阅读说明：本技术 苯并六元环衍生物及其应用 (Benzo-six-membered ring derivative and application thereof ) 是由 李丹 李洪林 赵振江 谢荣荣 苏明波 罗娜 李诗良 于 2020-06-12 设计创作，主要内容包括：本发明涉及作为治疗肝纤维化的苯并六元环衍生物及其应用。具体而言,本发明涉及Ⅰ所示化合物、含有Ⅰ式化合物的药物组合物及所述化合物在制备治疗肝纤维化相关疾病及其药物中的用途。(The invention relates to benzo-hexatomic ring derivatives for treating hepatic fibrosis and application thereof. In particular, the invention relates to a compound shown as I and a compound containing the formula IA pharmaceutical composition of the compound and application of the compound in preparing medicaments for treating hepatic fibrosis related diseases and medicaments thereof.)

1. The application of the compound shown in the general formula I, or the pharmaceutically acceptable salt or prodrug thereof, or the optically active isomer or solvate thereof in preparing the medicament for preventing or treating hepatic fibrosis:

in the formula:

x is selected from CH₂、O、S、NH；

A is a benzene ring with 1-5 substituents, each substituent is independently selected from halogen, cyano, hydroxy, C_1-6Alkyl or C substituted by halogen, preferably F, more preferably 1-5F_1-6Alkyl, C1-6 alkoxy or C substituted by halogen, preferably F, more preferably 1-5F_1-6An alkoxy group;

the ring A can also be selected from nitrogen-containing, sulfur-containing five-membered or six-membered saturated or unsaturated heterocyclic rings with 1-4 substituents, and each substituent is independently selected from halogen, cyano and boric acid;

the A heterocycle is selected from the following structures:

the ring B, C is not present at the same time,

the ring B is selected from aromatic benzene ring, aromatic heterocyclic ring, saturated or unsaturated five-membered six-membered ring, five-membered or six-membered saturated or unsaturated heterocyclic ring containing nitrogen, oxygen and sulfur,

the substituent R is independently selected from H, halogen, cyano, hydroxyl and C_1-6Alkyl or C containing 1-5F atoms_1-6Alkyl radical, C_1-6Alkoxy or C containing 1 to 5F atoms_1-6An alkoxy group, n-1-4,

the ring C is selected from aromatic benzene ring, aromatic heterocyclic ring, saturated or unsaturated five-membered six-membered ring, five-membered or six-membered saturated or unsaturated heterocyclic ring containing nitrogen, oxygen and sulfur,

the substituent R thereof₁Independently selected from H, halogen, optionally substituted C_1-6Alkyl, cyano, optionally substituted amino, carbonyl, hydroxy, C_1-3Carboxyl group (preferably COOH), C_1-6Alkoxy or C containing 1 to 5F atoms_1-6Alkoxy radical, C_1-6Deuterated alkoxy or C containing 1-5F atoms_1-6Deuterated alkoxy, n-1-4; or

When ring C is absent, R₁Is directly connected with the main body of the compound,

at this time, R₁Is H, carbonyl, halogen, optionally substituted phenyl, cyano, optionally substituted amino, optionally substituted 5-6 membered heterocyclyl containing 1-2 heteroatoms selected from N or O, hydroxy, C_1-3Carboxyl group (preferably COOH), C_1-3Carboxylate group (preferably methyl formate group), optionally substituted C_1-6Alkyl, optionally substituted C_1-10Alkoxy (preferably C)_1-6Alkoxy), optionally substituted C_2-10Alkoxy containing olefinic bond and acetylene bond, optionally substituted benzyloxy and optionally substituted C_1-10Alkylformyloxy, optionally substituted C_1-3Alkoxy methoxy, disubstituted OCH₂CH₂O and OCH₂O, optionally substituted C_1-6Alkoxycarbonyl, carbamoyl, amino, optionally substituted C_1-5Alkylcarboxamide, optionally substituted C_3-5Alkyl lactam group, optionally substituted C_1-6Alkylsulfonamido, optionally substituted C_3-5Alkyl internal sulfonamide, mercapto, optionally substituted C_1-5Alkylmercapto, optionally substituted C_1-5Alkylsulfonyl, optionally substituted C_3-5Cycloalkylsulfonyl, optionally substituted C_1-5Alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl, m ═ 1-2.

2. Use according to claim 1, wherein the compound is of formula (ii):

x is selected from CH₂、O、S、NH；

A is a benzene ring with 1-5 substituents, each substituent is independently selected from halogen, cyano, hydroxy, C_1-6Alkyl or C substituted by halogen, preferably F, more preferably 1-5F_1-6Alkyl, C1-6 alkoxy or C substituted by halogen, preferably F, more preferably 1-5F_1-6An alkoxy group;

R₄independently selected from H, hydroxy, F, cyano;

R₅is H, carbonyl, halogen, cyano, hydroxy, C_1-3Carboxy (preferably COOH), optionally substituted C_1-6Alkyl, optionally substituted C_1-10Alkoxy (preferably C)_1-6Alkoxy), optionally substituted C_2-10Alkoxy containing olefinic bond and acetylene bond, optionally substituted benzyloxy and optionally substituted C_1-10Alkylformyloxy, optionally substituted C_1-3Alkoxy methoxy, disubstituted OCH₂CH₂O and OCH₂O, optionally substituted C_1-6Alkoxycarbonyl, carbamoyl, amino, NR²R³Optionally substituted C_1-5Alkylcarboxamide, optionally substituted C_3-5Alkyl lactam radical, optionally substitutedC_1-6Alkylsulfonamido, optionally substituted C_3-5Alkyl internal sulfonamide, mercapto, optionally substituted C_1-5Alkylmercapto, optionally substituted C_1-5Alkylsulfonyl, optionally substituted C_3-5Cycloalkylsulfonyl, optionally substituted C_1-5Alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl, optionally substituted phenyl, q ═ 1-2.

3. Use according to claim 1, wherein the compound is of formula (iii):

wherein the content of the first and second substances,

x is selected from O, S, NH;

R₆is H, carbonyl, halogen, cyano, hydroxy, C_1-3Carboxy (preferably COOH), optionally substituted C_1-6Alkyl, optionally substituted C_1-10Alkoxy (preferably C)_1-6Alkoxy), optionally substituted C_2-10Alkoxy containing olefinic bond and acetylene bond, optionally substituted phenyl (preferably methylsulfonyl substituted phenyl), optionally substituted benzyloxy, optionally substituted C_1-10Alkylformyloxy, optionally substituted C_1-3Alkoxy methoxy, disubstituted OCH₂CH₂O and OCH₂O, optionally substituted C_1-6Alkoxycarbonyl, carbamoyl, amino, NR²R³Optionally substituted C_1-5Alkylcarboxamide, optionally substituted C_3-5Alkyl lactam group, optionally substituted C_1-6Alkylsulfonamido, optionally substituted C_3-5Alkyl internal sulfonamide, mercapto, optionally substituted C_1-5Alkylmercapto, optionally substituted C_1-5Alkylsulfonyl, optionally substituted C_3-5Cycloalkylsulfonyl, optionally substituted C_1-5Alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl;

R₇、R₈、R₉independently selected from hydrogen, Cl, F, cyano.

4. The use according to claim 1, wherein the compound is of the general formula (iv):

wherein the content of the first and second substances,

x is selected from O, S, NH;

R₁₀is independently selected from hydrogen, halogen, cyano, hydroxy, mercapto, C_1-3Carboxyl group (preferably COOH), C_1-3Carboxylic acid methyl ester group (preferably formic acid methyl ester group), C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfonamide group or alkylsulfonamide group substituted with halogen, preferably F, more preferably 1 to 5F, C_1-6Alkoxy, tetrazolyl, r ═ 1-5;

R₇、R₈、R₉independently selected from hydrogen, Cl, F, cyano.

5. Use according to claim 1, wherein the compound is of formula (v):

wherein the content of the first and second substances,

x is selected from O, S, NH;

R₁₀independently selected from C_1-6Deuterated methoxy, C_1-6Alkoxy or alkoxy substituted by halogen, preferably F, more preferably 1 to 5F; r₁₂Independently selected from cyano.

R₇、R₈、R₉Independently selected from hydrogen, Cl, F, cyano.

6. Use of a compound selected from the group consisting of:

7. a compound of formula I, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof:

in the formula:

x is selected from CH₂、O、S、NH；

A is a benzene ring with 1-5 substituents, each substituent is independently selected from halogen, cyano, hydroxy, C_1-6Alkyl or C substituted by halogen, preferably F, more preferably 1-5F_1-6Alkyl, C1-6 alkoxy or C substituted by halogen, preferably F, more preferably 1-5F_1-6An alkoxy group;

the ring A can also be selected from nitrogen-containing, sulfur-containing five-membered or six-membered saturated or unsaturated heterocyclic rings with 1-4 substituents, and each substituent is independently selected from halogen, cyano and boric acid;

the A heterocycle is selected from the following structures:

the ring B, C is not present at the same time,

the ring B is selected from aromatic benzene ring, aromatic heterocyclic ring, saturated or unsaturated five-membered six-membered ring, five-membered or six-membered saturated or unsaturated heterocyclic ring containing nitrogen, oxygen and sulfur,

the substituent R is independently selected from H, halogen, cyano, hydroxyl and C_1-6Alkyl or C containing 1-5F atoms_1-6Alkyl radical, C_1-6Alkoxy or C containing 1 to 5F atoms_1-6An alkoxy group, n-1-4,

the ring C is selected from aromatic benzene ring, aromatic heterocyclic ring, saturated or unsaturated five-membered six-membered ring, five-membered or six-membered saturated or unsaturated heterocyclic ring containing nitrogen, oxygen and sulfur,

the substituent R thereof₁Independently selected from H, halogen, cyano, hydroxy, C_1-6Alkoxy or C containing 1 to 5F atoms_1-6Alkoxy, n ═ 1-4; or

When ring C is absent, R₁Is directly connected with the main body of the compound,

at this time, R₁Is H, carbonyl, halogen, optionally substituted phenyl, cyano, hydroxy, C_1-3Carboxy (preferably COOH), optionally substituted C_1-6Alkyl, optionally substituted C_1-10Alkoxy (preferably C)_1-6Alkoxy), optionally substituted C_2-10Containing alkenesA bond, an alkoxy group of an acetylene bond, an optionally substituted benzyloxy group, an optionally substituted C_1-10Alkylformyloxy, optionally substituted C_1-3Alkoxy methoxy, disubstituted OCH₂CH₂O and OCH₂O, optionally substituted C_1-6Alkoxycarbonyl, carbamoyl, amino, optionally substituted C_1-5Alkylcarboxamide, optionally substituted C_3-5Alkyl lactam group, optionally substituted C_1-6Alkylsulfonamido, optionally substituted C_3-5Alkyl internal sulfonamide, mercapto, optionally substituted C_1-5Alkylmercapto, optionally substituted C_1-5Alkylsulfonyl, optionally substituted C_3-5Cycloalkylsulfonyl, optionally substituted C_1-5Alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl, m ═ 1-2.

8. The compound of claim 7, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein the compound is of the general formula (ii):

x is selected from CH₂、O、S、NH；

A is a benzene ring with 1-5 substituents, each substituent is independently selected from halogen, cyano, hydroxy, C_1-6Alkyl or C substituted by halogen, preferably F, more preferably 1-5F_1-6Alkyl, C1-6 alkoxy or C substituted by halogen, preferably F, more preferably 1-5F_1-6An alkoxy group;

R₄independently selected from H, hydroxy, F, cyano;

R₅is H, carbonyl, halogen, cyano, hydroxy, C_1-3Carboxy (preferably COOH), optionally substituted C_1-6Alkyl, optionally substituted C_1-10Alkoxy (preferably C)_1-6Alkoxy), optionally substituted C_2-10Alkoxy, optionally substituted, containing ethylenic, acetylenic bondsBenzyloxy, optionally substituted C_1-10Alkylformyloxy, optionally substituted C_1-3Alkoxy methoxy, disubstituted OCH₂CH₂O and OCH₂O, optionally substituted C_1-6Alkoxycarbonyl, carbamoyl, amino, NR²R³Optionally substituted C_1-5Alkylcarboxamide, optionally substituted C_3-5Alkyl lactam group, optionally substituted C_1-6Alkylsulfonamido, optionally substituted C_3-5Alkyl internal sulfonamide, mercapto, optionally substituted C_1-5Alkylmercapto, optionally substituted C_1-5Alkylsulfonyl, optionally substituted C_3-5Cycloalkylsulfonyl, optionally substituted C_1-5Alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl, optionally substituted phenyl, q ═ 1-2.

9. The compound of claim 7, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein the compound is of the general formula (iii):

wherein the content of the first and second substances,

x is selected from O, S, NH;

R₆is H, carbonyl, halogen, cyano, hydroxy, C_1-3Carboxy (preferably COOH), optionally substituted C_1-6Alkyl, optionally substituted C_1-10Alkoxy (preferably C)_1-6Alkoxy), optionally substituted C_2-10Alkoxy containing olefinic bond and acetylene bond, optionally substituted phenyl (preferably methylsulfonyl substituted phenyl), optionally substituted benzyloxy, optionally substituted C_1-10Alkylformyloxy, optionally substituted C_1-3Alkoxy methoxy, disubstituted OCH₂CH₂O and OCH₂O, optionally substituted C_1-6Alkoxycarbonyl, carbamoyl, amino, NR²R³Optionally substitutedC of (A)_1-5Alkylcarboxamide, optionally substituted C_3-5Alkyl lactam group, optionally substituted C_1-6Alkylsulfonamido, optionally substituted C_3-5Alkyl internal sulfonamide, mercapto, optionally substituted C_1-5Alkylmercapto, optionally substituted C_1-5Alkylsulfonyl, optionally substituted C_3-5Cycloalkylsulfonyl, optionally substituted C_1-5Alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl;

R₇、R₈、R₉independently selected from hydrogen, Cl, F, cyano.

10. The compound of claim 7, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein the compound is of the general formula (iv):

wherein the content of the first and second substances,

x is selected from O, S, NH;

R₁₀is independently selected from hydrogen, halogen, cyano, hydroxy, mercapto, C_1-3Carboxyl group (preferably COOH), C_1-3Carboxylic acid methyl ester group (preferably formic acid methyl ester group), C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfonamide group or alkylsulfonamide group substituted with halogen, preferably F, more preferably 1 to 5F, C_1-6Alkoxy, tetrazolyl, r ═ 1-5;

R₇、R₈、R₉independently selected from hydrogen, Cl, F, cyano.

11. The compound of claim 7, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein the compound is of the general formula (v):

wherein the content of the first and second substances,

x is selected from O, S, NH;

R₁₀independently selected from C_1-6Deuterated methoxy, C_1-6Alkoxy or alkoxy substituted by halogen, preferably F, more preferably 1 to 5F; r₁₂Independently selected from cyano.

R₇、R₈、R₉Independently selected from hydrogen, Cl, F, cyano.

12. A compound selected from the group consisting of:

Technical Field

The present invention relates to the field of pharmaceutical chemistry; in particular, the invention relates to a novel benzo-six-membered ring derivative and application thereof in preparing medicaments for treating hepatic fibrosis related diseases.

Background

Hepatic fibrosis refers to the pathophysiological process of abnormal proliferation of connective tissue in the liver caused by various pathogenic factors. It occurs in the course of liver repair and healing after various liver injuries, and long-term fibrosis progresses to cirrhosis. Investigation has shown that 70% of patients with chronic liver disease are accompanied by liver fibrosis, 25% of liver fibrosis in 10 years can further progress to cirrhosis, and 5% of them can progress to liver cancer. Among them, non-alcoholic steatohepatitis (NASH), which is the most rapidly progressing disease among non-alcoholic fatty liver diseases (NAFLD), is chronic hepatitis occurring in non-alcoholics. NASH histological changes were similar to alcoholic liver disease: steatosis, hepatocyte damage, inflammatory cell infiltration, fibrosis of different degrees, no hepatitis virus infection; the biggest difference with simple fatty liver is the appearance of hepatocyte injury and even fibrosis, which is considered to be a progressive subtype of NAFLD. The onset of NASH is often associated with obesity, mitochondrial dysfunction. In addition, NASH is closely associated with the occurrence of additional cardiovascular events, increased liver and tumor-related mortality.

During the process of liver fibrosis lesion, liver injury caused by various factors recruits various immune cells to generate various cytokines including TGF beta, fibroblasts are converted into fibroblasts under the action of the various cytokines, and activated liver astrocytes are important components of the fibroblasts. The activated liver fibroblasts can generate a plurality of extracellular matrixes to promote the healing after the injury, and at the moment, if the cause of the injury can be eliminated in time, the liver injury is healed and the normal function is recovered; if the cause of the injury cannot be removed in time, the liver is repeatedly injured, so that the unbalance of the generation and decomposition of extracellular matrix can be caused, fibrous connective tissue in the liver is abnormally deposited, the hepatic tissue presents fibrosis, and finally, the liver cirrhosis and even the liver cancer are caused. The fibrotic pathological process is complex and involves many mechanisms. Liver fibrosis has now been shown to be reversible. Intervention in either of these processes will have a positive effect on the reversal of liver fibrosis.

NASH and liver fibrosis are closely related to the overall metabolic imbalance of the liver, and many metabolic-related targets are currently being used to treat NASH and liver fibrosis. Including various enzyme proteins, cytokines and receptor-like proteins. In the process, enzyme molecular targets such as AMPK, ACC, IBAT, ASBT, Ketohexokinase, diglycol Acyltransferase and the like, transcription regulating molecular targets such as SREBP, CEBP and the like, Receptor antagonistic substances such as Sphingosine 1-Phosphate Receptor, GLP-1Receptor, FXR, Mineralocorticoid Receptor and the like are adopted.

The current search for advances in drug development targeting liver fibrosis is intense. Through the query of a Biomedtrack database, more than 70 drugs are found in the NASH accompanying the hepatic fibrosis development pipeline, more than 30 drugs enter clinical research, and more than half of the drugs are in the clinical II stage and above. The main drugs that have progressed the fastest in foreign clinical trials are GFT505, LJN452, and GS9674, respectively, all of which have completed phase II clinical studies, in which GFT505 received FDA Breakthrough Therapy approval (break through Therapy prescription) in 4 months of 2019, and many of which are in phase I/II clinical studies.

Although the international transnational medicine enterprises take hepatic fibrosis as the key research and development direction, the corresponding research and development strength is increased. However, the targeted therapy of hepatic fibrosis is still beginning in China, and the main clinical therapy mainly adopts the anti-inflammatory effect of the traditional Chinese medicine compound, so that a new targeted medicine is urgently needed.

Disclosure of Invention

The invention aims to provide a compound which has a novel structure, high efficiency and low toxicity and can be used for treating hepatic fibrosis, a pharmaceutical composition comprising the compound, a preparation method of the compound and application of the compound in preparing a medicament for preventing or treating hepatic fibrosis related diseases.

In a first aspect, the present invention provides a compound represented by general formula i, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, for use in the preparation of a medicament for preventing or treating liver fibrosis:

in the formula:

x is selected from CH₂、O、S、NH；

A is a benzene ring with 1-5 substituents, each substituent is independently selected from halogen, cyano, hydroxy, C_1-6Alkyl or C substituted by halogen, preferably F, more preferably 1-5F_1-6Alkyl, C1-6 alkoxy or C substituted by halogen, preferably F, more preferably 1-5F_1-6An alkoxy group;

the ring A can also be selected from nitrogen-containing, sulfur-containing five-membered or six-membered saturated or unsaturated heterocyclic rings with 1-4 substituents, and each substituent is independently selected from halogen, cyano and boric acid;

the A heterocycle is selected from the following structures:

the ring B, C is not present at the same time,

the ring B is selected from aromatic benzene ring, aromatic heterocyclic ring, saturated or unsaturated five-membered six-membered ring, five-membered or six-membered saturated or unsaturated heterocyclic ring containing nitrogen, oxygen and sulfur,

the substituent R is independently selected from H, halogen, cyano, hydroxyl and C_1-6Alkyl or C containing 1-5F atoms_1-6Alkyl radical, C_1-6Alkoxy or C containing 1 to 5F atoms_1-6An alkoxy group, n-1-4,

the ring C is selected from aromatic benzene ring, aromatic heterocyclic ring, saturated or unsaturated five-membered six-membered ring, five-membered or six-membered saturated or unsaturated heterocyclic ring containing nitrogen, oxygen and sulfur,

the substituent R thereof₁Independently selected from H, halogen, optionally substituted C_1-6Alkyl, cyano, optionally substituted amino, carbonyl, hydroxy, C_1-3Carboxyl group (preferably COOH), C_1-6Alkoxy or C containing 1 to 5F atoms_1-6Alkoxy radical, C_1-6Deuterated alkoxy or C containing 1-5F atoms_1-6Deuterated alkoxy, n-1-4; or

When ring C is absent, R₁Is directly connected with the main body of the compound,

at this time, R₁Is H, carbonyl, halogen, optionally substituted phenyl, cyano, optionally substituted amino, optionally substituted 5-6 membered heterocyclyl containing 1-2 heteroatoms selected from N or O, hydroxy, C_1-3Carboxyl group (preferably COOH), C_1-3Carboxylate group (preferably methyl formate group), optionally substituted C_1-6Alkyl, optionally substituted C_1-10Alkoxy (preferably C)_1-6Alkoxy), optionally substituted C_2-10Alkoxy containing olefinic bond and acetylene bond, optionally substituted benzyloxy and optionally substituted C_1-10Alkylformyloxy, optionally substituted C_1-3Alkoxy methoxy, disubstituted OCH₂CH₂O and OCH₂O, optionally substituted C_1-6Alkoxycarbonyl, carbamoyl, amino, optionally substituted C_1-5Alkylcarboxamide, optionally substituted C_3-5Alkyl lactam group, optionally substituted C_1-6Alkylsulfonamido, optionally substituted C_3-5Alkyl internal sulfonamide, mercapto, optionally substituted C_1-5Alkylmercapto, optionally substituted C_1-5Alkylsulfonyl, optionally substituted C_3-5Cycloalkylsulfonyl, optionally substituted C_1-5Alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl, m ═ 1-2.

In a specific embodiment, the compound is a compound of formula (ii):

x is selected from CH₂、O、S、NH；

A is a benzene ring with 1-5 substituents, each substituent is independently selected from halogen, cyano, hydroxy, C_1-6Alkyl or C substituted by halogen, preferably F, more preferably 1-5F_1-6Alkyl, C1-6 alkoxy or C substituted by halogen, preferably F, more preferably 1-5F_1-6An alkoxy group;

R₄independently selected from H, hydroxy, F, cyano;

R₅is H, carbonyl, halogen, cyano, hydroxy, C_1-3Carboxy (preferably COOH), optionally substituted C_1-6Alkyl, optionally substituted C_1-10Alkoxy (preferably C)_1-6Alkoxy), optionally substituted C_2-10Alkoxy containing olefinic bond and acetylene bond, optionally substituted benzyloxy and optionally substituted C_1-10Alkylformyloxy, optionally substituted C_1-3Alkoxy methoxy, disubstituted OCH₂CH₂O and OCH₂O, optionally substituted C_1-6Alkoxycarbonyl, carbamoyl, amino, NR²R³Optionally substituted C_1-5Alkylcarboxamide, optionally substituted C_3-5Alkyl lactam group, optionally substituted C_1-6Alkylsulfonamido, optionally substituted C_3-5Alkyl internal sulfonamide, mercapto, optionally substituted C_1-5Alkylmercapto, optionally substituted C_1-5Alkylsulfonyl, optionally substituted C_3-5Cycloalkylsulfonyl, optionally substituted C_1-5Alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl, optionally substituted phenyl, q ═ 1-2.

In a specific embodiment, the compound is a compound of formula (iii):

wherein the content of the first and second substances,

x is selected from O, S, NH;

R₆is H, carbonyl, halogen, cyano, hydroxy, C_1-3Carboxy (preferably COOH), optionally substituted C_1-6Alkyl, optionally substituted C_1-10Alkoxy (preferably C)_1-6Alkoxy), optionally substituted C_2-10Alkoxy containing olefinic bond and acetylene bond, optionally substituted phenyl (preferably methylsulfonyl substituted phenyl), optionally substituted benzyloxy, optionally substituted C_1-10Alkylformyloxy, optionally substituted C_1-3Alkoxy methoxy, disubstituted OCH₂CH₂O and OCH₂O, optionally substituted C_1-6Alkoxycarbonyl, carbamoyl, amino, NR²R³Optionally substituted C_1-5Alkylcarboxamide, optionally substituted C_3-5Alkyl lactam group, optionally substituted C_1-6Alkylsulfonamido, optionally substituted C_3-5Alkyl internal sulfonamide, mercapto, optionally substituted C_1-5Alkylmercapto, optionally substituted C_1-5Alkylsulfonyl, optionally substituted C_3-5Cycloalkylsulfonyl, optionally substituted C_1-5Alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl;

R₇、R₈、R₉independently selected from hydrogen, Cl, F, cyano.

In a specific embodiment, the compound is a compound of formula (iv):

wherein the content of the first and second substances,

x is selected from O, S, NH;

R₁₀is independently selected from hydrogen, halogen, cyano, hydroxy, mercapto, C_1-3Carboxyl group (preferably COOH), C_1-3Carboxylic acid methyl ester group (preferably formic acid methyl ester group)、C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfonamide group or alkylsulfonamide group substituted with halogen, preferably F, more preferably 1 to 5F, C_1-6Alkoxy, tetrazolyl, r ═ 1-5;

R₇、R₈、R₉independently selected from hydrogen, Cl, F, cyano.

In a specific embodiment, the compound is a compound of formula (v):

wherein the content of the first and second substances,

x is selected from O, S, NH;

R₁₀independently selected from C_1-6Deuterated methoxy, C_1-6Alkoxy or alkoxy substituted by halogen, preferably F, more preferably 1 to 5F; r₁₂Independently selected from cyano.

R₇、R₈、R₉Independently selected from hydrogen, Cl, F, cyano.

In a second aspect, the present invention provides a use of a compound selected from the group consisting of:

in a preferred embodiment, the medicament is in a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, powders.

In a third aspect, the present invention provides a compound of formula i, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof:

in the formula:

x is selected from CH₂、O、S、NH；

A is a benzene ring with 1-5 substituents, each substituent is independently selected from halogen, cyano, hydroxy, C_1-6Alkyl or C substituted by halogen, preferably F, more preferably 1-5F_1-6Alkyl, C1-6 alkoxy or C substituted by halogen, preferably F, more preferably 1-5F_1-6An alkoxy group;

the ring A can also be selected from nitrogen-containing, sulfur-containing five-membered or six-membered saturated or unsaturated heterocyclic rings with 1-4 substituents, and each substituent is independently selected from halogen, cyano and boric acid;

the A heterocycle is selected from the following structures:

the ring B, C is not present at the same time,

the ring B is selected from aromatic benzene ring, aromatic heterocyclic ring, saturated or unsaturated five-membered six-membered ring, five-membered or six-membered saturated or unsaturated heterocyclic ring containing nitrogen, oxygen and sulfur,

the substituent R is independently selected from H, halogen, cyano, hydroxyl and C_1-6Alkyl or C containing 1-5F atoms_1-6Alkyl radical, C_1-6Alkoxy or C containing 1 to 5F atoms_1-6An alkoxy group, n-1-4,

the ring C is selected from aromatic benzene ring, aromatic heterocyclic ring, saturated or unsaturated five-membered six-membered ring, five-membered or six-membered saturated or unsaturated heterocyclic ring containing nitrogen, oxygen and sulfur,

the substituent R thereof₁Independently selected from H, halogen, cyano, hydroxy, C_1-6Alkoxy or C containing 1 to 5F atoms_1-6Alkoxy, n ═ 1-4; or

When ring C is absent, R₁Is directly connected with the main body of the compound,

at this time, R₁Is H, carbonyl, halogen, optionally substituted phenyl, cyano, hydroxy, C_1-3Carboxy (preferably COOH), optionally substituted C_1-6Alkyl, optionally substituted C_1-10Alkoxy (preferably C)_1-6Alkoxy), optionally substituted C_2-10Alkoxy containing olefinic bond and acetylene bond, optionally substituted benzyloxy and optionally substituted C_1-10Alkylformyloxy, optionally substituted C_1-3Alkoxy methoxy, disubstituted OCH₂CH₂O and OCH₂O, optionally substituted C_1-6Alkoxycarbonyl, carbamoyl, amino, optionally substituted C_1-5Alkylcarboxamide, optionally substituted C_3-5Alkyl lactam group, optionally substituted C_1-6Alkylsulfonamido, optionally substituted C_3-5Alkyl internal sulfonamide, mercapto, optionally substituted C_1-5Alkylmercapto, optionally substituted C_1-5Alkylsulfonyl, optionally substituted C_3-5Cycloalkylsulfonyl, optionally substituted C_1-5Alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl, m ═ 1-2.

In a specific embodiment, the compound is a compound of formula (ii):

x is selected from CH₂、O、S、NH；

A is a benzene ring with 1-5 substituents, each substituent is independently selected from halogen, cyano, hydroxy, C_1-6Alkyl or C substituted by halogen, preferably F, more preferably 1-5F_1-6Alkyl, C1-6 alkoxy or C substituted by halogen, preferably F, more preferably 1-5F_1-6An alkoxy group;

R₄independently selected from H, hydroxy, F, cyano;

R₅is H, carbonyl, halogen, cyano, hydroxy, C_1-3Carboxy (preferably COOH), optionally substituted C_1-6Alkyl, optionally substituted C_1-10Alkoxy (preferably C)_1-6Alkoxy), optionally substituted C_2-10Alkoxy containing olefinic bond and acetylene bond, optionally substituted benzyloxy and optionally substituted C_1-10Alkylformyloxy, optionally substituted C_1-3Alkoxy methoxy, disubstituted OCH₂CH₂O and OCH₂O, optionally substituted C_1-6Alkoxycarbonyl, carbamoyl, amino, NR²R³Optionally substituted C_1-5Alkylcarboxamide, optionally substituted C_3-5Alkyl lactam group, optionally substituted C_1-6Alkylsulfonamido, optionally substituted C_3-5Alkyl internal sulfonamide, mercapto, optionally substituted C_1-5Alkylmercapto, optionally substituted C_1-5Alkylsulfonyl, optionally substituted C_3-5Cycloalkylsulfonyl, optionally substituted C_1-5Alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl, optionally substituted phenyl, q ═ 1-2.

In a specific embodiment, the compound is a compound of formula (iii):

wherein the content of the first and second substances,

x is selected from O, S, NH;

R₆is H, carbonyl, halogen, cyano, hydroxy, C_1-3Carboxy (preferably COOH), optionally substituted C_1-6Alkyl, optionally substituted C_1-10Alkoxy (preferably C)_1-6Alkoxy), optionally substituted C_2-10Alkoxy containing olefinic bond and acetylene bond, optionally substituted phenyl (preferably methylsulfonyl substituted phenyl), optionally substituted benzyloxy, optionally substituted C_1-10Alkylformyloxy, optionally substituted C_1-3Alkoxy methoxy, disubstituted OCH₂CH₂O and OCH₂O, optionally substituted C_1-6Alkoxycarbonyl, carbamoyl, amino, NR²R³Optionally substituted C_1-5Alkylcarboxamide, optionally substituted C_3-5Alkyl lactam group, optionally substituted C_1-6Alkylsulfonamido, optionally substituted C_3-5Alkyl internal sulfonamide, mercapto, optionally substituted C_1-5Alkylmercapto, optionally substituted C_1-5Alkylsulfonyl, optionally substituted C_3-5Cycloalkylsulfonyl, optionally substituted C_1-5Alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl;

R₇、R₈、R₉independently selected from hydrogen, Cl, F, cyano.

In a specific embodiment, the compound is a compound of formula (iv):

wherein the content of the first and second substances,

x is selected from O, S, NH;

R₁₀is independently selected from hydrogen, halogen, cyano, hydroxy, mercapto, C_1-3Carboxyl group (preferably COOH), C_1-3Carboxylic acid methyl ester group (preferably formic acid methyl ester group)、C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfonamide group or alkylsulfonamide group substituted with halogen, preferably F, more preferably 1 to 5F, C_1-6Alkoxy, tetrazolyl, r ═ 1-5;

R₇、R₈、R₉independently selected from hydrogen, Cl, F, cyano.

In a specific embodiment, the compound is a compound of formula (v):

wherein the content of the first and second substances,

x is selected from O, S, NH;

R₁₀independently selected from C_1-6Deuterated methoxy, C_1-6Alkoxy or alkoxy substituted by halogen, preferably F, more preferably 1 to 5F; r₁₂Independently selected from cyano.

R₇、R₈、R₉Independently selected from hydrogen, Cl, F, cyano.

In particular embodiments, the compound is a compound selected from the group consisting of:

in a fourth aspect, the present invention provides a pharmaceutical composition comprising a compound of the third aspect.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Detailed Description

The present inventors have made extensive and intensive studies to find out a group of benzo-six-membered ring derivatives having a novel structure, which are capable of inhibiting hepatic fibrosis, and have completed the present invention.

Definition of terms

Some of the groups referred to herein are defined as follows:

as used herein, "alkyl" refers to a saturated branched or straight chain or cycloalkyl group having a carbon chain length of 1 to 10 carbon atoms, with preferred alkyl groups including those varying in length from 1 to 5, 1 to 2, 1 to 6, 1 to 4, 3 to 8 carbon atoms. Examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, heptyl and the like. The alkyl group may be substituted with 1 or more substituents, for example, with halogen or haloalkyl. For example, the alkyl group may be an alkyl group substituted with 1 to 4 fluorine atoms, or the alkyl group may be an alkyl group substituted with a fluoroalkyl group.

As used herein, "alkenyl" generally refers to a monovalent hydrocarbon group having at least one double bond, generally containing 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, and may be straight or branched. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.

Herein, "ester group" generally means a carboxylic acid derivative having at least one ester group, generally containing 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms, and may be straight or branched. Examples of ester groups include, but are not limited to, methyl formate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, and the like.

As used herein, "hydroxyl" refers to a branched or straight chain alcohol having a carbon chain length of 1 to 10 carbon atoms, generally 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and may be straight or branched. Examples of ester hydroxyls include, but are not limited to, 1-hydroxy n-butyl, 1-hydroxyisobutyl, and the like.

As used herein, "amido" refers to a group of the formula "-R '-NH-C (O) -R", wherein R' may be selected from hydrogen or alkyl, and R may be selected from alkyl, alkenyl, alkynyl, or NR_cR_dSubstituted alkyl, by NR_cR_dSubstituted chainAlkenyl and NR_cR_dSubstituted alkynyl, alkyl substituted by halogen, alkenyl substituted by cyano, wherein R_cAnd R_dCan be selected from alkyl and alkenyl.

As used herein, "aryl" means a monocyclic, bicyclic or tricyclic aromatic group having 6 to 14 carbon atoms, and includes phenyl, naphthyl, phenanthryl, anthryl, indenyl, fluorenyl, tetralinyl, indanyl and the like. Aryl groups may be optionally substituted with 1-5 (e.g., 1, 2,3,4, or 5) substituents selected from: halogen, C_1-4Aldehyde group, C_1-6Alkyl, cyano, nitro, amino, amido, hydroxy, hydroxymethyl, halogen-substituted alkyl (e.g. trifluoromethyl), halogen-substituted alkoxy (e.g. trifluoromethoxy), carboxy, C_1-4Alkoxy, ethoxycarbonyl, N (CH)₃) And C_1-4Acyl, etc., heterocyclic or heteroaryl, etc.

As used herein, "heterocyclyl" includes, but is not limited to, 5-or 6-membered heterocyclic groups containing 1-3 heteroatoms selected from O, S or N, including, but not limited to, furyl, thienyl, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, piperidinyl, morpholinyl, and the like.

As used herein, "arylheterocyclyl" means a ring system containing 5 to 14 ring atoms and having 6, 10, or 14 electrons in common in the ring system. And the ring atoms contained are carbon atoms and 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur. Useful aryl heterocyclic groups include piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, including but not limited to pyrimidinyl and the like. The aryl heterocyclic group may be optionally substituted with 1 to 5 (e.g., 1, 2,3,4, or 5) substituents selected from the group consisting of: halogen, C_1-4Aldehyde group, C_1-6Straight or branched chain alkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, halogen-substituted alkyl (e.g. trifluoromethyl), halogen-substituted alkoxy (e.g. trifluoromethoxy), carboxy, C_1-4Alkoxy, ethoxycarbonyl, N (CH)₃) And C_1-4An acyl group.

Herein, "alkoxy" refers to an oxy group substituted with an alkyl group. Preferred alkoxy groups are alkoxy groups of 1 to 6 carbon atoms in length, more preferably 1 to 3 carbon atoms in length. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, propoxy, and the like. Alkoxy groups may be substituted with 1 or more substituents, for example with halogen or haloalkyl. For example, the alkoxy group may be an alkyl group substituted with 1 to 4 fluorine atoms, or the alkyl group may be an alkyl group substituted with a fluoroalkyl group.

Herein, "halogen" means fluorine, chlorine, bromine or iodine.

Herein, "optionally substituted" means that the substituent group it modifies may be optionally substituted with 1 to 5 (e.g., 1, 2,3,4, or 5) substituents selected from: halogen, C_1-4Aldehyde group, C_1-6Straight or branched chain alkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, halogen-substituted alkyl (e.g. trifluoromethyl), halogen-substituted alkoxy (e.g. trifluoromethoxy), carboxy, C_1-4Alkoxy, ethoxycarbonyl, N (CH)₃) And C_1-4An acyl group.

Compounds of the invention

The compounds of the invention possess therapeutic activity in the treatment of liver fibrosis. Specifically, the invention provides a compound shown as a general formula I, or a pharmaceutically acceptable salt or a prodrug thereof, or an optically active isomer or solvate thereof:

the substituents in formula I are each as described above.

In a preferred embodiment, the present invention provides a compound represented by the general formula (ii), or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof:

the substituents in formula II are each as described above.

In a preferred embodiment, the present invention provides a compound represented by the general formula (iii), or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof:

the substituents in formula III are each as described above.

In a preferred embodiment, the present invention provides a compound represented by the general formula (iv), or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof:

the substituents in formula IV are each as described above.

In a preferred embodiment, the present invention provides a compound represented by the general formula (v), or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof:

the substituents in formula V are each as described above.

In a specific embodiment, the present invention provides a compound selected from the group consisting of:

based on the compound of the invention, the invention provides a pharmaceutical composition which contains a therapeutically effective amount of the compound of the invention or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

Examples of pharmaceutically acceptable salts of the compounds of the present invention include, but are not limited to, inorganic and organic acid salts, such as hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate salts; and inorganic and organic base salts formed with bases such as sodium hydroxy, TRIS (hydroxymethyl) aminomethane (TRIS, tromethamine) and N-methylglucamine.

The pharmaceutical compositions of the present invention may be formulated in a form suitable for various routes of administration, including but not limited to, administration by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, nasal or topical routes for the treatment of tumors and other diseases. The amount administered is an amount effective to ameliorate or eliminate one or more symptoms. For the treatment of a particular disease, an effective amount is an amount sufficient to ameliorate or in some way reduce the symptoms associated with the disease. Such amounts may be administered as a single dose or may be administered according to an effective treatment regimen. The amount administered may be sufficient to cure the disease, but is generally administered to ameliorate the symptoms of the disease. Repeated administration is generally required to achieve the desired improvement in symptoms. The dosage of the drug will depend on the age, health and weight of the patient, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.

The pharmaceutical preparation of the present invention can be administered to any mammals as long as they can obtain the therapeutic effects of the compound of the present invention. Of these mammals, the most important is human.

The compound or the pharmaceutical composition thereof can be used for treating and preventing diseases related to hepatic fibrosis.

The pharmaceutical preparations of the present invention can be manufactured in a known manner. For example, by conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. In the manufacture of oral formulations, solid excipients and active compounds may be combined, optionally grinding the mixture. If desired or necessary after addition of suitable amounts of auxiliaries, the granulate mixture is processed to give tablets or dragee cores.

Suitable adjuvants are, in particular, fillers, for example sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate; and binders, such as starch pastes, including corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone. If desired, disintegrating agents such as the starches mentioned above, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate may be added. Adjuvants are, in particular, flow regulators and lubricants, for example silica, talc, stearates, such as calcium magnesium stearate, stearic acid or polyethylene glycol. If desired, a suitable coating resistant to gastric juices can be provided to the tablet core. For this purpose, concentrated saccharide solutions can be used. This solution may contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. For the preparation of coatings resistant to gastric juices, suitable cellulose solutions can be used, for example cellulose acetate phthalate or hydroxypropylmethyl cellulose phthalate. Dyes or pigments may be added to the coating of the tablet or lozenge core. For example, for identifying or for characterizing combinations of active ingredient doses.

The method of administration includes, but is not limited to, various methods of administration known in the art, and may be determined based on the actual condition of the patient. These methods include, but are not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, nasal, or topical routes of administration.

The invention has the advantages that:

1. the compound provided by the invention is a structure brand-new anti-hepatic fibrosis structure;

2. the compound provided by the invention has excellent inhibitory activity on hepatic fibrosis;

3. the compound provided by the invention lays a foundation for developing a medicine capable of inhibiting targeted hepatic fibrosis, has great industrialization and commercialization prospects and market value, and has remarkable economic benefit.

The technical solution of the present invention will be further described with reference to the following specific embodiments, but the following embodiments are not intended to limit the present invention, and all of the various application methods adopted according to the principles and technical means of the present invention belong to the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.

Materials and methods

Synthetic route for 2- (2,4, 5-trifluorophenyl) -3, 4-dihydro-2H-benzo [ H ] chroman-3-amine derivatives

Reagents and conditions: (a)1, 1-dichlordimethyl Ether, AgOTf, DCM, -78 ℃ to r.t., N₂，55.3％；(b)1,1-Dichlorodimethyl Ether,TiCl₄,0℃to r.t.,22.5％-79.0％；(c)AlCl₃,DCM,0℃to 40℃,40.5％-66.5％；(d)L-Pipecolinic,Toluene,120℃,N₂,10.2％-42.5％；(e)1)NaBH₄,THF/CH₃OH,r.t.；2)DIPEA,EtOH,r.t.；(f)Zn,HCl,EtOH,r.t.,10.8％-25.9％；(g)CH₃SO₂Na,L-Proline,NaOH,CuI,DMSO,130℃,N₂,88.8％；(h)CH₃OH,H₂SO₄,70℃,95.0％；(i)CH₃SO₂Cl,pyridine,DCM,0℃to r.t.,45.0％；(j)Tf₂O,Et₃N,DCM,-78℃to r.t.,68.1％；(k)(1)(3,6-Dihydro-2H-pyran-4-yl)-boronic acid pinacol ester,Pd(PPh₃)₄,Cs₂CO₃,DMF/H₂O,90℃,N₂；(2)Pd/C,H₂,MeOH,r.t.,73.3％for two steps；(l)(3-(methylsulfonyl)phenyl)boronic acid,Pd(PPh₃)₄,Cs₂CO₃,DMF/H₂O,95℃,N₂,73.0％；(m)morpholine,Pd₂(dba)₃,BINAP；t-BuOK,Toluene,100℃,N₂,49.0％；(n)NaOH,MeOH/H₂O,50℃,50.0％；(o)POCl₃,DMF,0℃to r.t.,69.6％.

Synthetic route to 2- (2,4, 5-trifluorophenyl) -6-phenyl-3, 4-dihydro-2H-chroman-3-amine derivatives

Reagents and conditions: (a) cs₂CO₃,PdCl₂(dppf)₂,DMF/H₂O,100℃,N₂,31.0-60.0％；(b)L-Pipecolinic,Toluene,120℃,N₂,23.0％-70.0％；(c)1)NaBH₄,THF/CH₃OH,r.t.；2)DIPEA,EtOH,r.t.；(d)Zn,HCl,EtOH,r.t.,10.0％-69.0％.

Synthetic route of 2- (2,4, 5-trifluorophenyl) -3, 4-dihydro-2H-benzo [ f ] chroman-3-amine derivative

Reagents and conditions: (a) BBr₃,DCM,-78℃to r.t.,77.6％；(b)CD₃I or CH₃CH₂I,K₂CO₃,MeCN,40℃～50℃,45.5％；(c)Zn,HCl,EtOH,r.t.,30.5％；(d)Optical resolution.

Synthetic route for 2-phenyl-3, 4-dihydro-2H-benzo [ f ] chroman-3-amines

Reagents and conditions: (a)1,1-Dichlorodimethyl Ether, TiCl₄,0℃to r.t.,74.5％；(b)AlCl₃,DCM,0℃to 40℃,70.0％；(c)L-Pipecolinic,Toluene,120℃,N₂,25％；(d)1)NaBH₄,THF/CH₃OH,r.t.；2)DIPEA,EtOH,r.t.,23％；(e)Zn,HCl,EtOH,r.t.,13％；(f)Optical resolution.

Example 1 specific Synthesis method

Synthesis of 1-methoxy-naphthalene derivatives (8c, 8e, 8g-j)

1-methoxy-4-methanesulfonylnaphthalene (8c)

1-iodo-4-methoxynaphthol (100.00mg,0.35mmol), sodium methylsulfinate (50.00mg, 0.42mmol), cuprous iodide (7.00mg,0.10mmol), L-proline (10.00mg,0.07mmol), sodium hydroxide (2.80mg,0.07mmol), anhydrous DMSO (5mL) were added to a 25mL three-necked reaction flask, stirred at 130 ℃ under nitrogen, and the progress of the reaction was monitored by TLC. After the reaction, cooling to room temperature, adding 10mL of water into the reaction system, extracting with ethyl acetate (10 mL. times.3), washing the organic phase with brine, and adding anhydrous Na₂SO₄Drying, purifying and separating by silica gel column chromatography (PE: EA is 10:1) to obtain 73.01mg of light yellow product with the yield of 87.9%.¹H NMR(400MHz,CDCl₃)δ8.60(dd,J＝40.4,26.8Hz,1H),8.39(d,J＝8.4Hz,1H),8.28(d,J＝8.3Hz,1H),7.71(t,J＝7.7Hz,1H),7.59(t,J＝7.6Hz,1H),6.87(d,J＝8.4Hz,1H),4.07(s,3H),3.18(s,3H).LC-MS(ESI)m/z237.05[M+H]⁺.

4-methoxy-1-naphthoic acid methyl ester (8e)

Adding 4-methoxy-1-naphthoic acid (1.00g, 4.95mmol) into a single 50mL two-mouth reaction bottle, adding 10mL methanol for dissolving, stirring in ice bath, slowly dropwise adding 1mL concentrated sulfuric acid, and after dropwise adding, heating to 70 ℃ and refluxing for 4 hours. Stopping stirring when the raw materials are completely converted, cooling the reaction solution to room temperature, drying the reaction solution under reduced pressure, adding 10mL of water, extracting with ethyl acetate (3X 10mL), and extracting the organic phase with saturated NaHCO₃Washing with brine respectively, and removing anhydrous Na₂SO₄Drying and purifying by silica gel column chromatography (PE: EA: 20:1) to obtain 1.01g of white oily product with the yield of 95.3%.¹H NMR(400MHz,CDCl₃)δ9.03(d,J＝8.7Hz,1H),8.31(t,J＝11.3Hz,1H),8.24(d,J＝8.3Hz,1H),7.63(t,J＝8.4Hz,1H),7.52(t,J＝8.1Hz,1H),6.81(d,J＝8.3Hz,1H),4.06(s,3H),3.97(s,3H).LC-MS(ESI)m/z 271.01[M+H]⁺.

N- (4-Methoxynaphthalene 1-yl) methanesulfonamide (8g)

4-Methoxynaphthalene-1 amine (1.57g, 9.06mmol) and pyridine (0.80mL, 9.97mmol) were placed in a 100mL reaction flask, methanesulfonyl chloride (1.14mL,9.06mmol) was added dropwise under ice bath, the temperature was controlled below 5 ℃ and the reaction was monitored by TLC. After the reaction, 3N NaOH solution was added, followed by extraction with dichloromethane, and the organic phase was washed with saturated brine and anhydrous Na₂SO₄Drying and finally purifying by silica gel column chromatography (PE: EA ═ 8: 1). 1.02g of light yellow product is obtained, the yield is 44.7%.¹H NMR(400MHz,DMSO-d6):δ9.47(s,1H),8.20(dd,J＝13.8,4.9Hz,2H),7.72-7.57(m,1H),7.56-7.50(m,1H),7.45(d,J＝8.2Hz,1H),6.98(d,J＝8.3Hz,1H),3.99(s,3H),2.98(s,3H).LC-MS(ESI)m/z 250.06[M-H]^-.

1,1, 1-trifluoro-N- (4-methoxynaphthalen-1-yl) methanesulfonamide (8h)

4-Methoxynaphthalene-1 amine (1.00g, 5.78mmol), triethylamine (1.78mL, 11.20mmol) and dichloromethane (15mL) were added dropwise to a 100mL reaction flask at-78 deg.C, trifluoromethanesulfonic anhydride (0.97mL, 5.78mmol) was added dropwise, the flask was then allowed to warm to room temperature and stirred, and the reaction was monitored by TLC. After the raw materials are completely converted, adding water into a reaction bottle for quenching, extracting with dichloromethane for three times, washing an organic phase with a saturated NaCl solution, and removing anhydrous Na₂SO₄Drying and purifying by silica gel column chromatography (PE: EA: 10:1) to obtain 1.20g of product with a yield of 68.2%.¹H NMR(400MHz,DMSO-d6)δ11.79(s,1H),8.23(d,J＝8.3Hz,1H),8.04(d,J＝8.4Hz,1H),7.71(t,J＝7.2Hz,1H),7.60(t,J＝7.3Hz,1H),7.46(d,J＝8.3Hz,1H),7.02(d,J＝8.3Hz,1H),4.01(s,3H).LC-MS(ESI)m/z 304.03[M-H]^-.

4- (4-Methoxynaphthalen-1-yl) tetrahydro-2H-pyran (8i)

1-bromo-4-methoxynaphthol (100.00mg,0.42mmol), 2- (3, 6-dihydro-2H-pyran-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane (79.60mg,0.50mmol), tetrakistriphenylphosphine palladium (97.00mg,0.08mmol), cesium carbonate (410.00mg,1.26mmol), DMF 2mL, water 0.5mL, nitrogen substitution three times, stirring at 90 ℃ and TLC monitoring. After the reaction was completed, when the system was cooled to room temperature, extraction was performed with ethyl acetate (10mL × 3), the organic phase was washed with saturated NaCl, and dried with anhydrous sodium sulfate to obtain a crude product to be reduced in the next step.

And (2) taking the crude product 4- (4-methoxynaphthalene-1-yl) -3, 6-dihydro-2H-pyran in the last step, adding Pd/C (10%) and a proper amount of methanol to dissolve, stirring at normal temperature under the condition of system hydrogen (1 atmosphere), and monitoring by TLC. After the reaction is finished, adding water to quenchThe reaction was quenched, extracted with ethyl acetate (10mL × 3), the organic phase was washed with brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE: EA ═ 10:1) to give 70.00mg of product, with a total yield of 51.1% in both steps.¹H NMR(400MHz,CDCl₃)δ8.33(dd,J＝8.3,1.1Hz,1H),8.04(d,J＝8.4Hz,1H),7.60-7.41(m,2H),7.27(d,J＝8.0Hz,1H),6.77(d,J＝8.0Hz,1H),4.20-4.06(m,2H),3.96(s,3H),3.75-3.59(m,2H),3.56-3.37(m,1H),2.02-1.79(m,4H).LC-MS(ESI)m/z 243.13[M+H]⁺.

1-methoxy-4- (3- (methylsulfonyl) phenyl) naphthalene (8j)

1-bromo-4-methoxynaphthalene (0.20g, 0.84mmol), (3- (methylsulfonyl) phenyl) phenylboronic acid (0.20g, 1.00mmol), cesium carbonate (274.00mg, 2.52mmol), palladium tetrakistriphenylphosphine (48.50mg,0.05mmol), anhydrous DMF 10mL, water 3mL in a 50mL reaction flask, nitrogen blanket, warming to 95 ℃ with stirring thoroughly, and monitoring by TLC. After the starting material had been substantially completely converted, it was extracted three times with water and ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and purified by column chromatography on silica gel (PE: EA ═ 8:1) to give 0.19g of product in 73.1% yield.¹H NMR(400MHz,CDCl₃)δ8.36(d,J＝8.2Hz,1H),8.06(s,1H),7.96(t,J＝9.7Hz,1H),7.82-7.71(m,2H),7.66(t,J＝7.7Hz,1H),7.57-7.41(m,2H),7.35(t,J＝8.6Hz,1H),6.88(d,J＝7.9Hz,1H),4.05(s,3H),3.11(s,3H).LC-MS(ESI)m/z 313.08[M+H]⁺

Synthesis of 1-methoxy-2-naphthaldehyde derivative (9a-h)

4-bromo-1-methoxy-2-naphthaldehyde (9a)

1, 1-Dichloromethyl Ether (0.73g, 6.35mmol), TiCl₄(2.00g,10.60mmol)，CH₂Cl₂Adding 5mL of the mixture into a 100mL three-mouth reaction bottle, stirring for 16min under an ice bath condition, and dropwise adding the mixture1-bromo 4-methoxynaphthalene (1.00g,4.24mmol) in dichloromethane (5mL) was stirred at ambient temperature and monitored by TLC. After the reaction is finished, 1mol/L hydrochloric acid solution is added, and CH is used₂Cl₂Extraction was carried out three times, and the organic phase was washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, evaporated in vacuo, and purified by silica gel column chromatography (PE: EA: 5:1) to obtain 500.00mg of a white powder with a yield of 22.4%.¹H NMR(400MHz,CDCl₃)δ10.26(s,1H),9.22(d,J＝8.5Hz,1H),8.22(d,J＝8.4Hz,1H),8.11(s,1H),7.78-7.69(m,1H),7.66(dd,J＝11.2,4.1Hz,1H),4.09(s,3H).LC-MS(ESI)m/z 266.11[M+H]⁺.

1-methoxy-4-methanesulfonyl-2-naphthaldehyde (9b)

A50 mL three-necked reaction flask was charged with the compound 1-methoxy-4- (methylsulfonyl) naphthalene (0.50g, 2.12mmol), silver trifluoromethanesulfonate (1.63g, 6.36mmol), and 10mL of dichloromethane, and the reaction system was stirred at-78 ℃ with nitrogen substitution three times. 1, 1-dichloromethyl methyl ether (0.73g, 6.36mmol) was added dropwise to the reaction solution, and after ten minutes, the mixture was transferred to room temperature and stirred, followed by TLC monitoring. After the reaction was complete, saturated NaHCO was slowly added under ice bath₃Filtering the solution under reduced pressure, extracting the filtrate with ethyl acetate (10mL) for three times, washing the organic phase with brine, and collecting the filtrate with anhydrous Na₂SO₄Drying and purification with 200-mesh 300-mesh silica gel column (PE: EA: 5:1) gave 0.31g of white solid in 55.3% yield.¹H NMR(400MHz,CDCl₃)δ10.57(s,1H),8.79(d,J＝8.6Hz,1H),8.75(s,1H),8.43(d,J＝8.4Hz,1H),7.96-7.83(m,1H),7.76(t,J＝7.7Hz,1H),4.24(s,3H),3.22(s,3H).LC-MS(ESI)m/z 265.04[M+H]⁺.

3-formyl-4-methoxy-1-naphthoic acid methyl ester (9c)

Synthesis procedure reference 9a gave 2.28g of a pale yellow solid in yield70.7％。¹H NMR(400MHz,CDCl₃)δ10.58(s,1H),9.02(d,J＝8.6Hz,1H),8.61(d,J＝4.0Hz,1H),8.61(s,1H),7.87-7.67(m,1H),7.65-7.58(m,1H),4.19(s,3H),4.00(s,3H).LC-MS(ESI)m/z 245.07[M+H]⁺.

N- (3-formyl-4-methoxynaphthalen-1-yl) methanesulfonamide (9d)

Synthesis procedure with reference to 9a, 1.50g of white powder was obtained in 58.1% yield.¹H NMR(400MHz,DMSO-d6)δ10.48(s,1H),9.81(s,1H),8.37-8.27(m,2H),7.87-7.78(m,1H),7.76-7.70(m,2H),4.14(s,3H),3.03(s,3H).LC-MS(ESI)m/z 278.05[M-H]^-.

1,1, 1-trifluoro-N- (3-formyl-4-methoxynaphthalenecarboxaldehyde-1-yl) methanesulfonamide (9e)

Synthesis procedure reference 9a gave 1.31g of a pale yellow solid in 33.1% yield.¹H NMR(400MHz,CDCl3)δ10.43(s,1H),8.23(d,J＝8.3Hz,1H),8.06(t,J＝7.9Hz,1H),7.84(s,1H),7.80-7.68(m,1H),7.65-7.56(m,1H),4.09(s,3H).LC-MS(ESI)m/z 332.02[M-H]^-.

1-methoxy-4- (tetrahydro-2H-pyran-4-yl) -2-naphthaldehyde (9f)

Synthesis procedure reference 9a gave 3.01g of a pale yellow solid in 79.1% yield.¹H NMR(400MHz,CDCl₃)δ10.60(s,1H),8.32(dd,J＝8.3,0.8Hz,1H),8.14(d,J＝8.5Hz,1H),7.78(s,1H),7.75-7.65(m,1H),7.63-7.58(m,1H),4.27-4.00(m,5H),3.69(td,J＝11.7,2.1Hz,2H),3.55-3.45(m,1H),2.08-1.86(m,4H).LC-MS(ESI)m/z 271.12[M+H]⁺.

1-methoxy-4- (3- (methylsulfonyl) phenyl) -2-naphthaldehyde (9g)

Synthesis procedure reference 9a gave 2.33g of a pale yellow solid in 55.2% yield.¹H NMR(400MHz,CDCl3)δ10.65(s,1H),8.43-8.32(m,1H),8.06(d,J＝1.2Hz,1H),8.03(t,J＝1.5Hz,1H),7.82(s,1H),7.80-7.75(m,2H),7.72(t,J＝7.5Hz,1H),7.69-7.62(m,2H),4.22(s,3H),3.14(s,3H).LC-MS(ESI)m/z 341.07[M+H]⁺.

1-methoxy-4-morpholine-1-naphthaldehyde (9h)

The compound 4-bromo-1-methoxy-2-naphthaldehyde (200.00mg,0.76mmol), morpholine (0.08mL,0.906mmol), Pd₂(dba)₃(3.68mg, 0.5% mol), BINAP (4.70mg,0.01mmol), potassium tert-butoxide (143.36mg,1.28mmol) were added to a 25mL three-necked flask, 10mL of toluene was added after nitrogen protection, the temperature was raised to 100 ℃ and the mixture was stirred and monitored by TLC. After the reaction was complete, it was cooled to room temperature, extracted three times with ethyl acetate (10mL), the organic phase was washed with brine, anhydrous Na₂SO₄Drying and purifying by 200-mesh 300-mesh silica gel column (PE: EA is 5: 1). 100.00mg of a pale yellow solid was obtained, with a yield of 48.8%.¹H NMR(400MHz,CDCl₃)δ10.58(s,1H),8.36-8.20(m,2H),7.75-7.70(m,1H),7.65-7.58(m,1H),7.47(s,1H),4.12(s,3H),3.98(dd,J＝15.8,11.1Hz,4H),3.22-3.04(m,4H).LC-MS(ESI)m/z 272.12[M+H]⁺.

Synthesis of 1-hydroxy-2-naphthaldehyde derivative (11a-j)

1-hydroxy-2-naphthaldehyde (11a)

Synthesis procedure reference 9a gave 2.33g of product as a yellow oil in 30.3% yield.¹H NMR(400MHz,CDCl₃)δ11.70(s,1H),9.00(s,1H),7.47(d,J＝8.0Hz,1H),6.81(d,J＝8.2Hz,1H),6.69(t,J＝7.5Hz,1H),6.58(t,J＝7.6Hz,1H),6.52(d,J＝8.6Hz,1H),6.40(d,J＝8.6Hz,1H).LC-MS(ESI)m/z 173.10[M+H]⁺.

1-hydroxy-4-methoxy-2-naphthaldehyde (11b)

Synthesis procedure reference 9a gave 2.01g of product as a pale yellow oil in 50.2% yield.¹H NMR(400MHz,CDCl₃)δ12.37(s,1H),9.91(s,1H),8.42(d,J＝8.2Hz,1H),8.21(d,J＝8.4Hz,1H),7.74-7.62(m,1H),7.60-7.55(m,1H),6.72(s,1H),3.99(s,3H).LC-MS(ESI)m/z 203.06[M+H]⁺.

4-bromo-1-hydroxy-2-naphthaldehyde (11c)

The compound 4-bromo-1-methoxy-2-naphthaldehyde (200.00mg,0.76mmol), dichloromethane (5mL) was added to a 50mL three-necked flask, stirred for 10 minutes in an ice bath, aluminum trichloride (301.25mg,2.27mmol) was added slowly, heated to 40 ℃ and monitored by TLC. After the reaction is finished, cooling to room temperature, adding dilute hydrochloric acid to quench the reaction, and using CH₂Cl₂Extracted three times (20mL), washed with organic brine and anhydrous Na₂SO₄Drying and purification on silica gel column (PE: EA ═ 5:1) gave 125.22mg of light yellow solid in 66.4% yield.¹H NMR(400MHz,CDCl₃)δ12.51(s,1H),9.82(s,1H),8.38(dd,J＝8.3,0.5Hz,1H),8.09(d,J＝8.5Hz,1H),7.83-7.70(m,1H),7.67(s,1H),7.63-7.48(m,1H).LC-MS(ESI)m/z251.10[M+H]⁺.

1-hydroxy-4-methanesulfonyl-2-naphthaldehyde (11d)

Synthesis procedure reference 11c to give a pale yellow solid 250g, yield 60.5%.¹H NMR(400MHz,DMSO)δ10.33(s,1H),8.59(d,J＝8.6Hz,1H),8.54(d,J＝8.5Hz,1H),8.49(s,1H),7.90-7.87(m,1H),7.80-7.72(m,1H),4.10(s,1H),3.34(s,3H).LC-MS(ESI)m/z 251.10[M+H]⁺.

3-formyl-4-hydroxy-1-naphthoic acid methyl ester (11e)

Synthesis procedure reference 11c gave 1.50g of a pale yellow solid in 65.5% yield.¹H NMR(400MHz,DMSO)δ10.25(s,1H),8.93(d,J＝8.6Hz,1H),8.48(s,1H),8.45(d,J＝8.2Hz,1H),7.98-7.78(m,1H),7.69(t,J＝7.4Hz,1H),3.94(d,J＝10.9Hz,3H).LC-MS(ESI)m/z 231.05[M+H]⁺.

N- (3-formyl-4-hydroxynaphthalen-1-yl) methanesulfonamide (11f)

Synthesis procedure reference 11c gave 1.22g of a pale yellow solid in 60.1% yield.¹H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.24(s,1H),9.59(s,1H),8.51-8.33(m,1H),8.26(d,J＝8.4Hz,1H),7.87-7.77(m,1H),7.73(s,1H),7.70-7.56(m,1H),3.04(s,3H).LC-MS(ESI)m/z 264.04[M-H]^-.

1,1, 1-trifluoro-N- (3-formyl-4-hydroxynaphthalen-1-yl) methanesulfonamide (11g)

Synthesis procedure reference 11c gave 1.01g of a pale yellow solid in 50.1% yield.¹H NMR(400MHz,DMSO-d6)δ12.31(s,1H),10.28(s,1H),8.45(d,J＝8.4Hz,1H),8.08(d,J＝8.4Hz,1H),7.90(t,J＝7.7Hz,1H),7.80-7.65(m,2H).LC-MS(ESI)m/z 318.01[M-H]^-.

1-hydroxy-4- (tetrahydro-2H-pyran-4-yl) -2-naphthaldehyde (11H)

Synthesis procedure reference 11c gave 2.53g of a pale yellow solid in 55.3% yield.¹H NMR(400MHz,CDCl₃)δ12.54(s,1H),9.96(d,J＝9.6Hz,1H),8.52(d,J＝7.6Hz,1H),8.04(d,J＝8.6Hz,1H),7.78-7.67(m,1H),7.56(dt,J＝19.0,5.9Hz,1H),7.36(s,1H),4.17(dt,J＝11.1,2.7Hz,2H),3.84-3.59(m,2H),3.45(m,1H),2.14-1.75(m,4H).LC-MS(ESI)m/z 257.10[M+H]⁺.

1-hydroxy-4-morpholine-2-naphthaldehyde (11i)

Synthesis procedure reference 11c gave 0.80g of pale yellow product in 40.0% yield.¹H NMR(400MHz,CDCl₃)δ12.50(s,1H),9.95(s,1H),8.59-8.14(m,2H),7.86-7.52(m,2H),7.19(d,J＝57.8Hz,1H),3.98(m,4H),3.06(m,4H).LC-MS(ESI)m/z 258.10[M+H]⁺.

1-hydroxy-4- (3- (methylsulfonyl) phenyl) -2-naphthaldehyde (11j)

Synthesis procedure reference 11c gave 1.50g of a pale yellow solid in 66.1% yield.¹H NMR(400MHz,CDCl₃)δ12.71(s,1H),10.01(s,1H),8.57(dd,J＝8.1,0.9Hz,1H),8.20-8.10(m,1H),8.05-7.88(m,1H),7.78(dt,J＝7.6,1.4Hz,1H),7.72(dd,J＝8.3,6.8Hz,2H),7.67(dt,J＝3.0,1.5Hz,1H),7.64(dd,J＝4.7,1.6Hz,1H),7.61(dt,J＝11.1,2.9Hz,1H),7.47(s,1H),3.14(s,3H).LC-MS(ESI)m/z 327.06[M+H]⁺.

Synthesis of 4-hydroxy-1H-indole-5-carbaldehyde (17)

5mL of DMF was taken in a 250mL three-necked flask, and phosphorus oxychloride (3.45g,22.56mmol) was added thereto and stirred in an ice bath. 4-hydroxyindole (1.00g, 7.52mmol) was weighed out and dissolved in 5mL of DMF, and the solution was added dropwise to the reaction system, followed by TLC to monitor the progress of the reaction. Adding ice water after the raw materials are completely converted, extracting with ethyl acetate (10mL) for three times, washing the organic phase with brine, and removing anhydrous Na₂SO₄Drying and purification by 200-mesh 300-mesh silica gel column (PE: EA: 8:1) to obtain 0.80g of the target product with the yield of 69.6%.¹H NMR(400MHz,DMSO-d6)δ11.79(s,1H),11.62(s,1H),10.03(s,1H),7.38(d,J＝8.5Hz,1H),7.36-7.33(m,1H),7.04(d,J＝8.5Hz,1H),6.72(m,1H).LC-MS(ESI)m/z162.05[M+H]⁺.

Synthesis of 2- (2,4, 5-trifluorophenyl) -3-nitro-2H-benzo [ H ] chroman derivative (13a-j)

2- (2,4, 5-trifluorophenyl) -3-nitro-2H-benzo [ H ] chroman (13a)

1-hydroxy-2-naphthaldehyde (150.00mg, 0.86mmol), 20mL of toluene, 2,4, 5-trifluorobenzonitroethylene (174.70mg, 0.86mmol) and L-pipecolic acid (110.90mg, 0.86mmol) were weighed into a 125mL three-necked flask, stirred overnight at 120 ℃ under nitrogen, and the solution gradually changed from light yellow to dark red. Cooling to room temperature, extracting with dichloromethane three times, anhydrous Na₂SO₄Drying, evaporating excessive toluene under reduced pressure, dissolving with dichloromethane, mixing with silica gel powder, and separating and purifying with silica gel column chromatography (PE: EA is 4:1) to obtain orange red target product 90.00mg with yield of 28.9%.¹H NMR(400MHz,CDCl₃)δ8.27(s,1H),8.11(d,J＝8.3Hz,1H),7.76(d,J＝8.1Hz,1H),7.60-7.52(m,1H),7.52-7.44(m,2H),7.35(d,J＝8.5Hz,1H),7.10(s,1H),6.98-6.95(m,2H).

2- (2,4, 5-trifluorophenyl) -3-nitro-6-methoxy-2H-benzo [ H ] chroman (13b)

The synthesis method referred to 13a, obtained 1.55g of orange-red solid with a yield of 30.2%.¹H NMR(400MHz,CDCl₃)δ8.24(s,1H),8.19(t,J＝9.6Hz,1H),8.06(t,J＝9.2Hz,1H),7.63-7.45(m,2H),7.06-6.95(m,2H),6.62(s,1H),5.30(s,1H),4.00(s,3H).

2- (2,4, 5-trifluorophenyl) -3-nitro-6-bromo-2H-benzo [ H ] chroman (13c)

The synthesis method referred to 13a gave 1.21g of orange-red solid with a yield of 29.5%.¹H NMR(400MHz,CDCl₃)δ8.20(s,1H),8.14(dd,J＝8.8,2.2Hz,1H),7.95(d,J＝13.8Hz,1H),7.67(d,J＝5.8Hz,1H),7.63(s,1H),7.59-7.51(m,1H),7.40-7.31(m,1H),7.13-6.98(m,2H).

2- (2,4, 5-trifluorophenyl) -3-nitro-6-methanesulfonyl-2H-benzo [ H ] chroman (13d)

Synthesis method referring to 13a, 1.02g of dark red solid was obtained with a yield of 10.5%.¹H NMR(400MHz,CDCl₃)δ8.70-8.60(m,1H),8.30(s,1H),8.26(d,J＝8.2Hz,2H),7.80(dd,J＝11.4,4.2Hz,1H),7.63(dd,J＝13.0,5.8Hz,1H),7.18(s,1H),7.15-6.99(m,2H),3.22(s,3H).

2- (2,4, 5-trifluorophenyl) -3-nitro-6-methanoate-2H-benzo [ H ] chroman (13e)

The synthesis method referred to 13a, obtained 2.55g of orange-red solid with a yield of 41.1%.¹H NMR(400MHz,CDCl₃)δ8.98(t,J＝7.3Hz,1H),8.28(s,1H),8.21(s,1H),8.18(d,J＝8.4Hz,1H),7.70(t,J＝8.5Hz,1H),7.57-7.51(m,1H),7.15(s,1H),7.09-6.97(m,2H),4.01(s,3H).

2- (2,4, 5-trifluorophenyl) -3-nitro-6-methanesulfonamido-2H-benzo [ H ] chroman (13f)

Synthesis method referring to 13a, 1.55g of dark red solid was obtained with a yield of 42.1%.¹H NMR(400MHz,CDCl₃)δ8.25(s,1H),8.18(d,J＝8.4Hz,1H),8.01(d,J＝8.5Hz,1H),7.69(t,J＝7.7Hz,1H),7.57(dd,J＝9.5,5.3Hz,2H),7.12(s,1H),7.11-6.97(m,2H),6.77(s,1H),3.04(s,3H).LC-MS(ESI)m/z 449.015[M-H]^-.

2- (2,4, 5-trifluorophenyl) -3-nitro-6- (1,1, 1-trifluoromethyl) sulfonylamino-2H-benzo [ H ] chroman (13g)

Synthesis method referring to 13a, 1.05g of dark red solid was obtained with a yield of 32.0%.¹H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.05(dd,J＝15.8,7.0Hz,2H),7.82-7.75(m,1H),7.73-7.67(m,2H),7.62(dd,J＝16.5,9.2Hz,2H),7.17(s,1H).LC-MS(ESI)m/z503.10[M-H]^-.

2- (2,4, 5-trifluorophenyl) -3-nitro-6- (tetrahydro-2H-pyran-4-yl) -2H-benzo [ H ] chroman (13H)

The synthesis method referred to 13a, obtained 1.55g of orange-red solid with a yield of 42.9%.¹H NMR(400MHz,CDCl₃)δ8.29(s,1H),8.18(d,J＝7.8Hz,1H),8.04(dd,J＝21.0,6.9Hz,1H),7.69-7.56(m,1H),7.50(t,J＝7.6Hz,1H),7.24(s,1H),7.10(s,1H),7.09-6.96(m,2H),4.41-3.92(m,2H),3.88-3.54(m,3H),3.50-3.34(m,1H),2.00-1.85(m,4H).

2- (2,4, 5-trifluorophenyl) -3-nitro-6-morpholinyl-2H-benzo [ H ] chroman (13i)

The synthesis method refers to 13a, and 2.01g of orange-red solid is obtained, and the yield is 40.2%.¹H NMR(400MHz,CDCl₃)δ8.24(d,J＝16.2Hz,1H),8.16(d,J＝8.4Hz,1H),8.12(d,J＝8.2Hz,1H),7.65-7.55(m,1H),7.50(t,J＝7.2Hz,1H),7.08(d,J＝6.7Hz,1H),7.07-6.99(m,2H),6.96(s,1H),4.29-3.63(m,4H),3.30-2.85(m,4H).LC-MS(ESI)m/z 443.10[M+H]⁺.

2- (2,4, 5-trifluorophenyl) -3-nitro-6- (3- (methylsulfonyl) phenyl) -2H-benzo [ H ] chroman (13j)

The synthesis was carried out as described for 13a, giving 1.55g of product in 38.1% yield.¹H NMR(400MHz,CDCl₃)δ8.29(s,1H),8.26-8.19(m,1H),8.04(dd,J＝7.0,1.3Hz,2H),7.80-7.65(m,3H),7.61-7.49(m,2H),7.34(s,1H),7.15(s,1H),7.13-6.99(m,2H),3.14(s,3H).

(9) Synthesis of 2- (2,4, 5-trifluorophenyl) -3-nitro-2, 7-dihydropyrano [2,3-e ] indole (18)

The synthesis method referred to 13a, obtained 1.95g of orange-red solid with a yield of 55.3%.¹H NMR(400MHz,DMSO-d6)δ11.61(s,1H),8.54(s,1H),7.75-7.55(m,1H),7.47-7.38(m,1H),7.33-7.28(m,2H),7.13(d,J＝8.4Hz,1H),6.99(s,1H),6.45-6.34(s,1H).LC-MS(ESI)m/z 345.01[M+H]⁺.

Synthesis of 2- (2,4, 5-trifluorophenyl) -3-nitro-3, 4-dihydro-2H-benzo [ H ] chroman derivative (14a-j)

2- (2,4, 5-trifluorophenyl) -3-nitro-3, 4-dihydro-2H-benzo [ H ] chroman (14a)

The compound 2- (2,4, 5-trifluorophenyl) -3-nitro-2H-benzo [ H]Chromene (500.00mg,1.40mmol), tetrahydrofuran 5mL, methanol 0.5mL were added to a 25mL three-necked flask, stirred in ice bath, and NaBH was added slowly₄Powder (266.00mg, 7.00mmol), TLC to monitor the progress of the reaction, and after completion of the reaction, saturated NH was added₄Cl solution, ethyl acetate (10mL) three times, organic phase with anhydrous Na₂SO₄Dried and the solvent evaporated under reduced pressure. The crude product was then dissolved in 5mL of ethanol, 0.25mL of DIPEA was added, stirred at room temperature and monitored by TLC. After the reaction was complete, ethyl acetate (10mL) was extracted three times, the organic phase was washed with brine, anhydrous Na₂SO₄Drying, evaporating under reduced pressure to remove the solvent to obtain a trans-racemate product, and putting the trans-racemate product into the next step of zinc powder reduction reaction.

14b-j reference 14a, the crude was used directly in the next reaction.

Synthesis of 2- (2,4, 5-trifluorophenyl) -3-nitro-2, 3,4, 7-tetrahydropyrano [2,3-e ] indole (19)

Synthetic methods referring to 14a, the crude was used directly in the next reaction.

Synthesis of trans-2- (2,4, 5-trifluorophenyl) -3, 4-dihydro-2H-benzo [ H ] chroman-3-amine derivative (15a-j)

trans-2- (2,4, 5-trifluorophenyl) -3, 4-dihydro-2H-benzo [ H ] chroman-3-amine (15a)

Weighing the compound trans-2- (2,4, 5-trifluorophenyl) -3-nitro-3, 4-dihydro-2H-benzo [ H ]]Chroman (325.00mg,0.90mmol), zinc powder (585.00mg,9.00mmol) and 2.4mL of 6N hydrochloric acid were added to a 25mL three-necked reaction flask, stirred at room temperature, monitored by TLC, and after the reaction was completed, saturated sodium bicarbonate was addedAdjusting the pH value of the solution to be alkalescent (7-8), performing suction filtration under reduced pressure, washing the filtrate with ethyl acetate and water, washing the filtrate with organic phase brine, drying the filtrate with anhydrous sodium sulfate, and performing silica gel column chromatography (200-300) for purification (PE: EA is 1:1) to obtain 75.00mg of white solid with the yield of 25.3 percent. Melting point: 300.1-301.5 ℃.¹H NMR(400MHz,DMSO-d6)δ7.95(d,J＝7.7Hz,1H),7.85(dd,J＝8.6,7.3Hz,1H),7.77-7.57(m,2H),7.51-7.39(m,3H),7.26(d,J＝8.4Hz,1H),5.03(d,J＝9.1Hz,1H),3.37(td,J＝9.5,5.4Hz,1H),3.18-2.99(m,1H),2.97-2.79(m,1H),2.03-1.44(s,2H).¹³C NMR(151MHz,DMSO-d6)δ156.43,149.46,148.76,146.83,133.20,128.18,127.90,126.23,125.90,124.41,124.17,121.41,120.52,117.73,116.07,106.58,77.46,48.65,34.97.HRMS(EI):calcd for C₁₉H₁₄F₃NO[M]⁺m/z 329.1027；found,329.1028.

trans-2- (2,4, 5-trifluorophenyl) -6-methoxy-3, 4-dihydro-2H-benzo [ H ] chroman-3-amine (15b)

Synthetic method referring to 15a, 22.20mg of white solid was obtained with a yield of 20.1%. Melting point: 346.1-347.8 ℃.¹H NMR(400MHz,DMSO-d6)δ8.14-8.01(m,1H),7.95-7.85(m,1H),7.76-7.54(m,2H),7.52-7.38(m,2H),6.71(s,1H),4.95(d,J＝9.0Hz,1H),3.93(s,3H),3.40-3.36(m,1H),3.05(dd,J＝16.7,5.4Hz,1H),2.86(dd,J＝16.6,10.1Hz,1H),1.61(s,2H).¹³C NMR(151MHz,DMSO-d6)δ156.38,149.35,149.15,146.82,142.53,126.54,125.65,125.12,124.75,124.37,121.86,121.36,117.65,115.57,106.54,105.94,77.26,56.11,48.89,35.40.HRMS(EI):calcd for C₂₀H₁₆F₃NO₂[M]⁺m/z 359.1133；found,359.1132.

trans-2- (2,4, 5-trifluorophenyl) -6-bromo-3, 4-dihydro-2H-benzo [ H ] chroman-3-amine (15c)

Synthesis ofMethod reference 15a gave 20.05mg of a white solid in 24.1% yield. Melting point: 372.5-373.9 ℃.¹H NMR(400MHz,DMSO-d6)δ8.02(dd,J＝10.0,9.1Hz,2H),7.73-7.68(m,1H),7.67(s,1H),7.66-7.60(m,2H),7.54(t,J＝8.1Hz,1H),5.05(d,J＝9.1Hz,1H),3.41-3.36(m,1H),3.09(dd,J＝16.7,5.2Hz,1H),2.99-2.79(m,1H),1.66(s,2H).¹³C NMR(151MHz,DMSO-d6)δ156.47,149.55,148.84,146.91,131.58,130.85,128.01,126.94,126.62,125.66,123.72,122.15,117.79,117.63,112.53,106.62,77.58,48.36,34.43.HRMS(EI):calcd for C₁₉H₁₃BrF₃NO[M]⁺m/z 407.0133；found,407.0134.

trans-2- (2,4, 5-trifluorophenyl) -6-methanesulfonyl-3, 4-dihydro-2H-benzo [ H ] chroman-3-amine (15d)

Synthetic method referring to 15a, 15.10mg of white solid was obtained with a yield of 11.5%. Melting point: 323.9-325.0 ℃.¹H NMR(400MHz,DMSO-d6)δ8.60(d,J＝8.6Hz,1H),8.18(d,J＝7.9Hz,1H),8.08(s,1H),7.84-7.79(m,2H),7.75-7.64(m,2H),5.23(d,J＝9.1Hz,1H),3.35(s,3H),3.21(dd,J＝10.5,5.2Hz,1H),3.00(dd,J＝16.5,10.3Hz,1H),1.80(s,2H).¹³C NMR(151MHz,DMSO-d6)δ156.54,153.81,149.66,146.86,132.33,128.82,128.43,127.93,127.03,124.88,124.28,123.43,122.73,117.90,115.13,106.70,78.19,48.16,44.65,34.32.HRMS(EI):calcd for C₂₀H₁₆F₃NO₃S[M]⁺m/z 407.0803；found,407.0801.

trans-2- (2,4, 5-trifluorophenyl) -6-carbomethoxy-3, 4-dihydro-2H-benzo [ H ] chroman-3-amine (15e)

Synthetic method referring to 15a, 55.15mg of white solid was obtained with a yield of 15.0%. Melting point: 377.1-378.5 ℃.¹H NMR(400MHz,DMSO-d6)δ8.92(d,J＝8.6Hz,1H),8.21-8.03(m,2H),7.83-7.62(m,3H),7.56(t,J＝7.6Hz,1H),5.18(d,J＝9.1Hz,1H),3.96(s,3H),3.45-3.43(m,1H),3.16(dd,J＝16.4,5.1Hz,1H),2.95(dd,J＝16.4,10.4Hz,1H),1.27(s,2H).¹³C NMR(151MHz,DMSO-d6)δ168.47,157.32,155.65,151.65,151.36,149.71,147.63,146.04,133.34(s),131.74,128.35,126.60,126.19,124.54,121.83,120.72,120.47,118.09,112.13(s),107.53,72.95,56.48,46.55.HRMS(EI):calcd for C₂₁H₁₆F₃NO₃[M]⁺m/z 387.1082；found,387.1080.

trans-2- (2,4, 5-trifluorophenyl) -6-methanesulfonamido-3, 4-dihydro-2H-benzo [ H ] chroman-3-amine (15f)

Synthetic method referring to 15a, 44.55mg of white solid was obtained with a yield of 12.0%. Melting point: 376.6-378.1 ℃.¹H NMR(400MHz,DMSO-d6)δ8.16(d,J＝8.3Hz,1H),7.96(d,J＝8.1Hz,1H),7.77-7.59(m,2H),7.51(dt,J＝14.9,7.0Hz,2H),7.27(s,2H),6.70(s,1H),5.05(d,J＝9.1Hz,1H),3.08(dd,J＝16.6,5.1Hz,1H),3.00(s,3H),2.89(dd,J＝16.4,10.3Hz,1H),1.77(s,2H).¹³C NMR(151MHz,DMSO-d6)δ156.50,149.52,147.96,146.86,130.46,126.87,126.61,126.27,125.82,124.95,124.05,123.92,121.62,117.73,115.80,106.66,77.59,48.53,34.78,22.97.HRMS(EI):calcd for C₂₀H₁₇F₃N₂O₃S[M]⁺m/z 422.0912；found,422.0911.

trans-2- (2,4, 5-trifluorophenyl) -6- (1,1, 1-trifluoromethyl) sulfonylamino-3, 4-dihydro-2H-benzo [ H ] chroman-3-amine (15g)

Synthetic method referring to 15a, 55.50mg of white solid was obtained with a yield of 15.0%. Melting point: 380.8-381.9 ℃.¹H NMR(400MHz,DMSO-d6)δ10.12(s,1H),8.40-8.28(m,1H),7.91(dd,J＝6.5,3.0Hz,1H),7.79-7.66(m,1H),7.56-7.47(m,1H),7.42(dd,J＝6.4,3.3Hz,2H),6.97(s,1H),5.50(d,J＝7.2Hz,1H),4.13(dd,J＝13.1,7.0Hz,1H),3.13(dd,J＝17.0,5.4Hz,1H),3.03(dd,J＝16.9,7.3Hz,1H).¹³C NMR(151MHz,DMSO-d6)δ156.14,150.21,146.78,141.78,132.00,130.73,129.14,125.86,125.24,125.04,124.78,123.74,121.32,120.72,118.28,117.62,112.53,107.40,71.85,47.12,28.77.HRMS(EI):calcd for C₂₀H₁₄F₆N₂O₃S[M]⁺m/z 476.0629；found,476.0628.

trans-2- (2,4, 5-trifluorophenyl) -6- (tetrahydro-2H-pyran-4-yl) -3, 4-dihydro-2H-benzo [ H ] chroman-3-amine (15H)

Synthetic method referring to 15a, 60.10mg of white solid was obtained with a yield of 15.1%. Melting point: 402.9-403.6 ℃.¹H NMR(400MHz,DMSO-d6)δ8.12(d,J＝8.5Hz,1H),7.98(d,J＝8.1Hz,1H),7.64(dt,J＝17.2,11.2Hz,2H),7.49(dd,J＝15.6,8.1Hz,1H),7.46-7.39(m,1H),7.15(s,1H),4.99(d,J＝9.1Hz,1H),4.02(dd,J＝21.1,9.0Hz,2H),3.62(dd,J＝15.7,9.1Hz,2H),3.56-3.45(m,1H),3.05(dd,J＝16.5,5.1Hz,1H),2.86(dd,J＝16.3,10.3Hz,1H),1.85-1.70(m,5H).¹³C NMR(151MHz,DMSO-d6)δ156.48,149.44,147.31,146.85,134.33,130.75,126.24,125.51,124.77,124.62,124.29,123.42,122.12,117.73,115.50,106.63,77.41,68.08,48.76,35.74,35.08,34.16.HRMS(EI):calcd for C₂₄H₂₂F₃NO₂[M]⁺m/z 413.1603；found,413.1602.

trans-2- (2,4, 5-trifluorophenyl) -6-morpholinyl-3, 4-dihydro-2H-benzo [ H ] chroman-3-amine (15i)

Synthetic method referring to 15a, 25.10mg of white solid was obtained with a yield of 23.5%. Melting point: 431.9 to 433.2 ℃.¹H NMR(400MHz,DMSO-d6)δ8.12(d,J＝7.9Hz,1H),7.93(d,J＝8.0Hz,1H),7.77-7.56(m,2H),7.54-7.38(m,2H),6.92(s,1H),4.97(d,J＝9.1Hz,1H),3.95-3.72(m,4H),3.34-3.30(m,1H),3.02(dt,J＝12.0,6.0Hz,1H),2.98-2.90(m,4H),2.84(dd,J＝16.5,10.2Hz,1H),1.61(s,2H).¹³C NMR(101MHz,DMSO-d6)δ150.70,148.10,145.26,142.86,139.89,128.29,126.00,125.87,125.39,124.26,123.55,121.89,117.62,117.01,115.57,106.59,77.36,67.15,53.88,48.80,35.16.HRMS(EI):calcd for C₂₃H₂₁F₃N₂O₂[M]⁺m/z 414.1555；found,414.1554.

trans-2- (2,4, 5-trifluorophenyl) -6-carboxy-3, 4-dihydro-2H-benzo [ H ] chroman-3-amine (15j)

Weighing 3-amino-2- (2,4, 5-trifluorophenyl) -3, 4-dihydro-2H-benzo [ H ]]Chromene-6-carboxylic acid methyl ester (20.00mg, 0.05mmol), dissolved in 2mL of methanol, added with aqueous sodium hydroxide (6.00mg, 0.15mmol), refluxed at 50 ℃, after the reaction is finished, the pH is adjusted to neutral with dilute hydrochloric acid, extracted with ethyl acetate (10mL) three times, and anhydrous Na₂SO₄Drying, and purifying by silica gel column chromatography (PE: EA: 1:2) to obtain white solid 10.10mg, yield 50.0%. Melting point: 484.5-485.6 ℃.¹H NMR(400MHz,DMSO-d6)δ9.01(d,J＝8.5Hz,1H),8.03(d,J＝6.7Hz,2H),7.78-7.62(m,2H),7.59(t,J＝7.1Hz,1H),7.49(t,J＝7.2Hz,1H),5.14(d,J＝9.0Hz,1H),3.12(dd,J＝16.4,5.1Hz,2H),2.92(dd,J＝16.3,10.3Hz,2H),1.91(s,2H).¹³C NMR(151MHz,DMSO-d6)δ172.00,156.35,154.12,149.45,143.19,132.78,129.92,129.24,128.36,128.09,127.35,126.15,123.75,122.63,117.90,116.93,106.64,77.07,48.31,34.45.HRMS(EI):calcd for C₂₀H₁₄F₃NO₃[M]⁺m/z 373.0926；found,373.0925.

trans-2- (2,4, 5-trifluorophenyl) -6- (3- (methylsulfonyl) phenyl) -3, 4-dihydro-2H-benzo [ H ] chroman-3-amine (15k)

Synthesis method referring to 15a, 10.50mg of white solid was obtained with a yield of 10.1%. Melting point: 430.5-431.6 ℃.¹H NMR(400MHz,DMSO-d6)δ8.19-8.08(m,1H),8.08-8.00(m,2H),7.95-7.82(m,2H),7.81-7.64(m,3H),7.60-7.48(m,2H),7.36(s,1H),5.14(d,J＝9.1Hz,1H),3.36(s,3H),3.18(dd,J＝16.6,5.2Hz,1H),2.98(dd,J＝16.5,10.2Hz,1H),1.73(s,2H).¹³C NMR(151MHz,DMSO-d6)δ156.49,149.59,149.03,148.75,146.88,141.66,141.49,135.45,130.60,130.50,130.09,129.70,128.32,127.08,126.17,126.04,125.09,124.60,124.02,122.04,117.74,115.92,106.67,77.73,48.60,43.97,34.75.HRMS(EI):calcd for C₂₆H₂₀F₃NO₃S[M]⁺m/z 483.1116；found,483.1115.

(13) Synthesis of trans-2- (2,4, 5-trifluorophenyl) -2,3,4, 7-tetrahydropyrano [2,3-e ] indole 3-amine (20)

Synthesis method referring to 15a, 125.00mg of white solid was obtained with a yield of 33.0%. Melting point: 310.1-313.5 ℃.¹H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.68-7.55(m,2H),7.22-7.13(m,1H),6.96(d,J＝8.4Hz,1H),6.81(d,J＝8.2Hz,1H),6.27(d,J＝2.0Hz,1H),4.93(d,J＝8.9Hz,1H),3.31(dd,J＝8.7,4.9Hz,1H),2.96(dd,J＝15.7,5.2Hz,1H),2.77(dd,J＝15.6,10.1Hz,1H),1.59(s,2H).¹³C NMR(151MHz,DMSO-d6)δ156.28,149.32,146.82,146.72,136.60,124.56,124.28,123.26,118.17,117.77,109.45,106.58,105.32,98.26,77.12,49.02,34.63.HRMS(EI):calcd for C₂₀H₁₄F₃NO₃[M]⁺m/z 318.0980；found,318.0982.

(14) Synthesis of 1,1, 1-trifluoro-N- (3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanesulfonamide (25e)

Taking 3- (4,4,5, 5-tetramethyl)1,3, 2-dioxaborolan-2-yl) aniline (1.00g, 4.76mmol), triethylamine (0.92g, 9.14mmol) and dichloromethane (10mL) were placed in a 100mL reaction flask and added with, for example, trifluoromethanesulfonic anhydride (1.29g, 4.76mmol) at-78 deg.C, after the addition was complete, the flask was moved to room temperature for continued stirring and the reaction was monitored by TLC. After the conversion of the raw materials is completed, adding water into a reaction bottle for quenching, extracting with dichloromethane (20mL) for three times, washing an organic phase with brine, and adding anhydrous Na₂SO₄Drying, column chromatography separation and purification (PE: EA is 5:1) to obtain 1.20g of product, and the yield is 68.2%.¹H NMR(400MHz,CDCl₃)δ7.65(d,J＝7.1Hz,1H),7.54(d,J＝1.9Hz,1H),7.40-7.26(m,3H),1.30-1.15(m,12H).LC-MS(ESI)m/z 350.09[M-H]^-.

Synthesis of 4-hydroxy- (1,1' -biphenyl) -3-carbaldehyde derivative (26a-j)

4-hydroxy- (1,1' -biphenyl) -3-carbaldehyde (26a)

5-bromo-2-hydroxybenzaldehyde (1.00g, 5.00mmol), phenylboronic acid (1.22g, 10.00mmol), cesium carbonate (4.88g, 15.00mmol), PdCl₂(dppf)₂(183.10mg, 0.25mmol) was added to the flask, toluene 30mL, water 5mL dissolved, nitrogen protected, heated to reflux at 100 ℃ and monitored by TLC. After the reaction was completed, the reaction mixture was filtered, and the filtrate was extracted three times with ethyl acetate (10mL) and then with anhydrous Na₂SO₄Drying, spin-drying the solution, and separating with silica gel column chromatography (PE: EA: 10:1) to obtain 0.80g of product with 80.1% yield.¹H NMR(400MHz,CDCl₃)δ11.01(s,1H),9.96(s,1H),7.79-7.72(m,2H),7.54(d,J＝7.3Hz,2H),7.45(t,J＝7.7Hz,2H),7.35(t,J＝7.3Hz,1H),7.07(d,J＝8.5Hz,1H).LC-MS(ESI)m/z 197.01[M-H]^-.

4-hydroxy-3 '- (methylsulfonyl) - [1,1' -biphenyl ] -3-carbaldehyde (26b)

Reference to 26a for the synthetic method1.22g of substance, yield 90.1%.¹H NMR(400MHz,CDCl₃)δ11.10(s,1H),10.02(s,1H),8.15(s,1H),7.93(t,J＝8.8Hz,1H),7.90-7.79(m,3H),7.74-7.65(m,1H),7.14(d,J＝8.6Hz,1H),3.13(s,3H).LC-MS(ESI)m/z 275.10[M-H]^-.

3' -formyl-4 ' -hydroxy- [1,1' -biphenyl ] -3-carboxylic acid methyl ester (26c)

The synthesis was as described for 26a, giving 1.10g of product in 85.9% yield.¹H NMR(400MHz,CDCl₃)δ11.05(s,1H),10.00(s,1H),8.24(t,J＝1.6Hz,1H),8.05-8.00(m,1H),7.84-7.78(m,2H),7.75(dd,J＝3.9,2.7Hz,1H),7.53(t,J＝7.8Hz,1H),7.10(d,J＝9.3Hz,1H),3.96(s,3H).LC-MS(ESI)m/z 255.10[M-H]^-.

N- (3' -formyl-4 ' -hydroxy- [1,1' -biphenyl ] -3-yl) methanesulfonamide (26d)

The synthesis was as described for 26a, giving 1.02g of product in 91.1% yield.¹H NMR(400MHz,CDCl₃)δ11.05(s,1H),9.97(s,1H),7.83-7.70(m,2H),7.48(s,1H),7.45(t,J＝7.8Hz,1H),7.38(d,J＝7.8Hz,1H),7.32(s,1H),7.29-7.24(m,1H),7.09(t,J＝12.1Hz,1H),3.10(s,3H).LC-MS(ESI)m/z 290.01[M-H]^-.

1,1, 1-trifluoro-N- (3' -formyl-4 ' -hydroxy- [1,1' -biphenyl ] -3-yl) methanesulfonamide (26e)

The synthesis was as described for 26a, giving 1.50g of product in 89.1% yield.¹H NMR(400MHz,DMSO-d6)δ11.97(s,1H),10.94(s,1H),10.34(s,1H),7.89(d,J＝2.5Hz,1H),7.81(dd,J＝8.6,2.5Hz,1H),7.55(t,J＝6.1Hz,1H),7.54-7.46(m,2H),7.25(dd,J＝7.9,1.0Hz,1H),7.14(d,J＝8.6Hz,1H).LC-MS(ESI)m/z 255.10[M-H]^-.

3' -formyl-4 ' -hydroxy- [1,1' -biphenyl ] -3-carboxylic acid (26f)

The synthesis was as described for 26a, giving 1.51g of product in 90.2% yield.¹H NMR(400MHz,DMSO-d6)δ13.03(s,1H),10.78(d,J＝174.9Hz,1H),10.34(s,1H),8.16(s,1H),7.98(d,J＝2.2Hz,1H),7.95-7.87(m,3H),7.59(t,J＝7.7Hz,1H),7.14(d,J＝8.6Hz,1H).LC-MS(ESI)m/z 241.10[M-H]^-.

4-hydroxy-3 '- (1H-tetrazol-5-yl) - [1,1' -biphenyl ] -3-carbaldehyde (26g)

The synthesis was as described for 26a, giving 0.51g of product in 31.2% yield.¹H NMR(600MHz,DMSO-d6)δ11.00(s,1H),10.45-10.33(m,1H),8.32(t,J＝1.5Hz,1H),8.06(d,J＝2.5Hz,1H),8.04(dd,J＝11.3,4.6Hz,1H),7.96(dd,J＝8.6,2.5Hz,1H),7.88-7.82(m,1H),7.67(t,J＝7.8Hz,1H),7.18(d,J＝4.0Hz,1H).LC-MS(ESI)m/z 241.10[M-H]^-.

3' -formyl-4 ' -hydroxy- [1,1' -biphenyl ] -3-carbonitrile (26h)

The synthesis was as described for 26a, giving 1.40g of product in 85.4% yield.¹H NMR(400MHz,CDCl₃)δ11.09(s,1H),10.00(s,1H),7.85-7.83(m,1H),7.82-7.78(m,1H),7.78-7.71(m,2H),7.67-7.63(m,1H),7.58(t,J＝7.7Hz,1H),7.13(d,J＝8.4Hz,1H).LC-MS(ESI)m/z 222.10[M-H]^-.

2',4' -difluoro-4-hydroxy- [1,1' -biphenyl ] -3-carbaldehyde (26i)

The synthesis was as described for 26a, giving 1.10g of product in 89.2% yield.¹H NMR(400MHz,CDCl₃)δ11.06(s,1H),9.95(s,1H),7.76-7.60(m,2H),7.39(td,J＝8.7,6.6Hz,1H),7.08(d,J＝8.6Hz,1H),7.03-6.88(m,2H).LC-MS(ESI)m/z 233.10[M-H]^-.

4-hydroxy-3 ',4' -dimethoxy- [1,1' -biphenyl ] -3-carbaldehyde (26j)

The synthesis was as described for 26a, giving 1.20g of product in 82.2% yield.¹H NMR(400MHz,CDCl₃)δ10.88(s,1H),9.87(s,1H),7.63(dd,J＝8.5,2.3Hz,1H),7.61(d,J＝2.2Hz,1H),7.02-6.98(m,1H),6.96(dd,J＝5.3,3.1Hz,2H),6.87-6.84(m,1H),3.87(s,3H),3.83(s,3H).LC-MS(ESI)m/z 257.01[M-H]^-.

Synthesis of 2- (2,4, 5-trifluorophenyl) -3-nitro-6-bromo-2H-chroman (22)

5-bromo-2-hydroxybenzaldehyde (1.00g, 5.00mmol), 20mL of toluene, 2,4, 5-trifluorobenzonitroethylene (1.12g, 5.50mmol), L-piperidine plus acid (0.65g, 5.00mmol) were added to a 100mL reaction flask under nitrogen and stirred overnight at 120 ℃. Cooling to room temperature, extracting with dichloromethane three times, anhydrous Na₂SO₄Drying, vacuum evaporating, and purifying by silica gel column chromatography (PE: EA 15:1) to obtain orange red target product 1.50g, with yield of 78.1%.¹H NMR(400MHz,CDCl₃)δ7.93(s,1H),7.39(d,J＝2.2Hz,1H),7.32(dt,J＝11.9,5.9Hz,1H),6.98-6.84(m,2H),6.73(s,1H),6.66(t,J＝10.2Hz,1H).

Synthesis of 2- (2,4, 5-trifluorophenyl) -3-nitro-6-phenyl-2H-chroman derivative (27a-j)

2- (2,4, 5-trifluorophenyl) -3-nitro-6-phenyl-2H-chroman (27a)

The synthesis method refers to 22, and 1.01g of the product is obtained, and the yield is 88.4%.¹H NMR(400MHz,CDCl₃)δ8.14(s,1H),7.56(dd,J＝8.4,2.1Hz,1H),7.54-7.51(m,2H),7.50(s,1H),7.43(t,J＝7.6Hz,2H),7.35(t,J＝7.3Hz,1H),7.09-6.94(m,2H),6.90(d,J＝8.4Hz,1H),6.84(s,1H).

2- (2,4, 5-trifluorophenyl) -3-nitro-6- (3- (methylsulfonyl) phenyl) -2H-chroman (27b)

The synthesis method refers to 22, and 1.31g of the product is obtained, and the yield is 90.4%.¹H NMR(400MHz,CDCl₃)δ8.21(s,1H),8.13(t,J＝1.6Hz,1H),7.94(t,J＝9.3Hz,1H),7.89-7.80(m,1H),7.69(t,J＝7.8Hz,1H),7.66-7.60(m,2H),7.12-7.01(m,2H),6.99(d,J＝8.0Hz,1H),6.90(s,1H),3.13(s,3H).

2- (2,4, 5-trifluorophenyl) -3-nitro-6- (3- (carbomethoxy) phenyl) -2H-chroman (27c)

The synthesis method refers to 22, and 1.21g of the product is obtained, and the yield is 86.4%.¹H NMR(400MHz,CDCl₃)δ8.22(s,1H),8.18(s,1H),8.03(d,J＝7.8Hz,1H),7.72(d,J＝7.8Hz,1H),7.62-7.60(m,1H),7.60(s,1H),7.52(t,J＝7.8Hz,1H),7.10-6.98(m,2H),6.94(d,J＝9.2Hz,1H),6.87(s,1H),3.95(s,3H).

2- (2,4, 5-trifluorophenyl) -3-nitro-6- (3- (methanesulfonamido) phenyl) -2H-chroman (27d)

The synthesis method refers to 22, 1.11g of product is obtained,the yield was 89.0%.¹H NMR(400MHz,CDCl₃)δ8.20(s,1H),7.61-7.56(m,2H),7.51-7.42(m,2H),7.38(d,J＝7.8Hz,1H),7.23(d,J＝7.6Hz,1H),7.13-7.00(m,2H),6.95(d,J＝9.1Hz,1H),6.89(s,1H),6.85(s,1H),3.09(s,3H).LC-MS(ESI)m/z 475.10[M-H]^-.

2- (2,4, 5-trifluorophenyl) -3-nitro-6- (3- ((1,1, 1-trifluoromethyl) methanesulfonamido) phenyl) -2H-chroman (27e)

The synthesis method refers to 22, and 1.20g of the product is obtained, wherein the yield is 87.0%.¹H NMR(400MHz,CDCl₃)δ8.10(s,1H),7.53-7.44(m,2H),7.41-7.33(m,4H),7.18(dd,J＝7.1,3.7Hz,1H),7.02-6.90(m,2H),6.86(d,J＝9.1Hz,1H),6.79(s,1H).LC-MS(ESI)m/z 529.01[M-H]^-.

2- (2,4, 5-trifluorophenyl) -3-nitro-6- (3- (carboxy) phenyl) -2H-chroman (27f)

The synthesis method refers to 22, and 1.10g of the product is obtained, with the yield being 89.0%.¹H NMR(400MHz,DMSO)δ10.29(s,1H),8.48(s,1H),8.17(s,1H),7.99(d,J＝1.8Hz,1H),7.92(d,J＝7.7Hz,1H),7.87(d,J＝7.8Hz,1H),7.72(dd,J＝8.5,1.9Hz,1H),7.67-7.54(m,2H),7.48(dd,J＝17.1,8.8Hz,1H),6.97(d,J＝8.5Hz,1H),6.88(s,1H).LC-MS(ESI)m/z 426.01[M-H]^-.

2- (2,4, 5-trifluorophenyl) -3-nitro-6- (3- (tetrazolyl) phenyl) -2H-chroman (27g)

The synthesis method refers to 22, and 0.20g of a product is obtained, and the yield is 23.1%.¹H NMR(400MHz,CDCl₃)δ8.00(s,1H),7.90-7.75(m,2H),7.72-7.62(m,2H),7.57(t,J＝6.9Hz,1H),7.51-7.43(m,2H),6.94-6.90(m,2H),6.63(s,2H).LC-MS(ESI)m/z 450.01[M-H]^-.

2- (2,4, 5-trifluorophenyl) -3-nitro-6- (3- (cyano) phenyl) -2H-chroman (27H)

The synthesis was as described for 22, giving 1.11g of product in 87.0% yield.¹H NMR(400MHz,CDCl₃)δ8.10(s,1H),7.74(d,J＝1.4Hz,1H),7.71-7.67(m,1H),7.62-7.54(m,1H),7.52-7.46(m,3H),7.02-6.92(m,2H),6.92-6.86(m,1H),6.80(s,1H).

2- (2,4, 5-trifluorophenyl) -3-nitro-6- (2, 4-difluorophenyl) -2H-chroman (27i)

The synthesis was as described for 22, giving 1.33g of product in 93.1% yield.¹H NMR(400MHz,CDCl₃)δ8.16(s,1H),7.54-7.46(m,2H),7.40-7.31(m,1H),7.11-7.08(m,2H),7.01-6.90(m,3H),6.87(s,1H),2.04(s,1H).

2- (2,4, 5-trifluorophenyl) -3-nitro-6- (3, 4-dimethoxyphenyl) -2H-chroman (27j)

The synthesis method refers to 22, and 1.43g of a product is obtained, and the yield is 90.1%.¹H NMR(400MHz,CDCl₃)δ8.07(s,1H),7.47-7.41(m,2H),6.99(dd,J＝8.2,2.1Hz,1H),6.97-6.92(m,2H),6.91(dd,J＝7.3,4.1Hz,1H),6.85(d,J＝8.3Hz,1H),6.81(d,J＝8.4Hz,1H),6.76(s,1H),3.86(s,3H),3.83(s,3H).

Synthesis of 2- (2,4, 5-trifluorophenyl) -3-nitro-6-bromo-3, 4-dihydro-2H-chroman (23)

The compound 2- (2,4, 5-trifluorophenyl) -3-nitro-6-bromo-2H-chromane (500.00mg,1.30mmol) was added to a 25mL reaction flask, THF 5mL and CH were added₃OH 0.5mL, stirring in ice bath, then slowly adding NaBH₄Solid (266.00mg, 7.00mmol), TLC to monitor the progress of the reaction, and after completion of the reaction, saturated NH was added₄Cl solution, extracting with ethyl acetate and water, and extracting organic phase with anhydrous Na₂SO₄Dried and the solvent evaporated under reduced pressure. The crude product was dissolved in 5mL of ethanol, 0.25mL of DIPEA was added, and the mixture was stirred at room temperature and monitored by TLC. After the reaction is finished, extracting with ethyl acetate and water for three times, washing an organic phase with brine and anhydrous Na₂SO₄Drying, and evaporating under reduced pressure to remove the solvent to obtain the trans-racemate product which is used as a raw material for the next reaction.

Synthesis of 2- (2,4, 5-trifluorophenyl) -3-nitro-6-phenyl-3, 4-dihydro-2H-chroman derivative (28a-j)

2- (2,4, 5-trifluorophenyl) -3-nitro-6-phenyl-3, 4-dihydro-2H-chroman (28a)

28a-j Synthesis method referring to Compound 23, the crude product was directly subjected to the next reaction.

Synthesis of trans-2- (2,4, 5-trifluorophenyl) -6-bromo-3, 4-dihydro-2H-chroman-3-amine (24)

Weighing the compound trans-2- (2,4, 5-trifluorophenyl) -3-nitro-6-bromo-3, 4-dihydro-2H-chroman (500.00mg,1.30mmol), zinc powder (845.00mg,13.00mmol), 5mL of ethanol and 4mL of 6N hydrochloric acid, adding the mixture into a 25mL three-port reaction bottle, stirring at normal temperature, monitoring by TLC, and adding saturated NaHCO after the reaction is finished₃Adjusting pH of the solution to 7-8, vacuum filtering, washing the filtrate with ethyl acetate and water, washing with organic phase brine, and removing anhydrous Na₂SO₄Drying, purifying with silica gel column chromatography (PE: EA is 1:1) to obtain white powderSolid 100.05mg, yield 21.6%. Melting point: 282.1-283.2 ℃.¹H NMR(400MHz,DMSO-d6)δ7.66-7.54(m,2H),7.34(d,J＝2.3Hz,1H),7.24(dd,J＝8.7,2.4Hz,1H),6.77(d,J＝8.7Hz,1H),4.86(d,J＝9.1Hz,1H),3.24(td,J＝9.7,5.2Hz,1H),2.97(dd,J＝16.6,5.1Hz,1H),2.73(dd,J＝16.5,10.6Hz,1H),1.58(s,2H).¹³C NMR(151MHz,DMSO-d6)δ156.36,153.63,149.45,146.78,132.32,130.32,125.07,123.71,118.51,117.79,112.43,106.52,77.25,48.02,34.42.HRMS(EI):calcd for C₁₅H₁₁BrF₃NO[M]⁺m/z356.9976；found,356.9975.

Synthesis of trans-2- (2,4, 5-trifluorophenyl) -6-phenyl-3, 4-dihydro-2H-chroman-3-amine derivative (29a-j)

trans-2- (2,4, 5-trifluorophenyl) -6-phenyl-3, 4-dihydro-2H-chroman-3-amine (29a)

The synthesis was performed with reference to compound 24, yielding 15.05mg of product in 78.5% yield. Melting point: 316.4-318.4 ℃.¹H NMR(400MHz,DMSO-d6)δ7.64-7.60(m,3H),7.47-7.43(m,2H),7.42-7.38(m 2H),7.35-7.27(m,1H),6.89(d,J＝8.4Hz,1H),4.90(d,J＝9.1Hz,1H),3.30(d,J＝4.4Hz,1H),3.05(dd,J＝16.4,5.1Hz,1H),2.80(dd,J＝16.2,10.6Hz,1H),1.24(s,2H).¹³C NMR(151MHz,DMSO-d6)δ156.43,154.00,149.51,146.77,140.36,133.25,129.30,128.31,127.19,126.66,126.06,123.99,122.65,117.78,116.79,106.53,77.29,48.44,34.86.HRMS(EI):calcd for C₂₁H₁₆F₃NO[M]⁺m/z 355.1184；found,355.1183.

trans-2- (2,4, 5-trifluorophenyl) -6- (3- (methylsulfonyl) phenyl) -3, 4-dihydro-2H-chroman-3-amine (29b)

The synthesis was performed with reference to compound 24, yielding 60.10mg of product in 70.0% yield. Melting point: 340.2-340.7 ℃.¹H NMR(400MHz,DMSO-d6)δ8.13(s,1H),7.98(d,J＝7.2Hz,1H),7.86(d,J＝7.1Hz,1H),7.70(t,J＝7.5Hz,1H),7.67-7.55(m,3H),7.52(d,J＝7.9Hz,1H),6.94(d,J＝8.2Hz,1H),4.93(d,J＝8.7Hz,1H),3.35-3.27(m,4H),3.07(d,J＝12.5Hz,1H),2.91-2.75(m,1H),1.63(s,2H).¹³C NMR(151MHz,DMSO-d6)δ156.38,154.70,149.50,146.81,142.02,141.52,131.60,131.39,130.43,128.71,126.45,125.40,124.81,123.89,122.99,117.81,117.03,106.59,77.40,48.38,43.95,34.75.HRMS(EI):calcd for C₂₂H₁₈F₃NO₃S[M]⁺m/z 433.0959；found,433.0959.

trans-2- (2,4, 5-trifluorophenyl) -6- (3- (carbomethoxy) phenyl) -3, 4-dihydro-2H-chroman-3-amine (29c)

The synthesis was performed with reference to compound 24, giving 50.10mg of product in 63.0% yield. Melting point: 393.8-394.6 ℃.¹H NMR(400MHz,DMSO-d6)δ8.15(t,J＝1.6Hz,1H),7.91(dd,J＝7.8,1.3Hz,2H),7.5-7.68(m,3H),7.50(d,J＝2.1Hz,1H),7.45(dd,J＝8.5,2.2Hz,1H),6.91(d,J＝8.4Hz,1H),4.91(d,J＝9.1Hz,1H),3.89(s,3H),3.29(dd,J＝9.7,5.1Hz,1H),3.07(dd,J＝16.4,5.1Hz,1H),2.81(dd,J＝16.3,10.7Hz,1H),1.59(s,2H).¹³C NMR(151MHz,DMSO-d6)δ166.72,156.37,154.41,149.45,146.78,140.86,132.06,131.49,130.72,129.87,128.47,127.85,127.04,126.20,123.94,122.92,117.82,116.98,106.58,77.37,52.70,48.40,34.77.HRMS(EI):calcd for C₂₃H₁₈F₃NO₃[M]⁺m/z 413.1239；found,413.1238.

trans-2- (2,4, 5-trifluorophenyl) -6- (3- (methanesulfonamido) phenyl) -3, 4-dihydro-2H-chroman-3-amine (29d)

The synthesis was performed with reference to compound 24, yielding 40.50mg of product in 85.0% yield. Melting point: 392.8-393.5 ℃.¹H NMR(400MHz,DMSO-d6)δ7.68-7.56(m,2H),7.43(d,J＝1.7Hz,1H),7.42-7.38(m,2H),7.38-7.33(m,2H),7.20-7.14(m,1H),6.93(d,J＝8.4Hz,1H),5.02(d,J＝8.9Hz,1H),3.46(m,1H),3.10(dd,J＝16.5,5.1Hz,1H),3.10(s,3H),2.94-2.82(m,1H),1.99(s,1H).¹³C NMR(151MHz,DMSO-d6)δ172.51,170.84,156.29,152.78,150.38,146.81,140.42,134.53,129.56,128.39,126.88,122.97,122.19,121.48,120.68,119.23,118.10,117.28,107.38,72.09,46.87,28.95.HRMS(EI):calcd for C₂₂H₁₉F₃N₂O₃S[M]⁺m/z 448.1068；found,448.1071.

trans-2- (2,4, 5-trifluorophenyl) -6- (3- ((1,1, 1-trifluoromethyl) methanesulfonamido) phenyl) -3, 4-dihydro-2H-chroman-3-amine (29e)

The synthesis was performed with reference to compound 24, yielding 50.50mg of product in 89.0% yield. Melting point: 397.0-397.9 deg.C.¹H NMR(400MHz,DMSO)δ8.49-7.97(s,1H),7.72(dd,J＝17.0,10.1Hz,1H),7.63(dd,J＝17.0,8.6Hz,1H),7.50-7.37(m,2H),7.33-7.23(m,2H),7.19(d,J＝7.6Hz,1H),7.09-6.95(m,2H),5.38(d,J＝8.0Hz,1H),4.14-4.02(m,1H),3.26-3.17(m,1H),3.08(dd,J＝16.3,8.7Hz,1H).¹³C NMR(151MHz,DMSO)δ156.37,153.94,149.72,146.80,141.48,139.38,133.07,130.28,128.36,126.30,123.23,122.37,122.01,118.66,118.07,117.82,116.99,106.80,76.38,60.23,48.13,33.48.HRMS(EI):calcd for C₂₂H₁₆F₆N₂O₃S[M]⁺m/z 502.0786；found,502.0781.

trans-2- (2,4, 5-trifluorophenyl) -6- (3- (carboxy) phenyl) -3, 4-dihydro-2H-chroman-3-amine (29f)

The synthesis was performed with reference to compound 24, yielding 20.50mg of product in 70.0% yield. Melting point: 500.8-501.6 ℃.¹H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.89(d,J＝7.4Hz,1H),7.78(d,J＝7.7Hz,1H),7.70-7.56(m,2H),7.55-7.46(m,2H),7.44(d,J＝8.5Hz,1H),6.91(d,J＝8.4Hz,1H),4.95(d,J＝9.1Hz,1H),3.40-3.31(m,1H),3.09(dd,J＝16.4,5.0Hz,1H),2.84(dd,J＝16.3,10.6Hz,1H).¹³C NMR(151MHz,DMSO-d6)δ168.47,157.32,155.65,151.65(s),151.36,149.71,147.63,146.04,133.34,131.74,128.35,126.60,126.19,124.54,121.83,120.72,120.47,118.09,112.13,107.53,72.95,56.48,46.55.HRMS(EI):calcd for C₂₂H₁₆F₃NO3[M]⁺m/z399.1082；found,399.1080.

trans-2- (2,4, 5-trifluorophenyl) -6- (3- (tetrazolyl) phenyl) -3, 4-dihydro-2H-chroman-3-amine (29g)

The synthesis was performed with reference to compound 24, giving 10.50mg of product in 10.5% yield. Melting point: 761.6-762.8 ℃.¹H NMR(400MHz,DMSO-d6)δ8.23(s,1H),8.10(s,1H),7.92(d,J＝7.5Hz,1H),7.72-7.57(m,2H),7.48(dt,J＝27.8,7.6Hz,4H),6.91(d,J＝8.4Hz,1H),4.93(d,J＝9.0Hz,1H),3.10(dd,J＝16.4,5.0Hz,1H),2.85(dd,J＝15.8,10.5Hz,1H),1.89(s,2H).¹³C NMR(151MHz,DMSO-d6)δ156.42,153.90,149.58,146.81,140.35,133.54,133.25,130.12,129.42,128.26,126.09,125.45,124.81,124.09,123.76,122.42,117.82,116.87,106.65,76.94,48.33,34.36.HRMS(EI):calcd for C₂₂H₁₆F₃N₅O[M]⁺m/z 423.1307；found,423.1306.

trans-2- (2,4, 5-trifluorophenyl) -6- (3- (cyano) phenyl) -3, 4-dihydro-2H-chroman-3-amine (29H)

The synthesis was performed with reference to compound 24, yielding 45.05mg of product in 79.5% yield. Melting point: 405.2-406.2 ℃.¹H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.94(d,J＝8.1Hz,1H),7.72(d,J＝7.7Hz,1H),7.66-7.53(m,4H),7.50(dd,J＝8.5,2.0Hz,1H),6.95(d,J＝8.5Hz,1H),5.16(d,J＝8.6Hz,1H),3.59(td,J＝9.1,5.5Hz,1H),3.28-3.11(m,1H),2.97(dd,J＝16.5,9.8Hz,1H).¹³C NMR(151MHz,DMSO-d6)δ156.35,154.21,149.91,146.75,141.23,131.29,130.73,130.45,130.04,128.75,126.59,122.46,121.58,119.31,117.89,117.13,112.47,106.90,75.65,47.96,32.23.HRMS(EI):calcd for C₂₂H₁₅F₃N₂O[M]⁺m/z 380.1136；found,380.1131.

trans-2- (2,4, 5-trifluorophenyl) -6- (2, 4-difluorophenyl) -3, 4-dihydro-2H-chroman-3-amine (29i)

The synthesis was performed with reference to compound 24, yielding 70.50mg of product in 80.5% yield. Melting point: 342.6-343.8 ℃.¹H NMR(400MHz,DMSO-d6)δ7.67-7.54(m,2H),7.54-7.48(m,1H),7.34-7.27(m,2H),7.27-7.22(m,1H),7.20-7.08(m,1H),6.89(d,J＝8.4Hz,1H),4.92(d,J＝9.1Hz,1H),3.30(td,J＝9.8,5.1Hz,1H),3.02(dd,J＝16.4,5.1Hz,1H),2.79(dd,J＝16.2,10.6Hz,1H),1.57(s,2H).¹³C NMR(151MHz,DMSO-d6)δ161.43,159.80,156.39,154.12,149.43,146.79,131.94,130.38,128.19,127.16,125.08,123.88,122.48,117.74,116.51,112.35,106.47,104.79,77.33,48.43,34.77.HRMS(EI):calcd for C₂₁H₁₄F₅NO[M]⁺m/z 391.0996；found,391.0995.

trans-2- (2,4, 5-trifluorophenyl) -6- (3, 4-dimethoxyphenyl) -3, 4-dihydro-2H-chroman-3-amine (29j)

The synthesis was performed with reference to compound 24, yielding 60.50mg of product in 81.5% yield. Melting point: 408.4-409.5 ℃.¹H NMR(400MHz,DMSO-d6)δ7.70-7.53(m,2H),7.46-7.38(m,2H),7.17(d,J＝2.0Hz,1H),7.13(dd,J＝8.3,2.1Hz,1H),7.00(dd,J＝12.7,8.7Hz,1H),6.89(d,J＝8.4Hz,1H),5.09(d,J＝8.6Hz,1H),3.84(s,3H),3.78(s,3H),3.55(td,J＝9.1,5.3Hz,1H),3.13(dd,J＝16.5,5.1Hz,1H),2.92(dd,J＝16.4,9.8Hz,1H).¹³C NMR(151MHz,DMSO-d6)δ156.34,153.05,149.83,149.49,148.52,146.82,133.65,133.10,127.98,126.11,122.82,121.27,118.76,117.90,116.78,112.64,110.56,106.90,75.69,60.23,56.02,32.60.HRMS(EI):calcd for C₂₃H₂₀F₃NO₃[M]⁺m/z 415.1395；found,415.1397.

Synthesis of trans-2- (2,4, 5-trifluorophenyl) -3-nitro-6-hydroxy-7-cyano-3, 4-dihydro-2H-benzo [ f ] chroman (5)

Weighing trans-2- (2,4, 5-trifluorophenyl) -3-nitro-6-methoxy-7-cyano-3, 4-dihydro-2H-benzo [ f)]Chroman (1.00g, 2.41mmol) in a 100mL three-necked flask, 10mL CH is added₂Cl₂Dissolve and stir at-78 deg.C for 10 min. Adding BBr₃(1.81g, 7.23mmol), the apparatus was transferred to ambient temperature, stirring was continued and the progress of the reaction was monitored by TLC. After the conversion of the raw materials is completed, dropwise adding CH under ice bath₃And (5) OH. CH for organic phase₂Cl₂(3X 15mL) extraction with anhydrous Na₂SO₄Drying and purification on silica gel column (200-300 mesh) (PE: EA: 5:1) gave 0.75g of tan product in 77.6% yield.¹H NMR(400MHz,DMSO-d6)δ10.65(s,1H),8.20(s,1H),8.02-7.95(m,1H),7.65(d,J＝8.9Hz,1H),7.61-7.50(m,1H),7.07(s,1H),6.98(d,J＝8.9Hz,1H),5.89(d,J＝11.0Hz,1H),5.86-5.79(m,1H),3.46(d,J＝6.0Hz,1H),3.10(dd,J＝14.5,4.6Hz,1H).LC-MS(ESI)m/z 399.21[M-H]^-.

Synthesis of trans-2- (2,4, 5-trifluorophenyl) -3-nitro-7-cyano-3, 4-dihydro-2H-benzo [ f ] chroman-6-substituted derivatives (6a and 6d)

trans-2- (2,4, 5-trifluorophenyl) -3-nitro-6- (methoxy-d 3) -7-cyano-3, 4-dihydro-2H-benzo [ f ] chroman (6a)

Weighing trans-2- (2,4, 5-trifluorophenyl) -3-nitro-6-hydroxy-7-cyano-3, 4-dihydro-2H-benzo [ f)]Chroman (1.00g,2.50mmol), deuterated iodomethane (0.40g,2.75mmol), potassium carbonate (0.79g,7.50mmol) are dissolved in a 100mL three-necked flask with the addition of 15mL acetonitrile. The temperature was raised to 40 ℃ and the reaction was monitored by TLC. After the reaction is finished, the reaction solution is cooled to room temperature, 10mL of water is added, ethyl acetate is extracted for three times, and anhydrous Na₂SO₄Drying and purifying by 200-mesh 300-mesh silica gel column (PE: EA: 8: 1). 0.68g of a pale yellow product is obtained in 65.4% yield.¹H NMR(400MHz,DMSO-d6)δ8.41(d,J＝2.7Hz,1H),7.81(d,J＝7.81Hz,2H),7.76-7.67(m,1H),7.61-7.50(m,1H),7.25(s,1H),7.16(d,J＝8.9Hz,1H),5.93(d,J＝7.8Hz,1H),5.82-5.77(m,1H),3.73-3.66(m,1H),3.60(m,1H).LC-MS(ESI)m/z 416.30[M-H]^-.

trans-2- (2,4, 5-trifluorophenyl) -3-nitro-6-ethoxy-7-cyano-3, 4-dihydro-2H-benzo [ f ] chroman (6b)

The synthesis method is referred to 6 a. This gave 0.80g of a pale yellow solid in 66.0% yield.¹H NMR(400MHz,CDCl₃)δ8.11(s,1H),7.69(d,J＝8.9Hz,1H),7.24-7.19(m,1H),7.07(d,J＝9.0Hz,1H),7.05-7.00(m,1H),6.99(s,1H),5.79(d,J＝7.6Hz,1H),5.34-5.29(m,1H),3.83(dd,J＝16.2,8.5Hz,1H),3.51(dd,J＝16.3,5.8Hz,1H).LC-MS(ESI)m/z427.39[M-H]^-.

Synthesis of trans-2- (2,4, 5-trifluorophenyl) -7-cyano-3, 4-dihydro-2H-benzo [ f ] chroman-3-amine-6-substituted derivatives (7a and 7d)

trans-2- (2,4, 5-trifluorophenyl) -6- (methoxy-d 3) -7-cyano-3, 4-dihydro-2H-benzo [ f ] chroman-3-amine (7a)

Weighing trans-2- (2,4, 5-trifluorophenyl) -3-nitro-6- (methoxyl-d 3) -7-cyano-3, 4-dihydro-2H-benzo [ f]Chroman (0.50g,1.20mmol), zinc powder (0.78g,12.00mmol), 4mL of 6N hydrochloric acid in a 50mL two-necked reaction flask, and 5mL of CH₃CH₃OH is dissolved, the mixture is fully stirred at normal temperature, and the progress of the reaction is monitored by TLC. After the conversion of the raw materials is completed, adding saturated bicarbonate to quench the reaction. The organic phase was extracted three times with ethyl acetate (3X 10mL) and Na anhydrous₂SO₄Drying and purifying by silica gel column (200-300 mesh) (PE: EA is 1: 1). 0.25g of white powder was obtained, the yield was 54.3%. Melting point: 434.96-436.90 ℃.¹H NMR(400MHz,DMSO-d6)δ8.45(s,1H),7.80(d,J＝8.9Hz,1H),7.77-7.64(m,2H),7.29(s,1H),7.10(d,J＝8.9Hz,1H),5.02(d,J＝9.1Hz,1H),3.48(dd,J＝9.3,5.5Hz,1H),2.88(dd,J＝16.1,9.9Hz,1H),1.75(s,2H).HRMS(EI):calcd for C₂₁H₁₂D₃F₃N₂O₂[M]⁺m/z 387.3765；found,387.3762.

trans-2- (2,4, 5-trifluorophenyl) -6-ethoxy-7-cyano-3, 4-dihydro-2H-benzo [ f ] chroman-3-amine (7d)

The synthesis method is referred to in fig. 7 a. 0.50g of white powder was obtained, and the yield was 55.0%. Melting point: 446.23-447.20 ℃.¹H NMR(400MHz,DMSO-d6)δ8.46(s,1H),7.80(d,J＝9.0Hz,1H),7.78-7.64(m,2H),7.29(s,1H),7.09(d,J＝8.9Hz,1H),5.02(d,J＝9.2Hz,1H),4.38-4.35(m,1H),3.47(d,J＝4.5Hz,1H),2.87(dd,J＝16.3,10.0Hz,1H),1.78(s,2H).HRMS(EI):calcd for C₂₂H₁₇F₃N₂O₂[M]⁺m/z 398.3852；found,398.3855.

2-methoxy-6-cyano-7-methoxy-1-naphthaldehyde (31)

The synthesis method is referred to 9 a. 2.00g of a white solid was obtained, yield 74.5%.¹H NMR(400MHz,DMSO-d₆):δ10.71(s,1H),8.77(s,1H),8.50(s,1H),8.29(d,J＝8.4Hz,1H),7.55(d,J＝8.8Hz,1H),4.09(s,3H),3.98(s,3H).LC-MS(ESI)m/z 242.10[M+1]⁺.

2-hydroxy-6-cyano-7-methoxy-1-naphthaldehyde (32)

The synthesis method is referred to as 11 a. 1.50g of a white yellow solid was obtained with a yield of 70.0%.¹H NMR(400MHz,DMSO-d₆):δ12.14(s,1H),10.68(s,1H),8.58(s,1H),8.35(s,1H),8.03(d,J＝9.2Hz,1H),7.11(d,J＝8.8Hz,1H),3.93(s,3H).LC-MS(ESI)m/z 296.10[M+1]⁺,294.10[M-1]^-.

2- (2, 5-trifluorophenyl) -6-methoxy-7-cyano-3-nitro-2H-chroman (33)

The synthesis method is referred to as 13 a. 1.50g of an orange solid was obtained in a yield of 40%.¹H NMR(400MHz,DMSO-d₆)δ9.13(s,1H),8.44(s,1H),7.97(d,J＝9.1Hz,1H),7.88(s,1H),7.35(td,J＝9.4,4.5Hz,1H),7.24(dd,J＝23.1,8.5Hz,2H),7.04(d,J＝8.9Hz,1H),6.99(s,1H),4.09(s,3H).LC-MS(ESI)m/z 395.08[M+1]⁺.

trans-2- (2, 5-trifluorophenyl) -6-methoxy-7-cyano-3-nitro-3, 4-dihydro-2H-benzo chromane (34)

Synthetic method referring to 6a, 1.10g of a pale yellow solid was obtained with a yield of 23%.¹H NMR(400MHz,CDCl₃)δ8.04(s,1H),7.63(d,J＝9.0Hz,1H),7.02(tt,J＝13.8,7.0Hz,4H),6.94(s,1H),5.86(d,J＝6.7Hz,1H),5.28(q,J＝6.5Hz,1H),3.97(s,3H),3.79(dd,J＝16.7,7.2Hz,1H),3.38(dd,J＝16.7,5.6Hz,1H).LC-MS(ESI)m/z 409.10[M-1]^-.

trans-2- (2, 5-difluorophenyl) -6-methoxy-7-cyano-3, 4-dihydro-2H-benzo chroman-3-amine (7c)

Synthetic reference 7 a. 1.00g of a white solid was obtained in a yield of 13%. The melting point is 233.7-235.1 ℃,¹H NMR(400MHz,DMSO-d₆)δ8.44(s,1H),7.79(d,J＝8.9Hz,1H),7.43-7.28(m,3H),7.25(s,1H),7.09(d,J＝8.9Hz,1H),5.17(d,J＝8.0Hz,1H),4.04(s,3H),3.64(d,J＝5.7Hz,1H),2.96(dd,J＝16.6,9.3Hz,1H).¹³C NMR(101MHz,DMSO-d₆)δ157.10,154.60,136.96,136.50,130.48,129.09,123.39,117.98,117.84,117.12,116.19,116.18,116.17,115.97,112.77,102.28,99.86,76.36,56.66,47.83,29.86.HRMS(ESI):calcd for C₂₀H₁₅F₂NO₃[M+H]⁺367.1020,found 367.1259.Purity:98.44％(t_R14.12min).

example 2 biological Activity assay

The experimental principle is as follows: normally, hepatic stellate cells are in a non-activated state, but in a state of long-term liver injury, hepatic stellate cells are activated and transformed into myofibroblasts, and a large amount of alpha-smooth actin (alpha-SMA) and extracellular matrix are produced to promote hepatic fibrosis. Among them, TGF-beta is an important fibroblast promoting factor, and can directly cause hepatic stellate cell activation and phenotype change 1. Therefore, whether the compound has the effect of inhibiting cell activation or not can be evaluated by utilizing the phenotype change of hepatic stellate cell LX2 induced by TGF-beta

The experimental steps are as follows:

1) culturing LX2 cells in a DMEM + 2% FBS medium for passage according to a ratio of 1: 2;

2) collecting cells when the growth density of LX2 is 80-90%, adding 1.5ml of pancreatin for 3 minutes, adding 3ml of MEM culture medium for termination, and collecting the cells in a 15ml centrifuge tube;

3) uniformly mixing 20 ul of cell liquid and 20 ul of trypan blue according to a ratio of 1:1, counting cells, and recording data; centrifuging a 15ml centrifuge tube for 5 minutes at 300 g;

4) resuspending the cells to 15000 cells/ml with DMEM, mixing well, and adding 500. mu.l/well to a # 352424 well plate with the gel;

5) after the cells are attached to the wall, starving for 12h by changing DMEM and 0.5% FBS;

6) preparing 10ng/ml of TGF-beta by using a DMEM medium, and preparing a compound by using a prepared TGF-beta solution;

7) adding the prepared compound into a 24-well plate, uniformly mixing at 500 mu l/well, placing in an incubator at 37 ℃, and incubating for 24 hours;

8) the cells were washed twice with PBS buffer, 100. mu.l of 1 × loading buffer was added to each well, and the cells were collected in 1.5ml EP tubes;

9) boiling the sample at 100 ℃ for 10 minutes, centrifuging and putting the sample into a refrigerator at-20 ℃ for later use;

10) cellular immunoblotting (western blot);

the experimental results are as follows:

ND: not testing

And (4) conclusion:

the 10 test compounds were able to reduce α -SMA expression in a concentration-dependent manner to varying degrees, thereby inhibiting activation of LX 2; wherein the relative inhibition activity of 7c-1, 7j and 15i is stronger at two concentrations of 1 and 10 mu M, and is obviously stronger than that of positive OCA; the 29i compound has stronger inhibiting effect under the concentration of 10 mu M; 7c-2, 7r, 7y, 15f, 7 exhibited an inhibitory activity at 10. mu.M comparable to that of the positive OCA at the same concentration, and was relatively weak at 1. mu.M. 29g had little inhibitory effect on LX 2.