Anti-inflammatory and analgesic compounds and their uses

Abstract

The present invention belongs to the field of medicinal chemistry, and specifically discloses an anti-inflammatory analgesic compound and its use. The compound of the present invention is a compound, an isomer, or a pharma- ceutically acceptable salt thereof having a structure represented by formula (I) or formula (II). The compound of the present application has a remarkable therapeutic effect on gouty arthritis in rats, and also has an excellent resistance effect against inflammatory factors. Therefore, it has potential applications in the fields of anti-inflammatory and analgesic drugs, particularly drugs for treating acute gouty arthritis, drugs for treating rheumatoid arthritis, drugs for reducing inflammatory factors, drugs for treating cytokine storms, or drugs for treating coronavirus pneumonia. [Formula 1] TIFF2024540514000108.tif53170

Description

[Technical Field]

[0001] This invention belongs to the field of medicinal chemistry and, more specifically, relates to compounds having anti-inflammatory or analgesic properties. [Background technology]

[0002] In recent years, with improvements in living standards, people's dietary habits have changed, and the number of gout patients has increased significantly. Gout has already become the second most common metabolic disease after diabetes. Such a disease is already recognized by the United Nations as one of the 20 most intractable diseases of the 21st century. According to data from the U.S. National Health and Nutrition Survey, the prevalence of gout among adults in the United States was 3.9% (approximately 8.3 million people) between 2007 and 2008 (Non-Patent Literature 1). According to a meta-analysis, in China, the overall prevalence of hyperuricemia was 13.3%, and gout was 1.1% (Non-Patent Literature 2). Over the past few decades, the incidence of gout has gradually increased due to the prevalence of complications that promote hyperuricemia (e.g., hypertension, obesity, metabolic syndromes, type 2 diabetes, chronic kidney disease) (Non-Patent Literature 3).

[0003] Gout is caused by chronic hyperuricemia. Uric acid is the end product of purine metabolism in the human body and has low solubility. Most of the uric acid in the body is excreted in urine through the kidneys. When metabolism in the body is disrupted, or when high-purine foods are consumed excessively over a long period, excess uric acid is produced in the body. Anion transporter protein 1 (URAT1) on the epithelial cell membrane of the kidney controls the reabsorption of most of the uric acid in the kidney. In the kidney, when there is a problem with the uric acid transport and excretion system, URAT1 causes the excess uric acid to be reabsorbed into the body, causing a continuous rise in blood uric acid concentration. 80-85% of patients with gout and hyperuricemia develop it because of insufficient renal uric acid excretion.

[0004] When the uric acid concentration in the blood exceeds 6.8-7.0 mg / dL, and the uric acid concentration exceeds the maximum solubility capacity of the blood, the blood uric acid concentration reaches saturation, and urate crystals are deposited in the synovial fluid of human tissues, cartilage of surrounding joints, the auricle of the ear, the olecranon capsule of the elbow, tendons, and kidneys (Non-Patent Literature 4). This crystal deposition causes recurrent inflammatory arthritis, the formation of gouty nodules, and ultimately progresses to severe chronic joint disease, sometimes even leading to bone erosion (Non-Patent Literature 5). When urate crystals form and are deposited in the subcutaneous tissue, gouty stones are formed, which can rupture the epidermal tissue of the body. Acute attacks are extremely painful and can cause infection. Gout can lead to urate nephropathy and uric acid urinary tract stones, sometimes resulting in renal failure. Severe gout can lead to a decline in a person's quality of life and increased medical costs.

[0005] When the concentration of urate in the joint cavity of a gout patient changes rapidly, urate microcrystals are formed. These crystals activate synovial endothelial cells, promoting the attachment and exudation of mononuclear macrophages. After engulfing the urate microcrystals, these cells secrete inflammatory factors, triggering an immune response. This condition is called "acute gouty arthritis." Acute gouty arthritis is the most common initial symptom of gout. A typical attack begins suddenly, sometimes explosively, often waking the patient in the middle of the night with foot pain. The pain is described as a sharp, biting sensation, accompanied by redness, swelling, warmth, and pain in the joint and surrounding tissues. In most cases, only a single joint is affected at the initial onset of acute gouty arthritis, most commonly the first joint of the big toe, followed by the dorsum of the foot, heel, ankle, knee, wrist, and elbow. Sometimes, multiple joints may be affected simultaneously.

[0006] Currently, there is no established effective treatment for acute gouty arthritis, and the goal of treatment in the acute phase of acute gouty arthritis is to rapidly suppress the symptoms of acute arthritis.

[0007] Guidelines and consensus recommendations across countries regarding anti-inflammatory and analgesic treatment for acute gout attacks are fundamentally similar. During the acute phase of a gout attack, early use of small doses of colchicine or nonsteroidal anti-inflammatory drugs (NSAIDs) (appropriate dose, short duration) is recommended. For patients who are not resistant to, ineffective, or contraindicated with the above drugs, systemic glucocorticoid treatment is recommended. For patients at risk of gastrointestinal bleeding or requiring long-term use of low-dose aspirin, the use of selective cyclooxygenase-2 (COX-2) inhibitors is recommended as a priority. For patients whose acute gout attacks affect multiple or large joints, or who experience systemic symptoms, systemic glucocorticoid treatment is recommended as the top priority. For patients with a visual analog pain scale (VAS) score of 7 or higher, or those involving two or more large joints, or those with polyarthritis, or those for whom a particular medication is ineffective, combination therapy with two anti-inflammatory and analgesic drugs, such as low-dose colchicine and an NSAID, or low-dose colchicine and a systemic glucocorticoid, is recommended (Non-Patent Literature 6).

[0008] Colchicine was the first drug used for anti-inflammatory and analgesic treatment of acute gouty arthritis and remains the first-line drug for acute gout attacks. Colchicine has the following effects (1) to (3): (1) It reduces the reaction of acute gout by suppressing the aggregation of leukocytes at the site of inflammation and weakening the phagocytic action of leukocytes on uric acid, thereby achieving rapid pain relief. (2) It achieves anti-inflammatory and analgesic effects by suppressing cell mitosis, binding to microtubule proteins to prevent microtubule formation, inhibiting phospholipase A, and also inhibiting tyrosine phosphorylation and leukotriene B4 production. (3) It controls inflammatory responses such as local redness, swelling, heat, and pain in the joint by suppressing interleukin-6 (IL-6) and other substances produced by local cells. During the acute attack phase of gout, patients are traditionally given 0.5-1 mg of colchicine orally every 1-2 hours until joint symptoms subside or until side effects such as diarrhea and vomiting occur and treatment must be discontinued. The therapeutic dose is usually 3-5 mg, and should not exceed 6 mg within 24 hours. The daily dose 72 hours after discontinuing the drug is 0.5-1.5 mg, taken in 7 divided doses. The therapeutic and toxic doses of colchicine are close. Generally, a dose of 0.5-0.8 mg / kg of colchicine is toxic to the body, and doses exceeding 0.8 mg / kg are fatal. In other countries, there have been reports of death 35 hours after ingesting 0.4 mg / kg of colchicine. Colchicine has many clinical side effects, which are clearly related to the dose. Common gastrointestinal reactions such as nausea, vomiting, diarrhea, and abdominal pain are precursors to severe poisoning, and the drug should be stopped immediately if these symptoms appear. Furthermore, colchicine can potentially damage the kidneys, which may manifest as hematuria or oligouria. It also has a direct suppressive effect on the bone marrow and can cause granulocytopenic aplastic anemia, so caution is required when using it, and the dose should be reduced when colchicine is used in patients with moderate to severe renal impairment (Non-Patent Literature 7). Patients with gout frequently experience attacks of acute gouty arthritis, requiring long-term medical treatment, and consequently, the toxicity and side effects of colchicine are factors that limit its use in the treatment of this disease.NSAIDs and COX-2 inhibitors are also first-line treatments for acute gouty arthritis, but these drugs have many toxicities and side effects, with NSAIDs in particular primarily causing gastrointestinal toxicity, including gastrointestinal ulcers, gastrointestinal perforation, and upper gastrointestinal bleeding. Glucocorticoids are mainly used in acute, severe attacks accompanied by severe systemic symptoms when treatment with colchicine or NSAIDs is ineffective. The Chinese gout guidelines recommend glucocorticoids as a second-line analgesic, and recommend systemic glucocorticoid treatment only when acute gout affects multiple or large joints, or when accompanied by systemic symptoms (Non-Patent Literature 8).

[0009] Inflammatory cytokines play a crucial role in the development of gout and can be used as adjuncts in the clinical diagnosis of acute gouty arthritis. Among these, IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) are major triggers for acute gouty arthritis and play significant roles in its development. Some scholars recommend IL-1β and IL-6 as indicators for assessing the degree of inflammation in acute gout. Wang Si-Qi et al. assessed the pain level of 72 acute gout patients who visited the gout outpatient clinic of Zhejiang Provincial Dermatology Hospital between January 2017 and December 2018 using a visual analog scale (VAS). They also measured the expression levels of IL-1β, IL-6, and TNF-α in the patients' serum and analyzed their correlations. The results showed a high correlation between serum IL-1β and IL-6 levels and pain level (Non-Patent Literature 9). Recently, IL-1 antagonists have been gradually used in the treatment and prevention of acute gouty arthritis. Internationally, IL-1 antagonists approved for rheumatic diseases include anakinra, canakinumab, and rilmiracept, but none of these are marketed in China. The American College of Rheumatology (ACR) recommended anakinra and canakinumab for the treatment of severe acute gouty arthritis in 2011 and 2012. In 2013, canakinumab was approved by the European Medicines Agency for gout patients who do not have resistance or for whom the use of common anti-inflammatory analgesics is contraindicated. TNF-α is an important inflammatory factor in the onset and progression of rheumatoid arthritis. TNF-α and its receptors are widely distributed in the serum and synovial fluid of rheumatoid arthritis patients. TNF-α plays a role in suppressing important proteins in inflammatory signaling pathways and promoting inflammatory responses. Clinically, TNF-α inhibitors, such as adalimumab, are used to treat rheumatoid arthritis.

[0010] Inflammatory cytokines also play a crucial role in the onset and progression of COVID-19. Clinically, a "cytokine storm" has been identified as a possible key factor in the rapid deterioration of symptoms caused by COVID-19. Also known as an immune system overreaction, a cytokine storm involves the rapid and massive release of many cytokines, such as IL-6, IL-1, IL-8, IFN, and TNF-α, primarily after a dysfunction of the immune system. This can cause widespread edema of lung tissue, inducing acute lung injury, acute respiratory distress syndrome, and multiple organ failure syndrome, and in the worst cases, death (Non-Patent Literature 10). The symptoms of a cytokine storm are indeed a critical turning point in the progression of a patient from mild to severe and critical condition, and are one of the causes of death in severe and critical patients (Non-Patent Literature 11).

[0011] Increasing evidence indicates that cytokine storms are involved in the pathogenesis of COVID-19. Studies have found significantly elevated serum cytokines, such as IL-6, in COVID-19 patients in a severely hypoxic state (Non-Patent Literature 12). HUANG et al. collected and analyzed case data from 41 hospitalized COVID-19 patients and found that ICU patients had higher levels of plasma IL-2, IL-7, IL-10, granulocyte colony-stimulating factor, chemokines, and TNF-α compared to other patients (Non-Patent Literature 13). This suggests that anti-inflammatory therapy may be an effective means of suppressing and preventing cytokine storms in COVID-19.

[0012] Clinically, there is currently no specific treatment for cytokine storms, and combination therapies involving antiviral drugs, glucocorticoids, targeted immunotherapy, and herbal medicines are frequently employed. Glucocorticoids remain the most common and effective drugs for directly suppressing cytokine storms; they are the most commonly used immunomodulators, regulating immune activity and reducing inflammation in various serious diseases. However, there is currently no clear evidence that COVID-19 patients benefit from glucocorticoid treatment; rather, they are more likely to face risks associated with glucocorticoid therapy (Non-Patent Literature 14). Therefore, in the absence of clinical trials, glucocorticoids should not be used to treat lung injury or shock caused by COVID-19. Besides glucocorticoids, several other drugs, such as immunosuppressants, can be used to treat cytokine storms.

[0013] Recently, colchicine has been reported to have shown positive effects in COVID-19 treatment trials, suggesting it may be an effective oral medication against COVID-19. Colchicine not only suppresses the function of neutral leukocytes but can also reduce the expression levels of several cytokines. These inflammatory cytokines increase after COVID-19 infection, and suppressing the "immune cell storm" caused by these factors is one of the current research directions in COVID-19 treatment. Currently, several clinical trials of colchicine-based COVID-19 treatment are underway worldwide. According to news released by the Montreal Heart Institute in Canada, a clinical trial showed that colchicine demonstrated a "compelling" therapeutic effect against COVID-19. This study recruited 4,488 patients infected with COVID-19 who were not yet hospitalized, and compared to the placebo group, patients treated with colchicine had a 21% lower risk of hospitalization or death. Nasopharyngeal nucleic acid testing of 4,159 patients showed that colchicine reduced hospitalizations by 25%, ventilator use by 50%, and mortality by 44% (Non-Patent Literature 15).

[0014] Following the publication of these research findings, a committee of experts from the Greek Ministry of Health approved the inclusion of colchicine in the oral medication treatment plan for COVID-19 patients in early 2021. However, due to colchicine's toxicity and side effects, it still needs to be handled with caution.

[0015] In recent years, targeted therapies for specific cytokines in cytokine storms have been used clinically. While these therapies have shown remarkable clinical efficacy, side effects should not be overlooked. One such side effect is called "cytokine release syndrome," a systemic immune storm in which large amounts of cytokines released by activated immune cells cause damage to multiple immune systems, and in the worst cases, can lead to death. [Prior art documents] [Non-patent literature]

[0016] [Non-Patent Document 1] Zhu Y, Pandya BJ, Choi HK. Prevalence of Gout and Hyperuricemia in the US General Population: The National Health and Nutrition Examination Survey 2007-2008[J]. Arthritis Rheum, 2011, 63(10): 3136-3141 [Non-Patent Document 2] Liu R, Han C, Wu D, et al. Prevalence of hyperuricemia andgout in mainland China from 2000 to 2014: A systematic review and meta-analysis[J]. Biomed Research International, 2015: 1-12 [Non-Patent Document 3] Khanna D, Fitzgerald JD, Khanna PP, et al. American College ofRheumatology Guidelines for Management of Gout. Part 1: Systematic Nonpharmacologic and Pharmacologic Therapeutic Approaches to Hyperuricemia[J]. Arthritis Care & Research, 2012, 64(10): 1432-1446

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[0017] Disclosure of the invention The present invention aims to provide a compound having a novel structure and exhibiting anti-inflammatory and analgesic effects. This compound effectively alleviates the symptoms of gouty arthritis, suppresses the levels of inflammatory factors in knee joint tissue, possesses excellent anti-inflammatory effects, and can be applied to the treatment of various inflammation-related diseases. [Means for solving the problem]

[0018] The technical solution of the present invention is as follows.

[0019] Compounds, isomers, or pharmaceutically acceptable salts thereof whose structure is represented by formula (I) or formula (II): [ka] In the formula, R 1 , R 2 , R 3 or R 4 are each independently hydrogen, deuterium, halogen, cyano group, C 1-3 alkoxy group, hydroxyl group, aldehyde group, carboxyl group, C 2-6 ester group, amido group, substituted amido group, C 1-3 alkyl group, substituted C 1-3 alkoxy group or substituted C 1-3 alkyl group, with the proviso that the substituent in said substitution is one or more selected from deuterium, halogen, hydroxyl group, carboxyl group, C 1-3 alkyl group or cyano group, or, R 1 , R 2 , R 3 and R 4 two adjacent groups among them are bonded to form -O-R 17 -O- group, and said R 17 is C 1-6 alkyl group, R 5 , R 6 , R 7 or R 8 are each independently hydrogen, deuterium, halogen, hydroxyl group, cyano group, carboxyl group, C 2-6 ester group, or substituted or unsubstituted (amino group, amido group, C 1-3 alkoxy group or C 1-3 alkyl group), with the proviso that the substituent in said substitution is one or more selected from deuterium, halogen, cyano group, C 1-3 alkyl group, C 1-3 haloalkyl group, R 9 is hydrogen, C 1-4 alkyl group or C 1-4 substituted alkyl group, with the proviso that the substituent in said substitution is one or more selected from deuterium, hydroxyl group, C1-2 alkoxy group or cyano group, X is a -C(=O)-, -S(=O)2-, -S(=O)-, -C(=NH)-, or substituted -C(=NH)- group, wherein the substituted substituent is selected from CN or SO2NH2. R 10 C 1-4 Alkyl alkyl group, substituted C 1-4 Alkyl alkyl group, C 3-6 Cycloalkyl groups, substituted C 3-6 Cycloalkyl group, amino group, C 1-4 alkylamino group, substituted C 1-4 Alkylamino group, C 3-6 Cycloalkylamino group, C 1-4 Alkoxy group, substituted C 1-4 It is an alkoxy group or a vinyl group, or R 9 and R 10 By joining, R 9 -NXR 10 This constitutes a cyclic group, wherein the substituted substituent is one or more selected from deuterium, halogen, or cyano groups. R 11 is hydrogen, deuterium, halogen, cyano group, C 1-2 Alkyl alkyl group, C 1-2 Alkoxy group, carboxyl group or C 1-3 It is an alkyl-substituted amide group, R 12 (C) is hydrogen, deuterium, halogen, hydroxyl group, cyano group, carboxyl group, or substituted or unsubstituted (C) 1-4 Alkyl alkyl group, C 3-6 Cycloalkyl groups, C 1-4 Alkoxy group, morpholinyl group, aminocarbonyl group, C 1-4 Alkylaminocarbonyl group or C 1-4 The alkoxycarbonyl group is, however, the substituted substituent is one or more selected from deuterium, halogen, or cyano groups, and (a)R 12 If R is hydrogen, 13 This includes cyano groups, aldehyde groups, carboxyl groups, boric acid groups, substituted C1-4 alkoxy groups, or substituted or unsubstituted (C) groups. 1-4Alkoxycarbonyl group, aminocarbonyl group, phenylaminocarbonyl group, pyridinylaminocarbonyl group, C 1-4 Alkylaminocarbonyl group, C 1-4 Alkoxycarbonylamino group, C 1-4 Alkylaminocarbonylamino group, C 2-6 Heterocycloalkylcarbonyl group, C 3-6 Heterocycloalkylketone group, C 1-2 Alkylcarbonyl group, sulfonylamino group, sulfonyloxy group, aminosulfonyl group, aminosulfonyloxy group, C 1-4 Alkylsulfonylamino group, C 1-4 Alkylaminosulfonyl group, C 1-4 Alkylaminosulfonylamino group, C 1-4 Alkyl sulfonyl oxy group, C 1-4 Alkylaminosulfonyloxy group, C 1-4 Alkylaminocarbonyloxy group, tetrazolyl group, triazolyl group, imidazolyl group, morpholinyl group, C 1-4 Alkylthio group, C 3-6 Cycloalkoxy group or C 3-6 (heterocycloalkoxy group), wherein the substituted substituents are deuterium, halogen, cyano group, hydroxyl group, phenyl group, pyridinyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterium-substituted alkyl groups or C 1-3 One or more types selected from haloalkyl groups, (b)R 12 If R is non-hydrogen, 13 (C) is a cyano group, aldehyde group, carboxyl group, boric acid group, or substituted or unsubstituted (C) 1-4 Alkoxycarbonyl group, aminocarbonyl group, phenylaminocarbonyl group, pyridinylaminocarbonyl group, C 1-4 Alkylaminocarbonyl group, C 1-4 Alkoxycarbonylamino group, C 1-4 Alkylaminocarbonylamino group, C 2-6 Heterocycloalkylcarbonyl group, C 3-6 Heterocycloalkylketone group, C1-4 alkylcarbonyl group, sulfonylamino group, sulfonyloxy group, aminosulfonyl group, aminosulfonyloxy group, C 1-4 alkylsulfonylamino group, C 1-4 alkylaminosulfonyl group, C 1-4 alkylaminosulfonylamino group, C 1-4 alkylsulfonyloxy group, C 1-4 alkylaminosulfonyloxy group, C 1-4 alkylaminocarbonyloxy group, heterocyclyl group, C 1-4 alkylamino group, C 3-6 cycloalkylamino group, C 3-6 heterocycloalkoxy group, C 3-6 heterocycloalkylamino group, C 1-4 alkylcarbonylamino group, C 1-4 alkoxy group, C 1-4 alkylthio group, C 3-6 cycloalkoxy group, C 3-6 heterocycloalkyl group or C 1-4 alkyl group), provided that the substituent of said substitution is one or more selected from deuterium, halogen, cyano group, hydroxyl group, phenyl group, pyridinyl group, C 1-3 alkyl group, C 1-3 deuterium-substituted alkyl group or C 1-3 haloalkyl group, R 14 is cyano group, carboxyl group, or substituted or unsubstituted (C 1-4 alkoxycarbonyl group, aminocarbonyl group, C 1-4 alkylaminocarbonyl group, C 1-4 alkoxycarbonylamino group, C 1-4 alkylaminocarbonylamino group, C 2-6 heterocycloalkylcarbonyl group, aminosulfonyl group, C 1-4 alkylaminosulfonyl group, heterocyclyl group, C 3-6 heterocycloalkyl group, C 3-6 heterocyclooxy group, C 1-4 alkoxy group, C 3-6 cycloalkoxy group, C3-6 Heterocycloalkoxy group or C 1-4 The alkyl group is, however, the substituted substituent is deuterium, halogen, cyano group, hydroxyl group, C 1-3 Alkyl or C 1-3 One or more types selected from haloalkyl groups, R 15 is hydrogen, deuterium, halogen, cyano group, C 1-2 Alkyl alkyl group, C 1-2 Alkoxy group, carboxyl group or C 1-3 It is an alkyl-substituted amide group, The condition is that the following (i) to (iii) are excluded; (i) In equation (I), R 1 ~R 3 R is a methoxy group, 4 ~R 9 is hydrogen, R 10 R is a methyl group, 11 ~R 12 is hydrogen, and R 15 If R is hydrogen, 13 C 1-4 Alkoxy group, C 1-4 Alkylthio group, deuterium-substituted C 1-4 Alkylthio group, C 1-4 It is an alkoxycarbonylamino group, a butylcarbonyl group, or a morpholinyl group. (ii) In equation (I), R 1 ~R 3 R is a methoxy group, 4 ~R 9 is hydrogen, R 10 is a deuterium-substituted methyl group, R 11 is hydrogen, R 12 It is deuterium, and R 13 R is a methoxy group, 15 It is deuterium. (iii) In equation (I), R 1 ~R 3 R is a methoxy group, 4 ~R 9 is hydrogen, R 10 R is a methyl group, 11 is hydrogen, R12 is bromo, R 13 R is a methoxy group, 15 It is a bromo.

[0020] In one preferred approach, the compound of the present invention is selected from compounds whose structure is represented by formula (III) or formula (IV). [ka]

[0021] In another preferred approach, the compounds of the present invention are selected from compounds whose structure is represented by formula (V) or formula (VI). [ka]

[0022] In one preferred solution, R 1 , R 2 , R 3 or R 4 Each of these is independently hydrogen, deuterium, halogen, cyano group, and C 1-3 Alkoxy group, aldehyde group, C 1-3 Alkyl alkyl group, substituted C 1-3 Alkoxy group or substituted C 1-3 It is an alkyl group, wherein the substituted substituents are deuterium, halogen, and C 1-3 One or more selected from alkyl groups or cyano groups, or R 1 and R 2 , R 2 and R 3 , or R 3 and R 4 The combination is -OR 17 -O- group constitutes the R 17 is C 1-5 It is an alkyl group, C 1-3 Alkyl alkyl groups are preferred.

[0023] In one preferred solution, R 1 and R2 , R 2 and R 3 , or R 3 and R 4 These groups combine to form -O-CH2-O-, -O-CH2CH2-O-, or -O-CH2CH2CH2-O-, -O-CH2C(CH3)2CH2-O-, and -OC(CH3)2C(CH3)2-O- groups.

[0024] In one preferred solution, R 5 , R 6 , R 7 or R 8 Each of these is independently hydrogen, deuterium, halogen, cyano group, carboxyl group, hydroxyl group, or amino group.

[0025] In one preferred solution, R 9 is hydrogen, C 1-4 Alkyl or C 1-4 A substituted alkyl group, wherein the substituted substituent is deuterium, a hydroxyl group, or C 1-2 It is one or more selected from alkoxy groups or cyano groups.

[0026] In one preferred solution, R 10 is C 1-4 Alkyl alkyl group, substituted C 1-4 Alkyl alkyl group, C 3-6 Cycloalkyl groups, substituted C 3-6 Cycloalkyl group, amino group, C 1-4 alkylamino group, substituted C 1-4 Alkylamino group, C 3-6 Cycloalkylamino group, C 1-4 Alkoxy group, substituted C 1-4 Alkoxy group or vinyl group, or R 9 -NXR 10 Composed of [ka] The group is a substituted group, wherein the substituted substituent is one or more selected from deuterium or cyano groups.

[0027] In one preferred solution, R 11 is hydrogen, deuterium, halogen, cyano group, C 1-2 Alkyl alkyl group, C 1-2 Alkoxy group, carboxyl group or C 1-3 It is an alkyl-substituted amide group.

[0028] In one preferred solution, R 12 (C) is hydrogen, deuterium, halogen, hydroxyl group, cyano group, or substituted or unsubstituted (C) 1-4 Alkyl alkyl group, C 3-6 Cycloalkyl groups, C 1-4 Alkoxy group, morpholinyl group, C 1-4 Alkylaminocarbonyl group or C 1-4 The substituent is an alkoxycarbonyl group, wherein the substituted substituent is one or more selected from deuterium, halogen, or cyano groups.

[0029] In one preferred solution, R 12 If R is hydrogen, 13 This includes cyano groups, aldehyde groups, carboxyl groups, boric acid groups, and substituted C groups. 1-4 alkoxy group, or substituted or unsubstituted (C 1-4 Alkoxycarbonyl group, aminocarbonyl group, phenylaminocarbonyl group, pyridinylaminocarbonyl group, C 1-4 Alkylaminocarbonyl group, C 1-4 Alkoxycarbonylamino group, C 1-4 Alkylaminocarbonylamino group, pyrrolidinylcarbonyl group, piperazinylcarbonyl group, morpholinylcarbonyl group, pyrrolidinyl ketone group, oxazolidinyl ketone group, morpholinyl ketone group, C 1-4 Alkylcarbonyl group, sulfonylamino group, sulfonyloxy group, aminosulfonyl group, aminosulfonyloxy group, C 1-4 Alkylsulfonylamino group, C 1-4 Alkylaminosulfonyl group, C 1-4 Alkylaminosulfonylamino group, C 1-4Alkylaminosulfonyloxy group, C 1-4 Alkylaminocarbonyloxy group, tetrazolyl group, triazolyl group, imidazolyl group, morpholinyl group, C 1-4 Alkylthio group, C 3-6 The substituent is a cycloalkoxy group or a tetrahydrofuranyloxy group, wherein the substituted substituent is deuterium, halogen, cyano group, hydroxyl group, phenyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterium-substituted alkyl groups or C 1-3 It is one or more types selected from haloalkyl groups.

[0030] In one preferred solution, R 12 However, if it is non-hydrogen, R 13 (C) is a cyano group, aldehyde group, carboxyl group, boric acid group, or substituted or unsubstituted (C) 1-4 Alkoxycarbonyl group, aminocarbonyl group, phenylaminocarbonyl group, pyridinylaminocarbonyl group, C 1-4 Alkylaminocarbonyl group, C 1-4 Alkoxycarbonylamino group, C 1-4 Alkylaminocarbonylamino group, C 2-6 Heterocycloalkylcarbonyl group, C 3-6 Heterocycloalkylketone group, C 1-4 Alkylcarbonyl group, sulfonylamino group, sulfonyloxy group, aminosulfonyl group, aminosulfonyloxy group, C 1-4 Alkylsulfonylamino group, C 1-4 Alkylaminosulfonyl group, C 1-4 Alkylaminosulfonylamino group, C 1-4 Alkyl sulfonyl oxy group, C 1-4 Alkylaminosulfonyloxy group, C 1-4 Alkylaminocarbonyloxy group, heterocyclyl group, C 1-4 Alkylamino group, C 3-6 Cycloalkylamino group, tetrahydrofuranyloxy group, tetrahydrofuranylamino group, C 1-4 Alkylcarbonylamino group, C 1-4Alkoxy group, C 1-4 Alkylthio group, C 3-6 Cycloalkoxy group, C 3-6 Heterocycloalkyl groups or C 1-4 (alkyl group), wherein the substituted substituents are deuterium, halogen, cyano group, hydroxyl group, phenyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterium-substituted alkyl groups or C 1-3 It is one or more types selected from haloalkyl groups.

[0031] In one preferred solution, R 14 (C) is a cyano group, a carboxyl group, or a substituted or unsubstituted (C) 1-4 Alkoxycarbonyl group, aminocarbonyl group, C 1-4 Alkylaminocarbonyl group, C 1-4 Alkoxycarbonylamino group, C 1-4 Alkylaminocarbonylamino group, N-pyrrolidinylcarbonyl group, aminosulfonyl group, C 1-4 Alkylaminosulfonyl group, heterocyclyl group, tetrahydrofuranyloxy group, C 1-4 Alkoxy group, C 3-6 Cycloalkoxy group or C 1-4 (alkyl group), where the substituted substituents are deuterium, halogen, cyano group, hydroxyl group, C 1-3 Alkyl or C 1-3 It is one or more types selected from haloalkyl groups.

[0032] In one preferred solution, R 15 is hydrogen, deuterium, halogen, cyano group, C 1-2 Alkyl alkyl group, C 1-2 Alkoxy group, carboxyl group or C 1-3 It is an alkyl-substituted amide group.

[0033] In another preferred solution, R 1 , R 2 or R 3 Each is independent of C 1-3 It is an alkoxy group, or R1 and R 2 or R 2 and R 3 The combination is -OR 17 -O- group constitutes the R 17 is C 1-2 It is an alkyl group.

[0034] In another preferred solution, R 4 These are hydrogen, deuterium, halogen, or cyano group.

[0035] In another preferred solution, R 9 is hydrogen or C 1-3 It is an alkyl group.

[0036] In another preferred solution, R 10 C 1-3 Alkyl alkyl group, substituted C 1-3 Alkyl alkyl group, C 3-6 Cycloalkyl group, amino group, C 1-4 Alkylamino group, C 1-3 It is an alkoxy group or a vinyl group, or R 9 and NXR 10 teeth [ka] The group is formed, wherein the substituted substituent is one or more selected from deuterium or cyano groups.

[0037] In another preferred solution, R 11 These are hydrogen, deuterium, or halogens.

[0038] In another preferred solution, R 12 (C) is hydrogen, deuterium, halogen, cyano group, or substituted or unsubstituted (C) 1-3 Alkyl alkyl group, C 3-5 Cycloalkyl groups, C 1-3 Alkoxy group, morpholinyl group, C 1-4 Alkylaminocarbonyl group or C 1-4The substituent is an alkoxycarbonyl group, wherein the substituted substituent is one or more selected from deuterium or halogens.

[0039] In another preferred solution, R 12 If R is hydrogen, 13 This includes cyano groups, aldehyde groups, carboxyl groups, boric acid groups, and substituted C groups. 1-4 alkoxy group, or substituted or unsubstituted (C 1-4 Alkoxycarbonyl group, aminocarbonyl group, phenylaminocarbonyl group, pyridinylaminocarbonyl group, C 1-4 Alkylaminocarbonyl group, C 1-4 Alkoxycarbonylamino group, C 1-4 Alkylaminocarbonylamino group, N-pyrrolidinylcarbonyl group, piperazinylcarbonyl group, morpholinylcarbonyl group, pyrrolidinyl ketone group, oxazolidinyl ketone group, 3-morpholinyl ketone group, C 1-2 Alkylcarbonyl group, sulfonylamino group, sulfonyloxy group, aminosulfonyl group, aminosulfonyloxy group, C 1-4 Alkylsulfonylamino group, C 1-4 Alkylaminosulfonyl group, C 1-4 Alkylaminosulfonylamino group, C 1-4 Alkylaminosulfonyloxy group, C 1-4 Alkylaminocarbonyloxy group, tetrazolyl group, triazolyl group, imidazolyl group, pyrazolyl group, morpholinyl group, C 1-4 Alkylthio group, C 3-6 The substituent is a cycloalkoxy group or a tetrahydrofuranyloxy group, wherein the substituted substituent is deuterium, halogen, cyano group, hydroxyl group, phenyl group, pyridinyl group, C 1-3 Alkyl, C1-3 deuterium-substituted alkyl, or C 1-3 It is one or more types selected from haloalkyl groups.

[0040] In another preferred solution, R 12 If R is non-hydrogen, 13(C) is a cyano group, aldehyde group, carboxyl group, boric acid group, or substituted or unsubstituted (C) 1-4 Alkoxycarbonyl group, aminocarbonyl group, phenylaminocarbonyl group, pyridinylaminocarbonyl group, C 1-4 Alkylaminocarbonyl group, C 1-4 Alkoxycarbonylamino group, C 1-4 Alkylaminocarbonylamino group, pyrrolidinyl ketone group, 2-oxazolidinyl ketone group, 3-morpholinyl ketone group, pyrrolidinyl carbonyl group, methylpiperazinyl carbonyl group, morpholinyl carbonyl group, C 1-4 Alkylcarbonyl group, sulfonylamino group, sulfonyloxy group, aminosulfonyl group, aminosulfonyloxy group, C 1-4 Alkylsulfonylamino group, C 1-4 Alkylaminosulfonyl group, C 1-4 Alkylaminosulfonylamino group, C 1-4 Alkyl sulfonyl oxy group, C 1-4 Alkylaminosulfonyloxy group, C 1-4 Alkylaminocarbonyloxy group, heterocyclyl group, C 1-4 Alkylamino group, C 3-6 Cycloalkylamino group, tetrahydrofuranyloxy group, tetrahydrofuranylamino group, C 1-4 Alkylcarbonylamino group, C 1-4 Alkoxy group, C 1-4 Alkylthio group, C 3-6 Cycloalkoxy group, C 3-6 Heterocycloalkyl groups or C 1-4 (alkyl group), wherein the substituted substituents are deuterium, halogen, cyano group, hydroxyl group, phenyl group, pyridinyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterium-substituted alkyl groups or C 1-3 It is one or more types selected from haloalkyl groups.

[0041] In another preferred solution, R 14 (C) is a cyano group, a carboxyl group, or a substituted or unsubstituted (C) 1-4Alkoxycarbonyl group, aminocarbonyl group, C 1-4 Alkylaminocarbonyl group, C 1-4 Alkoxycarbonylamino group, C 1-4 Alkylaminocarbonylamino group, N-pyrrolidinylcarbonyl group, aminosulfonyl group, C 1-4 Alkylaminosulfonyl group, heterocycloalkyl group, tetrazolyl group, triazolyl group, tetrahydrofuranyloxy group, C 1-4 Alkoxy group, C 3-6 Cycloalkoxy group or C 1-4 The alkyl group is, however, the substituted substituent is deuterium, halogen, cyano group, hydroxyl group, C 1-3 Alkyl or C 1-3 It is one or more types selected from haloalkyl groups.

[0042] In another preferred solution, R 14 (C) is a cyano group, a carboxyl group, or a substituted or unsubstituted (C) 1-4 Alkoxycarbonyl group, aminocarbonyl group, C 1-4 Alkylaminocarbonyl group, C 1-4 Alkoxycarbonylamino group, C 1-4 Alkylaminocarbonylamino group, N-pyrrolidinylcarbonyl group, aminosulfonyl group, C 1-4 Alkylaminosulfonyl group, pyridinyl group, oxazolidinyl group, isoxazolidinyl group, piperadinyl group, morpholinyl group, piperidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, hexahydropyrimidinyl group, tetrazolyl group, triazolyl group, tetrahydrofuranyloxy group, C 1-4 Alkoxy group, C 3-6 Cycloalkoxy group or C 1-4 The alkyl group is, however, the substituted substituent is deuterium, halogen, cyano group, hydroxyl group, C 1-3 Alkyl or C 1-3 It is one or more types selected from haloalkyl groups.

[0043] In another preferred solution, R 15These are hydrogen, deuterium, halogen, methyl group, ethyl group, halomethyl group, or halogenated ethyl group.

[0044] In another preferred solution, R 9 This is a hydrogen atom, a methyl group, or an ethyl group.

[0045] In another preferred solution, R 10 is a methyl group, ethyl group, cyclopropyl group, amino group, methylamino group, ethylamino group, dimethylamino group, diethylamino group, methoxy group, ethoxy group, cyanomethyl group or cyanoethyl group, or R 9 and NXR 10 teeth, [ka] It forms the basis.

[0046] In another preferred solution, R 12 These are hydrogen, deuterium, methyl group, ethyl group, halogen, cyano group, methoxy group, ethoxy group, morpholinyl group, aminocarbonyl group, phenylaminocarbonyl group, methylaminocarbonyl group, methyl formate group, or ethyl formate group.

[0047] In another preferred solution, R 12 If R is hydrogen, 13This includes cyano group, aldehyde group, carboxyl group, boric acid group, halomethoxy group, haloethoxy group, deuterium-substituted methoxy group, deuterium-substituted ethoxy group, methoxycarbonyl group, ethoxycarbonyl group, aminocarbonyl group, phenylaminocarbonyl group, pyridinylaminocarbonyl group, methylaminocarbonyl group, deuterium-substituted methylaminocarbonyl group, halomethylaminocarbonyl group, ethylaminocarbonyl group, dimethylaminocarbonyl group, methoxycarbonylamino group, ethoxycarbonylamino group, (methoxycarbonyl)(methyl)amino group, methylaminocarbonylamino group, ethylaminocarbonylamino group, dimethylaminocarbonylamino group, pyrrolidinylcarbonyl group, cyanopyrrolidinylcarbonyl group, piperadinylcarbonyl group, methylpiperazinylcarbonyl group, morphol These are a ylcarbonyl group, pyrrolidinyl ketone group, 2-oxazolidinyl ketone group, 3-morpholinyl ketone group, methylcarbonyl group, ethylcarbonyl group, sulfonylamino group, sulfonyloxy group, methylsulfonyloxy group, ethylsulfonyloxy group, hydroxylsulfonyloxy group, aminosulfonyl group, aminosulfonyloxy group, methylsulfonylamino group, ethylsulfonylamino group, methylaminosulfonyl group, methylaminosulfonylamino group, methylaminosulfonyloxy group, N-ethylmethylaminocarbonyloxy group, tetrazolyl group, triazolyl group, imidazolyl group, pyrazolyl group, morpholinyl group, methylthio group, ethylthio group, halomethylthio group, haloethylthio group, deuterium-substituted methylthio group, deuterium-substituted ethylthio group, or tetrahydrofuranyloxy group.

[0048] In another preferred solution, R 12 If R is non-hydrogen, 13These include cyano group, aldehyde group, carboxyl group, boric acid group, methoxycarbonyl group, ethoxycarbonyl group, methylaminocarbonyl group, dimethylaminocarbonyl group, aminocarbonyl group, phenylaminocarbonyl group, pyridinylaminocarbonyl group, ethylaminocarbonyl group, halomethylaminocarbonyl group, deuterium-substituted methylaminocarbonyl group, (methoxycarbonyl)(methyl)amino group, methylaminocarbonylamino group, and ethylaminocarbonylamino group. dimethylaminocarbonylamino group, pyrrolidinylcarbonyl group, cyanopyrrolidinylcarbonyl group, piperazinylcarbonyl group, methylpiperazinylcarbonyl group, morpholinylcarbonyl group, pyrrolidinyl ketone group, 2-oxazolidinyl ketone group, 3-morpholinyl ketone group, methylcarbonyl group, ethylcarbonyl group, sulfonylamino group, sulfonyloxy group, hydroxylsulfonyloxy group, aminosulfonyl group, aminosulfonyloxy group, methylsulfonyl The group is an amino group, ethylsulfonylamino group, methylaminosulfonyl group, ethylaminosulfonyl group, methylaminosulfonylamino group, methylaminosulfonyloxy group, N-ethylmethylaminocarbonyloxy group, tetrazolyl group, triazolyl group, methylamino group, ethylamino group, tetrahydrofuranyloxy group, tetrahydrofuranylamino group, methylcarbonylamino group, methoxy group, halomethoxy group, deuterium-substituted methoxy group, ethoxy group, haloethoxy group, deuterium-substituted ethoxy group, methylthio group, halomethylthio group, deuterium-substituted methylthio group, ethylthio group, haloethylthio group, deuterium-substituted ethylthio group, tetrahydrofuranyl group, piperadinyl group, piperidinyl group, methylpiperidinyl group, imidazolyl group, pyrazolyl group, morpholinyl group, pyridinyl group, tetrahydrocarbazole group, morpholinyl group, methyl group, ethyl group, propyl group, hydroxymethyl group, hydroxyethyl group, hamethyl group, or halogenated ethyl group.

[0049] In another preferred solution, R 11 It is either hydrogen or deuterium.

[0050] In another preferred solution, R 14is a methylaminocarbonyl group, dimethylaminocarbonyl group, cyano group, methoxycarbonyl group, ethoxycarbonyl group, carboxyl group, N-pyrrolidinylcarbonyl group, tetrahydrofuranyloxy group, methoxy group, ethoxy group, cyclopropoxy group, halomethoxy group, haloethoxy group, deuterium-substituted methoxy group, deuterium-substituted ethoxy group, methyl group, ethyl group, propyl group, hydroxymethyl group, hydroxyethyl group, tetrazolyl group, triazolyl group, morpholinyl group, halomethyl group or haloethyl group.

[0051] In another preferred embodiment, R 15 is hydrogen, deuterium, a methyl group, an ethyl group, a halomethyl group or a haloethyl group.

[0052] A compound, an isomer thereof or a pharmaceutically acceptable salt thereof according to the present invention, which is selected from the following:

Chemical Formula

[0053] Unless otherwise specifically limited, the technical terms described in the claims and the specification have the following meanings.

[0054] "Hydrogen" refers to protium (¹H), which is the main stable isotope of hydrogen.

[0055] "Deuterium" refers to a stable isotope of hydrogen, also called deuterium, and its elemental symbol is D.

[0056] "Halogen" refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0057] "Cyano group" refers to a -CN group.

[0058] "Alkyl group" refers to a saturated aliphatic radical having 1 to 20 carbon atoms, including straight-chain and branched groups (the numerical range described herein, for example "1 to 20", includes cases where the group is an alkyl group in this instance, and the number of carbon atoms ranges up to 20, such as having 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and so on). An alkyl group containing 1 to 4 carbon atoms is referred to as a lower alkyl group. When a lower alkyl group has no substituents, it is referred to as an unsubstituted lower alkyl group. More preferably, the alkyl group is a medium-sized alkyl group having 2 to 5 carbon atoms. Examples of the alkyl group in the present invention include a methyl group, ethyl group, propyl group, 2-propyl group, n-butyl group, isobutyl group, tert-butyl group, pentyl group, and the like. Most preferably, the alkyl group is a lower alkyl group having 2 to 4 carbon atoms, such as an ethyl group, propyl group, 2-propyl group, n-butyl group, isobutyl group or tert-butyl group, and the like. The alkyl group may be substituted or unsubstituted. In the description of groups, R' represents an alkyl group. A substituted alkyl group is a group in which one or more hydrogen atoms of the alkyl group are substituted with other groups. A haloalkyl group is a group in which one or more hydrogen atoms of the alkyl group are substituted with halogen.

[0059] "Alkoxy group" refers to a -OR' group, that is, groups of -O-(unsubstituted alkyl) and -O-(unsubstituted cycloalkyl), and more specifically refers to -O-(unsubstituted alkyl). Representative examples thereof include, but are not limited to, a methoxy group, ethoxy group, propoxy group, butoxy group, cyclopropoxy group, cyclobutoxy group, cyclopentoxy group, cyclohexyloxy group, and the like. A substituted alkoxy group is a group in which one or more hydrogen atoms of the alkoxy group are substituted with other groups.

[0060] The term "alkylthio group" refers to -SR', i.e., -S- (unsubstituted alkyl group) and -S- (unsubstituted cycloalkyl group), and further, -S- (unsubstituted alkyl group). Typical examples include, but are not limited to, methylthio group, ethylthio group, propylthio group, butylthio group, cyclopropylthio group, cyclobutylthio group, cyclopentylthio group, and cyclohexylthio group. A substituted alkylthio group is a group in which one or more H atoms of an alkylthio group are substituted by another group.

[0061] The "alkylamino group" is -NHR' or -N(R' 1 )(R' 2 ) represents a group, that is, a group in which one or two H atoms of the amino group are substituted by an alkyl group. 1-4 C of alkylamino group 1-4 This refers to a group that contains 1 to 4 carbon atoms. Typical examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, N,N-dimethylamino group, N,N-diethylamino group, N,N-dipropylamino group, methylethylamino group, methylpropylamino group, and ethylpropylamino group.

[0062] "Cycloalkylamino group" refers to a -NH-cycloalkyl group or a -N(cycloalkyl group 1)(cycloalkyl group 2) group, that is, a group in which one or two hydrogen atoms of an amino group are substituted by a cycloalkyl group. 3-6 C of the cycloalkylamino group 3-6 This refers to a group that contains 3-6 carbon atoms. Typical examples include, but are not limited to, cyclopropylalkylamino groups, cyclobutylalkylamino groups, and cyclopentylamino groups.

[0063] "Cycloalkyl group" refers to a monocyclic or bicyclic alkyl group having three or more carbon atoms, and includes, but is not limited to, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, and a bicycloheptyl group.

[0064] A "carbonyl group" refers to a C=O or -C(=O)- group.

[0065] "Hydroxyl group" refers to the -OH group.

[0066] The "aldehyde group" refers to the -CH(=O) group.

[0067] The term "carboxyl group" refers to the -COOH group.

[0068] The term "ester group" refers to a -COOR' group, i.e., a -COO-alkyl group. 2-6 C of the ester group 2-6 This indicates that the entire ester group contains 2-6 carbon atoms; for example, a C2 ester group represents methylformate, and a C6 ester group represents pentylformate. Common ester groups include, but are not limited to, methylformate, ethylformate, propylformate, isopropylformate, butylformate, and isobutylformate.

[0069] An "amide group" refers to an -NH(C=O) group. A substituted amide group is one in which the H atom of an amide group is replaced by another group.

[0070] The term "nitro group" refers to the -NO2 group.

[0071] The "amino group" refers to the -NH2 group.

[0072] The term "vinyl group" refers to the -CH=CH2 group.

[0073] The "alkylaminocarbonyl group" represents -C(=O)-NH-R' or -CO-N(R')2 groups, i.e., -C(=O)-NH-alkyl group or -C(=O)-N(alkyl group)2 groups. However, if there are two alkyl groups on N, these two alkyl groups may be the same or different. 1-4 C of alkylaminocarbonyl group 1-4This refers to a carbonyl group substituent on this group, called "C 1-4 The alkylamino group has 1 to 4 carbon atoms. Typical examples include, but are not limited to, methylaminocarbonyl group, ethylaminocarbonyl group, propylaminocarbonyl group, isopropylaminocarbonyl group, butylaminocarbonyl group, N,N-dimethylaminocarbonyl group, N,N-diethylaminocarbonyl group, N,N-dipropylaminocarbonyl group, methylethylaminocarbonyl group, methylpropylaminocarbonyl group, and ethylpropylaminocarbonyl group.

[0074] The "alkoxycarbonyl group" refers to the -COOR' group, that is, the -C(=O)-O-alkyl group, which is also conventionally called an ester group. 1-4 C of the alkoxycarbonyl group 1-4 In this group, the number of carbon atoms in the "alkoxy group" which is a carbonyl group substituent is between 1 and 4. Typical examples include, but are not limited to, the methoxycarbonyl group (also called the methyl formate group), the ethoxycarbonyl group (ethyl formate group), and the propoxycarbonyl group (also called the propylformate group).

[0075] The "aminocarbonyl group" refers to the -C(=O)-NH2 group. The "phenylaminocarbonyl group" refers to the -C(=O)-NHPh or -C(=O)-N(Ph)2 group, where Ph is phenyl.

[0076] The "alkylcarbonyl group" refers to the -C(=O)-R' group. 1-4 C of alkylcarbonyl group 1-4 In this group, the number of carbon atoms in the alkyl group that is a substituent on the carbonyl group is between 1 and 4. Typical examples include, but are not limited to, methyl carbonyl group, ethyl carbonyl group, and propyl carbonyl group.

[0077] The "alkoxycarbonylamino group" represents the -NH-C(=O)-OR' group, i.e., the -NH-C(=O)-O-alkyl group. 1-4Carbon atoms of alkoxycarbonylamino group 1-4 refers to an alkoxycarbonylamino group wherein the alkoxy group as the carbonylamino substituent has 1 to 4 carbon atoms. Representative examples include, but are not limited to, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, and isopropoxycarbonylamino groups.

[0078] "Alkylaminocarbonylamino group" represents a -NH-C(=O)-NHR' or -NH-C(=O)-N(R')2 group, provided that when there are two alkyl groups on the nitrogen atom, the two alkyl groups may be the same or different. Carbon 1-4 atoms of the alkyl group in alkylaminocarbonylamino group 1-4 refers to an alkylaminocarbonylamino group wherein the alkyl group in the alkylamino moiety has 1 to 4 carbon atoms. Representative examples include, but are not limited to, methylaminocarbonylamino, ethylaminocarbonylamino, propylaminocarbonylamino, isopropylaminocarbonylamino, butylaminocarbonylamino, N,N-dimethylaminocarbonylamino, N,N-diethylaminocarbonylamino, N,N-dipropylaminocarbonylamino, methylethylaminocarbonylamino, methylpropylaminocarbonylamino, and ethylpropylaminocarbonylamino groups.

[0079] "Morpholinyl group" is

Chemical Formula

[0080] "Pyridinyl group" is

Chemical Formula

[0081] "Oxazolidinyl group" is

Chemical Formula

[0082] The "isoxazolidinyl group" is [ka] This shows one of them.

[0083] The "piperidinyl group" is [ka] This shows one of them.

[0084] The "tetrahydrofuranyl group" is [ka] This shows one of them.

[0085] The "tetrahydrothienyl group" is [ka] This shows one of them.

[0086] "Hexahydropyrimidine" is, [ka] This shows one of them.

[0087] The "tetrazolyl group" is [ka] This shows one of them.

[0088] The "triazolyl group" is [ka] This shows one of them.

[0089] A "heterocycloalkyl group" is a cyclic saturated alkyl group having one or more heteroatoms such as O, N, S, and P as cyclic atoms. Typical examples include, but are not limited to, pyridinyl group, oxazolidinyl group, isoxazolidinyl group, piperazinyl group, morpholinyl group, piperidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, and hexahydropyrimidinyl group.

[0090] The term "heterocycloalkylcarbonyl group" refers to the "-C(=O)-heterocycloalkyl" group. 2-6 C of heterocycloalkylcarbonyl group 2-6 This refers to heterocycloalkanes with 2 to 6 carbon atoms as a carbonyl group substituent. Typical examples include, but are not limited to, pyrrolidinyl carbonyl group, oxazolidine carbonyl group, isoxazolidine carbonyl group, piperadinyl carbonyl group, morpholinyl carbonyl group, piperidinyl carbonyl group, tetrahydrofuranyl carbonyl group, tetrahydrothiophene carbonyl group, and hexahydropyrimidine carbonyl group.

[0091] The term "heterocycloalkylketone group" refers to a heterocycloalkyl group having a ketone group (C=O) on its cyclic atom. Typical examples include, but are not limited to, pyrrolidinyl ketone group, oxazolidinyl ketone group, isoxazolidinyl ketone group, morpholinyl ketone group, piperazinon group, piperidone group, and tetrahydrothiophenone group.

[0092] The "sulfonylamino group" refers to the -NH-S(O)2-OH group.

[0093] The term "sulfonyloxy group" refers to the -OS(O)2-OH group.

[0094] The "aminosulfonyl group" refers to the -S(O)2-NH2 group.

[0095] The "aminosulfonyloxy group" refers to the -OS(O)2-NH2 group.

[0096] The "alkylsulfonylamino group" refers to the -NH-S(O)2-R' group. 1-4 C of the alkylsulfonylamino group 1-4 This refers to a group in which the alkyl group substituted with the sulfonylamino group has 1 to 4 carbon atoms. Typical examples include, but are not limited to, methylsulfonylamino group, ethylsulfonylamino group, and propylsulfonylamino group.

[0097] "Alkylaminosulfonyl group" refers to a -S(O)2-NHR' or -S(O)2-N(R')2 group, where if there are two alkyl groups on N, these two alkyl groups may be the same or different. 1-4 The C1-4 in "alkylaminosulfonyl group" refers to the number of carbon atoms in the alkyl group substituted with the aminosulfonyl group being 1 to 4. Typical examples include, but are not limited to, methylaminosulfonyl group, ethylaminosulfonyl group, propylaminosulfonyl group, isopropylaminosulfonyl group, butylaminosulfonyl group, N,N-dimethylaminosulfonyl group, N,N-diethylaminosulfonyl group, and methylethylaminosulfonyl group.

[0098] "Alkylaminosulfonylamino group" refers to -NH-S(O)2-NHR' or -NH-S(O)2-N(R')2 group, where if there are two alkyl groups on N, these two alkyl groups may be the same or different. 1-4 C in the alkylaminosulfonylamino group 1-4This refers to an amino group (sulfonylamino group) whose substituent alkyl group has 1 to 4 carbon atoms. Typical examples include, but are not limited to, methylethylaminosulfonyl group, ethylaminosulfonylamino group, propylaminosulfonylamino group, isopropylaminosulfonylamino group, butylaminosulfonylamino group, N,N-dimethylethylaminosulfonyl group, N,N-diethylaminosulfonylamino group, and methylethylaminosulfonylamino group.

[0099] The "alkylsulfonyloxy group" refers to the -OS(O)2-R' group. 1-4 C of "alkylsulfonyloxy group" 1-4 This refers to a group in which the alkyl group substituted with the sulfonyloxy group has 1 to 4 carbon atoms. Typical examples include, but are not limited to, methylsulfonyloxy, ethylsulfonyloxy, and propylsulfonyloxy groups.

[0100] The "alkylaminosulfonyloxy group" refers to the -OS(O)2-NHR' or -OS(O)2-N(R')2 group. However, if there are two alkyl groups on N, these two alkyl groups may be the same or different. 1-4 C of the alkylaminosulfonyloxy group 1-4 This refers to an aminosulfonyloxy group in which the alkyl group substituted has 1 to 4 carbon atoms. Typical examples include, but are not limited to, methylaminosulfonyloxy group, ethylaminosulfonyloxy group, propylaminosulfonyloxy group, isopropylaminosulfonyloxy group, butylaminosulfonyloxy group, N,N-dimethylaminosulfonyloxy group, N,N-diethylaminosulfonyloxy group, and methylethylaminosulfonyloxy group.

[0101] The "alkylaminocarbonyloxy group" refers to a -OC(=O)-NHR' or -OC(=O)-N(R')2 group. However, if there are two alkyl groups on N, these two alkyl groups may be the same or different. 1-4C of "alkylaminocarbonyloxy group" 1-4 This refers to an aminocarbonyloxy molecule in which the alkyl group substituted has 1 to 4 carbon atoms. Typical examples include, but are not limited to, methylaminocarbonyloxy, ethylaminocarbonyloxy, propylaminocarbonyloxy, isopropylaminocarbonyloxy, butylaminocarbonyloxy, N,N-dimethylaminocarbonyloxy, N,N-diethylaminocarbonyloxy, and methylethylaminocarbonyloxy.

[0102] The term "cycloalkoxy group" refers to the "-O-cycloalkyl group". 3-6 C of "cycloalkoxy group" 3-6 This refers to a group containing 3 to 6 carbon atoms. Typical examples include, but are not limited to, cyclopropyloxy, cyclobutyloxy, and cyclopentyloxy groups.

[0103] "Hypercycloalkoxy group" refers to the "-O-heterocycloalkyl group" C 3-6 C of heterocycloalkoxy group 3-6 This refers to a group containing 3 to 6 carbon atoms. Typical examples include, but are not limited to, pyridinyloxy group, oxazolidineoxy group, isoxazolidineoxy group, piperazineoxy group, morpholinyloxy group, piperidinyloxy group, tetrahydrofuranyloxy group, tetrahydrothiophenoxy group, and hexahydropyrimidineoxy group.

[0104] "Heterocycloalkylamino group" refers to -NH-heterocycloalkyl group or -N(heterocycloalkyl)2 group. 3-6 C of heterocycloalkylamino group 3-6This refers to a group containing 3 to 6 carbon atoms. Typical examples include, but are not limited to, pyridinylamino groups, oxazolidinylamino groups, isoxazolidinylamino groups, piperazinylamino groups, morpholinylamino groups, piperidinylamino groups, tetrahydrofuranylamino groups, tetrahydrothiophenamino groups, and hexahydropyrimidineamino groups.

[0105] The "alkylcarbonylamino group" represents the -NH-C(=O)-R' group. 1-4 C of alkylcarbonylamino group 1-4 This refers to an alkyl group with 3 to 6 carbon atoms as a substituent. Typical examples include, but are not limited to, methyl carbonylamino group, ethyl carbonylamino group, propyl carbonylamino group, isopropyl carbonylamino group, butyl carbonylamino group, and isobutyl carbonylamino group.

[0106] A "heterocyclyl group" refers to a cyclic group in which, in addition to the C atom, heteroatoms such as N, O, S, and P are also cyclic atoms, and includes heterocycloalkyl groups and heteroaryl groups. Depending on the number of cyclic atoms, it includes three-membered heterocyclic groups, four-membered heterocyclic groups, five-membered heterocyclic groups, six-membered heterocyclic groups, and benzoheterocyclic groups. Common three-membered heterocyclic groups include epoxyethyl groups and thioepoxyethyl groups. Four-membered heterocyclic groups include tetrazole groups, β-propiolactones, and β-propiolactams. Five-membered heterocyclic groups include furan groups, thiophene groups, pyrrole groups, thiazole groups, imidazole groups, tetrazole groups, and triazole groups. Six-membered heterocyclic groups include pyridine groups, pyrimidine groups, and pyridazine groups. Fused ring heterocyclic groups include indole groups, quinoline groups, futanazine groups, and acridine groups.

[0107] The "boric acid group" is represented by the -B(OH)2 group.

[0108] A "pharmaceutically acceptable salt" is a salt consisting of the compound of formula (I) with an organic or inorganic acid, which retains the bioefficacy and properties of the parent compound. These salts include the following:

[0109] (1) Salts with an acid, obtained by the reaction of a free alkali of the parent compound with an inorganic or organic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid. Organic acids include, but are not limited to, acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, γ-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethylsulfonic acid, naphthyl-1-sulfonic acid, naphthyl-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid or malonic acid.

[0110] (2) A compound in which an acidic proton present in the parent compound is replaced by a metal ion, or a salt formed with an organic alkali complex compound. Examples of metal ions include alkali metal ions, alkaline earth metal ions, or aluminum ions, and examples of organic alkalis include ethanolamine, diethanolamine, triethanolamine, tromethamine, and N-methylglucosamine.

[0111] "Medicinal composition" refers to one or more of the compounds described herein or their pharmaceutically acceptable salts and prodrugs and other chemical components, such as mixtures of pharmaceutically acceptable carriers and excipients. The purpose of the medicinal composition is to facilitate the administration of the compound to a living organism.

[0112] In the following specification, unless otherwise specified, the compounds of formula (I) used as therapeutic active ingredients include the entire pharmaceutically acceptable salt, and these should be understood to be within the scope of the present invention. For convenience, in this specification, they will be abbreviated as “compounds of formula (I)”.

[0113] The present invention provides a pharmaceutical composition comprising, as an active ingredient, a compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrolyzable prodrug or ester thereof, and a pharmaceutically acceptable auxiliary component.

[0114] The compounds, isomers, or pharmaceutically acceptable salts of the present invention are used in the pharmaceutical field to produce anti-inflammatory agents, and in particular in the pharmaceutical field to treat acute gouty arthritis, gout, or coronavirus pneumonia.

[0115] Experiments have confirmed that the compound of this invention has a remarkable therapeutic effect on gouty arthritis in rats, significantly improving the gait of rats after molding and significantly reducing the rate of ankle joint swelling in rats after molding. The compound of this invention can reduce the TNF-α, IL-1β, and IL-6 content in the knee joint synovial tissue of rats after molding, and has excellent anti-inflammatory effects. The compound of this invention can be applied to the treatment of various inflammation-related diseases. For this reason, the compound of this invention has potential applications in the fields of anti-inflammatory drugs, particularly as treatments for acute gouty arthritis, rheumatoid arthritis, inflammatory factor-reducing drugs, cytokine storm treatments, or coronavirus pneumonia treatments. [Modes for carrying out the invention]

[0116] Best mode for carrying out the invention The present invention will be described in detail below with reference to the following examples, but the scope of protection of the present invention is not limited to the following examples. [Examples]

[0117] Example 1: Synthesis of (S)-N-(1,2,3-trimethoxy-10-methanesulfonylamino-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (2) [ka]

[0118] Step A: A mixture containing colchicine (800 mg, 2.0 mmol), concentrated aqueous ammonia (15 mL), and methanol (5 mL) was stirred at 30°C for 40 hours. Saturated saline solution (30 mL) was added, and the mixture was extracted with ethyl acetate (40 mL x 4) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain (S)-N-(10-amino-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (1) (699 mg). The yield was 90.9%.

[0119] Step B: To a solution of compound 1 (140 mg, 0.364 mmol) in pyridine (7 mL), methyl sulfonyl chloride (9 drops) was added, and the resulting mixture was stirred at 55°C for 3 hours. The solvent was evaporated under reduced pressure, (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was combined and washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (eluted with 200-300 mesh silica gel, petroleum ether:ethyl acetate = 1:1-1:6) to obtain (S)-N-(1,2,3-trimethoxy-10-methanesulfonylamino-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (2) (101 mg). The yield was 60.0%. 1 H NMR (DMSO-d6, 400MHz) δ9.72(s, 1H), 8.81(d, J=10.8Hz, 1H), 8.65(d, J=6.8Hz, 1H), 7.34(s, 1H), 7.27(d, J=10.8Hz, 1H), 6.80(s, 1H), 4.41-4.35(m, 1H), 3.86(s, 3H), 3.81(s, 3H), 3.55(s, 3H), 2.65-2.61(m, 1H), 2.28-2.18(m, 4H), 2.10-2.04(m, 1H), 1.93-1.81(m, 4H). MS(ESI, m / z):461.1[MH] - .

[0120] Example 2: Synthesis of (S)-N-(4-chloro-1,2,3,10,11-pentamethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (4) [ka]

[0121] Step A: A mixture containing colchicine (3.0 g, 7.51 mmol), NCS (1.30 g, 9.73 mmol), and acetic acid (30 mL) was stirred under nitrogen at 70°C for 3.5 hours. Most of the solvent was evaporated under reduced pressure, water (60 mL) was added, and the mixture was extracted with ethyl acetate (60 mL x 3). The organic phase was combined and washed with saturated brine (40 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (eluted with 200-300 mesh silica gel, ethyl acetate:methanol = 40:1-10:1) to obtain (S)-N-(4-chloro-1,2,3,10-tetramethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (3) (2.50 g). The yield was 76.7%.

[0122] Step B: A mixture containing compound 3 (2.70 g, 6.22 mmol), iodine (2.39 g, 9.42 mmol), silver nitrate (1.60 g, 9.42 mmol), and methanol (30 mL) was stirred overnight at 30°C. Water (90 mL) was added, and saturated sodium thiosulfate solution was added dropwise until the reddish-brown color disappeared. Extraction was performed with ethyl acetate (60 mL x 3), the organic phase was combined and washed with saturated brine (40 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (eluted with 200-300 mesh silica gel, ethyl acetate:methanol = 40:1-10:1) to obtain a yellow solid (1.48 g). This solid (600 mg) was taken and dissolved in DMF (6 mL), and cuprous cyanide (144 mg, 1.61 mmol) was added, and the resulting mixture was stirred at 100°C for 3 hours. Water (25 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was then washed sequentially with water (15 mL x 2) and saturated saline solution (15 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (eluted with 200-300 mesh silica gel, ethyl acetate:methanol = 50:1-20:1) to obtain (S)-N-(4-chloro-1,2,3,10,11-pentamethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (4) (240 mg). The yield was 20.5%. 1 H NMR (DMSO-d6, 400MHz) δ8.63(d, J=7.6Hz, 1H), 7.18(s, 1H), 7.08(s, 1H), 4.19-4.12(m, 1H), 3.91(s, 3H), 3.87(s, 3H) , 3.86(s, 3H), 3.80(s, 3H), 3.58(s, 3H), 3.13-3.08(m, 1H), 2.18-2.10(m, 1H), 1.98-1.89(m, 1H), 1.84-1.79(m, 4H). MS(ESI, m / z):464.1[M+H] + .

[0123] Example 3: Synthesis of (S)-N-(4-bromo-1,2,3,10,11-pentamethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptarene-7-yl)acetamide (6) [ka]

[0124] The experimental procedure for the synthesis of compound 6 was as described in Example 2, except that NBS was used instead of NCS in step A of Example 2. 1 H NMR (DMSO-d6, 400MHz) δ8.63(d, J=7.2Hz, 1H), 7.19(s, 1H), 7.10(s, 1H), 4.20-4.13(m, 1H), 3.93(s, 3H), 3. 89(s, 3H), 3.88(s, 3H), 3.83(s, 3H), 3.61(s, 3H), 3.16-3.12(m, 1H), 2.30-2.22(m, 1H), 1.98-1.76(m, 5H). MS(ESI, m / z):508.0[M+H] + .

[0125] Example 4: Synthesis of (S)-N-(4-bromo-10,11-diethoxy-1,2,3,-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (7) and (S)-N-(10,11-diethoxy-1,2,3,-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (8) [ka]

[0126] Step A: The experimental procedure for synthesizing compound 7 using compound 5 as a raw material is the same as in Step B of Example 2, except that ethanol and silver sulfate were used instead of methanol and silver nitrate in Step B of Example 2. 1H NMR (DMSO-d6, 400MHz) δ8.69(d, J=7.2Hz, 1H), 7.18(s, 1H), 7.14(s, 1H), 4.26-4.08(m, 5H), 3.98(s, 3H), 3.92(s, 3H), 3 .63(s, 3H), 3.20-3.16(m, 1H), 2.34-2.26(m, 1H), 2.00-1.91(m, 1H), 1.88(s, 3H), 1.86-1.81(m, 1H), 1.39-1.32(m, 6H). MS(ESI, m / z):536.0[M+H] + .

[0127] Step B: Diisopropylethylamine (120 mg, 0.929 mmol) and tetra(triphenylphosphine)palladium (93 mg, 0.0805 mmol) were added to a mixture containing compound 7 (200 mg, 0.373 mmol), ethanol (4 mL), water (2 mL), and toluene (12 mL). The resulting mixture was refluxed under nitrogen and stirred overnight. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed sequentially with water (15 mL x 2) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (eluted with 200-300 mesh silica gel, ethyl acetate:methanol = 100:1-30:1) to obtain (S)-N-(10,11-diethoxy-1,2,3,-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (8). 1 H NMR (DMSO-d6, 400MHz) δ8.57(d, J=7.6Hz, 1H), 7.10(s, 1H), 7.09(s, 1H), 6.78(s, 1H), 4.29-4.07(m, 5H), 3.84(s, 3H), 3 .79(s, 3H), 3.56(s, 3H), 2.63-2.58(m, 1H), 2.30-2.21(m, 1H), 2.03-1.97(m, 1H), 1.83-1.76(m, 4H), 1.33-1.26(m, 6H). MS(ESI, m / z):458.2[M+H] + .

[0128] Example 5: Synthesis of (S)-N-(11-iodo-1,2,3,10-tetramethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (12) and (S)-N-(11-cyano-1,2,3,9-tetramethoxy-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalen-7-yl)acetamide (13) [ka]

[0129] Step A: A mixture containing colchicine (6.0 g, 15.0 mmol), water (165 mL), concentrated hydrochloric acid (1.5 mL), and acetic acid (27.3 mL) was stirred at 100°C for 5 hours. The pH was adjusted to 5-6 using saturated sodium bicarbonate solution. Extraction was performed with ethyl acetate (200 mL x 3), the organic phase was combined and washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the crude product (S)-N-(10-hydroxy-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (9) (6.40 g). This compound was reacted directly in the next step without purification.

[0130] Step B: After adding NIS (3.59 g, 16.0 mmol) to a solution of the crude product of compound 9 (5.60 g) in acetonitrile (70 mL), the resulting mixture was stirred overnight at room temperature. Water (200 mL) was added, and the excess NIS was quenched with a 2 M sodium thiosulfate solution. Extraction was performed with ethyl acetate (200 mL x 3), the organic phase was combined and washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (eluted with 200-300 mesh silica gel, ethyl acetate:methanol = 80:1-20:1) to obtain (S)-N-(10-hydroxy-11-iodo-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (10) (4.0 g). The total yield of the reactions in Steps A and B was 59.6%.

[0131] Step C: Potassium carbonate (1.40 g, 10.1 mmol) and iodomethane (1.19 g, 8.38 mmol) were added to a solution of compound 10 (3.50 g, 6.85 mmol) in DMF (35 mL), and the resulting mixture was stirred overnight at room temperature. Water (140 mL) was added, and the mixture was extracted with ethyl acetate (70 mL x 3). The combined organic phases were washed sequentially with water (40 mL x 2) and saturated saline solution (40 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (eluted using 200-300 mesh silica gel, petroleum ether:ethyl acetate:methanol = 1:1:0 to 0:30:1) to obtain (S)-N-(11-iodo-1,2,3,9-tetramethoxy-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalen-7-yl)acetamide(11) (1.20 g, ethyl acetate:methanol = 5:1, Rf = 0.3) and (S)-N-(11-iodo-1,2,3,10-tetramethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide(12) (270 mg, ethyl acetate:methanol = 5:1, Rf = 0.5). The yields were 33.3% and 7.50%, respectively. Compound 12: 1 H NMR (DMSO-d6, 400MHz) δ8.61(d, J=7.2Hz, 1H), 7.78(s, 1H), 7.07(s, 1H), 6.79(s, 1H), 4.29-4.23(m, 1H), 3.90(s, 3H) , 3.85(s, 3H), 3.81(s, 3H), 3.64(s, 3H), 2.64-2.59(m, 1H), 2.29-2.25(m, 1H), 2.07-2.03(m, 1H), 1.85-1.79(m, 4H). MS(ESI, m / z):526.0[M+H] + .

[0132] Step D: To a solution of compound 11 (220 mg, 0.419 mmol) in DMF (5 mL), cuprous cyanide (100 mg, 1.12 mmol) was added, and the resulting mixture was stirred at 100°C for 3 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed sequentially with water (15 mL x 2) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (eluting 200-300 mesh silica gel, ethyl acetate:methanol = 40:1-10:1) to obtain (S)-N-(11-cyano-1,2,3,9-tetramethoxy-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalen-7-yl)acetamide (13). 1 H NMR (DMSO-d6, 400MHz) δ8.78(d, J=7.6Hz, 1H), 7.86(s, 1H), 7.19(s, 1H), 6.86(s, 1H), 4.40-4.35(m, 1H) , 4.00(s, 3H), 3.87(s, 3H), 3.83(s, 3H), 3.59(s, 3H), 2.62-2.60(m, 1H), 2.26-2.10(m, 3H), 1.91(s, 3H). MS(ESI, m / z):425.1[M+H] + .

[0133] Example 6: Synthesis of (S)-N-(11-bromo-1,2,3,10-tetramethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (14) and (S)-N-(11-bromo-1,2,3,9-tetramethoxy-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalen-7-yl)acetamide (15) [ka]

[0134] The experimental procedure for synthesizing compounds 14 and 15 using compound 9 as a starting material followed steps B and C of Example 5, except that NBS was used instead of NIS in step B of Example 5. Compound 14: 1H NMR (DMSO-d6, 400MHz) δ8.61(d, J=7.6Hz, 1H), 7.49(s, 1H), 7.08(s, 1H), 6.79(s, 1H), 4.29-4.23(m, 1H), 3.92(s, 3H) , 3.84(s, 3H), 3.79(s, 3H), 3.61(s, 3H), 2.64-2.59(m, 1H), 2.30-2.23(m, 1H), 2.05-1.99(m, 1H), 1.86-1.80(m, 4H). MS(ESI, m / z):478.0[M+H] + . Compound 15: 1 H NMR (DMSO-d6, 400MHz) δ8.72(d, J=7.2Hz, 1H), 8.19(s, 1H), 7.14(s, 1H), 6.84(s, 1H), 4.35-4.30(m, 1H) , 3.94(s, 3H), 3.85(s, 3H), 3.80(s, 3H), 3.59(s, 3H), 2.59-2.56(m, 1H), 2.22-2.05(m, 3H), 1.89(s, 3H). MS(ESI, m / z):478.0[M+H] + .

[0135] Example 7: Synthesis of (S)-N-(1,2,3,10-tetramethoxy-11-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (16) [ka]

[0136] A mixture containing compound 14 (150 mg, 0.314 mmol), methylboronic acid (38 mg, 0.635 mmol), potassium carbonate (216 mg, 1.57 mmol), and toluene (10 mL) was mixed with [1,1'-bis(diphenylphosphine)ferrocene]dichloride palladium (23 mg, 0.0314 mmol), and the resulting mixture was stirred overnight at 100°C under nitrogen. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (eluted using 200-300 mesh silica gel, ethyl acetate:dichloromethane:methanol = 1:1:0 to 30:10:1) to obtain (S)-N-(1,2,3,10-tetramethoxy-11-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (16). 1 H NMR (CDCl3, 400MHz) δ7.63(s, 1H), 7.02(s, 1H), 6.56(s, 1H), 6.31(d, J=6.0Hz, 1H), 4.64-4.59(m, 1H), 3.95-3.91(m, 9H), 3.66(s, 3H), 2.53-2.48(m, 1H), 2.40-2.27(m, 5H), 2.06(s, 3H), 2.00-1.93(m, 1H). MS(ESI, m / z):414.1[M+H] + .

[0137] Example 8: Synthesis of (S)-N-(1,2,3,9-tetramethoxy-11-methyl-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalen-7-yl)acetamide (17) [ka]

[0138] The experimental procedure for synthesizing compound 17 using compound 15 as a starting material was described in Example 7. 1H NMR (DMSO-d6, 400MHz) δ8.56(d, J=7.6Hz, 1H), 7.08(s, 1H), 7.07(s, 1H), 6.78(s, 1H), 4.32-4.26(m, 1H), 3 .85-3.80(m, 9H), 3.58(s, 3H), 2.63-2.58(m, 1H), 2.30-2.21(m, 4H), 2.04-1.98(m, 1H), 1.85-1.77(m, 4H). MS(ESI, m / z):414.1[M+H] + .

[0139] Example 9: Synthesis of N-{(S)-1,2,3-trimethoxy-9-oxy-10-{[(S)-tetrahydrofuran-3-yl]oxy}-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (18) and N-{(S)-1,2,3-trimethoxy-10-oxy-9-{[(S)-tetrahydrofuran-3-yl]oxy}-5,6,7,10-tetrahydrobenzo[a]heptalen-7-yl}acetamide (19) [ka]

[0140] Under nitrogen, azodicarboxylic acid diisopropyl (787 mg, 3.89 mmol) was added to a THF (5 mL) solution of compound 9 (500 mg, 1.30 mmol), triphenylphosphine (1.02 g, 3.89 mmol), and (R)-3-hydroxytetrahydrofuran (137 mg, 1.56 mmol), and the resulting mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the product was purified by manufacturing HPLC and SFC to obtain N-{(S)-1,2,3-trimethoxy-9-oxy-10-{[(S)-tetrahydrofuran-3-yl]oxy}-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (18) and N-{(S)-1,2,3-trimethoxy-10-oxy-9-{[(S)-tetrahydrofuran-3-yl]oxy}-5,6,7,10-tetrahydrobenzo[a]heptalen-7-yl}acetamide (19). Compound 18: 1¹H NMR (DMSO-d₆, 400 MHz) δ 8.57 (d, J=7.6 Hz, 1H), 7.13 (s, 1H), 7.11-7.03 (m, 2H), 6.77 (s, 1H), 5.15-5.13 (m, 1H), 4.36-4.29 (m, 1H), 3.95-3.91 (m, 1H), 3.87-3.82 (m, 5H), 3.78-3.73 (m, 4H), 3.52 (s, 3H), 2.61-2.57 (m, 1H), 2.33-2.20 (m, 2H), 2.07-1.95 (m, 2H), 1.88-1.86 (m, 4H). MS (ESI, m / z): 456.2 [M+H] + . Compound 19: 1 ¹H NMR (DMSO-d₆, 400 MHz) δ 8.67 (d, J=6.8 Hz, 1H), 7.22 (d, J=12.8 Hz, 1H), 7.02 (s, 1H), 6.94 (d, J=12.8 Hz, 1H), 6.80 (s, 1H), 5.12 (s, 1H), 4.34-4.30 (m, 1H), 3.99-3.95 (m, 1H), 3.91-3.78 (m, 9H), 3.56 (s, 3H), 2.59-2.56 (m, 1H), 2.35-2.26 (m, 1H), 2.21-2.03 (m, 3H), 1.93-1.87 (m, 4H). MS (ESI, m / z): 456.3 [M+H] + .

[0141] Example 10: N-{(S)-11-iodo-1,2,3-trimethoxy-9-oxy-10-{[(R)-tetrahydrofuran-3-yl]oxy}-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (20), N-{(S)-11-iodo-1,2,3-trimethoxy-10-oxy-9-{[(R)-tetrahydrofuran-3-yl]oxy}-5,6,7,10-tetrahydrobenzo[a]heptalen-7-yl}acetamide (21) Synthesis of N-{(S)-11-iodo-1,2,3-trimethoxy-9-oxy-10-{[(S)-tetrahydrofuran-3-yl]oxy}-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (22) and N-{(S)-11-iodo-1,2,3-trimethoxy-10-oxy-9-{[(S)-tetrahydrofuran-3-yl]oxy}-5,6,7,10-tetrahydrobenzo[a]heptalen-7-yl}acetamide (23) [ka]

[0142] The experimental procedure for synthesizing compounds 20 and 21, and 22 and 23 using compound 10 and (S)-3-hydroxytetrahydrofuran (or (R)-3-hydroxytetrahydrofuran) as starting materials was described in Example 9. Compound 20: 1 H NMR (CDCl3, 400MHz) δ8.08(s, 1H), 7.17(s, 1H), 6.50(s, 1H), 6.31(d, J=6.8Hz, 1H), 5.71-5.68(m, 1H), 4.60-4.53(m, 1H), 4.20-4.1 4(m, 1H), 4.02-3.83(m, 9H), 3.73(s, 3H), 2.55-2.50(m, 1H), 2.46-2.34(m, 2H), 2.27-2.14(m, 2H), 2.00(s, 3H), 1.79-1.72(m, 1H). MS(ESI, m / z):582.2[M+H] + . Compound 21: 1¹H NMR (CDCl₃, 400 MHz) δ 8.70 (s, 1H), 7.16 (s, 1H), 6.56 (s, 1H), 6.18 (d, J=6.0 Hz, 1H), 5.35-5.33 (m, 1H), 4.53-4.47 (m, 1H), 4.01-3.89 (m, 10H), 3.72 (s, 3H), 2.54-2.47 (m, 1H), 2.38-2.27 (m, 2H), 2.22-2.13 (m, 2H), 2.04-1.92 (m, 4H). MS (ESI, m / z): 582.2 [M+H] + . Compound 22: 1 ¹H NMR (CDCl₃, 400 MHz) δ 8.09 (s, 1H), 7.19 (s, 1H), 6.50 (s, 1H), 6.36 (d, J=6.8 Hz, 1H), 5.64-5.62 (m, 1H), 4.58-4.52 (m, 1H), 4.18-4.08 (m, 3H), 3.97-3.89 (m, 7H), 3.74 (s, 3H), 2.55-2.50 (m, 1H), 2.45-2.37 (m, 1H), 2.27-2.18 (m, 2H), 2.10-2.00 (m, 5H). MS (ESI, m / z): 582.1 [M+H] + . Compound 23: 1 ¹H NMR (CDCl₃, 400 MHz) δ 8.70 (s, 1H), 7.20 (s, 1H), 6.56 (s, 1H), 6.31 (s, 1H), 5.25 (s, 1H), 4.51-4.48 (m, 1H), 4.06-3.85 (m, 10H), 3.72 (s, 3H), 2.53-2.51 (m, 1H), 2.38-2.29 (m, 2H), 2.23-2.16 (m, 2H), 2.05-1.96 (m, 4H). MS (ESI, m / z): 582.1 [M+H] + .

[0143] Example 11: N-{(S)-1,2,3-trimethoxy-9-oxy-10-{[(R)-tetrahydrofuran-3-yl]oxy}-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (24), N-{(S)-1,2,3-trimethoxy-10-oxy-9-{[(R)-tetrahydrofuran-3-yl]oxy}-5,6,7,10-tetrahydrobenzo[a]heptalen-7-yl}acetamide ( 25) Synthesis of (S)-N-(1,2,3-trimethoxy-9-oxy-10-[(tetrahydrofuran-3-yl)oxy]-5,6,7,9-tetrahydrobenzo[a]heptadien-7-yl)acetamide (26) and (S)-N-(1,2,3-trimethoxy-10-oxy-9-[(tetrahydrofuran-3-yl)oxy]-5,6,7,10-tetrahydrobenzo[a]heptadien-7-yl)acetamide (27) [ka]

[0144] The experimental procedure for synthesizing compounds 24, 25, 26, and 27 using compound 9 and (S)-3-hydroxytetrahydrofuran (or 3-hydroxytetrahydrofuran) as starting materials is described in Example 9. Compound 24: 1 H NMR (DMSO-d6, 400MHz) δ8.57(d, J=7.6Hz, 1H), 7.13(s, 1H), 7.10-7.02(m, 2H), 6.77(s, 1H), 5.16-5.13(m, 1H), 4.35-4.30(m, 1H), 3.95-3. 91(m, 1H), 3.86-3.82(m, 5H), 3.79-3.75(m, 4H), 3.53(s, 3H), 2.61-2 .57(m, 1H), 2.34-2.18(m, 2H), 2.04-2.00(m, 2H), 1.92-1.84(m, 4H). MS (ESI, m / z): 456.4 [M+H] + . Compound 25: 1H NMR (DMSO-d6, 400MHz) δ8.65 (d, J=7.2Hz, 1H), 7.22 (d, J=12.8Hz, 1H), 6.96-6.93 (m, 2H), 6.81 (s, 1H), 5.16-5.13 (m, 1H), 4.34-4.29 (m, 1H), 3.99-3.95(m, 1H), 3.93-3.83(m, 4H), 3.81-3.74(m, 5H), 3.56(s, 3H), 2.58-2.55(m, 1H), 2.36-2.28(m, 1H), 2.22-2.02(m, 4H), 1.88(s, 3H). MS(ESI、m / z):456.4[M+H] + Compound 26: 1 H NMR (DMSO-d6, 400MHz) δ8.58 (d, J=7.2Hz, 1H), 7.13-7.02 (m, 3H), 6.77 (s, 1H), 5.14 (s, 1H), 4.34-4.29 (m, 1H), 3.96-3. 91 (m, 1H), 3.87-3.73 (m, 9H), 3.52 (s, 3H), 2.61-2.57 (m, 1H), 2.33-2.18 (m, 2H), 2.04-1.96 (m, 2H), 1.87-1.79 (m, 4H). MS(ESI、m / z):456.1[M+H] + Compound 27: 1 H NMR (DMSO-d6, 400MHz) δ8.68-8.65 (m, 1H), 7.24-7.21 (m, 1H), 7.02-6.93 (m, 2H), 6.81 (s, 1H), 5.14 (s, 1H), 4.33-4.28 (m, 1H), 3 .99-3.95 (m, 1H), 3.91-3.74 (m, 10H), 3.56 (s, 3H), 2.60-2.54 (m, 1H), 2.34-2.30 (m, 1H), 2.19-2.03 (m, 2H), 1.92-1.84 (m, 4H). MS(ESI、m / z):456.2[M+H] + .

[0145] Example 12: N-{(S)-1,2,3-trimethoxy-11-methyl-9-oxy-10-{[(R)-tetrahydrofuran-3-yl]oxy}-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (28), N-{(S)-1,2,3-trimethoxy-11-methyl-10-oxy-9-{[(R)-tetrahydrofuran-3-yl]oxy}-5,6,7,10-tetrahydrobenzo[a]heptalen-7-yl}acetamide (29) Synthesis of N-{(S)-1,2,3-trimethoxy-11-methyl-9-oxy-10-{[(S)-tetrahydrofuran-3-yl]oxy}-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (30) and N-{(S)-1,2,3-trimethoxy-11-methyl-10-oxy-9-{[(S)-tetrahydrofuran-3-yl]oxy}-5,6,7,10-tetrahydrobenzo[a]heptalen-7-yl}acetamide (31) [ka]

[0146] The experimental procedure for synthesizing compound 28 (or 29, 30, 31) using compound 20 (or 21, 22, 23) as a starting material was described in Example 7. Compound 28: 1 H NMR (DMSO-d6, 400MHz) δ8.56(d, J=7.6Hz, 1H), 7.09(d, J=4.4Hz, 2H), 6.77(s, 1H), 5.48-5.46(m, 1H), 4.33-4.27(m , 1H), 3.93-3.63(m, 10H), 3.58(s, 3H), 2.62-2.57(m, 1H), 2.34-2.20(m, 4H), 2.15-1.98(m, 3H), 1.85-1.77(m, 4H). MS(ESI, m / z):470.1[M+H] + . Compound 29: 1H NMR (DMSO-d6, 400MHz) δ8.62(d, J=7.6Hz, 1H), 7.45(d, J=0.8Hz, 1H), 6.98(s, 1H), 6.79(s, 1H), 5.13-5.10(m, 1H), 4.32-4.26 (m, 1H), 3.97-3.74(m, 10H), 3.57(s, 3H), 2.56-2.54(m, 1H), 2.32-2.24(m, 1H), 2.21(s, 3H), 2.18-1.97(m, 4H), 1.87(s, 3H). MS(ESI, m / z):470.1[M+H] + . Compound 30: 1 H NMR (DMSO-d6, 400MHz) δ8.57(d, J=7.6Hz, 1H), 7.09(d, J=5.6Hz, 2H), 6.76(s, 1H), 5.45-5.42(m, 1H), 4.32-4.26(m , 1H), 3.90-3.73(m, 10H), 3.58(s, 3H), 2.61-2.56(m, 1H), 2.28-2.20(m, 4H), 2.07-1.90(m, 3H), 1.84-1.76(m, 4H). MS(ESI, m / z):470.4[M+H] + . Compound 31: 1 H NMR (DMSO-d6, 400MHz) δ8.65(d, J=7.6Hz, 1H), 7.45(d, J=1.2Hz, 1H), 7.05(s, 1H), 6.80(s, 1H), 5.12-5.09(m, 1H), 4.34-4.28(m, 1H), 3.9 8-3.95(m, 1H), 3.91-3.78(m, 9H), 3.58(s, 3H), 2.57-2.53(m, 1H), 2.34-2.27(m, 1H), 2.22(s, 3H), 2.18-2.00(m, 3H), 1.94-1.88(m, 4H). MS(ESI, m / z):470.1[M+H] + .

[0147] Example 13: Synthesis of (S)-7-acetamido-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-methylformate (34) and (S)-7-acetamido-1,2,3-trimethoxy-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalen-9-methylformate (35) [ka]

[0148] Step A: A mixture containing trichloride phosphate (800 mg, 5.22 mmol), colchicine (2.0 g, 5.01 mmol), and DMF (40 mL) was stirred at room temperature for 4 hours. The mixture was quenched with cold water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was combined and washed with saturated brine (30 mL x 3), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (eluting 200-300 mesh silica gel, dichloromethane:methanol = 30:1-10:1) to obtain (S)-N-(10-chloro-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (32) and (S)-N-(9-chloro-1,2,3-trimethoxy-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalen-7-yl)acetamide (33).

[0149] Step B: Diisopropylethylamine (768 mg, 5.94 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]dichloride palladium (1.0 g, 1.37 mmol) were added to a methanol (40 mL) solution of compound 32 (2.40 g, 5.94 mmol), and the resulting mixture was stirred overnight at 80°C with carbon monoxide (50 psi). The mixture was then separated by manufacturing HPLC and SFC to obtain (S)-7-acetamido-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalene-10-methylformate (34). 1H NMR (DMSO-d6, 400MHz) δ8.61(d, J=7.2Hz, 1H), 7.65(d, J=9.2Hz, 1H), 7.13(d, J=9.2Hz, 1H), 7.09(s, 1H), 6.80(s, 1H), 4.29-4.23(m, 1H), 3.85(s, 3H), 3.79(s, 3H), 3.78(s, 3H), 3.57(s, 3H), 2.68-2.61(m, 1H), 2.29-2.24(m, 1H), 2.06-1.96(m, 1H), 1.85-1.76(m, 4H). MS(ESI, m / z):428.0[M+H] + .

[0150] The experimental procedure for step C was carried out in reference to step B, and (S)-7-acetamido-1,2,3-trimethoxy-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalen-9-methylformate (35). 1 H NMR (DMSO-d6, 400MHz) δ8.59(d, J=7.2Hz, 1H), 7.65(s, 1H), 7.24(d, J=12.8Hz, 1H), 6.96(d, J=12.8Hz, 1H), 6.85(s, 1H), 4 .26-4.19(m, 1H), 3.86(s, 3H), 3.80(s, 3H), 3.79(s, 3H), 3.61(s, 3H), 2.63-2.58(m, 1H), 2.26-2.05(m, 3H), 1.84(s, 3H). MS(ESI, m / z):428.1[M+H] + .

[0151] Example 14: Synthesis of (S)-N-{1,2,3-trimethoxy-9-oxy-10-(2,2,2-trifluoroethoxy)-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (36) and (S)-N-{1,2,3-trimethoxy-10-oxy-9-(2,2,2-trifluoroethoxy)-5,6,7,10-tetrahydrobenzo[a]heptalen-7-yl}acetamide (37) [ka]

[0152] A mixture containing compound 9 (500 mg, 1.30 mmol), potassium carbonate (717 mg, 5.19 mmol), acetonitrile (1.5 mL), 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (602 mg, 2.59 mmol), and DMF (3.5 mL) was microwaved at 150°C for 1.5 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was combined, washed with saturated brine (20 mL x 3), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the products were separated by manufacturing HPLC and SFC to obtain (S)-N-{1,2,3-trimethoxy-9-oxy-10-(2,2,2-trifluoroethoxy)-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (36) (290 mg) and (S)-N-{1,2,3-trimethoxy-10-oxy-9-(2,2,2-trifluoroethoxy)-5,6,7,10-tetrahydrobenzo[a]heptalen-7-yl}acetamide (37) (46 mg). The yields were 47.7% and 7.57%, respectively. Compound 36: 1 H NMR (DMSO-d6, 400MHz) δ8.61(d, J=7.6Hz, 1H), 7.19-7.17(m, 2H), 7.08(d, J=10.4Hz, 1H), 6.79(s, 1H), 4.94-4.78(m, 2H), 4.36- 4.30(m, 1H), 3.84(s, 3H), 3.79(s, 3H), 3.53(s, 3H), 2.63-2.58(m, 1H), 2.26-2.17(m, 1H), 2.07-1.97(m, 1H), 1.87-1.78(m, 4H). MS(ESI, m / z):468.1[M+H] + . Compound 37: 1 H NMR (DMSO-d6, 400MHz) δ8.59(d, J=7.6Hz, 1H), 7.30(d, J=12.8Hz, 1H), 7.21(s, 1H), 7.03(d, J=12.8Hz, 1H), 6.83(s, 1H), 4.9 3-4.76(m, 2H), 4.38-4.31(m, 1H), 3.85(s, 3H), 3.79(s, 3H), 3.58(s, 3H), 2.60-2.56(m, 1H), 2.21-2.02(m, 3H), 1.87(s, 3H). MS(ESI, m / z):468.0[M+H]+ .

[0153] Example 15: Synthesis of (S)-N-(10-cyano-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (38) [ka]

[0154] A mixture containing compound 32 (1.0 g, 2.48 mmol), zinc cyanide (880 mg, 7.49 mmol), tetra(triphenylphosphine)palladium (572 mg, 0.495 mmol), and DMF (20 mL) was stirred under nitrogen at 100°C for 1 hour. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phase was combined and washed with saturated brine (50 mL x 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was separated by manufacturing HPLC and SFC to obtain (S)-N-(10-cyano-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (38). 1 H NMR (DMSO-d6, 400MHz) δ8.63(d, J=7.2Hz, 1H), 8.07(d, J=9.6Hz, 1H), 7.16-7.12(m, 2H), 6.81(s, 1H), 4.30-4.23(m, 1H) ), 3.82(s, 3H), 3.79(s, 3H), 3.59(s, 3H), 2.67-2.62(m, 1H), 2.33-2.28(m, 1H), 2.03-2.00(m, 1H), 1.84-1.80(m, 4H). MS(ESI, m / z):395.4[M+H] + .

[0155] Example 16: Synthesis of (S)-N-(9-cyano-1,2,3-trimethoxy-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalen-7-yl)acetamide (39) [ka]

[0156] The experimental procedure for synthesizing compound 39 using compound 33 as a starting material was described in Example 15. 1 H NMR (DMSO-d6, 400MHz) δ8.57(d, J=7.2Hz, 1H), 7.94(s, 1H), 7.34(d, J=12.8Hz, 1H), 7.04(d, J=12.8Hz, 1H), 6.87(s , 1H), 4.28-4.22(m, 1H), 3.86(s, 3H), 3.79(s, 3H), 3.64(s, 3H), 2.61-2.58(m, 1H), 2.24-2.08(m, 3H), 1.87(s, 3H). MS(ESI, m / z):395.3[M+H] + .

[0157] Example 17: Synthesis of (S)-7-acetamido-1,2,3,10-tetramethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-11-methylformate (40) [ka]

[0158] The experimental procedure for synthesizing compound 40 using compound 12 as a starting material followed step B of Example 13. 1 H NMR (DMSO-d6, 400MHz) δ8.62(d, J=7.6Hz, 1H), 7.18(s, 1H), 6.94(s, 1H), 6.79(s, 1H), 4.30-4.26(m, 1H), 3.88(s, 3H) , 3.84(s, 6H), 3.78(s, 3H), 3.56(s, 3H), 2.62-2.59(m, 1H), 2.26-2.24(m, 1H), 2.03-2.01(m, 1H), 1.85-1.77(m, 4H). MS(ESI, m / z):458.4[M+H] + .

[0159] Example 18: Synthesis of (S)-1-methyl-(1,2,3,10-tetramethoxy-11-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)urea (44) [ka]

[0160] Step A: A mixture containing compound 16 (1.35 g, 3.27 mmol), triethylamine (330 mg, 3.27 mmol), DMAP (800 mg, 6.55 mmol), di-tert-butyl dicarbonate (2.30 g, 10.5 mmol), and acetonitrile (13 mL) was stirred at 80°C for 2 hours. Di-tert-butyl dicarbonate (1.40 g, 6.41 mmol) was then added, and the mixture was stirred overnight under reflux. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (eluting 200-300 mesh silica gel, petroleum ether:ethyl acetate = 2:3) to obtain (S)-acetyl(1,2,3,10-tetramethoxy-11-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)tert-butylcarbamate (41) (921 mg). The yield was 54.8%. 1 H NMR (DMSO-d6, 400MHz) δ7.18(s, 1H), 7.06(s, 1H), 6.78(s, 1H), 4.91-4.87(m, 1H), 3.84(s, 6H), 3.78(s, 3H), 3.57(s, 3) H), 2.72-2.67(m, 1H), 2.54-2.47(m, 1H), 2.36-2.31(m, 1H), 2.28(s, 3H), 2.24(s, 3H), 1.95-1.87(m, 1H), 1.49(s, 9H).

[0161] Step B: A methanol (8 mL) solution containing compound 41 (1.10 g, 2.14 mmol) and sodium methylate (463 mg, 8.57 mmol) was stirred at 40°C for 1 hour. Saturated ammonium chloride solution (25 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain (S)-(1,2,3,10-tetramethoxy-11-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)tert-butylcarbamate (42) (900 mg). The yield was 89.2%.

[0162] Step C: Compound 42 (900 mg, 1.91 mmol), trifluoroacetic acid (3 mL), and dichloromethane (10 mL) were mixed and stirred at room temperature for 4 hours. Water (30 mL) was added, the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (30 mL x 3) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (eluted with 200-300 mesh silica gel, dichloromethane:methanol = 200:3, 0.2% triethylamine) to obtain (S)-7-amino-1,2,3,10-tetramethoxy-11-methyl-6,7-dihydrobenzo[a]heptalene-9(5H)-ketone (43) (490 mg). The yield was 69.1%.

[0163] Step D: In an ice bath, carbamilkloride (102 mg, 1.09 mmol) was added dropwise to a solution of compound 43 (170 mg, 0.458 mmol) and triethylamine (139 mg, 1.38 mmol) in dichloromethane (5 mL). After addition, the resulting mixture was stirred overnight at room temperature, and then the temperature was raised to 35°C and stirred for 2 hours. Water (15 mL) was added, and the mixture was extracted with dichloromethane (30 mL x 2) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (eluted with 200-300 mesh silica gel, petroleum ether:ethyl acetate = 1:1-2:3) to obtain (S)-1-methyl-(1,2,3,10-tetramethoxy-11-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)urea (44). 1 H NMR (DMSO-d6, 400MHz) δ7.83(s, 1H), 7.25(s, 1H), 6.81(s, 1H), 6.61(d, J=8.4Hz, 1H), 5.77-5.73(m, 1H), 4.43-4.36(m, 1H), 3.85(s, 6H), 3.79(s, 3H), 3.50(s, 3H), 2.57-2.53(m, 7H), 2.21-2.16(m, 1H), 2.05-1.96(m, 1H), 1.81-1.73(m, 1H). MS(ESI, m / z):429.1[M+H] + .

[0164] Example 19: Synthesis of (S)-N-(1,2,3,10-tetramethoxy-11-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)propionamide (45) [ka]

[0165] The experimental procedure for synthesizing compound 45 was the same as in step D of Example 18, except that propionyl chloride was used instead of carbamil chloride in step D of Example 18. 1 H NMR (DMSO-d6, 400MHz) δ8.45(d, J=8.4Hz, 1H), 7.83(s, 1H), 7.29(s, 1H), 6.84(s, 1H), 4.56-4.49(m, 1H), 3.87(s, 6H), 3.8 1(s, 3H), 3.53(s, 3H), 2.58-2.55(m, 4H), 2.22-2.15(m, 3H), 2.09-2.01(m, 1H), 1.96-1.88(m, 1H), 1.02(t, J=7.6Hz, 3H). MS(ESI, m / z):428.1[M+H] + .

[0166] Example 20: Synthesis of (S)-7-acetamido-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formic acid (46), (S)-7-acetamido-1,2,3-trimethoxy-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalen-9-formic acid (47), (S)-7-acetamido-1,2,3-trimethoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (48), and (S)-7-acetamido-1,2,3-trimethoxy-N-methyl-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalen-9-formamide (49) [ka]

[0167] Step A: A mixture containing compound 34 (2.03 g, 2.34 mmol), 6 M hydrochloric acid (8.83 mL), and acetic acid (10 mL) was stirred at room temperature for 4 hours. Water (40 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 3) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by manufacturing HPLC to obtain (S)-7-acetamido-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalene-10-formic acid (46). 1 H NMR (DMSO-d6, 400MHz) δ8.68(d, J=7.2Hz, 1H), 8.26(d, J=10.0Hz, 1H), 8.41(d, J=10.0Hz, 1H), 7.38(s, 1H), 6.83(s, 1H), 4.36-4 .30(m, 1H), 3.86(s, 3H), 3.80(s, 3H), 3.59(s, 3H), 2.67-2.63(m, 1H), 2.26-2.23(m, 1H), 2.06-2.03(m, 1H), 1.90-1.82(m, 4H). MS(ESI, m / z):414.0[M+H] + .

[0168] Step B: In an ice bath, a mixture containing compound 46 (1.0 g, 2.42 mmol), diisopropylethylamine (1.56 g, 12.1 mmol), and DMF (10 mL) was mixed with HATU (1.38 g, 3.63 mmol), and the mixture was stirred at room temperature for 0.5 hours. Methylamine hydrochloride (196 mg, 2.90 mmol) was then added, and the mixture was stirred for 2 hours. Water (40 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was combined and washed with saturated saline solution (20 mL x 3), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by manufacturing HPLC and SFC to obtain (S)-7-acetamido-1,2,3-trimethoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (48). 1H NMR (DMSO-d6, 400MHz) δ9.24(q, J=4.4Hz, 1H), 8.63(d, J=7.2Hz, 1H), 8.19( d, J=10.0Hz, 1H), 7.29(d, J=10.0Hz, 1H), 7.23(s, 1H), 6.83(s, 1H), 4.33-4 .27(m, 1H), 3.85(s, 3H), 3.79(s, 3H), 3.58(s, 3H), 2.81(d, J=4.4Hz, 3H), 2 .67-2.62(m, 1H), 2.29-2.20(m, 1H), 2.08-2.00(m, 1H), 1.88-1.78(m, 4H). MS (ESI, m / z): 427.4 [M+H] + .

[0169] The experimental procedures for steps C and D followed the same procedure as steps A and B, respectively, except that compound 35 was used instead of compound 34 in step A, to obtain (S)-7-acetamido-1,2,3-trimethoxy-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalene-9-formic acid (47) and (S)-7-acetamido-1,2,3-trimethoxy-N-methyl-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalene-9-formamide (49). Compound 47: 1 H NMR (DMSO-d6, 400MHz) δ8.78(d, J=7.2Hz, 1H), 8.42(s, 1H), 7.50(d, J=12.8Hz, 1H), 7.26(d, J=12.8Hz, 1H), 6.88(s , 1H), 4.29-4.23(m, 1H), 3.87(s, 3H), 3.80(s, 3H), 3.62(s, 3H), 2.62-2.58(m, 1H), 2.26-2.07(m, 3H), 1.85(s, 3H). MS(ESI, m / z):414.0[M+H] + . Compound 49: 1H NMR (DMSO-d6, 400MHz) δ9.31(q, J=4.4Hz, 1H), 8.72(d, J=6.8Hz, 1H), 8.42(s, 1H), 7.28(d, J=12.8Hz, 1H), 7.07(d, J=12.8Hz, 1H), 6.85(s , 1H), 4.29-4.22(m, 1H), 3.86(s, 3H), 3.80(s, 3H), 3.60(s, 3H), 2.82(d, J=4.4Hz, 3H), 2.62-2.57(m, 1H), 2.21-2.06(m, 3H), 1.84(s, 3H). MS(ESI, m / z):427.4[M+H] + .

[0170] Example 21: Synthesis of (S)-N-(1,2,3-trimethoxy-10-triduteriomethoxy-11-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (51) [ka]

[0171] Step A: In an ice bath, (S)-N-(11-bromo-10-hydroxy-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (1.60 g, 3.43 mmol), deuterium-substituted methanol (0.5 mL), and triphenylphosphine (2.70 g, 10.3 mmol) were dissolved in THF (32 mL), to which diisopropyl azodicarboxylic acid (2.08 g, 10.3 mmol) was added. The resulting mixture was then stirred overnight at room temperature under nitrogen. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (eluted with 200-300 mesh silica gel, petroleum ether:ethyl acetate = 1:1-0:1) to obtain (S)-N-(11-bromo-1,2,3-trimethoxy-10-triduteriomethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (50) (589 mg). The yield was 35.7%.

[0172] The experimental procedure for step B was carried out with reference to Example 7, and (S)-N-(1,2,3-trimethoxy-10-triduteriomethoxy-11-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (51). 1 H NMR (DMSO-d6, 400MHz) δ8.54(d, J=7.6Hz, 1H), 7.07(s, 1H), 7.06(s, 1H), 6.76(s, 1H), 4.31-4.25(m, 1H), 3.83 (s, 3H), 3.79(s, 3H), 3.57(s, 3H), 2.61-2.56(m, 1H), 2.29-2.21(m, 4H), 2.05-1.95(m, 1H), 1.84-1.76(m, 4H). MS(ESI, m / z):417.2[M+H] + .

[0173] Example 22: Synthesis of (S)-N-[1,2,3-trimethoxy-9-oxy-10-(2-oxypyridinyl-1-yl)-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide (52) [ka]

[0174] In an ice bath, 60% sodium hydride (120 mg, 3.00 mmol) was added in batches to a solution of pyrrolidone (320 mg, 3.76 mmol) in THF (10 mL), and the mixture was stirred at this temperature for 0.5 hours. Colchicine (1.0 g, 2.50 mmol) was then added. After addition, the resulting mixture was stirred at room temperature for 3 hours. Saturated ammonium chloride solution (20 mL) was added to the reaction mixture and extracted with ethyl acetate (20 mL x 3). The organic phase was combined and washed with saturated brine (20 mL x 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was separated and purified by manufacturing HPLC to obtain (S)-N-[1,2,3-trimethoxy-9-oxy-10-(2-oxypyridinyl-1-yl)5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide (52). 1H NMR (DMSO-d6, 400MHz) δ8.59(d, J=7.6Hz, 1H), 7.56(d, J=10.0Hz, 1H), 7.14(s, 1H), 7.10(d, J=10.0Hz, 1H), 6.79(s, 1H), 4.35-4.29(m, 1H), 3.85(s, 3H), 3.79(s, 3H), 3.67-3.61(m, 2H), 3.57(s, 3H), 2.67-2.61(m, 1H), 2.42 (t, J=8.0Hz, 2H), 2.33-2.22(m, 1H), 2.11-1.99(m, 3H), 1.88-1.79(m, 4H). MS (ESI, m / z): 453.4 [M+H] + .

[0175] Example 23: Synthesis of (S)-(7-acetamido-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-yl)methylaminomethyl ester (54) [ka]

[0176] Step A: A mixture containing colchicine (5.0 g, 12.5 mmol), ethanol (50 mL), and a 30% aqueous methylamine solution (25 mL) was stirred at 80°C for 1 hour. The solvent was evaporated under reduced pressure, and a slurry was prepared with petroleum ether to obtain (S)-N-(10-methylamino-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (53) (4.90 g). The yield was 98.2%.

[0177] Step B: In an ice bath, 60% sodium hydride (602 mg, 15.1 mmol) was added in batches to a solution of compound 53 (1.0 g, 2.51 mmol) in THF (10 mL), and the mixture was stirred at this temperature for 30 minutes. Chloromethyl formate (2.57 g, 27.2 mmol) was then added, and the resulting mixture was stirred at room temperature for 1 hour. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was combined and washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by manufacturing HPLC to obtain (S)-(7-acetamido-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-yl)methylaminomethyl ester (54). 1 H NMR (DMSO-d6, 400MHz) δ8.62(d, J=7.6Hz, 1H), 7.57(d, J=10.4Hz, 1H), 7.17(s, 1H), 7.05(d, J=10.4Hz, 1H), 6.80(s, 1H), 4.36-4.30(m, 1H), 3 .85(s, 3H), 3.79(s, 3H), 3.59(s, 3H), 3.57(s, 3H), 3.07(s, 3H), 2.66- 2.61(m, 1H), 2.30-2.22(m, 1H), 2.08-1.99(m, 1H), 1.90-1.79(m, 4H). MS (ESI, m / z): 457.4 [M+H] + .

[0178] Example 24: (S)-7-acetamido-1,2,3-trimethoxy-N-ethyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (55), (S)-7-acetamido-1,2,3-trimethoxy-N-(triduterio)methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (56) (S)-7-acetamide-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (57), (S)-7-acetamide-1,2,3-trimethoxy-N-phenyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (58), (S)-7-acetamide-1,2,3- Trimethoxy-N,N-dimethyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (59), N-{(S)-10-[(S)-2-cyanopyrrolidan-1-carbonyl]-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (60), (S)-N-{1,2,3 Synthesis of -trimethoxy-9-oxy-10-(pyridinyl-1-carbonyl)-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (61) and (S)-N-{1,2,3-trimethoxy-10-(4-methylpiperazine-1-carbonyl)-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (62) [ka]

[0179] The experimental procedure for synthesizing compound 55 (or 56, 57, 58, 59, 60, 61, 62) using compound 46 and ethylamine (or triduteriomethylamine, ammonium chloride, aniline, dimethylamine, (S)-pyridinyl-2-acetonitrile, pyridinyl, N-methylpiperazine) as starting materials referred to step B of Example 20. Compound 55: 1H NMR (DMSO-d6, 400MHz) δ9.35 (s, 1H), 8.65 (d, J=6.0Hz, 1H), 8.18 (d, J=10.0H z, 1H), 7.29 (d, J=10.0Hz, 1H), 7.22 (s, 1H), 6.81 (s, 1H), 4.30-4.28 (m, 1H), 3.84(s, 3H), 3.79(s, 3H), 3.58(s, 3H), 3.51-3.46(m, 2H), 2.67-2.63(m, 1H) , 2.25-2.24(m, 1H), 2.03-2.00(m, 1H), 1.84-1.82(m, 4H), 1.12-1.10(m, 3H). MS (ESI, m / z): 441.4 [M+H] + Compound 56: 1 H NMR (DMSO-d6, 400MHz) δ9.22 (s, 1H), 8.64 (d, J=7.2Hz, 1H), 8.19 (d, J=10.0Hz, 1H), 7.29 (d, J=10.0Hz, 1H), 7.22 (s, 1H), 6.81 (s, 1H), 4.33-4.26 (m, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 3.58 (s, 3H), 2.67-2.62 (m, 1H), 2.26-2.24 (m, 1H), 2.03-1.98 (m, 1H), 1.84-1.82 (m, 4H). MS(ESI、m / z):430.4[M+H] + Compound 57: 1 H NMR (DMSO-d6, 400MHz) δ8.67 (d, J=2.4Hz, 1H), 8.62 (d, J=7.6Hz, 1H), 8.18 (d, J=10.0Hz, 1H), 7.72 (d, J=2.4Hz, 1H), 7.27 (d, J=10.0Hz, 1H), 7.22 (s, 1H ), 6.81 (s, 1H), 4.33-4.26 (m, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 3.58 (s, 3H), 2 .65-2.62 (m, 1H), 2.28-2.25 (m, 1H), 2.05-2.01 (m, 1H), 1.85-1.80 (m, 4H). MS (ESI, m / z): 413.0 [M+H] + Compound 58: 1H NMR (DMSO-d6, 400MHz) δ11.31 (s, 1H), 8.67 (d, J=7.6Hz, 1H), 8.12 (d, J=10.0Hz, 1H), 7.71-7.69 (m, 2H), 7.38-7.29 (m, 4H), 7.13-7.10 (m, 1H), 6. 82 (s, 1H), 4.36-4.29 (m, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 3.60 (s, 3H), 2.6 9-2.64 (m, 1H), 2.29-2.26 (m, 1H), 2.07-2.04 (m, 1H), 1.86-1.84 (m, 4H). MS(ESI、m / z):489.2[M+H] + Compound 59: 1 H NMR (DMSO-d6, 400MHz) δ8.60 (d, J=7.6Hz, 1H), 7.32 (d, J=9.2Hz, 1H), 7.11-7.08 (m, 2H), 6.79 (s, 1H), 4.33-4.27 (m, 1H), 3.84 (s, 3H ), 3.78(s, 3H), 3.57(s, 3H), 2.94(s, 3H), 2.83(s, 3H), 2.64-2.61(m, 1H), 2.31-2.29(m, 1H), 2.02-1.99(m, 1H), 1.85-1.81(m, 4H). MS(ESI、m / z):441.1[M+H] + Compound 60: 1 H NMR (DMSO-d6, 400MHz) δ8.61 (d, J=7.6Hz, 1H), 7.32 (d, J=9.2Hz, 1H), 7.11-7.08 (m, 2H), 6.80 (s, 1H), 4.90-4.87 (m, 1H), 4.32-4.27 (m, 1H ), 3.84(s, 3H), 3.79(s, 3H), 3.59(s, 3H), 3.35-3.29(m, 2H), 2.67-2.66(m, 1H), 2.33-2.21(m, 3H), 1.98-1.97(m, 3H), 1.85-1.81(m, 4H). MS(ESI、m / z):492.4[M+H] + Compound 61: 1H NMR (DMSO-d6, 400MHz) δ8.60(d, J=7.6Hz, 1H), 7.36(d, J=9.2Hz, 1H), 7.13-7.09(m, 2H), 6.80(s, 1H), 4.32-4.29(m, 1H), 3.86(s, 3H), 3.7 9(s, 3H), 3.58(s, 3H), 3.43-3.38(m, 2H), 3.23-3.20(m, 2H), 2.63-2.62(m, 1H), 2.30-2.28(m, 1H), 2.05-2.01(m, 1H), 1.87-1.83(m, 8H). MS(ESI, m / z):467.4[M+H] + . Compound 62: 1 H NMR (DMSO-d6, 400MHz) δ8.60(d, J=7.2Hz, 1H), 7.31(d, J=9.6Hz, 1H), 7.10-7.07(m, 2H), 6.79(s, 1H), 4.31-4.28(m, 1H), 3.85(s, 3H) ), 3.78(s, 3H), 3.58(s, 5H), 3.20(s, 2H), 2.63-2.62(m, 1H), 2.33-2.28(m, 5H), 2.19(s, 3H), 2.03-1.98(m, 1H), 1.85-1.81(m, 4H). MS(ESI, m / z):496.4[M+H] + .

[0180] Example 25: Synthesis of (S)-N-(1,2,3-trimethoxy-11-methyl-10-morpholinyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (63) [ka]

[0181] A solution of compound 51 (137 mg, 0.329 mmol) and morpholine (143 mg, 1.64 mmol) in acetonitrile (5 mL) was stirred at 85°C for 48 hours. The solvent was evaporated under reduced pressure. The product was purified by column chromatography (eluted with 200-300 mesh silica gel, dichloromethane:methanol = 100:1) to obtain (S)-N-(1,2,3-trimethoxy-11-methyl-10-morpholinyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (63). 1 H NMR (DMSO-d6, 400MHz) δ8.50(d, J=6.0Hz, 1H), 7.03(s, 1H), 6.86(s, 1H), 6.76(s, 1H), 4.27-4.22(m, 1H), 3.84(s, 3H), 3.79(s, 3H), 3.68-3.67(m, 4H), 3.58(s, 3H), 3.13-3.09(m, 2H), 3.00-2.96(m, 2H), 2.62-2.58(m, 1H) ), 2.39(s, 3H), 2.30-2.23(m, 1H), 2.02-1.97(m, 1H), 1.86-1.75(m, 4H). MS (ESI, m / z): 469.2 [M+H] + .

[0182] Example 26: Synthesis of (S)-N-(9-hydroxymethyl-1,2,3-trimethoxy-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptadien-7-yl)acetamide (66) [ka]

[0183] The experimental procedure for step A was the same as that of step A in Example 13, except that tribromide phosphate was used instead of trichloride phosphate in step A of Example 13 to obtain compounds 64 and 65.

[0184] Step B: A mixture containing compound 64 (1.0 g, 2.23 mmol), THF (10 mL), and tetra(triphenylphosphine)palladium (258 mg, 0.223 mmol) was stirred under nitrogen at room temperature for 30 minutes, and then tributyltin methanol (716.22 mg, 2.23 mmol) was added. After addition, the resulting mixture was stirred overnight at 65°C. After cooling to room temperature, insoluble matter was removed by filtration. The solvent was evaporated under reduced pressure, and the product was separated by manufacturing HPLC and SFC to obtain (S)-N-(9-hydroxymethyl-1,2,3-trimethoxy-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptadien-7-yl)acetamide (66). 1 H NMR (DMSO-d6, 400MHz) δ8.66(d, J=6.8Hz, 1H), 7.84(s, 1H), 7.21(d, J=12.8Hz, 1H), 6.84-6.81(m, 2H), 5.41-5.38(m, 1H), 4.5 0-3.36(m, 2H), 4.25-4.24(m, 1H), 3.85(s, 3H), 3.78(s, 3H), 3.57(s, 3H), 2.59-2.56(m, 1H), 2.17-2.04(m, 3H), 1.84(s, 3H). MS(ESI, m / z):400.0[M+H] + .

[0185] Example 27: Synthesis of (S)-N-(10-formyl-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptadien-7-yl)acetamide (68) [ka]

[0186] The experimental procedure for step A was carried out with reference to step B of Example 26, except that compound 65 was used instead of compound 64 in step B of Example 26 to obtain (S)-N-(10-hydroxymethyl-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptadien-7-yl)acetamide (67). 1H NMR (DMSO-d6, 400MHz) δ8.58(d, J=7.2Hz, 1H), 7.58(d, J=9.6Hz, 1H), 7.19(d, J=9.6Hz, 1H), 7.02(s, 1H), 6.78(s, 1H), 5.36(t, J=5.6Hz, 1H), 4.39- 4.33(m, 2H), 4.31-4.28(m, 1H), 3.84(s, 3H), 3.79(s, 3H), 3.54(s, 3H), 2. 62-2.56(m, 1H), 2.27-2.24(m, 1H), 2.02-1.99(m, 1H), 1.84-1.79(m, 4H). MS (ESI, m / z): 400.0 [M+H] + .

[0187] Step B: A mixture containing compound 67 (100 mg, 0.250 mmol), Dess-Martin oxidizing agent (127 mg, 0.30 mmol), and dichloromethane (10 mL) was stirred at room temperature for 2 hours. Insoluble matter was removed by filtration. The solvent was evaporated under reduced pressure, and the product was purified by manufacturing HPLC to obtain (S)-N-(10-formyl-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptadien-7-yl)acetamide (68). 1 H NMR (DMSO-d6, 400MHz) δ10.12(s, 1H), 8.66(d, J=7.2Hz, 1H), 7.82(d, J=9.2Hz, 1H), 7.28-7.24(m, 2H), 6.81(s, 1H), 4.31-4.2 5(m, 1H), 3.85(s, 3H), 3.79(s, 3H), 3.59(s, 3H), 2.67-2.63(m, 1H), 2.29-2.27(m, 1H), 2.03-2.00(m, 1H), 1.85-1.80(m, 4H). MS(ESI, m / z):398.3[M+H] + .

[0188] Example 28: Synthesis of (S)-N-[1,2,3-trimethoxy-9-oxy-10-sulfonamide-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide (69) [ka]

[0189] A DMSO (6 mL) solution of compound 32 (300 mg, 0.743 mmol) and sodium 3-methoxy-3-oxypropanesulfonate (155 mg, 0.891 mmol) was stirred at room temperature for 2 hours. Then, sodium methylate (40 mg, 0.740 mmol) was added, and the mixture was stirred continuously at this temperature for 15 minutes. Next, a 1 mL aqueous solution of hydroxylaminesulfonic acid (392 mg, 3.46 mmol) and sodium acetate (227 mg, 2.77 mmol) was added in sequence. After adding the compounds, the resulting mixture was stirred at room temperature overnight. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was combined, washed with saturated brine (20 mL x 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by manufacturing HPLC to obtain (S)-N-[1,2,3-trimethoxy-9-oxy-10-sulfonamide-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide (69). 1 H NMR (DMSO-d6, 400MHz) δ8.65(d, J=7.2Hz, 1H), 8.19(d, J=10.0Hz, 1H), 7.30(d, J=10.0Hz, 1H), 7.20(s, 1H), 7.09(s, 2H), 6.82(s, 1H), 4.30-4.27(m, 1H), 3.85(s, 3H), 3.79(s, 3H), 3.59(s, 3H), 2.67-2.52(m, 1H), 2.33-2.27(m, 1H), 2.06-1.99(m, 1H), 1.85-1.83(m, 4H). MS(ESI, m / z):449.4[M+H] + .

[0190] Example 29: Synthesis of (S)-N-[1,2,3-trimethoxy-10-morpholinyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]propionamide (74) [ka]

[0191] The experimental procedure for synthesizing compound 74 using colchicine as a starting material followed the steps A and B of Example 18, Example 25, step C of Example 18, and step B of Example 20, respectively, except that propyl acid was used instead of compound 46 in step B of Example 20 to obtain (S)-N-[1,2,3-trimethoxy-10-morpholinyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]propionamide (74). 1 H NMR (DMSO-d6, 400MHz) δ8.52(d, J=7.6Hz, 1H), 7.13(d, J=10.8Hz, 1H), 7.02(s, 1H), 6.91(d, J=10.8Hz, 1H), 6.81(s, 1H), 4.41-4.37(m, 1H), 3.89(s, 3H), 3.84(s, 3H), 3 .80-3.77(m, 4H), 3.58(s, 3H), 3.47-3.41(m, 2H), 3.36-3.33(m, 2H), 2.59-2.57(m, 1H), 2.21-2.18(m, 3H), 2.16-2.05(m, 1H), 1.95-1.90(m, 1H), 1.01(t, J=7.2Hz, 3H). MS(ESI, m / z):469.4[M+H] + .

[0192] Example 30: Synthesis of (S)-7-(tert-butoxycarbonyl)amino-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-methylformate (77), (S)-1,2,3-trimethoxy-7-(3-methylureido)-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-methylformate (79), and (S)-1,2,3-trimethoxy-N-methyl-7-(3-methylureido)-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (81) [ka]

[0193] The experimental procedures for synthesizing compounds 77, 78, 79, and 81 using compound 71 as a starting material followed steps A and B of Example 13, steps C and D of Example 18, and Example 20, respectively. Compound 77: 1 H NMR (DMSO-d6, 400MHz) δ7.75(d, J=7.6Hz, 1H), 7.64(d, J=9.6Hz, 1H), 7.17(s, 1H), 7.11(d, J=9.6Hz, 1H), 6.79(s, 1H), 4.06-4.00(m, 1H), 3. 85(s, 3H), 3.79(s, 3H), 3.78(s, 3H), 3.60(s, 3H), 2.63-2.58(m, 1H), 2.25-2.20(m, 1H), 2.01-1.98(m, 1H), 1.81-1.79(m, 1H), 1.33(s, 9H). MS (ESI, m / z): 486.3 [M+H] + . Compound 78:MS(ESI, m / z):386.0[M+H] + . Compound 79: 1 H NMR (DMSO-d6, 400MHz) δ7.62(d, J=9.6Hz, 1H), 7.15(s, 1H), 7.11(d, J=9.6Hz, 1H), 6.80-6.78(m, 2H), 5.79(q, J=4.4Hz, 1H), 4.19-4.12(m, 1H), 3.8 4(s, 3H), 3.79(s, 3H), 3.78(s, 3H), 3.56(s, 3H), 2.64-2.59(m, 1H), 2.47( d, J=4.4Hz, 3H), 2.26-2.24(m, 1H), 2.03-2.00(m, 1H), 1.74-1.71(m, 1H). MS (ESI, m / z): 443.1 [M+H] + . Compound 81: 1H NMR (DMSO-d6, 400MHz) δ9.30 (q, J=4.4Hz, 1H), 8.20 (d, J=10.0Hz, 1H), 7.30-7 .27(m, 2H), 6.82-6.80(m, 2H), 5.80(q, J=4.4Hz, 1H), 4.23-4.16(m, 1H), 3.85 (s, 3H), 3.79(s, 3H), 3.57(s, 3H), 2.81(d, J=4.4Hz, 3H), 2.63-2.60(m, 1H), 2 .47(d, J=4.4Hz, 3H), 2.23-2.21(m, 1H), 2.05-2.04(m, 1H), 1.74-1.73(m, 1H). MS(ESI, m / z):442.4[M+H] + .

[0194] Example 31: Synthesis of (S)-1,2,3-trimethoxy-7-(3-methylureido)-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalene-9-methylformate (82) [ka]

[0195] The experimental procedure for synthesizing compound 82 using compound 76 as a starting material followed sequentially with reference to steps B of Example 13 and steps C and D of Example 18. 1 H NMR (DMSO-d6, 400MHz) δ7.71(s, 1H), 7.23(d, J=12.8Hz, 1H), 6.94(d, J=12.8Hz, 1H), 6.84(s, 1H), 6.74(d, J=6.8Hz, 1H), 5.80(q, J=4.4Hz, 1H), 4.1 7-4.10(m, 1H), 3.85(s, 3H), 3.79(s, 3H), 3.77(s, 3H), 3.60(s, 3H), 2.58- 2.55(m, 1H), 2.47(q, J=4.4Hz, 3H), 2.21-2.16(m, 2H), 2.14-1.99(m, 1H). MS (ESI, m / z): 443.1 [M+H] + .

[0196] Example 32: Synthesis of (S)-N-{1,2,3-trimethoxy-10-(morpholine-4-carbonyl)-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (83) and (S)-N-{1,2,3-trimethoxy-9-(morpholine-4-carbonyl)-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalen-7-yl}acetamide (84) [ka]

[0197] The experimental procedure for synthesizing compound 83 or 84 using compound 46 (or 47) and morpholine as starting materials referred to step B of Example 20. Compound 83: 1 H NMR (DMSO-d6, 400MHz) δ8.60(d, J=7.6Hz, 1H), 7.35(d, J=9.6Hz, 1H), 7.11-7.08(m, 2H), 6.79(s, 1H), 4.31-4.28(m, 1H), 3.85(s, 3H), 3.78( s, 3H), 3.63-3.62(m, 2H), 3.57-3.54(m, 7H), 3.24-3.22(m, 2H), 2.68- 2.66(m, 1H), 2.33-2.32(m, 1H), 2.01-1.98(m, 1H), 1.85-1.80(m, 4H). MS (ESI, m / z): 483.4 [M+H] + . Compound 84: 1 H NMR (DMSO-d6, 400MHz) δ8.54(d, J=7.2Hz, 1H), 7.33(s, 1H), 7.25(d, J=12.8Hz, 1H), 6.94(d, J=12.8Hz, 1H), 6.84(s, 1H), 4.26-4.23(m, 1H), 3.8 5(s, 3H), 3.79(s, 3H), 3.66-3.52(m, 9H), 3.19(s, 2H), 2.63-2.58(m, 1H ), 2.26-2.23(m, 1H), 2.21-2.14(m, 1H), 2.03-2.01(m, 1H), 1.83(s, 3H). MS (ESI, m / z): 483.2 [M+H] + .

[0198] Example 33: Synthesis of (S)-N-{1,2,3-trimethoxy-11-methyl-9-oxy-10-(2,2,2-trifluoroethoxy)-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (87) and (S)-N-{1,2,3-trimethoxy-11-methyl-10-oxy-9-(2,2,2-trifluoroethoxy)-5,6,7,10-tetrahydrobenzo[a]heptalen-7-yl}acetamide (88) [ka]

[0199] The experimental procedure for synthesizing compounds 87 and 88 using compound 10 as a starting material is described in order with reference to Examples 7 and 14, except that a mixed solvent of dioxane and water was used instead of toluene in Example 7. Compound 87: 1 H NMR (DMSO-d6, 400MHz) δ8.58(d, J=7.2Hz, 1H), 7.15(s, 1H), 7.11(s, 1H), 6.78(s, 1H), 4.89-4.84(m, 1H), 4.75-4.70(m, 1H), 4.31-4.28( m, 1H), 3.84(s, 3H), 3.79(s, 3H), 3.58(s, 3H), 2.63-2.58(m, 1H), 2.33(s, 3H), 2.24-2.22(m, 1H), 2.03-1.99(m, 1H), 1.84-1.80(m, 4H). MS(ESI, m / z):482.4[M+H] + . Compound 88: 1 H NMR (DMSO-d6, 400MHz) δ8.57(d, J=7.2Hz, 1H), 7.52(s, 1H), 7.27(s, 1H), 6.81(s, 1H), 4.83-4.76(m, 2H), 4.34-4. 31(m, 1H), 3.85(s, 3H), 3.80(s, 3H), 3.59(s, 3H), 2.57-2.55(m, 1H), 2.25(s, 3H), 2.16-1.98(m, 3H), 1.86(s, 3H). MS(ESI, m / z):482.4[M+H] + .

[0200] Example 34: Synthesis of (S)-7-(ethylsulfonamide)-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalene-10-methylformate (89) [ka]

[0201] The experimental procedure for synthesizing compound 89 using compound 78 and ethyl sulfonyl chloride as starting materials followed the procedure described in step D of Example 18. 1 H NMR (DMSO-d6, 400MHz) δ8.08(d, J=7.6Hz, 1H), 7.66(d, J=9.2Hz, 1H), 7.40(s, 1H), 7.12(d, J=9.2Hz, 1H), 6.80(s, 1H), 3.95-3.91(m, 1H), 3.85(s, 3 H), 3.79(s, 6H), 3.52(s, 3H), 2.89-2.80(m, 2H), 2.65-2.60(m, 1H), 2.28- 2.20(m, 1H), 2.12-2.07(m, 1H), 1.86-1.79(m, 1H), 1.09(t, J=7.2Hz, 3H). MS (ESI, m / z): 478.4 [M+H] + .

[0202] Example 35: Synthesis of (S)-7-(tert-butoxycarbonyl)amino-1,2,3-trimethoxy-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalen-9-methylformate (90) and (S)-7-(ethylsulfonamide)-1,2,3-trimethoxy-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalen-9-methylformate (92) [ka]

[0203] The experimental procedure for synthesizing compounds 90 and 92 using compound 76 as a starting material followed steps B of Example 13 and steps C and D of Example 18, respectively. Compound 90: 1H NMR (DMSO-d6, 400MHz) δ7.71-7.69(m, 2H), 7.22(d, J=12.8Hz, 1H), 6.95(d, J=12.8Hz, 1H), 6.84(s, 1H), 4.01-3.9 4(m, 1H), 3.86(s, 3H), 3.79(s, 3H), 3.78(s, 3H), 3.65(s, 3H), 2.57-2.55(m, 1H), 2.21-2.03(m, 3H), 1.33(s, 9H). MS(ESI, m / z):486.3[M+H] + . Compound 92: 1 H NMR (DMSO-d6, 400MHz) δ8.10(d, J=7.6Hz, 1H), 7.96(s, 1H), 7.23(d, J=12.8Hz, 1H), 6.97(d, J=12.8Hz, 1H), 6.86(s, 1H), 3.97-3.91(m, 1 H), 3.86(s, 3H), 3.81(s, 3H), 3.79(s, 3H), 3.57(s, 3H), 2.87-2.73(m, 2H), 2.61-2.57(m, 1H), 2.25-2.07(m, 3H), 1.11(t, J=7.2Hz, 3H). MS(ESI, m / z):478.3[M+H] + .

[0204] Example 36: Synthesis of (S)-7-(3,3-dimethylureido)-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-methylformate (93) and (S)-7-(3,3-dimethylureido)-1,2,3-trimethoxy-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalen-9-methylformate (94) [ka]

[0205] The experimental procedure for synthesizing compound 93 or 94 using compound 78 (or 91) and dimethylcarbamoyl chloride as starting materials referred to step D of Example 18. Compound 93: 1H NMR (DMSO-d6, 400MHz) δ7.63(d, J=9.6Hz, 1H), 7.19(s, 1H), 7.12(d, J=9.6Hz, 1H), 6.86(d, J=7.2Hz, 1H), 6.80(s, 1H), 4.24-4.18( m, 1H), 3.85(s, 3H), 3.79(s, 3H), 3.78(s, 3H), 3.57(s, 3H), 2.79(s, 6H), 2.65-2.61(m, 1H), 2.27-2.23(m, 1H), 2.00-1.95(m, 2H). MS(ESI, m / z):457.4[M+H] + . Compound 94: 1 H NMR (DMSO-d6, 400MHz) δ7.81(s, 1H), 7.22(d, J=12.4Hz, 1H), 6.93(d, J=12.4Hz, 1H), 6.84-6.83(m, 2H), 4.26-4.1 9(m, 1H), 3.85(s, 3H), 3.79(s, 3H), 3.78(s, 3H), 3.59(s, 3H), 2.78(s, 6H), 2.58-2.56(m, 1H), 2.26-2.10(m, 3H). MS(ESI, m / z):457.4[M+H] + .

[0206] Example 37: Synthesis of (S)-N-{1,2,3-trimethoxy-9-oxy-10-(1H-tetrazole-1-yl)-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (95) [ka]

[0207] A mixture containing compound 1 (200 mg, 0.520 mmol), sodium azide (40.6 mg, 0.624 mmol), triethyl orthoformate (355 mg, 2.39 mmol), and acetic acid (5 mL) was stirred at 90°C for 2 hours. After cooling to room temperature, water (30 mL) was added, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. Extraction was performed with dichloromethane (30 mL x 2), the organic phase was combined and washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by manufacturing HPLC to obtain (S)-N-{1,2,3-trimethoxy-9-oxy-10-(1H-tetrazole-1-yl)-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (95). 1 H NMR (DMSO-d6, 400MHz) δ9.86(s, 1H), 8.70(d, J=7.2Hz, 1H), 7.25(d, J=10.0Hz, 1H), 7.40(s, 1H), 7.32(d, J=10.0Hz, 1H), 6.84(s, 1H), 4.39-4.35(m, 1H), 3.86(s, 3H), 3.81(s, 3H), 3.61(s, 3H), 2.70-2.66(m, 1H), 2.35-2.32(m, 1H), 2.30-2.05(m, 1H), 1.92-1.86(m, 4H). MS(ESI, m / z):438.3[M+H] + .

[0208] Example 38: Synthesis of (S)-N-{1,2,3-trimethoxy-9-oxy-10-(1H-1,2,4-triazole-1-yl)-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (96) [ka]

[0209] A mixture containing compound 32 (100 mg, 0.248 mmol), potassium carbonate (103 mg, 0.743 mmol), 1,2,4-triazole (34.2 mg, 0.495 mmol), copper(I) iodide (12.7 mg, 0.0669 mmol), and DMSO (2 mL) was microwaved at 80°C for 30 minutes. After cooling to room temperature, water (15 mL) was added and the mixture was extracted with dichloromethane (30 mL x 2). The organic phase was combined and washed with saturated saline (10 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by preparation HPLC to obtain (S)-N-{1,2,3-trimethoxy-9-oxy-10-(1H-1,2,4-triazole-1-yl)-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (96). 1 H NMR (DMSO-d6, 400MHz) δ9.33(s, 1H), 8.68(d, J=7.2Hz, 1H), 8.27(s, 1H), 8.17(d, J=10.4Hz, 1H), 7.40(s, 1H), 7.34(d, J=10.4Hz, 1H), 6.83(s , 1H), 4.39-4.33(m, 1H), 3.86(s, 3H), 3.80(s, 3H), 3.59(s, 3H), 2.68- 2.63(m, 1H), 2.32-2.29(m, 1H), 2.08-2.06(m, 1H), 2.05-1.86(m, 4H). MS (ESI, m / z): 437.2 [M+H] + .

[0210] Example 39: Synthesis of (S)-N-{10-(1H-imidazole-1-yl)-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (97) and (S)-N-{1,2,3-trimethoxy-10-(3-methyl-1H-pyrazole-1-yl)-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (98) [ka]

[0211] The experimental procedure for synthesizing compound 97 or 98 using compound 32 and imidazole (or 3-methyl-1H-pyrazole) as starting materials is described in Example 38. Compound 97: 1 H NMR (DMSO-d6, 400MHz) δ8.65(d, J=6.8Hz, 1H), 8.12(s, 1H), 7.72(dd, J=2.0, 10.0Hz, 1H), 7.56(s, 1H), 7.31(s, 1H), 7.17(dd, J=2.0, 10.0Hz, 1H), 7.05(s , 1H), 6.82(s, 1H), 4.38-4.32(m, 1H), 3.85(s, 3H), 3.80(s, 3H), 3.59(s, 3H) , 2.68-2.63(m, 1H), 2.32-2.29(m, 1H), 2.07-2.04(m, 1H), 1.87-1.85(m, 4H). MS(ESI, m / z):436.2[M+H] + . Compound 98: 1 H NMR (DMSO-d6, 400MHz) δ8.65-8.63(m, 2H), 8.20(d, J=10.8Hz, 1H), 7.34(s, 1H), 7.30(d, J=10.8Hz, 1H), 6.81(s, 1H), 6.34(d, J=2.4Hz, 1H) ), 4.38-4.32(m, 1H), 3.85(s, 3H), 3.80(s, 3H), 3.58(s, 3H), 2.66-2.61(m, 1H), 2.29-2.25(m, 4H), 2.07-2.04(m, 1H), 1.90-1.86(m, 4H). MS(ESI, m / z):450.2[M+H] + .

[0212] Example 40: Synthesis of (S)-N-(1,2,3-trimethoxy-9-oxy-10-(1H-1,2,3-triazole-1-yl)-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (99) and (S)-N-(1,2,3-trimethoxy-9-oxy-10-(2H-1,2,3-triazole-2-yl)-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (100) [ka]

[0213] The experimental procedures for synthetic compounds 99 and 100 were as described in Example 38, except that 1,2,3-triazole was used instead of 1,2,4-triazole in Example 38. Compound 99: 1 H NMR (DMSO-d6, 400MHz) δ8.67(d, J=7.2Hz, 1H), 8.64(s, 1H), 7.08(d, J=10.0Hz, 1H), 7.92(s, 1H), 7.38(s, 1H), 7.30(d, J=10.0Hz, 1H), 6.83(s , 1H), 4.40-4.33(m, 1H), 3.86(s, 3H), 3.81(s, 3H), 3.61(s, 3H), 2.70- 2.65(m, 1H), 2.35-2.32(m, 1H), 2.08-2.05(m, 1H), 1.89-1.86(m, 4H). MS (ESI, m / z): 437.2 [M+H] + . Compound 100: 1 H NMR (DMSO-d6, 400MHz) δ8.64(d, J=7.2Hz, 1H), 8.08(s, 2H), 7.83(d, J=10.0Hz, 1H), 7.29(s, 1H), 7.20(d, J=10.0Hz, 1H), 6.82(s, 1H), 4.36-4.30(m, 1H), 3.86(s, 3H), 3.80(s, 3H), 3.61(s, 3H), 2.69-2.64(m, 1H), 2.38-2.33(m, 1H), 2.07-2.03(m, 1H), 1.90-1.86(m, 4H). MS(ESI, m / z):437.1[M+H] + .

[0214] Example 41: Synthesis of (S)-7-acetamido-1,2,3-trimethoxy-10-morpholinyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalene-11-methylformate (101) [ka]

[0215] The experimental procedure for synthesizing compound 101 using compound 40 as a starting material was described in Example 25. 1H NMR (DMSO-d6, 400MHz) δ8.48(d, J=8.4Hz, 1H), 7.89(s, 1H), 7.26(s, 1H), 6.84(s, 1H), 4.61-4.56(m, 1H), 3.85(s, 3H), 3.83(s, 3H), 3.80(s, 3H), 3.71-3.51(m, 9H), 3.10(s, 2H), 2.58-2.55(m, 1H), 2.24-2.21(m, 1H), 2.08-2.04(m, 1H), 1.91-1.88(m, 4H). MS(ESI, m / z):513.4[M+H] + .

[0216] Example 42: Synthesis of (S)-7-(3-cyclopropylcarbamoyl)-1,2,3-trimethoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (102) and (S)-7-(3-cyclopropylcarbamoyl)-1,2,3-trimethoxy-N-methyl-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalen-9-formamide (103) [ka]

[0217] Compound 78 (or 91) and cyclopropanecarboxylic acid were used as starting materials to synthesize the corresponding amide, and then the acid obtained by hydrolyzing the methyl ester was condensed with methylamine to obtain compound 102 or 103. For specific experimental procedures, please refer to Example 20. Compound 102: 1H NMR (DMSO-d6, 400MHz) δ9.26(q, J=4.8Hz, 1H), 8.85(d, J=7.6Hz, 1H), 8.19(d, J= 9.6Hz, 1H), 7.30-7.26(m, 2H), 6.81(s, 1H), 4.36-4.29(m, 1H), 3.85(s, 3H), 3.7 9(s, 3H), 3.55(s, 3H), 2.81(d, J=4.8Hz, 3H), 2.67-2.63(m, 1H), 2.27-2.25(m, 1 H), 2.08-2.06(m, 1H), 1.88-1.86(m, 1H), 1.66-1.62(m, 1H), 0.67-0.57(m, 4H). MS(ESI, m / z):453.3[M+H] + . Compound 103: 1 H NMR (DMSO-d6, 400MHz) δ9.27(q, J=4.4Hz, 1H), 8.92(d, J=6.8Hz, 1H), 8.42( s, 1H), 7.28(d, J=12.8Hz, 1H), 7.07(d, J=12.8Hz, 1H), 6.85(s, 1H), 4.32-4 .26(m, 1H), 3.86(s, 3H), 3.79(s, 3H), 3.58(s, 3H), 2.82(d, J=4.8Hz, 3H), 2 .62-2.60(m, 1H), 2.20-2.09(m, 3H), 1.66-1.63(m, 1H), 0.65-0.57(m, 4H). MS (ESI, m / z): 453.3 [M+H] + .

[0218] Example 43: Synthesis of (S)-N-(8-bromo-1,2,3,10-tetramethoxy-11-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (105) and (S)-N-(8-bromo-1,2,3,9-tetramethoxy-11-methyl-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalen-7-yl)acetamide (106) [ka]

[0219] Step A: A mixture containing compounds 85 and 86 (1.0 g, 2.50 mmol) was dissolved in DMF (10 mL) and lithium bromide (220 mg, 2.53 mmol) and NBS (530 mg, 2.98 mmol) were added. The resulting mixture was stirred overnight at room temperature. Water (40 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was combined and washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the crude product (3.60 g) (partially containing DMF) of (S)-N-(8-bromo-9-hydroxy-1,2,3-trimethoxy-11-methyl-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalen-7-yl)acetamide (104). This compound was reacted directly to the next step without purification.

[0220] The experimental procedure for step B was carried out in reference to step C of Example 5, yielding (S)-N-(1,2,3,10-tetramethoxy-11-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (105) and (S)-N-(1,2,3,10-tetramethoxy-11-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (106). MS(ESI, m / z) of compound 105: 492.0[M+H] + . MS of compound 106 (ESI, m / z): 492.0[M+H] + .

[0221] Example 44: Synthesis of (S)-1,2,3-trimethoxy-9-oxy-7-(2-oxypiperidine-1-yl)-5,6,7,9-tetrahydrobenzo[a]heptalen-10-methylformate (108) [ka]

[0222] Step A: The experimental procedure for synthesizing compound 107 using compound 78 and 5-chloropentanoic acid as raw materials followed the procedure described in Step B of Example 20.

[0223] Step B: A mixture containing compound 107 (300 mg, 0.595 mmol), cesium carbonate (582 mg, 1.79 mmol), copper(I) iodide (34.0 mg, 0.179 mmol), and DMSO (4 mL) was microwaved at 80°C for 0.5 hours. After cooling to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was combined and washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was separated and purified by manufacturing HPLC and SFC to obtain (S)-1,2,3-trimethoxy-9-oxy-7-(2-oxypiperidine-1-yl)-5,6,7,9-tetrahydrobenzo[a]heptalen-10-methylformate (108). 1 H NMR (DMSO-d6, 400MHz) δ7.62(d, J=9.2Hz, 1H), 7.12(d, J=9.2Hz, 1H), 6.81(s , 1H), 6.77(s, 1H), 4.67-4.63(m, 1H), 3.84(s, 3H), 3.77(s, 6H), 3.67-3.64( m, 1H), 3.59(s, 3H), 3.45-3.41(m, 1H), 2.76-2.71(m, 1H), 2.35-2.19(m, 4H) , 2.05-1.99(m, 1H), 1.91-1.87(m, 1H), 1.78-1.74(m, 2H), 1.63-1.59(m, 1H). MS(ESI, m / z):468.4[M+H] + .

[0224] Example 45: Synthesis of (S)-1,2,3-trimethoxy-10-oxy-7-(2-oxypiperidine-1-yl)-5,6,7,10-tetrahydrobenzo[a]heptalen-9-methylformate (109) [ka]

[0225] The experimental procedure for synthesizing compound 109 using compound 91 and 5-chloropentanoic acid as starting materials followed steps B of Example 20 and Example 44. 1H NMR (DMSO-d6, 400MHz) δ7.43(s, 1H), 7.24(d, J=12.4Hz, 1H), 6.92(d, J=12.4Hz, 1H), 6.86(s, 1H), 4.65-4.60(m, 1H), 3.85(s, 3H), 3.79(s, 3H) , 3.78(s, 3H), 3.69-3.66(m, 1H), 3.60(s, 3H), 3.39-3.35(m, 1H), 2.69 -2.66(m, 1H), 2.46-2.42(m, 1H), 2.27-2.16(m, 4H), 1.88-1.62(m, 4H). MS (ESI, m / z): 468.4 [M+H] + .

[0226] Example 46: Synthesis of (S)-1,2,3-trimethoxy-9-oxy-7-(3-oxymorpholinyl)-5,6,7,9-tetrahydrobenzo[a]heptalene-10-methylformate (110) [ka]

[0227] The experimental procedure for synthesizing compound 110 using compound 78 and 2-(2-chloroethoxy)acetic acid as starting materials followed steps B of Example 20 and Example 43. 1 H NMR (DMSO-d6, 400MHz) δ7.64(d, J=9.2Hz, 1H), 7.14(d, J=9.2Hz, 1H), 6.83(s, 1H), 6.82(s, 1H), 4.62-4.60(m, 1H), 4.11-3.93(m, 4 H), 3.85(s, 3H), 3.78-3.71(m, 7H), 3.59-3.56(m, 4H), 2.76-2.73(m, 1H), 2.33-2.31(m, 1H), 2.23-2.21(m, 1H), 2.10-2.08(m, 1H). MS(ESI, m / z):470.1[M+H] + .

[0228] Example 47: Synthesis of (S)-1,2,3-trimethoxy-7-(N-methylacetamide)-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-methylformate (111) [ka]

[0229] In an ice bath, 60% sodium hydride (93.6 mg, 2.34 mmol) was added to a solution of compound 34 (500 mg, 1.17 mmol) in DMF (7 mL), and the mixture was stirred continuously at this temperature for 0.5 hours. Then, iodomethane (664 mg, 4.68 mmol) was added. After addition, the resulting mixture was stirred at room temperature for 1.5 hours. Saturated ammonium chloride solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was combined and washed with saturated brine (15 mL x 3), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by manufacturing HPLC to obtain (S)-1,2,3-trimethoxy-7-(N-methylacetamide)-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalene-10-methylformate (111). 1 H NMR (DMSO-d6, 400MHz) δ7.62(d, J=9.6Hz, 1H), 7.11(d, J=9.6Hz, 1H), 6.81(s, 1H), 6.79(s, 1H), 4.64-4.60(m, 1H) ), 3.84(s, 3H), 3.77(s, 6H), 3.58(s, 3H), 3.17(s, 3H), 2.75-2.70(m, 1H), 2.34-2.26(m, 2H), 2.02-1.95(m, 4H). MS(ESI, m / z):442.4[M+H] + .

[0230] Example 48: Synthesis of (S)-7-[(N-ethylsulfonyl)amino]-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-methylformate (112) and (S)-7-[(N-ethylsulfonyl)amino]-1,2,3-trimethoxy-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalen-9-methylformate (113) [ka]

[0231] The experimental procedure for synthesizing compound 112 or 113 using compound 78 (or 91) and N-ethylaminosulfonyl chloride as starting materials referred to step D of Example 18. Compound 112: 1 H NMR (DMSO-d6, 400MHz) δ7.77(d, J=8.4Hz, 1H), 7.64(d, J=9.6Hz, 1H), 7.41(s, 1H), 7.11(d, J=9.6Hz, 1H), 6.80(s, 1H), 6.77(t, J=6.0Hz, 1H), 3.87-3.79(m, 10H), 3.53(s, 3H), 2.73-2.59(m, 3H), 2.24-2.22(m, 1H), 2.09-1.99(m, 1H), 1.80-1.78(m, 1H), 0.86(t, J=7.2Hz, 3H). MS(ESI, m / z):493.4[M+H] + . Compound 113: 1 H NMR (DMSO-d6, 400MHz) δ7.96(d, J=8.4Hz, 1H), 7.77(d, J=7.2Hz, 1H), 7.22(d, J=12.8Hz, 1H), 6.95(d, J=12.8Hz, 1H), 6.86( s, 1H), 6.78(t, J=6.0Hz, 1H), 3.86-3.79(m, 10H), 3.58(s, 3H), 2.73-2.58(m, 3H), 2.19-2.16(m, 3H), 0.83(t, J=7.2Hz, 3H). MS(ESI, m / z):493.4[M+H] + .

[0232] Example 49: Synthesis of (S)-7-acrylamide-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalene-10-methylformate (114) and (S)-7-acrylamide-1,2,3-trimethoxy-10-oxy-5,6,7,10-tetrahydrobenzo[a]heptalene-9-methylformate (115) [ka]

[0233] The experimental procedure for synthesizing compound 114 or 115 using compound 78 (or 91) and acryloyl chloride as starting materials referred to step D of Example 18. Compound 114: 1 H NMR (DMSO-d6, 400MHz) δ8.84(d, J=7.2Hz, 1H), 7.65(d, J=9.6Hz, 1H), 7.15(d, J= 9.6Hz, 1H), 7.05(s, 1H), 6.81(s, 1H), 6.34-6.27(m, 1H), 6.08-6.03(m, 1H), 5.67 -5.62(m, 1H), 4.38-4.32(m, 1H), 3.85(s, 3H), 3.79(s, 3H), 3.77(s, 3H), 3.59(s, 3H), 2.69-2.64(m, 1H), 2.34-2.30(m, 1H), 2.08-2.05(m, 1H), 1.89-1.86(m, 1H). MS(ESI, m / z):440.3[M+H] + . Compound 115: 1 H NMR (DMSO-d6, 400MHz) δ8.82(d, J=6.8Hz, 1H), 7.62(s, 1H), 7.25(d, J=12.8Hz, 1H), 6.96(d, J=12.8Hz, 1H), 6.86(s, 1H), 6.32-6.25(m, 1H), 6.0 7-6.03(m, 1H), 5.65-5.62(m, 1H), 4.36-4.29(m, 1H), 3.86(s, 3H), 3.80 (s, 3H), 3.77(s, 3H), 3.63(s, 3H), 2.63-2.60(m, 1H), 2.28-2.13(m, 3H). MS (ESI, m / z): 440.2 [M+H] + .

[0234] Example 50: Synthesis of (S)-7-acetamido-4-chloro-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-methylformate (116) [ka]

[0235] The experimental procedure for synthesizing compound 116 followed step A of Example 2, except that compound 34 was used instead of colchicine in step A of Example 2. 1 H NMR (DMSO-d6, 400MHz) δ8.65(d, J=7.2Hz, 1H), 7.66(d, J=9.2Hz, 1H), 7.13(d, J=9.2Hz, 1H), 7.07(s, 1H), 4.18-4.15(m, 1H), 3. 91(s, 3H), 3.88(s, 3H), 3.79(s, 3H), 3.58(s, 3H), 3.16-3.11(m, 1H), 2.19-2.17(m, 1H), 1.96-1.93(m, 1H), 1.85-1.80(m, 4H). MS(ESI, m / z):462.3[M+H] + .

[0236] Example 51: Synthesis of (S)-N-{1,2,3-trimethoxy-9-oxy-10-(2-oxazolidan-3-yl)]-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (118) [ka]

[0237] Step A: A mixture containing colchicine (3.0 g, 7.51 mmol), ethanolamine (56.9 g, 932 mmol), and methanol (30 mL) was stirred at 30°C for 5 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was combined and washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (eluted with 200-300 mesh silica gel, ethyl acetate:methanol = 9:1) to obtain (S)-N-{10-[(2-hydroxyethyl)amino]-1,2,3-trimethoxy-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (117) (2.70 g). The yield was 83.9%. 1H NMR (400MHz, DMSO) δ8.64(d, J=7.6Hz, 1H), 7.61-7.58(m, 1H), 7.20(d, J=11.2 Hz, 1H), 7.11(s, 1H), 6.75-6.69(m, 2H), 5.00-4.97(m, 1H), 4.41-4.34(m, 1H) , 3.83(s, 3H), 3.78(s, 3H), 3.69-3.65(m, 2H), 3.48(s, 3H), 3.43-3.41(m, 2H) , 2.57-2.55(m, 1H), 2.22-2.14(m, 1H), 2.07-1.98(m, 1H), 1.89-1.82(m, 4H). MS(ESI, m / z):429.1[M+H] + .

[0238] Step B: Compound 117 (1.0 g, 2.33 mmol) and triethylamine (708 mg, 7.0 mmol) were added to a phthalonitrile (370 mg, 1.25 mmol) solution of dichloromethane (60 mL) in an ice bath. After adding the compounds, the resulting mixture was stirred at room temperature for 30 minutes. Water (100 mL) was added, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phase was combined and washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by manufacturing HPLC to obtain (S)-N-{1,2,3-trimethoxy-9-oxy-10-(2-oxazolidan-3-yl]-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide (118). 1 H NMR (400MHz, DMSO) δ8.60(d, J=7.6Hz, 1H), 7.69(d, J=10.4Hz, 1H), 7.17(s, 1 H), 7.13(d, J=10.4Hz, 1H), 6.80(s, 1H), 4.47-4.43(m, 2H), 4.36-4.29(m, 1H) , 4.10-4.04(m, 1H), 3.94-3.90(m, 1H), 3.85(s, 3H), 3.80(s, 3H), 3.57(s, 3H) , 2.67-2.61(m, 1H), 2.31-2.22(m, 1H), 2.08-2.00(m, 1H), 1.86-1.80(m, 4H). MS(ESI, m / z):455.4[M+H] + .

[0239] Example 52: Synthesis of (S)-N-{1,2,3-trimethoxy-10-(1-methyl-1H-pyrazole-4-yl)-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (119) [ka]

[0240] A mixture containing compound 32 (300 mg, 0.743 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole (232 mg, 1.11 mmol), potassium carbonate (308 mg, 2.23 mmol), water (3 mL), and dioxane (6 mL) was mixed with [1,1'-bis(diphenylphosphine)ferrocene]dichloride palladium (54 mg, 0.0743 mmol). The resulting mixture was stirred under nitrogen at 80°C for 4 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was combined, washed with saturated saline solution (20 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by manufacturing HPLC to obtain (S)-N-{1,2,3-trimethoxy-10-(1-methyl-1H-pyrazole-4-yl)-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl}acetamide (119). 1 H NMR (DMSO-d6, 400MHz) δ8.60-8.57(m, 2H), 8.11(s, 1H), 7.92(d, J=10.4Hz, 1H), 7.16-7.13(m, 2H), 6.79(s, 1H), 4.36-4.29(m, 1H) , 3.90(s, 3H), 3.84(s, 3H), 3.79(s, 3H), 3.56(s, 3H), 2.64-2.59(m, 1H), 2.30-2.25(m, 1H), 2.05-2.01(m, 1H), 1.88-1.84(m, 4H). MS(ESI, m / z):450.2[M+H] + .

[0241] Example 53: Synthesis of (S)-7-acetamido-1,2,3-trimethoxy-9-oxy-N-(pyridine-3-yl)-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (120) [ka]

[0242] The experimental procedure for synthesizing compound 120 using compound 46 and 3-aminopyridine as starting materials followed the procedure described in Step B of Example 20. 1 H NMR (DMSO-d6, 400MHz) δ11.36(s, 1H), 8.84(d, J=2.0Hz, 1H), 8.68(d, J=7.2Hz, 1H), 8 .33(dd, J=1.2, 4.4Hz, 1H), 8.19-8.16(m, 1H), 8.08(d, J=10.0Hz, 1H), 7.43-7.40(m, 1 H), 7.33-7.30(m, 2H), 6.83(s, 1H), 4.36-4.30(m, 1H), 3.86(s, 3H), 3.81(s, 3H), 3.6 1(s, 3H), 2.70-2.65(m, 1H), 2.29-2.24(m, 1H), 2.09-2.03(m, 1H), 1.90-1.82(m, 4H). MS(ESI, m / z):490.3[M+H] + .

[0243] Example 54: Synthesis of (S)-7-acetamido-2-hydroxy-1,3-dimethoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (121) and (S)-7-acetamido-1,3-dimethoxy-2-triduteriomethoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (122) [ka]

[0244] Step A: A mixture containing compound 48 (200 mg, 0.469 mmol) and sulfuric acid (2 mL) was stirred at 45°C for 7 hours. Isopropanol (5 mL) was added, and the mixture was placed in ice water (10 mL). Extraction was performed with dichloromethane (20 mL x 3). The combined organic phase was washed with saturated sodium bicarbonate solution (20 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by manufacturing HPLC to obtain (S)-7-acetamido-2-hydroxy-1,3-dimethoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (121) (50.8 mg). The yield was 26.2%. 1 H NMR (DMSO-d6, 400MHz) δ9.29(q, J=4.4Hz, 1H), 8.65(d, J=7.6Hz, 1H), 8.21(d, J=10.0Hz, 1H), 7.30(d, J=10.0Hz, 1H), 7.23(s, 1H), 6.70(s, 1H), 4.35-4.28(m, 1H), 3.82(s, 3H), 3.50(s, 3H), 2.81(d, J=4.8Hz, 3H), 2.5 9-2.55(m, 1H), 2.20-2.19(m, 1H), 2.02-1.99(m, 1H), 1.84-1.79(m, 4H). MS (ESI, m / z): 413.3 [M+H] + .

[0245] Step B: A mixture containing compound 121 (100 mg, 0.242 mmol), deuterium-substituted iodomethane (1.40 g, 9.65 mmol), potassium carbonate (101 mg, 0.731 mmol), and propyl ketone (3 mL) was stirred at 60°C for 1 hour. Water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by manufacturing HPLC to obtain (S)-7-acetamido-1,3-dimethoxy-2-triduteriomethoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (122). 1H NMR (DMSO-d6, 400MHz) δ9.25(q, J=4.4Hz, 1H), 8.63(d, J=7.2Hz, 1H), 8.19(d, J=10.0Hz, 1H), 7.29(d, J=10.0Hz, 1H), 7.23(s, 1H), 6.81(s, 1H), 4.33-4.27(m, 1H), 3.85(s, 3H), 3.58(s, 3H), 2.81(d, J=4.8Hz, 3H), 2.6 6-2.62(m, 1H), 2.26-2.24(m, 1H), 2.05-2.02(m, 1H), 1.86-1.82(m, 4H). MS (ESI, m / z): 430.4 [M+H] + .

[0246] Example 55: Synthesis of (S)-7-acetamido-2,3-dihydroxy-1-methoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (123) and (S)-7-acetamido-1-methoxy-2,3-di(triduteriomethoxy)-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (124) [ka]

[0247] Step A: In an ice bath, 16.8 mL of 1 M borontribromide dichloromethane solution was added dropwise to 138 mL of a solution of compound 48 (1.20 g, 2.81 mmol) in dichloromethane. After addition, the resulting mixture was stirred at 10°C for 4 hours. Methanol (10 mL) was added in batches, and the quenching reaction was carried out. The solvent was evaporated under reduced pressure, and the product was purified by manufacturing HPLC to obtain (S)-7-acetamido-2,3-dihydroxy-1-methoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (123) (300 mg). The yield was 26.8%. 1H NMR (DMSO-d6, 400MHz) δ9.32(q, J=4.4Hz, 1H), 8.62(d, J=7.2Hz, 1H), 8.22(d, J=10.0Hz, 1H), 7.30(d, J=10.0Hz, 1H), 7.23(s, 1H), 6.47(s , 1H), 4.36-4.30(m, 1H), 3.49(s, 3H), 2.81(d, J=4.8Hz, 3H), 2.46-2.43(m, 1H), 2.16-2.12(m, 1H), 2.02-1.99(m, 1H), 1.85-1.77(m, 4H). MS(ESI, m / z):399.0[M+H] + .

[0248] The experimental procedure for step B was carried out by referring to step B of Example 54, and (S)-7-acetamido-1-methoxy-2,3-di(triduteriomethoxy)-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (124). 1 H NMR (DMSO-d6, 400MHz) δ9.25(q, J=4.4Hz, 1H), 8.63(d, J=7.6Hz, 1H), 8.19(d, J=10.0Hz, 1H), 7.29(d, J=10.0Hz, 1H), 7.23(s, 1H), 6.80(s , 1H), 4.33-4.27(m, 1H), 3.58(s, 3H), 2.81(d, J=4.8Hz, 3H), 2.66-2.62(m, 1H), 2.26-2.24(m, 1H), 2.05-2.02(m, 1H), 1.87-1.82(m, 4H). MS(ESI, m / z):433.2[M+H] + .

[0249] Example 56: Synthesis of (S)-6-acetamido-13-methoxy-N-methyl-4-oxy-4,6,7,8-tetrahydroheptalene[1',2':4,5]benzo[1,2-d][1,3]dioxane-3-formamide(125) [ka]

[0250] A mixture containing compound 123 (150 mg, 0.377 mmol), chlorobromomethane (341 mg, 2.64 mmol), potassium carbonate (416 mg, 3.01 mmol), and N-methylpyrrolidone (3 mL) was stirred at 70°C for 1 hour. After cooling to room temperature, water (5 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by preparation HPLC to obtain (S)-6-acetamido-13-methoxy-N-methyl-4-oxy-4,6,7,8-tetrahydroheptalene[1',2':4,5]benzo[1,2-d][1,3]dioxane-3-formamide (125) (69 mg). The yield was 44.6%. 1 H NMR (DMSO-d6, 400MHz) δ9.28(q, J=4.4Hz, 1H), 8.60(d, J=7.6Hz, 1H), 8.22( d, J=10.0Hz, 1H), 7.29(d, J=10.0Hz, 1H), 7.23(s, 1H), 6.69(s, 1H), 6.09(dd , J=0.8, 6.8Hz, 2H), 4.35-4.29(m, 1H), 3.82(s, 3H), 2.82(d, J=4.8Hz, 3H), 2.62-2.57(m, 1H), 2.24-2.16(m, 1H), 2.06-1.96(m, 1H), 1.89-1.75(m, 4H). MS (ESI, m / z): 411.4 [M+H] + .

[0251] Example 57: Synthesis of (S)-6-acetamido-N-ethyl-13-methoxy-4-oxy-4,6,7,8-tetrahydroheptalene[1',2':4,5]benzo[1,2-d][1,3]dioxane-3-formamide (126) and (S)-6-acetamido-13-methoxy-4-oxy-N-phenyl-4,6,7,8-tetrahydroheptalene[1',2':4,5]benzo[1,2-d][1,3]dioxane-3-formamide (127) [ka]

[0252] The experimental procedure for synthesizing compound 126 (or 127) using compound 55 (or 58) as a starting material followed, in order, with reference to steps A of Example 55 and Example 56. Compound 126: 1 H NMR (DMSO-d6, 400MHz) δ9.37(t, J=5.6Hz, 1H), 8.61(d, J=7.2Hz, 1H), 8.20(d, J =10.0Hz, 1H), 7.28(d, J=10.0Hz, 1H), 7.22(s, 1H), 6.92(s, 1H), 6.10(d, J=5.6 Hz, 2H), 4.34-4.28(m, 1H), 3.81(s, 3H), 3.32-3.27(m, 2H), 2.62-2.57(m, 1H), 2.24-2.15(m, 1H), 2.06-1.98(m, 1H), 1.86-1.75(m, 4H), 1.12(t, J=7.2Hz, 3H). MS(ESI, m / z):425.4[M+H] + . Compound 127: 1 H NMR (DMSO-d6, 400MHz) δ11.34(s, 1H), 8.64(d, J=7.6Hz, 1H), 8.13(d, J=10.0Hz, 1H), 7.70(d, J=7.6Hz, 2H), 7.39-7.29(m, 4H), 7.14-7.11(m, 1H) , 6.71(s, 1H), 6.10(d, J=5.2Hz, 2H), 4.37-4.31(m, 1H), 3.83(s, 3H), 2.6 4-2.59(m, 1H), 2.27-2.18(m, 1H), 2.08-2.00(m, 1H), 1.88-1.78(m, 4H). MS (ESI, m / z): 473.4 [M+H] + .

[0253] Example 58: Synthesis of (S)-7-acetamido-1,2-dihydroxy-3-methoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (128) and (S)-8-acetamido-4-methoxy-N-methyl-10-oxy-6,7,8,10-tetrahydroheptalen[1',2':3,4]benzo[1,2-d][1,3]dioxane-11-formamide (129) [ka]

[0254] Step A: A mixture containing compound 48 (800 mg, 1.88 mmol) and sulfuric acid (8 mL) was stirred at 60°C for 0.5 hours, then the temperature was raised to 75°C and stirred continuously for 1.5 hours. (S)-7-acetamido-1,2-dihydroxy-3-methoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (126) was obtained. The mixture was cooled to room temperature, and the reaction mixture was placed in ice water (20 mL) batch by batch, and the pH was adjusted to 5-6 with a 20% sodium hydroxide solution. The mixture was extracted with a dichloromethane / methanol mixed solvent (20 mL x 3) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by manufacturing HPLC to obtain (S)-7-acetamido-1,2-dihydroxy-3-methoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (128) (370 mg). The yield was 49.4%. MS (ESI, m / z): 399.1 [M+H] + .

[0255] The experimental procedure for step B was carried out with reference to Example 56, and (S)-8-acetamido-4-methoxy-N-methyl-10-oxy-6,7,8,10-tetrahydroheptalene[1',2':3,4]benzo[1,2-d][1,3]dioxane-11-formamide (129). 1 H NMR (DMSO-d6, 400MHz) δ9.16(q, J=4.8Hz, 1H), 8.60(d, J=7.6Hz, 1H), 8.17(d, J=9.6Hz, 1H), 7.50(d, J=9.6Hz, 1H), 7.22(s, 1H), 6.67(s, 1H), 6.14(s, 1H), 6.08(s, 1H), 4.40-4.34(m, 1H), 3.88(s, 3H), 2.81(d, J=4.8Hz, 3H), 2 .70-2.63(m, 1H), 2.31-2.26(m, 1H), 2.11-2.08(m, 1H), 1.92-1.85(m, 4H). MS (ESI, m / z): 411.4 [M+H] + .

[0256] Example 59: Synthesis of (S)-7-acetamido-1-hydroxy-2,3-dimethoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (131) and (S)-7-acetamido-2,3-dimethoxy-1-triduteriomethoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (132) [ka]

[0257] Step A: In an ice bath, tin tetrachloride (11.2 g, 42.8 mmol) was added dropwise to a solution of compound 48 (500 mg, 1.17 mmol) and chloride acetate (3.30 g, 42.0 mmol) in dichloromethane (5 mL). After addition, the resulting mixture was stirred at 30°C for 12 hours. Water (20 mL) was added, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phase was combined and washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain crude product (900 mg) of acetic acid {(S)-7-acetamido-2,3-dimethoxy-10-methylaminoformyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-1-yl}ester (130). This compound was reacted directly to the next step without purification.

[0258] Step B: A mixture containing the crude product of compound 130 (900 mg) and 4 M hydrochloric acid (10 mL) was stirred at 25°C for 12 hours. Water (30 mL) was added, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phase was combined and washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by manufacturing HPLC to obtain (S)-7-acetamido-1-hydroxy-2,3-dimethoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (131) (220 mg). The total reaction yield for steps A and B was 45.6%. MS (ESI, m / z): 413.2 [M + H] + .

[0259] The experimental procedure for step C was carried out with reference to step B of Example 54, and (S)-7-acetamido-2,3-dimethoxy-1-triduteriomethoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (132). 1 H NMR (DMSO-d6, 400MHz) δ9.25(q, J=4.8Hz, 1H), 8.64(d, J=7.2Hz, 1H), 8.19(d, J=10.0Hz, 1H), 7.29(d, J=10.0Hz, 1H), 7.22(s, 1H), 6.80(s, 1H), 4.31-4.28(m, 1H), 3.84(s, 3H), 3.79(s, 3H), 2.80(d, J=4.8Hz, 3H), 2.6 6-2.62(m, 1H), 2.29-2.20(m, 1H), 2.08-2.00(m, 1H), 1.84-1.79(m, 4H). MS (ESI, m / z): 430.4 [M+H] + .

[0260] Example 60: Synthesis of (S)-7-acetamido-2-difluoromethoxy-1,3-dimethoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (133) [ka]

[0261] A mixture containing compound 48 (200 mg, 0.485 mmol), sodium difluorochloroacetate (74 mg, 0.485 mmol), cesium carbonate (316 mg, 0.970 mmol), and DMF (2 mL) was stirred at 70°C for 2 hours. After cooling to room temperature, water (15 mL) was added, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phase was combined and washed with saturated brine (15 mL x 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by manufacturing HPLC to obtain (S)-7-acetamido-2-difluoromethoxy-1,3-dimethoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (133). 1H NMR (DMSO-d6, 400MHz) δ9.19(q, J=4.4Hz, 1H), 8.68(d, J=7.2Hz, 1H), 8.16(d, J=10.0H) z, 1H), 7.32(d, J=10.0Hz, 1H), 7.23(s, 1H), 7.18(s, 0.25H), 7.00(d, J=2.8Hz, 0.5H), 6 .96(s, 1H), 6.81(s, 0.25H), 4.34-4.28(m, 1H), 3.88(s, 3H), 3.54(s, 3H), 2.81(d, J=4 .8Hz, 3H), 2.74-2.69(m, 1H), 2.34-2.26(m, 1H), 2.10-2.01(m, 1H), 1.90-1.83(m, 4H). MS(ESI, m / z):463.3[M+H] + .

[0262] Example 61: (S)-7-acetamido-2-hydroxy-1-methoxy-3-triduteriomethoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (134) and (S)-7-acetamido-3-hydroxy-1-methoxy-2-triduteriomethoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (135) , and synthesis of (S)-7-acetamido-1,2-dimethoxy-3-triduteriomethoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (136) and (S)-7-acetamido-3-difluoromethoxy-1-methoxy-2-triduteriomethoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (137) [ka]

[0263] Step A: Potassium carbonate (520 mg, 3.76 mmol) and deuterium-substituted iodomethane (200 mg, 1.38 mmol) were added to a solution of compound 123 (500 mg, 1.25 mmol) in DMF (5 mL), and the resulting mixture was stirred at 50°C for 0.5 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed sequentially with water (10 mL x 2) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the products were separated by manufacturing HPLC and SFC to obtain (S)-7-acetamido-2-hydroxy-1-methoxy-3-triduteriomethoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (134) and (S)-7-acetamido-3-hydroxy-1-methoxy-2-triduteriomethoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (135). Compound 134: 1 H NMR (DMSO-d6, 400MHz) δ9.28(q, J=4.4Hz, 1H), 8.79(s, 1H), 8.63(d, J=7.6Hz, 1H), 8.20(d, J=10.0Hz, 1H), 7.30(d, J=10.0Hz, 1H), 7.23(s, 1H), 6.70(s, 1H), 4.39-4.26(m, 1H), 3.50(s, 3H), 2.81(d, J=4.8Hz, 3H), 2.6 0-2.55(m, 1H), 2.22-2.20(m, 1H), 2.03-1.99(m, 1H), 1.84-1.77(m, 4H). MS (ESI, m / z): 416.4 [M+H] + . Compound 135: 1H NMR (DMSO-d6, 400MHz) δ9.77(s, 1H), 9.28(q, J=4.4Hz, 1H), 8.62(d, J=7.6Hz, 1H), 8.20(d, J=10.0Hz, 1H), 7.29(d, J=10.0Hz, 1H), 7.22(s, 1H), 6.58(s, 1H), 4.34-4.28(m, 1H), 3.57(s, 3H), 2.81(d, J=4.8Hz, 3H), 2.6 0-2.55(m, 1H), 2.19-2.17(m, 1H), 2.02-1.99(m, 1H), 1.84-1.75(m, 4H). MS (ESI, m / z): 416.4 [M+H] + .

[0264] The experimental procedure for step B was the same as that of step B in Example 54, except that iodomethane was used instead of the deuterium-substituted iodomethane in step B of Example 54, to obtain (S)-7-acetamido-1,2-dimethoxy-3-triduteriomethoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (136). 1 H NMR (DMSO-d6, 400MHz) δ9.25(q, J=4.4Hz, 1H), 8.64(d, J=7.6Hz, 1H), 8.20(d, J=9.6Hz, 1H), 7.29(d, J=9.6Hz, 1H), 7.23(s, 1H), 6.80(s, 1H), 4 .33-4.27(m, 1H), 3.79(s, 3H), 3.58(s, 3H), 2.81(d, J=4.8Hz, 3H), 2.66 -2.62(m, 1H), 2.26-2.24(m, 1H), 2.05-2.02(m, 1H), 1.87-1.82(m, 4H). MS (ESI, m / z): 430.4 [M+H] + .

[0265] The experimental procedure for step C was carried out with reference to Example 60 to obtain (S)-7-acetamido-3-difluoromethoxy-1-methoxy-2-triduteriomethoxy-N-methyl-9-oxy-5,6,7,9-tetrahydrobenzo[a]heptalen-10-formamide (137). 11H NMR (DMSO-d6, 400 MHz) δ 9.17 (q, J=4.4 Hz, 1H), 8.66 (d, J=7.2 Hz, 1H), 8.16 (d, J=10.0 Hz, 1H), 7.41 (s, 0.25H), 7.31 (d, J=10.0 Hz, 1H), 7.22-7.21 (m, 1.5H), 7.04 (s, 0.25H), 6.94 (s, 1H), 4.30-4.24 (m, 1H), 3.59 (s, 3H), 2.81 (d, J=4.8 Hz, 3H), 2.70-2.65 (m, 1H), 2.27-2.23 (m, 1H), 2.03-2.00 (m, 1H), 1.87-1.82 (m, 4H). MS (ESI, m / z): 466.0 [M+H] + .

[0266] Example 62: Pharmacological Experiment A of the Compound on Rat Gouty Arthritis

[0267] Experimental Materials (1) Test Drugs Compounds 2, 17, 26 and 27 were triturated with 0.5% CMC-Na before use, prepared into suspensions of corresponding concentration (0.06 mg / mL) for oral administration, and the administration volume was 10 mL / kg. Colchicine was purchased from Sa'en Chemical Technology (Shanghai) Co., Ltd., with lot number 49ETRRAS, triturated with 0.5% CMC-Na before use, prepared into a suspension of corresponding concentration (0.06 mg / mL) for oral administration, and the administration volume was 10 mL / kg.

[0268] (2) Experimental Animals Sprague Dawley (SD) rats are SPF grade, male, with body weight of 180~240 g, purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd., with license number SCXK (Zhejiang) 2019-0001, and animal qualification certificate number 20210119Aazz0619000545 (Zhejiang).

[0269] Experimental Methods Grouping Method The SD rats consisted of 70 male rats weighing 180-240g. They were randomly divided into 7 groups of 10 rats each. Each group consisted of a blank control group (0.5% CMC-Na), a model group (0.5% CMC-Na), a positive control colchicine group, two compound groups, seventeen compound groups, twenty-six compound groups, and twenty-seven compound groups. The dosage for all groups was 0.6 mg / kg. The test substance for each group was prepared as a suspension of the corresponding concentration, and the administration volume for all groups was 10 mL / kg.

[0270] Model construction and dosing scheme A crystalline arthritis model was created by injecting urate crystals (40 mg / mL into the left ankle joint cavity of each rat) into the joint cavity. Different doses of the test drug were administered orally. The start of administration was defined as day 1 of the study, and the drug was administered once daily for 10 consecutive days (7 days of pre-administration before molding, molding on day 8, and then administration for 3 consecutive days). The study was completed on day 10.

[0271] (3) Test indicators Toenail volume Measure the volume of the toenails before group administration, before urate injection, and at 2, 4, 8, 10, 24, and 48 hours after injection. Walking style evaluation Simultaneously with measuring the volume of the toenails, observe and evaluate the degree of lameness in the molding joint. Pain assessment Simultaneously with measuring toenail volume, assess the degree of pain using the flexion-extension joint pain test.

[0272] (4) Data processing and statistical methods The data obtained from the test was statistically analyzed using IBM SPSS Statistics 22.0. The entire quantitative data was displayed as mean ± SEMs, and the data was analyzed using SPSS 22.0 statistical software, followed by a test of uniformity of variance for the parameters.

[0273] Experimental results Toenail volume The toenail volume data for each rat group is shown in Table 1. At each time point after molding, the toenail volume of the rats in the model group was significantly larger than that of the normal control group (P<0.001). In the colchicine group, the toenail volume of rats at 2h, 4h, 8h, 10h, and 48h after molding was significantly smaller than that of the model group (P<0.01). Each tested compound group was able to reduce the toenail volume of rats at different time points after molding. Compounds 2 and 26 significantly reduced the toenail volume at 2h, 4h, and 48h after molding, compound 17 significantly reduced the toenail volume at 2h, 8h, 24h, and 48h after molding, and compound 27 significantly reduced the toenail volume at 2h, 4h, 8h, 10h, and 48h after molding.

[0274] [Table 1]

[0275] Walking style evaluation The evaluation of rat gait for each group is shown in Table 2. At each time point after molding, the evaluation of rat gait in the model group was significantly higher than that of the normal control group (P<0.001). The colchicine group improved rat gait (P<0.05 or P<0.01) at 2h, 24h, and 48h after molding. Each tested compound group was able to improve rat gait at different time points after molding. Compound 2 clearly improved gait at 2h, 8h, 24h, and 48h after molding, compounds 17 and 26 clearly improved gait at 2h, 8h, and 24h after molding, and compound 27 clearly improved gait (P<0.05 or P<0.01) at 2h, 24h, and 48h after molding.

[0276] [Table 2]

[0277] (3) Pain assessment The pain assessments for each rat group are shown in Table 3. At each time point after molding, the rat pain assessment in the model group was significantly higher than that of the normal control group (P<0.001). The colchicine group improved rat pain (P<0.05 or P<0.01) at 2h, 8h, 24h, and 48h after molding. Each tested compound group improved rat pain at different time points after molding. Compound 2 significantly improved pain at 2h, 4h, 8h, 10h, 24h, and 48h after molding. Compound 17 significantly improved gait at 2h, 8h, and 24h after molding. Compound 26 significantly improved gait at 2h after molding. Compound 27 significantly improved gait (P<0.05 or P<0.01) at 2h, 8h, 10h, 24h, and 48h after molding.

[0278] [Table 3]

[0279] Example 63: Pharmacological experiment B on gouty arthritis of a compound in rats

[0280] Experimental materials Receptor Compounds 12, 16, 19, 30, 34, 36, 38, 40, 44, 48, 49, 52, 58, 69, 83, 98, 102, 119, 121, and 122 were polished with 0.5% CMC-Na before use and prepared into suspensions of the corresponding concentrations (0.12 mg / mL) for oral administration, with a dosage volume of 0.5 mL / 100 g. Colchicine was purchased from MCE Corporation, lot number 41632, and was polished with 0.5% CMC-Na before use and prepared into suspensions of the corresponding concentrations (0.12 and 0.24 mg / mL) for oral administration, with a dosage volume of 0.5 mL / 100 g.

[0281] Laboratory animals The Sprague Dawley (SD) rats were SPF grade, male, weighing 180-220g, purchased from SCXK Laboratory Animals Co., Ltd., with production license number SCXK(■)2017-0005 and quality conformity certificate number 20170005054931.

[0282] (3) Experimental reagents Sodium urate was purchased from Sigma and prepared as a 25 mg / mL suspension in physiological saline containing 10% Tween-80.

[0283] Experimental method Grouping method 240 male SD rats were used, and after one week of adaptation, their body weight was 180-220g. They were randomly divided into 24 groups, each containing 10 rats. Each group consisted of a blank control group (0.5% CMC-Na), a model group (0.5% CMC-Na), a positive control low-dose colchicine group (0.6 mg / kg), a positive control high-dose colchicine group (1.2 mg / kg), and various compound groups. The dosage for each compound group was 0.6 mg / kg. The test substance for each group was prepared as a suspension of the corresponding concentration, and the administration volume was 10 mL / kg for all groups.

[0284] Model construction and dosing scheme 250 mg of sodium urate was taken, 9 mL of physiological saline was added, and 1 mL of Zween-80 solution was added. The mixture was heated and stirred to prepare a 10 mL sodium urate solution. Rats were fixed, and 0.2 mL of sodium urate solution was injected into the right ankle joint and knee joint cavity, respectively, to construct a rat gouty arthritis model.

[0285] The positive drug and the test compound were administered orally for 7 days prior to molding, once daily, molded on the 8th day, and then continued orally for 3 days after molding.

[0286] Test indicators Walking style evaluation The rats were evaluated using the improved gait classification standard introduced by Coderre et al. The gait of each rat was observed and classified before molding and at 2, 4, 8, 10, 24, and 48 hours after molding. The gait classification standard is as follows: 0 min: normal gait; 1 min: mild lameness, the rat's lower limb is slightly bent; 2 min: moderate lameness, the rat's lower limb is slightly touching the ground; 3 min: severe lameness, the rat's lower limb is off the ground and it walks on three legs. The average value for each group was calculated and compared with the model group.

[0287] Ankle joint swelling rate The circumference of the right ankle joint or the change in ankle volume (volume method) of the measured leg was measured using a soft measuring tape before molding and at 2, 4, 8, 10, 24, and 48 hours after molding, and the degree and percentage of ankle joint swelling were calculated. Swelling degree (mm) = Measured circumference (mm) - Base circumference (mm) Swelling rate (%) = Swelling degree (mm) / Base circumference (mm) × 100%

[0288] Data Processing and Statistical Methods Each test's quantitative data is presented as an average number. Intergroup comparisons were examined by testing for statistical significance using the ANOVA-Dunnett T test, with P<0.05 being the significance index.

[0289] Experimental results Walking style evaluation The gait evaluations for each rat group are shown in Table 4. Compared to the control group, the gait evaluation of the model group significantly improved at 8 and 10 hours after molding (P<0.05), however, gait began to recover at 24 hours after molding. At 4, 8, 10, and 24 hours after molding, the low-dose and high-dose colchicine groups clearly improved rat gait (P<0.05) compared to the model group, and the gait of compound groups 12, 16, 19, 30, 34, 36, 38, 40, 44, 48, 49, 52, 58, 69, 83, and 98 at different time points was clearly improved (P<0.05 or P<0.01).

[0290] [Table 4]

[0291] Ankle joint swelling rate The ankle joint swelling rate of rats in each group is shown in Table 5. Compared with the control group, the ankle joint swelling rate of the model group at each time point after molding was significantly increased (P<0.01). Compared with the model group at the same time point, both the low-dose colchicine group and the high-dose colchicine group significantly reduced the ankle joint swelling rate of rats after molding (P<0.01). All test compounds significantly reduced the ankle joint swelling rate of rats at different time points after molding (P<0.05 or P<0.01).

[0292]

Table 5

[0293] Example 64: Pharmacological experiment A of the compound on inflammatory factor levels

[0294] Experimental materials Test drugs Compounds 14, 17 and 26 were triturated with 0.5% CMC-Na before use, prepared into suspensions with corresponding concentration (0.06 mg / mL) for oral administration, and the administration volume was 10 mL / kg. Colchicine was purchased from Saen Chemical Technology (Shanghai) Co., Ltd., with lot number 49ETRRAS. Before use, it was triturated with 0.5% CMC-Na, prepared into a suspension with corresponding concentration (0.06 mg / mL) for oral administration, and the administration volume was 10 mL / kg.

[0295] Experimental animals Sprague Dawley (SD) rats were SPF-grade male rats, with a body weight of 180~240 g. They were purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd., with the permit number SCXK (Zhejiang) 2019-0001, and the animal qualification certificate number was 20210119Aazz0619000545 (Zhejiang).

[0296] Experimental method Grouping method There were 60 male SD rats, weighing 180-240g, randomly divided into 6 groups of 10 rats each. Each group consisted of a blank control group (0.5% CMC-Na), a model group (0.5% CMC-Na), a positive control group (colchicine), compound 14 groups, compound 17 groups, and compound 26 groups, all administered at a dose of 0.6 mg / kg. The test substance for each group was prepared as a suspension of the corresponding concentration, and the administration volume was 10 mL / kg.

[0297] Model construction and dosing scheme A crystalline arthritis model was created by injecting urate crystals (40 mg / mL into the left ankle joint cavity of each rat) into the joint cavity. Different doses of the test drug were administered orally. The start of administration was defined as day 1 of the study, and the drug was administered once daily for 10 consecutive days (7 days of pre-administration before molding, molding on day 8, and then administration for 3 consecutive days). The study was completed on day 10.

[0298] Test indicators inflammatory factors At the end of the experiment (day 10), the animals were dissected, synovial exudate from the ankle joint cavity of the molded area was collected, and IL-6 and TNF-α levels were measured.

[0299] Data Processing and Statistical Methods The data obtained from the test was analyzed using IBM SPSS Statistics 22.0. The data was analyzed using SPSS 22.0 statistical software, and a test of homogeneity of variance was performed on the parameters.

[0300] Experimental results TNF-α The results of the reduction in TNF-α in the knee joint synovial tissue of each rat group are shown in Table 6. Colchicine was able to reduce the TNF-α content in the rat knee joint synovial tissue after molding. All compound groups were able to reduce the TNF-α content in the rat knee joint synovial tissue after molding.

[0301] [Table 6]

[0302] IL-6 The results of the reduction in IL-6 in the knee joint synovial tissue of each rat group are shown in Table 7. Colchicine was able to reduce the IL-1β content in the rat knee joint synovial tissue after molding. All compound groups were able to reduce the IL-6 content in the rat knee joint synovial tissue after molding.

[0303] [Table 7]

[0304] Example 65: Pharmacological experiment B on the inflammatory factor levels of a compound

[0305] Experimental materials Receptor Compounds 19, 34, 38, 44, 48, 49, 55, 58, 60, 61, 69, 81, 95, 97, 98, 99, 100, 108, 112, 119, 121, and 122 were polished with 0.5% CMC-Na before use and prepared into suspensions of the corresponding concentrations (0.12 mg / mL) for oral administration, with a dosage volume of 0.5 mL / 100 g. Colchicine was purchased from MCE Corporation, lot number 41632, and was polished with 0.5% CMC-Na before use and prepared into suspensions of the corresponding concentrations (0.12 and 0.24 mg / mL) for oral administration, with a dosage volume of 0.5 mL / 100 g.

[0306] Laboratory animals The Sprague Dawley (SD) rats were SPF grade, male, weighing 180-220g, purchased from SCXK Laboratory Animals Co., Ltd., with production license number SCXK(■)2017-0005 and quality conformity certificate number 20170005054931.

[0307] Experimental reagents Sodium urate was purchased from Sigma and prepared as a 25 mg / mL suspension in physiological saline containing 10% Tween-80. The IL-1β and TNF-α test reagent kits (ELISA method) were purchased from Wuhan Yiruit Biotechnology Co., Ltd. The IL-6 test reagent kit (ELISA method) was purchased from Hangzhou Lianke Biotechnology Co., Ltd.

[0308] Experimental method Grouping method 260 male SD rats were used, and after one week of adaptation, their body weight was 180-220g. They were randomly divided into 26 groups, each containing 10 rats. Each group consisted of a blank control group (0.5% CMC-Na), a model group (0.5% CMC-Na), a positive control low-dose colchicine group (0.6 mg / kg), a positive control high-dose colchicine group (1.2 mg / kg), and various compound groups. The dosage for each compound group was 0.6 mg / kg. The test substance for each group was prepared as a suspension of the corresponding concentration, and the administration volume for each group was 10 mL / kg.

[0309] Model construction and dosing scheme 250 mg of sodium urate was taken, 9 mL of physiological saline was added, and 1 mL of Zween-80 solution was added. The mixture was heated and stirred to prepare a 10 mL sodium urate solution. Rats were fixed, and 0.2 mL of sodium urate solution was injected into the right ankle joint and knee joint cavity, respectively, to construct a rat gouty arthritis model.

[0310] The positive drug and the test compound were administered orally for 7 days prior to molding, once daily, molded on the 8th day, and then continued orally for 3 days after molding.

[0311] Test indicators inflammatory factors For the measurement of IL-1β, IL-6, and TNF-α in synovial tissue, rats were euthanized by decapitation 48 hours after molding, and synovial tissue from the knee joint of the subject was excised. Tissue homogenates were prepared, and the content of IL-1β, IL-6, and TNF-α in the synovial tissue was measured using an ELISA reagent kit, and the reduction rate of each inflammatory factor level was calculated.

[0312] Data Processing and Statistical Methods Each test measurement data is shown as a percentage decrease.

[0313] Experimental results TNF-α The results of the TNF-α reduction rate in the knee joint synovial tissue of each rat group are shown in Table 8. Both the low-dose and high-dose colchicine groups were able to reduce the TNF-α content in the rat knee joint synovial tissue after molding. Each compound group was able to reduce the TNF-α content in the rat knee joint synovial tissue after molding, and all of them were clearly superior to colchicine in suppressing the TNF-α content in the rat knee joint synovial tissue after molding.

[0314] [Table 8]

[0315] IL-1β The results of the IL-1β reduction rate in the knee joint synovial tissue of each rat group are shown in Table 9. Both the low-dose and high-dose colchicine groups were able to reduce the IL-1β content in the rat knee joint synovial tissue after molding. All compound groups were able to reduce the IL-1β content in the rat knee joint synovial tissue after molding, and the inhibition of IL-1β content in the rat knee joint synovial tissue after molding by most compounds was clearly superior to that of colchicine.

[0316] [Table 9]

[0317] IL-6 The results of the reduction in IL-6 in the knee joint synovial tissue of each rat group are shown in Table 10. Both the low-dose and high-dose colchicine groups were able to reduce the IL-6 content in the knee joint synovial tissue after molding. All compound groups were able to reduce the IL-6 content in the rat knee joint synovial tissue after molding, and the inhibition of IL-6 content in the rat knee joint synovial tissue after molding by most compounds was clearly superior to that of colchicine.

[0318] [Table 10]

[0319] Example 66: Acute toxicity study of single-dose mice with compounds 34, 48, 55, and 58

[0320] Experimental materials Compounds 34, 48, 55, and 58 were polished with 0.5% CMC-Na before use and prepared into suspensions of the corresponding concentrations for oral administration, with a dosage volume of 0.1 mL / 10 g. Colchicine was purchased from Saen Chemical Technology (Shanghai) Co., Ltd., lot number 49ETRRAS, and was polished with 0.5% CMC-Na before use and prepared into suspensions of the corresponding concentrations for oral administration, with a dosage volume of 0.1 mL / 10 g.

[0321] 2. Test animals and rearing conditions ICR mice, SPF grade, body weight 18-20g, 6-8 weeks old. Provided by Nantong University. Laboratory animal production license: SCXK(Su)2016-0010, laboratory animal use license: SYXK(Su)2017-0035.

[0322] Experimental methods and results ICR mice were randomly divided into 18 groups: a normal group, a colchicine group (50 mg / kg), a group receiving compound 34 at 50 mg / kg, a group receiving compound 34 at 100 mg / kg, a group receiving compound 34 at 400 mg / kg, a group receiving compound 34 at 600 mg / kg, a group receiving compound 48 at 50 mg / kg, a group receiving compound 48 at 100 mg / kg, a group receiving compound 48 at 400 mg / kg, and a group receiving compound 48 at 600 mg / kg. The study consisted of groups of 6 animals each, with an equal number of males and females. After an overnight fast, each animal was given a single oral dose of 0.1 mL / 10 g. The normal group received a 0.5% CMC-Na solution in a volume corresponding to their body weight. After administration, the animals' condition was observed, their body weight was measured daily, and the number of deaths was recorded. The animals were observed continuously for 14 days.

[0323] The dose and mortality rates for each mouse group are shown in Table 11. No immediate toxic reactions were observed after administration of each compound group, and no delayed toxic reactions were observed during the observation period from 24 hours to 14 days. The animals were in good condition, gained weight, and all mice survived. The maximum tolerated doses for compounds 34, 48, 55, and 58 in acute toxicity tests in mice all exceeded 600 mg / kg, but the maximum tolerated dose for colchicine in mice was less than 50 mg / kg.

[0324] [Table 11]

[0325] Example 67: Drug metabolism kinetics experiments in SD rats with compounds 48, 55, 56, 58, 69, 124, 125, and 132

[0326] Experimental materials Receptor Preparation of compound storage solution: Appropriate amounts of each solid powder were taken, a certain amount of DMSO was added, and vortex sonication was performed to obtain a storage solution of 20 mg / mL.

[0327] Preparation of oral test compounds: An appropriate amount of compound storage solution was taken for each compound, a fixed amount of Solutol HS15 solution was added, and after swirling for 1 minute, a fixed amount of physiological saline was added and thoroughly mixed to obtain a 1 mg / mL solution.

[0328] Preparation of test compounds for intravenous injection: An appropriate amount of compound storage solution was taken for each compound, a fixed amount of Solutol HS15 solution was added, and after swirling for 1 minute, a fixed amount of physiological saline was added and thoroughly mixed to obtain a 0.5 mg / mL solution.

[0329] Laboratory animals SD rat, male, SPF grade, 6-8 weeks old. Purchased from JH Laboratory Animal Co. LTD. License number: SCXK(SH)2017-0012, Certificate number: 20170012022077.

[0330] Experimental method Dosage and method of administration The test animals were fasted overnight before oral administration, fed 4 hours after administration, and allowed to drink water freely during that time. Two sets of administration were set up for each test compound: one for intravenous administration and the other for oral administration. See Table 12 below for specific dosages and methods of administration.

[0331] [Table 12]

[0332] Experimental Procedure Blood samples (150 μL / sample) were collected from the jugular vein of SD rats before administration and at 5 minutes (intravenous administration only), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration. These samples were placed in a centrifuge tube containing the anticoagulant heparin sodium and centrifuged at 4°C and 2000 g for 5 minutes to obtain plasma. Plasma samples were analyzed using LC / MS / MS to determine the concentration of each test compound in the plasma samples.

[0333] Drug metabolism kinetics analysis Non-compartment model-related parameters were calculated using the "WinNonlin" (registered trademark) Professional software.

number

[0334] Experimental results The SD rat drug metabolism kinetics parameters for each test compound obtained based on the above method are shown in Table 13. Each compound of the present invention exhibits favorable drug metabolism kinetics parameters, high bioavailability, and superiority over colchicine.

[0335] [Table 13]

[0336] The above describes only preferred specific embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Even if a person skilled in the art makes equivalent substitutions or modifications to the technical scope disclosed by the present invention based on the technical solutions and inventive ideas of the present invention, these are all included within the scope of protection of the present invention.

Claims

1. Compounds or pharmaceutically acceptable salts thereof whose structure is represented by formula (III): 【Chemistry 2】 During the ceremony, R １ , R ２ , or R ３ Each is independent of C １－３ Alkoxy group, hydroxyl group, or substituted C １－３ It is an alkoxy group, wherein the substituted substituent is deuterium. or R １ and R ２ or R ２ and R ３ are bonded to form -O-R １７ -O- group, and said R １７ is C １－３ alkylene group, R ４ It is hydrogen, R ５ , R ６ , R ７ or R ８ Each is independently hydrogen, R ９ It is hydrogen, X is -C (=O)- or -S (=O) ２ - It is a base, R １０ C １－４ Alkyl alkyl group, C ３－６ Cycloalkyl groups, or C １－４ Alkylamino group, or R ９ -N-X-R １０ Composed of 【Transformation 3】 It is the basis, R １１ It is hydrogen, R １２ is hydrogen, halogen, or C １－４ It is an alkyl group, (a) R １２ If R is hydrogen, １３ is a cyano group, or a substituted or unsubstituted (C １－４ Alkoxycarbonyl group, phenylaminocarbonyl group, C １－４ Alkylaminocarbonyl group, pyrrolidinylcarbonyl group, piperazinylcarbonyl group, morpholinylcarbonyl group, aminosulfonyl group, tetrazolyl group, triazolyl group, imidazolyl group, or C ３－６ It is a cycloalkoxy group, however, R １３ The substituents inside are deuterium, cyano group, or C １－３ One or more alkyl groups selected from the alkyl groups, (b) R １２ If R is non-hydrogen, １３ C ２－６ Heterocycloalkylcarbonyl group or C １－４ It is an alkoxy group, R １５ It is hydrogen.

2. The compound is selected from compounds whose structure is represented by formula (V), the compound according to claim 1 or a pharmaceutically acceptable salt thereof: 【Chemistry 4】 During the ceremony, R １ , R ２ or R ３ Each is independent of C １－３ It is an alkoxy group, or R １ and R ２ or R ２ and R ３ The combination is -O-R １７ -O- groups are formed, and the R １７ is C １－２ It is an alkyl group, R ４ It is hydrogen, R ９ It is hydrogen, X is -C (=O)- or -S (=O) ２ - It is a base, R １０ C １－３ Alkyl alkyl group, C ３－６ Cycloalkyl groups, or C １－４ It is an alkylamino group, or R ９ and N-X-R １０ teeth, 【Transformation 5】 Constituting the base, R １１ It is hydrogen, R １２ is hydrogen, halogen, or C １－３ It is an alkyl group, and (a) R １２ If R is hydrogen, １３ is a cyano group, or a substituted or unsubstituted (C １－４ Alkoxycarbonyl group, phenylaminocarbonyl group, C １－４ Alkylaminocarbonyl group, N-pyrrolidinylcarbonyl group, piperazinylcarbonyl group, morpholinylcarbonyl group, aminosulfonyl group, tetrazolyl group, triazolyl group, imidazolyl group, or C ３－６ It is a cycloalkoxy group, however, R １３ The substituents inside are deuterium, cyano group, or C １－３ One or more alkyl groups selected from the alkyl groups, (b) R １２ If R is non-hydrogen, １３ This is a pyrrolidinyl carbonyl group, a methylpiperazinyl carbonyl group, a morpholinyl carbonyl group, or C １－４ It is an alkoxy group, R １５ It is hydrogen.

3. R １ , R ２ , or R ３ Each is independent of C １－３ It is an alkoxy group, or R １ and R ２ Or R ２ and R ３ They combine to form -O-R １７ -O- groups are formed, and the R １７ is C １－２ It is an alkylene group, R ４ It is hydrogen, R ９ It is hydrogen, X is -C (=O)- or -S (=O) ２ - It is a base, R １０ represents a methyl group, an ethyl group, a cyclopropyl group, an amino group, a methylamino group, an ethylamino group, a dimethylamino group or a diethylamino group, or R ９ and N-X-R １０ is 【Transformation 6】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, comprising a group.

4. R １２ is hydrogen, deuterium, methyl group, ethyl group, cyano group, methoxy group, ethoxy group, methyl formate group, or ethyl formate group, and (a) R １２ If R is hydrogen, １３ These are cyano group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, phenylaminocarbonyl group, pyridinylaminocarbonyl group, methylaminocarbonyl group, deuterium-substituted methylaminocarbonyl group, halomethylaminocarbonyl group, ethylaminocarbonyl group, dimethylaminocarbonyl group, pyrrolidinylcarbonyl group, cyanopyrrolidinylcarbonyl group, piperadinylcarbonyl group, methylpiperazinylcarbonyl group, morpholinylcarbonyl group, pyrrolidinyl ketone group, aminosulfonyl group, tetrazolyl group, triazolyl group, imidazolyl group, pyrazolyl group, or tetrahydrofuranyloxy group. (b) R １２ If R is non-hydrogen, １３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is a cyano group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a methylaminocarbonyl group, a dimethylaminocarbonyl group, an aminocarbonyl group, a phenylaminocarbonyl group, an ethylaminocarbonyl group, a halomethylaminocarbonyl group, a deuterium-substituted methylaminocarbonyl group, a pyrrolidinylcarbonyl group, a cyanopyrrolidinylcarbonyl group, a piperadinylcarbonyl group, a methylpiperazinylcarbonyl group, a morpholinylcarbonyl group, a pyrrolidinyl ketone group, an aminosulfonyl group, a tetrazolyl group, a triazolyl group, a tetrahydrofuranyloxy group, a methoxy group, a halomethoxy group, a deuterium-substituted methoxy group, an ethoxy group, a haloethoxy group, or a deuterium-substituted ethoxy group.

5. A compound selected from the following or a pharmaceutically acceptable salt thereof: 【Transformation 7】 【change】 【change】 【change】 【change】

6. A pharmaceutical composition comprising, as an active ingredient, a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary ingredient.

7. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof for the manufacture of an anti-inflammatory or analgesic medicine.

8. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 for the manufacture of a drug for the treatment of arthritis.

9. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof for manufacturing an agent for acute gouty arthritis, an agent for treating rheumatoid arthritis, an agent for reducing inflammatory factors, an agent for treating cytokine storms, or an agent for treating coronavirus pneumonia.

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