Tricyclic compound and its preparation method and medical use

Abstract

A tricyclic compound, a preparation method and medical use thereof. In particular, it relates to a compound represented by general formula (I), a pharmaceutical composition containing the same, a preparation method and use thereof in preventing and / or treating various diseases caused by toxic aldehydes. The definition of each group in general formula (I) is the same as that in the specification.

Description

Technical Field

[0001] The present application relates to a tricyclic compound for preventing and / or treating diseases caused by biologically active carbonyl substances, a preparation method thereof, and a pharmaceutical composition containing the tricyclic compound. Background Art

[0002] Active carbonyl compounds represented by aldehyde compounds refer to all highly active electrophilic compounds containing one or more carbonyl groups. They have a wide range of sources and are involved in many life behaviors and physiological activities. Aldehydes are ubiquitous in the environment, from air, water, soil to food, daily necessities and indoor living places (Koren and Bisesi, CRC press, 2002). The natural sources of aldehydes include a series of pathways such as plants, animals, microorganisms and natural life processes (O'Brien et al., Critical reviews in toxicology, 2005, 35 (7): 609-662.). Among them, plants are the main source of aldehydes, such as vanillin, cinnamaldehyde, benzaldehyde, citral, crotonaldehyde, etc., which are usually plant-derived aldehydes (Koren and Bisesi, CRC press, 2002; Feron et al., Mutation Research / Genetic Toxicology, 1991, 259 (3-4): 363-385.). Anthropogenic sources are mainly automobile exhaust, burning of substances, smoking, overcooking of certain foods, industrial emissions, etc. The aldehydes produced from these sources include formaldehyde, acetaldehyde, benzaldehyde, propionaldehyde, acrolein, glyoxal, glutaraldehyde, crotonaldehyde, m-tolualdehyde, 2,5-dimethylbenzaldehyde, 3-hydroxybenzaldehyde, etc. (Koren and Bisesi, CRC press, 2002; O'Brien et al., Critical reviews in toxicology, 2005, 35(7):609-662.; Marnett et al., Health Effects Institute National Academy, 1988.).In addition to these sources, aldehydes are also produced in the body through different physiological processes, such as lipid peroxidation, biotransformation of drugs and foods, intermediates in biosynthesis and decomposition pathways, and end products of enzymatic reactions. Endogenous production pathways can all produce aldehydes (Feron et al., Mutation Research / Genetic Toxicology, 1991, 259(3-4): 363-385.; O'Brien et al., Critical reviews in toxicology, 2005, 35(7): 609-662.). The aldehydes usually produced through these metabolic pathways are 4-hydroxy-2-nonenal, nonenal, acetaldehyde, acrolein, glutamate γ-semialdehyde, malondialdehyde, glyoxal, methylglyoxal, ethanolaldehyde, glyceraldehyde, lactaldehyde, etc. (Esterbauer et al., Free radical Biology and medicine, 1991, 11(1): 81-128.; Voulgaridou et al., Mutation Research / Fundamental and Molecular Mechanisms of Mutagenesis, 2011, 711(1-2): 13-27.; Nelson et al., Currentopinion in pharmacology, 2017, 33: 56-63.; Barrera et al., Antioxidants & redoxsignaling, 2015, 22(18): 1681-1702.).

[0003] Most active carbonyl compounds have high reactivity. They can act as electrophiles and react with nucleophiles to form adducts. This electrophilic-nucleophilic reaction and the adducts formed therefrom are the main reasons for aldehydes to exert their physiological functions and cause toxicity. Their overexpression and clearance disorders involve but are not limited to mitochondrial damage, membrane damage, endoplasmic reticulum stress, activation of inflammatory mediators, immune dysfunction, etc. (Moghe et al., Toxicological Sciences, 2015, 143 (2): 242-255.). For example, 4-hydroxy-2-nonenal and nonenal produced during lipid peroxidation are very easy to react with low molecular weight compounds or macromolecules (such as proteins and DNA) under physiological systems. Existing reports indicate that diseases related to their adducts include cancer, neurodegenerative diseases, chronic inflammatory diseases and autoimmune diseases (Barrera et al., Antioxidants & redox signaling, 2015, 22 (18): 1681-1702.). Under normal physiological system, aldehydes are in equilibrium, but when this equilibrium is disturbed, aldehydes and proteins, nucleic acids and phospholipids will be produced, as well as advanced lipid oxidation end products (ALE) and advanced glycation end products (AGE) will be generated and accumulated (Singh et al., The Korean Journal of Physiology & Pharmacology, 2014, 18 (1): 1-14.). For example, methylglyoxal, a byproduct of glucose metabolism, can react with arginine (Arg) and lysine (Lys) on proteins to form imidazolinone and carboxyethyl lysine; glyoxal, a product of carbohydrate and ascorbate self-oxidation, can react with Lys to form carboxymethyl lysine. Dicarbonyl can directly and specifically act on Arg residues, and Arg residues are most likely to be located at the functional sites of proteins. Therefore, Arg modification leads to the loss of side chain guanidinyl groups and important functional Arg residues. Under normal circumstances, the protein carbonylation content is usually 1-5%, but its content increases during aging and disease. Proteins modified by methylglyoxal and glyoxal will be recognized by the body as misfolded proteins and directly degraded by the proteasome (Thornalley et al., Nucleic acids research, 2010, 38(16): 5432-5442).

[0004] Carbonyl stress caused by reactive carbonyl compounds can lead to nonspecific modification of proteins and genetic material, thus causing cytotoxicity. Carbonyl stress can mediate mitochondrial protein dysfunction and increased reactive oxygen formation (Yao and Brownlee, Diabetes, 2010, 59(1): 249-255.), crystallin and inflammatory protein expression (Yao and Brownlee, Diabetes, 2010, 59(1): 249-255.; Ahmed et al., Diabetologia, 2005, 48(8): 1590-1603.), abnormal blood lipid-related lipoproteins (Rabbani et al., Diabetologia. 233 SPRING ST, NEW YORK, NY 10013 USA: SPRINGER, 2009, 52: S498-S499.), activation of mitochondrial apoptosis pathways (Chan et al., Journal of cellular Biochemistry, 2007, 100(4): 1056-1069.), cell detachment from the extracellular matrix and apoptosis (Dobler et al., Diabetes, 2006, 55(7): 1961-1969.). Protein damage caused by reactive carbonyl substances is not only caused by carbonyl stress, but also by oxidative stress formed by enhancing the generation of reactive oxygen species to modify the amino acid side chain residues of specific proteins, leading to protein carbonylation and causing changes in protein activity and function. Protein carbonylation reversibly and irreversibly changes the spatial conformation of the polypeptide chain, partially or completely inhibiting protein activity, thereby causing cell dysfunction and tissue damage.

[0005] In addition, highly reactive carbonyl compounds can also reduce enzyme activity by modifying the enzyme structure. For example, the reductase activity of liver mitochondrial cytochrome C is negatively correlated with protein carbonylation, indicating that protein oxidation can significantly reduce enzyme activity (Bruno et al., Journal of proteome research, 2009, 8 (4): 2070-2078.). Reactive carbonyl substances increase protein oxidation and carbonylation by inhibiting key cellular enzymes such as glutathione reductase and peroxidase (Shangari et al., Biochemical Pharmacology, 2006, 71 (11): 1610-1618.). In humans and mice, adipocyte fatty acid binding protein-4 and epidermal fatty acid binding protein-5 are carbonylated, resulting in a decrease in their ability to bind fatty acids, a decrease in fat hydrolysis and obesity. Fatty acid transport proteins contain two cysteine ​​(Cys) residues that are also susceptible to carbonylation (Febbraio et al., Cellular Lipid Binding Proteins. Springer, Boston, MA, 2002: 193-197.). Fatty acid binding proteins prevent the lipotoxicity of long-chain fatty acids by binding or cross-linking with oxidized active long-chain fatty acids. Depletion of liver fatty acid binding proteins will transform non-alcoholic fatty liver disease into non-alcoholic steatohepatitis (Charlton et al., Hepatology, 2009, 49 (4): 1375-1384.).

[0006] Compared with reactive oxygen free radicals, reactive carbonyl substances derived from lipids and carbohydrates are more stable, can be integrated into or even escape cell degradation, and can attack targets after formation. Therefore, these soluble active mediators and AGE precursors are not only cytotoxic, but also act as mediators and transmitters of oxidative stress and tissue damage, play the role of "cytotoxic second messengers", and are risk factors for multiple diseases throughout the body. Existing studies have reported that human diseases associated with reactive carbonyls include cardiovascular diseases, such as atherosclerosis, hypertension, and cardiopulmonary dysfunction; respiratory diseases, such as airway neuroinflammation, chronic obstructive pulmonary disease, respiratory allergies, and asthma; neurodegenerative diseases, such as Alzheimer's disease; diabetes and its complications; eye diseases, such as dry eye, cataract, retinopathy, keratoconus, Fuchs' corneal endothelial dystrophy, retinitis pigmentosa, glaucoma, allergic conjunctivitis, and uveitis; skin diseases, such as psoriasis, psoriasis, contact dermatitis, atopic dermatitis, acne, and Sjögren's syndrome; autoimmune diseases, such as lupus erythematosus; nervous system diseases, such as autism, central nervous system toxicity, and amyotrophic lateral sclerosis; digestive system diseases, such as neurohepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, and ulcerative colitis; and obesity, cancer, and aging-related diseases. Therefore, reducing or eliminating reactive carbonyls can improve or alleviate these pathological symptoms.

[0007] It has not been proposed in the art to treat various conditions associated with reactive carbonyl species by administering small molecule therapeutic agents that act as traps for reactive carbonyl species (e.g., malondialdehyde, 4-hydroxynonenal). Therefore, there is a need to treat, prevent, and / or reduce the risk of diseases or conditions involving reactive carbonyl toxicity in the pathogenesis. The present invention addresses such needs. Summary of the invention

[0008] After intensive research, the inventors have designed and synthesized a series of tricyclic compounds, which can be used to prevent and treat diseases associated with active carbonyl compounds.

[0009] Therefore, an object of the present invention is to provide a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0010]

[0011] in:

[0012] A 1 Select from N or CR 1 ;

[0013] A 2 Select from N or CR 2 ;

[0014] A 3 Select from N or CR 3 ;

[0015] A 4 Select from N or CR 4 ;

[0016] Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from Q;

[0017] R 1 and R 2 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O) m R a 、-S(O) m NR a R b 、-NHS(O) m R a ;

[0018] R 3 and R 4 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O) m R a 、-S(O) m NR a R b 、-NHS(O) m R a ;

[0019] R 5 and R 6Each is independently selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0020] or R 5 and R 6 Together with the carbon atom to which they are attached, they form a cycloalkyl or heterocyclic group; the cycloalkyl or heterocyclic group is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl;

[0021] Q is selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O) m R a 、-S(O) m NR a R b 、-NHS(O) m R a wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0022] R a and R b Each is independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0023] or R a and R b Together with the nitrogen atom to which they are attached, they form a nitrogen-containing heterocyclic group, which is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl;

[0024] m is an integer from 0 to 2.

[0025] In one embodiment, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein A 3 Selected from CR 3 ; A 4 Selected from CR 4 ; R 3 and R 4 are independently selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, C 1 -C 6 Preferably, R 3 and R 4 are each independently hydrogen.

[0026] In another embodiment, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein A 1 Selected from CR 1 ; A 2 Select from N or CR 2 ; R 1 and R 2 are independently selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, C 1 -C 6 Preferably, R 1 and R 2 are each independently hydrogen.

[0027] In another embodiment, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0028] in,

[0029] Ring A is C 3 -C 8 Cycloalkyl or 5 to 8 membered heterocyclic group, preferably C 5 -C 6 Cycloalkyl or 5- to 7-membered heterocyclyl; the cycloalkyl or heterocyclyl is optionally further substituted by one or more groups selected from Q;

[0030] Q is selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O) m R a 、-S(O) m NR a R b 、-NHS(O) m R a wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0031] R a and R b Each is independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0032] or R a and R bTogether with the nitrogen atom to which they are attached, they form a nitrogen-containing heterocyclic group, which is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl;

[0033] m is an integer from 0 to 2.

[0034] In another embodiment, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0035] in,

[0036] Ring A is C 6 -C 10 Aryl or 5-6 membered heteroaryl, the C 6 -C 10 The aryl or 5-6 membered heteroaryl is optionally further substituted with one or more groups selected from Q;

[0037] Q is selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O) m R a 、-S(O) m NR a R b 、-NHS(O) m R a wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0038] R a and R bEach is independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0039] or R a and R b Together with the nitrogen atom to which they are attached, they form a nitrogen-containing heterocyclic group, which is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl;

[0040] m is an integer from 0 to 2.

[0041] In another embodiment, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring A is selected from The ring A is optionally further substituted by one or more groups selected from Q;

[0042] Q is as defined in the general formula (I).

[0043] In another embodiment, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein Q is selected from halogen, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl, 5-6 membered heterocyclic group, C 6 -C 10 Aryl, 5-6 membered heteroaryl, wherein the C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl, 5-6 membered heterocyclic group, C 6 -C 10Aryl and 5-6 membered heteroaryl are optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0044] Preferably, Q is selected from halogen, oxo, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 6 -C 10 Aryl, the C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 6 -C 10 Aryl is optionally further selected from halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, C 1 -C 6 The haloalkoxy group is substituted with one or more groups.

[0045] In another embodiment, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0046]

[0047] in:

[0048] A 2 is selected from N or CH;

[0049] A 5 and A 6 Each independently selected from -O-, -S-, -NH-, -CH 2 -、-CH 2 -O-; preferably -O-;

[0050] Q is selected from halogen, oxo, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 6 -C10 Aryl, the C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 6 -C 10 Aryl is optionally further selected from halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, C 1 -C 6 One or more haloalkoxy groups are substituted;

[0051] n is 0, 1, or 2;

[0052] R 5 , R 6 As defined in general formula (I).

[0053] In another embodiment, the compound represented by the general formula (I) or (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0054]

[0055] in:

[0056] A 2 is selected from N or CH;

[0057] A 5 and A 6 Each independently selected from -O-, -S-, -NH-, -CH 2 -、-CH 2 -O-; preferably -O-;

[0058] Q 1 Selected from halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, the C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl is optionally further selected from halogen, C 1 -C 6 Alkyl, C 1 -C6 Alkoxy, C 1 -C 6 Haloalkyl, C 1 -C 6 One or more haloalkoxy groups are substituted;

[0059] R 7 Selected from hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, C 1 -C 6 Haloalkoxy;

[0060] p is 0, 1, or 2;

[0061] R 5 , R 6 As defined in general formula (I).

[0062] In another embodiment, the compound represented by the general formula (I), (II) or (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0063] in:

[0064] R 5 and R 6 are independently selected from hydrogen, halogen, amino, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl; said C 1 -C 6 Alkyl, C 3 -C 6 The cycloalkyl group is optionally further substituted with one or more groups selected from halogen;

[0065] or R 5 With R 6 Together with the carbon atom to which they are attached, they form C 3 -C 6 Cycloalkyl or 5- to 6-membered heterocyclic group; the cycloalkyl or heterocyclic group is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl.

[0066] In another embodiment, the compound represented by the general formula (I), (II) or (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0067] R 5 and R 6 Each independently selected from C 1 -C 6 Alkyl group, preferably methyl group.

[0068] Typical compounds of the present invention include, but are not limited to:

[0069]

[0070]

[0071]

[0072]

[0073] or its tautomer, meso racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt.

[0074] The present invention further provides a method for preparing the compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which comprises the following steps:

[0075]

[0076] The compound Ig is reacted with an alkyl Grignard reagent to obtain a compound of formula (I), wherein the alkyl Grignard reagent is preferably methylmagnesium chloride or methylmagnesium bromide; the reaction is preferably carried out in a solvent, wherein the solvent is preferably anhydrous tetrahydrofuran;

[0077] Among them A 1 , A 2 , A 3 , A 4 , Ring A, R 5 , R 6 As defined in general formula (I).

[0078] The present invention further provides a pharmaceutical composition, which contains the compound represented by the general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0079] The present invention further provides the use of the compound represented by the general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or its pharmaceutically acceptable salt or a pharmaceutical composition containing the same in the preparation of a toxic aldehyde capture agent.

[0080] The present invention further provides the use of the compound represented by the general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or a pharmaceutical composition containing the same in the preparation of a drug for preventing and / or treating diseases associated with active carbonyl compounds.

[0081] Another aspect of the present invention provides a compound represented by the general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a toxic aldehyde capture agent.

[0082] On the other hand, the present invention provides a compound represented by the general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or a pharmaceutical composition containing the same, which is used as a drug; preferably, the drug is used to prevent and / or treat diseases associated with active carbonyl compounds.

[0083] On the other hand, the present invention provides a compound represented by the general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used for preventing and / or treating diseases associated with active carbonyl compounds.

[0084] A method for preventing and / or treating diseases associated with active carbonyl compounds, comprising administering to a patient in need thereof a preventive or therapeutically effective amount of a compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0085] According to the present invention, the diseases associated with active carbonyl compounds can be eye diseases, skin diseases, autoimmune diseases, digestive system diseases, cardiovascular diseases, respiratory system diseases, neurodegenerative diseases, obesity, cancer and aging-related diseases; preferably eye diseases, more preferably allergic conjunctivitis and dry eye.

[0086] The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the following: sweeteners, flavoring agents, colorants and preservatives to provide pleasing and palatable pharmaceutical preparations. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets for mixing. These excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as microcrystalline cellulose, crosslinked sodium carboxymethyl cellulose, corn starch or alginic acid; binders such as starch, gelatin, polyvinyl pyrrolidone or gum arabic; lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release action over a longer period of time. For example, water soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time extending materials such as ethylcellulose, cellulose acetate butyrate may be used.

[0087] Oral preparations may also be provided in hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oily vehicle such as peanut oil, liquid paraffin or olive oil.

[0088] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersants or wetting agents, which may be naturally occurring phosphatides such as lecithin, or condensation products of alkylene oxides with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain fatty alcohols, for example, heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, for example, polyethylene oxide sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene oxide dehydrated sorbitan monooleate. The aqueous suspension may also contain one or more preservatives, for example ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, for example sucrose, saccharin or aspartame.

[0089] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. Oil suspensions can contain thickeners such as beeswax, hard paraffin or cetyl alcohol. Sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

[0090] Dispersible powders and granules suitable for preparing aqueous suspensions may provide the active ingredient by adding water and a dispersant or wetting agent, suspending agent or one or more preservatives for mixing. Suitable dispersants, wetting agents and suspending agents are as described above. Other excipients such as sweeteners, flavoring agents and coloring agents may also be added. These compositions may be preserved by adding an antioxidant such as ascorbic acid.

[0091] The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyethylene oxide sorbitol monooleate. Emulsions can also contain sweeteners, flavoring agents, preservatives, and antioxidants. Syrups and elixirs prepared with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose can be used. Such preparations can also contain a demulcent, a preservative, a coloring agent, and an antioxidant.

[0092] The pharmaceutical composition of the present invention may be in the form of a sterile injectable aqueous solution. Acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerol and processed to form a microemulsion. The injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, the solution and microemulsion may be preferably administered in a manner that maintains a constant circulating concentration of the compound of the present invention. To maintain this constant concentration, a continuous intravenous drug delivery device may be used.

[0093] The pharmaceutical composition of the present invention can be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared by known techniques with the above-mentioned suitable dispersants, wetting agents and suspending agents. The sterile injection preparation can also be a sterile injection solution or suspension prepared in a non-toxic parenteral acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. In addition, sterile fixed oil can be conveniently used as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic glycerol mono- or di-esters can be used. In addition, fatty acids such as oleic acid can also be used to prepare injections.

[0094] The pharmaceutical composition of the present invention may be in a form for topical administration, such as creams, suspensions, emulsions, ointments, gels, drops, oils, lotions, films, patches, tapes, inhalants, sprays. Intraocular administration may be in the form of subconjunctival, subfascial capsules; retrobulbar or intravitreal injections, accumulation injections or implants. The compounds administered by these routes may be in the form of solutions or suspensions. The compounds administered by accumulation injection may contain a pharmaceutically acceptable carrier or excipient. These pharmaceutically acceptable carriers or excipients may be natural or synthetic, and may be biodegradable or non-biodegradable, and promote drug release in a controlled manner. Implants for controlled release of compounds may be composed of natural or synthetic, biodegradable or non-biodegradable materials. The carrier is acceptable because it is compatible with the other components of the composition and is not harmful to the patient. Some examples of carriers include sugars such as lactose glucose and sucrose; starches such as corn starch and potato starch; cellulose; and cyclodextrins.

[0095] It is well known to those skilled in the art that the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health condition, the patient's behavior, the patient's diet, the administration time, the administration method, the excretion rate, the combination of drugs, etc. In addition, the best treatment method, such as the mode of treatment, the daily dosage of the general compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment plans.

[0096] The present invention can contain the compound shown in general formula (I), and its pharmaceutically acceptable salt, hydrate or solvate as active ingredient, mixed with pharmaceutically acceptable carrier or excipient to prepare composition, and prepared into clinically acceptable dosage form. Derivatives of the present invention can be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions, etc. The compounds of the present invention can be used as the only active ingredient, or can be used in combination with other therapeutic agents. Combined therapy is achieved by administering each therapeutic component simultaneously, separately or successively.

[0097] Detailed description of the invention

[0098] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0099] The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, that is, the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14C, hydrogen isotopes include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl and bromine include 79 Br and 81 Br.

[0100] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0101] The term "alkylene" refers to straight-chain and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v-(v is an integer from 1 to 10, preferably an integer from 1 to 6), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene, etc.; alkylene may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available connection point, and the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate. When the number of substituents in the alkylene is greater than or equal to 2, the substituents may be fused together to form a ring structure.

[0102] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0103] The term "alkenylene" refers to straight and branched divalent alkenyl groups, wherein alkenyl is as defined above.

[0104] The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl, etc. Alkynyl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0105] The term "alkynylene" refers to straight and branched divalent alkynyl groups, wherein alkynyl is as defined above.

[0106] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused and bridged cycloalkyls.

[0107] The term "spirocycloalkyl" refers to a polycyclic group in which a carbon atom (called a spiral atom) is shared between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 5 to 12 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0108]

[0109] The term "condensed cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of condensed cycloalkyls include:

[0110]

[0111] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 12 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0112]

[0113] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0114] The term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, but does not include -OO-, -OS- or -SS- ring parts, and the remaining ring atoms are carbon. Preferably, it contains 3 to 10 ring atoms, of which 1 to 4 are heteroatoms; most preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably, it contains 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups.

[0115] The term "spiro heterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more of the ring atoms is selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 5 to 12 yuan, more preferably 7 to 10 yuan. According to the number of shared spiral atoms between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably, it is a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0116]

[0117] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0118]

[0119] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system, and one or more of the ring atoms is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 5 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0120]

[0121] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0122] wait.

[0123] The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0124] The term "aryl" or "aromatic ring" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group with a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:

[0125]

[0126] The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0127] The term "heteroaryl" or "heteroaromatic ring" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0128]

[0129] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0130] The term "alkoxy" refers to-O-(alkyl) and-O-(cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described above. The non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0131] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0132] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0133] The term "hydroxy" refers to an -OH group.

[0134] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0135] The term "amino" refers to -NH 2 .

[0136] The term "cyano" refers to -CN.

[0137] The term "nitro" refers to -NO2 .

[0138] The term "oxo" or "oxo" refers to =0.

[0139] The term "carboxy" refers to -C(O)OH.

[0140] The term "thiol" refers to -SH.

[0141] The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0142] The term "acyl" refers to a compound containing a -C(O)R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0143] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0144] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0145] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0146] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.

[0147] "Carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. BRIEF DESCRIPTION OF THE DRAWINGS

[0148] Figure 1 This is a graph showing the time variation of the capture reaction of the example compounds of the present invention on nonenal.

[0149] Figure 2 This is a graph showing the therapeutic scoring results of the compound of Example 12 of the present invention in the C48 / 80-induced allergic conjunctivitis animal model in Wistar rats. DETAILED DESCRIPTION

[0150] The compounds of the present invention and their preparation are further understood by way of examples, which illustrate some methods of preparing or using the compounds. However, it is to be understood that these examples do not limit the scope of the present invention. Variations of the present invention known now or further developed are considered to fall within the scope of the present invention described herein and claimed.

[0151] The compounds of the present invention are prepared using convenient starting materials and common preparation steps. The present invention provides typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants. However, unless otherwise specified, other reaction conditions can also be adopted. The optimized conditions may change with the use of specific reactants or solvents, but in general, the reaction optimized steps and conditions can be determined.

[0152] In addition, some protecting groups may be used in the present invention to protect certain functional groups from unnecessary reactions. Protecting groups suitable for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art. For example, TW Greene and GM Wuts's "Protective Groups in Organic Preparations" (3rd edition, Wiley, New York, 1999 and references therein) describes in detail the protection or deprotection of a large number of protecting groups.

[0153] The separation and purification of compounds and intermediates are carried out according to specific needs by appropriate methods and steps, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer chromatography, preparative high performance liquid chromatography or a combination of the above methods. The specific use method can refer to the examples described in the present invention. Of course, other similar separation and purification means can also be adopted. Conventional methods (including physical constants and spectral data) can be used to characterize them.

[0154] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The NMR measurements were performed using a Bruker 300 NMR spectrometer and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethylsilane (TMS).

[0155] Mass spectra were measured using LC (Waters 2695) / MS (Quattro Premier xE) mass spectrometer (manufacturer: Waters) (Photodiode Array Detector).

[0156] The preparative liquid chromatography method used an LC6000 high performance liquid chromatograph (manufacturer: Chuangxin Tongheng).

[0157] The thin layer chromatography silica gel plate used was Qingdao Ocean Chemical GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) had a size of 0.20 mm to 0.25 mm, and the size used in preparative thin layer chromatography (Prep-TLC) to separate and purify the product was 0.5 mm.

[0158] Column chromatography generally uses Qingdao marine silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.

[0159] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from online shopping malls, Beijing Coupling, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Shanghai Inokai, Anaiji Chemical, Shanghai Bid, etc.

[0160] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0161] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0162] Reaction solvent, organic solvent or inert solvent are each expressed as the solvent used that does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine, etc. Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0163] The chemical reactions described in the present invention are generally carried out under normal pressure. The reaction temperature is between -78°C and 200°C. The reaction time and conditions are, for example, between -78°C and 200°C at one atmosphere, and are completed within about 1 to 24 hours. If the reaction is left overnight, the reaction time is generally 16 hours. In the embodiments, unless otherwise specified, the reaction temperature is room temperature, which is 20°C to 30°C.

[0164] The reaction progress in the examples was monitored by thin layer chromatography (TLC), and the developing solvent systems used in the reaction were: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, C: acetone, and the volume ratio of the solvent was adjusted according to the polarity of the compound.

[0165] The eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying compounds include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and trifluoroacetic acid can also be added for adjustment.

[0166] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those known to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention.

[0167] Example

[0168] Example 1: Preparation of 2-(6-amino-2,3-dihydrofuro[3,2-g]quinolin-7-yl)propan-2-ol (1)

[0169]

[0170] Step 1: Preparation of N-(2,3-dihydrobenzofuran-5-yl)acetamide (1a)

[0171] At room temperature, 2,3-dihydrobenzofuran-5-amine (10.0 g, 74.0 mmol) was dissolved in 1,4-dioxane (100 mL). The temperature was lowered to 0°C, and then acetic anhydride (1.50 g, 148 mmol) and pyridine (5.85 g, 74.0 mmol) were added. The reaction was stirred at 25°C for 16 hours, 200 mL of water was added to the reaction solution, and the mixture was extracted with 300 mL of ethyl acetate. The aqueous phase was extracted twice with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 10: 1) to obtain 11.0 g of the title product as a white solid, with a yield of 84.6%.

[0172] Step 2: Preparation of N-(6-nitro-2,3-dihydrobenzofuran-5-yl)acetamide (1b)

[0173] At room temperature, dissolve N-(2,3-dihydrobenzofuran-5-yl)acetamide (10.0 g, 75.2 mmol) in acetic acid (300 mL), cool to 0°C, slowly drop nitric acid (4.98 g, 79.1 mmol). Heat to 30°C and stir to react for 1 hour, cool to 15°C, add 500 mL of ice water to the reaction solution, filter, wash the filter cake three times with water, dry the filter cake, and obtain 9.00 g of the title product as a yellow solid, with a yield of 71.8%.

[0174] Step 3: Preparation of 6-nitro-2,3-dihydrobenzofuran-5-amine (1c)

[0175] At room temperature, N-(6-nitro-2,3-dihydrobenzofuran-5-yl)acetamide (8.00 g, 36.2 mmol) was dissolved in ethanol (300 mL), and hydrochloric acid (50 mL, 33%) was added dropwise, and stirred at 75°C for 2 hours. After the reaction solution was cooled, ammonia water was added dropwise until it was weakly alkaline, filtered, and the filter cake was dried to obtain 6.00 g of the title product as an orange-red solid, with a yield of 92.1%.

[0176] Step 4: Preparation of 5-iodo-6-nitro-2,3-dihydrobenzofuran (1d)

[0177] At room temperature, dissolve 6-nitro-2,3-dihydrobenzofuran-5-amine (7.00 g, 38.9 mmol) in hydrochloric acid (20 mL). Heat to 100°C, stir for 10 minutes, cool to 0°C, and drop saturated sodium nitrite solution (3.22 g, 46.7 mmol). Stir and react at 0°C for 30 minutes, then drop potassium iodide solution (9.68 g, 58.3 mmol). Heat to 70°C, stir and react for 2 hours. Pour the reaction solution into saturated NaHSO 3 The solution was extracted with 300 mL of ethyl acetate, and the organic phase was washed with hydrochloric acid (50 mL, 10%), NaOH solution (50 mL), Na 2 SO 3 The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 5:1) to obtain 5.20 g of the title product as a yellow solid, with a yield of 46.4%.

[0178] Step 5: Preparation of 5-iodo-2,3-dihydrobenzofuran-6-amine (1e)

[0179] At room temperature, 5-iodo-6-nitro-2,3-dihydrobenzofuran (5.00 g, 17.2 mmol) was dissolved in ethanol (80 mL) and water (8 mL), and NH 4 Cl (646 mg, 12.0 mmol) and iron powder (6.27 g, 112 mmol). Stir the reaction at 78°C for 4 hours, filter through diatomaceous earth, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 1:1) to obtain 3.40 g of the title product as a black solid, with a yield of 75.9%.

[0180] Step 6: Preparation of methyl 6-amino-2,3-dihydrobenzofuran-5-carboxylate (1f)

[0181] 5-iodo-2,3-dihydrobenzofuran-6-amine (3.20 g, 12.2 mmol) was dissolved in methanol (50 mL) at room temperature, and triethylamine (1.98 g, 19.6 mmol), Pd(dppf)Cl 2 (897 mg, 1.23 mmol), replace CO gas three times. Stir at 90°C for 16 hours. Filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 5: 1) to obtain 1.80 g of the title product as a yellow solid, yield: 78.3%.

[0182] Step 7: Preparation of (6-amino-2,3-dihydrobenzofuran-5-yl)methanol (1 g)

[0183] At room temperature, dissolve methyl 6-amino-2,3-dihydrobenzofuran-5-carboxylate (1.60 g, 8.60 mmol) in tetrahydrofuran (30 mL), cool to 0°C, and slowly add lithium aluminum tetrahydride (326 mg, 8.60 mmol) in batches. Stir the reaction at room temperature for 0.5 hours, add 50 mL of water to the reaction solution, extract with 50 mL of dichloromethane, and extract the aqueous phase twice with 50 mL of dichloromethane. Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 1: 1) to obtain 0.70 g of the title product as a white solid, with a yield of 49.3%.

[0184] Step 8: Preparation of 6-amino-2,3-dihydrobenzofuran-5-carbaldehyde (1h)

[0185] At room temperature, (6-amino-2,3-dihydrobenzofuran-5-yl)methanol (600 mg, 3.60 mmol) was dissolved in DCM (30 mL), and manganese dioxide (6.30 g, 72.7 mmol) was added. The mixture was stirred at room temperature for 4 hours. Filtered through celite, the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 5:1) to obtain 270 mg of the title product as a yellow solid, with a yield of 46.6%.

[0186] Step 9: Preparation of 1-(3-ethoxy-2,3-dioxopropyl)pyridinium-1-ammonium bromide (1i)

[0187] Pyridine (320 mg, 4.05 mmol) was dissolved in EtOH (15 mL) at room temperature, and ethyl 3-bromo-2-oxopropanoate (718 mg, 3.68 mmol) was added under nitrogen atmosphere, and the mixture was stirred at 65°C for 2 hours. The reaction solution was directly used in the next step.

[0188] Step 10: Preparation of 1-(7-(ethoxycarbonyl)-2,3-dihydrofuran[3,2-g]quinolin-6-yl)pyridin-1-ium bromide (1j)

[0189] The reaction solution from the previous step was cooled to 18-22°C, 6-amino-2,3-dihydrobenzofuran-5-carbaldehyde (270 mg, 1.65 mmol) and pyridine (700 mg, 8.47 mmol) were added, and the mixture was stirred at 80°C overnight under nitrogen atmosphere. The reaction solution was directly used in the next step.

[0190] Step 11: Preparation of ethyl 6-amino-2,3-dihydrofuro[3,2-g]quinoline-7-carboxylate (1k)

[0191] The reaction solution of the previous step was cooled to 70°C, morpholine (800mg, 9.20mmol) was added, and stirred at 80°C for 18 hours under a nitrogen atmosphere. 50mL of water was added to the reaction solution, and the mixture was extracted with 50mL of dichloromethane. The aqueous phase was extracted twice with 50mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 1:2) to obtain 500mg of the title product as a yellow solid.

[0192] Step 12: Preparation of 2-(6-amino-2,3-dihydrofuro[3,2-g]quinolin-7-yl)propan-2-ol (1)

[0193] Under nitrogen atmosphere, methylmagnesium chloride (3N, 3.4 mL, 10.2 mmol) was added to THF (20 mL) at 0°C, and ethyl 6-amino-2,3-dihydrofurano[3,2-g]quinoline-7-carboxylate (1k) (400 mg, 1.50 mmol) dissolved in THF (10 mL) was added, and stirred at room temperature for 4 hours. 50 mL of water was added to the reaction solution, and the mixture was extracted with 50 mL of dichloromethane, and the aqueous phase was extracted twice with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um, 220 nm, 100 A, mobile phase: acetonitrile / water, gradient: 20-90%) to obtain 18.0 mg of the title compound as a light yellow solid, yield: 5.10%.

[0194] LC-MS: m / z 245.12 [M+H] + .

[0195] 1H NMR (400MHz, DMSO) δ7.42 (s, 1H), 7.17 (s, 1H), 6.92 (s, 1H), 5.58 (d, J=36.8Hz, 3H), 4.55 (t, J=8.3Hz, 2H), 3.28 (s, 2H), 1.58 (s, 6H).

[0196] Example 2: Preparation of 2-(7-amino-2,3-dihydrofuro[2,3-g]quinolin-6-yl)propan-2-ol (2)

[0197]

[0198]

[0199] Step 1: Preparation of tert-butyl (2,3-dihydrobenzofuran-5-yl)carbamate (2a)

[0200] At room temperature, 2,3-dihydrobenzofuran-5-carboxylic acid (10.0 g, 61.0 mmol) was dissolved in tert-butyl alcohol (80 mL) and methanol (30 mL), and then triethylamine (14.0 g, 69.5 mmol) was added. Under nitrogen atmosphere, diphenylphosphoryl azide (20.0 g, 73.1 mmol) was slowly added dropwise. The reaction was stirred at 90°C for 5 hours, and saturated NaHCO was added to the reaction solution. 3 The aqueous solution was adjusted to a pH of 10-11, extracted with 800 mL of ethyl acetate, and the aqueous phase was extracted twice with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 5: 1) to obtain 9.80 g of the title product as a white solid, with a yield of 69.6%.

[0201] Step 2: Preparation of tert-butyl (6-bromo-2,3-dihydrobenzofuran-5-yl)carbamate (2b)

[0202] At room temperature, tert-butyl (2,3-dihydrobenzofuran-5-yl)carbamate (9.80 g, 43.0 mmol) was dissolved in acetonitrile (100 mL), cooled to 0°C, and NBS (8.20 g, 45.2 mmol) was added in portions. Stir at 65°C for 1 hour. The reaction solution was poured into NaHCO 3 The solution was extracted with 800 mL of ethyl acetate, and the aqueous phase was extracted twice with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 5: 1) to obtain 3.60 g of the title product as a white solid, with a yield of 27.6%.

[0203] Step 3: Preparation of 6-bromo-2,3-dihydrobenzofuran-5-amine (2c)

[0204] At room temperature, tert-butyl (6-bromo-2,3-dihydrobenzofuran-5-yl)carbamate (3.50 g, 11.2 mmol) was dissolved in dioxane (50 mL), and dioxane hydrochloric acid solution (30 mL) was added. The reaction was stirred at room temperature for 2 hours, and the reaction solution was poured into NaHCO 3 The solution was adjusted to alkaline, extracted with 50 mL of dichloromethane, and the aqueous phase was extracted twice with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 4: 1) to obtain 2.60 g of the crude yellow solid title product.

[0205] Step 4: Preparation of methyl 5-amino-2,3-dihydrobenzofuran-6-carboxylate (2d)

[0206] 6-Bromo-2,3-dihydrobenzofuran-5-amine (2.60 g, 12.2 mmol) was dissolved in methanol (30 mL) at room temperature, and then triethylamine (1.97 g, 19.5 mmol) and Pd(dppf)Cl were added. 2 (0.893 g, 1.22 mmol), replace CO gas three times. Stir at 90°C for 16 hours. Filter the reaction solution, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 5:1) to obtain 2.00 g crude yellow solid title product.

[0207] Step 5: Preparation of (5-amino-2,3-dihydrobenzofuran-6-yl)methanol (2e)

[0208] At room temperature, methyl 5-amino-2,3-dihydrobenzofuran-6-carboxylate (1.80 g, 9.30 mmol) was dissolved in tetrahydrofuran (20 mL), then cooled to 0°C, and lithium borohydride (354 mg, 9.30 mmol) was slowly added in batches. The reaction was stirred at room temperature for 0.5 hours, 50 mL of water was added to the reaction solution, and it was extracted with 50 mL of dichloromethane, and the aqueous phase was extracted twice with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 1: 1) to obtain 1.00 g of the title product as a yellow solid, with a yield of 62.5%.

[0209] Step 6: Preparation of 5-amino-2,3-dihydrobenzofuran-6-carbaldehyde (2f)

[0210] At room temperature, (5-amino-2,3-dihydrobenzofuran-6-yl)methanol (600 mg, 3.64 mmol) was dissolved in DCM (30 mL), and manganese dioxide (6.33 g, 72.7 mmol) was added thereto. The mixture was stirred at room temperature for 4 hours. Filtered through celite, the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 5:1) to obtain 50.0 mg of the title product as a yellow solid, with a yield of 8.40%.

[0211] Step 7: Preparation of 1-(3-ethoxy-2,3-dioxopropyl)pyridinium-1-ammonium bromide (1i)

[0212] Pyridine (797 mg, 4.08 mmol) was dissolved in EtOH (15 mL) at room temperature, and ethyl 3-bromo-2-oxopropanoate (355 mg, 4.50 mmol) was added under nitrogen atmosphere. The mixture was stirred at 65° C. for 2 hours, and the reaction solution was directly used in the next step.

[0213] Step 8: Preparation of 1-(6-(ethoxycarbonyl)-2,3-dihydrofuro[2,3-g]quinolin-7-yl)pyridin-1-ium bromide (2 g)

[0214] The reaction mixture of the previous step was cooled to 18-22°C, and 5-amino-2,3-dihydrobenzofuran-6-carbaldehyde (2f) (50.0 mg, 0.600 mmol) and pyridine (743 mg, 9.40 mmol) were added. The mixture was stirred at 80°C overnight under nitrogen atmosphere, and the reaction mixture was directly used in the next step.

[0215] Step 9: Preparation of ethyl 7-amino-2,3-dihydrofuro[2,3-g]quinoline-6-carboxylate (2h)

[0216] The reaction solution of the previous step was cooled to 70°C, morpholine (887mg, 10.2mmol) was added, and stirred at 80°C for 18 hours under a nitrogen atmosphere. 50mL of water was added to the reaction solution, and the mixture was extracted with 50mL of dichloromethane. The aqueous phase was extracted twice with 50mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 1:2) to obtain 67.0mg of the title product as a yellow solid.

[0217] Step 10: Preparation of 2-(7-amino-2,3-dihydrofuro[2,3-g]quinolin-6-yl)propan-2-ol (2)

[0218] Under nitrogen atmosphere, methylmagnesium chloride (3N, 0.26mL, 5.60mmol) was added to THF (5mL) at 0°C, and then ethyl 7-amino-2,3-dihydrofuran[2,3-g]quinoline-6-carboxylate (67.0mg, 0.260mmol) dissolved in THF (2mL) was added, and stirred at room temperature for 4 hours. 50mL of water was added to the reaction solution, and it was extracted with 50mL of dichloromethane, and the aqueous phase was extracted twice with 50mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 220nm, 100A, mobile phase: acetonitrile / water, gradient: 20-90%), and purified to obtain 5.00mg of the title product as a white solid, with a yield of 1.20%.

[0219] LC-MS: m / z 245.12 [M+H] + .

[0220] 1 H NMR (400MHz, DMSO) δ7.73 (s, 1H), 7.13 (s, 1H), 6.81 (s, 1H), 4.66-4.62 (m, 5H), 3.37-3.32 (m, 2H), 1.73 (s, 6H).

[0221] Example 3: Preparation of 2-(3-amino-7,8-dihydro-6H-cyclopenta[g]quinolin-2-yl)propan-2-ol (3)

[0222]

[0223] Step 1: Preparation of 6-bromo-2,3-dihydro-1H-inden-5-amine (3a)

[0224] At room temperature, 2,3-dihydro-1H-indene-5-amine (10.0 g, 75.2 mmol) was dissolved in toluene (100 mL), and NBS (16.0 g, 90.2 mmol) was slowly added in batches. The reaction was stirred at 25°C for 12 hours, 100 mL of water was added to the reaction solution, and the mixture was extracted with 100 mL of ethyl acetate. The aqueous phase was extracted twice with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 10: 1) to obtain 7.50 g of the title product as a yellow solid, with a yield of 47.3%.

[0225] Step 2: Preparation of methyl 6-amino-2,3-dihydro-1H-indene-5-carboxylate (3b)

[0226] 6-Bromo-2,3-dihydro-1H-inden-5-amine (3.50 g, 16.6 mmol) was dissolved in methanol (50 mL) at room temperature, and then triethylamine (2.68 g, 26.5 mmol), Pd(dppf)Cl 2 (1.20 g, 1.65 mmol). Replace the CO gas three times. Stir at 90°C for 16 hours. Filter the reaction solution, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 5:1) to obtain 1.00 g of the title product as a white solid, with a yield of 31.6%.

[0227] Step 3: Preparation of (6-amino-2,3-dihydro-1H-inden-5-yl)methanol (3c)

[0228] At room temperature, methyl 6-amino-2,3-dihydro-1H-indene-5-carboxylate (1.00 g, 5.23 mmol) was dissolved in tetrahydrofuran (10 mL). Then the temperature was lowered to 0°C, and lithium aluminum tetrahydride (198 mg, 5.23 mmol) was slowly added in batches. The reaction was stirred at room temperature for 0.5 hours, 50 mL of water was added to the reaction solution, and the mixture was extracted with 50 mL of dichloromethane, and the aqueous phase was extracted twice with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 1: 1) to obtain 340 mg of the title product as a white solid, with a yield of 39.8%.

[0229] Step 4: Preparation of 6-amino-2,3-dihydro-1H-indene-5-carbaldehyde (3d)

[0230] At room temperature, (6-amino-2,3-dihydro-1H-inden-5-yl)methanol (320 mg, 1.96 mmol) was dissolved in DCM (30 mL). Manganese dioxide (3.40 g, 39.3 mmol) was added thereto and stirred at room temperature for 4 hours. Filtered through celite, the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 5:1) to obtain 140 mg of the title product as a yellow solid, yield: 44.4%.

[0231] Step 5: Preparation of 1-(3-ethoxy-2,3-dioxopropyl)pyridinium-1-ammonium bromide (1i)

[0232] Pyridine (120 mg, 1.38 mmol) was dissolved in EtOH (10 mL) at room temperature, and ethyl 3-bromo-2-oxopropanoate (269 mg, 1.24 mmol) was added under nitrogen atmosphere, and the mixture was stirred at 65°C for 2 hours. The reaction solution was directly used in the next step.

[0233] Step 6: Preparation of 1-(2-(ethoxycarbonyl)-7,8-dihydro-6H-cyclopenta[g]quinolin-3-yl)pyridin-1-ium bromide (3f)

[0234] The reaction mixture of the previous step was cooled to 18-22°C, and 6-amino-2,3-dihydro-1H-indene-5-carbaldehyde (140 mg, 0.62 mmol) and pyridine (251 mg, 3.17 mmol) were added. The mixture was stirred at 80°C overnight under nitrogen atmosphere, and the reaction mixture was directly used in the next step.

[0235] Step 7: Preparation of ethyl 3-amino-7,8-dihydro-6H-cyclopenta[g]quinoline-2-carboxylate (3 g)

[0236] The reaction solution of the previous step was cooled to 70°C and morpholine (300 mg, 3.45 mmol) was added. The temperature was then raised to 80°C and stirred at 80°C for 18 hours under a nitrogen atmosphere. 50 mL of water was added to the reaction solution, and the mixture was extracted with 50 mL of dichloromethane. The aqueous phase was extracted twice with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 1: 2) to obtain 100 mg of the title product as a yellow solid.

[0237] Step 8: Preparation of 2-(3-amino-7,8-dihydro-6H-cyclopenta[g]quinolin-2-yl)propan-2-ol (3)

[0238] Under nitrogen atmosphere, methylmagnesium chloride (3N, 0.78mL, 2.34mmol) was added to THF (10mL) at 0°C, and then ethyl 3-amino-7,8-dihydro-6H-cyclopenta[g]quinoline-2-carboxylate (100mg, 0.390mmol) dissolved in THF (10mL) was added, and stirred at room temperature for 4 hours. 50mL of water was added to the reaction solution, and it was extracted with 50mL of dichloromethane, and the aqueous phase was extracted twice with 50mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 220nm, 100A, mobile phase: acetonitrile / water, gradient: 20-90%) to obtain 27.0mg of the title product as a yellow solid, with a yield of 35.9%.

[0239] LC-MS: m / z 243.10 [M+H] + .

[0240] 1H NMR (400MHz, DMSO) δ7.53 (s, 1H), 7.37 (s, 1H), 7.14 (s, 1H), 5.70 (s, 3H), 2.94 (t, J=7.3Hz, 4H), 2.03 (d, J=7.3Hz, 2H), 1.59 (s, 6H).

[0241] Example 4: Preparation of 2-(3-amino-6,8-dihydrofuro[3,4-g]quinolin-2-yl)propan-2-ol (4)

[0242]

[0243] Step 1: Preparation of 6-iodo-1,3-dihydroisobenzofuran-5-amine (4a)

[0244] At room temperature, 1,3-dihydroisobenzofuran-5-amine (5.00 g, 37.0 mmol) was dissolved in dichloromethane (80 mL) and methanol (30 mL), and NaHCO 3 (4.67 g, 55.5 mmol), and then slowly drip a solution of iodine chloride diluted with dichloromethane. Stir the reaction at 25°C for 1 hour, and add 100 mL of saturated NaHSO 3 The solution was extracted with 300 mL of ethyl acetate, and the aqueous phase was extracted twice with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 5: 1) to obtain 3.30 g of the title product as a yellow solid, with a yield of 34.1%.

[0245] Step 2: Preparation of methyl 6-amino-1,3-dihydroisobenzofuran-5-carboxylate (4b)

[0246] At room temperature, 6-iodo-1,3-dihydroisobenzofuran-5-amine (2.90 g, 11.1 mmol) was dissolved in methanol (30 mL), and then triethylamine (1.80 g, 17.8 mmol), Pd(dppf)Cl 2 (0.810 g, 1.11 mmol), replace CO gas three times. Stir at 90°C for 16 hours. Filter the reaction solution, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 5: 1) to obtain 2.00 g of the title product as a yellow solid, with a yield of 75.6%.

[0247] Step 3: Preparation of (6-amino-1,3-dihydroisobenzofuran-5-yl)methanol (4c)

[0248] At room temperature, methyl 6-amino-1,3-dihydroisobenzofuran-5-carboxylate (1.80 g, 9.30 mmol) was dissolved in tetrahydrofuran (20 mL), then cooled to 0°C, and lithium aluminum tetrahydride (354 mg, 9.30 mmol) was slowly added in batches. The reaction was stirred at room temperature for 0.5 hours, 50 mL of water was added to the reaction solution, and it was extracted with 50 mL of dichloromethane, and the aqueous phase was extracted twice with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 1: 1) to obtain 1.00 g of the title product as a yellow solid, with a yield of 62.5%.

[0249] Step 4: Preparation of 6-amino-1,3-dihydroisobenzofuran-5-aminocarbaldehyde (4d)

[0250] At room temperature, (6-amino-1,3-dihydroisobenzofuran-5-yl)methanol (900 mg, 5.45 mmol) was dissolved in DCM (30 mL), and manganese dioxide (9.48 g, 109 mmol) was added thereto. The mixture was stirred at room temperature for 4 hours. Filtered through celite, the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 5:1) to obtain 300 mg of the title product as a yellow solid, with a yield of 34.2%.

[0251] Step 5: Preparation of 1-(3-ethoxy-2,3-dioxopropyl)pyridinium-1-ammonium bromide (1i)

[0252] Pyridine (797 mg, 4.08 mmol) was dissolved in EtOH (15 mL) at room temperature. Ethyl 3-bromo-2-oxopropanoate (355 mg, 4.50 mmol) was added under nitrogen atmosphere. The mixture was stirred at 65° C. for 2 hours. The reaction solution was directly used in the next step.

[0253] Step 6: Preparation of 1-(2-(ethoxycarbonyl)-6,8-dihydrofuro[3,4-g]quinolin-3-yl)pyridin-1-ium bromide (4e)

[0254] The reaction mixture in the previous step was cooled to 18-22°C, 6-amino-1,3-dihydroisobenzofuran-5-aminocarbaldehyde (300 mg, 1.84 mmol) and pyridine (743 mg, 9.40 mmol) were added, and the mixture was stirred at 80°C overnight under a nitrogen atmosphere. The reaction mixture was directly used in the next step.

[0255] Step 7: Preparation of ethyl 3-amino-6,8-dihydrofuro[3,4-g]quinoline-2-carboxylate (4f)

[0256] The reaction solution of the previous step was cooled to 70°C, morpholine (887mg, 10.2mmol) was added, and the reaction was stirred at 80°C for 18 hours under a nitrogen atmosphere. 50mL of water was added to the reaction solution, and the mixture was extracted with 50mL of dichloromethane. The aqueous phase was extracted twice with 50mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 1: 2) to obtain 240mg of the title product as a yellow solid.

[0257] Step 8: Preparation of 2-(3-amino-6,8-dihydrofuro[3,4-g]quinolin-2-yl)propan-2-ol (4)

[0258] Under nitrogen atmosphere, methylmagnesium chloride (3N, 1.87mL, 5.60mmol) was added to THF (10mL) at 0°C, and then ethyl 3-amino-6,8-dihydrofuran[3,4-g]quinoline-2-carboxylate (220mg, 0.85mmol) dissolved in THF (10mL) was added, and stirred at room temperature for 4 hours. 50mL of water was added to the reaction solution, and it was extracted with 50mL of dichloromethane, and the aqueous phase was extracted twice with 50mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 220nm, 100A, mobile phase: acetonitrile / water, gradient: 20-90%) to obtain 18.0mg of the title product as a white solid, with a yield of 4.80%.

[0259] LC-MS: m / z 245.12 [M+H] + .

[0260] 1 H NMR (400MHz, DMSO) δ7.61 (s, 1H), 7.46 (s, 1H), 7.21 (s, 1H), 5.83 (s, 2H), 5.72 (s, 1H), 5.05 (s, 4H), 1.60 (s, 6H).

[0261] Example 5: Preparation of 2-(7-amino-2,2-difluoro-[1,3]dioxol[4,5-g]quinolin-6-yl)propan-2-ol (5)

[0262]

[0263] Step 1: Preparation of 2,2-difluoro-6-iodobenzo[d][1,3]dioxolan-5-amine (5a)

[0264] At room temperature, 2,2-difluorobenzo[d][1,3]dioxolan-5-amine (9.00 g, 52.0 mmol) was dissolved in DMF (100 mL), to which NIS (12.3 g, 54.6 mmol) was slowly added, and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA=3:1) to obtain 5.00 g of the title product as a light yellow solid, with a yield of 32.1%.

[0265] Step 2: Preparation of methyl 6-amino-2,2-difluorobenzo[d][1,3]dioxolane-5-carboxylate (5b)

[0266] 2,2-Difluoro-6-iodobenzo[d][1,3]dioxolan-5-amine (3.00 g, 10.0 mmol) was dissolved in methanol (50 mL) at room temperature, and then triethylamine (1.62 g, 16.1 mmol) and Pd(dppf)Cl were added. 2 (734 mg, 1.00 mmol), CO was introduced. Stirred at 90°C for 16 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 3:1) to obtain 1.40 g of the title product as a yellow solid, with a yield of 60.4%.

[0267] Step 3: Preparation of (6-amino-2,2-difluorobenzo[d][1,3]dioxolan-5-yl)methanol (5c)

[0268] Methyl 6-amino-2,2-difluorobenzo[d][1,3]dioxolane-5-carboxylate (3.00 g, 13.0 mmol) was dissolved in THF (100 mL) at room temperature. LiAlH 4 (542 mg, 14.3 mmol), stirred for 1 hour. 5 mL of water was added to the reaction solution to quench, extracted with DCM (20 mL), and the aqueous phase was extracted twice with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 10: 1-3: 1) to obtain 1.40 g of the title product as a light yellow solid, yield: 53.1%.

[0269] Step 4: Preparation of 6-amino-2,2-difluorobenzo[d][1,3]dioxolane-5-carbaldehyde (5d)

[0270] At room temperature, (6-amino-2,2-difluorobenzo[d][1,3]dioxolan-5-yl)methanol (1.30 g, 6.40 mmol) was dissolved in DCM (100 mL), and manganese dioxide (11.1 g, 128 mmol) was added, and stirred at room temperature for 4 hours. Filtered through celite, the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA=10:1-3:1=100:1-4:1) to obtain 600 mg of the title product as a light yellow solid, yield: 46.6%.

[0271] Step 5: Preparation of 1-(3-ethoxy-2,3-dioxopropyl)pyridinium-1-ammonium bromide (1i)

[0272] Pyridine (195 mg, 2.47 mmol) was dissolved in EtOH (15 mL) at room temperature, and ethyl 3-bromo-2-oxopropanoate (438 mg, 2.24 mmol) was added under nitrogen atmosphere. The mixture was stirred at 65° C. for 2 hours, and the reaction solution was directly used in the next step.

[0273] Step 6: Preparation of 1-(6-(ethoxycarbonyl)-2,2-difluoro-[1,3]dioxol[4,5-g]quinolin-7-yl)pyridin-1-ium bromide (5e)

[0274] The reaction solution from the previous step was cooled to 18-22°C, 6-amino-2,2-difluorobenzo[d][1,3]dioxolane-5-carbaldehyde (200 mg, 1.00 mmol) and pyridine (183 mg, 2.32 mmol) were added, and the mixture was stirred at 80°C for 9 hours under a nitrogen atmosphere. The reaction solution was directly used in the next step.

[0275] Step 7: Preparation of ethyl 7-amino-2,2-difluoro-[1,3]dioxolane[4,5-g]quinoline-6-carboxylate (5f)

[0276] The reaction solution of the previous step was cooled to 70°C, morpholine (487mg, 5.60mmol) was added, and then the temperature was raised to 80°C. Under a nitrogen atmosphere, the mixture was stirred at 80°C for 4 hours. 50mL of water was added to the reaction solution, and the mixture was extracted with 50mL of dichloromethane. The aqueous phase was extracted twice with 50mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA=10:1-3:1=100:1-4:1) to obtain 110mg of the title product as a brown-yellow solid, with a yield of 37.3%.

[0277] Step 8: Preparation of 2-(7-amino-2,2-difluoro-[1,3]dioxol[4,5-g]quinolin-6-yl)propan-2-ol (5)

[0278] Under nitrogen atmosphere, methylmagnesium chloride (3N, 0.97mL, 2.92mmol) was added dropwise to THF (10mL) at 0°C, and then ethyl 7-amino-2,2-difluoro-[1,3]dioxopenta[4,5-g]quinoline-6-carboxylate (100mg, 0.338mmol) dissolved in THF (10mL) was added and stirred at room temperature for 2 hours. 5mL of water was added to quench. 15mL of water was added to the reaction solution, extracted with 40mL of dichloromethane, and the aqueous phase was further extracted with 30mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile / water, gradient: 10%-50%) to obtain 8.00mg of the title product as a white solid, with a yield of 10.5%.

[0279] LC-MS: m / z 283.00 [M+H] + .

[0280] 1 H NMR (400 MHz, DMSO-d 6 ) δ7.59 (s, 1H), 7.56 (s, 1H), 7.27 (s, 1H), 5.95 (s, 2H), 5.73 (s, 1H), 1.59 (s, 6H).

[0281] Example 6: Preparation of 2-(7-amino-2-methyl-2-phenyl-[1,3]dioxol[4,5-g]quinolin-6-yl)propan-2-ol (6)

[0282]

[0283] Step 1: Preparation of 2-methyl-5-nitro-2-phenylbenzo[d][1,3]dioxolane (6a)

[0284] At room temperature, 4-nitrobenzene-1,2-diphenol (16.0 g, 103 mmol) and phenylacetylene (13.6 g, 113.6 mmol) were added to anhydrous toluene (20 mL), and Ru was added thereto. 3 (CO) 12 (1.36 g, 2.00 mmol). Under nitrogen atmosphere, the reaction solution was heated to 80°C and stirred for 16 hours. The product was concentrated under reduced pressure and the residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA=100:0 to PE / EA=10:0) to obtain 12.0 g of a brown oily crude product with a yield of 45.3%.

[0285] LC-MS: m / z 258.0 [M+H] +.

[0286] Step 2: Preparation of 2-methyl-2-phenylbenzo[d][1,3]dioxolan-5-amine (6b)

[0287] At room temperature, 2-methyl-5-nitro-2-phenylbenzo[d][1,3]dioxolane (12.0 g, 46.7 mmol) was added to tetrahydrofuran (40 mL) and ethyl acetate (40 mL), palladium carbon (3.60 g, 30% wt) was added thereto, and stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA=3:1) to obtain 8.40 g of a brown oily compound, with a yield of 70.0%.

[0288] LC-MS: m / z 228.0 [M+H] + .

[0289] Step 3: Preparation of 6-bromo-2-methyl-2-phenylbenzo[d][1,3]dioxolan-5-amine (6c)

[0290] At room temperature, 2-methyl-2-phenylbenzo[d][1,3]dioxolane-5-amine (8.40 g, 37.0 mmol) was added to chloroform (30 mL). Under ice bath, dibromohydantoin (DBDMH) (5.29 g, 18.5 mmol) was added to the reaction solution, and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, a saturated sodium bisulfite solution was added to the reaction solution, and then the mixture was extracted three times with ethyl acetate (40 mL). The organic phase was washed twice with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA=5:1) to obtain 3.78 g of a brown oily compound with a yield of 33.5%.

[0291] LC-MS: m / z 305.8 [M+H] + .

[0292] Step 4: Preparation of ethyl 6-amino-2-methyl-2-phenylbenzo[d][1,3]dioxolane-5-carboxylate (6d)

[0293] At room temperature, 6-bromo-2-methyl-2-phenylbenzo[d][1,3]dioxolane-5-amine (3.78 g, 12.4 mmol) was dissolved in ethanol (20 mL), and triethylamine (7.51 g, 74.4 mmol), palladium acetate (556 mg, 2.48 mmol), and 1,3-bis(diphenylphosphino)propane (DPPP) (1.53 g, 3.72 mmol) were added. Carbon monoxide was replaced three times, and the mixture was heated under reflux under a carbon monoxide atmosphere for 16 hours. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: DCM / EA=100:1) to obtain 1.70 g of the title compound as a light yellow solid. The yield was 45.9%.

[0294] LC-MS: m / z 300.0 [M+H] + .

[0295] Step 5: Preparation of 6-amino-2-methyl-2-phenylbenzo[d][1,3]dioxolane-5-carboxylic acid (6e)

[0296] At 0°C, ethyl 6-amino-2-methyl-2-phenylbenzo[d][1,3]dioxolane-5-carboxylate (1.70 g, 5.67 mmol) was dissolved in tetrahydrofuran (5 mL) and methanol (5 mL), and then water (5 mL) and NaOH (2.27 g, 56.7 mmol) were added. Stir at room temperature for 16 hours. The pH was adjusted to 6-5 with dilute hydrochloric acid, and then extracted three times with ethyl acetate (20 mL). The organic phase was washed twice with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.42 g of a yellow oily compound with a yield of 93.4%.

[0297] LC-MS: m / z 271.9 [M+H] + .

[0298] Step 6: Preparation of 6-amino-N-methoxy-N,2-dimethyl-2-phenylbenzo[d][1,3]dioxolane-5-carboxamide (6f)

[0299] At room temperature, 6-amino-2-methyl-2-phenylbenzo[d][1,3]dioxolane-5-carboxylic acid (1.42 g, 5.23 mmol) and N,O-dimethylhydroxylamine hydrochloride (2.54 g, 26.2 mmol) were added to N,N-dimethylformamide (50 mL), and then HATU (3.97 g, 10.5 mmol) and DIEA (2.64 g, 20.5 mmol) were added, and stirred at room temperature for 2 hours. The reaction solution was poured into 20 mL of ice water, stirred for 5 minutes, and then extracted three times with ethyl acetate (60 mL). The organic phase was washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA=3:1) to obtain 900 mg of a yellow oily compound with a yield of 56.3%.

[0300] LC-MS: m / z 315.0 [M+H] + .

[0301] Step 7: Preparation of 6-amino-2-methyl-2-phenylbenzo[d][1,3]dioxolane-5-carbaldehyde (6 g)

[0302] At room temperature, 6-amino-N-methoxy-N,2-dimethyl-2-phenylbenzo[d][1,3]dioxolane-5-carboxamide (900 mg, 2.85 mmol) was added to tetrahydrofuran (15 mL). The temperature was lowered to 0°C, and then lithium aluminum tetrahydride (217 mg, 5.71 mmol) was added and stirred at room temperature for 2 hours. After the reaction was completed, the temperature was lowered to 0°C, and water (0.22 mL), 15% NaOH (0.22 mL), and water (0.66 mL) were added dropwise to the reaction solution in sequence, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain 500 mg of a yellow oily compound with a yield of 68.9%.

[0303] LC-MS: m / z 255.9 [M+H] + .

[0304] Step 8: Preparation of ethyl 7-amino-2-methyl-2-phenyl-[1,3]dioxol[4,5-g]quinoline-6-carboxylate (6h)

[0305] At room temperature, in a dry 100 mL three-necked flask, 1-(3-ethoxy-2,3-dioxopropyl)pyridinium-1-ammonium bromide (574 mg, 2.96 mmol) was dissolved in ethanol (5 mL), pyridine (232 mg, 2.96 mmol) was added, and the mixture was heated to 65°C and stirred for 1 hour. The mixture was cooled to room temperature, 6-amino-2-methyl-2-phenylbenzo[d][1,3]dioxolane-5-carbaldehyde (500 mg, 1.96 mmol) and pyridine (465 mg, 5.88 mmol) were added, the mixture was heated to 85°C and stirred for 5 hours. The mixture was cooled to room temperature, tetrahydropyrrole (417 mg, 5.88 mmol) was added, the mixture was heated to 85°C and stirred again for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1:1) to obtain 220 mg of the title compound as a yellow solid. The yield was 21.4%.

[0306] LC-MS: m / z 350.8 [M+H] + .

[0307] Step 9: Preparation of 2-(7-amino-2-methyl-2-phenyl-[1,3]dioxol[4,5-g]quinolin-6-yl)propan-2-ol (6)

[0308] At room temperature, in a dry 100 mL three-necked flask, ethyl 7-amino-2-methyl-2-phenyl-[1,3]dioxol[4,5-g]quinoline-6-carboxylate (220 mg, 0.628 mmol) was dissolved in tetrahydrofuran (10 mL), the temperature was cooled to 0°C, 3 M methylmagnesium bromide solution (2.09 mL, 6.28 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was quenched by adding aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 2:1) to give 32.5 mg of the title compound as a light yellow solid. The yield was 15.4%.

[0309] LC-MS: m / z 336.9 [M+H] + .

[0310] 1 H NMR (CDCl 3 , 400MHz) δ7.62-7.60 (m, 2H), 7.39-7.35 (m, 4H), 7.14 (s, 1H), 6.82 (s, 1H), 4.56 (s, 3H), 2.04 (s, 3H), 1.72 (d, J=5.5Hz, 6H).

[0311] Example 7: Preparation of 3-amino-2-(2-hydroxypropan-2-yl)-7-methyl-6,7-dihydro-8H-pyrrolo[3,4-g]quinolin-8-one (7)

[0312]

[0313] Step 1: Preparation of methyl 2-methyl-5-nitrobenzoate (7a)

[0314] At room temperature, in a dry 250mL three-necked flask, dissolve 2-methyl-5-nitrobenzoic acid (10.0g, 55.2mmol) in methanol (100mL). Cool to 0°C, slowly drop thionyl chloride (13.1g, 110mmol), after the addition is complete, heat the reaction solution to reflux, stir and react for 2 hours. Cool to room temperature, concentrate under reduced pressure, and separate and purify the residue by silica gel column chromatography (mobile phase: PE / EA=2:1) ​​to obtain 10.0g of the title compound as a light yellow solid, with a yield of 92.9%.

[0315] LCMS: m / z 196.1 [M+H] + .

[0316] Step 2: Preparation of methyl 2-(bromomethyl)-5-nitrobenzoate (7b)

[0317] At room temperature, methyl 2-methyl-5-nitrobenzoate (5.00 g, 25.6 mmol) was added to a dry 250 mL single-necked flask, and carbon tetrachloride (100 mL), N-bromosuccinimide (NBS) (9.10 g, 51.2 mmol), and azobisisobutyronitrile (AIBN) (420 mg) were added, and the mixture was heated to 80°C and stirred for 16 hours. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA=10:1) to obtain 3.50 g of the title compound as a light yellow solid, with a yield of 50.1%.

[0318] LCMS: m / z 273.9 [M+H] + .

[0319] Step 3: Preparation of 2-methyl-6-nitroisoindolin-1-one (7c)

[0320] At room temperature, methyl 2-(bromomethyl)-5-nitrobenzoate (25.0 g, 91.6 mmol) was dissolved in methanol (250 mL) and added to a 500 mL dry three-necked flask. Methylamine tetrahydrofuran solution (55.0 mL, 110 mmol) was slowly added. The mixture was reacted at room temperature for 18 hours, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM / EA=20:1) to obtain 12.8 g of the title compound as a light yellow solid. The yield was 72.7%.

[0321] LCMS: m / z 193.0 [M+H] + .

[0322] Step 4: Preparation of 6-amino-2-methylisoindolin-1-one (7d)

[0323] At room temperature, add 2-methyl-6-nitroisoindolin-1-one (12.8 g, 66.7 mmol) and methanol (150 mL) to a dry 250 mL single-necked flask, add palladium carbon (2.56 g), replace the hydrogen four times, and stir for 16 hours under a hydrogen atmosphere. The reactant is filtered, the filtrate is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: DCM / EA=10:1) to obtain 8.00 g of the title compound as a light yellow solid, with a yield of 73.7%.

[0324] LCMS: m / z 163.0 [M+H] + .

[0325] Step 5: Preparation of 6-amino-5-bromo-2-methylisoindolin-1-one (7e)

[0326] To a dry 500mL three-necked flask at room temperature, 6-amino-2-methylisoindolin-1-one (8.00 g, 49.4 mmol) and chloroform (200 mL) were added, and dibromohydantoin (7.06 g, 24.7 mmol) was slowly added in batches. The mixture was stirred for 1 hour and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM / EA=30:1, DCM / MeOH=50:1) to give 2.10 g of the title compound as a light yellow solid. The yield was 17.9%.

[0327] LCMS: m / z 240.9 [M+H] + .

[0328] Step 6: Preparation of ethyl 6-amino-2-methyl-1-oxoisoindoline-5-carboxylate (7f)

[0329] At room temperature, in a dry 100 mL three-necked flask, 6-amino-5-bromo-2-methylisoindolin-1-one (1.05 g, 4.38 mmol) was dissolved in ethanol (20 mL), and triethylamine (TEA) (4.41 g, 43.8 mmol), palladium acetate (178 mg, 0.876 mmol), 1,3-bis(diphenylphosphino)propane (DPPA) were added, and carbon monoxide was replaced three times. Under a carbon monoxide atmosphere, the mixture was heated to reflux for 16 hours. After the reaction was completed, the temperature was lowered and filtered. The filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM / MeOH=20:1) to obtain 540 mg of the title compound as a light yellow solid in a yield of 52.7%.

[0330] LCMS: m / z 235.0 [M+H] + .

[0331] Step 7: Preparation of 6-amino-5-(hydroxymethyl)-2-methylisoindolin-1-one (7 g)

[0332] At room temperature, in a dry 100 mL three-necked flask, ethyl 6-amino-2-methyl-1-oxoisoindoline-5-carboxylate (450 mg, 1.92 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (144 mg, 3.84 mmol) was slowly added. The reaction was allowed to react at room temperature for 1 hour. After the reaction was completed, methanol was added to quench the reaction, and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane / methanol=10:1) to give 300 mg of the title compound as a light yellow solid. The yield was 81.5%.

[0333] LCMS: m / z 193.0 [M+H] + .

[0334] Step 8: Preparation of 6-amino-2-methyl-1-oxoisoindoline-5-carbaldehyde (7h)

[0335] At room temperature, in a dry 100 mL three-necked flask, 6-amino-5-(hydroxymethyl)-2-methylisoindolin-1-one (300 mg, 1.56 mmol) was dissolved in dichloromethane (10 mL), and manganese dioxide (1.36 g, 15.6 mmol) was added. The mixture was heated to reflux for 2 hours, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane / methanol=20:1) to give 180 mg of the title compound as a light yellow solid. The yield was 61.6%.

[0336] LCMS: m / z 191.0 [M+H] + .

[0337] Step 9: Preparation of ethyl 3-amino-7-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-2-carboxylate (7i)

[0338] At room temperature, 1-(3-ethoxy-2,3-dioxopropyl)pyridinium-1-ammonium bromide (147 mg, 0.760 mmol) was dissolved in ethanol (5 mL). Pyridine (70.0 mg, 0.890 mmol) was added, heated to 65°C, and stirred for 1 hour. The mixture was cooled to room temperature, 6-amino-2-methyl-1-oxoisoindoline-5-carboxaldehyde (120 mg, 0.630 mmol) and pyridine (130 mg, 1.65 mmol) were added, heated to 85°C, and stirred for 5 hours. The mixture was cooled to room temperature, tetrahydropyrrole (130 mg, 1.65 mmol) was added, heated to 85°C, and stirred again for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA=1:1) to obtain 60.0 mg of the title compound as a yellow solid, with a yield of 33.5%.

[0339] LCMS: m / z 286.0 [M+H] + .

[0340] Step 10: Preparation of 3-amino-2-(2-hydroxypropan-2-yl)-7-methyl-6,7-dihydro-8H-pyrrolo[3,4-g]quinolin-8-one (7)

[0341] At room temperature, in a dry 100 mL three-necked flask, ethyl 3-amino-7-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-2-carboxylate (58.0 mg, 0.203 mmol) was dissolved in tetrahydrofuran (10 mL). The mixture was cooled to 0°C, and methylmagnesium bromide solution (0.700 mL, 2.03 mmol) was added. The mixture was stirred at room temperature for 1 hour, and then quenched by adding ammonium chloride solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified twice by preparative thin layer chromatography (mobile phase: petroleum ether / ethyl acetate = 2:1) to obtain 10.6 mg of the title compound as a light yellow solid, with a yield of 19.6%.

[0342] LCMS: m / z 271.9 [M+H] + .

[0343] 1 H NMR (CDCl 3 , 400MHz) δ7.90 (s, 1H), 7.64 (s, 1H), 7.30 (s, 1H), 3.86 (s, 2H), 3.73 (s, 3H), 1.77 (s, 6H).

[0344] Example 8: Preparation of 3-amino-2-(2-hydroxypropan-2-yl)-6,7-dihydro-8H-pyrrolo[3,4-g]quinolin-8-one (8)

[0345]

[0346] Step 1: Preparation of 2-benzyl-6-nitroisoindolin-1-one (8a)

[0347] At room temperature, methyl 2-(bromomethyl)-5-nitrobenzoate (40.0 g, 146 mmol) was dissolved in methanol (400 mL), added to a 1 L dry three-necked flask, and benzylamine (39.0 g, 365 mmol) was slowly added. The mixture was reacted at room temperature for 3 hours, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane / ethyl acetate = 20:1) to obtain 35.6 g of the title compound as a light yellow solid. The yield was 90.8%.

[0348] LCMS: m / z 268.9 [M+H] + .

[0349] Step 2: Preparation of 6-amino-2-benzylisoindolin-1-one (8b)

[0350] At room temperature, 2-benzyl-6-nitroisoindolin-1-one (400 g, 149 mmol) and methanol (300 mL) were added to a dry 500 mL single-necked flask, and palladium carbon (8.00 g) was added. The hydrogen gas was replaced four times and stirred for 16 hours under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane / ethyl acetate = 10:1) to obtain 32.0 g of the title compound as a light yellow solid. The yield was 89.9%.

[0351] LCMS: m / z 239.0 [M+H] + .

[0352] Step 3: Preparation of 6-amino-2-benzyl-5-bromoisoindolin-1-one (8c)

[0353] To a dry 500mL three-necked flask at room temperature, 6-amino-2-benzylisoindolin-1-one (21.0 g, 130 mmol) and chloroform (210 mL) were added, and dibromohydantoin (18.6 g, 65.1 mmol) was slowly added in batches. The mixture was stirred for 1 hour and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 200:1) to give 3.58 g of the title compound as a yellow solid. The yield was 8.7%.

[0354] LCMS: m / z 316.9 [M+H]+ .

[0355] Step 4: Preparation of ethyl 6-amino-2-benzyl-1-oxoisoindoline-5-carboxylate (8d)

[0356] At room temperature, 6-amino-2-benzyl-5-bromoisoindolin-1-one (4.66 g, 14.7 mmol), ethanol (100 mL), triethylamine (14.8 g, 147 mmol), palladium acetate (660 mg, 2.94 mmol), 1,3-bis(diphenylphosphino)propane (1.82 g, 4.41 mmol) were added to a dry 250 mL autoclave, and carbon monoxide was replaced three times. The reaction was heated under reflux for 16 hours under a carbon monoxide atmosphere. After the reaction was completed, the temperature was lowered and filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 50:1) to obtain 3.35 g of the title compound as a light yellow solid, with a yield of 73.5%.

[0357] LCMS: m / z 311.0 [M+H] + .

[0358] Step 5: Preparation of 6-amino-2-benzyl-5-(hydroxymethyl)isoindolin-1-one (8e)

[0359] At room temperature, in a dry 250 mL three-necked flask, ethyl 6-amino-2-benzyl-1-oxoisoindoline-5-carboxylate (3.35 g, 10.8 mmol) was dissolved in tetrahydrofuran (70 mL). Under nitrogen atmosphere, lithium aluminum hydride (821 mg 21.6 mmol) was slowly added at 0°C, and the mixture was reacted at 0°C for 1 hour. After the reaction was completed, water (0.82 mL), 15% sodium hydroxide (0.82 mL), and water (2.5 mL) were added in sequence to quench the reaction, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 20:1) to obtain 2.00 g of the title compound as a khaki solid, with a yield of 69%.

[0360] LCMS: m / z 268.9 [M+H] + .

[0361] Step 6: Preparation of 6-amino-2-benzyl-1-oxoisoindoline-5-carbaldehyde (8f)

[0362] At room temperature, 6-amino-2-benzyl-5-(hydroxymethyl)isoindolin-1-one (1.00 g, 3.70 mmol) was dissolved in dichloromethane (70 mL), and manganese dioxide (9.70 g, 112 mmol) was added. The mixture was heated under reflux for 2 hours, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane / methanol=20:1) to give 538 mg of the title compound as a yellow solid. The yield was 54.6%.

[0363] LCMS: m / z 266.9 [M+H] + .

[0364] Step 7: Preparation of ethyl 3-amino-7-benzyl-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-2-carboxylate (8 g)

[0365] At room temperature, 1-(3-ethoxy-2,3-dioxopropyl)pyridinium-1-ammonium bromide (414 mg, 2.14 mmol) was dissolved in ethanol (8 mL), pyridine (191 mg, 2.42 mmol) was added, and the mixture was heated to 65°C and stirred for 1 hour. The mixture was cooled to room temperature, and 6-amino-2-benzyl-1-oxoisoindoline-5-carboxaldehyde (538 mg, 2.02 mmol) and pyridine (383 mg, 4.84 mmol) were added. The mixture was heated to 85°C and stirred for 5 hours. The mixture was cooled to room temperature, and tetrahydropyrrole (359 mg, 5.05 mmol) was added. The mixture was heated to 85°C and stirred again for 5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 100:1) to obtain 320.0 mg of the title compound as a yellow solid with a yield of 43.8%.

[0366] LCMS: m / z 361.8 [M+H] + .

[0367] Step 8: Preparation of ethyl 3-amino-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-2-carboxylate (8h)

[0368] At room temperature, in a dry 50 mL three-necked flask, ethyl 3-amino-7-benzyl-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-2-carboxylate (200 mg, 0.55 mmol) was dissolved in 1,2-dichloroethane (2 mL), trifluoromethanesulfonic acid (2 mL) was added, and the mixture was reacted at 100°C for 6 hours. The temperature was cooled to room temperature, saturated aqueous sodium bicarbonate solution (40 mL) was added, and the mixture was extracted with dichloromethane (100 mL×2). The organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane / methanol=50:1) to give 80 mg of the title compound as a yellow solid. The yield was 53.6%.

[0369] LCMS: m / z 271.9 [M+H] + .

[0370] Step 9: Preparation of 3-amino-2-(2-hydroxypropan-2-yl)-6,7-dihydro-8H-pyrrolo[3,4-g]quinolin-8-one (8)

[0371] At room temperature, add methylmagnesium bromide solution (10 mL) to a dry 50 mL three-necked flask. Under nitrogen atmosphere, add a solution of ethyl 3-amino-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-2-carboxylate (80.0 mg, 0.294 mmol) in tetrahydrofuran (1 mL) dropwise to the reaction system at 0°C. Stir at room temperature for 3 hours. Add water to quench, extract with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by silica gel column chromatography (mobile phase: dichloromethane / methanol = 20:1) to obtain 7.70 mg of the title compound as a light yellow solid, with a yield of 10.2%.

[0372] LCMS: m / z 257.9 [M+H] + .

[0373] 1 H NMR (CD 3 OD, 400MHz) δ8.21 (s, 1H), 7.64 (s, 1H), 7.27 (s, 1H), 4.51 (s, 2H), 1.70 (s, 6H).

[0374] Example 9: Preparation of 8-amino-7-(2-hydroxypropan-2-yl)-2H-[1,4]oxazino[2,3-g]quinolin-3(4H)-one (9)

[0375]

[0376] Step 1: Preparation of 3-methoxy-4-(2,2,2-trifluoroacetylamino)benzoic acid (9a)

[0377] At room temperature, 4-amino-3-methoxybenzoic acid (5.00 g, 29.9 mmol) was dissolved in ethyl acetate (200 mL), and a mixed solution of trifluoroacetic anhydride (5 mL, 35.9 mmol) and ethyl acetate (50 mL) was slowly added dropwise. The mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and concentrated under reduced pressure twice to obtain 9.00 g of the crude title compound as a grey solid.

[0378] Step 2: Preparation of 5-methoxy-2-nitro-4-(2,2,2-trifluoroacetylamino)benzoic acid (9b)

[0379] At room temperature, 3-methoxy-4-(2,2,2-trifluoroacetylamino)benzoic acid (9.00 g, 34.2 mmol) was dissolved in sulfuric acid (96 mL). The solution was cooled in an ice bath while stirring. A mixed solution of nitric acid (3.30 g) and sulfuric acid (24 mL) was added dropwise under cooling while maintaining the temperature below 10°C. After the addition was completed, the mixture was further stirred for 10 min. The reaction solution was dropped into ice water, filtered, the filter cake was washed with 200 mL of water, and dried under reduced pressure to obtain 7.20 g of the title compound as a light brown solid. Yield: 68.3%.

[0380] Step 3: Preparation of 4-amino-5-hydroxy-2-nitrobenzoic acid (9c)

[0381] 5-Methoxy-2-nitro-4-(2,2,2-trifluoroacetylamino)benzoic acid (7.00 g, 22.7 mmol) was dissolved in 20% sodium hydroxide solution (50 mL) at room temperature. The mixture was stirred at 100°C for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature and concentrated hydrochloric acid (21 mL) was added dropwise under ice bath cooling. The mixture was concentrated under reduced pressure and filtered with anhydrous ethanol (420 mL). The filtrate was concentrated under reduced pressure to obtain 7.20 g crude product of the title compound as a brown solid.

[0382] Step 4: Preparation of methyl 4-amino-5-hydroxy-2-nitrobenzoate (9d)

[0383] At room temperature, 4-amino-5-hydroxy-2-nitrobenzoic acid (7.20 g, 36.4 mmol) was dissolved in MeOH (477 mL), concentrated sulfuric acid (20 mL) was added thereto, and the mixture was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA=10:1-1:1) to give 2.10 g of the title product as a purple solid. Yield: 27.2%.

[0384] Step 5: Preparation of methyl 6-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (9e)

[0385] At room temperature, methyl 4-amino-5-hydroxy-2-nitrobenzoate (2.10 g, 9.90 mmol) was dissolved in DMF (20 mL), chloroacetyl chloride (1.76 g, 10.4 mmol) was slowly added dropwise, stirred at room temperature for 24 hours, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 10:1-3:1) to obtain 1.60 g of the title product as a light yellow solid, with a yield of 47.1%.

[0386] Step 6: Preparation of methyl 6-amino-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (9f)

[0387] At room temperature, methyl 6-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (1.60 g, 6.34 mmol) was dissolved in ethanol (20 mL) and water (2 mL), and iron powder (2.10 g, 38.1 mmol) and ammonium chloride (204 mg, 4.44 mmol) were added thereto. The mixture was stirred at 78°C for 4 hours, extracted with 50 mL of ethyl acetate, and the aqueous phase was extracted twice with 30 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA=10:1-1:1) to obtain 900 mg of the title product as a light yellow solid, with a yield of 63.8%.

[0388] Step 7: Preparation of 6-amino-7-(hydroxymethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (9 g)

[0389] At room temperature, methyl 6-amino-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (900 mg, 4.05 mmol) was dissolved in THF (40 mL). Under nitrogen atmosphere, DIBAL-H (16.0 mL, 1 M) was added dropwise at -78°C and stirred at room temperature for 24 hours. 5 mL of water was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate (50 mL). The aqueous phase was extracted twice with 50 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 100:1-10:1) to obtain 340 mg of the title product as a light yellow solid, with a yield of 43.2%.

[0390] Step 8: Preparation of 6-amino-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde (9h)

[0391] At room temperature, 6-amino-7-(hydroxymethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (340 mg, 1.75 mmol) was dissolved in DCM (30 mL), and manganese dioxide (2.12 g, 26.2 mmol) was added, and stirred at room temperature for 4 hours. Filtered through celite, the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 100:1-10:1) to obtain 180 mg of the title product as a light yellow solid, yield: 53.5%.

[0392] Step 9: Preparation of 1-(3-ethoxy-2,3-dioxopropyl)pyridinium-1-ammonium bromide (1i)

[0393] Pyridine (195 mg, 2.47 mmol) was dissolved in EtOH (15 mL) at room temperature, and ethyl 3-bromo-2-oxopropanoate (438 mg, 2.24 mmol) was added under nitrogen atmosphere. The mixture was stirred at 65° C. for 2 hours, and the reaction solution was directly used in the next step.

[0394] Step 10: Preparation of 1-(7-(ethoxycarbonyl)-3-oxo-3,4-dihydro-2H-[1,4]oxazino[2,3-g]quinolin-8-yl)pyridin-1-ium bromide (9i).

[0395] The reaction solution from the previous step was cooled to 18-22°C, 6-amino-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde (180 mg, 0.938 mmol) and pyridine (183 mg, 2.32 mmol) were added, and the mixture was stirred at 80°C for 9 h under a nitrogen atmosphere. The reaction solution was directly used in the next step.

[0396] Step 11: Preparation of ethyl 8-amino-3-oxo-3,4-dihydro-2H-[1,4]oxazino[2,3-g]quinoline-7-carboxylate (9j)

[0397] The reaction solution of the previous step was cooled to 70°C, morpholine (487mg, 5.60mmol) was added, and the temperature was raised to 80°C. Under a nitrogen atmosphere, the mixture was stirred at 80°C for 4 hours. 50mL of water was added to the reaction solution, and the mixture was extracted with 50mL of dichloromethane. The aqueous phase was extracted twice with 50mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane / ethyl acetate = 10:1-2:1) to obtain 70.0mg of the title product as a brown solid, with a yield of 26.0%.

[0398] Step 12: Preparation of 8-amino-7-(2-hydroxypropan-2-yl)-2H-[1,4]oxazino[2,3-g]quinolin-3(4H)-one (9)

[0399] Under nitrogen atmosphere, methylmagnesium chloride (3N, 0.97mL, 2.92mmol) was added dropwise to THF (10mL) at 0°C, and 8-amino-3-oxo-3,4-dihydro-2H-[1,4]oxazine[2,3-g]quinoline-7-carboxylic acid ethyl ester (70.0mg, 0.244mmol) dissolved in THF (10mL) was added and stirred at room temperature for 2 hours. 5mL of water was added to quench. 15mL of water was added to the reaction solution, extracted with 40mL of dichloromethane, and the aqueous phase was further extracted with 30mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile / water, gradient: 10%-50%) to obtain 7.00 mg of the title product as a white solid, yield: 1.00%.

[0400] LC-MS: m / z 274..00 [M+H] + .

[0401] 1 H NMR (300 MHz, DMSO-d 6 ) δ10.9 (s, 1H), 7.17 (s, 1H), 7.07 (s, 2H), 5.74 (s, 2H), 5.65 (s, 1H), 4.62 (s, 2H), 1.57 (s, 6H).

[0402] Example 10: Preparation of 8-amino-7-(2-hydroxypropan-2-yl)-4-methyl-2H-[1,4]oxazino[2,3-g]quinolin-3(4H)-one (10)

[0403]

[0404] Step 1: Preparation of methyl 4-methyl-6-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (10a)

[0405] At room temperature, iodomethane (3.72 g, 26.2 mmol) was added to a solution of methyl 6-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (9e) (6.00 g, 23.8 mmol) and potassium carbonate (6.57 g, 47.6 mmol) in N,N-dimethylformamide (100 mL), and stirred at 60°C for 3 hours. The reaction solution was diluted with ethyl acetate (400 mL) and washed with water (200 mL×3). The organic phases were combined, dried, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 1:1) to obtain 6.30 g of the title product as a yellow solid, with a yield of 99.5%.

[0406] LC-MS: m / z 267 [M+H] + .

[0407] For steps 2 to 8, refer to steps 6 to 12 of the synthesis of Example 9.

[0408] The residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile / water, gradient: 10%-50%) to obtain 6.00 mg of the title product as a white solid, yield: 1.00%.

[0409] LC-MS: m / z 288[M+H] + .

[0410] 1 H NMR (400 MHz, CDCl 3 -d) δ7.49 (s, 1H), 7.12 (s, 1H), 7.07 (s, 1H), 4.67 (s, 2H), 3.47 (s, 3H), 1.76 (s, 6H).

[0411] Example 11: Preparation of 2-(9-amino-3,4-dihydro-2H-naphtho[2,3-b][1,4]dioxepan-8-yl)propan-2-ol (11)

[0412]

[0413]

[0414] Step 1: Preparation of 1,4,6,7-tetrabromonaphthalene-2,3-diol (11a)

[0415] At room temperature, naphthalene-2,3-diol (3.00 g, 18.7 mmol) was added to acetic acid (30 mL), bromine (5.77 g, 36.1 mmol) was added thereto, and the reaction solution was heated to 120°C and stirred for 45 minutes. The mixture was cooled to room temperature, poured into ice water, extracted with ethyl acetate, concentrated under reduced pressure, and the residue was recrystallized from acetic acid to obtain 6.00 g of the title compound as a yellow solid, with a yield of 67.0%.

[0416] Step 2: Preparation of 6,7-dibromonaphthalene-2,3-diol (11b)

[0417] At room temperature, add 1,4,6,7-tetrabromonaphthalene-2,3-diol (5.00 g, 11.0 mmol) to acetic acid (100 mL), add stannous chloride (20.0 g, 88.0 mmol), heat the reaction solution to 120°C and stir for 45 minutes. Cool to room temperature, concentrate under reduced pressure, and recrystallize the residue from toluene. Obtain 3.00 g of the crude title compound as a white solid.

[0418] LC-MS: m / z 316.1[MH] + .

[0419] Step 3: Preparation of 8,9-dibromo-3,4-dihydro-2H-naphtho[2,3-b][1,4]dioxepane (11c).

[0420] At room temperature, 6,7-dibromonaphthalene-2,3-diol (4.80 g, 15.0 mmol) and 1,3-dibromopropane (20 mL) were added to ethanol (50 mL), potassium carbonate (5.17 g, 37.5 mmol) was added thereto, and the reaction solution was heated to 85°C in a sealed tube and stirred for 24 hours. The mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent: EA / PE=3:1) to obtain 1.90 g of the title compound as a white solid, with a yield of 35.1%.

[0421] Step 4: Preparation of N-(9-bromo-3,4-dihydro-2H-naphtho[2,3-b][1,4]dioxepan-8-yl)-1,1-diphenylmethanimine (11d)

[0422] At room temperature, 8,9-dibromo-3,4-dihydro-2H-naphtho[2,3-b][1,4]dioxepane (1.90 g, 5.34 mmol), diphenylmethylaniline (1.09 g, 5.60 mmol), sodium tert-butoxide (615 mg, 6.40 mmol), tridibenzylideneacetone dipalladium (489 mg, 0.534 mmol), 1,1′-binaphthyl-2,2′-bisdiphenylphosphine (618 mg, 1.07 mmol) were added to anhydrous toluene (100 mL). Under nitrogen atmosphere, the system was heated to 85° C. and stirred for reaction for 24 hours. The mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (developing solvent: EA) to give 900 mg of the title compound as a light yellow oil. Yield: 36.9%.

[0423] Step 5: Preparation of 9-bromo-3,4-dihydro-2H-naphtho[2,3-b][1,4]dioxepane-8-amine (11e)

[0424] N-(9-bromo-3,4-dihydro-2H-naphtho[2,3-b][1,4]dioxepan-8-yl)-1,1-diphenylmethanimine (900 mg, 1.97 mmol) was added to tetrahydrofuran (50 mL) and 3 M hydrochloric acid (10 mL) at room temperature, and the system was then stirred at room temperature for 16 hours and concentrated under reduced pressure. The residue was extracted with ethyl acetate and washed with saturated sodium carbonate solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was separated and purified by silica gel column chromatography (developing solvent: EA) to give 450 mg of the title compound as a light yellow oil. Yield: 78.0%.

[0425] Step 6: Preparation of methyl 9-amino-3,4-dihydro-2H-naphtho[2,3-b][1,4]dioxepane-8-carboxylate (11f)

[0426] At room temperature, 9-bromo-3,4-dihydro-2H-naphtho[2,3-b][1,4]dioxepan-8-amine (450 mg, 1.53 mmol), 1,1′-bis(diphenylphosphinoferrocenepalladium dichloride) (112 mg, 0.0153 mmol), and triethylamine (248 mg, 2.46 mmol) were added to methanol (35 mL), and the air in the bottle was replaced with carbon monoxide. The system was heated to 90°C and stirred for 16 hours under a carbon monoxide atmosphere. The mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (developing solvent: PE / EA=1:2) to obtain 130.0 mg of the title compound as a light yellow oil, with a yield of 31.0%.

[0427] Step 7: Preparation of 2-(9-amino-3,4-dihydro-2H-naphtho[2,3-b][1,4]dioxepan-8-yl)propan-2-ol (11).

[0428] Methylmagnesium chloride (3 mol / L, 2.00 mL) was added to anhydrous tetrahydrofuran (10 mL) at room temperature, and then slowly added dropwise to anhydrous tetrahydrofuran (15 mL) of 9-amino-3,4-dihydro-2H-naphtho[2,3-b][1,4]dioxepane-8-carboxylic acid methyl ester (100 mg, 0.366 mmol) at 0°C under a nitrogen atmosphere, and stirred for 1 hour. After the reaction was completed, the reaction solution was quenched with a saturated aqueous ammonium chloride solution (10 mL), extracted with ethyl acetate (40 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (chromatographic column model: Gemini-C18 150 x 21.2 mm, 5 um, mobile phase: acetonitrile / water, gradient: 10%-90%) to obtain 20.0 mg of the title compound as a white solid, with a yield of 30.0%.

[0429] LC-MS: m / z 256.1[M-17] + .

[0430] 1 H NMR (400MHz, DMSO) δ7.42 (s, 1H), 7.25 (s, 1H), 7.03 (s, 1H), 6.76 (s, 1H), 5.76-5.29 (m, 3H), 4.09-4.07 (m, 4H), 2.07-2.06 (m, 2H), 1.58 (s, 6H).

[0431] Example 12: Preparation of 2-(7-amino-2-methyl-2-phenyl-naphtho[2,3-d][1,3]dioxolan-6-yl)propan-2-ol (12)

[0432]

[0433]

[0434] Step 1: Preparation of 6,7-dibromo-2-methyl-2-phenylnaphtho[2,3-d][1,3]dioxolane (12a)

[0435] At room temperature, acetophenone (2.11 g, 17.6 mmol) was added to anhydrous toluene (150 mL) of 6,7-dibromonaphthalene-2,3-diol (5.30 g, 16.8 mmol) and p-toluenesulfonic acid (57.7 mg, 0.335 mmol), and the mixture was stirred at 140°C for 3 days. The reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1) to obtain 4.20 g of the title compound as a white solid, with a yield of 59.9%.

[0436] LC-MS: m / z=419 [M+H] + .

[0437] Step 2: Preparation of N-(7-bromo-2-methyl-2-phenylnaphtho[2,3-d][1,3]dioxolan-6-yl)-1,1-diphenylmethanimine (12b)

[0438] At room temperature and under nitrogen atmosphere, tri(dibenzylideneacetone)dipalladium (758 mg, 0.828 mmol) and 1,1′-binaphthyl-2,2′-bisdiphenylphosphine (772 mg, 1.24 mmol) were added to a solution of 6,7-dibromo-2-methyl-2-phenylnaphtho[2,3-d][1,3]dioxolane (3.46 g, 8.28 mmol) in dibenzhydrylamine (1.65 g, 9.11 mmol) and sodium tert-butoxide (1.19 g, 12.4 mmol) in toluene (50 mL), and stirred at 85° C. overnight under nitrogen atmosphere. The reaction solution was cooled and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate=10:1) to obtain 2.75 g of the title compound as a yellow solid, with a yield of 64.1%.

[0439] LC-MS: m / z=520[M+H] + .

[0440] Step 3: Preparation of 7-bromo-2-methyl-2-phenylnaphtho[2,3-d][1,3]dioxolan-6-amine (12c)

[0441] At room temperature, dilute hydrochloric acid (20 mL, 1 mol / L) was added to a tetrahydrofuran (40 mL) solution of N-(7-bromo-2-methyl-2-phenylnaphtho[2,3-d][1,3]dioxolan-6-yl)-1,1-diphenylmethanimine (2.15 g, 4.14 mmol) and stirred at room temperature for 30 minutes. The reaction solution was adjusted to pH 8 with saturated sodium bicarbonate aqueous solution, and ethyl acetate (100 mL×2) was added for extraction. The organic phases were combined, dried, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate=10:1) to obtain 1.30 g crude product of the title product as an off-white solid.

[0442] LC-MS: m / z=356[M+H] + .

[0443] Step 4: Preparation of methyl 7-amino-2-methyl-2-phenylnaphtho[2,3-d][1,3]dioxolane-6-carboxylate (12d)

[0444] At room temperature, 1,1′-bis(diphenylphosphinoferrocene)palladium dichloride (61.8 mg, 0.0845 mmol) was added to a methanol (10 mL) solution of 7-bromo-2-methyl-2-phenylnaphtho[2,3-d][1,3]dioxolane-6-amine (300 mg, 0.845 mmol) and triethylamine (136 mg, 1.35 mmol), and the air in the bottle was replaced with carbon monoxide. Under a carbon monoxide atmosphere, the system was heated to 90° C. and stirred for 16 hours. The reaction solution was cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate=5:1) to obtain 300 mg of the title compound as a yellow solid, with a yield of 79.6%.

[0445] LC-MS: m / z=336[M+H] + .

[0446] Step 5: Preparation of 2-(7-amino-2-methyl-2-phenyl-naphtho[2,3-d][1,3]dioxolan-6-yl)propan-2-ol (12)

[0447] At room temperature, under nitrogen atmosphere, add methyl 7-amino-2-methyl-2-phenylnaphtho[2,3-d][1,3]dioxolane-6-carboxylate (300 mg, 0.895 mmol) to a solution of methyl magnesium bromide (2.09 mL, 3 mol / L) in anhydrous tetrahydrofuran (10 mL). Stir at 0°C for 3 hours under nitrogen atmosphere. The reaction solution is quenched with saturated aqueous ammonium chloride solution (10 mL), extracted with ethyl acetate (40 mL×2), the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is separated by preparative liquid chromatography (chromatographic column model: Gemini-C18 150*21.2 mm, 5 um, mobile phase: acetonitrile / water 0.05% formic acid, gradient: 2 min-30% to 22 min-70%) to obtain 20.0 mg of the title compound as a white solid, yield: 6.67%.

[0448] LC-MS: m / z=336[M+H] + .

[0449] 1 H NMR (400 MHz, DMSO-d 6 )δ7.65-7.55(m, 2H), 7.48-7.35(m, 4H), 7.08(s, 1H), 6.89(s, 1H), 6.77(s, 1H), 5.66-5.22(m, 3H), 1.99(s, 3H), 1.57(d, J=6.0Hz, 6H).

[0450] Examples 12A and 12B: Preparation of (S)-2-(7-amino-2-methyl-2-phenyl-naphtho[2,3-d][1,3]dioxolan-6-yl)propan-2-ol and (R)-2-(7-amino-2-methyl-2-phenyl-naphtho[2,3-d][1,3]dioxolan-6-yl)propan-2-ol (12A and 12B)

[0451]

[0452] Compound 12A and Compound 12B were separated from Compound 12 by supercritical fluid chromatography (SFC).

[0453] SFC separation conditions:

[0454] Chromatographic column model: CHIRALPAK OJ-H 250mm×20mm, 5μm

[0455] Mobile phase: 40% MEOH (NH40H 0.2%)

[0456] Flow rate: 40g / min

[0457] 12A: Retention time: 13.99 min.

[0458] LC-MS: m / z=318.10 [M-17] + .

[0459] 1 H NMR (400 MHz, DMSO-d 6 )δ7.65-7.55(m, 2H), 7.48-7.35(m, 4H), 7.08(s, 1H), 6.89(s, 1H), 6.77 (s, 1H), 5.47 (s, 2H), 5.31 (s, 1H),, 1.99 (s, 3H), 1.57 (d, J=6.0Hz, 6H).

[0460] 12B: retention time: 17.44 min.

[0461] LC-MS: m / z=318.10 [M-17] + .

[0462] 1 H NMR (400 MHz, DMSO-d 6 )δ7.65-7.55(m, 2H), 7.48-7.35(m, 4H), 7.08(s, 1H), 6.89(s, 1H), 6.77 (s, 1H), 5.47 (s, 2H), 5.31 (s, 1H),, 1.99 (s, 3H), 1.57 (d, J=6.0Hz, 6H).

[0463] Example 13: Preparation of 2-(7-amino-2-methyl-2-(p-tolyl)-naphtho[2,3-d][1,3]dioxol-6-yl)propan-2-ol (13)

[0464]

[0465] Compound 13 was prepared according to the synthetic method of Example 12, except that 4-methylacetophenone was used instead of acetophenone, to obtain 15.0 mg of the title compound as an off-white solid. Yield: 5.00%.

[0466] Separation was performed by preparative liquid chromatography (chromatographic column model: Gemini-C18 150*21.2 mm, 5 um, mobile phase: acetonitrile / water 0.05% ammonia water, gradient: 2 min-60% to 22 min-60%).

[0467] LC-MS: m / z=350[M+H] + .

[0468] 1H NMR (400 MHz, DMSO-d 6 )δ7.50-7.43(m, 2H), 7.37(s, 1H), 7.22(d, J=8.0Hz, 2H), 7.06(s, 1H), 6.87(s, 1H), 6. 77 (s, 1H), 5.46 (s, 2H), 5.31 (s, 1H), 2.29 (s, 3H), 1.97 (s, 3H), 1.56 (d, J=5.9Hz, 6H).

[0469] Example 14: Preparation of 2-(7-amino-2-(4-chlorophenyl)-2-methyl-naphtho[2,3-d][1,3]dioxolan-6-yl)propan-2-ol (14)

[0470]

[0471]

[0472] Compound 14 was prepared according to the synthetic method of Example 12, except that 4-chloroacetophenone was used instead of acetophenone, to obtain 70.0 mg of the title compound as an off-white solid. The yield was 58.0%.

[0473] Separation was performed by preparative liquid chromatography (chromatographic column model: Gemini-C18 150*21.2 mm, 5 um, mobile phase: acetonitrile / water 0.05% ammonia water, gradient: 2 min-60% to 22 min-60%).

[0474] LC-MS: m / z=351.90 [M-17] + .

[0475] 1 H NMR (400 MHz, DMSO-d 6 )δ7.62 (d, J=2.0Hz, 1H), 7.60 (d, J=2.0Hz, 1H), 7.49 (d, J=2.0Hz, 1H), 7.48 (d, J=1.9Hz, 1H), 7.39 (s, 1H ), 7.09 (s, 1H), 6.90 (s, 1H), 6.78 (s, 1H), 5.48 (s, 2H), 5.33 (s, 1H), 1.99 (s, 3H), 1.56 (d, J=6.4Hz, 6H).

[0476] Example 15: Preparation of 2-(7-amino-2-(4-chloro-2-fluorophenyl)-2-methyl-naphtho[2,3-d][1,3]dioxolan-6-yl)propan-2-ol (15)

[0477]

[0478] Compound 15 was prepared according to the synthetic method of Example 12, except that 4-chloro-2-fluoroacetophenone was used instead of acetophenone, to obtain 15.0 mg of the off-white solid title compound. Yield: 15.0%.

[0479] Separation was performed by preparative liquid chromatography (chromatographic column model: Gemini-C18 150*21.2 mm, 5 um, mobile phase: acetonitrile / water 0.05% ammonia water, gradient: 2 min-60% to 22 min-60%).

[0480] LC-MS: m / z=388[M+H] + .

[0481] 1 H NMR (400 MHz, DMSO-d 6 )δ7.60(t, J=8.4Hz, 1H), 7.58-7.53(m, 1H), 7.40(s, 1H), 7.35-7.30(m, 1H), 7.12(s, 1H) , 6.94 (s, 1H), 6.78 (s, 1H), 5.50 (s, 2H), 5.32 (s, 1H), 2.05 (s, 3H), 1.57 (d, J=6.8Hz, 6H).

[0482] Example 16: Preparation of 2-(7-amino-2-(3-chlorophenyl)-2-methyl-naphtho[2,3-d][1,3]dioxolan-6-yl)propan-2-ol (16)

[0483]

[0484] Compound 16 was prepared according to the synthetic method of Example 12, except that 3-chloro-acetophenone was used instead of acetophenone, to obtain 33.0 mg of the title compound as an off-white solid. The yield was 16.5%.

[0485] Separation was performed by preparative liquid chromatography (chromatographic column model: Gemini-C18 150*21.2 mm, 5 um, mobile phase: acetonitrile / water 0.05% ammonia water, gradient: 2 min-60% to 22 min-60%).

[0486] LC-MS: m / z=370[M+H] + .

[0487] 1 H NMR (400 MHz, DMSO-d 6)δ7.63-7.60(m, 1H), 7.59-7.53(m, 1H), 7.49-7.44(m, 2H), 7.39(s, 1H), 7.11(s, 1H), 6 .93 (s, 1H), 6.78 (s, 1H), 5.49 (s, 2H), 5.32 (s, 1H), 2.01 (s, 3H), 1.57 (d, J=7.6Hz, 6H).

[0488] Example 17: Preparation of 2-(7-amino-2-(2-chlorophenyl)-2-methyl-naphtho[2,3-d][1,3]dioxolan-6-yl)propan-2-ol (17)

[0489]

[0490] Compound 17 was prepared according to the synthetic method of Example 12, except that 2-chloro-acetophenone was used instead of acetophenone, to obtain 29.6 mg of the off-white solid title compound with a yield of 11.8%.

[0491] Separation was performed by preparative liquid chromatography (chromatographic column model: Gemini-C18 150*21.2 mm, 5 um, mobile phase: acetonitrile / water 0.05% ammonia water, gradient: 2 min-60% to 22 min-60%).

[0492] LC-MS: m / z=370[M+H] + .

[0493] 1 H NMR (400 MHz, DMSO-d 6 )δ7.80-7.70(m, 1H), 7.57-7.51(m, 1H), 7.47-7.34(m, 3H), 7.12(s, 1H), 6.93(s , 1H), 6.78 (s, 1H), 5.49 (s, 2H), 5.32 (s, 1H), 2.12 (s, 3H), 1.56 (d, J=8.4Hz, 6H).

[0494] Example 18: Preparation of 2-(7-amino-2-(3-fluorophenyl)-2-methyl-naphtho[2,3-d][1,3]dioxolan-6-yl)propan-2-ol (18)

[0495]

[0496] Compound 18 was prepared according to the synthetic method of Example 12, except that 3-fluoroacetophenone was used instead of acetophenone, to obtain 40.0 mg of the off-white solid title compound with a yield of 20.0%.

[0497] Separation was performed by preparative liquid chromatography (chromatographic column model: Gemini-C18 150*21.2 mm, 5 um, mobile phase: acetonitrile / water 0.05% ammonia water, gradient: 2 min-60% to 22 min-60%).

[0498] LC-MS: m / z=354[M+H] + .

[0499] 1 H NMR (400 MHz, DMSO-d 6 )δ7.51-7.42(m, 2H), 7.42-7.37(m, 2H), 7.28-7.20(m, 1H), 7.10(s, 1H), 6.92(s , 1H), 6.78 (s, 1H), 5.50 (s, 2H), 5.32 (s, 1H), 2.00 (s, 3H), 1.57 (d, J=7.4Hz, 6H).

[0500] Example 19: Preparation of 2-(7-amino-2-(2-fluorophenyl)-2-methyl-naphtho[2,3-d][1,3]dioxolan-6-yl)propan-2-ol (19)

[0501]

[0502]

[0503] Compound 19 was prepared according to the synthetic method of Example 12, except that 2-fluoroacetophenone was used instead of acetophenone, to obtain 17.0 mg of the off-white solid title compound in a yield of 6.0%.

[0504] Separation was performed by preparative liquid chromatography (chromatographic column model: Gemini-C18 150*21.2 mm, 5 um, mobile phase: acetonitrile / water 0.05% ammonia water, gradient: 2 min-60% to 22 min-60%).

[0505] LC-MS: m / z=354[M+H] + .

[0506] 1 H NMR (400 MHz, DMSO-d 6 )δ7.64-7.56(m, 1H), 7.50-7.42(m, 1H), 7.39(s, 1H), 7.34-7.26m, 1H), 7.25-7.19(m, 1H), 7.11 (s, 1H), 6.93 (s, 1H), 6.78 (s, 1H), 5.49 (s, 2H), 5.32 (s, 1H), 2.06 (s, 3H), 1.57 (d, J=7.6Hz, 6H).

[0507] Example 20: Preparation of 2-(7-amino-2-ethyl-2-(4-fluorophenyl)-naphtho[2,3-d][1,3]dioxolan-6-yl)propan-2-ol (20)

[0508]

[0509] Compound 20 was prepared according to the synthetic method of Example 12, except that 4-fluoropropiophenone was used instead of acetophenone, to obtain 20.0 mg of the title compound as an off-white solid. The yield was 7.1%.

[0510] Separation was performed by preparative liquid chromatography (chromatographic column model: Gemini-C18 150*21.2 mm, 5 um, mobile phase: acetonitrile / water 0.05% ammonia water, gradient: 2 min-60% to 22 min-60%).

[0511] LC-MS: m / z=368[M+H] + .

[0512] 1 H NMR (400 MHz, DMSO-d 6 )δ7.66-7.57(m, 2H), 7.47(s, 1H), 7.30-7.21(m, 2H), 7.15(s, 1H), 7.01(s, 1H), 6.97 (s, 1H), 2.29 (q, J=7.3Hz, 2H), 1.58 (d, J=4.9Hz, 6H), 0.92 (t, J=7.3Hz, 3H).

[0513] Example 21: Preparation of 2-(7-amino-2-(4-methoxyphenyl)-2-methyl-naphtho[2,3-d][1,3]dioxolan-6-yl)propan-2-ol (21)

[0514]

[0515] Compound 21 was prepared according to the synthetic method of Example 12, except that 1-(4-methoxyphenyl)ethane-1-one was used instead of acetophenone, to obtain 40.0 mg of the off-white solid title compound. The yield was 30.0%.

[0516] Separation was performed by preparative liquid chromatography (chromatographic column model: Gemini-C18 150*21.2 mm, 5 um, mobile phase: acetonitrile / water 0.05% ammonia water, gradient: 2 min-60% to 22 min-60%).

[0517] LC-MS: m / z=347.9 [M-17] + .

[0518] 1 H NMR (400 MHz, DMSO-d 6 ) δ7.54-7.47 (m, 3H), 7.16 (s, 1H), 7.04 (s, 2H), 6.98-6.94 (m, 2H), 5.68 (s, 3H), 3.75 (s, 3H), 1.99 (s, 3H), 1.58 (d, J=5.5Hz, 6H).

[0519] Example 22: Preparation of 2-(7-amino-2-(4-fluorophenyl)-2-methyl-naphtho[2,3-d][1,3]dioxolan-6-yl)propan-2-ol (22)

[0520]

[0521] Compound 22 was prepared according to the synthetic method of Example 12, except that 4-fluoroacetophenone was used instead of acetophenone, to obtain 20.0 mg of the off-white solid title compound with a yield of 6.6%.

[0522] Separation was performed by preparative liquid chromatography (chromatographic column model: Gemini-C18 150*21.2 mm, 5 um, mobile phase: acetonitrile / water 0.05% ammonia water, gradient: 2 min-60% to 22 min-60%).

[0523] LC-MS: m / z=354[M+H] + .

[0524] 1 H NMR (400 MHz, DMSO-d 6 )δ7.70-7.58(m, 2H), 7.38(s, 1H), 7.24(t, J=8.9Hz, 2H), 7.09(s, 1H), 6.90(s, 1H), 6.78 (s, 1H), 5.48 (s, 2H), 5.31 (s, 1H), 1.99 (s, 3H), 1.57 (d, J=6.7Hz, 6H).

[0525] Example 23: Preparation of 2-(7-amino-2-cyclopropyl-2-phenyl-naphtho[2,3-d][1,3]dioxolan-6-yl)propan-2-ol (23)

[0526]

[0527] Compound 23 was prepared according to the synthetic method of Example 12, except that cyclopropylbenzophenone was used instead of acetophenone, to obtain 10.0 mg of the off-white solid title compound. Yield: 10.0%.

[0528] Separation was performed by preparative liquid chromatography (chromatographic column model: Gemini-C18 150*21.2 mm, 5 um, mobile phase: acetonitrile / water 0.05% ammonia water, gradient: 2 min-60% to 22 min-60%).

[0529] LC-MS: m / z=362[M+H] + .

[0530] 1 H NMR (400 MHz, DMSO-d 6 )δ7.64-7.55(m, 2H), 7.47-7.38(m, 3H), 7.36(s, 1H), 7.05(s, 1H), 6.87(s, 1H), 6.76(s, 1 H), 5.47 (s, 2H), 5.31 (s, 1H), 1.80-1.70 (m, 1H), 1.56 (d, J=3.1Hz, 6H), 0.68-0.52 (m, 4H).

[0531] Biological evaluation

[0532] Test Example 1: Measurement of Aldehyde Capture Rate Analysis Test

[0533] The aldehyde capture test disclosed in the present invention uses nonenal, a stable lipid metabolite, as a model aldehyde to react with the example compounds. The specific scheme is as follows.

[0534] 0.05 mM of each compound of the present invention was accurately weighed and dissolved in 1.2 mL of a mixed solvent (v / v = 1:1) of triolein (Aladdin, G105172-5 g) and linoleic acid (Aladdin, L100442-25 g). Then, 2.5 mL of a 20% (Aladdin, C125030-25g) in PBS (Solebao, P1020) solution, placed at room temperature and stirred overnight. After the example compound is fully dissolved, 0.025mM nonenal (Sigma, 255653-5G) is added thereto and stirred vigorously at room temperature. At 0, 45, 90, 135, 180, 225, 345, 465 and 1500 minutes, 200μL of the sample is drawn and added to 800μL of acetonitrile (Fisher, A995), vortexed vigorously for 2 minutes, and centrifuged at a low speed of 1000r / min for 3 minutes. The supernatant is transferred to a sample injection bottle, and the nonenal in the reaction mixture is quantitatively monitored and analyzed by high performance liquid chromatography.

[0535] Liquid chromatograph: Waters I Class;

[0536] Column: ACQUITY UPLC HSS T3 1.8 μm;

[0537] Column temperature: 40°C;

[0538] Liquid phase conditions: Mobile phase A: acetonitrile solution containing 0.1% formic acid; B: aqueous solution containing 0.1% formic acid;

[0539] Flow rate: 0.4 mL / mL;

[0540] Injection volume: 0.5 mL.

[0541] Mobile phase gradient:

[0542] Time (min) A％ 0 10 0.5 10 2.5 95 3.4 95 3.5 10 4.0 10

[0543] In the developed detection method, the retention time of the pattern aldehyde nonenal was 2.42 minutes.

[0544] The change of the compound of the present invention and nonenal with the reaction time is shown in the figure Figure 1 The aldehyde consumption behavior of the embodiments of the present invention is shown in Table 1 below.

[0545] Table 1 Aldehyde consumption behavior of the compounds of the present invention at different time points

[0546]

[0547]

[0548] a. The aldehyde capture rate is represented by the slope of the capture curve per unit time. The larger the absolute value of the slope, the faster the capture rate.

[0549] from Figure 1 As can be seen from Table 1 above, the compounds of the present invention have aldehyde capturing ability.

[0550] Test Example 2: Therapeutic effect of the compound of the present invention on animal models of allergic conjunctivitis

[0551] C48 / 80 is a polymer formed by the condensation of N-methyl-p-methoxyphenylethylamine and formaldehyde. It can directly act on G protein and induce mast cell degranulation. After mast cell degranulation, active substances such as histamine and kinin are released, which can cause acute type I allergic reactions such as capillary dilation and increased permeability. If it is applied topically to the ocular surface, it can cause allergic conjunctivitis.

[0552] Female Wistar rats were used as research subjects. Wistar rats (Viton Lihua) were randomly divided into groups, with 6 animals in each group. The groups were as follows: normal control group, model control group, positive drug group, and example administration group. The normal control group did not undergo modeling verification, while the other groups all underwent modeling. The positive drug was emedastine fumarate eye drops ( Alcon, H20181192). The model establishment, administration and evaluation process are as follows:

[0553] The animals were anesthetized by inhalation (isoflurane, Hebei Yipin Pharmaceutical Co., Ltd., C002151205; anesthesia parameters: flow rate: 1.0 L / min, oxygen pressure: 0.1 MPa, solubility: 4.5%, anesthesia time: 5 minutes). 10 μL C48 / 80 solution (Sigma, C2313-100MG, 200 mg / mL, prepared in 0.9% saline) was taken with a 10 μL pipette and dripped onto the corneal surface of both eyes of the animal, and the upper and lower eyelids were gently closed for 10 seconds to prevent the outflow of the drug solution.

[0554] After 10 minutes of stimulation, different drugs were given according to the group settings. The same drug treatment was given to both eyes of the same animal, 10 μL per eye. The eyelids were closed for 10 seconds in the same way. 20 minutes after the drug administration, the animals were observed with a handheld slit lamp microscope (LYL-S, Jiangfeng, Jiangxi) for ophthalmic examination, and the clinical scores of each animal were performed according to the McDonald-Shadduck scoring system (GB / T28538-2012). The results were calculated as the average of the animals in each group.

[0555] The results are as follows Figure 2 As shown, according to the evaluation principle of the McDonald-Shadduck scoring system, the score value is positively correlated with the severity of eye inflammation. The compound of Example 12 of the present invention has a good therapeutic effect on allergic conjunctivitis induced by C48 / 80 in Wistar rats.

Claims

1. A compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, in: A 2 Selected from N; A 5 and A 6 are each independently selected from -O-; Q is selected from halogen; n is 1 or 2; R 5 and R 6 Each is independently selected from hydrogen and C1-C6 alkyl.

2. A compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, in: A 2 is selected from N or CH; A 5 and A 6 are each independently selected from -O-; Q1 is selected from C1-C6 alkyl, C3-C6 cycloalkyl; R 7 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy; p is 0, 1, or 2; R 5 and R 6 Each is independently selected from hydrogen and C1-C6 alkyl.

3. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

4. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

5. Use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 4 in the preparation of a toxic aldehyde scavenger.

6. Use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 4 in the preparation of a medicament for preventing and / or treating diseases associated with active carbonyl compounds.

7. The use according to claim 6, wherein the disease is selected from eye diseases, skin diseases, autoimmune diseases, digestive system diseases, cardiovascular diseases, respiratory system diseases, neurodegenerative diseases, obesity, cancer and aging-related diseases.

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