WO2017152725A1 - Retinoid compound, preparation method therefor, intermediates thereof and application thereof - Google Patents

Abstract

Disclosed are a retinoid compound, a preparation method therefor, intermediates thereof and an application thereof. The retinoid compound I of the present invention has a good tumor growth inhibition rate.

Description

Retinoic acid compound, preparation method thereof, intermediate and application thereof

The present application claims priority to Chinese Patent Application No. CN201610141143.3, filed on March 11, 2016, and to Chinese Patent Application No. CN201610310944.8, filed on May 11, 2016. This application cites the entire text of the above-mentioned Chinese patent application.

Technical field

The invention relates to a retinoic acid compound, a preparation method thereof, an intermediate and an application thereof.

Background technique

Tazarotene is a retinol drug with RAR subtype selectivity (J Am Acad Dermatol. 1997, 37, S12.), mainly used for local epithelial hyperplasia of the skin (psoriasis, psoriasis, Treatment of acne, etc.). Tazarotene is present as a prodrug of ethyl ester. The drug enters the body and is metabolized by enzyme to obtain the carboxyl-type active metabolite Tazarotenic acid, which can selectively interact with RARβ and RARγ receptors, and also has a certain effect on RARβ, but has a weak effect on RXR.

Summary of the invention

The problem to be solved by the present invention is to provide a retinoic acid compound, a preparation method thereof, an intermediate and application thereof for the purpose of overcoming defects such as poor inhibition rate of tumor cells by tazarotene, and the compound inhibits tumor cells. The rate is better.

The present invention provides a compound, an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof, of formula I,

Wherein U is CR ^9a or N; V is CR ^9b or N; X is CR ^9c or N; W is CR ^9d or N;

In the U, V, X and W, R ^9a , R ^9b , R ^9c and R ^9d are each independently hydrogen, hydroxy, nitro, cyano, halogen (for example fluorine, chlorine, bromine or iodine), C _1- C ₆ alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl), halogen-substituted C ₁ -C ₆ Alkyl (the halogen may be fluorine, chlorine, bromine or iodine; the C ₁ -C ₆ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl a "halo-substituted C ₁ -C ₆ alkyl group" such as a trifluoromethyl group, a C ₁ -C ₆ alkoxy group (eg, a methoxy group, an ethoxy group); Base, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy or hexyloxy), -NR ¹⁰ R ¹¹ ,

Or -COOR ¹⁴ ;

The R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ^{14 are} independently hydrogen or a C ₁ -C ₆ alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, tert-butyl, pentyl or hexyl);

AE, EG and GZ are independently single or double bonds; when A, E, G or Z is connected to two single bonds, the corresponding A, E, G and Z are independently: -(CR ² R ³ ) -, -C(=O)-, -(NR ⁴ )-, -(N→O)-, -O-, -S-, -S(=O)- or -SO ₂ -; when A When E, G or Z is connected to a single bond and a double bond, the corresponding A, E, G and Z are independently: -(CR ⁵ )= or -N=;

Said R ² , R ³ , R ⁴ and R ^{5 are} independently hydrogen, hydroxy, halogen (for example fluorine, chlorine, bromine or iodine), C ₁ -C ₆ alkyl (for example methyl, ethyl, positive) Propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or yl), C ₂ -C ₆ alkenyl (eg vinyl or propenyl), halogen substituted C ₁ -C ₆ Alkyl (the halogen may be fluorine, chlorine, bromine or iodine; the C ₁ -C ₆ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, tert-butyl, pentyl or hexyl; said "halogen-substituted C ₁ -C ₆ alkyl" such as trifluoromethyl), C ₁ -C ₆ alkoxy (eg methoxy, Ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy or hexyloxy), C ₁ -C ₆ acyl (eg acetyl or Formyl), C ₆ -C ₁₀ aryl (eg phenyl) or "heteroatom is an oxygen, sulfur or nitrogen atom, a C ₃ -C ₆ heteroaryl group having 1 to 2 heteroatoms" (eg Pyridyl or pyrimidinyl);

m is 0, 1, 2 or 3;

When a plurality of R ^{1 are} substituted, the substituents are the same or different; R ¹ is hydrogen, hydroxy, nitro, cyano, halogen (e.g., fluorine, chlorine, bromine or iodine), C ₁ -C ₆ alkyl (e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl), halogen-substituted C ₁ -C ₆ alkyl (the halogen may be Fluorine, chlorine, bromine or iodine; the C ₁ -C ₆ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl; the "halogen-substituted C ₁ -C ₆ alkyl group" such as trifluoromethyl), C ₁ -C ₆ alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy Oxyl, n-butoxy, isobutoxy, tert-butoxy, pentyloxy or hexyloxy), -NR ⁶ R ⁷ or -COOR ⁸ ;

The R ⁶ , R ⁷ and R ^{8 are} independently hydrogen or a C ₁ -C ₆ alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl) Base, pentyl or hexyl);

Y is -CN, -COOR ¹⁵ or -CO ₂ NHR ¹⁶ ;

Said R ¹⁵ and R ^{16 are} independently hydrogen, C ₁ -C ₆ alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl) Or a hexyl group, a C ₂ -C ₆ alkenyl group (for example, a vinyl or propenyl group) or a C ₁ -C ₆ acyl group (for example, a formyl group or an acetyl group);

The compound I is not

Preferably, said A, E, G and Z are connectable to a ring as shown below:

The definitions of R ² , R ³ and R ⁵ are as described above.

Preferably, in the compound I, at least one of the U, V, X and W (for example, 1, 2, 3 or 4) is N.

More preferably, in the compound I, when two of the U, V, X and W are N, the compound I may be any of the following compounds:

Wherein, A, E, G, Z, R ¹ , m, Y, R ^9a , R ^9b , R ^9c and R ^9d are as defined above.

Preferably, in the compound A, when Y is -COOR ¹⁵ , the R ¹⁵ is hydrogen or ethyl.

Preferably, in the compound A, the Z is -(CR ² R ³ )-, -S-, -S(=O)- or -SO ₂ -; more preferably, the A , E, G, and Z are connected into a ring as shown below:

The definitions of R ² and R ³ are as described above.

More preferably, in the compound A, when the Y is COOH, the Z is -S-.

More preferably, in the compound A, when the Y is COOEt, the Z is -(CR ² R ³ )-, -S(=O)- or -SO ₂ -.

Preferably, in the compound B, when the Y is -COOR ¹⁵ , the R ¹⁵ is a methyl group or an ethyl group.

Preferably, in the compound B, the Z is -(CR ² R ³ )-, -S- or -S(=O)-; more preferably, the A, E, G and Z is connected to the ring shown below:

The definitions of R ² and R ³ are as described above.

More preferably, in the compound B, when the Y is COOMe, the Z is -(CR ² R ³ )-, and R ² and R ³ are as defined above.

More preferably, in the compound B, when the Y is COOEt, the Z is -(CR ² R ³ )- or -S-, and R ² and R ³ are as defined above.

More preferably, in the compound B, when the Y is CN, the Z is -(CR ² R ³ )-, -S- or -S(=O)-, R ² and R The definition of ³ is as described above.

Preferably, in the compound C, when the Y is -COOR ¹⁵ , the R ¹⁵ is hydrogen or ethyl.

Preferably, in the compound C, the Z is -(CR ² R ³ )-, -S- or -S(=O)-; more preferably, the A, E, G and Z is connected to the ring shown below:

The definitions of R ² and R ³ are as described above.

More preferably, in the compound C, when the Y is COOH, the Z is -S-.

More preferably, when the compound C, when the Y is COOEt, said Z is ^{- (CR 2 R 3) -} , - S- or -S (= O) -, R 2 , and The definition of R ³ is as described above.

Preferably, in the compound I, when one of the U, V, X and W is N, the compound I may be any of the following compounds:

Wherein, A, E, G, Z, R ¹ , m, Y, R ^9a , R ^9b , R ^9c and R ^9d are as defined above.

Preferably, in the compound D, when the Y is -COOR ¹⁵ , the R ¹⁵ is hydrogen or ethyl.

Preferably, in the compound D, the Z is -(CR ² R ³ )-; more preferably, the A, E, G and Z are linked to a ring as shown below:

The definitions of R ² and R ³ are as described above.

Preferably, in the compound E, the Y is CN.

Preferably, in the compound E, the Z is -(CR ² R ³ )-; more preferably, the A, E, G and Z are linked to a ring as shown below:

The definitions of R ² and R ³ are as described above.

Preferably, in the compound I, when the U is CR ^9a , V is CR ^9b , X is CR ^9c , and W is CR ^9d , the structure is as shown in compound F:

Wherein, A, E, G, Z, R ¹ , m, Y, R ^9a , R ^9b , R ^9c and R ^9d are as defined above.

Preferably, in the compound F, at least one of the R ^9a , R ^9b , R ^9c and R ^9d (for example, 1, 2, 3 or 4) is not hydrogen.

Preferably, in the compound F, when the Y is -COOR ¹⁵ , the R ¹⁵ is hydrogen, methyl or ethyl.

Preferably, in the compound F, the Z is -(CR ² R ³ )-, -S-, -S(=O)- or -SO ₂ -; more preferably, the A , E, G, and Z are connected into a ring as shown below:

The definitions of R ² , R ³ and R ⁵ are as described above.

More preferably, the compound I is any one of the following compounds:

The present invention also provides a process for the preparation of a compound of formula I, which comprises the steps of: coupling a compound II and III to obtain a compound I;

Wherein X ¹ is halogen (e.g., fluorine, chlorine, bromine or iodine).

In the preparation method of the compound I, the conditions of the coupling reaction may be conventional conditions of the coupling reaction in the art, and the present invention particularly preferably has the following conditions: protection of a protective gas (for example, argon). Next, in an organic solvent (such as DMF), in a catalyst (such as Pd / Cu catalyst; said "Pd / Cu catalyst" such as Pd (PPh ₃ ) ₂ Cl ₂ and CuI) and a base (such as diisopropylamine) Compounds II and III may be subjected to a coupling reaction in the presence of triethylamine or the like to obtain a compound I.

The compound I can be further subjected to flexible functional group conversion and adjustment (including but not limited to chemical operations such as esterification, ester hydrolysis, reduction, acylation, oxidation, etc.) to obtain a compound I having a different functional group.

Preferably, the method for preparing the compound I may further comprise the steps of: deprotecting the compound IV to obtain the compound III;

In the preparation method of the compound III, the conditions of the deprotection reaction may be conventional conditions for the deprotection reaction in the art, and the present invention particularly preferably has the following conditions: in an organic solvent (for example, tetrahydrofuran), Compound IV may be subjected to a deprotection reaction in the presence of a base (for example, tetra-n-butylammonium fluoride) to obtain a compound III.

Preferably, the preparation method of the compound I may further comprise the steps of: coupling the compound V and the trimethylethynyl silane to obtain the compound IV;

Wherein X ² is a halogen (e.g., bromine or iodine).

In the preparation method of the compound I, the conditions of the coupling reaction may be conventional conditions of the coupling reaction in the art, and the present invention particularly preferably has the following conditions: protection of a protective gas (for example, argon). Next, in an organic solvent (such as DMF), in a catalyst (such as Pd / Cu catalyst; said "Pd / Cu catalyst" such as Pd (PPh ₃ ) ₂ Cl ₂ and CuI) and a base (such as diisopropylamine) The compound and trimethylethynylsilane are subjected to a coupling reaction in the presence of triethylamine or the like to obtain a compound IV.

The invention also provides a compound as shown in formula II, III, IV or V,

Wherein, the definitions of A, E, G, Z, R ¹ , m, X ¹ , Y, U, V, X and W are as described above.

The invention also provides the use of a compound of formula I, an enantiomer, diastereomer or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a primary tumor . Such tumors include, but are not limited to, melanoma, esophageal cancer, gastric cancer, lung cancer, liver cancer, ovarian cancer, colon cancer, renal cancer, cholangiocarcinoma, breast cancer or prostate cancer.

The invention also provides the use of a compound of formula I, an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prophylaxis and/or Treatment of metastatic tumors. The tumor includes, but is not limited to, melanoma, esophageal cancer, gastric cancer, lung cancer, liver cancer, ovarian cancer, colon cancer, renal cancer, cholangiocarcinoma, breast cancer, prostate cancer.

The invention also provides the use of a compound of formula I, an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prophylaxis and/or Treatment, leukemia and/or lymphoma.

The invention also provides the use of a compound of formula I, an enantiomer, diastereomer or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in animal fetal development, One or more of internal environment stability, vision, morphogenesis, skin aging, and control of cell differentiation.

The invention also provides the use of a compound of formula I, an enantiomer, diastereomer or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of psoriasis .

The invention also provides the use of a compound, an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof, of formula I, for the manufacture of a medicament for the treatment of acne.

The invention also provides a pharmaceutical composition comprising a compound of formula I, an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The pharmaceutical composition can be administered orally, by injection, or topically. The pharmaceutical composition is administered by the oral route, and the composition may be, but is not limited to, the following forms: tablets, capsules, suspensions, solutions, emulsions, microspheres or nanosphere suspensions, or controlled release. Lipid vesicles or polymer vesicles. For administration by injection, the composition may be a solution or suspension for infusion or injection. Generally, the compounds of the invention are administered at a daily dose of from about 0.01 mg/kg to 100 mg/kg body weight in divided doses of 1-3. The concentration of the compounds of the invention used systemically is generally from 0.01% to 10% by weight, preferably from 0.01% to 1% by weight, based on the weight of the composition. The pharmaceutical composition is particularly useful for treating skin and mucosal diseases by topical administration, and may be in the form of a liquid, a paste or a solid, especially an ointment, a cream, In the form of a solution, a gel, a spray, a suspension, or a patch. It may also be a microsphere or nanosphere suspension, or a controlled release lipid vesicle or polymer vesicle or a gelled or polymeric patch. The concentration of the topically applied compound is usually from 0.001% to 10% by weight, preferably from 0.01% to 1% by weight, based on the total weight of the composition.

The pharmaceutical compositions may also contain inert additives, or a pharmaceutically active ingredient that is positively associated with the pharmaceutical composition, or a mixture of such ingredients. Of course, those skilled in the art will be careful to select the optional compound to be added to the above composition such that the advantages inherent in the present invention are not or substantially unaffected by the intended additives.

In the present application, a "C ₁ -C ₆ acyl" refers to an alkyl group containing 1 to 6 carbon atoms, such as an acyl group containing one carbon atom refers to HC (O) - (i.e. formyl), The acyl group having 2 carbon atoms is CH ₃ C(O)- (i.e., acetyl); and may also include propionyl, butyryl or valeryl.

In the present invention, the following terms appearing in the specification and claims of the present invention have the following meanings unless otherwise stated:

The term "alkyl" refers to a saturated straight or branched monovalent hydrocarbon radical having from one to twenty carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-butyl, 2-butyl, 2-methyl-2 -propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2 -methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl , 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-g Base, 1-octyl.

The term "alkenyl" refers to a straight, branched or cyclic non-aromatic hydrocarbon radical containing the specified number of carbon atoms and at least one carbon to carbon double bond. Preferably there is one carbon-carbon double bond and up to four non-aromatic carbon-carbon double bonds may be present. Thus, "C ₂ -C ₁₂ alkenyl" means an alkenyl group having 2 to 12 carbon atoms. The "C ₂ -C ₆ alkenyl group" means an alkenyl group having 2 to 6 carbon atoms, and includes a vinyl group, a propenyl group, a butenyl group, a 2-methylbutenyl group, and a cyclohexenyl group.

The term "aryl" (including when used alone and when included in other groups) refers to any stable monocyclic or bicyclic carbon ring which may be up to 7 atoms in each ring, at least one of which is an aromatic ring. Examples of the above aryl unit include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. It will be understood that in the case where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the linkage is carried out through an aromatic ring.

The term "arylhetero" or "heteroaryl" (including when used alone and in other groups) denotes a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is an aromatic ring and Containing from 1 to 4 heteroatoms selected from O, N, and S. Heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, oxazolyl, porphyrin, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl , benzothienyl, benzofuranyl, quinolyl, isoquinolinyl, oxazolyl, isoxazolyl, fluorenyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, Pyrrolyl, tetrahydroquinoline. "Heteroaryl" is also understood to include any nitrogen-containing heteroaryl N-oxide derivative. In the case where the heteroaryl substituent is a bicyclic substituent and one ring is a non-aromatic ring or does not contain a hetero atom, it is understood that the linkage is carried out by an aromatic ring or by a hetero atom on the ring, respectively.

The term "halogen" includes F, Cl, Br, I.

The term "pharmaceutically acceptable salt" refers to a conventional acid addition or base addition salt which retains the biological effectiveness and properties of Compound I, which is formed from a suitable non-toxic organic or inorganic acid, or an organic or inorganic base. Examples of acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphorous acid, sulfuric acid, phosphoric acid, and those derived from organic acids. And nitric acid, such as formic acid, acetic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, maleic acid, lactic acid, tartaric acid, succinic acid, Fumar Acid, mandelic acid, malic acid, camphorsulfonic acid, etc. Examples of base addition salts include salts derived from ammonium, potassium, sodium, calcium, and quaternary ammonium hydroxides such as tetramethylammonium hydroxide. Chemical modification of a pharmaceutical compound (i.e., a drug) to a salt is a technique well known to pharmacists to achieve improved physical and chemical stability, hygroscopicity, flowability, and solubility of the compound.

"Pharmaceutically acceptable" in the term "pharmaceutically acceptable carrier" means that the subject to whom the particular compound is administered is pharmaceutically acceptable and substantially non-toxic.

The above preferred conditions can be arbitrarily combined without departing from the ordinary knowledge in the art, that is, preferred embodiments of the present invention.

The reagents and starting materials used in the present invention are commercially available.

The positive progress of the present invention is that the compound of the present application has a better inhibition rate against tumor cells.

DRAWINGS

Figure 1: WYC-103 induces differentiation and apoptosis of melanoma B16-F1TRC cells

Figure 2: WYC-209 induces differentiation and apoptosis of melanoma B16-F1TRC cells

Figure 3: Inhibition of WYC-209 against lung cancer A549 tumor regenerative cells, wherein Figure 3a shows inhibition of lung cancer A549 treated with WYC-209 on day 0; Figure 3b shows treatment of lung cancer A549 with WYC-209 on day 3 Inhibition.

Figure 4: Inhibition of WYC-209 against breast cancer MCF-7 tumor regenerative cells, wherein Figure 4a shows inhibition of breast cancer MCF-7 treated with WYC-209 on day 0; Figure 4b shows use on day 3 WYC-209 treatment of breast cancer MCF-7 inhibition.

Figure 5: Inhibition of WYC-209 against melanoma MDA-MB-435S tumor regenerative cells, wherein Figure 5a shows the inhibition of treatment of melanoma MDA-MB-435S with WYC-209 on day 0; Figure 5b shows On day 3, WYC-209 was used to treat the inhibition of melanoma MDA-MB-435S.

Figure 6: Inhibition of WYC-209 against ovarian cancer A2780 tumor regenerative cells, wherein Figure 6a shows the inhibition of ovarian cancer A2780 treated with WYC-209 on day 0; Figure 6b shows treatment with WYC-209 on day 3 Inhibition of ovarian cancer A2780.

Fig. 7: Study on the inhibitory effect of WYC-209 on tumor regenerative cells of gastric cancer Hs-746T, wherein Fig. 7a shows the inhibition of treatment of gastric cancer Hs-746T with WYC-209 on day 0; Fig. 7b shows the use of WYC- on day 3 209 treatment of gastric cancer Hs-746T inhibition.

Figure 8: Inhibition of WYC-209 against breast cancer MDA-MB-231 tumor regenerative cells, wherein Figure 8a shows the inhibition of treatment of breast cancer MDA-MB-231 with WYC-209 on day 0; Figure 8b shows On day 3, WYC-209 was used to treat the inhibition of breast cancer MDA-MB-231.

Figure 9: WYC-331 against ovarian cancer A2780 and breast cancer MDA-MB-231 tumor regenerative cell inhibitory activity, wherein Figure 9a shows the inhibition of ovarian cancer A2780 treated with WYC-331 on day 3; Figure 9b shows On day 3, WYC-331 was used to treat the inhibition of breast cancer MDA-MB-231.

Figure 10: WYC-209 cytotoxicity study (WYC-209 inhibits B16 growth but has no significant effect on 3T3 cells); wherein, Figure 10a shows treatment of 3T3 cells with 10 μM WYC-209 for 18 hours; Figure 10b shows no WYC-209, B16 cells were treated with 10 μM WYC-209 for 48 hours.

Figure 11: WYC-331 cytotoxicity study; wherein, Figure 11a shows that 3T3 cells were treated with 1 μM, 10 μM WYC-331 for 24 hours; Figure 11b shows that B16 cells were treated with 1 μM, 10 μM WYC331 for 24 hours, respectively.

Figure 12: Inhibition of subcutaneous melanoma by WYC-103, tumor volume on day 19 of the experiment.

Figure 13: Study on the inhibitory effect and in vivo toxicity of WYC-103 on subcutaneous melanoma.

Figure 14: Inhibition of subcutaneous melanoma by WYC-103, tumor volume on day 26 of the experiment.

Figure 15: Inhibition of lung metastatic melanoma by WYC-103; wherein, Figure 15a shows the injection of 3000 melanoma regenerative cells, administration of WYC103, lung tissue on day 29 of the experiment; Figure 15b shows the injection of 3000 melanoma regenerative cells DMSO was administered to the lung tissue on the 29th day of the experiment; Fig. 15c shows the injection of 3000 melanoma regenerative cells, WYC103, lung tissue on the 35th day of the experiment; Fig. 15d shows the injection of 3000 melanoma regenerative cells, given DMSO, the 35th day of the experiment Lung tissue; Figure 15e shows lung tissue administered to WYC103 on day 37 of the experiment; Figure 15f shows lung tissue on day 37 of the experiment given DMSO.

Figure 16: Inhibition of lung metastatic melanoma by WYC-209, wherein Figure 16a shows lung tissue administered to DMSO; Figure 16b shows lung tissue administered with 1.0 μM WYC-209; Figure 16c shows administration of 10 μM WYC-209 Lung tissue.

Figure 17: Single crystal structure diagram of WYC-209A.

Figure 18: Single crystal structure diagram of WYC-209B.

detailed description

The invention is further illustrated by the following examples, which are not intended to limit the invention. The experimental methods in the following examples which do not specify the specific conditions are selected according to conventional methods and conditions, or according to the product specifications.

Example 1: Methyl 4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)-2-hydroxybenzoate

The commercial starting material 6-ethynyl-4,4-dimethylbenzothiopyran (202.8 mg, 1 mmol) and the compound methyl 2-hydroxy-4-iodobenzoate (292.1 mg, 1 mmol) were added to the flask. was added _{Pd (PPh 3) 2 Cl 2} (14mg, 0.02mmol), CuI (7.6mg, 0.04mmol), and replaced with argon for three times to exclude oxygen gas is added by syringe 2mL of dry DMF, 0.2mL dry iPr ₂ NH, reaction at room temperature for 8 h, TLC tracking. After completion of the reaction, it was quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with EtOAc EtOAc EtOAc. : EtOAc = 100:1 to 20:1) gave product WYC-101 (296 mg, 81%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.79 (d, 1H), 7.53 (d, 1H), 7.18-7.20 (dd, 1H), 7.12 (d, 1H), 7.06-7.07 (d, 1H), 7.00-7.02 (dd, 1H), 3.95 (s, 3H), 3.03-3.06 (m, 2H), 1.94-1.97 (m, 1H), 1.34 (s, 6H); ¹³ C NMR (101 MHz, CDCl ₃ ) Δ170.09,161.38,161.12,153.37,142.25,134.10,130.91,130.00,129.85,129.24,126.73,122.45,120.25,117.90,111.95,93.23,88.03,77.48,77.16,76.84,52.52,37.27,32.54,29.99,23.43; ESI(+)-MS: 353.3 [M+1] ⁺ .

Example 2: Methyl 4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)-2-hydroxymethylbenzoate

The compound 6-ethynyl-4,4-dimethylbenzothiopyran (202.8 mg, 1 mmol) and the compound methyl 2-hydroxymethyl-4-iodobenzoate (292 mg, 1 mmol) were added to the flask and added Pd(PPh ₃ ) ₂ Cl ₂ (14 mg, 0.02 mmol), CuI (7.6 mg, 0.04 mmol), protected with argon and replaced with 3 times of gas to remove oxygen, and 2 mL of dry DMF, 0.2 mL of dried iPr was added by syringe. ₂ NH, reaction at room temperature for 8 h, TLC tracking. After completion of the reaction, it was quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with EtOAc EtOAc EtOAc. : EtOAc = 100:1 to 50:1) gave product WYC-102 (300 mg, 82%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.78 (d, 1H), 7.53 (d, 1H), 7.18-7.20 (dd, 1H), 7.11-7.13 (dd, 1H), 7.11 (d, 1H), 7.07 (d, 1H), 3.98 (s, 3H), 3.89 (s, 3H), 3.03-3.06 (m, 1H), 1.94-1.97 (m, 1H), 1.34 (s, 6H); ¹³ C NMR ( 101MHz, CDCl ₃₎ δ166.25,159.05,142.07,133.98,133.58,131.89,129.90,129.13,128.85,126.70,123.39,119.42,117.88,114.84,92.50,88.07,77.48,77.16,76.84,56.18,52.18,37.23,33.06 , 30.06, 23.31; ESI(+)-MS: 367.4 [M+1] ⁺ .

Example 3: Ethyl 4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)-2-hydroxybenzoate

The compound 6-ethynyl-4,4-dimethylbenzothiopyran (202.8 mg, 1 mmol) and the compound 2-hydroxy-4-iodobenzoic acid ethyl ester (292 mg, 1 mmol) were placed in a flask and Pd ( PPh ₃ ) ₂ Cl ₂ (14 mg, 0.02 mmol), CuI (7.6 mg, 0.04 mmol), protected with argon and replaced with 3 times of gas to remove oxygen, and 2 mL of dry DMF, 0.2 mL of dried iPr ₂ NH was added by syringe. , reaction at room temperature for 8 h, TLC tracking. After completion of the reaction, it was quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with EtOAc EtOAc EtOAc. : EtOAc = 100:1 to 50:1) gave product WYC-103 (300 mg, 82%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.80 (d, 1H), 7.52 (s, 1H), 7.18-7.20 (d, 1H), 7.12 (s, 1H), 7.06-7.07 (s, 1H), 7.00-7.02 (s, 1H), 4.39-4.44 (q, 2H), 3.04-3.06 (t, 2H), 1.95-1.97 (t, 2H), 1.44 (t, 3H), 1.35 (s, 6H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 169.97, 161.45, 142.27, 134.07, 130.80, 130.02, 129.91, 129.26, 126.74, 122.37, 120.25, 117.94, 112.22, 93.19, 88.02, 77.48, 77.36, 77.16, 76.84, 61.71, 37.30 , 33.12, 30.11, 29.85, 23.37, 14.34; ESI(+)-MS: 367.5 [M+1] ⁺ .

Example 4: Ethyl 4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)-2-hydroxymethylbenzoate

The compound 6-ethynyl-4,4-dimethylbenzothiopyran (202.8 mg, 1 mmol) and the compound ethyl 2-hydroxymethyl-4-iodobenzoate (306 mg, 1 mmol) were added to the flask and added Pd(PPh ₃ ) ₂ Cl ₂ (14 mg, 0.02 mmol), CuI (7.6 mg, 0.04 mmol), protected with argon and replaced with 3 times of gas to remove oxygen, and 2 mL of dry DMF, 0.2 mL of dried iPr was added by syringe. ₂ NH, reaction at room temperature for 8 h, TLC tracking. After completion of the reaction, it was quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with EtOAc EtOAc EtOAc. : EtOAc = 100:1 to 50:1) gave product WYC-104 (293 mg, 77%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 1.7 Hz, 1H), 7.20 (dd, J = 8.2, 1.7 Hz, 1H), 7.14 –7.11(m,1H),7.11–7.05(m,2H), 4.36(q,J=7.1Hz,2H),3.93(s,3H),3.07–3.04(m,2H),1.95–1.98(m) , 2H), 1.39 (t, 3H), 1.35 (s, 6H); ¹³ C NMR (101MHz, CDCl3) δ 165.81, 159.12, 142.28, 133.97, 131.77, 129.96, 129.19, 128.70, 126.76, 123.42, 119.93, 117.98, 114.94, 92.39, 77.48, 77.37, 77.16, 76.85, 61.07, 56.25, 37.31, 33.13, 30.14, 29.85, 23.37, 14.46; ESI(+)-MS: 381.4 [M+1] ⁺ .

Example 5: 4-((4,4-Dimethyldihydrothiothiopyran-6-)ethynyl)-2-hydroxybenzoic acid

The compound WYC-103 (183 mg, 0.5 mmol) was dissolved in 5 mL of THF, and 1 mL of a 0.5 M aqueous NaOH solution was added dropwise thereto, and the mixture was reacted at room temperature for 8 hours, followed by TLC. After the reaction, it was neutralized with 0.5 M HCl to pH 7, diluted with ethyl acetate, washed with saturated aqueous ammonium chloride, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. PE: EtOAc = 10:1 to 1:1) gave product WYC-105 (144 mg, 85%). _{^{1 H NMR (500MHz, cdcl 3}} ) δ10.50 (s, 1H), 7.86-7.84 (d, 1H), 7.53 (d, 1H), 7.21-7.19 (dd, 1H), 7.14 (d, 1H), 7.08-7.06(d,1H),7.05-7.04(dd,1H),3.07-3.04(m,1H),1.98-1.95(m,1H),1.35(s,6H); ¹³ C NMR(125MHz,CDCl3 ) δ 171.84, 161.46, 142.17, 131.83, 130.58, 129.91, 129.16, 126.63, 120.24, 117.56, 110.03, 89.85, 37.15, 32.99, 29.97, 29.70, 23.24; ESI (-)-MS: 337.1 [M-1] ^- .

Example 6: Methyl 4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)-2-hydroxymethylbenzoate

The compound WYC-104 (190 mg, 0.5 mmol) was dissolved in 5 mL of THF, and 1 mL of a 0.5 M aqueous NaOH solution was added dropwise thereto, and the mixture was reacted at room temperature for 8 hours, followed by TLC. After the reaction, it was neutralized with 0.5 M HCl to pH 7, diluted with ethyl acetate, washed with saturated aqueous ammonium chloride, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. PE: EtOAc = 10:1 to 4:1) gave product WYC-106 (151 mg, 86%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ10.60 (s, 1H), 8.14 (d, J = 7.9Hz, 1H), 7.54 (s, 1H), 7.28 (m, 2H), 7.22 (m, 1H) , 7.08 (d, J = 7.9 Hz, 1H), 4.12 (s, 3H), 3.06 (m, 2H), 1.96 (m, 2H), 1.35 (s, 6H); ¹³ C NMR (101 MHz, CDCl ₃ ) Δ165.02,157.85,142.36,134.56,133.90,130.59,130.00,129.21,126.81,125.42,117.51,116.99,114.42,94.06,87.56,77.48,77.36,77.16,76.84,56.98,37.22,33.12,30.10,29.83,23.37; ESI(-)-MS: 351.2[M-1] ^- .

Example 7: Methyl 4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)-3-hydroxybenzoate

The compound 6-ethynyl-4,4-dimethylbenzothiopyran (202.8 mg, 1 mmol) and the compound methyl 3-hydroxy-4-iodobenzoate (278.1 mg, 1 mmol) were added to the flask and Pd was added. (PPh ₃ ) ₂ Cl ₂ (14 mg, 0.02 mmol), CuI (7.6 mg, 0.04 mmol), protected with argon gas and replaced with 3 times of gas to remove oxygen, and 2 mL of dry DMF, 0.2 mL of dry iPr2NH was added by syringe. The reaction was carried out for 8 h at room temperature and followed by TLC. After completion of the reaction, it was quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with EtOAc EtOAc EtOAc. : EtOAc = 100:1 to 10:1) gave product WYC-107 (245 mg, 71%). _{^{1 H NMR (500MHz, cdcl 3}} ) δ7.64 (d, J = 1.5Hz, 1H), 7.58 (dd, J = 8.0,1.6Hz, 1H), 7.52 (d, J = 1.7Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.19 (dd, J = 8.2, 1.7 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 6.02 (s, 1H), 3.91 (s, 3H) , 3.06–3.04 (m, 2H), 1.94–1.97 (m, 2H), 1.34 (s, 6H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 166.45, 156.21, 142.31, 134.62, 131.53, 131.43, 129.70, 128.97 , 126.73, 121.48, 117.03, 115.72, 114.61, 99.27, 81.86, 77.37, 77.05, 76.74, 52.33, 37.06, 32.99, 29.94, 23.24; ESI (+)-MS: 353.4 [M+1] ⁺ .

Example 8: Methyl 4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)-3-hydroxymethylbenzoate

The compound 6-ethynyl-4,4-dimethylbenzothiopyran (202.8 mg, 1 mmol) and the compound methyl 3-hydroxymethyl-4-iodobenzoate (292.1 mg, 1 mmol) were added to the flask. Add Pd(PPh ₃ ) ₂ Cl ₂ (14 mg, 0.02 mmol), CuI (7.6 mg, 0.04 mmol), protect with argon and replace the gas three times to remove oxygen, add 2 mL of dry DMF, 0.2 mL dry with a syringe. iPr2NH, reaction at room temperature for 8 h, TLC tracking. After completion of the reaction, it was quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with EtOAc EtOAc EtOAc. : EtOAc = 100:1 to 10:1) gave product WYC-108 (275 mg, 75%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.61 - 7.63 (d, 1H), 7.52 - 7.56 (m, 3H), 7.21 - 7.23 (dd, 1H), 7.05 - 7.07 (d, 1H), 3.97 (s , 3H), 3.93 (s, 3H), 3.03-3.06 (m, 1H), 1.94-1.97 (m, 1H), 1.34 (s, 6H); ¹³ C NMR (126MHz, cdcl ₃ ) δ 166.59, 159.56, 141.99 , 133.50, 133.19, 130.64, 129.80, 129.14, 126.49, 121.75, 118.27, 111.25, 96.82, 84.38, 77.26, 77.01, 76.76, 56.07, 52.29, 37.24, 32.97, 29.98, 23.22; ESI(+)-MS: 367.3[ M+1] ⁺ .

Example 9: 4-((4,4-Dimethyldihydrothiothiopyran-6-)ethynyl)-3-hydroxymethylbenzoic acid

The compound WYC-108 (190 mg, 0.5 mmol) was dissolved in 5 mL of THF, and 1 mL of a 0.5 M aqueous NaOH solution was added dropwise thereto, and reacted at room temperature for 8 hours, followed by TLC. After the reaction, it was neutralized with 0.5 M HCl to pH 7, diluted with ethyl acetate, washed with saturated aqueous ammonium chloride, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. PE: EtOAc = 10:1 to 2:1) gave product WYC-110 (1541 mg, 80%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ7.69 (dd, 1H), 7.61 (s, 1H), 7.58-7.55 (m, 2H), 7.23 (dd, 1H), 7.07 (d, 1H), 3.99 ( s, 3H), 3.06 - 3.04 (m, 2H), 1.97 - 1.95 (m, 2H), 1.34 (s, 6H); ESI (+)-MS: 339.3 [M+1] ⁺ .

Example 10: 2-cyano-5-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)pyrimidine

The commercial starting material 4,4-dimethyl-6-ynylthiopyran (202.8 mg, 1.0 mmol) and 2-cyano-5-chloropyrimidine (93 mg, 0.67 mmol) were added to a single-necked flask. was added _{Pd (PPh 3) 2 Cl 2} (23mg, 0.03mmol), CuI (19mg, 0.1mmol), and replaced with argon for three times to exclude oxygen gas is added by syringe 2mL of dry DMF, 0.25mL dry Et ₃ N, heated to 50 degrees for 22 h, TLC tracking. After the reaction was completed, it was cooled to room temperature, and was quenched with a saturated aqueous solution of ammonium chloride, diluted with ethyl acetate, and washed with saturated aqueous ammonium chloride and saturated sodium chloride, and then dried over anhydrous sodium sulfate. Flash column chromatography (PE: EtOAc = 30:1) gave product WYC-202 (133 mg, 65%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.89 (s, 2H), 7.55 (d, J = 1.6 Hz, 1H), 7.21. (dd, J = 8.2, 1.7 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 3.11 - 3.03 (m, 2H), 2.01 - 1.93 (m, 2H), 1.35 (s, 6H); ¹³ C NMR (126MHz, CDCl ₃ ) δ 159.21, 142.59, 141.79, 136.33, 130.15, 129.31,126.98,122.88,116.13,115.70,101.85,81.24,37.02,33.15,30.02,23.42.ESI (+) - MS: 306.3 [M + 1] +.

Example 11: Ethyl 2-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)pyrimidine-5-carboxylate

The compound 4,4-dimethyl-6-ynylthiopyran (202.8 mg, 1.0 mmol) and ethyl 2-chloropyrimidine (156 mg, 0.83 mmol) were added to the flask, and Pd (PPh ₃ ) was added. ₂ Cl ₂ (42 mg, 0.06 mmol), CuI (19 mg, 0.1 mmol), protected with argon and replaced with 3 times of gas to remove oxygen, and added 2 mL of dry DMF, 0.3 mL of dry Et ₃ N with a syringe, and heated to 80 degree reaction 22h, TLC tracking. After completion of the reaction, the mixture was cooled to room temperature, and then diluted with aq. Chromatography (PE: EtOAc = 15:1) gave product WYC-203 (257 mg, 73%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ9.24 (s, 2H), 7.69 (d, J = 1.7Hz, 1H), 7.33 (dd, J = 8.2,1.8Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 4.45 (q, J = 7.1 Hz, 1H), 3.11 - 2.99 (m, 2H), 1.99 - 1.92 (m, 2H), 1.43 (t, J = 7.1 Hz, 3H), 1.33 ( s,6H); ¹³ C NMR (126MHz, CDCl ₃ ) δ 163.52, 158.44, 155.85, 142.39, 136.48, 131.36, 130.15, 126.83, 121.88, 115.96, 92.65, 87.97, 62.14, 37.09, 33.14, 30.05, 23.43, 14.38. ESI (+) - MS: 353.2 [M + 1] +.

Example 12: Methyl 5-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)pyrimidine-2-carboxylate

Compound WYC-202 (50 mg, 0.164 mmol) was added to a flask, and a solution of 0.5 mL of water and 0.5 mL of methanol in NaOH (20 mg, 0.491 mmol) was added and reacted at 60 ° C for 5 h, followed by TLC. After the reaction of the starting material was completed, it was neutralized to neutral with 1 mol/L HCl; diluted with ethyl acetate, washed with saturated sodium hydrogencarbonate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Column chromatography (PE: EtOAc = 15:1) gave product WYC-204 (39 mg, 74%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ8.63 (s, 2H), 7.51 (d, J = 0.7Hz, 1H), 7.17 (dd, J = 8.1,0.9Hz, 1H), 7.07 (d, J = 8.2Hz, 1H), 4.04 (s , 3H), 3.11-2.91 (m, 2H), 2.04-1.90 (m, 2H), 1.34 (s, 6H); 13 C NMR (126MHz, CDCl 3) δ164.02,161.24 , 142.32, 134.10, 129.72, 128.97, 126.77, 117.65, 113.33, 94.71, 81.81, 55.37, 37.28, 33.12, 30.11, 23.36. ESI(+)-MS: 339.2 [M+1] ⁺ .

Example 13: Ethyl 5-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)pyrimidine-2-carboxylate

The compound WYC-202 (50 mg, 0.164 mmol) was added to a flask, sodium ethoxide (34 mg, 0.492 mmol) was added, and 5 mL of ethanol was added thereto, and the reaction was carried out at 45 ° C overnight, followed by TLC. After the reaction of the starting material is completed, it is neutralized to neutral with an acidic resin. The mixture is filtered, and the filtrate is diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Column chromatography (PE: EtOAc = 8:1) gave product WYC- 205 (36 mg, 62%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ8.62 (s, 2H), 7.51 (s, 1H), 7.17 (dd, J = 8.1,0.8Hz, 1H), 7.07 (d, J = 8.1Hz, 1H) , 4.45 (q, J = 7.1 Hz, 2H), 3.09 - 3.00 (m, 2H), 2.00 - 1.92 (m, 2H), 1.45 (t, J = 7.1 Hz, 3H), 1.34 (s, 6H); ¹³ C NMR (126 MHz, CDCl ₃ ) δ 163.61, 161.23, 142.32, 134.05, 129.72, 128.97, 126.77, 117.71, 113.13, 94.60, 81.91, 64.11, 37.30, 33.13, 30.11, 23.36, 14.55. ESI(+)-MS: 353.5[M+1] ⁺ .

Example 14: 2-((4,4-Dimethyldihydrothiopyran-6-)ethynyl)pyrimidine-5-carboxylic acid

Compound WYC-203 (50 mg, 0.142 mmol) was added to the flask, 2 mL of 2.0 mol/L NaOH solution was added, 2 mL of methanol was added, and the reaction was carried out at 45 °C for 5 h, followed by TLC. After the reaction of the raw materials was completed, it was neutralized with 1 mol/L HCl to weak acidity; diluted with ethyl acetate, extracted, washed with saturated sodium chloride, and the organic phase was dried over anhydrous sodium sulfate, filtered, dried, and purified. Methylene chloride:methanol = 15:1) gave product WYC-206 (41 mg, 89%). ¹ H NMR (400 MHz, CD ₃ OD) δ 9.21 (s, 2H), 7.71 (d, J = 1.6 Hz, 1H), 7.29 (dd, J = 8.2, 1.8 Hz, 1H), 7.11 (d, J) = 8.2 Hz, 1H), 3.14 - 3.06 (m, 2H), 2.05 - 1.92 (m, 2H), 1.36 (s, 6H); ¹³ C NMR (101 MHz, CD ₃ OD) δ 167.13, 159.54, 155.24, 143.92, 137.92,131.86,130.67,127.84,117.11,111.42,92.11,88.26,49.64,49.43,49.21,49.00,48.79,48.57,48.36,38.12,33.99,30.18,23.98.ESI(+)-MS:325.3[M+1 ] ⁺ .

Example 15: 2-cyano-5-((4,4-dimethyl-1-oxodithiothiopyran-6-)ethynyl)pyrimidine

WYC-202 (30 mg, 0.098 mmol) was added to the flask, 2 mL of dry dichloromethane was added, and the mixture was cooled to 0 °C in an ice water bath, then mCPBA (24 mg, 0.098 mmol) was added, and the reaction was carried out for 1 hour in an ice water bath and then moved to room temperature for 2 h. , TLC tracking. After the reaction was completed, it was quenched with sodium thiosulfate solution, diluted with ethyl acetate, washed with saturated sodium hydrogen sulfate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. : EtOAc = 1 : 2) gave product WYC-207 (27 mg, 86%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ8.95 (s, 2H), 7.82 (d, J = 8.1Hz, 1H), 7.64 (d, J = 1.5Hz, 1H), 7.55 (dd, J = 8.0, 1.5 Hz, 1H), 3.30–3.08 (m, 2H), 2.44 (ddd, J=15.0, 10.1, 2.0 Hz, 1H), 1.93 (ddd, J=15.1, 9.2, 2.1 Hz, 1H), 1.49 (s) , 3H), 1.36 (s, 3H); ¹³ C NMR (126MHz, CDCl ₃ ) δ 159.64, 145.41, 142.59, 131.57, 130.38, 130.36, 124.24, 121.99, 115.52, 99.38, 83.14, 43.53, 34.76, 31.38, 31.31, 29.96. ESI(+)-MS: 322.3 [M+1] ⁺ .

Example 16: Ethyl 5-((4,4-dimethyl-1-oxodithiothiopyran-6-)ethynyl)pyrimidine-2-carboxylate

WYC-205 (70 mg, 0.2 mmol) was added to the flask, 3 mL of dry dichloromethane was added, and the mixture was cooled to 0 °C in an ice water bath, then mCPBA (49 mg, 0.2 mmol) was added, and the reaction was carried out for 1 hour in an ice water bath and then moved to room temperature for 2 h. , TLC tracking. After the reaction was completed, it was quenched with sodium thiosulfate solution, diluted with ethyl acetate, washed with saturated sodium hydrogen sulfate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. : EtOAc = 1 : 2) gave product WYC-208 (68 mg, 93%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ8.66 (s, 2H), 7.75 (d, J = 8.0Hz, 1H), 7.59 (s, 1H), 7.49 (d, J = 7.7Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 3.16 (dt, J = 20.8, 11.7 Hz, 2H), 2.46 (dd, J = 14.5, 10.3 Hz, 1H), 1.90 (dd, J = 14.6, 8.0 Hz, 2H), 1.48 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H), 1.34 (s, 3H); ¹³ C NMR (126 MHz, CDCl ₃ ) δ 163.95, 161.56, 145.06, 131.11, 130.39, 129.99, 125.91, 112.28, 93.14, 84.74, 64.30, 43.37, 34.61, 31.36, 31.23, 29.76, 14.52. ESI(+)-MS: 369.4 [M+1] ⁺ .

Example 17: Ethyl 2-((4,4-dimethyl-1-oxodithiothiopyran-6-)ethynyl)pyrimidine-5-carboxylate

WYC-203 (48 mg, 0.14 mmol) was added to the flask, 3 mL of dry dichloromethane was added, and the mixture was cooled to 0 °C in an ice water bath, then mCPBA (34 mg, 0.14 mmol) was added, and the reaction was carried out for 1 hour in an ice water bath and then moved to room temperature for 2 h. , TLC tracking. After the reaction was completed, it was quenched with sodium thiosulfate solution, diluted with ethyl acetate, washed with saturated sodium hydrogen sulfate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. : EtOAc = 1 : 2) gave product WYC-209 (43 mg, 84%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ9.29 (s, 2H), 7.82-7.75 (m, 2H), 7.66 (d, J = 7.9Hz, 1H), 4.47 (q, J = 7.1Hz, 2H) , 3.24 (t, J = 11.1 Hz, 1H), 3.15 - 3.07 (m, 1H), 2.43 (dd, J = 14.0, 10.4 Hz, 1H), 1.92 (dd, J = 14.9, 8.8 Hz, 1H), 1.47 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H), 1.34 (s, 3H); ¹³ C NMR (126MHz, CDCl ₃ ) δ 163.33, 158.54, 155.32, 145.19, 132.61, 131.06, 130.22, 124.22 , 122.62, 89.60, 89.35, 62.32, 34.75, 31.36, 31.25, 29.93, 14.39. ESI(+)-MS: 369.4 [M+1] ⁺ ; HRMS-ESI (m/z)calculated C ₂₀ H ₂₁ N ₂ O ₃ S,369.1273[M+1] ⁺ ,found 369.1267.

WYC-209A: 2-((4,4-Dimethyl-1S-oxodithiothiopyran-6-)ethynyl)pyrimidine-5-carboxylic acid ethyl ester

Diethyl D-tartrate (82.7 mg, 0.4 mmol) was dissolved in anhydrous CH ₂ Cl ₂ (1 mL), and Ti(iso-PrO) ₄ (0.2 mmol, 58 uL) was quickly added at 16 °C and stirred for 3 minutes. Water (3.6 uL, 0.2 mmol) was added dropwise and stirring was continued for 20 minutes. It was then cooled to -20 degrees, and WYC-203 (69 mg, 0.2 mmol) and cumene hydroperoxide (74 uL, 0.4 mmol) were quickly added, and the reaction was stopped after 3 hours. The reaction liquid was poured into 10 mL of a mixed solution of ferrous sulfate (0.2 g), citric acid (67 mg), dioxane and diethyl ether (2:1:2), and stirred for 15 minutes. The aqueous phase was extracted with diethyl ether, the organic layers were washed with 0.5M K ₂ CO _3, saturated sodium chloride, and the organic phase was dried over anhydrous sodium sulfate, filtered, spin dry, flash column chromatography (PE: EtOAc = 1: 2 ) The product WYC-209A (43 mg, 84%, ee% = 90%) was obtained. Recrystallization from diethyl ether gave WYC-209A (25 mg, ee% = 99%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ9.29 (s, 2H), 7.82-7.75 (m, 2H), 7.66 (d, J = 7.9Hz, 1H), 4.47 (q, J = 7.1Hz, 2H) , 3.24 (t, J = 11.1 Hz, 1H), 3.15 - 3.07 (m, 1H), 2.43 (dd, J = 14.0, 10.4 Hz, 1H), 1.92 (dd, J = 14.9, 8.8 Hz, 1H), 1.47 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H), 1.34 (s, 3H); ¹³ C NMR (126MHz, CDCl ₃ ) δ 163.33, 158.54, 155.32, 145.19, 132.61, 131.06, 130.22, 124.22 , 122.62, 89.60, 89.35, 62.32, 34.75, 31.36, 31.25, 29.93, 14.39. ESI (+)-MS: 369.4 [M+1] ⁺ . Ee% was determined by chiral HPLC conditions as follows: Agilent 1260 infinity liquid chromatograph, column Lux Cellulose-1 250*4.6 mm, mobile phase: acetonitrile/H ₂ O = 80:20, 20 degrees, 0.7 mL/min , retention time 8.592min.

WYC-209B: 2-((4,4-Dimethyl-1R-oxodithiothiopyran-6-)ethynyl)pyrimidine-5-carboxylic acid ethyl ester

Diethyl L-tartrate (82.7 mg, 0.4 mmol) was dissolved in anhydrous CH ₂ Cl ₂ (1 mL), and Ti(iso-PrO) ₄ (0.2 mmol, 58 uL) was quickly added at 16 °C and stirred for 3 minutes, slowly. Water (3.6 uL, 0.2 mmol) was added dropwise and stirring was continued for 20 minutes. It was then cooled to -20 degrees, and WYC-203 (69 mg, 0.2 mmol) and cumene hydroperoxide (74 uL, 0.4 mmol) were quickly added, and the reaction was stopped after 3 hours. The reaction liquid was poured into 10 mL of a mixed solution of ferrous sulfate (0.2 g), citric acid (67 mg), dioxane and diethyl ether (2:1:2), and stirred for 15 minutes. The aqueous layer was extracted with EtOAc. EtOAc (EtOAc)EtOAc. WYC-209B (43 mg, 84%, ee% = 90%). Recrystallization from diethyl ether gave WYC-209B (25 mg, ee% = 99%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ9.29 (s, 2H), 7.82-7.75 (m, 2H), 7.66 (d, J = 7.9Hz, 1H), 4.47 (q, J = 7.1Hz, 2H) , 3.24 (t, J = 11.1 Hz, 1H), 3.15 - 3.07 (m, 1H), 2.43 (dd, J = 14.0, 10.4 Hz, 1H), 1.92 (dd, J = 14.9, 8.8 Hz, 1H), 1.47 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H), 1.34 (s, 3H); ¹³ C NMR (126MHz, CDCl ₃ ) δ 163.33, 158.54, 155.32, 145.19, 132.61, 131.06, 130.22, 124.22 , 122.62, 89.60, 89.35, 62.32, 34.75, 31.36, 31.25, 29.93, 14.39. ESI (+)-MS: 369.4 [M+1] ⁺ . Among them, ee% was determined by chiral HPLC conditions as follows: Agilent 1260 infinity liquid chromatograph, column Lux Cellulose-1 250*4.6 mm, mobile phase: acetonitrile / H ₂ O = 80:20, 20 degrees, 0.7 mL /min, retention time 9.147min.

The single crystal structure diagrams of WYC-209A and WYC-209B are shown in Fig. 17 and Fig. 18, respectively. The crystal belongs to the monoclinic system, the space group is P21, and the unit cell parameters are:

α=90°, β=103.010(3)°, γ=90°, unit cell volume

In the unit cell, the unit number is Z=4 and the density is 1.314Mg/m ³ .

Table 1 atomic coordinates (x10 ⁴ ) and equivalent isotropic position parameters

Example 18: 2-((4,4-Dimethyl-1-oxodithiothiopyran-6-)ethynyl)pyrimidine-5-carboxylic acid

WYC-206 (34 mg, 0.105 mmol) was added to the flask, 1.5 mL of dry dichloromethane was added, and the mixture was cooled to 0 ° C in an ice water bath, then m-CPBA (26 mg, 0.105 mmol) was added, and the reaction was carried out for 1 hour in an ice water bath and then moved to room temperature. The next reaction was 2 h, and TLC was followed. After the reaction was completed, it was quenched with sodium thiosulfate solution, diluted with ethyl acetate, washed with saturated sodium hydrogen sulfate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. : MeOH = 12:1) gave product WYC-210 (23 mg, 68%). ¹ H NMR (500 MHz, pyridine) δ 9.66 (s, 2H), 7.99 - 7.85 (m, 2H), 7.65 (d, J = 7.8 Hz, 1H), 3.20 (t, J = 10.7 Hz, 1H), 3.14–3.02 (m, 1H), 2.32 (dd, J = 12.9, 10.4 Hz, 1H), 1.72 (dd, J = 13.2, 9.4 Hz, 1H), 1.25 (s, 3H), 1.18 (s, 3H) ¹³ C NMR (126 MHz, pyridine) δ 166.30, 159.03, 155.15, 145.73, 142.20, 132.56, 130.90, 130.31, 125.00, 124.29, 90.65, 88.52, 43.70, 34.73, 30.89, 30.62, 29.97. ESI(+)-MS: 341.1[M+1] ⁺ .

Example 19: 2-Amino-4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)benzoic acid

The compound 6-ethynyl-4,4-dimethylbenzothiopyran (405.6 mg, 2 mmol) and the compound 2-amino-4-iodobenzoic acid (263 mg, 1 mmol) were placed in a flask, and Pd(PPh ₃ ) was added. ₂ Cl ₂ (42 mg, 0.06 mmol), CuI (23 mg, 0.12 mmol), argon gas was applied and replaced with 3 times to remove oxygen, and 10 mL of dry DMF, 0.2 mL of dry Et ₃ N was added by syringe and heated to 75 Degree reaction 12h, TLC tracking. After completion of the reaction, the mixture was cooled to room temperature, and then diluted with aq. Chromatography (PE: EtOAc = 5:1) gave product WYC-212 ( 286 g, 85%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ7.88 (d, J = 8.3Hz, 1H), 7.52 (d, J = 1.7Hz, 1H), 7.18 (dd, J = 8.1,1.8Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 1.3 Hz, 1H), 6.81 (dd, J = 8.3, 1.5 Hz, 1H), 3.08 - 3.02 (m, 3H), 1.99 - 1.94 ( m, 2H), 1.35 (s, 6H); ¹³ C NMR (126MHz, CDCl ₃ ) δ 165.25, 165.23, 163.21, 161.20, 142.29, 134.42, 133.26, 133.25, 131.70, 131.64, 129.97, 129.27, 126.75, 125.15, 125.12 , 117.73, 117.05, 116.92, 116.66, 116.47, 98.04, 98.02, 81.71, 61.62, 37.29, 33.13, 30.09, 23.38, 14.42. ESI(+)-MS: 338.3 [M+1] ⁺ .

Example 20: 2-Acetylamino-4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)benzoic acid

WYC-212 (200 mg, 0.3 mmol) was added to the flask, 10 mg of DMAP was added, 5 mL of dry pyridine was added under argon atmosphere, cooled to 0 °C in an ice water bath, 43 μl of acetyl chloride was added dropwise, and the reaction was carried out for 10 min in an ice water bath. After moving to room temperature for 5 h, TLC was followed. After the reaction is completed, it is quenched with methanol, diluted with ethyl acetate, diluted with EtOAc EtOAc EtOAc EtOAc. Column chromatography (PE: EtOAc = 20:1) gave product WYC-213 (195 mg, 87%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ8.13 (d, J = 8.1Hz, 1H), 7.64 (d, J = 1.3Hz, 1H), 7.58 (dd, J = 8.1,1.5Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.21 (dd, J = 8.1, 1.8 Hz, 1H), 7.09 (d, J = 8.1 Hz, 1H), 3.09 - 3.03 (m, 2H), 2.47 (s, 3H), 1.99-1.92 (m, 2H ), 1.35 (s, 6H). 13 C NMR (126MHz, CDCl 3) δ160.95,159.37,146.56,142.37,134.76,132.31,131.05,130.06,129.32,128.95,128.49, 126.82, 117.47, 115.64, 95.32, 87.52, 37.23, 33.13, 30.09, 23.39, 21.54. ESI(+)-MS: 380.4 [M+1] ⁺ .

Example 21: 6-ethynyl-4,4-dimethyl-1-oxodithiothiopyran

6-ethynyl-4,4-dimethylbenzothiopyran (2.03 g, 10 mmol) was added to the flask, and 27 mL of dry dichloromethane was added thereto, and the mixture was cooled to 0 ° C in ice water, and then mCPBA (1.73 g, 10 mmol) was added. After reacting for 10 min in an ice water bath, the reaction was carried out to room temperature for 1 h, and then moved to room temperature for 2 h, followed by TLC. After the reaction was completed, it was quenched with sodium thiosulfate solution, diluted with ethyl acetate, washed with saturated sodium hydrogen sulfate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. : EtOAc = 3:1) gave 1-oxo-6-ethynyl-4,4-dimethylbenzothiopyran (1.43 g, 72%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ7.41 (d, J = 8.0Hz, 1H), 7.26 (s, 1H), 7.15 (d, J = 8.0Hz, 1H), 2.93-2.74 (m, 3H) , 2.14 (ddd, J = 14.6, 10.5, 1.7 Hz, 1H), 1.58 (ddd, J = 15.0, 8.7, 1.8 Hz, 1H), 1.14 (s, 3H), 1.01 (s, 3H); ¹³ C NMR (126MHz, CDCl ₃ ) δ 144.82, 138.91, 131.70, 130.53, 130.17, 125.60, 82.69, 79.39, 43.23, 34.47, 31.27, 31.13, 29.67. ESI (+)-MS: 219.3 [M+1] ⁺ .

Example 22: 2-Amino-4-((4,4-dimethyl-1-oxodithiothiopyran-6-)ethynyl)benzoic acid

The compound 1-oxo-6-ethynyl-4,4-dimethylbenzothiopyran (263 mg, 1.0 mmol) and the compound 2-amino-4-iodobenzoic acid (262 mg, 1.2 mmol) were added to the flask. Add Pd(PPh ₃ ) ₂ Cl ₂ (42 mg, 0.06 mmol), CuI (23 mg, 0.0412 mmol), protect with argon and replace the gas three times to remove oxygen, and add 4 mL of dry DMF, 0.2 mL of dry Et. ₃ N, heated to 70 ° for 8 h, TLC tracking. After completion of the reaction, the mixture was cooled to room temperature, and then diluted with aq. Chromatography (PE: EtOAc = 50:1) ^{1 H NMR (500MHz, pyridine)} δ8.37 (d, J = 8.1Hz, 1H), 7.92 (d, J = 8.0Hz, 1H), 7.86 (s, 1H), 7.59 (s, 1H), 7.36 ( s, 1H), 7.03 (d, J = 8.1 Hz, 1H), 5.67 (s, 1H), 3.20 - 3.14 (m, 1H), 3.11 - 3.05 (m, 1H), 2.38 (ddd, J = 14.2, 10.3, 1.7 Hz, 1H), 1.74 - 1.68 (m, 1H), 1.26 (s, 3H), 1.17 (s, 3H); ¹³ C NMR (126 MHz, pyridine) δ 171.06, 152.34, 145.52, 140.46, 132.80, 131.65 , 130.43, 130.20, 127.92, 126.32, 119.79, 118.58, 112.43, 91.82, 90.33, 55.01, 43.59, 34.63, 30.93, 30.63, 29.80. ESI (+)-MS: 354.3 [M+1] ⁺ .

Example 23: Methyl 2-amino-4-((4,4-dimethyl-1-oxodithiothiopyran-6-)ethynyl)benzoate

WYC-214 (150 mg, 0.425 mmol) was added to the flask, sodium carbonate (176 mg, 1.275 mmol) was added, and 3 mL of dry DMF and methyl iodide (40 μl, 0.637 mmol) were added under argon and heated slowly to 100 °. Reaction 6h, TLC tracking. After the reaction was completed, it was cooled to room temperature, diluted with EtOAc EtOAc (EtOAc)EtOAc. :1) The product WYC-215 (143 mg, 92%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ7.84 (d, J = 8.3Hz, 1H), 7.73 (d, J = 8.1Hz, 1H), 7.58 (d, J = 1.5Hz, 1H), 7.48 (dd , J = 8.0, 1.6 Hz, 1H), 6.87 (d, J = 1.3 Hz, 1H), 6.81 (dd, J = 8.3, 1.5 Hz, 1H), 3.88 (s, 3H), 3.20 (ddd, J = 12.9, 10.6, 2.2 Hz, 1H), 3.10 (ddd, J = 13.1, 8.7, 2.3 Hz, 1H), 2.46 (ddd, J = 14.9, 10.5, 2.2 Hz, 1H), 1.89 (ddd, J = 15.1, 8.7, 2.2 Hz, 3H), 1.47 (s, 3H), 1.33 (s, 3H); ¹³ C NMR (126 MHz, CDCl ₃ ) δ 168.19, 150.04, 144.92, 138.59, 131.48, 131.30, 130.34, 130.18, 128.13, 126.44 , 119.72, 119.64, 111.06, 90.93, 90.26, 51.84, 43.28, 34.57, 31.36, 31.21, 29.73. ESI(+)-MS: 368.4 [M+1] ⁺ .

Example 24: Ethyl 2-amino-4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)benzoate

Add WYC-212 (50mg, 0.15mmol) to the flask, add 2mL absolute ethanol under argon protection, ice bath to 0 degree, add 0.15mL concentrated sulfuric acid, add temperature and reflux reaction for 4h, TLC tracking . After the reaction is completed, it is cooled to room temperature, neutralized with 2 mol/L sodium hydroxide to neutrality, washed with saturated sodium chloride, and the organic phase is dried over anhydrous sodium sulfate, filtered, spin-dried, flash column chromatography (PE: EtOAc = 10:1) gave product WYC-216 (14 mg, 25%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.84 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.17 (dd, J = 8.1, 1.7 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.83 (d, J = 1.3 Hz, 1H), 6.79 (dd, J = 8.3, 1.4 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.06 -3.03 (m, 2H), 1.97 - 1.94 (m, 2H), 1.39 (t, J = 7.1 Hz, 3H), 1.34 (s, 6H). ¹³ C NMR (126 MHz, CDCl ₃ ) δ 167.92, 150.10, 142.22 , 133.72, 131.35, 129.95, 129.19, 129.02, 126.70, 119.55, 119.39, 118.23, 110.80, 91.99, 88.37, 60.61, 37.36, 33.12, 30.13, 23.37, 14.50. ESI(+)-MS: 366.4 [M+1] ⁺ .

Example 25: Ethyl 2-acetamido-4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)benzoate

WYC-216 (80 mg, 0.22 mmol) was added to the flask, 6 mg of DMAP was added, 2 mL of dry pyridine was added under argon atmosphere, cooled to 0 °C in an ice water bath, and acetyl chloride (31 μl, 0.44 mmol) was added dropwise, ice After reacting for 10 min in a water bath, it was moved to room temperature for 9 h, and was followed by TLC. After the reaction is completed, it is quenched with methanol, diluted with ethyl acetate, diluted with EtOAc EtOAc EtOAc EtOAc EtOAc. Column chromatography (PE: EtOAc = 10:1) gave product WYC-217 (71 mg, 79%). ¹ H NMR (500MHz, CDCl ₃ ) δ 11.12 (s, 1H), 8.88 (d, J = 1.4 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 1.7 Hz) , 1H), 7.20 (dd, J = 3.6, 1.7 Hz, 1H), 7.18 (dd, J = 3.8, 1.7 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.06–3.03 (m, 2H), 2.24 (s, 3H), 1.97–1.94 (m, 2H), 1.42 (t, J = 7.1 Hz, 3H), 1.35 (s, 6H). _{^{13 C NMR (126MHz, CDCl 3}} ) δ169.17,168.11,142.25,141.59,133.98,130.81,130.17,130.04,129.24,126.70,125.26,122.97,118.06,114.16,93.43,88.37,61.65,37.36,33.13,30.13,25.68 , 23.38, 14.34. ESI (+)-MS: 408.4 [M+1] ⁺ .

Example 26: Ethyl 2-amino-4-((4,4-dimethyl-1-oxodithiothiopyran-6-)ethynyl)benzoate

The compound 2-amino-4-iodobenzoic acid ethyl ester (262.0 mg, 1.2 mmol) and the compound 1-oxo-6-ethynyl-4,4-dimethylbenzothiopyran (263.0 mg, 1 mmol) were added. the flask was added _{Pd (PPh 3) 2 Cl 2} (42mg, 0.06mmol), CuI (23mg, 0.12mmol), and replaced with argon for three times to exclude oxygen gas is added by syringe 15mL of dry DMF, 0.2mL Dry Et ₃ N, heated to 75 ° for 12 h, TLC tracking. After completion of the reaction, the mixture was cooled to room temperature, and then diluted with aq. Chromatography (DCM: MeOH = 40:1) ^{1 H NMR (500MHz, pyridine)} δ8.39 (d, J = 8.1Hz, 1H), 7.97-7.82 (m, 2H), 7.61 (s, 1H), 7.38 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 3.25 - 3.01 (m, 2H), 2.40 (ddd, J = 14.2, 10.3, 1.7 Hz, 1H), 1.73 (ddd, J = 14.8, 8.8, 1.5 Hz, 1H), 1.28 ( s, 3H), 1.19 (s, 3H). ¹³ C NMR (126MHz, pyridine) δ 171.75, 153.03, 150.76, 150.74, 150.55, 150.53, 150.33, 150.31, 146.21, 141.15, 133.49, 132.34, 131.12, 130.89, 128.61, 127.01, 120.48, 119.27, 113.12, 92.51, 91.02, 44.28, 35.32, 31.62, 31.32, 30.49. ESI(+)-MS: 382.4 [M+1] ⁺ .

Example 27: Methyl 2-methylamino-4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)benzoate

WYC-212 (100 mg, 0.3 mmol) was added to the flask, sodium carbonate (125 mg, 0.9 mmol) was added, and 3 mL of dry DMF and iodomethane (28 μl, 0.445 mmol) were added under argon and heated slowly to 100 °. Reaction 4h, TLC tracking. After the reaction was completed, it was cooled to room temperature, diluted with EtOAc EtOAc (EtOAc)EtOAc. :1) The product WYC-219 (43 mg, 39%) and 3-69-2-2 (45 mg, 43%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ7.87 (d, J = 8.2Hz, 1H), 7.54 (s, 1H), 7.20 (d, J = 8.1Hz, 1H), 7.06 (d, J = 8.1Hz , 1H), 6.88 (s, 1H), 6.78 (d, J = 8.2 Hz, 1H), 3.86 (s, 3H), 3.08 - 3.02 (m, 2H), 2.95 (s, 3H), 1.99 - 1.94 ( m,2H), 1.35 (s, 6H). ¹³ C NMR (126MHz, CDCl ₃ ) δ 168.77, 151.15, 142.24, 133.75, 131.64, 130.02, 129.68, 129.24, 126.71, 118.37, 118.24, 114.31,110.05,92.11,88.89 , 51.79, 37.38, 33.14, 30.15, 23.39. ESI(+)-MS: 366.2 [M+1] ⁺ .

Example 28: Methyl 2-amino-4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)benzoate

Compound WYC-212 (100 mg, 0.3 mmol) was added to the flask, potassium carbonate (125 mg, 0.9 mmol) was added, and 3 mL of dry DMF was added under dry argon, and MeI (28 μL, 0.445 mmol) was added dropwise at 100 °C. 8h, after the reaction of the starting material was completed, it was cooled to room temperature, diluted with ethyl acetate, washed with 1 mol/L HCl solution, washed with saturated sodium bicarbonate, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Dry, flash column chromatography (EtOAc: EtOAc = 20:1) ¹ H NMR (500 MHz, cdCl ₃ ) δ 7.83 (d, J = 8.3 Hz, 1H), 7.52 (d, J = 1.7 Hz, 1H), 7.18 (dd, J = 8.1, 1.8 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.86 (d, J = 1.4 Hz, 1H), 6.81 (dd, J = 8.3, 1.5 Hz, 1H), 3.88 (s, 3H), 3.08 - 3.02 (m, 2H), 2.00 - 1.93 (m, 2H), 1.35 (s, 6H). ¹³ C NMR (126MHz, cdcl ₃ ) δ 168.25, 149.81, 142.19, 133.74, 131.31, 129.92, 129.16, 129.15, 126.67, 119.74, 119.47, 118.15,110.58,92.12,88.28,51.75,37.32,33.08,30.09,23.34.ESI (+) - MS: 352.4 [M + 1] +.

Example 29: 2-Acetylamino-4-((4,4-dimethyl-1-oxodithiothiopyran-6-)ethynyl)benzoic acid

WYC-214 (152 mg, 0.42 mmol) was added to the flask, 10 mg of DMAP was added, 5 mL of dry dichloromethane, 0.212 mL of triethylamine was added under argon atmosphere, and the mixture was cooled to 0 degree in ice water bath, and added dropwise. The acid chloride (67 μl, 0.84 mmol) was reacted in an ice water bath for 10 min, then transferred to room temperature for 12 h, followed by TLC. After the reaction is completed, it is quenched with methanol, diluted with ethyl acetate, diluted with EtOAc EtOAc EtOAc EtOAc. Column chromatography (PE: EtOAc = 1 : 3) gave product WYC-221 (147 mg, 89%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ8.12 (d, J = 8.3Hz, 1H), 7.63 (d, J = 1.3Hz, 1H), 7.57 (dd, J = 8.1,1.5Hz, 1H), 7.54 (d, J = 1.7 Hz, 1H), 7.21 (dd, J = 8.1, 1.8 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 3.07 - 3.03 (m, 2H), 2.46 (s, 3H), 1.99–1.94 (m, 2H), 1.35 (s, 6H). ¹³ C NMR (126MHz, CDCl ₃ ) δ 160.87, 159.36, 146.58, 142.34, 134.73, 132.26, 131.01, 130.04, 129.30, 128.95, 128.45, 126.80, 117.45, 115.64, 95.28, 87.51, 37.21, 33.11, 30.07, 23.38, 21.54. ESI(+)-MS: 396.2 [M+1] ⁺ .

Example 30: 2-(3-bromophenyl)acetaldehyde

2-(3-Bromophenyl)ethanol (676 μl, 5 mmol) was added to the flask, 10 mL of dry dichloromethane was added, and DMP (2.5 g, 6 mmol) was taken in an ice water bath. The reaction was carried out for 0.5 h, followed by TLC. After the reaction is completed, it is cooled to 0 °C, quenched with sodium thiosulfate solution, diluted with ethyl acetate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. EtOAc = 15:1) gave 2-(3-bromophenyl)acetaldehyde (0.86 g, 87%). _{1H NMR (300MHz, CDCl 3)} δ9.74 (1H, t, J = 2.0), 7.46-7.37 (2H, m), 7.30-7.14 (2H, m), 3.67 (2H, d, J = 2.0). ¹³ C NMR (75 MHz, CDCl ₃ ) δ 198.9, 134.5, 133.0, 131.0, 130.9, 128.7, 123.3, 60.8. ESI (+)-MS: 199.1 [M+1] ⁺ .

Example 31: Ethyl 4-(3-bromophenyl)-2-butenoate

2- (3-bromophenyl) acetaldehyde (400mg, 2.02mmol) and _{Ph 3 PCH = CO 2 Et (} 703mg, 2.02mmol) added to the flask was added 10mL of dry toluene under an argon atmosphere and heated to 90 Degree reaction 8h, TLC tracking. After the reaction was completed, it was cooled to 0 °, diluted with ethyl acetate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate, filtered and evaporated to dry Ethyl (3-bromophenyl)-2-butenoate (514 mg, 96%). E-form: ¹ H NMR (500MHz, CDCl ₃ ) δ 7.36 (d, J = 8.0 Hz, 1H), 7.31 (s, 1H), 7.17 (t, J = 7.8 Hz, 1H), 7.11 - 6.99 ( m, 2H), 5.80 (dt, J = 15.6, 1.6 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.47 (dd, J = 6.8, 1.0 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H). ¹³ C NMR (126MHz, CDCl ₃ ) δ 166.29, 146.15, 140.06, 131.88, 130.29, 129.90, 127.53, 123.02, 122.77, 77.41, 77.16, 76.91, 60.44, 38.00, 14.32.Z-form: _{^{1 H NMR (500MHz, CDCl 3}} ) δ7.38 (s, 1H), 7.36-7.33 (m, 1H), 7.16 (dd, J = 4.1,1.4Hz, 2H), 6.30 (dt, J = 11.4,7.6 Hz, 1H), 5.88 (dt, J = 11.4, 1.7 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 4.00 (dd, J = 7.6, 1.4 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). ¹³ C NMR (126MHz, CDCl ₃ ) δ 166.33, 146.76, 141.84, 131.76, 130.25, 129.60, 127.41, 122.74, 120.73, 60.23, 34.73, 14.39.

Example 32: Ethyl 4-(3-bromophenyl)butanoate

Ethyl 4-(3-bromophenyl)-2-butenoate (1.05 g, 3.92 mmol) was added to a flask, and (10% wt) dry Pd/C (220 mg, 0.194 mmol) was added and protected under argon 20 mL of ethyl acetate was added thereto, and hydrogen gas was introduced and replaced with 3 times of gas, and reacted at normal temperature and normal pressure for 24 hours, followed by TLC. After completion of the reaction, the title compound wasjjjjjjjjjjjjjjjjjjj ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.32 (dd, J = 9.5, 1.3 Hz, 2H), 7.16 - 7.08 (m, 2H), 4.12 (q, J = 7.1 Hz, 2H), 2.64 - 2.59 ( m, 2H), 2.30 (t, J = 7.4 Hz, 2H), 1.96 - 1.90 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H). ¹³ C NMR (126 MHz, CDCl ₃ ) δ 173.27, 143.87 , 131.59, 130.01, 129.18, 127.22, 122.51, 60.40, 34.82, 33.57, 26.36, 14.33. ESI (+)-MS: 271.2 [M+1] ⁺ .

Example 33: 5-(3-bromophenyl)-2-methyl-2-pentanol

Ethyl 4-(3-bromophenyl)butanoate (0.53 g, 1.96 mmol) was added to a flask, and 15 mL of tetrahydrofuran was added under argon atmosphere, cooled to 0 ° with ice water, and methyl bromide was added dropwise. Magnesium (2 mL, 5.89 mmol) was reacted at 0 °C for 3 h, and reacted for 1 h at room temperature, followed by TLC. After the completion of the reaction, the mixture was cooled to 0 °, quenched with ice water, diluted with ethyl acetate, diluted with EtOAc EtOAc. Filtration, spin-drying, flash column chromatography (EtOAc:EtOAc:EtOAc) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37 - 7.26 (m, 2H), 7.22 - 7.10 (m, 2H), 2.62 (dt, J = 15.0, 7.7 Hz, 2H), 1.76 - 1.64 (m, 2H) ), 1.56 - 1.47 (m, 2H), 1.22 (s, 6H). ¹³ C NMR (126MHz, CDCl ₃ ) δ 144.81, 131.40, 129.84, 128.81, 127.05, 122.33, 70.73, 43.29, 35.95, 29.22, 26.00. (+) - MS: 257.1 [ M + 1] +.

Example 34: 7-Bromo-4,4-dimethyl-3,4-dihydronaphthyl-1-(2H)-one

5-(3-Bromophenyl)-2-methyl-2-pentanol (340 mg, 1.33 mmol) was added to the flask, 2 mL of dry dichloromethane was added under argon and cooled to 0. 0.2 mL of concentrated sulfuric acid was added dropwise, and reacted at room temperature for 4 h, followed by TLC. After the reaction is completed, it is diluted with water, neutralized with 1 mol/l sodium hydroxide, diluted with ethyl acetate, diluted with ethyl acetate, washed with saturated sodium carbonate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate, filtered and dried. Obtained 320 mg of white solid; 320 mg of solid was added to the flask, 4.3 mL of toluene was added, and then 71 mg of chromium trioxide was dissolved in a mixed solution of 0.648 mL of acetic acid and 0.342 mL of acetic anhydride, and a solution of chromium trioxide was placed in an ice water bath. It was added to the flask and reacted for 2 h, followed by TLC. After completion of the reaction, the mixture was diluted with EtOAc EtOAc EtOAc EtOAc (EtOAc) :1) The product 7-bromo-4,4-dimethyl-3,4-dihydronaphthyl-1-(2H)-one (268 mg, 80%) was obtained. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.37 (dd, J = 8.5, 1.6 Hz, 1H), 7.33 - 7.21 (m, 2H), 2.24 - 2.05 (m, 2H), 1.87 - 1.77 (m, 1H) ), 1.58 - 1.49 (m, 1H), 1.35 (s, 3H), 1.30 (s, 3H). ¹³ C NMR (126 MHz, CDCl ₃ ) δ 197.03, 151.09, 136.63, 132.77, 130.15, 128.04, 120.57, 36.86, 35.04, 33.89, 29.65. ESI(+)-MS: 253.1 [M+1] ⁺ .

Example 35: 7-Bromo-4,4-dimethyl-1-phenyl-1,2,3,4-tetrahydronaphthalen-1-ol

Add 7-bromo-4,4-dimethyl-3,4-dihydronaphthyl-1-(2H)-one (340 mg, 1.35 mmol) to a flask and add 3 mL of tetrahydrofuran under ice-protection, ice The mixture was cooled to 0 ° under a water bath, phenylmagnesium bromide (2.7 mL, 2.7 mmol) was added dropwise, and the mixture was reacted at 0 ° C for 0.5 h, and reacted at room temperature for 18 h, followed by TLC. After the completion of the reaction, the mixture was cooled to 0 °, quenched with ice water, diluted with ethyl acetate, diluted with EtOAc EtOAc. Filtration, spin-drying, flash column chromatography (PE:EtOAc = 100:1) afforded product 7-bromo-4,4-dimethyl-1-phenyl-1,2,3,4-tetrahydronaphthyl- 1-Alcohol (280 mg, 63%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39 - 7.08 (m, 8H), 2.24 - 2.05 (m, 2H), 1.87 - 1.77 (m, 1H), 1.58 - 1.49 (m, 1H), 1.35 (s) , 3H), 1.30 (s, 3H). ¹³ C NMR (126MHz, CDCl ₃ ) δ 148.11, 145.41, 143.32, 131.50, 131.18, 128.46, 128.08, 127.15, 126.59, 119.96, 75.87, 37.69, 34.77, 34.09, 31.56, 31.45. ESI(+)-MS: 331.1 [M+1] ⁺ .

Example 36: 6-Bromo-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene

Add 7-bromo-4,4-dimethyl-1-phenyl-1,2,3,4-tetrahydronaphthalen-1-ol (260 mg, 0.79 mmol) to the flask and add p-toluenesulfonic acid (27 mg, 0.16 mmol), 2 mL dry toluene was added under argon atmosphere, and reacted at 75 ° for 0.5 h, followed by TLC. After the reaction is completed, it is cooled to room temperature, quenched with ice water, diluted with EtOAc EtOAc EtOAc EtOAc PE: EtOAc = 250: 1) gave the product 6-bromo-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene (224 mg, 91%). ¹ H NMR (500MHz, CDCl ₃ ) δ 7.44 - 7.40 (m, 2H), 7.39 - 7.33 (m, 4H), 7.24 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 2.1 Hz, 1H), 6.03 (t, J = 4.7Hz, 1H), 2.36 (d, J = 4.7Hz, 2H), 1.34 (s, 6H). 13 C NMR (126MHz, CDCl 3) δ145.59,144.16,140.35,138.75 , 136.15, 133.57, 131.80, 130.41, 128.72, 128.56, 127.87, 127.46, 127.02, 125.79, 119.96, 63.05, 38.87, 33.65, 28.18. ESI (+)-MS: 312.1 [M+1] ⁺ .

Example 37: ((5,5-Dimethyl-8-phenyl-5,6-dihydronaphthyl-2-)ethynyl)trimethylsilane

The compound 6-bromo-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene (310 mg, 1.0 mmol) and the compound trimethylethynyl silane (0.28 μL, 2 mmol) were added to the flask. Add Pd(PPh ₃ ) ₂ Cl ₂ (21 mg, 0.03 mmol), CuI (11 mg, 0.06 mmol), protect with argon and replace the gas three times to remove oxygen, and add 5 mL of dry DMF, 0.2 mL of dry Et. ₃ N, reaction at room temperature overnight, TLC tracking. After completion of the reaction, it is quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with EtOAc EtOAc. Petroleum ether) gave the product ((5,5-dimethyl-8-phenyl-5,6-dihydronaphthyl-2-)ethynyl)trimethylsilane (275 mg, 83%). ¹ H NMR (500MHz, CDCl ₃ ) δ 7.44 - 7.38 (m, 2H), 7.36 - 7.32 (m, 4H), 7.28 (d, J = 7.9 Hz, 10H), 7.11 (d, J = 1.6 Hz, 1H), 5.97 (t, J = 4.7 Hz, 1H), 2.33 (d, J = 4.7 Hz, 2H), 1.31 (s, 6H), 0.19 (s, 9H). ¹³ C NMR (126 MHz, CDCl ₃ ) δ146.01,140.79,139.09,133.98,131.51,129.25,128.83,128.49,127.29,127.27,123.92,120.66,105.45,93.41,38.88,33.90,28.19,0.16.ESI(+)-MS:331.2[M+1] ⁺ .

Example 38: 6-ethynyl-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene

((5,5-Dimethyl-8-phenyl-5,6-dihydronaphthyl-2-)ethynyl)trimethylsilyl (300 mg, 0.91 mmol) was added to the flask, and TBAF (30 mg, 0.115 mmol), 2 mL of dry tetrahydrofuran, reacted for 4 h, followed by TLC. After completion of the reaction, it was diluted with ethyl acetate, washed with saturated brine, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate, filtered, dried, and then purified by column chromatography (PE: EA=1000:1) The product 6-ethynyl-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene (225 mg, 96.6%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ77.47-77.34 (m, 7H), 77.22 (d, J = 1.6Hz, 1H), 76.04 (t, J = 4.7Hz, 1H), 72.98 (s, 1H) , 72.39 (d, J = 4.7 Hz, 2H), 71.38 (s, 6H). ¹³ C NMR (126MHz, CDCl ₃ ) δ 146.23, 140.58, 138.97, 134.13, 131.41, 129.62, 128.77, 128.49, 127.34, 127.27, 124.04 , 119.59, 83.98, 76.59, 38.83, 33.85, 28.18. ESI(+)-MS: 259.2 [M+1] ⁺ .

Example 39: Methyl 4-((5,5-dimethyl-8-phenyl-5,6-dihydronaphthyl-2-)ethynyl)-2-hydroxybenzoate

Compound 6-ethynyl-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene (116 mg, 0.45 mmol) and methyl 2-hydroxy-4-iodobenzoate (250 m, 0.1 mmol) Add to the flask, add Pd(PPh ₃ ) ₂ Cl ₂ (9.5 mg, 0.0135 mmol), CuI (5.1 mg, 0.027 mmol), protect with argon and replace the gas three times to remove oxygen, and add 3 mL of dry with a syringe. DMF, 0.2mL under dry Et ₃ N, 75 of the reaction 8h, TLC trace. After completion of the reaction, it is quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with EtOAc EtOAc. PE: EA = 500: 1) The product WYC-301 (155 mg, 79%) was obtained. _{^{1 H NMR (500MHz, CDCl 3}} ) δ10.75 (s, 1H), 7.76 (d, J = 8.2Hz, 1H), 7.43 (dd, J = 7.7,7.1Hz, 7H), 7.37 (dd, J = 9.3, 3.7 Hz, 4H), 7.21 (d, J = 1.3 Hz, 1H), 7.09 (d, J = 1.2 Hz, 1H), 6.97 (dd, J = 8.2, 1.2 Hz, 1H), 6.02 (t, J = 4.6 Hz, 1H), 3.94 (s, 3H), 2.37 (d, J = 4.7 Hz, 2H), 1.36 (s, 6H). ¹³ C NMR (126 MHz, CDCl ₃ ) δ 170.27, 161.31, 146.42, 140.63 , 138.99, 134.24, 131.17, 130.83, 129.82, 129.20, 128.80, 128.54, 127.41, 127.38, 124.18, 122.47, 120.36, 120.07, 111.98, 92.99, 87.93, 52.47, 38.85, 33.94, 28.19. ESI(+)-MS: 409.3[M+1] ⁺ .

Example 40: Ethyl 4-((5,5-dimethyl-8-phenyl-5,6-dihydronaphthyl-2-)ethynyl)-2-hydroxybenzoate

The compound WYC-301 (250 mg, 0.613 mmol) was added to a flask, sodium ethoxide (125 mg, 1.83 mmol) was added, and 5 mL of ethanol was added thereto, and the reaction was carried out overnight at room temperature, followed by TLC. After the reaction of the starting material is completed, it is neutralized to neutral with an acidic resin. The mixture is filtered, and the filtrate is diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Column chromatography (PE: EA = 100:1) gave product WYC-302 (230 mg, 92%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ10.82 (s, 1H), 7.77 (d, J = 8.2Hz, 1H), 7.45-7.39 (m, 3H), 7.38-7.34 (m, 4H), 7.19 ( d, J = 1.5 Hz, 1H), 7.07 (d, J = 1.4 Hz, 1H), 6.95 (dd, J = 8.2, 1.5 Hz, 1H), 6.01 (t, J = 4.7 Hz, 1H), 4.40 ( q, J = 7.1 Hz, 2H), 2.37 (d, J = 4.7 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H), 1.35 (s, 6H). ¹³ C NMR (126 MHz, CDCl ₃ ) Δ169.92,161.39,146.40,140.65,139.01,134.25,131.18,130.70,129.83,129.20,128.82,128.55,127.42,127.39,124.19,122.39,120.37,120.11,112.25,92.89,87.99,61.68,38.86,33.96,28.21, 14.32. ESI(+)-MS: 423.4 [M+1] ⁺ .

Example 41: Ethyl 2-fluoro-4-iodobenzoate

2-Fluoro-4-iodobenzoic acid (1.0 g, 3.76 mmol) was added to the flask, and 10 mL of absolute ethanol was added under argon atmosphere, and the mixture was heated to 0 ° with ice water, and 0.5 mL of concentrated sulfuric acid was added dropwise. The temperature was refluxed for 4 h, and TLC was followed. After the reaction is completed, it is cooled to room temperature, and the sulfuric acid is neutralized with 1 mol/L sodium hydroxide to neutrality, washed with saturated sodium hydrogencarbonate, washed with saturated sodium chloride, and then dried over anhydrous sodium sulfate. Dry, flash column chromatography (EtOAc: EtOAc = 15:1) _{^{1 H NMR (500MHz, CDCl 3}} ) δ7.62-7.57 (m, 1H), 7.52 (dd, J = 8.3,1.6Hz, 1H), 7.49 (dd, J = 9.9,1.5Hz, 1H), 4.36 ( q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H). ¹³ C NMR (126MHz, CDCl ₃ ) δ 163.87, 163.84, 162.18, 160.06, 133.48, 133.45, 133.05, 133.04, 126.54, 126.34 , 118.76, 118.68, 99.59, 99.52, 61.59, 14.29. ESI(+)-MS: 294.1 [M+1] ⁺ .

Example 42: Ethyl 2-fluoro-4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)benzoate

The compound 6-ethynyl-4,4-dimethylbenzothiopyran (275 mg, 1.36 mmol) and ethyl 2-fluoro-4-iodobenzoate (200 mg, 0.68 mmol) were added to the flask, and Pd (PPh) was added. _{3) 2 Cl 2 (28.6mg,} 0.0408mmol), CuI (15.5mg, 0.0816mmol), and replaced with argon for three times to exclude oxygen gas is added by syringe 3mL of dry DMF, 0.3mL of dry Et ₃ N The reaction was carried out at 80 °C for 6 h, and TLC was followed. After completion of the reaction, it is quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with EtOAc EtOAc. PE: EA = 200: 1) The product WYC-303 (215 mg, 86%) was obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.90 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 1.7 Hz, 1H), 7.32 (dd, J = 8.1, 1.4 Hz, 1H), 7.28 (d, J = 1.4 Hz, 1H), 7.25 (d, J = 1.4 Hz, 1H), 7.19 (dd, J = 8.2, 1.7 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.07 - 3.03 (m, 2H), 1.98 - 1.94 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.35 (s, 6H). ¹³ C NMR (126MHz, CDCl ₃ ) δ 164.12, 164.09, 162.75, 160.68, 142.32, 134.45, 132.15, 132.14, 129.98, 129.20, 127.08, 127.05, 126.78, 119.79, 119.60, 117.57, 93.98, 87.00, 86.98, 61.55, 37.25, 33.12 , 30.09, 23.37, 14.40. ESI(+)-MS: 369.4 [M+1] ⁺ .

Example 43: 2-Fluoro-4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)benzoic acid

The compound WYC-303 (15 mg, 0.04 mmol) was added to a flask, sodium ethoxide (8.3 mg, 0.12 mmol) was added, and 1 mL of tetrahydrofuran was added and allowed to react overnight at room temperature, followed by TLC. After the reaction of the starting material is completed, it is neutralized to neutral with an acidic resin. The mixture is filtered, and the filtrate is diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Column chromatography (PE: EA = 1:1) gave product WYC-304 (11 mg, 80%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.79 (t, J = 7.9 Hz, 1H), 7.53 (d, J = 1.7 Hz, 1H), 7.35 (dd, J = 8.1, 1.5 Hz, 1H), 7.30 (dd, J = 11.3, 1.4 Hz, 1H), 7.19 (dd, J = 8.1, 1.8 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 3.07 - 3.04 (m, 3H), 1.98 - 1.95 (m, 2H), 1.35 (s, 6H). ¹³ C NMR (126MHz, CDCl ₃ ) δ 167.53, 163.34, 161.26, 142.36, 134.65, 132.80, 131.19, 131.11, 130.04, 129.25, 127.25, 127.22, 126.81, 119.89 , 119.70, 117.45, 116.98, 94.69, 86.92, 37.24, 33.14, 30.09, 23.39. ESI(+)-MS: 339.3 [M+1] ⁺ .

Example 44: Ethyl 4-((5,5-dimethyl-8-phenyl-5,6-dihydronaphthyl-2-)ethynyl)-2-fluorobenzoate

Compound 6-ethynyl-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene (180 mg, 0.7 mmol) and 2-fluoro-4-iodo-benzoic acid ethyl ester (410 mg, 1.4 mmol) Add to the flask, add Pd(PPh ₃ ) ₂ Cl ₂ (30 mg, 0.042 mmol), CuI (16.0 mg, 0.084 mmol), protect with argon and replace the gas three times to remove oxygen, and add 5 mL of dry DMF with a syringe. 0.5 mL of dry Et ₃ N, reacted at 70 ° for 8 h, and traced by TLC. After completion of the reaction, it is quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with EtOAc EtOAc. PE: EA = 200: 1) The product WYC-305 (215 mg, 72%) was obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.87 (t, J = 7.8 Hz, 1H), 7.44 - 7.39 (m, 7H), 7.37 (ddd, J = 6.3, 3.4, 1.5 Hz, 4H), 7.29 - 7.26 (m, 1H), 7.24 - 7.18 (m, 2H), 6.02 (t, J = 4.7 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 2.37 (d, J = 4.7 Hz, 2H) ), 1.39 (t, J = 7.1 Hz, 3H), 1.35 (s, 6H). ¹³ C NMR (126MHz, CDCl ₃ ) δ 164.12, 164.09, 162.70, 160.63, 146.67, 140.62, 138.95, 134.33, 132.08, 132.07, 131.17,129.92,129.84,129.20,128.82,128.57,127.53,127.41,127.17,127.14,124.25,119.91,119.77,119.72,118.51,118.43,93.66,86.96,86.94,61.55,38.84,33.98,28.20,14.39. +)-MS: 425.5 [M+1] ⁺ .

Example 45: 4-((5,5-Dimethyl-8-phenyl-5,6-dihydronaphthyl-2-)ethynyl)-2-fluorobenzoic acid

The compound WYC-305 (70 mg, 0.19 mmol) was added to a flask, sodium ethoxide (26 mg, 0.38 mmol) was added, and 2 mL of tetrahydrofuran was added thereto, and the reaction was carried out overnight at room temperature, followed by TLC. After the reaction of the starting material is completed, it is neutralized to neutral with an acidic resin. The mixture is filtered, and the filtrate is diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Column chromatography (PE: EA = 2:1) gave product WYC-306 (53 mg, 75%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ7.95 (t, J = 7.9Hz, 1H), 7.44-7.39 (m, 7H), 7.39-7.35 (m, 4H), 7.30 (dd, J = 8.2,1.4 Hz, 1H), 7.24 (d, J = 1.3 Hz, 1H), 7.19 (d, J = 1.5 Hz, 1H), 6.02 (t, J = 4.7 Hz, 1H), 2.37 (d, J = 4.7 Hz, 2H), 1.35 (s, 6H). ¹³ C NMR (126MHz, CDCl ₃ ) δ 167.97, 163.32, 161.23, 146.83, 140.60, 138.92, 134.36, 132.74, 131.22, 129.24, 128.83, 128.58, 127.57, 127.43, 127.36, 127.33 , 124.29, 120.02, 119.83, 119.64, 116.90, 94.43, 86.86, 38.84, 34.00, 28.20. ESI (+)-MS: 395.4 [M+1] ⁺ .

Example 46: Ethyl 3-fluoro-4-iodobenzoate

3-Fluoro-4-iodobenzoic acid (0.95 g, 3.57 mmol) was added to the flask, 5 mL of absolute ethanol was added under argon atmosphere, and the mixture was cooled to 0 ° with ice water, and 0.3 mL of concentrated sulfuric acid was added dropwise. The temperature was refluxed for 4 h, and TLC was followed. After the reaction is completed, it is cooled to room temperature, and the sulfuric acid is neutralized with 1 mol/L sodium hydroxide to neutrality, washed with saturated sodium hydrogencarbonate, washed with saturated sodium chloride, and then dried over anhydrous sodium sulfate. Dry, flash column chromatography (EtOAc: EtOAc = 15:1) _{^{1 H NMR (500MHz, CDCl 3}} ) δ7.80 (dd, J = 8.2,6.2Hz, 1H), 7.65 (dd, J = 8.4,1.8Hz, 1H), 7.53 (dd, J = 8.2,1.8Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H). ¹³ C NMR (126 MHz, CDCl ₃ ) δ 164.99, 164.97, 162.64, 160.67, 139.61, 139.59, 132.94, 132.89, 126.51, 126.48, 116.46, 116.26, 87.88, 87.67, 61.65, 14.33. ESI(+)-MS: 295.1 [M+1] ⁺ .

Example 47: Ethyl 4-iodo-3-nitrobenzoate

4-Iodo-3-nitrobenzoic acid (1.9 g, 6.48 mmol) was added to the flask, 10 mL of absolute ethanol was added under argon atmosphere, and the mixture was cooled to 0 ° with ice water, 0.6 mL of concentrated sulfuric acid was added dropwise, and the addition was completed. After the temperature was raised and refluxed for 6 h, TLC was followed. After the reaction is completed, it is cooled to room temperature, and the sulfuric acid is neutralized with 1 mol/L sodium hydroxide to neutrality, washed with saturated sodium hydrogencarbonate, washed with saturated sodium chloride, and then dried over anhydrous sodium sulfate. Dry, flash column chromatography (EtOAc: EtOAc =EtOAc) _{^{1 H NMR (500MHz, CDCl 3}} ) δ8.39 (d, J = 2.0Hz, 1H), 8.10 (d, J = 8.2Hz, 1H), 7.85 (dd, J = 8.2,2.0Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). ¹³ C NMR (126MHz, CDCl ₃ ) δ 164.03, 153.15, 142.33, 133.47, 131.96, 125.98, 92.02, 62.16, 14.29. ESI(+)-MS: 322.1 [M+1] ⁺ .

Example 48: Ethyl 3-fluoro-4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)benzoate

The compound 6-ethynyl-4,4-dimethylbenzothiopyran (405.6 mg, 2 mmol) and ethyl 3-fluoro-4-iodobenzoate (294 mg, 1.0 mmol) were added to the flask, and Pd (PPh) was added. ₃ ) ₂ Cl ₂ (84 mg, 0.12 mmol), CuI (46.0 mg, 0.24 mmol), protected with argon and replaced with 3 times of gas to remove oxygen, and 5 mL of dry DMF, 0.5 mL of dry Et ₃ N was added by syringe. The reaction was carried out at 70 °C for 8 h, and TLC was followed. After completion of the reaction, it is quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with EtOAc EtOAc. PE: EA = 500: 3) The product WYC-307 (250 mg, 68%) was obtained. _{^{1 H NMR (500MHz, CDCl 3}} ) δ7.81 (dd, J = 8.0,1.3Hz, 1H), 7.76 (dd, J = 9.8,1.3Hz, 1H), 7.56 (dd, J = 11.1,4.2Hz, 2H), 7.22 (dd, J = 8.1, 1.6 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.05 (dd, J = 7.1, 5.1 Hz, 2H), 1.98–1.94 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.35 (s, 6H). ¹³ C NMR (126 MHz, CDCl ₃ ) δ 165.25, 165.23, 163.21, 161.20, 142.29,134.42,133.26,133.25,131.70,131.64,129.97,129.27,126.75,125.15,125.12,117.73,117.05,116.92,116.66,116.47,98.04,98.02,81.71,61.62,37.29,33.13,30.09,23.38,14.42. ESI(+)-MS: 369.3 [M+1] ⁺ .

Example 49: Ethyl 3-nitro-4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)benzoate

The compound 6-ethynyl-4,4-dimethylbenzothiopyran (405.6 mg, 2 mmol) and ethyl 3-nitro-4-iodobenzoate (303 mg, 1.0 mmol) were added to the flask and Pd ( PPh ₃ ) ₂ Cl ₂ (84 mg, 0.12 mmol), CuI (46.0 mg, 0.24 mmol), protected with argon and replaced with 3 times of gas to remove oxygen, and 5 mL of dry DMF, 0.5 mL of dry Et ₃ N was added by syringe. At 70 °, the reaction was carried out for 8 h, and TLC was followed. After completion of the reaction, it is quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with EtOAc EtOAc. PE: EA = 50: 1) gave product WYC-308 (384 mg, 97%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ8.69 (d, J = 1.2Hz, 1H), 8.20 (dd, J = 8.1,1.6Hz, 1H), 7.74 (d, J = 8.1Hz, 1H), 7.57 (s, 1H), 7.23-7.25 (m, 1H), 7.08 (d, J = 8.2 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 3.04 (dd, J = 7.2, 4.9 Hz, 2H), 1.98 - 1.85 (m, 2H), 1.41 (t, J = 7.1 Hz, 3H), 1.34 (s, 6H). ¹³ C NMR (126MHz, CDCl ₃ ) δ 164.34, 149.33, 142.43, 135.66, 134.63, 133.24, 130.35, 130.30, 129.65, 126.86, 126.01, 123.20, 117.23, 101.65, 84.50, 62.11, 37.16, 33.12, 30.04, 23.43, 14.43. ESI(+)-MS: 396.2 [M+1] ⁺ .

Example 50: 3-Nitro-4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)benzoic acid

Compound WYC-308 (100 mg, 0.25 mmol) was added to a flask, sodium ethoxide (35 mg, 0.5 mmol) was added, and 2 mL of ethanol was added and allowed to react overnight at room temperature, followed by TLC. After the reaction of the starting material is completed, it is neutralized to neutral with an acidic resin. The mixture is filtered, and the filtrate is diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Column chromatography (DCM: MeOH = 20:1) gave product WYC- s (83mg, 90.4%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ8.78 (s, 1H), 8.26 (d, J = 8.1Hz, 1H), 7.78 (d, J = 8.0Hz, 1H), 7.58 (s, 1H), 7.24 (s, 1H), 7.09 (d, J = 8.1 Hz, 1H), 3.10 - 3.04 (m, 2H), 2.00 - 1.93 (m, 2H), 1.36 (s, 6H). ¹³ C NMR (101 MHz, CDCl) ₃ ) δ168.58, 149.36, 142.46, 135.91, 134.83, 133.69, 130.42, 129.73, 126.89, 126.73, 124.17, 117.12, 102.51, 84.56, 37.14, 33.13, 30.11, 30.04, 23.45. ESI(+)-MS:3[M +1] ⁺ .

Example 51: 3-Fluoro-4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)benzoic acid

The compound WYC-307 (332 mg, 0.9 mmol) was added to a flask, sodium ethoxide (83 mg, 1.2 mmol) was added, and 7 mL of ethanol was added thereto, and the reaction was carried out overnight at room temperature, followed by TLC. After the reaction of the starting material is completed, it is neutralized to neutral with an acidic resin. The mixture is filtered, and the filtrate is diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Column chromatography (PE: EA = 1:1) gave product WYC-310 (303 mg, 99%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.85 (dd, J = 8.1,1.2Hz, 1H), 7.80 (dd, J = 9.7,1.1Hz, 1H), 7.61-7.56 (m, 1H), 7.54 ( d, J = 1.5 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 3.11 - 2.99 (m, 2H), 1.99 - 1.90 (m, 2H) ), 1.34(s,6H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 169.23, 163.46, 160.95, 142.34, 134.64, 133.45, 130.03, 129.32, 126.79, 125.79, 117.62, 117.27, 117.04, 110.16, 98.73, 81.63, 37.28, 33.15, 30.10, 23.40. ESI(+)-MS: 341.2 [M+1] ⁺ .

Example 52: Ethyl 3-nitro-4-((4,4-dimethyl-1-oxodithiothiopyran-6-)ethynyl)benzoate

WYC-308 (100 mg, 0.25 mmol) was added to the flask, 5 mL of dry dichloromethane was added, and the mixture was cooled to 0 °C in an ice water bath, then m-CPBA (60 mg, 0.25 mmol) was added, and the reaction was carried out for 1 hour in an ice water bath and then moved to room temperature. Reaction 2h, TLC tracking. After the reaction was completed, it was quenched with sodium thiosulfate solution, diluted with ethyl acetate, washed with saturated sodium hydrogen sulfate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. : EA = 3: 1) gave the product WYC-311 (92 mg, 88%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ8.73 (d, J = 1.6Hz, 1H), 8.26 (dd, J = 8.1,1.7Hz, 1H), 7.80 (dd, J = 13.0,8.1Hz, 2H) , 7.66 (d, J = 1.5 Hz, 1H), 7.57 (dd, J = 8.0, 1.6 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 3.23 (ddd, J = 12.8, 10.3, 2.3 Hz, 1H), 3.12 (ddd, J = 13.1, 9.1, 2.3 Hz, 1H), 2.44 (ddd, J = 15.1, 10.3, 2.3 Hz, 1H), 1.91 (ddd, J = 15.1, 9.0, 2.3 Hz, 1H), 1.48 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H), 1.35 (s, 3H). ¹³ C NMR (126 MHz, CDCl ₃ ) δ 164.10, 149.65, 145.16, 139.98, 134.95, 133.42, 131.67, 131.30, 130.53, 130.26, 126.01, 125.35, 122.13, 98.90, 86.27, 62.24, 43.39, 34.67, 31.36, 31.24, 29.89, 14.40. ESI(+)-MS: 412.2 [M+1] ⁺ .

Example 53: Ethyl 3-fluoro-4-((4,4-dimethyl-1-oxodithiothiopyran-6-)ethynyl)benzoate

The compound 1-oxo-6-ethynyl-4,4-dimethylbenzothiopyran (223 mg, 1.2 mmol) and ethyl 3-fluoro-4-iodobenzoate (200 mg, 0.8 mmol) were placed in a flask. Add Pd(PPh ₃ ) ₂ Cl ₂ (32 mg, 0.0459 mmol), CuI (17.5 mg, 0.0918 mmol), protect with argon gas and replace the gas three times to remove oxygen, add 3 mL of dry DMF, 0.3 mL dry with a syringe. Et ₃ N, reaction at 75 ° for 8 h, TLC tracking. After completion of the reaction, it is quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with EtOAc EtOAc. PE: EA = 3: 2) The product was obtained as WYC-312 (254 mg, 82.5%). ¹ H NMR (500MHz, CDCl ₃ ) δ 7.84 (dd, J = 8.0, 1.5 Hz, 1H), 7.81 - 7.75 (m, 2H), 7.63 - 7.58 (m, 2H), 7.54 (dd, J = 8.0 , 1.6 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.22 (ddd, J = 12.9, 10.4, 2.3 Hz, 1H), 3.11 (ddd, J = 13.1, 8.9, 2.4 Hz, 1H) , 2.46 (ddd, J = 15.1, 10.4, 2.3 Hz, 1H), 1.91 (ddd, J = 15.1, 8.9, 2.3 Hz, 1H), 1.49 (s, 3H), 1.41 (t, J = 7.1 Hz, 4H) ), 1.35 (s, 4H). ¹³ C NMR (126MHz, CDCl ₃₃ ) δ 165.04, 163.42, 161.41, 145.01, 139.21, 133.49, 132.58, 132.52, 132.26, 132.18, 131.33, 130.29, 130.27, 128.67, 128.57, 125.87, 125.22, 125.19, 116.78, 116.60, 116.06, 115.93, 96.03, 96.00, 84.16, 61.73, 43.34, 34.62, 31.36, 31.22, 29.81, 14.40. ESI(+)-MS: 385.2 [M+1] ⁺ .

Example 54: Ethyl 2,3-difluoro-4-iodobenzoate

2,3-Difluoro-4-iodobenzoic acid (0.5 g, 1.76 mmol) was added to the flask, 4 mL of absolute ethanol was added under argon, ice water was added to 0 °, and 0.3 mL of concentrated sulfuric acid was added dropwise. After the addition was completed, the temperature was refluxed for 6 h, and TLC was followed. After the reaction is completed, it is cooled to room temperature, and the sulfuric acid is neutralized with 1 mol/L sodium hydroxide to neutrality, washed with saturated sodium hydrogencarbonate, washed with saturated sodium chloride, and then dried over anhydrous sodium sulfate. Dry, flash column chromatography (EtOAc: EtOAc =EtOAc) _{^{1 H NMR (500MHz, CDCl 3}} ) δ7.55 (ddd, J = 8.4,5.2,1.8Hz, 1H), 7.44 (ddd, J = 8.4,6.3,1.8Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H). ¹³ C NMR (126MHz, CDCl ₃ ) δ 163.13, 163.10, 163.08, 152.43, 152.31, 150.69, 150.56, 150.46, 150.35, 148.56, 148.44, 133.21. 133.17, 127.48, 127.44, 121.24, 121.18, 88.19, 88.01, 61.98, 14.27. ESI(+)-MS: 313.1 [M+1] ⁺ .

Example 55: Ethyl 2,3-difluoro-4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)benzoate

The compound 2,3-difluoro-4-iodobenzoic acid ethyl ester (200 mg, 0.64 mmol) and 6-ethynyl-4,4-dimethylbenzothiopyran (195 mg, 0.96 mmol) were added to the flask and added Pd(PPh ₃ ) ₂ Cl ₂ (20 mg, 0.0288 mmol), CuI (11 mg, 0.0576 mmol), protected with argon and replaced with 3 times of gas to remove oxygen, and 2 mL of dry DMF, 0.2 mL of dry Et _{3 was} added by syringe. Reaction at N, 75 ° for 8 h, TLC tracking. After completion of the reaction, it is quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with EtOAc EtOAc. PE: EA = 100: 1) The product WYC-313 (215 mg, 82%) was obtained. _{^{1 H NMR (500MHz, CDCl 3}} ) δ7.65 (ddd, J = 8.3,6.5,1.8Hz, 1H), 7.54 (d, J = 1.7Hz, 1H), 7.28 (ddd, J = 8.0,4.9,1.9 Hz, 1H), 7.21 (dd, J = 8.2, 1.8 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.07 - 3.03 (m, 2H) ), 1.97 - 1.93 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.34 (s, 6H). ¹³ C NMR (126MHz, CDCl ₃ ) δ 163.34, 152.40, 152.29, 151.69, 151.58, 150.38 , 150.27, 149.60, 149.49, 142.32, 134.92, 129.98, 129.27, 127.01, 126.98, 126.76, 126.01, 125.97, 120.13, 120.07, 118.59, 118.51, 117.25, 99.26, 99.23, 80.63, 80.60, 61.87, 37.18, 33.09, 30.02 , 23.35, 14.33. ESI(+)-MS: 387.2 [M+1] ⁺ .

Example 56: 2,3-Difluoro-4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)benzoic acid

Compound WYC-313 (84 mg, 0.218 mmol) was added to a flask, sodium ethoxide (44.4 mg, 0.653 mmol) was added, and 2 mL of ethanol was added and allowed to react overnight at room temperature, followed by TLC. After the reaction of the starting material is completed, it is neutralized to neutral with an acidic resin. The mixture is filtered, and the filtrate is diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Column chromatography (PE: EA = 1:1) gave product WYC-314 (68 mg, 87.5%). ^{1 H NMR (500MHz, pyridine)} δ8.01 (t, J = 7.4Hz, 1H), 7.82 (s, 1H), 7.45 (t, J = 7.2Hz, 1H), 7.40 (d, J = 8.1Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 2.95 - 2.89 (m, 2H), 1.78 - 1.71 (m, 2H), 1.19 (s, 6H). ESI (-)-MS: 357.2 [M -1] ^- .

Example 57: Ethyl 2,3-difluoro-4-((4,4-dimethyl-1-oxodithiothiopyran-6-)ethynyl)benzoate

WYC-313 (90 mg, 0.233 mmol) was added to the flask, 5 mL of dry dichloromethane was added, and the mixture was cooled to 0 °C in an ice water bath, then m-CPBA (58 mg, 0.233 mmol) was added, and the reaction was carried out for 1 hour in an ice water bath and then moved to room temperature. Reaction 2h, TLC tracking. After the reaction was completed, it was quenched with sodium thiosulfate solution, diluted with ethyl acetate, washed with saturated sodium hydrogen sulfate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. : EA = 3: 1) gave the product WYC-315 (76 mg, 78%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ7.76 (d, J = 8.0Hz, 1H), 7.71-7.65 (m, 1H), 7.62 (s, 1H), 7.53 (dd, J = 8.0,0.8Hz, 1H), 7.32 (dd, J = 10.4, 3.9 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.26 - 3.18 (m, 1H), 3.15 - 3.07 (m, 1H), 2.44 (ddd , J=14.8, 10.3, 2.0 Hz, 1H), 1.90 (ddd, J = 15.1, 8.9, 2.0 Hz, 1H), 1.47 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H), 1.34 ( s,3H). ¹³ C NMR (126MHz, CDCl ₃ ) δ 163.22, 163.20, 163.17, 152.69, 152.58, 151.65, 151.54, 150.66, 150.55, 149.55, 145.10, 139.57, 131.40, 130.30, 130.27, 127.25, 127.22, 126.15, 126.12,125.41,121.05,120.99,117.60,117.59,117.50,117.48,97.09,97.05,82.93,82.90,62.02,43.34,34.63,31.34,31.21,29.82,14.32.ESI(+)-MS:403.1[M+1 ] ⁺ .

Example 58: Methyl 3-acetamido-4-iodobenzoate

The compound 3-amino-4-iodobenzoic acid methyl ester (1.5 g, 5.43 mmol) was added to the flask, 20 mL of dry dichloromethane, 4.5 mL of dry triethylamine was added, and 0.77 mL of acetyl chloride was added dropwise in an ice water bath. The reaction was allowed to proceed overnight at room temperature and was followed by TLC. After the reaction was completed, it was quenched with EtOAc EtOAc (EtOAc)EtOAc.EtOAc. :1) The product was obtained as methyl 3-acetamido-4-iodobenzoate (1.34 _g , 77.5%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ8.75 (s, 1H), 7.86 (d, J = 8.3Hz, 1H), 7.54-7.39 (m, 2H), 3.90 (s, 3H), 2.25 (s, 3H). ¹³ C NMR (126 MHz, CDCl ₃ ) δ 168.29, 166.28, 138.97, 138.54, 131.46, 126.74, 122.89, 96.10, 52.44, 24.78. ESI (+)-MS: 320.1 [M+1] ⁺ .

Example 59: Methyl 3-acetamido-4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)benzoate

The compound 3-acetamido-4-iodobenzoic acid methyl ester (319 mg, 1 mmol) and 6-ethynyl-4,4-dimethylbenzothiopyran (304 mg, 1.5 mmol) were added to the flask, and Pd (PPh) was added. ₃ ) ₂ Cl ₂ (47 mg, 0.0675 mmol), CuI (26 mg, 0.135 mmol), protected with argon and replaced with 3 times of gas to remove oxygen, and 5 mL of dry DMF, 0.3 mL of dry Et ₃ N, 70 The reaction was carried out for 8 h, and TLC was followed. After completion of the reaction, it is quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with EtOAc EtOAc. PE: EA = 10:1) gave the product WYC- 316 (298 mg, 76%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ9.00 (s, 1H), 7.97 (s, 1H), 7.74 (dd, J = 8.1,1.2Hz, 1H), 7.57-7.50 (m, 2H), 7.18 ( Dd, J = 8.1, 1.7 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 3.91 (s, 3H), 3.10 - 3.02 (m, 2H), 2.26 (s, 3H), 1.98 - 1.93 (m, 2H), 1.35 ( s, 6H). 13 C NMR (126MHz, CDCl 3) δ168.23,166.55,142.53,138.77,135.02,131.51,130.80,129.71,128.90,126.92,124.65,120.35,117.03,110.11, 99.62, 83.25, 52.42, 37.09, 33.11, 30.02, 25.03, 23.36. ESI(+)-MS: 394.2 [M+1] ⁺ .

Example 60: Ethyl 3-acetamido-4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)benzoate

Compound WYC-316 (56 mg, 0.142 mmol) was added to a flask, sodium ethoxide (29 mg, 0.426 mmol) was added, and 2 mL of ethanol was added and allowed to react overnight at room temperature, followed by TLC. After the reaction of the starting material is completed, it is neutralized to neutral with an acidic resin. The mixture is filtered, and the filtrate is diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Column chromatography (PE: EA = 20:1) gave product WYC-317 (48 mg, 83%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ9.00 (s, 1H), 7.97 (s, 1H), 7.75 (d, J = 8.0Hz, 1H), 7.53 (d, J = 7.2Hz, 2H), 7.18 (dd, J = 8.1, 1.3 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.09 - 3.02 (m, 2H), 2.26 (s, 3H), 1.98–1.94 (m, 2H), 1.39 (t, J = 7.1 Hz, 3H), 1.35 (s, 6H). ¹³ C NMR (126 MHz, CDCl ₃ ) δ 168.22, 166.08, 142.53, 138.76, 135.00, 131.47,131.21,129.72,128.91,126.93,124.64,120.38,117.07,110.12,99.54,83.31,61.39,37.11,33.12,30.04,25.03,23.36,14.44.ESI(+)-MS:408.2[M+1] ⁺ .

Example 61: Ethyl 3-acetamido-4-((4,4-dimethyl-1-oxodithiothiopyran-6-)ethynyl)benzoate

WYC-317 (86 mg, 0.211 mmol) was added to the flask, 2 mL of dry dichloromethane was added, and the mixture was cooled to 0 °C in an ice water bath, then m-CPBA (37 mg, 0.211 mmol) was added, and the reaction was carried out for 1 hour in an ice water bath and then moved to room temperature. Reaction 2h, TLC tracking. After the reaction was completed, it was quenched with sodium thiosulfate solution, diluted with ethyl acetate, washed with saturated sodium hydrogen sulfate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. : EA = 1:1) gave the product WYC-318 (80 mg, 98.6%). ¹ H NMR (500 MHz, CDCl ₃₃ ) δ 8.98 (s, 1H), 7.93 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 1.3 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.50 (dd, J = 8.0, 1.3 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.24 (dd, J = 17.2, 6.3 Hz, 1H) , 3.17–3.09 (m, 1H), 2.45 (ddd, J=14.8, 10.3, 1.9 Hz, 1H), 2.27 (s, 3H), 1.91 (ddd, J = 15.1, 8.9, 2.0 Hz, 1H), 1.48 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H), 1.35 (s, 3H). ¹³ C NMR (126MHz, CDCl ₃ ) δ 168.29, 165.92, 145.31, 139.07, 131.97, 131.91, 131.19, 130.44, 129.98,125.33,124.80,124.76,120.86,115.83,97.48,85.94,61.51,43.40,34.66,31.36,31.27,29.79,14.43.ESI (+) - MS: 424.1 [M + 1] +.

Example 62: 3-Acetylamino-4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)benzoic acid

The compound WYC-316 (63 mg, 0.16 mmol) was added to a flask, sodium ethoxide (14 mg, 0.2 mmol) was added, and 2 mL of tetrahydrofuran, 0.2 mL of water was added, and the reaction was allowed to stand overnight at room temperature, followed by TLC. After the reaction of the starting material is completed, it is neutralized to neutral with an acidic resin. The mixture is filtered, and the filtrate is diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Column chromatography (PE: EA = 1:1) gave product WYC-319 (34 mg, 56%). ESI(+)-MS: 380.2 [M+1] ⁺ .

Example 63: Ethyl 5-bromopyridazine-2-carboxylate

5-bromopyridazine-2-carboxylic acid (1.0 g, 5 mmol) was added to the flask, 5 mL of absolute ethanol was added under argon atmosphere, and the mixture was cooled to 0 ° with ice water, 0.3 mL of concentrated sulfuric acid was added dropwise, and the temperature was raised after the addition was completed. The reflux reaction was carried out for 6 h, followed by TLC. After the reaction is completed, it is cooled to room temperature, and the sulfuric acid is neutralized with 1 mol/L sodium hydroxide to neutrality, washed with saturated sodium hydrogencarbonate, washed with saturated sodium chloride, and then dried over anhydrous sodium sulfate. Dry, flash column chromatography (EtOAc: EtOAc = 50:1) _{^{1 H NMR (500MHz, CDCl 3}} ) δ9.01 (d, J = 1.3Hz, 1H), 8.76 (d, J = 1.3Hz, 1H), 4.47 (q, J = 7.1Hz, 2H), 1.41 (t , J = 7.1 Hz, 3H). ¹³ C NMR (126MHz, CDCl ₃ ) δ 163.39, 147.30, 146.31, 144.65, 141.89, 62.67, 14.30. ESI (+)-MS: 231.2 [M+1] ⁺ .

Example 64: Ethyl 2-((4,4-dimethyl-1,1-dioxothiochroman-6-)ethynyl)pyrimidine-5-carboxylate

WYC-209 (1.1 g, 3 mmol) was added to the flask, 20 mL of dry dichloromethane was added, and the mixture was cooled to 0 °C in an ice water bath, then mCPBA (0.663 g, 3.6 mmol) was added, and the reaction was carried out for 10 min in an ice water bath and then transferred to room temperature for 3 h. After moving to room temperature for 4 h, TLC was followed. After the reaction was completed, it was quenched with sodium thiosulfate solution, diluted with ethyl acetate, washed with saturated sodium hydrogen sulfate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. : EtOAc = 1 : 5) gave product WYC-320 (0.99 g, 89%). _{^{1 H NMR (500MHz, cdcl 3}} ) δ9.29 (s, 2H), 7.94 (d, J = 8.2Hz, 1H), 7.76 (d, J = 1.3Hz, 1H), 7.68 (dd, J = 8.2, 1.5 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 3.46 - 3.37 (m, 2H), 2.45 - 2.39 (m, 2H), 1.44 (s, 6H). ¹³ C NMR (126 MHz, cdcl ₃ ) δ163.22,158.51,155.10,145.17,138.59,132.27,131.31,125.41,124.24,122.74,89.85,88.71,62.32,47.06,35.49,34.47,30.71,14.35.ESI(+)-MS:385.4[M+1 ] ⁺ .

Example 65: Methyl 3-acetamido-4-((4,4-dimethyl-1-oxodithiothiopyran-6-)ethynyl)benzoate

WYC-316 (107 mg, 0.272 mmol) was added to the flask, and 3.5 mL of dry dichloromethane was added thereto. After cooling to 0 °C in an ice water bath, m-CPBA (67.3 mg, 0.272 mmol) was added, and the reaction was carried out for 1 hour in an ice water bath. The reaction was carried out for 2 h at room temperature and followed by TLC. After the reaction was completed, it was quenched with sodium thiosulfate solution, diluted with ethyl acetate, washed with saturated sodium hydrogen sulfate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. : EA = 1:1) gave the product WYC-321 (84 mg, 78%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ8.97 (s, 1H), 7.96 (s, 1H), 7.80-7.72 (m, 2H), 7.60 (d, J = 1.4Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.49 (dd, J = 8.0, 1.3 Hz, 1H), 3.90 (s, 3H), 3.14 (ddt, J = 12.9, 8.9, 6.4 Hz, 2H), 2.45 (ddd, J =14.8, 10.3, 1.7 Hz, 1H), 2.26 (s, 3H), 1.90 (ddd, J = 15.0, 8.9, 1.9 Hz, 1H), 1.47 (s, 3H), 1.34 (s, 3H). ¹³ C NMR (126MHz, CDCl ₃₎ δ168.28,166.37,145.28,139.65,139.09,131.94,131.52,131.18,130.41,129.95,125.29,124.74,120.91,115.97,97.52,85.89,52.49,43.37,34.63,31.32,31.25,29.76 , 24.99. ESI (+)-MS: 410.3 [M+1] ⁺ .

Example 66: Ethyl 5-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)pyrazine-2-carboxylate

The compound 5-bromopyridazine-2-carboxylic acid ethyl ester (600 mg, 2.61 mmol) and 6-ethynyl-4,4-dimethylbenzothiopyran (635 mg, 3.13 mmol) were added to the flask, and Pd (PPh) was added. ₃ ) ₂ Cl ₂ (66 mg, 0.094 mmol), CuI (36 mg, 0.188 mmol), protected with argon and replaced with 3 times of gas to remove oxygen, and 6 mL of dry DMF, 0.4 mL of dry Et ₃ N, 80 was added by syringe. The reaction was carried out for 8 h, and TLC was followed. After completion of the reaction, it is quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with EtOAc EtOAc. PE: EA = 50: 1) The product WYC-322 (656 mg, 71.5%) was obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.20 (d, J = 1.4 Hz, 1H), 8.76 (d, J = 1.4 Hz, 1H), 7.58 (d, J = 1.7 Hz, 1H), 7.23 (dd , J = 8.2, 1.8 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 3.02 - 2.97 (m, 2H), 1.92 - 1.87 (m, 2H), 1.41 (t, J = 7.1 Hz, 3H), 1.29 (s, 6H). ¹³ C NMR (126MHz, CDCl ₃ ) δ 163.65, 146.68, 145.70, 143.08, 142.31, 140.30, 136.14, 130.54, 129.51, 126.74 , 116.00, 97.55, 85.68, 62.37, 36.91, 32.99, 29.89, 23.27, 14.31. ESI (+)-MS: 353.5 [M+1] ⁺ .

Example 67: 5-((4,4-Dimethyldihydrothiothiopyran-6-)ethynyl)pyrazine-2-carboxylic acid

Compound WYC-322 (50 mg, 0.14 mmol) was added to a flask, sodium ethoxide (29 mg, 0.426 mmol) was added, and 2 mL of ethanol was added and allowed to react overnight at room temperature, followed by TLC. After the reaction of the starting material is completed, it is neutralized to neutral with an acidic resin. The mixture is filtered, and the filtrate is diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Column chromatography (DCM: MeOH = 15:1) gave product WYC-323 (43 mg, 95%). ^{1 H NMR (500MHz, pyridine)} δ9.65 (s, 1H), 9.05 (s, 1H), 7.84 (d, J = 1.4Hz, 1H), 7.41 (dd, J = 8.1,1.4Hz, 1H), 7.23 (d, J = 8.1Hz, 1H), 2.98-2.88 (m, 2H), 1.81-1.72 (m, 2H), 1.19 (s, 6H). 13 C NMR (126MHz, pyridine) δ166.73,147.26,146.43 , 143.36, 142.96, 142.56, 136.52, 130.88, 129.89, 127.24, 116.79, 96.42, 86.89, 36.94, 33.05, 29.59, 23.30. ESI (+)-MS: 325.2 [M+1] ⁺ .

Example 68: Ethyl 5-((4,4-dimethyl-1-oxodithiothiopyran-6-)ethynyl)pyrazine-2-carboxylate

WYC-322 (100 mg, 0.284 mmol) was added to the flask, 3.5 mL of dry dichloromethane was added, and the mixture was cooled to 0 °C in an ice water bath, then m-CPBA (49 mg, 0.284 mmol) was added, and the mixture was reacted for 1 hour in an ice water bath and then transferred to room temperature. The next reaction was 2 h, and TLC was followed. After the reaction was completed, it was quenched with sodium thiosulfate solution, diluted with ethyl acetate, washed with saturated sodium hydrogen sulfate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. : EA = 1:2) The product WYC-324 (78 mg, 75%) was obtained. ¹ H NMR (500 MHz, CDCl ₃₃ ) δ 9.29 (d, J = 1.4 Hz, 1H), 8.87 (d, J = 1.4 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.71 (d) , J = 1.5 Hz, 1H), 7.61 (dd, J = 8.1, 1.6 Hz, 1H), 4.52 (q, J = 7.1 Hz, 2H), 3.29 - 3.06 (m, 2H), 2.43 (ddd, J = 15.1, 10.2, 2.3 Hz, 1H), 1.91 (ddd, J = 15.1, 9.2, 2.3 Hz, 1H), 1.47 (dd, J = 8.8, 5.5 Hz, 6H), 1.34 (s, 3H). ¹³ C NMR (126MHz, CDCl ₃ ) δ163.62,147.07,145.93,145.25,142.41,141.29,140.60,132.05,130.63,130.25,124.32,94.92,87.36,62.70,43.44,34.73,31.35,31.25,29.91,14.41.ESI(+) -MS: 396.2 [M + 1] +.

Example 69: Ethyl 2-chloro-4-iodobenzoate

2-Chloro-4-iodobenzoic acid (1.0 g, 3.55 mmol) was added to the flask, 7 mL of absolute ethanol was added under argon atmosphere, and the mixture was heated to 0 ° with ice water, and 0.4 mL of concentrated sulfuric acid was added dropwise. The temperature was refluxed for 5 h, and TLC was followed. After the reaction is completed, it is cooled to room temperature, and the sulfuric acid is neutralized with 1 mol/L sodium hydroxide to neutrality, washed with saturated sodium hydrogencarbonate, washed with saturated sodium chloride, and then dried over anhydrous sodium sulfate. Dry, flash column chromatography (EtOAc:EtOAc =EtOAc) _{^{1 H NMR (500MHz, CDCl 3}} ) δ7.82 (d, J = 1.6Hz, 1H), 7.65 (dd, J = 8.2,1.6Hz, 1H), 7.52 (d, J = 8.2Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H). ¹³ C NMR (126MHz, CDCl ₃ ) δ 165.22, 139.57, 135.95, 134.63, 132.47, 129.91, 98.35, 61.87, 14.32. ESI(+)-MS:311.3[M+1] ⁺

Example 70: Ethyl 2-chloro-4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)benzoate

The compound 2-chloro-4-iodobenzoic acid ethyl ester (310 mg, 1 mmol) and 6-ethynyl-4,4-dimethylbenzothiopyran (244 mg, 1.2 mmol) were added to the flask, and Pd (PPh ₃ ) was added. ₂ Cl ₂ (28 mg, 0.04 mmol), CuI (11.4 mg, 0.06 mmol), protected with argon and replaced with 3 times of gas to remove oxygen, and 3 mL of dry DMF, 0.3 mL of dry Et ₃ N, 80 The reaction was carried out for 8 h, and TLC was followed. After completion of the reaction, it is quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with EtOAc EtOAc. PE: EA = 50: 1) gave the product WYC- 325 (365 mg, 95%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ7.81 (d, J = 8.1Hz, 1H), 7.59 (d, J = 1.5Hz, 1H), 7.52 (d, J = 1.7Hz, 1H), 7.42 (dd , J=8.1, 1.5 Hz, 1H), 7.18 (dd, J=8.2, 1.8 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 4.40 (q, J=7.1 Hz, 2H), 3.06 -3.02 (m, 2H), 1.97 - 1.93 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.34 (s, 6H). ¹³ C NMR (126 MHz, CDCl ₃ ) δ 165.27, 142.26, 134.37 , 133.89, 133.65, 131.41, 129.92, 129.38, 129.30, 129.14, 128.27, 126.72, 117.56, 93.73, 86.76, 61.71, 37.21, 33.06, 30.04, 23.32, 14.33. ESI(+)-MS: 385.2 [M+1] ⁺ .

Example 71: Ethyl 2-chloro-4-((4,4-dimethyldihydro-1-oxobenzothiopyran-6-)ethynyl)benzoate

WYC-325 (100 mg, 0.26 mmol) was added to the flask, 3 mL of dry dichloromethane was added, and the mixture was cooled to 0 °C in an ice water bath, then m-CPBA (60 mg, 0.26 mmol) was added, and the reaction was carried out for 1 hour in an ice water bath and then moved to room temperature. Reaction 2h, TLC tracking. After the reaction was completed, it was quenched with sodium thiosulfate solution, diluted with ethyl acetate, washed with saturated sodium hydrogen sulfate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. : EA = 1:3) gave the product WYC-326 (86 mg, 83%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ7.79 (d, J = 8.1Hz, 1H), 7.71 (d, J = 8.1Hz, 1H), 7.59 (d, J = 1.5Hz, 1H), 7.57 (d , J=1.5 Hz, 1H), 7.46 (dd, J=8.0, 1.5 Hz, 1H), 7.42 (dd, J=8.1, 1.6 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 3.17 (ddd, J = 12.7, 10.5, 2.1 Hz, 1H), 3.06 (ddd, J = 13.1, 8.8, 2.2 Hz, 1H), 2.41 (ddd, J = 14.9, 10.4, 2.1 Hz, 1H), 1.85 (ddd , J = 15.1, 8.8, 2.2 Hz, 1H), 1.43 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H), 1.30 (s, 3H). ¹³ C NMR (126 MHz, CDCl ₃ ) δ 165. 05,144.93,138.96,133.81,133.81,131.36,131.23,130.19,130.08,130.05,129.58,127.12,125.66,91.67,89.03,61.74,43.16,34.45,31.20,31.06,29.59,14.22.ESI(+)-MS:401.2 [M+1] ⁺ .

Example 72: 2-Chloro-4-((4,4-dimethyldihydrothiothiopyran-6-)ethynyl)benzoic acid

The compound WYC-325 (100 mg, 0.26 mmol) was added to a flask, sodium ethoxide (29 mg, 0.426 mmol) was added, and 2 mL of ethanol was added thereto, and the reaction was carried out overnight at room temperature, followed by TLC. After the reaction of the starting material is completed, it is neutralized to neutral with an acidic resin. The mixture is filtered, and the filtrate is diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Column chromatography (PE: EA = 1:2) gave product WYC-327 (89 mg, 94%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.98 (d, J = 8.1 Hz, 1H), 7.61 (s, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.44 (d, J = 7.9 Hz , 1H), 7.18 (dd, J = 8.2, 1.6 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 3.07 - 3.04 (m, 2H), 1.98 - 1.94 (m, 2H), 1.35 ( s,6H). ¹³ C NMR (126MHz, CDCl ₃ ) δ 170.29, 142.32, 134.90, 134.53, 134.00, 132.52, 130.02, 129.51, 129.36, 129.25, 127.76, 126.79, 117.54, 94.44, 86.79, 37.25, 33.12, 30.09, 23.39. ESI(+)-MS: 355.2 [M+1] ⁺ .

Example 73: 2-cyano-5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthyl-2-)ethynyl)pyrimidine

The compound 6-ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (50 mg, 0.235 mmol) and 2-cyano-5-bromopyrimidine (49.9 mg, 0.271 mmol) added to the flask was added _{Pd (PPh 3) 2 Cl 2} (14mg, 0.02mmol), CuI (5.6mg, 0.03mmol), and replaced with argon for three times to exclude oxygen gas is added by syringe 2mL dried DMF, 0.14 mL of dry Et ₃ N, heated to 70 ° C for 8 h, TLC tracking. After completion of the reaction, the mixture was cooled to room temperature, diluted with a saturated aqueous solution of sodium hydrogen sulfate, diluted with ethyl acetate, washed with ethyl acetate, washed with saturated sodium chloride, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Chromatography (PE: EtOAc = 10:0 to 10:1) gave product WYC-329 (75 mg, 77%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ8.90 (s, 2H), 7.52 (d, J = 1.4Hz, 1H), 7.38-7.29 (m, 2H), 1.70 (s, 4H), 1.31 (s, 6H), 1.29 (s, 6H). ¹³ C NMR (101MHz, CDCl3) δ 159.24, 147.92, 145.68, 141.75, 130.54, 129.00, 127.11, 122.82, 117.86, 115.58, 101.75, 80.64, 77.35, 77.04, 76.72, 34.78, 34.73,34.59,34.31,31.77,31.64.ESI(+)-MS:338.4[M+1]+.ESI(+)-MS:3[M+1] ⁺

Example 74: 2-Amino-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthyl-2-)ethynyl)benzoic acid

6-ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (100 mg, 0.47 mmol) and 2-amino-4-iodobenzoic acid (141.8 mg, 0.54) Ment) was added to the flask, Pd(PPh ₃ ) ₂ Cl ₂ (28 mg, 0.04 mmol), CuI (11.2 mg, 0.059 mmol) was added, and the gas was removed with argon gas and replaced with 3 times to remove oxygen, and 2 mL of dried was added by syringe. DMF, 0.28 mL of dry Et ₃ N, heated to 50 ° for 8 h, TLC tracking. After completion of the reaction, the mixture was cooled to room temperature, and then diluted with aq. Chromatography (PE: EtOAc = 50:1 to 10:1) gave product WYC-330 (97 mg, 60%). ^{1 H NMR (400MHz, MeOD)} δ7.81 (s, 1H), 7.46 (s, 1H), 7.33 (d, J = 8.2Hz, 1H), 7.24 (d, J = 8.2Hz, 1H), 6.88 ( s, 1H), 6.68 (s, 1H), 1.72 (s, 4H), 1.30 (s, 6H), 1.29 (s, 6H). ESI (+)-MS: 348.3 [M+1] ⁺ .

Example 75: Ethyl 2-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthyl-2-)ethynyl)pyrimidine-5-carboxylate

6-ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (50 mg, 0.235 mmol) and ethyl 2-chloropyrimidine-4-carboxylate (50.3 mg, 0.27 mmol) was added to the flask, Pd(PPh ₃ ) ₂ Cl ₂ (14 mg, 0.02 mmol), CuI (5.6 mg, 0.03 mmol) was added, and the gas was removed with argon gas and replaced with 3 times to remove oxygen, and 1 mL of the solution was added by syringe. DMF, 0.14 mL of dry Et ₃ N, heated to 70 ° C for 8 h, TLC tracking. After completion of the reaction, the mixture was cooled to room temperature, and then diluted with aq. Chromatography (PE: EtOAc = 100:1 to 50:1) gave product WYC-331 (67.2mg, 79%). ^{1 H NMR (500MHz, cdcl3)} δ9.26 (s, 2H), 7.67 (d, J = 1.7Hz, 1H), 7.45 (dd, J = 8.2,1.8Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 1.69 (s, 4H), 1.44 (t, J = 7.1 Hz, 3H), 1.29 (s, 6H), 1.28 (s, 6H). ^{13 C NMR (101MHz, CDCl3)} δ163.42,158.33,155.80,148.01,145.46,131.77,129.86,126.94,121.83,117.66,92.54,87.31,62.02,34.81,34.77,34.58,34.31,31.72,31.60.ESI (+) -MS: 363.3 [M+1] ⁺ .

Example 76: Methyl 3-hydroxy-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthyl-2-)ethynyl)benzoate

6-ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (120 mg, 0.566 mmol) and methyl 3-hydroxy-4-iodobenzoate (180.7 mg) , 0.65 mmol) was added to the flask, Pd(PPh ₃ ) ₂ Cl ₂ (33.7 mg, 0.048 mmol), CuI (13.5 mg, 0.072 mmol) was added, and the gas was protected with argon gas and replaced with 3 times to remove oxygen, and added by a syringe. 3 mL of dry DMF, 0.338 mL of dry Et ₃ N, reacted at 70 ° for 8 h, followed by TLC. After completion of the reaction, it is quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with EtOAc EtOAc. PE: EA = 50:1 to 10:1) gave the product WYC-332 (118 mg, 58%). ^{1 H NMR (400MHz, CDCl3)} δ8.23 (s, 1H), 7.95 (dd, J = 8.2,1.4Hz, 1H), 7.85 (d, J = 1.9Hz, 1H), 7.63 (dd, J = 8.3 , 1.9 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.01 (d, J = 0.8 Hz, 1H), 3.96 (s, 3H), 1.74(s,4H), 1.38(s,6H), 1.33 (d, J=4.9Hz, 6H). ¹³ C NMR (126MHz, cdcl3) δ 167.34, 159.55, 154.18, 146.62, 145.60, 133.81, 127.20, 127.09, 125.67, 124.35, 123.49, 122.72, 120.13, 112.70, 100.54, 77.25, 76.99, 76.74, 52.10, 35.01, 34.90, 34.43, 34.42, 31.84, 31.72. ESI(+)-MS: 363.2 [M+1] ⁺ .

Example 77: 2-((5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthyl-2-)ethynyl)-5-cyanopyridine

6-ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (60 mg, 0.283 mmol) and 2-chloro-5-cyanopyridine (59.5 mg, 0.325 Adding to the flask, adding Pd(PPh3)2Cl2 (16.8 mg, 0.024 mmol), CuI (6.8 mg, 0.036 mmol), protecting with argon gas and replacing the gas three times to remove oxygen, adding 2 mL of dry DMF with a syringe, 0.17 mL of dry Et3N was reacted at 70 ° C for 8 h, followed by TLC. After completion of the reaction, it is quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with EtOAc EtOAc. PE: EA = 100: 1 to 20: 1) The product WYC-333 (59 mg, 67%) was obtained. _{^{1 H NMR (500MHz, cdcl 3}} ) δ8.86 (dd, J = 2.1,0.8Hz, 1H), 7.93 (dd, J = 8.2,2.2Hz, 1H), 7.60 (dd, J = 8.2,0.8Hz, 1H), 7.58 (d, J = 1.7 Hz, 1H), 7.36 (dd, J = 8.2, 1.7 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 1.69 (s, 4H), 1.29 ( s, 6H), 1.29 (s, 6H). ¹³ C NMR (126MHz, cdcl ₃ ) δ 152.56, 147.56, 147.09, 145.45, 139.13, 130.99, 129.26, 126.92, 126.59, 118.07, 116.52, 107.95, 95.22, 86.91, 77.25 , 76.99,76.74,34.81,34.76,34.52,34.28,31.73,31.61.ESI (+) - MS: 315.6 [M + 1] +.

Example 78: Ethyl 5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthyl-2-)ethynyl)pyrimidine-2-carboxylate

Compound WYC-329 (15 mg, 0.0475 mmol) was dissolved in 2 mL of ethanol, sodium ethoxide (9.7 mg, 0.143 mmol) was added, and stirred at room temperature overnight. After the reaction was finished, neutralized with 1 mol/L HCl to weakly acidic; The ester was diluted, washed with saturated sodium bicarbonate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. 334 (15 mg, 88%). ^{1 H NMR (400MHz, CDCl3)} δ8.63 (s, 2H), 7.47 (d, J = 1.2Hz, 1H), 7.33-7.24 (m, 2H), 4.45 (q, J = 7.1Hz, 2H), 1.69 (s, 4H), 1.45 (t, J = 7.1 Hz, 3H), 1.30 (s, 6H), 1.28 (s, 6H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 163.53, 161.19, 146.22, 145.28, 129.93,128.61,126.82,119.29,113.07,94.57,81.42,77.35,77.04,76.72,63.94,34.91,34.85,34.41,34.25,31.77,31.68,14.42.ESI(+)-MS:362.3[M+1] ⁺ .

Example 79: Methyl 2-hydroxy-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthyl-2-)ethynyl)benzoate

6-ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (50 mg, 0.205 mmol) and compound c (75.3 mg, 0.271 mmol) were added to the flask and added Pd(PPh ₃ ) ₂ Cl ₂ (14 mg, 0.02 mmol), CuI (5.6 mg, 0.03 mmol), protected with argon and replaced with 3 times of gas to remove oxygen, and 2 mL of dry DMF, 0.14 mL of dried Et. ₃ N, heated to 70 ° for 8 h, TLC tracking. After completion of the reaction, the mixture was cooled to room temperature, diluted with a saturated aqueous solution of sodium hydrogen sulfate, diluted with ethyl acetate, washed with ethyl acetate, washed with saturated sodium chloride, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Chromatography (PE) gave the product (45.2 mg, 61%). ^{1 H NMR (400MHz, CDCl3)} δ10.76 (s, 1H), 7.80 (d, J = 8.2Hz, 1H), 7.48 (s, 1H), 7.29 (d, J = 0.8Hz, 2H), 7.13 ( d, J = 1.4 Hz, 1H), 7.03 (dd, J = 8.2, 1.5 Hz, 1H), 3.96 (s, 3H), 1.69 (s, 4H), 1.30 (s, 6H), 1.28 (s, 6H) ).ESI(+)-MS: 363.3[M+1] ⁺ .

Example 80: 2-Hydroxy-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthyl-2-)ethynyl)benzoic acid

The former product (30 mg, 0.082 mmol) was added to a flask, 2 mL of a 2.0 mol/L NaOH solution was added, 2 mL of methanol was added, and the reaction was carried out at 55 ° C overnight. After the reaction of the starting material is completed, it is neutralized with 1 mol/L HCl to a pH of 5-6; diluted with ethyl acetate, extracted, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Chromatography (PE: EA = 100:0 to 10:1) gave product WYC-335 (26.3 mg, 93%). ^{1 H NMR (400MHz, DMSO)} δ7.80 (d, J = 8.1Hz, 1H), 7.53 (d, J = 1.6Hz, 1H), 7.39 (d, J = 8.2Hz, 1H), 7.31 (dd, J = 8.2, 1.6 Hz, 1H), 7.12 - 7.04 (m, 2H), 1.65 (s, 4H), 1.26 (s, 6H), 1.25 (s, 6H). ¹³ C NMR (101 MHz, DMSO) δ 171. 27,160.85,146.07,145.05,130.58,129.74,129.16,128.67,126.98,122.01,119.29,118.76,92.56,87.48,40.12,39.91,39.70,39.49,39.29,39.08,38.87,34.36,34.25,34.08,33.89,31.39, 31.32. ESI(-)-MS: 347.3 [M-1] ^- .

Example 81: 2-Acetylamino-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthyl-2-)ethynyl)benzoic acid

WYC-330 (52 mg, 0.15 mmol) was added to the flask, 1 mg of DMAP was added, 3 mL of dry pyridine was added under argon atmosphere, cooled to 0 °C in an ice water bath, 7.8 μl of acetyl chloride was added dropwise, and the reaction was carried out in an ice water bath. After 5 min, it was moved to room temperature for 5 h, and was traced by TLC. After the reaction is completed, it is quenched with methanol, diluted with ethyl acetate, diluted with EtOAc EtOAc EtOAc EtOAc. Column chromatography (PE: EtOAc = 20:1) gave product WYC-336 (39.5mg, 85%). ^{1 H NMR (400MHz, CDCl3)} δ8.13 (d, J = 8.1Hz, 1H), 7.66 (d, J = 1.2Hz, 1H), 7.60 (dd, J = 8.1,1.5Hz, 1H), 7.51 ( s, 1H), 7.32 (d, J = 1.0 Hz, 2H), 2.47 (s, 3H), 1.69 (d, J = 5.7 Hz, 4H), 1.31 (s, 6H), 1.29 (s, 6H). ESI(-)-MS: 388.4 [M-1] ^- .

Example 82: Methyl 5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthyl-2-)ethynyl)pyridine-2-carboxylate

6-ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (60 mg, 0.283 mmol) and methyl 5-bromo-pyridine-2-carboxylate (70 mg, 0.325 mmol) was added to the flask, Pd(PPh ₃ ) ₂ Cl ₂ (16.8 mg, 0.024 mmol), CuI (6.8 mg, 0.036 mmol) was added, and the gas was protected with argon and replaced with 3 times to remove oxygen, and 2 mL was added by syringe. Dry DMF, 0.17 mL of dry Et ₃ N, reacted at 70 ° C for 8 h, followed by TLC. After completion of the reaction, it is quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with EtOAc EtOAc. PE: EA = 100: 1 to 20: 1) The product was obtained (68.7 mg, 70%). ^{1 H NMR (400 MHz, CDCl} 3) δ8.85 (dd, J = 2.0,0.7Hz, 1H), 8.12 (dd, J = 8.1,0.7Hz, 1H), 7.94 (dd, J = 8.1,2.1Hz , 1H), 7.51 (s, 1H), 7.32 (d, J = 1.0 Hz, 2H), 4.02 (d, J = 4.5 Hz, 3H), 1.69 (d, J = 5.5 Hz, 4H), 1.31 (s) , 6H), 1.29 (s, 6H). ESI (+)-MS: 348.2 [M+1] ⁺ .

Example 83: 5-((5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthyl-2-)ethynyl)pyridine-2-carboxylic acid

The above product (50 mg, 0.143 mmol) was added to a flask, 2 mL of a 2.0 mol/L NaOH solution was added, 2 mL of methanol was added, and the reaction was carried out at 55 ° C overnight. After the reaction of the starting material is completed, it is neutralized with 1 mol/L HCl to a pH of 5-6; diluted with ethyl acetate, extracted, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Chromatography (PE: EA = 20:1 to 5:1) gave product WYC-337 (42.2mg, 88%). ^{1 H NMR (400MHz, MeOD)} δ8.67 (s, 1H), 8.00 (d, J = 7.9Hz, 1H), 7.94 (dd, J = 8.1,2.0Hz, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.30 (dd, J = 8.2, 1.7 Hz, 1H), 1.73 (s, 4H), 1.31 (s, 6H), 1.29 (s, 6H) ). ESI(+)-MS: 334.4 [M+1] ⁺ .

Example 84: Ethyl methyl ester 5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthyl-2-)ethynyl)pyrimidine-2-carboxylate

Compound WYC-329 (15 mg, 0.0475 mmol) was dissolved in 2 mL of methanol, sodium methoxide (7.7 mg, 0.143 mmol) was added, and stirred at room temperature overnight. After the reaction was finished, neutralized with 1 mol/L HCl to weakly acidic; The ester was diluted, washed with saturated sodium bicarbonate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. 338 (14.9 mg, 90%). ^{1 H NMR (500MHz, cdcl3)} δ8.64 (s, 2H), 7.47 (d, J = 1.2Hz, 1H), 7.34-7.27 (m, 2H), 4.05 (s, 3H), 1.69 (s, 4H ), 1.30 (s, 6H), 1.28 (s, 6H). ESI (+)-MS: 348.4 [M+1] ⁺ .

Example 85: Ethyl 2-hydroxy-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthyl-2-)ethynyl)benzoate

WYC-335 (15mg, 0.043mmol) was added to the flask, 0.8mL absolute ethanol was added under argon protection, ice water bath to 0 °C, 3μl concentrated sulfuric acid was added dropwise, and the reaction was heated and refluxed for 4 hours after TLC tracking. . After the reaction is completed, it is cooled to room temperature, and the sulfuric acid is neutralized with 1 mol/L of sodium hydroxide to neutrality, washed with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution, and the organic phase is dried over anhydrous sodium sulfate, filtered, and dried. Flash column chromatography (PE: EtOAc = 100:1 to 10:1) gave product WYC-339 (14 mg, 87%). ESI(+)-MS: 377.3 [M+1] ⁺ .

Example 86: Ethyl 3-hydroxy-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthyl-2-)ethynyl)benzoate

Compound WYC-332 (50 mg, 0.143 mmol) was added to a flask, 2 mL of a 2.0 mol/L NaOH solution was added, 2 mL of methanol was added, and the reaction was carried out at 55 ° C overnight. After the reaction of the starting material is completed, it is neutralized with 1 mol/L HCl to a pH of 5-6; diluted with ethyl acetate, extracted, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Chromatography (PE: EA = 20:1 to 5:1) gave the carboxylic acid product (47 mg, 87%). The product (25 mg, 0.072 mmol) was placed in a flask, 1.5 mL of absolute ethanol was added under argon atmosphere, and the mixture was heated to 0 ° with ice water, and 5 μL of concentrated sulfuric acid was added dropwise thereto. After the completion of the dropwise addition, the mixture was heated to reflux for 4 hours, and was subjected to TLC. After the reaction is completed, it is cooled to room temperature, and the sulfuric acid is neutralized with 1 mol/L of sodium hydroxide to neutrality, washed with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution, and the organic phase is dried over anhydrous sodium sulfate, filtered, and dried. Flash column chromatography (PE: EtOAc = 50:1 to 10:1) gave product WYC-340 (24 mg, 90%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ8.24 (s, 1H), 7.95 (dd, J = 8.2,1.4Hz, 1H), 7.84 (d, J = 1.9Hz, 1H), 7.63 (dd, J = 8.3, 1.9 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.01 (d, J = 0.8 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.73 (s, 4H), 1.43 (t, J = 7.1 Hz, 3H), 1.37 (s, 6H), 1.32 (s, 6H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 166. 91,159.50,154.23,146.62,145.62,133.74,127.23,127.15,126.07,124.37,123.49,122.73,120.12,112.68,100.57,60.95,35.03,34.92,34.44,31.86,31.74;ESI(+)-MS:377.4[M +1] ⁺ .

Example 87: Ethyl 5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthyl-2-)ethynyl)pyridine-2-carboxylate

WYC-337 (25mg, 0.075mmol) was added to the flask, 1.5mL absolute ethanol was added under argon protection, ice water bath was added to 0 degree, 5μl concentrated sulfuric acid was added dropwise, and the reaction was heated and refluxed for 4 hours after TTG tracking. TLC tracking . After the reaction is completed, it is cooled to room temperature, and the sulfuric acid is neutralized with 1 mol/L of sodium hydroxide to neutrality, washed with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution, and the organic phase is dried over anhydrous sodium sulfate, filtered, and dried. Flash column chromatography (PE: EtOAc = 50:1 to 10:1) gave product WYC-341 (24 mg, 90%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ8.85 (dd, J = 2.0,0.6 Hz, 1H), 8.11 (dd, J = 8.1,0.7Hz, 1H), 7.92 (dd, J = 8.1,2.1Hz, 1H), 7.50 (t, J = 1.2, 1H), 7.34 (d, J = 2.5 Hz, 1H), 7.26 (dd, J = 8.4, 2.1 Hz, 3H), 4.49 (q, J = 7.2 Hz, 2H) ), 1.69 (s, 4H), 1.45 (t, J = 6.8 Hz, 3H), 1.30 (s, 6H), 1.28 (s, 6H). ESI (+)-MS: 362.7 [M+1] ⁺ .

Example 88: Methyl 5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthyl-2-)ethynyl)pyridazine-2-carboxylate

6-ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (60 mg, 0.283 mmol) and methyl 2-chloropyridazine-4-carboxylate (56 mg, 0.325 mmol) was added to the flask, Pd(PPh ₃ ) ₂ Cl ₂ (16.8 mg, 0.024 mmol), CuI (6.8 mg, 0.036 mmol) was added, and the gas was protected with argon and replaced with 3 times to remove oxygen, and 2 mL was added by syringe. Dry DMF, 0.17 mL of dry Et ₃ N, reacted at 70 ° C for 8 h, followed by TLC. After completion of the reaction, it is quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with EtOAc EtOAc. PE: EA = 100: 1 to 20: 1) gave the product (55 mg, 56%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ9.28 (d, J = 1.4Hz, 1H), 8.83 (d, J = 1.4Hz, 1H), 7.61 (d, J = 1.7Hz, 1H), 7.40 (dd , J=8.2, 1.7 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H), 4.06 (s, 3H), 1.70 (s, 4H), 1.30 (s, 6H), 1.29 (s, 6H) ¹³ C NMR (101 MHz, CDCl ₃ ) δ 164.18, 147.91, 146.83, 145.74, 145.57, 143.39, 140.07, 131.12, 129.38, 127.01, 117.83, 97.82, 85.11, 77.34, 77.23, 77.02,76.70,53.19,34.80,34.76, 34.58, 34.31, 31.75, 31.62. ESI(+)-MS: 349.2 [M+1] ⁺ .

Example 89: Ethyl 5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthyl-2-)ethynyl)pyrazine-2-carboxylate

The above product (35 mg, 0.1 mmol) was added to a flask, and 1.5 mL of a 2.0 mol/L NaOH solution was added thereto, and 1.5 mL of methanol was added; and the reaction was carried out at 55 ° C overnight. After the reaction of the starting material is completed, it is neutralized with 1 mol/L HCl to a pH of 5-6; diluted with ethyl acetate, extracted, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Chromatography (PE: EA = 20:1 to 5:1) gave the carboxylic acid product (28.3 mg, 85%). The product (25 mg, 0.075 mmol) was placed in a flask, 1.5 mL of absolute ethanol was added under argon atmosphere, and the mixture was cooled to 0 ° with ice water, and 5 μl of concentrated sulfuric acid was added dropwise. After the addition was completed, the mixture was heated to reflux for 4 hours, and was subjected to TLC. After the reaction is completed, it is cooled to room temperature, and the sulfuric acid is neutralized with 1 mol/L of sodium hydroxide to neutrality, washed with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution, and the organic phase is dried over anhydrous sodium sulfate, filtered, and dried. Flash column chromatography (PE: EtOAc = 50:1 to 10:1) gave product WYC-342 (20 mg, 75%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ9.26 (d, J = 1.4Hz, 1H), 8.82 (d, J = 1.4Hz, 1H), 7.60 (d, J = 1.6Hz, 1H), 7.38 (dd , J = 8.2, 1.7 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 4.51 (q, J = 7.1 Hz, 2H), 1.68 (s, 4H), 1.45 (t, J = 7.1 Hz) , 3H), 1.29 (s, 6H), 1.27 (s, 6H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 163.72, 147.84, 146.83, 145.72, 145.53, 143.21, 140.41, 131.09, 129.37, 127.00, 117.87, 97.61 , 85.15, 77.38, 77.07, 76.75, 62.42, 34.81, 34.76, 34.56, 34.30, 31.75, 31.62. ESI(+)-MS: 363.6 [M+1] ⁺ .

Effect Example 1. In vitro growth inhibition activity of melanoma-derived cells (TRCs)

Melanoma B16-F1 cells were incubated with 3D fibrin glue medium (90-Pa) for 5 days, and the desired melanoma tumor regenerative cells were screened (Nat. Mater. 2012, 11, 734). Subsequently, the culture medium was separately treated with collagenase and neutral protease II to release melanoma tumor regenerative cells, and the resulting regenerated cells were transferred to a fresh preparation medium and resuspended, and maintained in a single cell state. Melanoma B16-F1 regenerative cells were inoculated in 3D fibrin glue medium (90-Pa) for 5 days, with 0.1% DMSO as a negative control group, Tazarotene and Bexarotene. For the positive control drugs, the drugs were added at a concentration of 10 μM, incubated for 5 days, and the tumor clone size was observed and measured, and the inhibition rate of each drug for melanoma B16-F1 tumor regenerative cells was calculated. The results of the test for inhibiting cell activity of the compound comprising the compound against melanoma B16-F1 are shown in Table 2 below.

Table 2: Test results of melanoma B16-F1 regenerative cell inhibitory activity

The inhibition rate of the regenerative cells of melanoma tumor B16-F1 showed that most of the compounds showed significant tumor growth inhibitory activity at a concentration of 10 μM, such as compound WYC-103 (86.8%), WYC-207 (92.5%), WYC-209 (98.8%), WYC-209A (98.9%), WYC-209B (98.7%), WYC-212 (93.2%), WYC-217 (90.3%), WYC-218 (90.4%), WYC- 329 (94.5%), WYC-331 (96.0%), etc., the corresponding tumor clones were basically not used for growth or growth very slowly. The results were not only in sharp contrast with the negative control group, but also met or exceeded the inhibitory activity of the positive drug Tazarotene (67.6%) and Bexarotene (63.3%) on tumor clone growth.

A dose-effect curve study of tumor growth inhibition was then performed on compounds exhibiting significant tumor clonal growth inhibitory activity in the primary screening. Tumor clones administered by equivalence gradient were fixed, DAPI nuclear staining and volume measurement, inhibition rate calculation and dose-response curve regression were performed to determine the compounds with better activity WYC-103, WYC-209, WYC-320, WYC- The IC _{50 of} 329 and WYC-331 is shown in Table 3 below.

Table 3: regeneration section cytostatic compound lists IC ₅₀ for melanoma B16-F1

Among them, the compounds WYC-103 and WYC-209 for the inhibition and differentiation of melanoma tumor B16-F1 regenerative cells are shown in the electron micrograph (Fig. 1, Fig. 2). In Fig. 1 and Fig. 2, cell survival was observed by DAPI staining. Apoptosis was shown by PI staining, and merge showed a superposition of DAPI and PI staining images.

2. Study on the inhibitory activity of compound WYC-209 on the growth of various tumor regenerative cells

Many of the above compounds show excellent inhibitory activity against melanoma B16-F1 tumor regenerative cell proliferation, and WYC-209 inhibitory activity is particularly excellent. Therefore, we have further studied the growth inhibitory activity of this compound against other six human tumor regenerative cells, including lung cancer cell A549, breast cancer cell MCF-7, melanoma cell MDA-MB-435S, ovarian cancer cell A2780, gastric cancer cell. Hs-746T, breast cancer cell MDA-MB-231.

The above human tumor cells were separately incubated with 3D fibrin glue medium (90-Pa) for 5 days, and the desired tumor regenerative cells were selected. Subsequently, the medium was separately treated with collagenase and neutral protease II to release the tumor-regenerating cells, and then the resulting regenerated cells were transferred to a fresh preparation medium and resuspended, and maintained in a single cell state. Single tumor regenerative cells were inoculated in 3D fibrin glue medium (90-Pa) for 5 days, and 0.1% DMSO was used as a negative control group (DMSO group in Fig. 3 to Fig. 8), with no drug added as a blank group ( In Fig. 3 to Fig. 8, the None group) was studied by administration from 0 days and administration from 3 days, respectively, and the tumor clone volume was calculated and measured.

The results showed that compared with the blank control group, the compound WYC-209 can effectively inhibit the proliferation of various tumor regenerative cells at 1.0 μM, which greatly blocked the volume growth of tumor clones. The volume of tumor clones was only blank group. 25-30% (Fig. 3-8, Fig. 3-8 refers to drug9# for WYC-209). When the concentration of WYC-209 was increased to 10 μM, the proliferation of the above six tumor regenerative cells was inhibited at a higher level, and the volume of the tumor clone was even less than 10% of the volume of the blank group. Especially for Hs-746T, the use of compound WYC-209 can even reverse the growth trend of tumor clones.

3. Study on the inhibitory activity of compound WYC-331 on the growth of various tumor regenerative cells

Compound WYC-331 showed good inhibitory activity against melanoma B16-F1 tumor regenerative cell proliferation, and then we investigated the inhibitory activity of this compound against ovarian cancer A2780 and breast cancer MDA-MB-231 tumor regenerative cells.

The above human tumor cells were separately incubated with 3D fibrin glue medium (90-Pa) for 5 days, and the desired tumor regenerative cells were selected. Subsequently, the medium was separately treated with collagenase and neutral protease II to release the tumor-regenerating cells, and then the resulting regenerated cells were transferred to a fresh preparation medium and resuspended, and maintained in a single cell state. Single tumor regenerative cells were inoculated in 3D fibrin glue medium (90-Pa) for 5 days, 0.1% DMSO as a negative control group (DMSO group in Fig. 9), and no drug addition as a blank group (Fig. 9) In the middle group, the drug was administered at a concentration of 0.1 μM, 1.0 μM, and 10 μM from the third day, and the tumor clone volume was observed and measured.

The results showed that compared with the blank control group, the compound WYC-331 could completely inhibit the proliferation of ovarian cancer A2780 tumor regenerative cells and breast cancer MDA-MB-231 tumor regenerative cells at 10 μM, which greatly blocked the tumor. The volume of the clones increased, and the volume of the tumor clones was only 10-15% of the blank group. For MDA-MB-231 tumor regenerative cells, the use of compound WYC-331 even reversed the growth trend of tumor clones (Fig. 9, where #31 indicates WYC-331). At the same time, cell staining studies found that tumor clones inhibited by WYC-331 remained viable, and only a few cells showed apoptosis.

4. Toxicity study of compounds WYC-209 and WYC-331

We used the mouse embryonic fibroblast 3T3 cell line and melanoma cell B16-F1 as models to study the in vitro toxicity of compounds WYC-209 and WYC-331, respectively. The effects of compounds WYC-209 and WYC-331 on the proliferation of mouse embryonic fibroblasts 3T3 and melanoma cells B16-F1 were compared at 10 μM. The results showed that the compound WYC-209 did not affect the proliferation of mouse embryonic fibroblasts 3T3, nor induced apoptosis of this type of cells; at the same time, compound WYC-209 could significantly block the growth of melanoma cell clones, and at 6- 48 hours showed significant apoptosis. This experiment shows that the compound WYC-209 has a certain specificity for melanoma tumor-regeneration cells, has a weak effect on ordinary cells, and has less cytotoxicity (Fig. 10).

Under the same conditions, the compound WYC-331 strongly inhibited the proliferation of melanoma cells B16-F1, but at the same time did not show significant apoptosis-inducing effects on mouse embryonic fibroblasts 3T3 and melanoma cells B16-F1. This shows that the compound WYC-331 also has some selectivity for melanoma-regenerating cells, and no obvious is observed. Cytotoxicity, but the mechanism of action may be different from the compound WYC-209 (Figure 11).

5. Study on the inhibitory activity of compound WYC-103 on subcutaneous transplantation of melanoma

We established a subcutaneous implantation model of melanoma B16-F1 in immunocompetent mice (C57BL/6, female, 6-8 weeks) to study the inhibitory activity of compound WYC-103 in situ tumors. B16-F1 cells were incubated with 3D fibrin glue medium (90-Pa) for 5 days, and the desired tumor regenerative cells were screened. Subsequently, the medium was treated with collagenase and neutral protease II to release tumor regenerative cells. The resulting regenerated cells are then pipetted into the new preparation medium and maintained in a single cell resuspended state.

Six immunocompetent mice were randomly divided into two groups: the drug-administered group and the DMSO-negative control group. The melanoma model was subcutaneously implanted by subcutaneous injection of 30,000 melanoma-derived cells. Subsequently, it was administered by tail vein injection according to the body weight of the mouse and the blood volume. From day 0, the drug-administered group was treated with WYC-103 once every 2 days according to the blood concentration of 10 μM. The survival of the mice was observed by normal feeding, and the results were as follows. After 19 days of experimentation, the subcutaneous melanoma volume of the drug-administered group was significantly smaller than that of the DMSO control group. According to statistical analysis, the tumor volume of the drug-administered group was only 50% of the control group (Fig. 12).

To further confirm the inhibitory effect of compound WYC-103 on subcutaneously implanted tumors of melanoma B16-F1, we repeated this experiment. In this experiment, 18 immunocompetent mice (C57BL/6, female, 6-8 weeks) were randomly divided into the drug-administered group, the positive control group (BMS-453 positive drug) and the DMSO negative control group. In the group, 30,000 melanoma regenerative cells were injected by subcutaneous injection to establish a subcutaneous implantation model of melanoma. Subsequently, it was administered by tail vein injection according to the body weight of the mouse and the blood volume. From day 0, the drug-administered group was injected with WYC-103 once every 2 days according to the blood concentration of 10 μM; the positive control group was administered in the same manner with BMS-453 (WYC-114) as the positive drug; 0.1% DMSO was injected once in the same manner.

By the 20th day from the start of the experiment, all the mice in the positive drug control group died. On the 26th day from the start of the experiment, 50% of the mice in the drug-administered group and the negative control group died. According to statistics, the tumor volume of the mice in the drug-administered group was only 50% of the negative control group, and the growth of the subcutaneous transplanted tumors of the mice in the drug-administered group was significantly inhibited. The mouse body weight study showed that the body weight of the mice in the administration group was stable and balanced, and no obvious side effects were observed (Fig. 13, wherein drug3# indicates WYC-103, drug14# indicates BMS-453). In the positive drug control group, the body weight of the control group was significantly reduced, indicating that there was a large toxic side effect of the individual; while the negative control group mice had a significant increase in body weight due to the large tumor volume (Fig. 14). Further dissection experiments on mice in each group showed that a large number of foamy abnormal structures appeared in the peritoneal cavity of the dead mice in the positive control group, which may be the cause of death in this group of mice. No abnormalities were found in the abdominal cavity of the mice in the drug-administered group and the negative control group. This experiment shows that WYC-103 is much better than BMS-453 in terms of the efficacy and overall toxic side effects of subcutaneous melanoma inhibition.

6. Activity of compound WYC-103 to inhibit melanoma metastasis to the lungs

To investigate whether compound WYC-103 can inhibit the metastasis of melanoma to the lungs and prevent secondary tumors. Health, we established a mouse melanoma lung cancer metastasis model. First, 12 mice with normal immune function (C57BL/6, female, 6-8 weeks) were randomly selected as the matrix, and 3000 melanoma regenerative cells were injected into the mice via the tail vein to establish a lung cancer metastasis model. The model mice were randomly divided into two groups: the drug-administered group and the negative control group. According to the body weight and blood volume of the mice, the compounds WYC-103 (to the drug) and DMSO (negative control group) were subjected to 10 μM blood according to the tail vein injection method. The drug concentration and 0.1% of the dose were injected every two days.

On the 29th day of the experiment, the first control group died in the negative control group. For the convenience of comparison, the mice in one administration group were killed at the same time. According to the dissection, the negative control group showed obvious melanoma lung metastasis tumor tissue. However, the lung tissue of the mice in the administration group was all normal. On the 35th day of the experiment, the second control group died in the negative control group, and a large number of melanoma lung metastasis tumor tissues appeared in the negative control group, while the lung tissues in the corresponding administration group were all normal. By the 37th day of the experiment, 3 mice died in the negative control group, and only 1 mouse remained in the negative control group, so all the mice in both groups were sacrificed and anatomically compared. According to the dissection, 3 negative control mice showed severe melanoma lung metastasis, while the lung tissues of the mice in the administration group were all normal.

According to the experimental statistics, 5 of the 6 mice in the negative control group showed obvious melanoma lung metastasis and all died, and the remaining one survived healthily; while the lung tissues of 6 mice in the drug-administered group were healthy and intact. And without any signs of melanoma metastasis, it prevented the occurrence of metastatic melanoma with 100% efficiency. At the same time, according to statistical analysis, the average lung weight of the mice in the administration group was only 1/3 of the negative control group (Fig. 15, "+" in Fig. 15e and 15f indicates metastasis, and "-" indicates no metastasis).

The experiment showed that the compound WYC-103 could effectively prevent melanoma-derived cells from metastasizing to the lungs to form secondary lung tumors at a blood concentration of 10 μM, and WYC-103 showed no obvious side effects during the whole experiment. It is hopeful that it will be further used for the prevention and treatment of human metastatic cancer.

7. Activity of compound WYC-209 to inhibit melanoma metastasis to the lungs

To investigate whether compound WYC-209 can inhibit melanoma metastasis to the lungs and prevent secondary tumorigenesis, we conducted this experiment. B16-F1 cells were incubated with 3D fibrin glue medium (90-Pa) for 5 days, and the desired tumor regenerative cells were screened. Subsequently, the medium was treated with collagenase and neutral protease II to release tumor regenerative cells. The resulting regenerated cells were pipetted into a fresh preparation medium and maintained in a single cell resuspended state. Subsequently, 24 immunocompetent mice were randomly selected from immunocompetent mice (C57BL/6, female, 6-8 weeks), divided into low-dose group (1.0 μM) and high-dose group (10 μM). Three study groups were in the DMSO negative control group, with 8 mice in each group. The 30,000 melanoma regenerative cells (ten times the animal model used in the compound WYC-103) were injected into the mice via the tail vein to establish a model of melanoma B16-F1 to lung metastasis. Subsequently, it was administered by tail vein injection according to the body weight of the mouse and the blood volume. From the 5th day, the drug-administered group was intravenously injected with WYC-209 every 2 days according to the plasma concentrations of 1.0 μM and 10 μM, respectively, and the DMSO group was administered 0.1% in the same manner. DMSO was used as a negative control, and there was no significant difference in body weight between the groups. Observe the statistical results of normal feeding.

On the 23rd day of the experiment, one mouse died in the DMSO group (the lung tissue map is shown in Figure 8a, Figure 8). By the 30th day, all the remaining mice were killed, and 6 of the 8 mice in the DMSO group showed obvious melanoma metastasis in the lungs, and no abnormalities were found in the liver and stomach (see Figure 1a, No. 1 to No. 7). Figure). During the same period (the 29th night), one mouse died in the 1.0 μM administration group (Fig. 16b, Figure 8); 4 of the 8 mice in the 1.0 μM administration group developed melanin in the lungs. No abnormalities were found in the metastatic tissues of the tumor, liver and stomach (Fig. 16b, Figures 1 to 7 are lung tissue maps of the experiment for 30 days). In the same period, only one of the 8 mice in the 10 μM administration group developed melanoma metastasis in the lungs, and no abnormalities were found in the liver and stomach. By the 30th day, 6 mice (75%) in the DMSO group had pulmonary metastasis melanoma, 4 mice (50%) in the 1.0 μM administration group had pulmonary metastatic melanoma, and only 10 in the 10 μM administration group. Only mice (12.5%) suffered from metastatic melanoma in the lungs (see Figure 16c for details). Figures 1 to 5 show the lung tissue map for 30 days, and Figures 6-8 show experiments 29, 24, and 20 respectively. Lung tissue map). The lung tissue weight of each group also showed statistically significant differences. The DMSO group >1.0 μM administration group >10 μM administration group ("+" indicates metastasis in Fig. 16, "-" indicates no metastasis).

This experiment shows that compound WYC-209 can effectively prevent melanoma-derived cells from metastasized to the lungs to form secondary lung tumors at a blood concentration of 1.0 μM, which can be 87.5% at 10.0 μM blood concentration. Efficiency prevents metastatic melanoma cells from metastasized to the lungs to form secondary lung tumors. Compared with the DMSO group, 75% of the lung metastasis melanoma mortality rate, WYC-209 showed strong secondary tumor suppression and even healing activity in mice with immune function. At the same time, WYC-209 showed no obvious side effects during the whole experiment, and it is hopeful to be further used for the prevention and treatment of various primary or metastatic cancers in humans.

In summary, the above in vitro activity experiments showed that the compounds WYC-103, WYC-209 and WYC-331 had strong inhibitory effects on melanoma-regenerating cells, and the inhibitory activity of melanin-regenerating cells reached 0.45, respectively. μM, 0.25 μM and 0.017 μM. WYC-209 has strong anti-tumor cells such as lung cancer cell A549, breast cancer cell MCF-7, melanoma cell MDA-MB-435S, ovarian cancer cell A2780, gastric cancer cell Hs-746T, breast cancer cell MDA-MB-231 Inhibition.

In vivo activity experiments showed that WYC-103 had a strong inhibitory effect on subcutaneous transplantation of melanoma in mice. Compared with the blank group, the tumor volume was only 50% of the blank control group at 10 μM working concentration. At 10μM working concentration, WYC-103 and WYC-209 inhibited the metastasis of melanoma-derived cells to the lungs with 100% and 87%, respectively, bringing new treatments for the prevention and treatment of metastasis of human tumors.

In vitro experimental examples also confirmed that WYC-209 and WYC-331 had no effect on the growth of 3T3 cell clones and could not induce apoptosis of 3T3 cells. At the same time, the in vitro and in vivo activity studies of WYC-103 and WYC-209 demonstrate that these compounds are highly safe. As can be seen from the above biological study examples, the patent relates to compounds The prevention and treatment of leukemia, lymphoma, primary solid tumors and metastatic tumors offer new possibilities.

While the invention has been described with respect to the preferred embodiments of the embodiments of the embodiments of the invention modify. Accordingly, the scope of the invention is defined by the appended claims.

Claims (14)

1. a compound of formula I, an enantiomer thereof, a diastereomer or a pharmaceutically acceptable salt,

   

   Wherein U is CR ^9a or N; V is CR ^9b or N; X is CR ^9c or N; W is CR ^9d or N;

   In the U, V, X and W, R ^9a , R ^9b , R ^9c and R ^{9d are} independently hydrogen, hydroxy, nitro, cyano, halogen, C ₁ -C ₆ alkyl, halogen substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -NR ¹⁰ R ¹¹ ,

   

   -COOR ¹⁴ ;

   Said R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ^{14 are} independently hydrogen or C ₁ -C ₆ alkyl;

   AE, EG and GZ are independently single or double bonds; when A, E, G or Z is connected to two single bonds, the corresponding A, E, G and Z are independently: -(CR ² R ³ ) -, -C(=O)-, -(NR ⁴ )-, -(N→O)-, -O-, -S-, -S(=O)- or -SO ₂ -; when A When E, G or Z is connected to a single bond and a double bond, the corresponding A, E, G or Z is independently: -(CR ⁵ )= or -N=;

   The R ² , R ³ , R ⁴ and R ^{5 are} independently hydrogen, hydroxy, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, halogen substituted C ₁ -C ₆ alkyl, alkoxy is C ₁ -C _6, a C ₁ -C ₆ acyl, C ₆ -C ₁₀ aryl group, or "hetero atom is oxygen, sulfur or nitrogen atom, a hetero atom number of 1 to 2 of C ₃ -C ₆ heteroaryl";

   m is 0, 1, 2 or 3;

   When substituted with a plurality of R ¹ , the substituents are the same or different; R ¹ is hydrogen, hydroxy, nitro, cyano, halogen, C ₁ -C ₆ alkyl, halogen-substituted C ₁ -C ₆ alkyl , C ₁ -C ₆ alkoxy, -NR ⁶ R ⁷ or -COOR ⁸ ;

   Said R ⁶ , R ⁷ and R ^{8 are} independently hydrogen or C ₁ -C ₆ alkyl;

   Y is -CN, -COOR ¹⁵ or -CO ₂ NHR ¹⁶ ;

   Said R ¹⁵ and R ^{16 are} independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₁ -C ₆ alkyl acyl;

   The compound I is not

   
2. The compound of formula I according to claim 1, wherein

   When R ² , R ³ , R ⁴ and R ^{5 are} independently halogen, the "halogen" is fluorine, chlorine, bromine or iodine;

   And/or, when R ² , R ³ , R ⁴ and R ^{5 are} independently “C ₁ -C ₆ alkyl”, the “C ₁ -C ₆ alkyl group” is a methyl group, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl;

   And/or, when R ² , R ³ , R ⁴ and R ^{5 are} independently “C ₂ -C ₆ alkenyl group”, the “C ₂ -C ₆ alkenyl group” is vinyl or Propylene group

   And/or, when said R ² , R ³ , R ⁴ and R ^{5 are} independently "halogen-substituted C ₁ -C ₆ alkyl", said "halogen-substituted C ₁ -C ₆ alkane""base" is trifluoromethyl;

   And/or, when R ² , R ³ , R ⁴ and R ^{5 are} independently “C ₁ -C ₆ alkoxy group”, the “C ₁ -C ₆ alkoxy group” is A Oxyl, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy or hexyloxy;

   And/or, when R ² , R ³ , R ⁴ and R ^{5 are} independently “C ₁ -C ₆ acyl group”, the “C ₁ -C ₆ acyl group” is acetyl or formyl group. ;

   And/or, when R ² , R ³ , R ⁴ and R ^{5 are} independently “C ₆ -C ₁₀ aryl group”, the “C ₆ -C ₁₀ aryl group” is a phenyl group;

   And/or, said R ² , R ³ , R ⁴ and R ^{5 are} independently a C ₃ -C ₆ heteroaryl group having a hetero atom of an oxygen, sulfur or nitrogen atom and having 1 to 2 hetero atoms. "when the" heteroatom is oxygen, sulfur or nitrogen atom, a hetero atom number of 1 to 2 is C ₃ -C heteroaryl _"6 is pyridyl or pyrimidinyl;

   And/or, when said R ¹ is "halogen", said "halogen" is fluorine, chlorine, bromine or iodine;

   And/or, when R ¹ is "C ₁ -C ₆ alkyl group", the "C ₁ -C ₆ alkyl group" is methyl group, ethyl group, n-propyl group, isopropyl group, N-butyl, isobutyl, tert-butyl, pentyl or hexyl;

   And/or, when R ¹ is “halogen-substituted C ₁ -C ₆ alkyl”, the “halogen-substituted C ₁ -C ₆ alkyl” is trifluoromethyl;

   And/or, when R ¹ is “C ₁ -C ₆ alkoxy”, the “C ₁ -C ₆ alkoxy group” is a methoxy group, an ethoxy group, a n-propoxy group or a different group. Propyloxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy or hexyloxy;

   And/or, when R ⁶ , R ⁷ and R ^{8 are} independently “C ₁ -C ₆ alkyl”, the “C ₁ -C ₆ alkyl group” is methyl, ethyl, N-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl;

   And/or, when R ^9a , R ^9b , R ^9c and R ^{9d are} independently “halogen”, the “halogen” is fluorine, chlorine, bromine or iodine;

   And/or, when R ^9a , R ^9b , R ^9c and R ^{9d are} independently “C ₁ -C ₆ alkyl group”, the “C ₁ -C ₆ alkyl group” is a methyl group, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl;

   And/or, when said R ^9a , R ^9b , R ^9c and R ^{9d are} independently "halogen-substituted C ₁ -C ₆ alkyl", said "halogen-substituted C ₁ -C ₆ alkane""base" is trifluoromethyl;

   And / or, said R ^9a, R ^9b, R ^9c and R ^9d is independently "C ₁ -C ₆ alkoxy group", the "C ₁ -C ₆ alkoxy" is methoxy , ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy or hexyloxy;

   And / or, according to ^{R 10, R 11, R 12} , R 13 and R ¹⁴ is independently "C ₁ -C ₆ alkyl of", "C ₁ -C ₆ alkyl" is the Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl;

   And "C ₁ -C ₆ alkyl of the" / or said R ¹⁵ and R ¹⁶ is independently "C ₁ -C ₆ alkyl" and the methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl;

   And / or said R ¹⁵ and R ¹⁶ is independently "C ₂ -C ₆ alkenyl group", a "C ₂ -C ₆ alkenyl groups" as the vinyl or propenyl group;

   And/or, when R ¹⁵ and R ^{16 are} independently a "C ₁ -C ₆ acyl group", the "C ₁ -C ₆ acyl group" is a formyl group or an acetyl group.
3. A compound of formula I according to claim 1 or 2, characterized in that

   One, two, three or four of the U, V, X and W are N, or the U is CR ^9a , V is CR ^9b , X is CR ^9c , and W is CR ^9d ;

   And/or, the A, E, G, and Z are connected as a ring as shown below:

   

   
4. A compound of formula I according to claim 3, characterized in that

   When two of the U, V, X and W are N, the compound I is any one of the following compounds,

   

   Alternatively, when one of U, V, X and W is N, the compound I is any one of the following compounds,

   

   Alternatively, when the U is CR ^9a , V is CR ^9b , X is CR ^9c , and W is CR ^9d , the structure of the compound I is as shown in the compound F,

   

   In the compound F, one, two, three or four of the R ^9a , R ^9b , R ^9c and R ^9d are not hydrogen.
5. The compound of formula I according to claim 4, wherein

   In the compound A, when Y is -COOR ¹⁵ , the R ¹⁵ is hydrogen or ethyl;

   And/or, in the compound A, the Z is -(CR ² R ³ )-, -S-, -S(=O)- or -SO ₂ -; preferably, the A , E, G, and Z are connected into a ring as shown below:

   

   

   And / or, the compound B, when said Y is -COOR ^15, said R ¹⁵ is methyl or ethyl;

   And/or, in the compound B, the Z is -(CR ² R ³ )-, -S- or -S(=O)-; preferably, the A, E, G and Z is connected to the ring shown below:

   

   And/or, in the compound C, when the Y is -COOR ¹⁵ , the R ¹⁵ is hydrogen or an ethyl group;

   And/or, in the compound C, the Z is -(CR ² R ³ )-, -S- or -S(=O)-; preferably, the A, E, G and Z is connected to the ring shown below:

   

   And/or, in the compound D, when the Y is -COOR ¹⁵ , the R ¹⁵ is hydrogen or an ethyl group;

   And / or, in the compound D, the Z is ^{- (CR 2 R 3) -} ; Preferably, said A, E, G and Z are joined into a ring as shown below:

   

   And/or, in the compound E, the Y is CN;

   And/or, in the compound E, the Z is -(CR ² R ³ )-; preferably, the A, E, G and Z are linked to a ring as shown below:

   

   And/or, in the compound F, when the Y is -COOR ¹⁵ , the R ¹⁵ is hydrogen, methyl or ethyl;

   And/or, in the compound F, the Z is -(CR ² R ³ )-, -S-, -S(=O)- or -SO ₂ -; preferably, the A , E, G, and Z are connected into a ring as shown below:

   

   
6. A compound of formula I according to claim 5, characterized in that

   In the compound A, when the Y is COOH, the Z is -S-;

   And/or, in the compound A, when the Y is COOEt, the Z is -(CR ² R ³ )-, -S(=O)- or -SO ₂ -;

   And/or, in the compound B, when the Y is COOMe, the Z is -(CR ² R ³ )-;

   And/or, in the compound B, when the Y is COOEt, the Z is -(CR ² R ³ )- or -S-;

   And/or, in the compound B, when the Y is COOEt, the Z is -(CR ² R ³ )- or -S-;

   And/or, in the compound B, when the Y is CN, the Z is -(CR ² R ³ )-, -S- or -S(=O)-;

   And/or, in the compound C, when the Y is COOH, the Z is -S-;

   And/or, in the compound C, when the Y is COOEt, the Z is -(CR ² R ³ )-, -S- or -S(=O)-.
7. The compound of formula I according to claim 1, wherein said compound I is any one of the following compounds:

   

   

   
8. The method for preparing a compound of the formula I according to any one of claims 1 to 7, which comprises the steps of: coupling a compound II and III to obtain a compound I;

   

   Wherein X ¹ is a halogen.
9. a compound as shown in Formula II, III, IV or V,

   

   Wherein A, E, G, Z, R ¹ , m, Y, U, V, X and W are all as defined in any one of claims 1 to 7; X ¹ is a halogen; and X ² is a halogen.
10. The use of a compound of formula I, an enantiomer, diastereomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, for the preparation of a medicament, The drug is used to treat primary tumors.
11. The use of a compound of formula I, an enantiomer, diastereomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, for the preparation of a medicament, The drug is used to prevent and/or treat metastatic tumors.
12. The use of a compound of formula I, an enantiomer, diastereomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, for the preparation of a medicament, The drug is used for prevention and/or treatment, leukemia and/or lymphoma.
13. The use of a compound of formula I, an enantiomer, diastereomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, for the preparation of a medicament, The drug is used for one or more of animal fetal development, homeostasis, vision, morphogenesis, skin aging, and control of cell differentiation.
14. A pharmaceutical composition comprising a compound of formula I, an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof, according to any one of claims 1-7. And a pharmaceutically acceptable carrier.

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