2 Hz, IH), 7.65 (ά, J = 8.4 Hz, 2H), 7.89 (d, J = 15.2 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.4 Hz, IH), 8.15 (s, IH), 8.64 (s, IH). HRMS (EI+ ): found 366.0916[M] ⁺ , (Calcd for C ₂₁ H ₁₈ 0 ₄ S: 366.0926) . Example - 33: 2-(Γ-hydroxy-2,-methylsulfoxide)ethyl-5,6-methylenedioxy-benzothiophene

(8e)

 The compound 8c was used as a starting material to give a white solid 2-(1 '-hydroxy-2,-methylsulfoxide)ethyl-5,6-methylenedioxy-benzothiophene as a white solid. 8e) (96%).

^{! HNMR (CDCI3) δ: 2.74} (s, 3H), 2.03-3.30 (m, 2H), 5.68 (dxd, J = 9.2 Hz, 2.8Hz), 6.01 (s, 1H), 7.12 (s, 1H), 7.13 (s, 1H), 7.20 (s, IH). MS (ESI ⁺ ) m/z: 307 [M+Na] ⁺ . HRMS (ESI+ ): found 307.00916 [M+Na] ⁺ , (Calcd for C ₁₂ H ₁₂ 0 ₄ S ₂ Na: 307.00747). Example 34: 2-(Indolyl-hydroxy)ethyl-5-methoxycarbonyl-benzothiophene (If)

 The compound lc was used as a starting material to give a pale pink solid of 2-(1'-hydroxy)ethyl-5-methoxycarbonyl-benzothiophene (If) (92%).

iHNMR (CDCI3) δ: 1.67 (d, J = 6.4 Hz), 2.18 (s, lH), 3.95 (s, 3H), 5.22 (q _; J = 6.4 Hz, 2H), 7.25 (s, IH), 7.84 (d, J = 8.4 Hz, IH), 7.95 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 8.41 (s, IH). MS (EI ⁺ ) m/z : 236 [M]+. HRMS (EI+ ): found 236.0498 [M]+, (Calcd for C ₁₂ H ₁₂ 0 ₃ S: 236.0507). Example 35: 2-(Γ-hydroxy)ethyl-6-methoxycarbonyl-benzothiophene (2f)

 The compound 2c was used as a starting material to give a white solid (2-(1'-hydroxy)ethyl-6-methoxycarbonyl-benzothiophene (2f) (92%).

_{^{] HNMR (CDC1 3) δ:}} 1.67 (d, J = 6.4 Hz), 1.80 (s, lH), 3.95 (s, 3H), 5.23 (q; J = 6.4 Hz, 2H), 7.24 (s, 1H) , 7.74 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H) _;

7.95 (d, J = 8.4 Hz, IH), 8.53 (s, IH). MS (EI+) m/z: 236 [M]+. HRMS (EI+ ): found 236.0507 [M]+, (Calcd for C ₁₂ H ₁₂ 0 ₃ S: 236.0507).

 Example 36: -2-cinnamoyl-6-ethoxycarbonyl-benzothiophene (2dA)

2c and benzaldehyde compound as the raw material, the procedure of Example 31 to give a pale yellow solid 2- reaction cinnamoyl -6- ethoxycarbonyl - benzothiophene ^{(2 dA) (17%)} .

λΉΝΜΚ (CDCI3) δ: 1.45 (t, J = 7.2 Hz, 3H), 4.44 (q, J = 7.2 Hz, 2H), 7.45-7.47 (m, 3H), 7.54 (d, J = 15; 6 Hz, IH), 7.69-7.71 (m, 2H), 7.93 (ά, J = 15.6 Hz, IH), 7.97 (d, J = 8.4 Hz, IH), 8.08 (d, J = 8.4 Hz, IH), 8.14 ( s, IH), 8.63 (s, IH). MS (EI+) m/z: 336 [M] ⁺ . HRMS (EI+ ): found 336.0793[M] ⁺ , (Calcd for C ₂₀ H ₁₆ O ₃ S: 336.0820 ).

 Example 37: -2-[3,-(2",3",4"-Trimethoxyphenyl)acryloyl]-5-ethoxycarbonyl-benzothiophene (IdE)

 Using compound lc and 2,3,4-trimethoxybenzaldehyde as starting materials, the reaction of Example 31 gave a yellow solid (3⁄4)-2-[3,-(2",3",4"-trimethoxy. Benzo)acryloyl]-5-ethoxycarbonyl-benzothiophene (IdE) (30%)

^{! HNMR (CDCI3) δ: 1.44} (t, J = 7.2 Hz, 3H), 3.91 (s, 3H), 3.94 (s, 3H), 3.99 (s, 3H), 4.44 (q, J = 7.2 Hz, 2H ), 6.75 (d, J = 8.8 Hz, IH), 7.42 (d, J = 8.8 Hz, IH), 7.59 (d, J = 15.6 Hz, 1H), 7.94 (d, J = 8.4 Hz, IH), 8.08(d, J = 15.6 Hz, IH), 8.11-8.14 (m, 2H), 8.64(s, IH). HRMS (EI+ ): found 426.1147[M]+, (Calcd for C ₂₃ H ₂₂ 0 ₆ S : 426.1137). Example 38: (E 2-[3,-(2",3",4,,-Trimethoxyphenyl)acryloyl]-6-ethoxycarbonyl-benzothiophene (2dE) Using compound 2c and 2,3,4-trimethoxybenzaldehyde as starting materials, the reaction of Example 31 gave a yellow-green oil (E 2-[3,-(2",3",4,,- Trimethoxybenzene)acryloyl]-6-ethoxycarbonyl-benzothiophene (2dE) (32%).

_{^{! HNMR (CDC1 3) δ:}} 1.44 (t, J = 7.2 Hz, 3H), 3.91 (s, 3H), 3.94 (s, 3H), 3.99 (s, 3H), 4.44 (q, J = 7.2 Hz, 2H), 6.75 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 15.6 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H) , 8.09 (d, J = 15.6 Hz, 1H), 8.09 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.63 (s, 1H). HRMS (EI ⁺ ): found 426.1125 [M] ⁺ , (Calcd for C ₂₃ H ₂₂ 0 ₆ S: 426.1137). Example 39: -2-cinnamoyl-5-ethoxycarbonyl-benzothiophene (IdA)

 The compound lc and benzaldehyde were used as a starting material to give a yellow solid, fE 2- cinnamyl-5-ethoxycarbonyl-benzothiophene (IdA) (62%).

^{! HNMR (CDCI3) δ: 1.44} (t, J = 7.2 Hz, 3H), 4.44 (q, J = 7.2 Hz, 2H), 7.54 (s, 3H), 7.59 (d, J = 15.2 Hz, 1H), 7.68-7.69 (m, 2H), 7.91 (d, J= 15.2 Hz, 1H) _: 7.94 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 8.15 (s, 1H) MS (ΕΓ) m/z: 336 [M] ⁺ . HRMS (EI ⁺ ): found 336.0796 [M] ⁺ , (Calcd for C ₂₀ H ₁₆ O ₃ S: 336.0820). Example 40: E 2-[3,-(2,--Chlorophenyl)acryloyl]-5-ethoxycarbonyl-benzothiophene (ldBl) was synthesized from compound lc and o-chlorobenzaldehyde. The reaction of the method of Example 31 gave a yellow solid of 2-[3,-(2"-chlorophenyl)acryloyl]-5-ethoxycarbonyl-benzothiophene (ldBl) (62%).

 ^MR (CDCI3) δ: 1.44 (t, J = 7.2 Hz, 3H), 4.44 (q, J = 7.2 Hz, 2H),

7.35-7.37 (m, 2H), 7.47 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 15.6 Hz, 1H), 7.79 (dxd, J = 8.0 Hz, 2.4 Hz, 1H), 7.95 ( d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.17 (s, 1H), 8.30 (d, J = 15.6 Hz, 1H), 8.65 (s, 1H). MS ( EI+) m/z: 370 [M]+, 372 [M+2] ⁺ . HRMS (EI+ ): found 370.0418 [M]+, (Calcd for C ₂ oH ₁₅ 0 ₃ SCl: 370.0430). Example 41: -2-[3'-(2"-chlorophenyl)acryloyl]-5-methoxycarbonyl-benzothiophene (ldB2) Using compound lc and o-chlorobenzaldehyde as starting materials, according to the examples 31 method reaction to get brown Yellow solid-2-[3'-(2"-chlorophenyl)acryloyl]-5-methoxycarbonyl-benzothiophene (ldB2) (25%):

¹ H NMR (CDCI3) δ: 3.97 (s, 3H), 7.34-7.39 (m, 2H), 7.47 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 15.6 Hz, 1H), 7.79 (dxd , J = 8.0 Hz, 2.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.16 (s, 1H), 8.30 (d, J = 15.6 Hz, 1H), 8.64 (s, 1H). MS (EI ⁺ ) m/z: 356[M] ⁺ , 358[M+2] ⁺ . HRMS (EI+ ): found 356.0254 [M]+, (Calcd for C ₁₉ H ₁₃ 0 ₃ SC1: 356.0274). Example 42: (E 2-[3,-(2,--chlorophenyl)acryloyl]-6-ethoxycarbonyl-benzothiophene (2dB) using compound 2c and o-chlorobenzaldehyde as raw materials, according to The reaction of Example 31 was carried out to give a brown-yellow solid (3⁄4-2-[3,-(2"-chlorophenyl)acryloyl]-6-ethoxycarbonyl-benzothiophene (2%) (20%).

¹ HNMR (CDCI3) δ: 1.44 (t, J = 7.2 Hz, 3H), 4.44 (q, J = 7.2 Hz, 2H), 7.35-7.37 (m, 2H), 7.47 (d, J = 8.8 Hz, 1H ), 7.51 (d, J = 15.6 Hz, 1H), 7.79 (dxd, J = 8.0 Hz, 2.0 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.13 (s, 1H), 8.30 (d, J = 15.6 Hz, 1H), 8.63 (s, 1H). MS (EI+) m/z: 370 [M]+. HRMS (EI ⁺ ): found 370.0420 [M] ⁺ , (Calcd for C ₂₀ H ₁₅ O ₃ SCl: 370.0430). Example 43: 3⁄4)-2-[3,-(3",4"-Dimethoxyphenyl)acryloyl]-6-ethoxycarbonyl-benzothiophene (2dD)

 The compound 2c and 3,4-dimethoxybenzaldehyde were used as a starting material to give a brown oil (E2-[3,-(3",4,-dimethoxybenzene). Acrylo]-6-ethoxycarbonyl-benzothiophene (2dD) (10%).

^{! HNMR (CDCI3) δ: 1.45} (t, J = 7.2 Hz, 3H), 3.96 (s, 3H), 3.98 (s, 3H), 4.44 (q, J = 7.2 Hz, 2H), 6.93 (d, J = 8.4 Hz, 1H), 7.20 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 15.6 Hz, 1H), 7.88 (d, J = 15.6 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H), 8.63 (s, 1H). MS (EI+) m/z: 396[M] +. HRMS (EI+): found 396.1015 [M]+, (Calcd for C ₂₂ H ₂₀ O ₅ S: 396.1031). Example 44: (E 2-[3,-(3", 4"-Dimethoxyphenyl)acryloyl]-5-ethoxycarbonyl-benzothiophene (ldD)

 The compound lc and 3,4-dimethoxybenzaldehyde were used as a starting material to give a yellow oily product, f3⁄4-2-[3'-(3", 4"-dimethoxybenzene)propene, according to the procedure of Example 31. Acyl]-5-ethoxycarbonyl-benzothiophene (ldD) (10%).

!HNMR (CDC1 ₃ ) δ: 1.44 (t, J 7.2 Hz, 3H), 3.94 (s, 3H), 3.98 (s, 3H),

4.45 (q, J = 7.2 Hz, 2H), 6.93 (d, J 8.4 Hz, 1H), 7.20 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 15.2 Hz , 1H), 7.88 (d, J = 15.2 Hz, 1H), 7.95 (ά, J = 8.8 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 8.17 (s, 1H), 8.65 (s , 1H). MS (EI+) m/z: 396[M]+. HRMS (EI+): found 396.1032 [M]+, (Calcd for C ₂₂ H ₂₀ O ₅ S: 396.1031).

 Example 45: 2-(2,-Methylsulfonyl)acetyl-5-methoxy-benzofuran (l id)

 Using the compound 11c as a starting material, the pale yellow solid 2-(2'-methylsulfonyl)acetyl-5-methoxy-benzofuran (57.0%) was obtained.

¹ HNMR ( CDCI3 ) 5: 3.16 (s, 3H), 3.86 (s, 3H), 4.58 (s, 2H), 7.10 (d, J = 2.4 Hz, 1H), 7.17 (dxd, J = 9.0 Hz, 2.4 Hz, 1H), 7.49 (d, J = 9.0 Hz, 1H), 7.65 (s,

1H). MS (EI+) m/z: 268[M] ⁺ . HRMS (EI+ ): found 268.0416[M]+, (Calcd for

C ₁₂ H ₁₀ O ₅ S: 268.0405).

 Example 46: 2-(anthracene-hydroxy-2,-methylsulfoxide)ethyl-5-methoxy-benzofuran (l ie) Using compound 11c as a starting material, the reaction was obtained in the same manner as in Example 10 Yellow solid 2-(anthracene-hydroxy-2,-methylsulfoxide)ethyl-5-methoxy-benzofuran (l ie) (89%).

^{] HNMR (CDCI3) δ: 2.75} (s, 3H), 3.12-3.37 (m, 2H), 3.84 (s, 3H), 5.50-5.56 (m 1H), 6.71 (d, J = 5.2 Hz, 1H), 6.88 (dxd, J = 8.8 Hz, 2.4 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H). MS (ESI +) m / z : 277.3 [M + Na] + HRMS (ESI +):. Found 277.05280 [M + Na] +, (Calcd for C 12 H 14 O 4 SNa: 277.05105). Example 47: (E 2-[3,-(4,,-methoxyphenyl)acryloyl]-5,6-dimethoxy-indole (G33-1) Using 2-acetyl-5,6-dimethoxyanthracene and p-methoxybenzaldehyde as starting materials, the reaction of Example 31 was carried out to obtain a solid (T 2-[3'-(4"-methoxybenzene). )acryloyl]-5,6-dimethoxy-oxime (74.5%) ₀

^J H NMR (CDC1 ₃ ) δ: 3.73 (s, 3H), 3.85 (s, 3H), 3.92 (s, 3H), 6.67 (d, J = 15.2 Hz, 1H), 6.80 (s, 1H), 6.95 (s, 1H), 7.09 (s, 2H), 7.38 (s, 1H), 7.54 (d, J = 15.2 Hz, 1H), 7.68 (s, 2H), 11.63 (br, 1H). MS(EI+) m/z: 337 [M] ⁺ . Example 48: Methyl-2-[3,-(4"-methoxyphenyl)acryloyl]-5,6-dimethoxy-oxime

(G33-2)

 Using 1-methyl-2-acetyl-5,6-dimethoxyanthracene and p-methoxybenzaldehyde as starting materials, the reaction of Example 31 gave a solid methyl-2-[3'-(4 "-Methoxybenzene)acryloyl]-5,6-dimethoxy-oxime (77.1%).

lR NMR (CDCI3) δ: 3.60 (s, 3H), 3.73 (s, 3H), 3.85 (s, 3H), 3.92 (s, 3H), 6.67 (d, J = 15.2 Hz, 1H), 6.57 (s , 2H), 7.09 (s, 2H), 7.41 (s, 1H), 7.54 (d, J = 15.2 Hz, 1H), 7.68 (s, 2H). MS(EI+) m/z: 351 [M] ⁺ Example 49: (Ελΐ-chloroethyl-2-[3,-(4"-methoxyphenyl)acryloyl]-5,6-dimethoxy-indole (G33-3)

 Using 1-chloroethyl-2-acetyl-5,6-dimethoxyanthracene and p-methoxybenzaldehyde as starting materials, the reaction of Example 31 gave the solid chloroethyl-2-[3,- (4"-Methoxybenzene)acryloyl]-5,6-dimethoxy-anthracene (70.2%).

 ^ NMR (CDCI3) δ: 2.14 ( m,3H), 3.70 (s, 3H), 3.82 (s, 3H), 3.92 (s, 3H),

5.80 (m, 1H), 6.66 (d, J = 15.2 Hz, 1H), 6.59 (s, 2H), 7.1 l(s, 2H), 7.38 (s, 1H), 7.53 (d, J= 15.2 Hz, 1H), 7.71 (s, 2H). MS (EI ⁺ ) m/z: 399[M]+. Example 50: 1-acetyl-2-[3,-(4"-fluorophenyl)acryloyl ]-5,6-dimethoxy-anthracene (G33-4)

Using 1,2-diacetyl-5,6-dimethoxyanthracene and p-fluorobenzaldehyde as starting materials, the reaction of Example 31 gave solid-1-acetyl-2-[3,-(4" -Fluorophenyl)acryloyl]-5,6-dimethoxy-oxime (72.6%). ^{! H NMR (CDCI3) δ:} 2.19 (m, 3H), 3.73 (s, 3H), 3.94 (s, 3H), 6.68 (d, J = 15.2 Hz, 1H), 6.81 (s, 2H), 7.1 l (s, 2H), 7.43 (s, 1H), 7.53 (d, J = 15.2 Hz, 1H), 7.69 (s, 2H). MS (EI ⁺ ) m/z: 367 [M] ⁺ . Example 51 : (E)-\-( 2,-Hydroxyethyl)-2-[3,-(4"-fluorophenyl)acryloyl]-5-acetoxy-indole (G33-5)

 Using 1-(2,-hydroxyethyl)-2-acetyl-5-acetoxyindole and p-fluorobenzaldehyde as starting materials, the reaction of Example 31 gave a solid (2,-hydroxyethyl)-2. -[3,-(4"-Fluorophenyl)acryloyl]- 5-acetoxy-oxime (70.5%).

^{! H NMR (CDCI3) δ:} 2.33 (s, 3H), 4.08 (m, 4H), 4.30 (s, lH), 6.70 (d, J = 15.2 Hz, 1H), 7.02 (m, 2H), 7.35 ( m, 4H), 7.42 (s, 1H), 7.53 (d, J = 15.2 Hz, 1H) _; 7.80 (m, 1H). MS(EI+) m/z: 367 [M]+. Example 52: ( E)-\-( 2,-aminoethyl)-2-[3,-(4"-fluorophenyl)acryloyl]-5-acetoxy-indole (G33-6)

 Using 1-( 2,-aminoethyl)-2-acetyl-5-acetoxy anthracene and p-fluorobenzaldehyde as starting materials, the reaction of Example 31 gave the solid-1-(2,-aminoethyl) -2-[3,-(4"-fluorophenyl)acryloyl]-5-acetoxy-oxime (58.0%).

 lU NMR (CDCI3) δ: 2.33 ( s, 3H), 3.12 (m, 2H), 4.11 (m, 2H), 5.80 (s, 2H), 6.68 (d, J = 15.2 Hz, 1H), 6.98 (m , (2H) : 366 [M]+. Example 53: E)-\-(2,-methoxyethyl)-2-[3,-(4"-fluorophenyl)acryloyl]-5-acetoxy- Π引哚(G33-7)

 Using 1-(2,-methoxyethyl)-2-acetyl-5-acetoxyindole and p-fluorobenzaldehyde as starting materials, the reaction of Example 31 gave a solid £ 1-(2,-A Oxyethyl)-2-[3,-(4"-fluorophenyl)acryloyl]-5-acetoxy-oxime (70.5%).

 !H NMR (CDCI3) δ: 2.32 ( s, 3H), 3.24 ( s, 3H), 3.85 (m, 2H), 4.08 (m, 2H),

6.68 (d, J = 15.2 Hz, 1H), 7.02 (m, 2H), 7.36(m, 4H), 7.41 (s, 1H), 7.53 (d, J = 15.2 Hz, IH), 7.82 (m, IH). MS (EI+) m/z: 381 [M]+. Example 54: 2-ethoxycarbonyl-4-methyl-benzothiophene (lg)

 Using 6-methyl 2-nitrobenzaldehyde and ethyl decylacetate as starting materials, the procedure of Example 1 was carried out to obtain solid particles 2-ethoxycarbonyl-4-methyl-benzothiophene (69.3%). .

 1HNMR (CDC13) 5: 1.45 (t, J = 7.2 Hz, 3H), 2.35 (s, 3H), 4.46 (q, J = 7.2

Hz, 2H), 7.38 (m, 2H), 7.74 (m, 1H), 7.98 (s, 1H). MS (EI+) m/z: 220 [M] +. Example 55: 2-Heptanoyl-5,6-dimethyl-benzothiophene (17) as 4, 5-dimethyl-2-nitro -benzaldehyde, ethanethiol and 1-chlorooctyl-2-one as starting materials, reacted according to the method of Example 19 to give solid 2-heptanoyl-5,6-dimethyl-benzothiophene (17) (50 %).

1HNMR (CDC1 ₃ )S: 0.96 (t, J = 7.2 Ηζ, 3H), 1.30 (m, 6H), 1.48 (m, 2H),

2.35 (s, 6H), 2.89 (m, 2H), 7.54 (s, 2H), 7.86 (s, IH). MS(EI ⁺ ) m/z: 274 [M]+. Example 56: ² - Oxyformyl-5,6-diaminobenzothiophene (18b)

The solid 2-pentoxycarbonyl-5,6-diaminobenzothiophene (61%) was synthesized by the method of Example 1 using 5,6-diamino-6-nitrobenzaldehyde and amyl thioglycolate as starting materials. . 1H MR (CDC1 ₃ )6: 0.90 (t, · / = 7.2 Hz,, 3H), 1.30 (m, 4H), 1.75 (m, 2H),

4.35 (m, 2H), 5.80 (s, 4H), 6.73 (s, 1H), 6.80 (s, 1H), 8.22 (s, lH). MS (EI+) m/z: 278 [M] ⁺ . Example 57: 2-keto acid-benzothiophene (19)

 Starting from 2-nitrobenzaldehyde and decyl 2-carbonylpropionic acid, solid 2-keto acid-benzothiophene (51.5%) was obtained by the method of Example 1.

^MR ( CDC1 ₃ ) iHNMR (CDC1 ₃ ) 5: 7.32 (t, J = 7.0 Hz, IH), 7.49 (t, J = 7.0 Ηζ, ΙΗ), 7.76 (d, J = 7.0 Hz, 1H), 7.79 (d, «/ = 7.0 Hz, 1H), 7.94(s, 1H), 12.6 (s, IH). MS(EI+) m/z: 206 [M]+. Example 58: 2- ( Γ , V -dicarbonyl)pentylbenzothiophene (20)

2-nitrobenzaldehyde and 1-decyl- 2,3-dione were used as raw materials, and the method of Example 1 was combined. The solid was obtained as 2-( Γ , 2, -dicarbonyl)pentylbenzothiophene (40.2%).

^! ΗΝΜΚ ( CDC1 ₃ ) ^! HNMR (CDC1 ₃ ) 5: 0.96 (t, J 7.2 Hz,, 3 H), 1.65 (m, 2H), 2.40 (m, 2H), 7.33 (t, J = 7.0 Hz, IH), 7.46 (t, J = 8.0 Hz, lH), 7.70 (d, J = 7.0 Hz, IH), 7.82 (d, J = 8.0 Hz, 1H), 8.05 (s, IH). MS (EI ⁺ m/z: 232 [M]+. Example 59: 2-(butylsulfoxide)acetyl-5,6-diamino-benzothiophene (18c)

 Starting from compound 18b (2-pentyloxycarbonyl-5,6-diaminobenzothiophene), the compound was reacted according to the method of Example 2 to give a solid 2-(butylsulfoxide)acetyl-5,6-diamino. - Benzothiophene (18c) (80%).

^J HNMR ( CDC1 ₃ ) δ: 0.90 (t, J = 7.2 Hz, 3H), 1.33 (m, 4H), 1.78 (m, 2H), AB system (4.28, 4.36, J = 13.2 Hz, 2H), 5.80 (s, 4H), 6.72(s, 1H), 6.78(s, 1H), 7.88 (s, lH). MS (EI+) m/z: 306 [M] ⁺ . Example 60: 2-(4' -chloroheptyloxycarbonyl)-5,6-dimethoxy-benzothiophene (21b)

 The compound 2-nitro-4,5-dimethoxybenzaldehyde and thioglycolic acid-4'-chloroheptyl ester were used as the starting materials to obtain the solid 2-(4'-chloroheptyloxycarbonyl) according to the method of Example 15. -5,6-Dimethoxy-benzothiophene (21b) (55%).

iHNMR (CDC1 ₃ ) 6: 0.96 (t, J = 7.2 Hz, 3H), 1.33 (m, 2H), 1.60 (m,

6H), 3.46(m, 1H), 3.73(s, 3H), 3.96(s, 3H), 4.28 (m, 2H), 7.18(s, IH), 7.25(s,

IH), 8.30 (s, IH). MS (EI+) m/z: 370 [M] +. Example 61: 2-(4,-chlorohexylsulfenyl)acetyl-5,6-dimethoxy -Benzothiophene (21c) Using compound 21b as a starting material, the compound was reacted according to the method of Example 2 to give solid 2-(4,-chlorohexylsulfoxide)acetyl-5,6-dimethoxy-benzothiophene (21c) ) ( 85%)

iHNMR (CDC1 ₃ ) 5: 0.96 (t, J = 7.2 Hz, 3H), 1.33 (m, 4H), 1.56 (m, 4H), 3.46 (m, IH), 3.73 (s, 3H), 3.95 (s) , 3H), AB system (4.30, 4.39, J = 13.2 Hz, 2H), 7.19(s, 1H), 7.26(s, 1H), 8.25(s, IH). MS (EI+) m/z: 398 [ M] +.

Example 63: 2-(6,-Hydroxyhexyl)oxycarbonyl-5,6-dimethoxy-benzothiophene (22b) as compound 2-nitro-4,5-dimethoxybenzaldehyde and Thioglycolic acid-6 '-hydroxyhexyl ester is the original The reaction was carried out in the same manner as in Example 15 to give solid 2-(6,-hydroxyhexyl)oxycarbonyl-5,6-dimethoxy-benzothiophene (22b) (50%).

_{^{! HNMR (CDC1 3) 5:}} 1.28 (m, 4H), 1.48 (m, 2H), 1.76 (m, 2H), 3.52 (m, 2H), 3.73 (s, 3H), 3.95 (s, 3H), 4.26 (m, 2H), 5.02(s, IH), 7.21(s, IH), 7.30(s, 1H), 8.09(s, IH). MS (EI+) m/z: 338 [M] +· Implementation Example 63: 2-(6,-Hydroxypentylsulfenyl)acetyl-5,6-dimethoxy-benzothiophene (22c) Using compound 22b as a starting material, the compound was obtained by the method of Example 2 to give a solid 2- (6'-hydroxypentyl sulfoxide) acetyl, 6-dimethoxy-benzothiophene (22c) (81%)

'HNMR (CDC1 ₃ ) 5: 1.29 (m, 4H), 1.50 (m, 2H), 1.76 (m, 2H), 3.53 (m, 2H), 3.73 (s, 3H), 3.96 (s, 3H), AB system (4.30, 4.39, J = 13.2 Hz, 2H), 5.16(s, 1H),

7.29(s, IH), 7.32(s, IH), 8.16(s, IH). MS (EI+) m/z: 366 [M] +.

 Example 64: 2-(6,-Methoxyhexyl)oxycarbonyl-5,6-dimethoxy-benzothiophene (23b) as compound 2-nitro-4,5-dimethoxybenzene Formaldehyde and thioglycolic acid-6'-methoxyhexyl ester were used as raw materials, and reacted according to the method of Example 15 to obtain a solid 2-(6'-methoxyhexyl)oxycarbonyl-5,6-dimethoxy-benzene. And thiophene (23b) (63%).

l NMR (CDC1 ₃ )S: 1.29 (m, 4H), 1.46 (m, 2H), 1.75 (m, 2H), 3.24 (s, 3H),

3.37 (m, 2H), 3.72(s, 3H), 3.93(s, 3H), 4.25 (m, 2H), 7.19(s, IH), 7.28 (s, IH), 8.19(s, IH). MS (EI+) m/z: 352 [M] +. Example 65: 2-(6,-methoxypentylsulfenyl)acetyl-5,6-dimethoxy-benzothiophene (23c) Compound 23b was used as a starting material and was reacted according to the procedure of Example 2 to give solid 2-(6'-methoxypentylsulfenyl)acetyl-5,6-dimethoxy-benzothiophene (23c) (86%)

_{^{! HNMR (CDC1 3) S:}} 1.31 (m, 4H), 1.48 (m, 2H), 1.76 (m, 2H), 3.24 (s, 3H),

3.38 (s, 1H), 3.73 (s, 3H), AB system (s, IH). MS (EI+) m/z: 380 [M] +.

 Example 66: 2-ethoxycarbonyl-5,6-ethylmethylenedioxy-benzothiophene (24b)

Starting from 3,4-ethylmethylenedioxy-6-nitrobenzaldehyde and ethyl decylacetate, the solid 2-ethoxyform-5,6-ethyl-methylide was synthesized according to the method of Example 1. Dioxo-benzothiophene (68.5%)

lHNMR (CDCI3) δ: 0.96 (m, 3H), 1.42 (t, J = 7.2 Hz, 3H), 2.13 (m, 2H), 4.37 (q, J 7.2 Hz, 2H), 6.04 (m, 1H), 7.21(s, 1H), 7.26(s, IH), 7.91(s, IH). MS (EI+) m/z: 278 [M] ⁺ .

 Example 67: 2-Ethoxycarbonyl-5,6-(2,-chloroethyl)methylenedioxy-benzothiophene (25b) with 3,4-(2,-chloroethyl)- The bis-oxo-6-nitrobenzaldehyde and ethyl decylacetate were used as starting materials, and the solid 2-ethoxycarbonyl-5,6-(2,-chloroethyl)methylenedioxy was synthesized according to the method of Example 1. - benzothiophene (25b) (62.0%).

^{! HNM (CDCI3) δ: 1.43} (t, J = 7.2 Hz, 3H), 1.59 (d, J = 5.0 Hz, 3H), 4.38 (q, J = 7.2 Hz, 2H), 4.63 (m, IH), 6.23(m, 1H), 7.18(s, 1H), 7.23(s, IH), 7.96(s, IH). MS (ΕΓ) m/z: 312 [M] ⁺ .

 Example 68: 2-ethoxycarbonyl-5,6-(1,-hydroxyethyl)methylenedioxy-benzothiophene (26b) with 3,4-(indolyl-hydroxyethyl)methylene Dioxy-6-nitrobenzaldehyde and ethyl decylacetate were used as starting materials, and solid 2-ethoxycarbonyl-5,6-(indolyl-hydroxyethyl)methylenedioxy-benzene was synthesized according to the method of Example 1. Thiophene (26b) (68.0%)

^X WMR ( CDCI3 ) δ: 1.42 (t, J = 7.2 Hz, 3H), 2.28 (m, 2H), 3.53 ( m, 2H) , 4.38 (q, J = 7.2 Hz, 2H), 5.16(s,lH ), 5.96(m, IH), 7.18(s, IH), 7.25(s, 1H), 7.98(s, IH). MS (EI+) m/z: 294 [M]+.

 Example 69: 2-Ethoxycarbonyl-5,6-(anthracene-aminoethyl)methylenedioxy-benzothiophene (27b) with 3,4-(-aminoethyl)methylenedioxy Using -6-nitrobenzaldehyde and ethyl decylacetate as starting materials, a solid 2-ethoxycarbonyl-5,6-(indolyl-aminoethyl)methylenedioxy-benzothiophene was synthesized according to the method of Example 1. (26b) (68.0%).

^{! HNMR (CDCI3) δ: 1.42} (t, J = 7.2 Hz, 3H), 2.35 (m, 2H), 2.65 (m, 2H), 4.12 (s, lH), 4.38 (q, J = 7.2 Hz, 2H ), 5.98(m, IH), 7.16(s, 1H), 7.27(s, IH), 8.02(s, IH). MS (EI+) m/z: 293 [M] ⁺ .

Example 70: 2- ethoxycarbonyl -5,6- (Γ - methoxyethyl) methylenedioxy - benzothiophene (28b) with _3, 4- (1 - methoxyethyl Methylene dioxy-6 nitrobenzaldehyde and ethyl thioglycolate As a raw material, a solid 2-ethoxycarbonyl-5,6-(-methoxyethyl)methylenedioxy-benzothiophene (26b) (68.0%) was obtained.

^MR CDCl^S: 1.42(t, J= 7.2 Hz, 3H), 2.26(m,2H), 3.24( s, 3H), 3.37 ( m, 2H) , 4.38(q, J = 7.2 Hz, 2H) , 5.98(m, 1H), 7.18(s, 1H), 7.25(s, 1H), 8.03(s, 1H). MS (EI+) m/z: 308[M] ⁺ .

Claims

Rights request

 A benzopenta-unsaturated heterocyclic compound having a structure represented by the formula I or a pharmaceutically acceptable salt thereof,

 In the formula,

X represents 0, S or NR ₇ , wherein R ₇ represents H, a hydrocarbyl group, a halogenated hydrocarbyl group, a carbonyl hydrocarbyl group, a hydroxyhydrocarbyl group, an aminohydrocarbyl group or a hydrocarbyloxy group;

 Y represents CO or CRi'OH; Ι represents the following groups: H, OH, 'hydrocarbyl group, carboxyl group, acyl group, decyloxy group, sulfonic acid group having 1 to 18 carbons;

' ^ represents the following groups: H, OH, a hydrocarbon group having 1 to 18 carbons, a carboxyl group, an acyl group, a decyloxy group, a sulfonic acid group, a CH ₂ S(0) _n R ₈ or R ₉ substituted phenylpropenyl group; R ₈ represents H, a hydrocarbon group having 1 to 18 carbons, a halogenated hydrocarbon group, a hydroxyalkyl group or a hydrocarbyloxy group, n = 1 - 2; R ₉ represents H, a hydrocarbyl group, an alkoxy group, a halogen group, a carboxyl group, an amino group or a substituted group. Amino; and ^ can be the same as or different from Ι;

R ₂ represents the following groups: H, a hydrocarbon group having 1 to 18 carbons, a halogen, an acyl group, a carboxyl group, an amino group or a substituted amino group, a sulfonic acid group, a nitrile group or an acyl alkoxy group;

 Represents the following groups: H, a hydrocarbyl group, a decyloxy group, a halogen group, a carboxyl group, an amino group or a substituted amino group, an acyl group, an ester group or a sulfonic acid group;

 Represents the following groups: H, a hydrocarbyl group, a decyloxy group, a halogen, a carboxyl group, an amino group or a substituted amino group, an acyl group, an ester group or a sulfonic acid group;

1 ₅ represents the following groups: H, a hydrocarbyl group, an alkoxy group, a halogen, a carboxyl group, an amino group or a substituted amino group, an acyl group, an ester group or a sulfonic acid group;

Represents the following groups: H, hydrocarbyl, alkoxy, halogen, carboxyl, amino or substituted ammonia a base, an acyl group, an ester group or a sulfonic acid group; or

R ₄ and R ₅ are bonded together by carbon, oxygen or nitrogen to form a 5-7 membered ring structure or a 5-7 membered ring structure having a substituent R _{1 ()} , wherein R _{1 ()} represents H, a hydrocarbon group, a halogen group Hydrocarbyl group, carbonyl hydrocarbyl group, hydroxyhydrocarbyl group, aminohydrocarbyl group or hydrocarbyloxy group. .

The benzo five-membered unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the benzo five-membered unsaturated heterocyclic compound comprises 2-substituted phenylacryloyl-benzothiophene, 2 a compound obtained by substituting a phenylacryloyl-benzofuran, a 2-substituted phenylacryloyl-hydrazine or a benzene ring moiety, and R ₅ is condensed with formaldehyde to form an ortho-diphenyl ether structure.

 The benzo five-membered unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the benzo five-membered unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof comprises a substituent at the 2-position A benzothiophene, benzofuran or an anthracene compound which is a 2-hydroxyoxyacyl group or a 2-hydrocarbylacyl group.

 The benzo five-membered unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the benzo five-membered unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof comprises a substituent at the 2-position a benzothiophene, benzofuran or anthracene compound which is 2-(2,-methylsulfone or methylsulfoxideacetyl) or 2-(2,-methylsulfone or methylsulfoxide-substituted-oxime-hydroxy)ethyl .

 The benzo five-membered unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, which comprises:

 2-ethoxycarbonyl-benzothiophene

 2-(2,-methylsulfoxide)-acetylbenzothiophene

2-( ² ,-methylsulfonyl)acetyl-benzothiophene

 2-ethoxycarbonyl-5,6-methylenedioxy-benzothiophene

 2-(2,-Methylsulfoxide)acetyl-5,6-methylenedioxy-benzothiophene

 2-(2,-Methylsulfonyl)acetyl -5,6-methylenedioxy-benzothiophene

 2-ethoxycarbonyl-benzofuran

 2-(2,-methylsulfoxide)-acetylbenzofuran

2-ethoxycarbonyl-4-chloro-benzothiophene 2-(Γ-hydroxy-2'-methylsulfoxide)-ethyl-benzothiophene

2-ethoxycarbonyl-4-methoxy-benzofuran

 2-ethoxycarbonyl-5-methoxy-benzofuran

 2-ethoxycarbonyl-6-methoxy-benzofuran

 2-ethoxycarbonyl-7-methoxy-benzofuran

 2-ethoxycarbonyl-5,6-dimethoxy-benzothiophene

 2-ethoxycarbonyl-7-fluoro-benzofuran

 2-ethoxycarbonyl-5,7-dichloro-benzofuran

 2-ethoxycarbonyl-5-methoxycarbonyl-benzothiophene

 2-acetyl-5-methoxycarbonyl-benzothiophene

 2-ethoxycarbonyl-6-methoxycarbonyl-benzothiophene

 2-acetyl-5-carboxy-benzothiophene

 2-acetyl-6-methoxycarbonyl-benzothiophene

 2-acetyl-6-carboxy-benzothiophene

 2-(2,-Methylsulfoxide)acetyl-4-chloro-benzothiophene

 2-(2,-Methylsulfoxide)acetyl-4-methoxy-benzofuran

 2-(2,-Methylsulfoxide)acetyl-5-methoxy-benzofuran

 2-(2,-Methylsulfoxide)acetyl-5,6-dimethoxy-benzothiophene

 2_(2,-Methylsulfoxide)acetyl-6-methoxy-benzofuran

 2-(2,-Methylsulfoxide)acetyl-7-methoxy-benzofuran

 2-ethoxycarbonyl-6-diethylamino-benzofuran

 (£ 2-[3,-(4"-methoxyphenyl)acryloyl]-6-ethoxycarbonyl-benzothiophene

CE)-2-[3,-(4,--methoxyphenyl)acryloyl]-5-ethoxycarbonyl-benzothiophene

2-(1,-hydroxy-2,-methylsulfoxide)ethyl-5,6-methylenedioxy-benzothiophene

2-(Γ-hydroxy)ethyl-5-methoxycarbonyl-benzothiophene

2-(1,-hydroxy)ethyl-6-methoxycarbonyl-benzothiophene 2-cinnamoyl-6-ethoxycarbonyl-benzothiophene

(3⁄4)-2-[3,-(2",3",4"-trimethoxyphenyl)acryloyl]-5-ethoxycarbonyl-benzothiophene

(3⁄4-2-[3,-(2,,,3",4"-Trimethoxyphenyl)acryloyl]-6-ethoxycarbonyl-benzothiophene-2-cinnamoyl-5-ethoxymethyl Acyl-benzothiophene

(E 2-[3,-(2,--Chlorophenyl)acryloyl]-5-ethoxycarbonyl-benzothiophene^-2-[3,-(2"-chlorophenyl)acryloyl] -5-methoxycarbonyl-benzothiophene

 (E 2- [3,-(2,--chlorophenyl)acryloyl]-6-ethoxycarbonyl-benzothiophene

 (3⁄4-2-[3,-(3",4"-Dimethoxyphenyl)acryloyl]-6-ethoxycarbonyl-benzothiophene

 (3⁄4>-2-[3,-(3",4"-Dimethoxyphenyl)acryloyl]-5-ethoxycarbonyl-benzothiophene

 2-(2'-Methylsulfonyl)acetyl-5-methoxy-benzofuran

 2-(1,-hydroxy-2,-methylsulfoxide)ethyl-5-methoxy-benzofuran

 -2-[3 '-(4"-methoxyphenyl)acryloyl]-5,6-dimethoxy-oxime

Small methyl _ ₂ _[ ₃ , _(4"-methoxyphenyl) acryloyl]-5,6-dimethoxy-H 哚

 Small chloroethyl -2-[3,-(4"-methoxyphenyl)acryloyl]-5,6-dimethoxy-oxime

(3⁄4>small acetyl-2-[3,-(4"-fluorophenyl)acryloyl]-5,6-dimethoxy-oxime

 (3⁄4 small (2,-hydroxyethyl)-2-[3,-(4,--fluorophenyl)acryloyl]-5-acetoxy"

(Ε 1-(2,-aminoethyl)-2-[3,-(4"-fluorophenyl)acryloyl]-5-acetoxy-oxime

(Ε 1-(2,-methoxyethyl)-2-[3,-(4"-fluorophenyl)acryloyl]- 5-acetoxy-oxime

2-ethoxycarbonyl-4-methyl-benzothiophene

2-heptyl-5,6-dimethyl-benzothiophene

 2-pentoxycarbonyl-5,6-diaminobenzothiophene

2-keto acid-benzothiophene .

2-(Γ, 2'-dicarbonyl)pentylbenzothiophene

2-(butyl sulfoxide) acetyl -5,6-diamino-benzothiophene

2-(4'-chloroheptyloxycarbonyl)-5,6-dimethoxy-benzothiophene

2-(4,-chlorohexylsulfoxide)acetyl-5,6-dimethoxy-benzothiophene 2-(6,-hydroxyhexyl)oxycarbonyl-5,6-dimethoxy-benzothiophene

 2-(6,-hydroxypentylsulfonyl)acetyl-5,6-dimethoxy-benzothiophene

 2-(6,-methoxyhexyl)oxycarbonyl-5,6-dimethoxy-benzothiophene

 2-(6,-methoxypentyl sulfoxide group:) acetyl-5,6-dimethoxy-benzothiophene

 2-ethoxycarbonyl-5,6-ethylmethylenedioxy-benzothiophene

 2-ethoxycarbonyl-5,6-(2,-chloroethyl)methylenedioxy-benzothiophene

 2-ethoxycarbonyl-5,6-(1,-hydroxyethyl)methylenedioxy-benzothiophene

 2-ethoxycarbonyl-5,6-(1,-aminoethyl)methylenedioxy-benzothiophene

 2-ethoxycarbonyl-5,6-(1,-methoxyethyl)methylenedioxy-benzothiophene

 2-acetylbenzothiophene

 ^-2-(3,-(4"-Methoxybenzene)acryloyl)-benzothiophene

 2-acetyl-benzofuran

 A process for producing a benzo five-membered unsaturated heterocyclic compound having a structure represented by the formula (I) or a pharmaceutically acceptable salt thereof, according to Claim 1, which is characterized in that:

A. When X in the formula (I) is S, Y represents CO or CR OH, and when CH ₂ S(0)nR ₈ or R _{9 is} substituted for the phenylpropenyl structure, the method shown in Scheme 1 or Route 2 is firstly obtained. Intermediate ( IV ) wherein R ₂ , R ₃ , R ₅ , R ₆ , R ₈ , R ₉ , n, Ι are as defined in claim 1, Ru represents Η, ΟΗ, and contains 1-18 carbons Hydrocarbyl, carboxyl, acyl, alkoxy or sulfonate; Route 1:

The synthesis method comprises the following steps: using a substituted o-nitrobenzaldehyde (Π) as a starting material, and using a mercaptoethanol to carry out an aromatic nucleophilic substitution reaction under the catalysis of an alkaline reagent, the Ν0 _{2 of the} raw material is taken by an ethylthio group. R,

 .R 11

Generation, intermediate (III) is formed; a halogenated reagent 0 (Z represents a leaving group), which is reacted with an intermediate (III) under the catalysis of an alkaline reagent to obtain a derivative of a 2-substituted acylbenzothiophene (W) );

 Route 2:

 II IV

The synthesis method comprises the following steps: using substituted o-nitrobenzaldehyde (II) as a starting material, and catalyzing with an alkaline reagent, with a thiol reagent

Directly reacting to obtain a derivative of the 2-substituted acylbenzothiophene (W);

 Further, the intermediate (W) can be separately reacted to obtain the corresponding compound of the formula I:

When one or more of R ₃ , , ₅ , R ₆ is an ester group, the intermediate (W) is hydrolyzed under basic conditions to give a carboxylic acid derivative (V) wherein R ₃ ', R , R ₅ ', R ₆ ' correspond to the group after hydrolysis of R ₃ , R ₄ , R ₅ , R _{6 respectively}

 b. Intermediate (W) is reduced to give the corresponding hydroxy derivative (YD

; or c. When R„ is a methyl group, the intermediate (IV) is aldehyde-condensed with the R ₉ substituted phenyl formaldehyde intermediate (VII) to obtain a compound in which the R _{9 is} substituted with a phenylacryloyl group ( )

d. When R _u is alkoxy, intermediate (IV) can be reacted as follows to give the corresponding compound of formula I:

 XI

 Intermediate (W) is reacted with a sulfinylmethyl derivative under strong base and heating to obtain the compound 2-(2,-substituted methyl sulfoxide) acylbenzothiophene derivative (IX), and the oxidation and reduction are continued. The compound 2-(2,-substituted methylsulfonylacetyl)benzothiophene derivative (X) and 2-(2,-substituted sulfone or methyl sulfoxide-hydrazine-hydroxy)ethylbenzothiophene derivative are respectively obtained. (XI);

B. When X in the formula (I) is 0, Y represents CO or CR OH, and RJ is CH ₂ S(0) nR ₈ , the synthesis thereof is carried out by the method shown in Scheme 3 to obtain an intermediate (XIII), wherein, R ₂ , R ₃ , R 4 , R ₅ , R ₆ , R ₈ , n, R ' are as defined in claim 1, R ₁₂ represents the following groups: H, OH, a hydrocarbon group having 1 to 18 carbons, a carboxyl group, an acyl group , decyloxy, sulfonic acid

Route 3:

The synthesis method is as follows: using substituted o-hydroxybenzaldehyde GOO as a starting material, in alkaline reagent

R ₂ is reacted with a halogenating agent 0 (Z represents a leaving group) to form a 2-carbonyl group (XIII ) compound;

Wherein, when R ₁₂ is an alkoxy group, the intermediate (XIII) can be reacted as follows to obtain the corresponding compound of the formula I:

 XVI

 The intermediate (ΧΙΠ) is further reacted with a sulfinylmethyl derivative under strong base and heating to obtain a 2-(2'-substituted methyl sulfoxide) acylbenzofuran derivative (XIV), (XIV) continues Oxidation and reduction give the compound 2-(2,-substituted sulfone)acetobenzofuran derivative (XV) and 2-(2,-substituted sulfone or methyl sulfoxide-hydroxy)ethylbenzofuran derived, respectively. Object (XVI);

C. When X in the formula (I) is NR ₇ and Y represents CO, when R _{9 is} substituted for the phenylpropenyl structure, the synthesis is carried out by the method shown in Scheme 4, wherein R ₂ , R ₃ , R 4 , R ₅ , R ₆ , R ₇ , R ₉ are defined as in claim 1 ;

Route 4:

The synthesis method comprises the following steps: using substituted NR ₇ -2-acetyl oxime (XVII ) as a starting material, and performing aldol condensation with the substituted phenylformaldehyde intermediate (VII) under the catalysis of an alkaline reagent to obtain 2 positions. R ₉ substituted phenylacryloyl target (XVIII ).

 The use of a benzopenta-unsaturated heterocyclic compound having the structure of the formula I or a pharmaceutically acceptable salt thereof according to Claim 1 for the preparation of a medicament for treating osteoporosis.

 A pharmaceutical composition for anti-osteoporosis, which comprises a therapeutically effective amount of the benzo five-membered unsaturated heterocyclic compound of claim 1 or a pharmaceutically acceptable salt thereof, and Containing one or more pharmaceutically acceptable pharmaceutical adjuvants.

 The pharmaceutical composition according to claim 8, wherein the benzo five-membered unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof is used as an active ingredient in an amount of from 0.1% to 99.5% by weight in the pharmaceutical composition. .

 The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition contains the active ingredient in an amount of 0.5% to 99.5% by weight.

 11. Use of a composition according to claim 8 for the manufacture of an anti-osteoporosis drug.