Pyrrole derivatives, their preparation method and uses

Abstract

The present invention discloses a pyrrole derivative, its preparation method and its use. The compound has a significant suppressive and inhibitory effect on DHODH, and may be used as a specific inhibitor of DHODH, or as a drug for treating diseases caused by fungal infection. It may also be used to prepare agricultural fungicides, and has a wide range of potential applications.

Description

[Technical Field]

[0001] The present invention relates to the technical field of medicine, and in particular to compounds used as fungal dihydroorotate dehydrogenase (DHODH) inhibitors, their preparation methods and uses. [Background technology]

[0002] DHODH is a flavin-dependent mitochondrial enzyme that catalyzes the fourth step in the synthesis of pyrimidine nucleotides. Pyrimidines are important components in RNA and DNA biosynthesis, and DHODH inhibitors inhibit the activity of DHODH, thereby depleting intracellular pyrimidine nucleotides and suppressing cell growth.

[0003] As evidenced by abundant clinical evidence, inhibitors of human dihydroorotate dehydrogenase (hDHODH) are used to treat cancer, autoimmune diseases, inflammation, etc., and inhibitors of viral or fungal dihydroorotate dehydrogenase are used to treat diseases caused by viral or fungal infections.

[0004] Invasive fungal infections, known as hidden killers, are one of the leading causes of death in patients with tumors, AIDS, and organ transplants. Currently, the use of many broad-spectrum antibiotics and other potent drugs has dramatically increased the number of patients infected with fungi worldwide. Fungal infections include Aspergillus and sporozoites. Treatments that can combat drug-resistant and intractable pathogen infections remain an unmet medical need. Pulmonary aspergillosis affects approximately 300 million people worldwide, including approximately 240,000 in Europe. Without timely diagnosis and long-term antifungal treatment, the 5-year mortality rate approaches 80%.

[0005] Because it is difficult to find a drug target compatible with the human body, currently, only four types of antifungal drugs are available for human use: 1) Polyenes (e.g., amphotericin B): These bind to ergosterol (a fungal membrane component) and their target is similar to cholesterol in mammalian cells. 2) Azoles (e.g., itraconazole): These inhibit ergosterol synthesis via cytochrome p450, which is also present in mammalian cells. 3) Allylamines (e.g., terbinafine): These inhibit ergosterol synthesis via the fungus-specific enzyme squalene cyclooxygenase. 4) Echinocandins (e.g., micafungin): These target β-glucan synthesis, which is specific to fungal cell walls, and have fewer side effects.

[0006] Further complicating the treatment of fungal infections is the fact that various fungal pathogens are resistant to all four classes of antifungal drugs, which has prompted researchers to design new anti-infective strategies and drugs. Therefore, it is necessary and important to further develop DHODH inhibitors that are more effective, safer, and have fewer side effects. Summary of the Invention [Problem to be solved by the invention]

[0007] The main technical problem that the present invention aims to solve is to provide a compound that can effectively inhibit fungi. In order to solve the above technical problems, one technical solution adopted in the present invention is as follows:

[0008] The present invention provides a compound having the structure of Formula I, or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable hydrate, solvate, or salt compound thereof: JPEG0007737734000001.jpg79170 Ring B is selected from a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocycloalkyl; R 1 are each independently selected from hydrogen, halogen, cyano, =O, hydroxy, -NH2, carboxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted 3-12 membered cycloalkyl, substituted or unsubstituted 3-12 membered heterocycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, ester, acyl, amido, sulfinyl, sulfonyl, sulfonamide, and sulfinamide groups; or two R 1 and atoms bonded thereto form a substituted or unsubstituted 3- to 12-membered hydrocarbon ring or a substituted or unsubstituted 3- to 12-membered heterohydrocarbon ring, Any two of the R 1 is the two Rs of two adjacent substitution sites. 1 , or two Rs at two non-adjacent substitution sites 1 , or two R at the same substitution site 1 and other similar situations.

[0009] R 2 , R 3 , R 4 are each independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, -NH2, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted 3-12 membered cycloalkyl, substituted or unsubstituted 3-12 membered heterocycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, acyl group, ester group, amide group, sulfonyl group, sulfonamide group, boronic acid group, boronic acid ester group, and phosphoryl group, or R 2 , R 3 or R 2 , R 3 and the atoms bonded thereto form a substituted or unsubstituted heteroaromatic ring,

[0010] R 5 is selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl, substituted or unsubstituted 3- to 12-membered cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocycloalkyl, substituted or unsubstituted heteroaryl groups, and substituted or unsubstituted heteroaryl groups; R 6 is selected from hydrogen, a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted 2- to 10-membered heteroalkyl group, a substituted or unsubstituted 3- to 12-membered cycloalkyl group, a substituted or unsubstituted 3- to 12-membered heterocycloalkyl group, and a substituted or unsubstituted alkenyl group;

[0011] R 7 is selected from hydrogen, halogen, cyano, =O, hydroxy, -NH2, carboxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted 3-12 membered cycloalkyl, substituted or unsubstituted 3-12 membered cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, acyl, ester, amide, sulfonyl, sulfonamide, boronic acid, boronic acid ester, or any two R 7 and atoms bonded thereto form a substituted or unsubstituted 3- to 12-membered hydrocarbon ring or a substituted or unsubstituted 3- to 12-membered heterohydrocarbon ring, R 9are each independently selected from hydrogen, halogen, nitro, cyano, hydroxy, -NH2, =O, carboxyl, a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted 2-10 membered heteroalkyl group, a substituted or unsubstituted 3-12 membered cycloalkyl group, a substituted or unsubstituted 3-12 membered heterocycloalkyl group, a substituted or unsubstituted C2-C10 ester group, a substituted or unsubstituted C2-C10 alkynyl, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, an acyl group, an ester group, an amide group, a sulfonyl group, a sulfonamide group, a boric acid group, a boric acid ester group, a phosphoryl group, or any two R 9 and the atoms bonded thereto constitute a substituted or unsubstituted hydrocarbon ring or a substituted or unsubstituted heterohydrocarbon ring, Z 1 , Z 2 , Z 3 are each independently N or CR 8 is selected from

[0012] R 8 are each independently selected from hydrogen, halogen, nitro, cyano, hydroxy, -NH2, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted 3-12 membered cycloalkyl, substituted or unsubstituted 3-12 membered heterocycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, acyl group, ester group, amide group, sulfonyl group, sulfonamide group, boronic acid group, boronic acid ester group, phosphoryl group, or any two R 8 and atoms bonded thereto form a substituted or unsubstituted 5- to 9-membered alkenyl ring, a substituted or unsubstituted 5- to 9-membered heteroalkenyl ring, a substituted or unsubstituted benzene ring, or a substituted or unsubstituted 5- to 9-membered heteroaromatic ring, or an adjacent R 8 , R 9a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted 2- to 6-membered heteroalkyl group, a substituted or unsubstituted acyl group, a substituted or unsubstituted ester group, a substituted or unsubstituted amido group, a substituted or unsubstituted sulfonyl group, a substituted or unsubstituted sulfonamido group, a substituted or unsubstituted sulfinyl group, or a substituted or unsubstituted sulfinamido group, n1, n2, and n3 are each independently selected from 0, 1, 2, 3, 4, 5, and 6; n4 and n9 are each independently selected from 1, 2, and 3; L is a single bond, O, S, S(=O), S(=O)2, C(=O), or NR 10 , -(CR 11 R 12 )n5-, -S(=O)n6NR 13 -, -NR 14 S(=O)n7NR 15 -, -C(=O)NR 16 -, -NR 17 C(=O)NR 18 -, C2-C4 alkenylene, C2-C4 alkynylene; n5 is selected from 1, 2, 3, and 4, and n6 and n7 are independently selected from 0, 1, and 2, respectively;

[0013] R 10 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 are each independently selected from hydrogen, acyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl, substituted or unsubstituted 3- to 12-membered cycloalkyl group, substituted or unsubstituted 3- to 12-membered cycloalkyl group, and substituted or unsubstituted alkenyl; Or, R 11 , R 12 is independently selected at each occurrence from hydrogen, halogen, hydroxyl, and C1-C10 alkyl; where R 1 , R 2 , R 3 , R 4 , R 5 , R6 , R 7 , R 8 , R 9 , R 10 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 are each independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxy, cyano, -NH2, nitro, carboxyl, acyl, ester group, amide, aryl, heteroaryl, sulfinyl, sulfonyl, sulfonamide, and sulfinamide groups.

[0014] The "R 1 is, for each occurrence, independently selected from ..." means that R 1 If n1 is greater than 1, the number of different R 1 may be selected from the same or different groups. For example, when n1=2, one R 5 may be selected from substituted or unsubstituted alkyl groups, and another R 1 may be selected from halogen, or when n1=2, two R 1 may be selected from substituted or unsubstituted alkyl groups, as well as other similar situations. JPEG0007737734000002.jpg31170

[0015] "R 2 , R 3 and together constitute a substituted or unsubstituted C1-C6 alkyl group" means that R 2 and R 3 These two substituents are bonded together to form an alkyl group with two connecting ends, for example, -CH2CH2CH2-, -CH2CH2CH2CH2, etc., and the same applies to other similar situations. JPEG0007737734000003.jpg26170

[0016] Furthermore, Z2 is CR 8 and Z 1 , Z 3 are N or CR respectively. 8 are independently selected from Furthermore, Z 2 , Z 3 is CR 8 and Z 1 is N or CR 8 is selected from.

[0017] Furthermore, ring A is a substituted or unsubstituted 5- to 7-membered ring, and the heteroatom in ring A is selected from O, N, and S.

[0018] Furthermore, R 1 are each independently selected from hydrogen, halogen, cyano, =O, hydroxy, -NH2, carboxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2-7 membered heteroalkyl, substituted or unsubstituted 3-9 membered cycloalkyl, substituted or unsubstituted 3-9 membered heterocycloalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-10 membered heteroaryl, ester, acyl, amido, sulfinyl, sulfonyl, sulfonamide, and sulfinamido groups, or any two R 1 and the atoms bonded thereto form a substituted or unsubstituted 3- to 6-membered hydrocarbon ring, where R 1 the substituents are selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, cyano, amino, carboxyl, acyl, ester, amide, aryl, and heteroaryl groups; Furthermore, R 1 are each independently selected from hydrogen, halogen, cyano, ═O, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 7-membered heteroalkyl, substituted or unsubstituted 3- to 9-membered cycloalkyl, substituted or unsubstituted 3- to 9-membered heterocycloalkyl, or two R 1and the atoms bonded thereto form a substituted or unsubstituted 3- to 6-membered hydrocarbon ring, where R 1 The substituents are selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, and amino.

[0019] Furthermore, R 1 are each independently selected from hydrogen, halogen, ═O, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted 2- to 5-membered alkoxy group, a substituted or unsubstituted 3- to 6-membered cycloalkyl, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl, or two R 1 and the atoms attached thereto form a substituted or unsubstituted 3- to 6-membered cycloalkyl, where R 1 the substituents are selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, and amino; Furthermore, R 1 are each independently selected from hydrogen, halogen, ═O, halogen-substituted or unsubstituted C1-C4 alkyl groups, halogen-substituted or unsubstituted 3- to 6-membered cycloalkyl groups, or two R 1 and the atoms attached thereto form a substituted or unsubstituted 3- to 6-membered cycloalkyl;

[0020] Furthermore, R 1 are each independently selected from hydrogen, F, Cl, ═O, fluorine-substituted or unsubstituted C1-C4 alkyl groups, halogen-substituted or unsubstituted cyclopropyl groups, or two R 1 and the atoms to which they are attached constitute a substituted or unsubstituted cyclopropyl group.

[0021] JPEG0007737734000004.jpg32170 Furthermore, n1 is selected from 0, 1, 2, 3, and 4, and further selected from 0, 1, and 2.

[0022] The present invention further provides a compound having the structure shown in Formula II, or a tautomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable hydrate, solvate, or salt compound thereof: JPEG0007737734000005.jpg55170J, Y, and T represent a single bond, O, S, S(=O), S(=O)2, and CR, respectively. 21 R 22 , C=O, NR 23 are independently selected from

[0023] R 21 , R 22 , R 23 , R 24 are each independently selected from hydrogen, halogen, hydroxyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkenyl groups, or R 21 , R 22 and the atoms bonded thereto form a substituted or unsubstituted 3- to 6-membered cycloalkyl group, and R 21 , R 22 , R 23 , R 24 each substituent is independently selected from halogen, hydroxyl, —NH, an ester group, an acyl group, a C1-C4 alkyl group, and a 3- to 6-membered cycloalkyl group; Z 1 is N or CR 8 is selected from

[0024] R 8 is selected from hydrogen, halogen, nitro, cyano, hydroxyl, -NH2, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted 3-12 membered cycloalkyl, substituted or unsubstituted 3-12 membered heterocycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-9 membered heteroaryl group, acyl group, ester group, amide group, sulfonyl group, sulfonamide group, boronic acid group, boronic acid ester group, phosphoryl group, or R 8 , R24 and atoms bonded thereto constitute a substituted or unsubstituted 5- to 7-membered alkene ring, a substituted or unsubstituted 5- to 7-membered heteroalkene ring, a substituted or unsubstituted benzene ring, or a substituted or unsubstituted 5- to 7-membered heteroaromatic ring,

[0025] R 19 , R 20 are each independently selected from hydrogen, halogen, cyano, carboxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted 3-12 membered cycloalkyl, substituted or unsubstituted 3-12 membered heterocycloalkyl, substituted or unsubstituted C2-C10 alkenyl, acyl group, ester group, amide group, sulfonyl group, sulfonamide, or R 19 and R 20 together constitute =O, or R 19 and R 20 and the atoms bonded thereto form a substituted or unsubstituted 3- to 6-membered cycloalkyl group, or R 18 and R 19 a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted 2- to 6-membered heteroalkyl group, a substituted or unsubstituted acyl group, a substituted or unsubstituted ester group, a substituted or unsubstituted amido group, a substituted or unsubstituted sulfonyl group, a substituted or unsubstituted sulfonamido group, a substituted or unsubstituted sulfinyl group, or a substituted or unsubstituted sulfinamido group;

[0026] R 25 , R 26 , R 27 , R 28 is, at each occurrence, independently selected from hydrogen, halogen, cyano, hydroxyl, -NH2, carboxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted 3-12 membered cycloalkyl, substituted or unsubstituted 3-12 membered heterocycloalkyl acyl group, substituted or unsubstituted C2-C10 alkenyl group, acyl group, ester group, amide group, sulfonyl group, sulfonamide group, or R 25 , R 26together constitute =O, or R 27 , R 28 together constitute =O, or R 25 , R 26 and the atoms bonded thereto form a substituted or unsubstituted 3- to 6-membered cycloalkyl group, or R 27 , R 28 and the atoms bonded thereto form a substituted or unsubstituted 3- to 6-membered cycloalkyl group,

[0027] R 8 , R 19 , R 20 , R 25 , R 26 , R 27 , R 28 are independently selected from halogen, C1-C10 alkyl, 3- to 12-membered cycloalkyl, 2- to 10-membered heteroalkyl, 3- to 6-membered heterocycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, hydroxyl, cyano, -NH2, carboxyl, acyl, an ester group, an amide group, a phenyl group, a 5- to 9-membered heteroaryl group, sulfinyl, sulfonyl, sulfonamide, and sulfinamide groups; Furthermore, R 21 , R 22 are each independently selected from hydrogen, halogen, a hydroxyl group, a halogen-substituted or unsubstituted C1-C4 alkyl group, or R 21 , R 22 and the atoms attached thereto form a substituted or unsubstituted cyclopropyl group, and R 23 is selected from hydrogen and C1-C4 alkyl.

[0028] JPEG0007737734000006.jpg58170

[0029] Additionally, ring A is selected from the following substituted or unsubstituted groups: JPEG0007737734000007.jpg86170Further, ring A is selected from the following substituted or unsubstituted groups: In certain embodiments of the invention, ring A is selected from the following substituted or unsubstituted groups: JPEG0007737734000009.jpg47170

[0030] Furthermore, ring A is selected from the following substituted or unsubstituted groups: JPEG0007737734000010.jpg23170

[0031] Furthermore, L can be a single bond, S, S(=O), S(=O)2, C(=O), -(CR 11 R 12 )n5-, -C(=O)NR 16 -, C2-C4 alkynylene; Furthermore, L is selected from a single bond and a C2-C4 alkynylene group; In certain embodiments of the invention, L is a single bond.

[0032] The present invention further provides a compound having the structure of Formula III or Formula IV, or a tautomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable hydrate, solvate, or salt compound thereof: JPEG0007737734000011.jpg99170W 1 , W 2 are each independently selected from O, CH, CHF, CF, NH, and NCH, preferably O, CF, and CH; Z 1 is N or CR 8 is selected from

[0033] R 8 is selected from hydrogen, halogen, cyano, hydroxyl, -NH2, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2- to 5-membered alkoxy, substituted or unsubstituted 2- to 5-membered nitrogen-containing heteroalkyl group, substituted or unsubstituted 3- to 6-membered cycloalkyl, substituted or unsubstituted C2-C4 alkenyl, acyl group, ester group, amide group, boronic acid group, boronic acid ester group, or R8 , R 19 together form a substituted or unsubstituted C1-C2 alkyl group, a substituted or unsubstituted 2-membered heteroalkyl, or a substituted or unsubstituted ester group, JPEG0007737734000012.jpg56170Furthermore, R 8 is selected from H, F, -OH, -B(OH)2, or R 8 , R 19 and the atoms bonded thereto constitute the group shown below, JPEG0007737734000013.jpg15170 In a specific embodiment of the present invention, R 8 is selected from H and F. In certain embodiments of the present invention, R 24 is selected from hydrogen and halogen, preferably selected from H, F, Cl, and more preferably H.

[0034] Furthermore, R 25 , R 26 , R 27 , R 28 is, at each occurrence, independently selected from hydrogen, halogen, cyano, hydroxyl, -NH2, carboxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted 3- to 6-membered cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C2-C6 alkenyl, acyl, ester, amide, sulfonyl, sulfonamide, or R 25 , R 26 together constitute =O, or R 27 , R 28 together constitute =O, or R 25 , R 26 and the atoms bonded thereto form a substituted or unsubstituted 3- to 6-membered cycloalkyl group, or R 27 , R 28 and the atoms bonded thereto form a substituted or unsubstituted 3- to 6-membered cycloalkyl group, Furthermore, R 25 , R 26 , R 27 , R 28is, at each occurrence, independently selected from hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, acyl, ester group, or R 25 , R 26 together constitute =O, or R 27 , R 28 together constitute =O, or R 25 , R 26 and the atoms bonded thereto form a substituted or unsubstituted 3- to 6-membered cycloalkyl group, or R 27 , R 28 and the atoms bonded thereto form a substituted or unsubstituted 3- to 6-membered cycloalkyl group,

[0035] R 25 , R 26 , R 27 , R 28 are independently selected from halogen, C1-C6 alkyl, 3- to 6-membered cycloalkyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heterocycloalkyl, hydroxyl, cyano, -NH2, carboxyl, acyl, ester group, amide group, sulfinyl group, sulfonyl, sulfonamide, and sulfinamide; Furthermore, R 25 and R 27 is independently selected at each occurrence from hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted 3- to 6-membered cycloalkyl, acyl, and ester groups; R 26 , R 28 is H, Or, R 25 , R 26 together constitute =O, or R 27 , R 28 together constitute =O, or R 25 , R 26 and the atoms bonded thereto form a substituted or unsubstituted 3- to 6-membered cycloalkyl group, or R 27 , R 28and the atoms bonded thereto form a substituted or unsubstituted 3- to 6-membered cycloalkyl group, Furthermore, R 25 , R 26 , R 27 , R 28 is H.

[0036] Furthermore, R 19 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 7-membered heteroalkyl, acyl, and ester groups; R 20 is H or R 19 , R 20 together constitute =O, or R 19 , R 20 and the atoms bonded thereto form a substituted or unsubstituted 3- to 6-membered cycloalkyl group, or, or R 19 , R 8 are either of the above R 19 , R 8 It constitutes a group composed of:

[0037] Furthermore, R 19 , R 20 are both H, and R 19 , R 20 together constitute =O, or R 19 , R 20 and the atoms attached thereto comprise a substituted or unsubstituted cyclopropyl group; or, or R 19 , R 8 are either of the above R 19 , R 8 It constitutes a group composed of: Furthermore, R 19 , R 20 are both H.

[0038] Further, Ring B is selected from phenyl, naphthyl, a substituted or unsubstituted 5- to 10-membered heteroaryl group, an unsubstituted 3- to 9-membered cycloalkyl group, and a substituted or unsubstituted 3- to 9-membered heterocycloalkyl group; Further, Ring B is selected from substituted or unsubstituted 5- to 6-membered heteroaryl groups; Additionally, Ring B is selected from the following substituted or unsubstituted groups: Phenyl group, pyrimidinyl group, pyridyl group, pyrazinyl group, pyridinyl group, thienyl group, pyrazolyl group, imidazolyl group, oxazolyl group, thiazolyl group, triazolyl group, tetrazolyl group, thiadiazolyl group, oxadiazolyl group.

[0039] In certain embodiments of the present invention, Ring B is selected from a pyrimidinyl group, a pyridyl group, a pyridinyl group, a thiazolyl group, a triazolyl group, and an oxadiazolyl group, preferably a pyrimidinyl group, a pyridyl group, a pyriazinyl group, and a thiazolyl group, and more preferably a pyrimidinyl group.

[0040] Furthermore, R 7 is selected from hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C1-C6 alkyl, unsubstituted 2- to 7-membered heteroalkyl, substituted or unsubstituted 3- to 6-membered cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, acyl, ester, amide, sulfonyl, and sulfonamide groups, or two adjacent R 7 and the atoms to which they are bonded constitute a substituted or unsubstituted 3- to 6-membered hydrocarbon ring or a substituted or unsubstituted 3- to 6-membered heterohydrocarbon ring, and R 7 The heteroatoms in the heteroalkyl group, heterocycloalkyl group, heteroaryl group, and heterohydrocarbon ring are selected from one or more of N, O, and S,

[0041] Furthermore, R 7 are each independently selected from hydrogen, halogen, cyano, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted 2- to 7-membered oxygen-containing heteroalkyl group, a substituted or unsubstituted 2- to 7-membered nitrogen-containing heteroalkyl group, a substituted or unsubstituted 3- to 6-membered cycloalkyl group, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group, a sulfonamido group, or two adjacent R 7and the atoms bonded thereto form a substituted or unsubstituted 3- to 6-membered heterohydrocarbon ring, and R 7 are independently selected from halogen, C1-C6 alkyl, 3- to 6-membered cycloalkyl, 2- to 7-membered heteroalkyl, 3- to 6-membered heterocycloalkyl, hydroxy, cyano, -NH2, acyl, ester group, amide group, sulfinyl group, sulfonyl, sulfonamide, and sulfinamide, and n2 is selected from 0, 1, 2, 3, 4, and 5; JPEG0007737734000014.jpg58170

[0042] JPEG0007737734000015.jpg53170Furthermore, R 7 is selected from F, —OCH 3 , —CF 3 , —CH 3 , —OH, and cyano, and further, n 2 is 1.

[0043] Furthermore, R 5 is selected from substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted 3- to 6-membered cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl; R 5 the substituents are selected from halogen, C1-C6 alkyl, 3- to 6-membered cycloalkyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heterocycloalkyl, hydroxyl group, cyano group, amino group, acyl group, ester group, amide group, sulfinyl, sulfonyl, sulfonamide, and sulfinamide groups; Furthermore, R 5 is selected from substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyridyl, and substituted or unsubstituted pyrimidinyl, preferably substituted or unsubstituted phenyl; R 5 The substituents of R are selected from halogen or C1-C6 alkyl, and R 5 The substituents are selected from F, Cl, and C1-C4 alkyl.

[0044] Furthermore, R 2 , R 3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, -NH2, substituted or unsubstituted C1-C6 alkyl, unsubstituted 2- to 6-membered heteroalkyl group, substituted or unsubstituted 3- to 6-membered cycloalkyl group, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C2-C6 alkenyl, acyl group, ester group, amide group, sulfonyl group, sulfonamide group, or R 2 and R 3 together form a substituted or unsubstituted C3-C4 alkyl group or a substituted or unsubstituted 3- to 4-membered heteroalkyl group, and R 2 , R 3 are independently selected from halogen, C1-C6 alkyl, 3- to 6-membered cycloalkyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heterocycloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, hydroxyl, cyano, -NH2, nitro, carboxyl, acyl, ester group, amide group, sulfinyl group, sulfonyl, sulfonamide, and sulfinamide; R 4 is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C2-C4 alkenyl;

[0045] Furthermore, R 2 , R 3 are each hydrogen, cyano, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2-5 membered heteroalkyl, or R 2 , R 3 are independently selected from the group consisting of substituted or unsubstituted C3-C4 alkyl groups and substituted or unsubstituted 3- to 4-membered heteroalkyl groups; R 2 , R 3 each substituent is independently selected from halogen, hydroxyl, C1-C4 alkyl, 3- to 6-membered cycloalkyl, 2- to 4-membered heteroalkyl, 3- to 6-membered heterocycloalkyl, and C2-C4 alkenyl; R 4 is selected from hydrogen, methyl, JPEG0007737734000016.jpg69170Furthermore, R2 , R 3 The substituents of are each selected from F, Cl, and hydroxyl.

[0046] Furthermore, R 6 is selected from hydrogen, halogen-substituted or unsubstituted C1-C6 alkyl groups, and substituted or unsubstituted 3- to 6-membered cycloalkyl groups; Furthermore, R 6 is selected from hydrogen, fluorine-substituted or unsubstituted C1-C4 alkyl, and is preferably H. The compounds are selected from the following structures, or in the R or S configuration: JPEG0007737734000017.jpg39170JPEG0007737734000018.jpg247170JPEG0007737734000019.jpg239170JPEG00077377340 00020.jpg237170JPEG0007737734000021.jpg238170JPEG0007737734000022.jpg229170JPEG0007737734000023.jpg114170

[0047] The present invention further provides a pharmaceutical composition, wherein the active ingredient of the pharmaceutical composition is selected from one or a combination of two or more of any of the compounds of the present invention or their stereoisomers, solvates, hydrates, pharmaceutically acceptable salts, esters, cocrystals, N-oxides, isotope-labeled compounds, metabolites, and prodrugs.

[0048] The present invention further provides the use of a compound of the present application or a stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or co-crystal thereof in the preparation of a DHODH inhibitor.

[0049] The present invention further provides the use of a compound of the present application or a stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or co-crystal thereof in the preparation of a medicament for treating or preventing a fungal infection or a disease caused by a fungal infection.

[0050] The present invention further provides the use of the compound of the present application or a stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or co-crystal thereof in the preparation of a disinfectant.

[0051] Furthermore, the fungus is selected from one or more of the following organisms: Absidia, ACRemonium, Alternaria, Aspergillus, Bipolaris, Blastomyces, Blumeria, Cladosporium, Coccidioides, Colletotrichium, Curvularia, Encephalitozoon, Epicoccum, Epidermophyton, Exophiala, Exserohilum, Fusarium, Histoplasma, Leptosphaeria, MiCRosporum, Mycosphaerella, Neurospora, Paecilomyces, Penicillium, Phytophthora, Plasmopara, Pneumocystis, Pyricularia, Pythium, Puccinia, Rhizoctonia, Rhizomucor, Scedosporium, Scopula riopsis, Trichophyton, Trichosporon, Ustilago,

[0052] Furthermore, the fungus is selected from one or more of Aspergillus, Scedosporium, and Fusarium, preferably Aspergillus and / or Scedosporium, and more preferably Aspergillus.

[0053] Further, the fungus is selected from one or more of A. fumigatus, A. flavus, A. terreus, A. niger, A. lentulus, S. apiospermum, S. prolificans, and S. species.

[0054] Further, the fungus is selected from one or more of A. fumigatus, A. flavus, A. terreus, A. niger, and S. prolificans. Furthermore, the disease caused by fungal infection is selected from systemic fungal infection diseases and superficial fungal infection diseases.

[0055] Furthermore, the systemic fungal infection disease is selected from pulmonary aspergillosis, allergic bronchopulmonary aspergillosis, systemic aspergillosis, asthma, coccidioidomycosis, South American blastomycosis, sporotrichosis, pigmented yeast mycosis, dark nasal bacterial disease, blastomycosis, histoplasmosis, keloid plastomycosis, nintrananal mycosis, disseminated spore silk bacterial disease, cystic fibrosing fungal colonization, and sinusitis.

[0056] The superficial fungal disease is selected from tinea unguium, onychomycosis, and tinea pedis.

[0057] The present invention also provides intermediates for preparing the above compounds as follows, such as M-9, IM2, IM3, etc. The compounds or their analogs can be further synthesized using the intermediates.

[0058] The present invention also provides a method for preparing the compounds of the present invention, which method comprises preparing intermediate M-9. JPEG0007737734000024.jpg37170

[0059] M-7 and M-8 react to produce compound M-9, and the reaction type is selected from one or more of a substitution reaction, a condensation reaction, a reduction reaction, a free radical reaction, and a metal-catalyzed coupling reaction; R T4 is selected from halogen, an aldehyde group, and a halogen-substituted C1-C6 alkylsulfonate group (e.g., trifluoromethanesulfonate); R F1 , R F2represent functional groups which can be converted to form a cyclic structure with the atom bonded thereto, and are each independently selected from hydrogen, halogen, nitro, cyano, aldehyde, hydroxyl, carboxyl, substituted C1-C6 alkyl, substituted C1-C6 alkoxy, or substituted or unsubstituted hydroxysulfonyl, sulfoxide, ketone, amino, ester, amide, hydroxymethyl, and aminomethyl, wherein the substituents are selected from halogen, hydroxyl, carboxyl, and ester groups;

[0060] R N is selected from an amino group or a functional group convertible to an amino group, preferably an amino group, a nitro group, a carboxyl group, an ester group, or a halogen atom, and more preferably an amino group or a nitro group; R B is selected from hydrogen or a functional group convertible to hydrogen, and further selected from hydrogen, butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), benzyl (Bn), methoxybenzyl (PMB), and 2,4-methoxybenzyl (DMB); R 1 , R 9 , Z 1 , Z 2 , Z 3 , n1, n3, n4, and n9 are as defined in the compounds of the present invention.

[0061] Any reaction conditions that can form the ring structure of the present invention by connecting existing substituents such as hydrogen, halogen, nitro, cyano, aldehyde group, hydroxyl group, carboxyl group, substituted C1-C6 alkyl group, substituted C1-C6 alkoxy group, mercapto group, sulfone group, sulfoxide group, ketone group, amino group, ester group, amide group, hydroxymethyl group, aminomethyl, etc. can be applied to the present invention.

[0062] Furthermore, R T4 is selected from halogens, and R F1is selected from halogen, aldehyde group, ester group, sulfonyl chloride group, and hydroxymethyl group; R F2 is selected from hydrogen, hydroxymethyl.

[0063] In some embodiments of the present invention, M-7 and M-8 are first prepared by reacting R T4 to the NH of M-8 via Furthermore, R T4 is selected from F and Cl, and R F1 is selected from an aldehyde group, an ester group, a sulfonyl chloride group, and a hydroxymethyl group; R F2 is hydrogen and hydroxymethyl, Furthermore, R T4 The reaction conditions for coupling with NH of M-8 are to mix M-7, M-8, a base and a solvent and react them,

[0064] Furthermore, the base is selected from inorganic bases, preferably sodium carbonate and / or potassium carbonate, more preferably potassium carbonate; Further, the solvent is selected from one or more of DMSO, DMF, and toluene; Furthermore, the reaction temperature is 80-120°C, preferably 100°C. In some embodiments of the present invention, R F1 is an aldehyde group, and R F2 is hydrogen, and the ring-forming reaction step is as follows: JPEG0007737734000025.jpg48170

[0065] In some embodiments of the present invention, R F1 is hydroxymethyl and R F2 is hydroxymethyl, and the ring-forming reaction step is as follows: JPEG0007737734000026.jpg38170M-9'' undergoes a dehydration condensation reaction to produce M-9, and M-9'' then undergoes dehydration condensation with concentrated sulfuric acid to produce M-9-2.

[0066] In some embodiments of the present invention, M-7 and M-8 are simultaneously coupled to form a ring to give M-9 in a single reaction step.

[0067] Furthermore, R F1 is F and R F2 is hydroxymethyl and R T4 is selected from F, and the reaction process is as follows: JPEG0007737734000027.jpg28170M-7' and M-8' react with the action of a base to produce M-9-3, and the base is selected from KOH and / or NaOA.

[0068] Furthermore, the preparation of the compound of the present invention further includes the preparation of intermediate IM-2, the synthetic route of which is as follows: JPEG0007737734000028.jpg66170(1) Compound M-9 and IM-4 are reacted under the action of a base or a transition metal catalyst to produce M-10; (2) R in compound M-10 N Convert to -NH2, (3) Compound M-11 is reacted with S-5 in the presence of a base (e.g., NaH) or a reducing agent (e.g., sodium borohydride) to produce IM-2 (R 6 is H, this step is omitted), R T1 , R T5 are independently selected from halogen, an aldehyde group, and a halogen-substituted C1-C6 alkyl sulfonate group; R 6 , R 7 , n2 are as defined in the compounds of the present invention.

[0069] Conventional reaction conditions for converting substituents such as nitro, carboxyl, ester, and halogen groups to amino groups can all be applied to the present invention. For example, a nitro group can be converted to an amino group by reduction, and the reduction can be carried out under palladium-carbon catalytic hydrogenation conditions in the presence of hydrogen or in the presence of iron powder or zinc powder.

[0070] Furthermore, the base in step (1) is an inorganic base, preferably potassium carbonate and / or sodium carbonate, and the transition metal catalyst in step (1) is a palladium catalyst, further selected from one or more of tetraphenylphosphine palladium, palladium acetate, tris(dibenzylideneacetone)dipalladium, [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride, bis(triphenylphosphine)palladium dichloride, and t-BuXPhos-Pd-G3.

[0071] Further, by the action of a base, compounds IM-2 and IM-1 are converted into the compounds according to any one of claims 1 to 26, and the structure of compound IM-1 is as follows: JPEG0007737734000029.jpg36170 where, Lg 3 is selected from leaving groups, preferably halogen, C1-C6 alkoxy groups, and halogen-substituted C1-C6 alkylsulfonate groups; R 2 , R 3 , R 4 , R 5 , L is as defined in the compounds of the present invention.

[0072] Furthermore, the preparation of the compound of the present invention further includes the preparation of intermediate IM-3, the synthetic route of which is as follows: JPEG0007737734000030.jpg76170(1)M-9 R N Convert to -NH2, (2) M-12 and S-5 are reacted in the presence of a base (e.g., NaH) or a reducing agent (e.g., sodium borohydride) to produce M-13 (R 6is H, this step is omitted), (3) M-13 and IM-1 are reacted in the presence of a base or a condensing agent to form IM-3; Lg 3 is selected from leaving groups, preferably halogen, a C1-C6 alkoxy group, or a halogen-substituted C1-C6 alkylsulfonate group; R 2 , R 3 , R 4 , R 5 , L is as defined in the compounds of the present invention.

[0073] Further, the base in step (3) is N,N-diisopropylethylamine (DIEA), and the condensing agent in step (3) is selected from one or more of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), or O-(7-azabenzotriazol-1-yl)-N,N,N′,N′′-tetramethylurea hexafluorophosphate (HATU).

[0074] Furthermore, the compounds IM-3 and IM-4 are reacted under the action of a base to produce the compound according to any one of claims 1 to 26, and the structure of the compound IM-4 is as follows: JPEG0007737734000031.jpg26170where, R T1 is selected from halogen, C1 to C6 alkoxy, and halogen-substituted C1 to C6 alkylsulfonic acid ester groups.

[0075] JPEG0007737734000032.jpg32170 "Sinusitis" includes, but is not limited to, rhinosinusitis, maxillary sinus inflammation, frontal sinusitis, antral gastritis, sphenoid sinusitis, and the like.

[0076] Pharmaceutical compositions of the compounds of the invention or their stereoisomers, solvates, hydrates, pharmaceutically acceptable salts, or co-crystals may contain a pharmaceutically acceptable excipient.

[0077] "Pharmaceutically acceptable" in the present invention is meant to encompass any substance that does not interfere with the effectiveness of the biological activity of the active ingredient and that is not toxic to the host.

[0078] The pharmaceutically acceptable excipient of the present invention is a collective term for all additional materials other than the main drug in a pharmaceutical preparation. The excipient should have the following characteristics: (1) no toxic effects or side effects on the human body; (2) stable chemical properties and insensitive to temperature, pH, storage time, etc.; (3) no incompatibility with the main drug, resulting in no impact on the therapeutic efficacy or quality control of the main drug; and (4) no interaction with packaging materials. Examples of excipients in the present invention include, but are not limited to, fillers (diluents), lubricants (flow aids or anti-adherents), dispersants, wetting agents, binders, regulators, solubilizers, antioxidants, bacteriostats, emulsifiers, disintegrants, etc. Examples of binders include syrup, gum arabic, gelatin, sorbitol, astragalus gum, cellulose and its derivatives (e.g., microcrystalline cellulose, sodium carboxymethylcellulose, ethyl cellulose, or hydroxypropyl cellulose), pyromethyl cellulose, gelatin pulp syrup, starch slurry, polyvinylpyrrolidone, etc. Fillers include lactose, powdered sugar, dextrin, starch and its derivatives, cellulose and its derivatives, calcium sulfate (e.g., inorganic calcium salts, calcium phosphate, calcium phosphate, precipitated calcium carbonate, etc.), sorbitol, or glycine. Lubricants include finely powdered silica gel, magnesium stearate, talc powder, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol, etc. Disintegrants include starch and its derivatives (e.g., carboxymethyl starch, sodium starch glycolate, etc., pregelatinized starch, modified starch, hydroxypropyl starch, corn starch, etc.), polyvinylpyrrolidone, or microcrystalline cellulose. Wetting agents include sodium lauryl sulfate, water, alcohol, etc. Antioxidants include sodium sulfite, sodium bisulfite, sodium metabisulfite, butylbenzoic acid, etc. Bacteriostatic agents include 0.5% phenol, 0.3% cresol, 0.5% trichlorobutanol, etc. Modifiers include hydrochloric acid, citric acid, potassium (sodium) hydroxide, sodium citrate, buffers (including sodium dihydrogen phosphate, disodium phosphate), etc. Emulsifiers include polysorbate-80, sorbitan, Pranib F-68, oleyl esters, soybean phospholipids, etc.Solubilizers include polysorbate-80, bile, glycerin, and the like. The term "pharmaceutically acceptable salt" refers to a salt formed between the compound of the present invention and an acid or base, suitable for use as a drug salt. The above acids and bases are broadly defined as Lewis acids and Lewis bases. Acids suitable for salt formation include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0079] The method of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, but typical administration methods include, but are not limited to, oral, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.

[0080] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or is mixed with the following ingredients: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. For capsules, tablets, and pills, the dosage form may also contain a buffer.

[0081] Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as casings and other materials known in the art. They may also contain opacifying agents, and the release of the active compound or compounds of the mixture may be delayed in a certain part of the digestive tract. Examples of encapsulating materials that can be used include polymeric substances and waxy substances. If necessary, the active compound may be formed into a microencapsulated form with one or more of the above-mentioned excipients.

[0082] The liquid dosage form for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.In addition to the active compound, the liquid dosage form may contain an inert diluent such as water or other solvents used in the prior art, and solubilizers and emulsifiers include, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, or mixtures thereof.

[0083] Besides these inert diluents, compositions may also include adjuvants, such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0084] In addition to the active compound, suspensions may contain suspending agents such as, for example, ethoxylated isooctadecanol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum methoxide, agar, or mixtures thereof.

[0085] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions; suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0086] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalants. The active ingredient may be mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or sprays as required.

[0087] The compound of the present invention can also be used in an injection preparation, which is selected from a liquid injection preparation (water injection), a sterile powder for injection (powder injection), or an injection tablet (a die pad or press sheet prepared by a sterile manufacturing method, which is dissolved in water for injection immediately before use and used for subcutaneous or intramuscular injection).

[0088] In addition to the compound, the injectable powder contains at least an excipient, which is an ingredient intentionally added to a drug and should not have any pharmacological properties in the amount used, but contributes to the processing, dissolution or dissolution of the drug, delivery of the drug via the targeted drug delivery route, or stability.

[0089] "Substituted" means that a hydrogen atom in a molecule is replaced with another, different atom or molecule. "Membered" refers to the number of skeletal atoms that constitute the ring. In the present invention, a "single bond" refers to a situation where there is only one linking key, and may be understood as "none." JPEG0007737734000033.jpg21170

[0090] "Alkyl" refers to an aliphatic hydrocarbon group, and refers to a saturated hydrocarbon group. The alkyl moiety may be a straight-chain alkyl group or a branched alkyl group. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, butyl, pentyl, hexyl, and the like.

[0091] C1-Cn as used in the present invention includes C1 to C2, C1 to C3 ... C1 to Cn, where n is an integer greater than 1, and as a prefix of a substituent, indicates the minimum and maximum number of carbon atoms in the substituent, for example, "C1 to C6 alkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms.

[0092] The term "hydrocarbon ring" refers to a ring structure in which all of the ring skeleton is carbon atoms, and the carbon atoms may be joined by single or double bonds. The hydrocarbon ring includes saturated hydrocarbon rings, alkene rings, and aromatic ring structures. An "alkene ring" is a group that contains a carbon-carbon double bond in the ring backbone.

[0093] "Heteroalkyl" refers to an alkyl group containing heteroatoms, including, but not limited to, O, S, N, P, etc., and includes alkoxy, thioalkyl, aminoalkyl, etc. "Alkenyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon double bond. Alkenyl groups can be straight-chain or branched.

[0094] "Alkenylene" refers to a divalent hydrocarbon group, including straight or branched chains, containing one or more carbon-carbon double bonds, such as -CH=CH-, -CHCH=CH-, etc. When a compound of the present invention contains an alkenylene, the compound may exist in a pure E (entgegen) form, a pure Z (zusammen) form, or any mixture thereof. "Alkynyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond. The alkynyl group may be straight-chained or branched. JPEG0007737734000034.jpg16170

[0095] An "amide" is a chemical structure having the formula -C(O)NHR or NHC(O)R, and when there are two linked ends, the structure is -C(O)NH(CH)- or -NHC(O)(CH)-, where R is selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc., and a is a natural number.

[0096] A "sulfonyl" is a chemical structure having the formula -S(=O)R, and when there are two linked ends, the structure is -S(=O)(CH)-, where R is selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, etc., and a is a natural number.

[0097] A "sulfinyl" is a chemical structure having the formula -S(=O)R; when there are two linked ends, the structure is -S(=O)(CH)a-, where R is selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, etc., and a is a natural number.

[0098] A "sulfonamide" is a chemical structure having the formula -S(=O)2NHR or -NHC(O)R, or if two linked ends are present, the structure is -S(=O)2NH(CH2)a- or -NHS(=O)2(CH2)a-, where R is selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc., and a is a natural number.

[0099] A "sulfinamide" is a chemical structure having the formula -S(=O)NHR or -NHS(O)R, or if two linked ends are present, the structure is -S(=O)NH(CH2)a- or -NHS(=O)(CH2)a-, where R is selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc., and a is a natural number.

[0100] "Phosphoryl" is a chemical structure having the formula -P(=O)RR'; when there are two linked ends, the structure is -P(=O)R(CH2)a-, where R, R' are independently selected from alkyl, heteroalkyl, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, hydroxyl, amino, etc., and a is a natural number.

[0101] An "ester group" refers to a chemical structure having the formula -C(O)OR or -OC(O)R, and when there are two linked ends, the structure is -C(O)O(CH)- or -OC(O)(CH)-, where R is selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc., and a is a natural number.

[0102] "Acyl" refers to a chemical structure having the formula -C(O)R, and when there are two linked ends, the structure is -C(O)(CH)-, where R is selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc., and a is a natural number.

[0103] "Cycloalkyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent. For example, "C3-C6 cycloalkyl" means a C3 to C6 cycloalkyl. In the present invention, the cycloalkyl group may further include a non-aryl structure having an unsaturated bond on the ring skeleton. "Heterocycloalkyl" refers to a structure having at least one heteroatom cycloalkyl group in the ring backbone. Heteroatoms include, but are not limited to, O, S, N, P, Si, and the like.

[0104] "Ring" refers to any covalently closed structure, including, for example, a carbocyclic ring (e.g., aryl or cycloalkyl), a heterocyclic ring (e.g., heteroaryl or heterocycloalkyl), an aromatic group (e.g., aryl or heteroaryl), or a non-aromatic group (e.g., cycloalkyl or heterocycloalkyl). In the present invention, a "ring" may be monocyclic or polycyclic, and may be fused, spiro, or bridged. Typical heterocycloalkyl groups include, but are not limited to, the following structures: JPEG0007737734000035.jpg32170

[0105] "Aryl" refers to a planar ring having a delocalized pi-electron system and containing 4n+2 pi-electrons, where n is an integer. The aryl ring may be composed of 5, 6, 7, 8, 9, or more than 9 atoms. Aryl includes, but is not limited to, phenyl, naphthyl, phenanthryl, anthryl, fluorenyl, indenyl, and the like. Typical heteroaryl groups include, but are not limited to, the following structures: JPEG0007737734000036.jpg31170 "Halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0106] The alkyl group, heteroalkyl group, cyclic group, heterocyclic group, amino group, ester group, carbonyl group, amido group, sulfonyl group, phosphoryl group, boronic acid group, boric acid ester group, guanidyl group, acylguanidino group, aryl group, heteroaryl group, imino group, and the like described herein may be an unsubstituted alkyl group, heteroalkyl group, cyclic group, heterocyclic group, amino group, ester group, carbonyl group, amido group, sulfonyl group, phosphoryl group, boronic acid group, boric acid ester group, guanidyl group, acylguanidino group, aryl group, heteroaryl group, or imino group, or may be a substituted alkyl group, heteroalkyl group, cyclic group, heterocyclic group, amino group, ester group, carbonyl group, amido group, sulfonyl group, phosphoryl group, boronic acid group, boric acid ester group, guanidyl group, acylguanidino group, aryl group, heteroaryl group, or imino group.

[0107] In the above, unless otherwise specified, the term "substituted" means that the referenced group may be substituted with one or more additional groups, each of which is independently selected from alkyl, cycloalkyl, aryl, carboxyl, heteroaryl, heterocycloalkyl, hydroxyl, alkoxy, alkylthio, aryloxy, o=, guanidino, cyano, nitro, acyl, halogen, haloalkyl, amino, and the like.

[0108] The beneficial effects of the present invention are as follows: The present invention provides a series of compounds that have significant inhibitory effects on DHODH activity, providing a new scheme for treating diseases such as fungal infections in which DHODH is a therapeutic target, and can be used to prepare drugs for treating related diseases and agricultural fungicides, thereby having broad potential applications. [Brief explanation of the drawings]

[0109] [Figure 1] FIG. 1 shows the first experiment on survival rate in a mouse bloodstream infection model with Aspergillus fumigatus. [Figure 2]FIG. 2 shows a second experiment on survival rate in a mouse Aspergillus fumigatus bloodstream infection model. DETAILED DESCRIPTION OF THE INVENTION

[0110] The technical solutions of the present invention will be described clearly and completely below, but obviously, the described embodiments are not all embodiments but only a part of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments that can be obtained by those skilled in the art without any inventive efforts also belong to the protection scope of the present invention.

[0111] Reaction monitoring is performed using thin-layer chromatography (TLC) or liquid-phase mass spectrometry (LC-MS). The developer systems used for purification on silica gel columns or thin-layer preparative plates include, but are not limited to, dichloromethane / methanol, n-hexane / ethyl acetate, and petroleum ether / ethyl acetate. The volume ratio of the solvents is adjusted according to the polarity of the compounds, or by adding aqueous ammonia or triethylamine. The developer systems used for reverse-phase preparative purification include, but are not limited to, (a) water in phase A and acetonitrile in phase B, and (b) water in phase A and methanol in phase B. Unless otherwise specified in the examples, the reaction temperature is room temperature (20° C.-30° C.). Unless otherwise specified, the reagents used in the examples may be commercially available. In the present invention, the structure of a compound can be determined by mass spectrometry (MS) and / or nuclear magnetic resonance (NMR) 1 Determined by H NMR instrument. Chemical abbreviations have the following meanings:

[0112] DMF: N,N-dimethylformamide THF: tetrahydrofuran DIEA: N,N-diisopropylethylamine PE: Petroleum ether EA: Ethyl acetate DCM: dichloromethane HATU: O-(7-azobenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate DMSO: dimethyl sulfoxide Tol.: Toluene K2CO3: Potassium carbonate AcOH: acetic acid t-BuXPhos-Pd-G3: (2-dibutylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate t-BuONa: Sodium tert-butoxide 2-Ethoxyethanol: Ethoxyethanol ethylene glycol ether TBAB: tetrabutylammonium bromide

[0113] Example 1 Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(2-(5-fluoropyrimidin-2-yl)-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-8-yl)-2-oxoacetamide (T-1) JPEG0007737734000037.jpg124170JPEG0007737734000038.jpg40170

[0114] Step 1: Preparation of (Z)-2-(hydroxyimino)-3-oxo-3-phenylpropionate (A-2)

[0115] Compound A-1 (10.0 g, 52.1 mmol) and glacial acetic acid (20 mL) were added to a reaction flask. Then, a solution prepared from sodium nitrite (15.8 g, 229.2 mmol) and water (30 mL) was slowly added dropwise to the reaction mixture. The temperature was maintained between 0 and 10 °C during the addition. After 2 h, the addition was completed and the mixture was allowed to react at room temperature for 1 h. LC-MS analysis showed the reaction was complete. 20 mL of water was added, and the mixture was stirred for 1 h. The mixture was then suction filtered and the filter cake was washed with 15 mL of water. The resulting filter cake was dissolved in dichloromethane (20 mL), washed successively with water (2 × 30 mL) and saturated brine (2 × 30 mL), dried over anhydrous Na2SO4, and evaporated in vacuo to give 8.1 g of white solid product A-2. The yield was 70%.

[0116] Step 2: Preparation of diethyl 5-methyl-3-phenyl-1H-pyrrole-2,4-diethyldicarboxylate (A-3)

[0117] Zinc powder (7.4 g, 113.2 mmol), anhydrous sodium acetate (7.7 g, 93.9 mmol), ethyl acetoacetate (5.5 g, 42.3 mmol), and glacial acetic acid (2 mL) were added to a reaction flask and heated to 60 ° C in an oil bath. Next, a solution prepared from compound A-2 (8.1 g, 36.7 mmol) and glacial acetic acid (3 mL) was added to the reaction system in three portions. After 1 hour, the addition was completed, and the temperature was raised to 70 ° C. and the reaction was continued for 3 hours. After that, zinc powder (3.7 g, 56.6 mmol) was added and the reaction was continued for 1 hour. TLC showed that the reaction of the raw materials was complete. The reaction mixture was cooled to room temperature, filtered under suction, evaporated under vacuum, and added with toluene (1 mL) twice. The residue was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous Na2SO4. The crude product after evaporation was purified using a silica gel column to obtain 7.0 g of pink solid product A-3 in a 62% yield.

[0118] Step 3: Preparation of 1,5-dimethyl-3-phenyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester (A-4)

[0119] Sodium hydride (1.9 g, 47.5 mmol, 60%) and THF (28 mL) were added to the reaction flask. A solution of compound A-3 (7.0 g, 23.2 mmol) in THF (28 mL) was slowly added dropwise at 0 °C. After 1 h, the addition was stopped and the mixture was allowed to react at room temperature for 1 h. After that, the mixture was placed in an ice-water bath, and methyl iodide (8.3 g, 58.5 mmol) was slowly added. The mixture was allowed to react at room temperature for 18 h. LC-MS showed the reaction was complete. The reaction mixture was quenched with water, 1N hydrochloric acid solution (14 mL) was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous Na2SO4, and evaporated in vacuo to give 6.5 g of crude yellow solid product A-4. The yield was 89%.

[0120] Step 4: Preparation of 1,5-dimethyl-3-phenyl-1H-pyrrole-2,4-dicarboxylic acid (A-5)

[0121] Compound A-4 (6.5 g, 22.60 mmol) and ethanol (33 mL) were added to a reaction flask, and an aqueous solution (26 mL) of sodium hydroxide (9.000 g, 226.00 mmol) was added. The reaction mixture was heated to reflux for 18 hours. TLC showed complete reaction of the starting materials. The reaction mixture was evaporated under vacuum to remove the ethanol. The resulting residue was dissolved in water (10 mL) and cooled to 0 °C. The pH of the solution was adjusted to approximately 2 with concentrated hydrochloric acid. The solution was stirred below 10 °C for 1 hour, filtered under suction, and the filter cake was washed successively with water (10 mL) and petroleum ether (10 mL). It was then evaporated to dryness under vacuum below 60 °C to obtain 4.8 g of a gray solid product, A-5. The yield was 90%.

[0122] Step 5: Preparation of 1,2-dimethyl-4-phenyl-1H-pyrrole (A-6)

[0123] Compound A-5 (4.8 g, 18.5 mmol) and ethanolamine (13 mL) were added to a reaction flask, and the reaction mixture was purged with nitrogen gas and reacted at 175 °C for 1 hour. LC-MS showed the reaction was complete. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, and the crude product after vacuum evaporation was purified using a silica gel column to obtain 2.9 g of white solid product A-6. The yield was 91%.

[0124] Step 6: Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetyl chloride (A)

[0125] Compound A-6 (100 mg, 0.58 mmol) and DCM (2 mL) were added to a reaction flask, and oxalyl chloride (81 mg, 0.64 mmol) was slowly added at 0 °C. After the addition was completed, the reaction was allowed to proceed at room temperature for 1 hour. LC-MS showed that the reaction was complete. The resulting reaction mixture was used directly in the next reaction without further workup.

[0126] Step 7: Preparation of 2-(4-(5-fluoropyrimidin-2-yl)-piperazin-1-yl)-5-nitrobenzaldehyde (1-3)

[0127] Compound 1-1 (500 mg, 2.96 mmol), 1-2 (539 mg, 2.96 mmol), DMSO (3 mL), and potassium carbonate (613 mg, 4.44 mmol) were added to a reaction flask, and the reaction mixture was heated to 100°C, stirred, and reacted overnight. LC-MS showed that the reaction was complete. After cooling, the reaction mixture was diluted with water and filtered. The filter cake was dried to obtain 950 mg of product 1-3. The yield was 97%.

[0128] Step 8: Preparation of (Z)-N'-(2-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-5-nitrobenzylidene)-4-methylbenzenesulfonyl hydrazide (1-5)

[0129] Compound 1-3 (1.8 g, 5.43 mmol), 1-4 (1.1 g, 5.91 mmol), toluene (30 mL), and THF (20 mL) were added to a reaction flask, and the reaction mixture was stirred at room temperature and allowed to react overnight. TLC showed that the starting materials had reacted completely. After evaporating the reaction mixture under vacuum, 2.8 g of crude product 1-5 was obtained and used directly in the next reaction.

[0130] Step 9: Preparation of 2-(5-fluoropyrimidin-2-yl)-8-nitro-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indole (1-6)

[0131] Compound 1-5 (2.8 g, 5.6 mmol), toluene (50 mL), and NaH (60% in mineral oil, 1.3 g, 32.5 mmol) were added to a reaction flask, and the reaction mixture was heated to 130 °C and stirred for 1 h. LC-MS showed the reaction was complete. The mixture was cooled to room temperature, cooled in an ice bath, and quenched by dilution with water. The mixture was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, and evaporated in vacuo. Purification by silica gel column chromatography afforded 1.2 g of product 1-6. The yield for the two steps was 70%.

[0132] Step 10: Preparation of 2-(5-fluoropyrimidin-2-yl)-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-8-amine (1-7)

[0133] Compound 1-6 (80 mg, 0.25 mmol), methanol (20 mL), and Pd / C (50 mg) were added to a reaction flask, and the atmosphere was replaced with hydrogen gas. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. TLC showed that the reaction of the raw materials was complete. After filtration, the filtrate was evaporated under vacuum to obtain 70 mg of crude product 1-7, which was used directly in the next reaction.

[0134] Step 11: Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(2-(5-fluoropyrimidin-2-yl)-1,2,3,4,10,10a-hexahydropyrazine[1,2-a]indol-8-yl)-2-oxoacetamide (T-1)

[0135] Compound 1-7 (70 mg, 0.25 mmol), DCM (5 mL), and DIEA (95 mg, 0.74 mmol) were added to a reaction flask and cooled in an ice bath. Compound A (77 mg, 0.29 mmol) in DCM (1 mL) was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature overnight. LC-MS showed the reaction was complete. Water was added to the reaction mixture, and the mixture was extracted twice with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, evaporated in vacuo, and purified using a silica gel column to obtain 62 mg of product T-1. The yield was 50%.

[0136] LC-MS(ESI)m / z(M+H) + :511.2 1 H NMR(400MHz,DMSO-d6)δ10.09(s,1H),8.47(d,J=0.8Hz,2H),7.26-7.21(m,2H),7.16-7. 09(m,3H),6.86-6.83(m,1H),6.83~6.79(m,1H),6.39(d,J=8.4Hz,1H),6.09(s,1H),4.6 6-4.61(m,1H),4.58-4.52(m,1H),3.81(s,3H),3.66-3.60(m,1H),3.00(td,J=12.8,3.2 Hz,1H),2.94-2.83(m,2H),2.78(td,J=12.0,3.2Hz,1H),2.53-2.50(m,2H),2.32(s,3H).

[0137] Example 2 Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(2-(5-fluoropyrimidin-2-yl)-2,3,4,5,11,11a-hexahydro-1H-[1,4]diazepine[1,2-a]indol-9-yl)-2-oxoacetamide (T-2-a) and 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-2,3,4,5,11,11a-hexahydro-1H-[1,4]diazepine[1,7-a]indol-9-yl)-2-oxoacetamide (T-2-b) JPEG0007737734000039.jpg127170

[0138] Step 1: Preparation of 4-(2-formyl-4-nitrophenyl)-1,4-diaza-1-carboxylic acid butyl ester (2-2)

[0139] Compound 1-1 (2.0 g, 11.8 mmol), 2-1 (2.4 g, 12.0 mmol), DMSO (50 mL), and potassium carbonate (2.5 g, 18.1 mmol) were added to a reaction flask in this order, and the reaction mixture was heated to 100°C, stirred, and reacted overnight. LC-MS showed that the reaction was complete. After cooling, the reaction mixture was diluted with water and extracted with EA. The organic phases were combined, evaporated in vacuo, and purified on a silica gel column to obtain 4.0 g of product 2-2. The yield was 97%.

[0140] Step 2: Preparation of (Z)-4-(4-nitro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)-butyl-1,4-diaza-1-carboxylate (2-3)

[0141] Compound 2-2 (700 mg, 2.0 mmol), 1-4 (410 mg, 2.2 mmol), and toluene (10 mL) were added to the reaction flask in this order, and the reaction mixture was stirred at room temperature and allowed to react overnight. TLC showed that the starting materials had reacted completely. After evaporating the reaction mixture under vacuum, 1.1 g of crude product 2-3 was obtained and used directly in the next reaction.

[0142] Step 3: Preparation of 9-nitro-4,5,11,11a-tetrahydro-1H-[1,4]diaza[1,2-a]indole-2(3H)-carboxylic acid butyl ester (2-4-a) and 9-nitro-1,2,4,5,11,11a-hexahydro-3H-[1,4]diazepine[1,7-a]indole-3-carboxylic acid butyl ester (2-4-b).

[0143] Compound 2-3 (1.11 g, 2.14 mmol), toluene (50 mL), and NaH (515 mg, 12.88 mmol) were added to a reaction flask, and the reaction mixture was heated to 130 °C and stirred for 1 h. LC-MS showed the reaction was complete. The mixture was cooled to room temperature, cooled in an ice bath, and quenched by diluting with water. The mixture was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, evaporated in vacuo, and purified on a silica gel column to give 280 mg of product 2-4-a and 230 mg of product 2-4-b. The yields for the two steps were 42% and 34%, respectively.

[0144] Step 4: Preparation of 9-nitro-2,3,4,5,11,11a-hexahydro-1H-[1,4]diaza[1,2-a]indole hydrochloride (2-5-a)

[0145] Compound 2-4-a (280 mg, 0.84 mmol) and a solution of hydrogen chloride in 1,4-dioxane (2 mL) were added to a reaction flask, and the reaction mixture was stirred at room temperature for 1 hour. TLC showed that the starting material had reacted completely. 1,4-dioxane (20 mL) was added to dilute the mixture, and then the mixture was evaporated under vacuum to give 260 mg of crude product 2-5-a, which was used directly in the next reaction.

[0146] Step 5: Preparation of 2-(5-fluoropyrimidin-2-yl)-9-nitro-2,3,4,5,11,11a-hexahydro-1H-[1,4]diaza[1,2-a]indole (2-6-a)

[0147] Compound 2-5-a (260 mg, 0.85 mmol), DMF (3 mL), 2-chloro-5-fluoropyrimidine (140 mg, 1.06 mmol), and K2CO3 (760 mg, 5.50 mmol) were added to a reaction flask in this order. The reaction mixture was heated to 100 °C and stirred overnight. LC-MS analysis indicated the reaction was complete. After cooling to room temperature, water was added to the reaction mixture, followed by two extractions with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, evaporated in vacuo, and purified using a silica gel column to obtain 140 mg of product 2-6-a. The yield for the two steps was 50%.

[0148] Step 6: Preparation of 2-(5-fluoropyrimidin-2-yl)-2,3,4,5,11,11a-hexahydro-1H-[1,4]diazepine[1,2-a]indol-9-amine (2-7-a)

[0149] Compound 2-6-a (140 mg, 0.42 mmol), methanol (10 mL), and Pd / C (50 mg) were added to a reaction flask in this order. The atmosphere was replaced with hydrogen gas, and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. TLC showed that the starting materials had completely reacted. After filtration, the filtrate was evaporated under vacuum to obtain 120 mg of crude product 2-7-a, which was used directly in the next reaction.

[0150] Step 7: Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(2-(5-fluoropyrimidin-2-yl)-2,3,4,5,11,11a-hexahydro-1H-[1,4]diazepine[1,2-a]indol-9-yl)-2-oxoacetamide (T-2-a)

[0151] Compound 2-7-a (60 mg, 0.20 mmol), DCM (5 mL), and DIEA (130 mg, 1.00 mmol) were added to a reaction flask and cooled in an ice bath. A solution of compound A (75 mg, 0.29 mmol) in DCM (1 mL) was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature overnight. LC-MS showed the reaction was complete. Water was added to the reaction mixture, and the mixture was extracted twice with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, evaporated in vacuo, and purified using a thin-layer preparative plate to obtain 22 mg of product T-2-a. The yield was 21%.

[0152] LC-MS(ESI)m / z(M+H) + :525.2 1 H NMR(400MHz,DMSO-d6)δ10.06(s,1H),8.45(d,J=0.8Hz,2H),7.25~7.20(m,2H),7.16-7.09(m,3H) ),6.81-6.76(m,2H),6.31(d,J=8.8Hz,1H),6.09(s,1H),4.40(dd,J=14.0Hz,3.2Hz,1H),4.14-4 .05(m,1H),3.80(s,3H),3.67-3.56(m,2H),3.52-3.42(m,1H),3.21(dd,J=14.0,10.0Hz,1H),3. 04(dd,J=16.0,9.2Hz,1H),2.64-2.56(m,1H),2.56-2.50(m,1H),2.31(s,3H),1.98-1.84(m,2H).

[0153] Compound T-2-b was synthesized in the same manner as in steps 4 to 7 of Example 2.

[0154] LC-MS(ESI)m / z(M+H) + :525.2 1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),8.43(d,J=0.8Hz,2H),7.24-7.19(m,2H),7.15~ 7.08(m,3H),6.78-6.72(m,2H),6.24(d,J=8.4Hz,1H),6.08(s,1H),4.13-3.95(m,2H) ,3.86-3.81(m,1H),3.80(s,3H),3.76-3.70(m,1H),3.70-3.50(m,3H),3.07(dd,J=16 .0,8.8Hz,1H),2.85-2.76(m,1H),2.31(s,3H),2.06-1.99(m,1H),1.85-1.75(m,1H).

[0155] Example 3 Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazine[1,2-d][1,4]oxazin-8-yl)-2-oxoacetamide (T-3) JPEG0007737734000040.jpg94170

[0156] Step 1: Preparation of 8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-butylcarboxylate (3-3)

[0157] Compound 3-1 (680 mg, 3.15 mmol) and DMSO (10 mL) were added to a reaction flask, followed by the addition of 3-2 (500 mg, 3.15 mmol) and potassium hydroxide (530 mg, 9.45 mmol). The reaction mixture was purged with nitrogen gas, and the reaction mixture was heated to 60 °C and stirred overnight. LC-MS showed the reaction was complete. After cooling, water was added to the reaction mixture and extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous Na2SO4, and the crude product was evaporated in vacuo and purified on a silica gel column to give 650 mg of product 3-3. The yield was 61%.

[0158] Step 2: Preparation of 8-nitro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine hydrochloride (3-4)

[0159] Compound 3-3 (650 mg, 1.94 mmol) and 1,4-dioxane (3 mL) were added to a reaction flask. Then, a solution of hydrogen chloride in 1,4-dioxane (4 M in 1,4-dioxane, 10 mL) was added to the reaction mixture, and the reaction mixture was stirred and reacted at room temperature for 2 hours. TLC showed that the starting materials had reacted completely. After evaporating the reaction mixture under vacuum, 550 mg of crude product 3-4 was obtained, which was used directly in the next reaction without further purification.

[0160] Step 3: Preparation of 3-(5-fluoropyrimidin-2-yl)-8-nitro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine (3-5)

[0161] Compound 3-4 (550 mg, crude product) and DMF (10 mL) were added to a reaction flask, followed by the addition of 2-chloro-5-fluoropyrimidine (324 mg, 2.43 mmol) and potassium carbonate (840 mg, 6.08 mmol). The reaction mixture was purged with nitrogen gas, and the reaction mixture was heated to 100 °C and stirred overnight. LC-MS showed the reaction was complete. After cooling, water was added to the reaction mixture and extracted twice with ethyl acetate. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous Na2SO4, and evaporated under vacuum. The crude product was purified on a silica gel column to give 330 mg of product 3-5. The yield for the two steps was 51%.

[0162] Step 4: Preparation of 3-(5-fluoropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-amine (3-6)

[0163] Compound 3-5 (330 mg, 0.99 mmol) and methanol (10 mL) were added to a reaction flask, followed by the addition of Pd / C (66 mg). The reaction mixture was purged with nitrogen gas and then with hydrogen gas. The mixture was stirred at room temperature under a hydrogen atmosphere and allowed to react overnight. TLC showed that the starting materials had reacted completely. The reaction mixture was filtered, and the filtrate was evaporated under vacuum and purified on a silica gel column to obtain 150 mg of product 3-6. The yield was 50%.

[0164] Step 5: Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-oxoacetamide (T-3)

[0165] Compound 3-6 (50 mg, 0.17 mmol), DIEA (66 mg, 0.51 mmol), and DCM (3 mL) were added to a reaction flask. The reaction mixture was purged with nitrogen gas and cooled to 0 °C in an ice bath. A solution of compound A (52 mg, 0.20 mmol) in DCM (2 mL) was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred overnight. LC-MS showed the reaction was complete. Water was added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, and the crude product was evaporated in vacuo and purified on a thin-layer preparative plate to obtain 80 mg of product T-3. The yield was 91%.

[0166] LC-MS(ESI)m / z(M+H) + :527.2 1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),8.50(s,2H),7.25~7.20(m,2H),7.16-7.09 (m,3H),6.77-6.72(m,1H),6.68(dd,J=8.8,2.4Hz,1H),6.64(d,J=2.4Hz,1H),6.1 0(s,1H),4.65-4.51(m,2H),4.34(dd,J=10.8Hz,2.4Hz,1H),3.92(dd,J=10.8Hz, 8.8Hz,1H),3.84-3.76(m,4H),3.12-2.96(m,2H),2.72-2.55(m,2H),2.32(s,3H).

[0167] Examples 4 to 6: Preparation of Compounds T-4 to T-6 Using the preparation method of compound T-3, but using different raw materials (including using 1,2,3-trifluoro-5-nitrobenzene (4-2) instead of compound 3-2 in step 1 of Example 3, and using (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid butyl ester (5-1) and (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid butyl ester (6-1) instead of compound 3-1 in step 1 of Example 3), compounds T-4 to T-6 were obtained. The structural formulas, LC-MS and 1 The H-NMR data are shown in Table 1.

[0168] Table 1: Structures, LC-MS and NMR of Examples 4-6 1 H-NMR data JPEG0007737734000041.jpg91170JPEG0007737734000042.jpg116170

[0169] Example 7 Preparation of N-(3-(5-cyanopyrimidin)-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetamide (T-7) JPEG0007737734000043.jpg101170

[0170] Step 1: Preparation of 8-amino-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-butylcarboxylate (7-1)

[0171] Compound 3-3 (1 g, 2.99 mmol) and methanol (20 mL) were added to a reaction flask, followed by the addition of Pd / C (200 mg). The reaction mixture was purged with nitrogen gas and then with hydrogen gas. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. TLC showed that the reaction of the raw materials was complete. The reaction mixture was filtered, and the filtrate was evaporated under vacuum and purified on a silica gel column to obtain 850 mg of product 7-1. The yield was 93%.

[0172] Step 2: Preparation of butyl 8-(2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetamido-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (7-2)

[0173] Compound 7-1 (0.85 g, 2.79 mmol), DIEA (1.08 g, 8.37 mmol), and DCM (5 mL) were added to a reaction flask. The reaction mixture was purged with nitrogen gas and cooled to 0 °C in an ice bath. A solution of compound A (0.73 g, 2.79 mmol) in DCM (5 mL) was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 4 h. LC-MS showed the reaction was complete. Water was added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, and the crude product was evaporated in vacuo and purified using a silica gel column to obtain 1.20 g of product 7-2. The yield was 81%.

[0174] Step 3: Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-oxoacetamide (7-3)

[0175] Compound 7-2 (1.20 g, 2.26 mmol) and a dichloromethane solution (15 mL) were added to a reaction flask, and trifluoroacetic acid (5 mL) was added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature and reacted for 4 hours. TLC showed that the reaction of the raw materials was complete. The pH of the reaction mixture was adjusted to approximately 8 with saturated sodium bicarbonate solution, and an appropriate amount of water was added to the reaction mixture. The mixture was extracted three times with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, evaporated in vacuo, and purified using a silica gel column to obtain 900 mg of product 7-3. The yield was 92%.

[0176] Step 4: Preparation of N-(3-(5-cyanopyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetamide (T-7)

[0177] Compound 7-3 (50 mg, 0.12 mmol) and DMF (1 mL) were added to a reaction flask, followed by the addition of 7-4 (26 mg, 0.18 mmol) and potassium carbonate (50 mg, 0.36 mmol). The reaction mixture was purged with nitrogen gas, and the reaction mixture was heated to 100 °C and stirred overnight. LC-MS showed the reaction was complete. After cooling, water was added to the reaction mixture and extracted twice with ethyl acetate. The combined organic phases were washed with water, saturated brine, and dried over anhydrous Na2SO4. The crude product was evaporated in vacuo and purified on a thin-layer preparative plate to obtain 30 mg of product T-7. The yield was 48%.

[0178] LC-MS(ESI)m / z(M+H) + :534.2 1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.81(s,2H),7.24-7.21(m,2H),7.15~7.10(m ,3H),6.75(d,J=8.8Hz,1H),6.70-6.63(m,2H),6.11(s,1H),4.84-4.70(m,2H),4.36 (dd,J=10.8Hz,2.8Hz,1H),3.98-3.91(m,1H),3.89-3.83(m,1H),3.81(s,3H),3.26 -3.16(m,1H),3.09-2.99(m,1H),2.89-2.80(m,1H),2.67-2.58(m,1H),2.33(s,3H).

[0179] Examples 8-15: Preparation of Compounds T-8 to T-15 Compounds T-8 to T-15 were prepared using the method for preparing compound T-7, but with different starting materials (2-chloro-5-methoxypyrimidine (8-4), 2-chloro-5-(trifluoromethyl)pyrimidine (9-4), 2,4-dichloropyrimidine (10-4), 2-chlorothiazole-5-nitrile (12-4), 3,6-difluoropyridazine (13-4), 2,5-difluoropyridine (14-4), and 2-bromo-5-methyl-1,3,4-oxadiazole (15-4) were used instead of compound 7-4 in Step 4 of Example 7). Their structural formulas, LC-MS, and 1 H-NMR data are shown in Table 2.

[0180] Table 2: Structural formulas, LC-MS and chromatograms of Examples 8-15 1 H-NMR data JPEG0007737734000044.jpg220170JPEG0007737734000045.jpg177170

[0181] Example 16 Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-oxamide (T-16) JPEG0007737734000046.jpg40170JPEG0007737734000047.jpg34170

[0182] Step 1: Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoro-6-methoxy-1,6-methoxy-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-oxoacetamide (16-1)

[0183] Compound 7-3 (120 mg, 0.28 mmol), 2-chloro-5-fluoro-6-methoxy-1,6-dihydropyrimidine (45 mg, 0.28 mmol), DMF (3 mL), and potassium carbonate (154 mg, 1.11 mmol) were added to a reaction flask in this order. The reaction mixture was heated to 100 °C, stirred, and reacted overnight. LC-MS showed the reaction was complete. After cooling, the reaction mixture was diluted with water and extracted with EA. The organic phases were combined, spun dry in vacuo, and purified on a silica gel column to obtain 50 mg of product 16-1. The yield was 32%.

[0184] Step 2: Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-oxamide (T-16)

[0185] Compound 16-1 (30 mg, 0.05 mmol) and pyridine hydrochloride (300 mg) were added to a reaction flask, and the reaction system was protected by purging with nitrogen gas. The temperature was raised to 140 °C and the reaction was stirred for 30 minutes. TLC showed that the reaction of the raw materials was complete. The crude product was cooled to room temperature and separated and purified by reverse phase filtration (C-18 column) to obtain 15 mg of product T-16. The yield was 50%.

[0186] LC-MS(ESI)m / z(M+H) + :543.2 1 H NMR(400MHz,DMSO-d6)δ10.16(s,1H),7.66(s,1H),7.24-7.18(m,2H),7.15 ~7.09(m,3H),6.75~6.71(m,1H),6.67-6.63(m,1H),6.63~6.60(m,1H),6.0 9(s,1H),4.41-4.26(m,2H),4.26-4.21(m,1H),3.91-3.84(m,1H),3.79(s, 3H), 3.75-3.68 (m, 1H), 2.99-2.88 (m, 2H), 2.63-2.52 (m, 2H), 2.31 (s, 3H).

[0187] Example 17 Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-oxamide (T-17) JPEG0007737734000048.jpg40170

[0188] Compound 7-3 (110 mg, 0.26 mmol), 3-bromo-1-methyl-1H-1,2,4-triazole (82.5 mg, 0.50 mmol), THF (10 mL), sodium tert-butoxide (99 mg, 1.03 mmol), and t-BuXPhos-Pd-G3 (99 mg, 0.12 mmol) were added to a reaction flask in that order. The air in the reaction flask was purged with nitrogen gas. Under nitrogen protection, the reaction mixture was heated to 90 °C, stirred, and reacted overnight. LC-MS analysis indicated that approximately 30% of the starting material 7-3 was not completely reacted. After cooling, the reaction mixture was diluted with water and extracted with EA. The organic phases were combined, spun dry in vacuo, and purified on a thin-layer preparative plate to obtain 20 mg of product T-17. The yield was 15%.

[0189] LC-MS(ESI)m / z(M+H) + :512.2 1 H NMR(400MHz,DMSO-d6)δ10.17(s,1H),8.12(s,1H),7.24-7.20(m,2H),7.15~7.09(m,3H),6 .73(d,J=8.8Hz,1H),6.66(dd,J=8.8,2.4Hz,1H),6.62(d,J=2.4Hz,1H),6.10(s,1H),4.30 (dd,J=10.8Hz,2.4Hz,1H),3.98-3.85(m,3H),3.80(s,3H),3.77-3.72(m,1H),3.69(s,3H) ,3.08-2.99(m,1H),2.92-2.83(m,1H),2.69-2.61(m,1H),2.55-2.51(m,1H),2.32(s,3H).

[0190] Example 18 Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazolin-9-yl)-2-oxoacetamide (T-18) JPEG0007737734000049.jpg58170JPEG0007737734000050.jpg39170

[0191] Step 1: Preparation of 3-(hydroxymethyl)-4-(2-(methoxycarbonyl)-4-nitrophenyl)piperazine-1-carboxylic acid butyl ester (18-2)

[0192] Compound 18-1 (2.0 g, 10.0 mmol), 3-1 (2.2 g, 10.2 mmol), and N,N-dimethylformamide (12 mL) were added to a single-neck flask. Potassium carbonate (2.8 g, 20.3 mmol) was then added, and the reaction mixture was heated to 100 °C, stirred, and reacted overnight. TLC monitoring indicated the reaction was complete. After cooling, water (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL × 4). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous Na2SO4, and the crude product was evaporated in vacuo and purified by column chromatography to obtain 2.7 g of product 18-2. The yield was 68%.

[0193] Step 2: Preparation of 3-(hydroxymethyl)-4-(2-(hydroxymethyl)-4-nitrophenyl)piperazine-1-carboxylic acid butyl ester (18-3)

[0194] Compound 18-3 (500 mg, 1.3 mmol) and methanol (10 mL) were added to a reaction flask. The reaction mixture was purged with nitrogen gas and cooled in an ice bath. Sodium borohydride (239 mg, 6.3 mmol) was added in portions to the reaction mixture. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. TLC showed that the reaction of the starting material was complete. The mixture was diluted with water to quench the reaction, extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, evaporated in vacuo, and purified on a silica gel column to obtain 450 mg of product 18-3. The yield was 97%.

[0195] Step 3: Preparation of 9-nitro-1,2,3,4,4a,5-hexahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazacycloheptane (18-4)

[0196] Compound 18-3 (400 mg, 1.1 mmol) was added to a reaction flask, followed by the addition of concentrated sulfuric acid (3 mL). The reaction mixture was heated to 140 °C, stirred, and reacted for 30 min. LC-MS showed the reaction was complete. After cooling to room temperature, saturated aqueous sodium carbonate was slowly added to adjust the pH of the reaction to 8. The mixture was directly concentrated to dryness under reduced pressure, dispersed in DCM / MeOH (10 / 1), stirred for 10 min, and filtered under suction. The filtrate was evaporated under vacuum to give 440 mg of crude product 18-4, which was used directly in the next reaction without further purification.

[0197] Step 4: Preparation of 3-(5-fluoropyrimidin-2-yl)-9-nitro-1,2,3,4,4a,5-hexahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazacycloheptane (18-5)

[0198] Compound 18-4 (440 mg, crude product), DMF (6 mL), 2-chloro-5-fluoropyrimidine (428 mg, 3.24 mmol), and K2CO3 (448 mg, 3.24 mmol) were added to a reaction flask, and the reaction mixture was heated to 100 °C, stirred, and reacted for 4 h. LC-MS showed the reaction was complete. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, evaporated in vacuo, and purified on a silica gel column to give 175 mg of product 18-5. The yield for the two steps was 47%.

[0199] Step 5: Preparation of 3-(5-fluoropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazacycloheptan-9-amine (18-6)

[0200] Compound 18-5 (70 mg, 0.20 mmol), methanol (6 mL), aqueous ammonia (0.5 mL), and Pd / C (50 mg) were added to a reaction flask in this order. The atmosphere was replaced with hydrogen gas, and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. TLC showed that the reaction of the raw materials was complete. After filtration, the filtrate was evaporated in vacuo to obtain 50 mg of crude product 18-6, which was used directly in the next reaction.

[0201] Step 6: Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazolin-9-yl)-2-oxoacetamide (T-18)

[0202] Compound T-18 was synthesized in the same manner as in Step 11 of Example 1.

[0203] LC-MS(ESI)m / z(M+H) + :541.2 1 H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.49(s,2H),7.26-7.21(m,2H),7.16-7.05(m ,4H),6.91(d,J=2.4Hz,1H),6.85(d,J=8.8Hz,1H),6.11(s,1H),4.63(d,J=12.0Hz,1 H),4.45(d,J=12.0Hz,1H),4.18-4.08(m,2H),3.84(s,3H),3.72-3.67(m,1H),3.63 -3.53(m,2H),3.49-3.42(m,1H),3.34-3.28(m,2H),2.98-2.91(m,1H),2.33(s,3H).

[0204] Example 19 Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-6,6-dioxide-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]thiazin-8-yl)-2-oxamide (T-19) JPEG0007737734000051.jpg67170JPEG0007737734000052.jpg44170

[0205] Step 1: Preparation of 2-(allylsulfonyl)-1-chloro-4-nitrobenzene (19-2)

[0206] Compound 19-1 (500 mg, 1.95 mmol), NaSO (492 mg, 3.90 mmol), and water (8 mL) were added to a reaction flask, and the reaction mixture was heated to 100 °C with stirring and allowed to react for 1 hour. TLC monitoring showed that no raw materials remained. After the reaction mixture was cooled to room temperature, 3-bromopropylene (1.2 g, 9.92 mmol) and tetrabutylammonium bromide (39 mg, 0.12 mmol) were added to the reaction mixture, and the reaction mixture was heated to 70 °C with stirring and allowed to react overnight. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous NaSO, and the crude product was evaporated in vacuo and purified by column chromatography to obtain 260 mg of product 19-2. The yield was 51%.

[0207] Step 2: Preparation of 1-chloro-2-((2,3-dibromopropyl)sulfonyl)-4-nitrobenzene (19-3)

[0208] Compound 19-2 (260 mg, 1.0 mmol) and DCM (5 mL) were added to a reaction flask, the reaction mixture was purged with nitrogen gas, and a solution of bromine (319 mg, 2.0 mmol) in DCM (0.1 mL) was added dropwise to the reaction mixture, followed by stirring at room temperature overnight. TLC showed the reaction of the starting material was complete. The reaction mixture was evaporated in vacuo to give 418 mg of crude product 19-3, which was used directly in the next reaction without further purification.

[0209] Step 3: Preparation of 8-nitro-1,2,3,4,4a,5,6a,7-octahydrobenzo[b]pyrazino[1,2-d][1,4]thiazine 6,6-dioxide (19-4)

[0210] Compound 19-3 (418 mg, crude product) and ethylene glycol ether (5 mL) were added to a reaction flask, followed by ethylenediamine (240 mg, 4.0 mmol). The mixture was stirred at room temperature for 2 hours. TLC monitoring showed no remaining starting materials. The reaction mixture was heated to 135 °C, stirred, and reacted for 6 hours. LC-MS showed the reaction was complete. After cooling to room temperature, saturated sodium bicarbonate solution was added and stirred for 20 minutes. The mixture was directly concentrated to dryness under reduced pressure, dispersed in DCM / MeOH (10 / 1), stirred for 10 minutes, and filtered under suction. The filtrate was evaporated under vacuum. The resulting crude product was purified by column chromatography to obtain 133 mg of product 19-4. The yield was 47%.

[0211] Step 4: Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-6,6-dioxide-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]thiazin-8-yl)-2-oxamide (T-19) Compound T-19 was synthesized in the same manner as in steps 3 to 5 of Example 3.

[0212] LC-MS(ESI)m / z(M+H) + :575.2 1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),8.53(s,2H),7.55(d,J=2.4Hz,1H),7.27-7.19(m,3H),7. 15~7.06(m,4H),6.13(s,1H),4.70-4.63(m,1H),4.58-4.50(m,1H),4.11-4.04(m,1H),3.87(dd ,J=14.0Hz,2.4Hz,1H),3.84(s,3H),3.78-3.69(m,1H),3.47(dd,J=14.0Hz,12.0Hz,1H),3.21( dt,J=7.0,4.1Hz,1H),3.06(dd,J=12.8,10.8Hz,1H),2.94(td,J=12.0,3.2Hz,1H),2.34(s,3H).

[0213] Example 20 Preparation of (R)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-(3-(5-sulfanylpyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)acetamide (T-20) JPEG0007737734000053.jpg32170

[0214] Step 1: Preparation of 2-chloropyrimidine-5-sulfonamide (20-2)

[0215] Compound 20-1 (50 mg, 0.24 mmol) was added to a single-neck flask, followed by the addition of dichloromethane (1 mL) to dissolve the compound. The reaction mixture was cooled to 0 °C in an ice bath, and then 1,4-dioxane solution (1 mL, 0.4 M, Adams) was added and the mixture was allowed to react in an ice bath for 2 h. TLC monitoring showed the reaction was complete. Dilute hydrochloric acid was added dropwise to the reaction mixture to adjust the pH to 6. The solvent in the reaction mixture was spin-dried, and the crude product was separated and purified using a silica gel column for column chromatography to obtain 30 mg of the desired product 20-2. The yield was 66%.

[0216] Step 2: Preparation of (R)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-(3-(5-sulfanylpyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)acetamide (T-20)

[0217] Compound 20-2 (30 mg, 0.15 mmol) was added to a single-neck flask, followed by the addition of acetonitrile (3 mL) to dissolve the compound. Compound 20-3 (60 mg, 0.14 mmol) (prepared using the synthetic method for 7-3 in Example 7) and potassium carbonate (32 mg, 0.23 mmol) were added and the mixture was stirred at room temperature for 4 hours. TLC monitoring showed the reaction was complete. After spin-drying the solvent in the reaction system, water was added to the reaction system, followed by extraction with ethyl acetate three times. The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, and the crude product after vacuum evaporation was purified by column chromatography to obtain 53 mg of product T-20. The yield was 65%.

[0218] LC-MS(ESI)m / z(M+H) + :588.2 1 H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.70(s,2H),7.40(s,2H),7.26-7.20(m,2H),7. 17-7.09(m,3H),6.79-6.74(m,1H),6.71-6.63(m,2H),6.11(s,1H),4.84-4.72(m,2H), 4.37(dd,J=10.8,2.4Hz,1H),3.99-3.90(m,1H),3.89-3.81(m,1H),3.80(s,3H),3.24 -3.14(m,1H),3.07-2.99(m,1H),2.82(t,J=12.0,1H),2.67-2.56(m,1H),2.32(s,3H).

[0219] Example 21 Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-3-(5-fluoropyrimidin-2-yl)-5-oxo-1,2,3,4,4a,5,6,7-octahydrobenzo[f]pyrazino[1,2-a][1,4]diazepin-9-yl)-2-oxoacetamide (T-21) JPEG0007737734000054.jpg127170

[0220] Step 1: Preparation of 4-(butoxycarbonyl)-1-(2-cyano-4-nitrophenyl)piperazine-2-carboxylic acid (21-3)

[0221] Compound 21-1 (1.5 g, 6.51 mmol), compound 21-2 (1.6 g, 9.77 mmol), potassium carbonate (2.7 g, 19.53 mmol), and 1,4-dioxane (6 mL) were added to a reaction flask in this order, and the reaction mixture was heated to 80 °C and stirred overnight. LC-MS analysis showed the reaction was complete. After cooling, the reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous Na2SO4. The crude product obtained after vacuum evaporation was purified on a silica gel column to give 2.2 g of product 21-3. The yield was 90%.

[0222] Step 2: Preparation of 1-(butyl)3-methyl4-(2-cyano-4-nitrophenyl)piperazine-1,3-dicarboxylic acid (21-4)

[0223] Compound 21-3 (300 mg, 0.80 mmol) and DMF (1.5 M) were added to a reaction flask, followed by potassium carbonate (275 mg, 1.99 mmol). Iodomethane was added dropwise to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 4 hours. TLC showed that the reaction of the raw materials was complete. Water was poured into the reaction mixture, which was then extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous Na2SO4, and the crude product obtained after vacuum evaporation was purified on a silica gel column to give 271 mg of product 21-4. The yield was 87%.

[0224] Step 3: Preparation of 9-nitro-5-oxo-1,2,4a,5,6,7-hexahydrobenzo[f]pyrazino[1,2-a][1,4]diaza-3(4H)-butylcarboxylate (21-5)

[0225] Compound 21-4 (258 mg, 0.66 mmol) and THF (0.5 mL) were added to a reaction flask, followed by dropwise addition of borane in tetrahydrofuran (1 M in THF, 3.2 mL). The reaction mixture was stirred at room temperature for 6 hours. TLC showed complete conversion of the starting material. The reaction mixture was quenched by dropwise addition of methanol, stirred for 30 minutes, and then the solvent was removed by vacuum rotary evaporation. Potassium carbonate (274 mg, 1.98 mmol) and methanol (6 mL) were added to the resulting residue, and the reaction mixture was heated to reflux overnight. LC-MS showed the reaction was complete. After cooling, water was added to the reaction mixture and extracted twice with ethyl acetate. The combined organic phases were washed successively with water and saturated brine, dried over anhydrous Na2SO4, and the crude product obtained after vacuum evaporation was purified on a silica gel column to give 106 mg of product 21-5. The yield was 44%.

[0226] Step 4: Preparation of 9-nitro-2,3,4,4a,6,7-hexahydrobenzo[f]pyrazine[1,2-a][1,4]diaz-5(1H)-one hydrochloride (21-6)

[0227] Compound 21-5 (100 mg, 0.28 mmol) and a 1,4-dioxane solution of hydrogen chloride (4 M in 1,4-dioxane, 3 mL) were added to a reaction flask, and the reaction mixture was stirred at room temperature for 1 h. TLC showed that the reaction of the starting material was complete. After evaporating the reaction mixture under vacuum, 85 mg of crude product 21-6 was obtained, which was used directly in the next reaction without further purification.

[0228] Step 5: Preparation of 3-(5-fluoropyrimidin-2-yl)-9-nitro-2,3,4,4a,6,7-hexahydrobenzo[f]pyrazine[1,2-a][1,4]diaza-5(1H)-one (21-7)

[0229] Compound 21-6 (85 mg, crude product) and DMF (3 mL) were added to a reaction flask, followed by potassium carbonate (116 mg, 0.84 mmol) and 2-chloro-5-fluoropyrimidine (56 mg, 0.42 mmol). The reaction mixture was heated to 100 °C and stirred overnight. LC-MS showed the reaction was complete. After cooling, water was added to the reaction mixture and extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous Na2SO4, and the crude product was evaporated in vacuo and purified on a silica gel column to give 63 mg of product 21-7. The yield for the two steps was 63%.

[0230] Step 6: Preparation of 9-amino-3-(5-fluoropyrimidin-2-yl)-2,3,4,4a,6,7-hexahydrobenzo[f]pyrazine[1,2-a][1,4]diaza-5(1H)-one (21-8)

[0231] Compound 21-7 (60 mg, 0.17 mmol) and methanol (2 mL) were added to a reaction flask, followed by the addition of Raney-Ni (15 mg) and aqueous ammonia (3 drops). The reaction mixture was then purged with hydrogen gas three times. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. TLC showed that the reaction of the raw materials was complete. The reaction mixture was filtered, and the filtrate was evaporated under vacuum to obtain 40 mg of crude product 21-8, which was used directly in the next reaction without further purification.

[0232] Step 7: Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-5-oxo-1,2,3,4,4a,5,6,7-octahydrobenzo[f]pyrazino[1,2-a][1,4]diazepin-9-yl)-2-oxoacetamide (T-21)

[0233] Compound 21-8 (40 mg, crude), DCM (2 mL), and EtN (34 mg, 0.34 mmol) were added to a reaction flask. The reaction mixture was purged with nitrogen gas and then cooled to 0 °C in an ice-water bath. A solution of compound a (53 mg, 0.20 mmol) in DCM (2 mL) was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 1 h. LC-MS showed the reaction was complete. The reaction mixture was poured into water and extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous NaSO, and the crude product was evaporated in vacuo and purified on a thin-layer preparative plate to obtain 16 mg of product T-21. The yield for the two steps was 17%.

[0234] LC-MS(ESI)m / z(M+H) + :554.2 1 H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.51(d,J=0.4Hz,2H),8.33(dd,J=6.8, 4.4Hz,1H),7.23-7.19(m,2H),7.14-7.04(m,4H),6.97-6.92(m,2H),6.10(s, 1H),4.76-4.68(m,1H),4.59-4.49(m,2H),3.83(s,3H),3.60(dd,J=13.6,7.2 Hz,1H),3.31-3.26(m,2H),3.20-3.10(m,2H),3.09-3.00(m,1H),2.32(s,3H).

[0235] Example 22 Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(8-(5-fluoropyrimidin-2-yl)-6,6a,7,8,9,10-hexahydropyrazine[1,2-d]pyridyl[3,2-b][1,4]oxazin-3-yl)-2-oxamide (T-22) JPEG0007737734000055.jpg65170JPEG0007737734000056.jpg40170

[0236] Step 1: Preparation of 3-nitro-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido and [3,2-b][1,4]oxazine-8(6H)-butylcarboxylate (22-2)

[0237] Compound 3-1 (1.16 g, 5.36 mmol) and DMF (10 mL) were added to a reaction flask, followed by 22-1 (950 mg, 5.38 mmol) and potassium carbonate (2.23 g, 16.14 mmol). The reaction mixture was purged with nitrogen gas, heated to 80 °C, and stirred overnight. LC-MS showed the reaction was complete. After cooling, water was added to the reaction mixture and extracted twice with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous Na2SO4, and the crude product obtained after vacuum evaporation was purified on a silica gel column to give 160 mg of product 22-2. The yield was 9%.

[0238] Step 2: Preparation of 3-nitro-6,6a,7,8,9,10-hexahydropyrazine[1,2-d]pyrido and [3,2-b][1,4]oxazine trifluoroacetate (22-3)

[0239] Compound 22-2 (160 mg, 0.48 mmol) and dichloromethane (4 mL) were added to a reaction flask, followed by trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 2 hours. TLC showed that the reaction of the raw materials was complete. After evaporating the reaction mixture under vacuum, 200 mg of crude product 22-3 was obtained and used directly in the next reaction without further purification.

[0240] Step 3: Preparation of 8-(5-fluoropyrimidin-2-yl)-3-nitro-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido and [3,2-b][1,4]oxazine (22-4)

[0241] Compound 22-3 (200 mg, crude product) and DMF (5 mL) were added to a reaction flask, followed by potassium carbonate (199 mg, 1.44 mmol) and 2-chloro-5-fluoropyrimidine (96 mg, 0.72 mmol). The reaction mixture was purged with nitrogen gas, and the reaction mixture was heated to 100 °C and stirred overnight. LC-MS showed the reaction was complete. After cooling, water was added to the reaction mixture and extracted twice with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous Na2SO4, and evaporated in vacuo. The crude product obtained was purified on a silica gel column to give 130 mg of product 22-4. The yield for the two steps was 82%.

[0242] Step 4: Preparation of 8-(5-fluoropyrimidin-2-yl)-6,6a7,8,9,10-hexahydropyrazino[1,2-d]pyrido and [3,2-b][1,4]oxazin-3-amine (22-5)

[0243] Compound 22-4 (60 mg, 0.18 mmol), ethanol (2 mL), and water (0.5 mL) were added to a reaction flask, followed by the addition of NH4Cl (49 mg, 0.92 mmol) and iron powder (51 mg, 0.90 mmol). The reaction mixture was heated to 60 °C and stirred for 4 h. LC-MS showed the reaction was complete. After cooling, the reaction mixture was filtered under suction. The filtrate was evaporated under vacuum. The crude product was purified on a silica gel column to give 40 mg of product 22-5. The yield was 73%.

[0244] Step 5: Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(8-(5-fluoropyrimidin-2-yl)-6,6a,7,8,9,10-hexahydropyrazine[1,2-d]pyridyl[3,2-b][1,4]oxazin-3-yl)-2-oxamide (T-22)

[0245] Compound 22-5 (40 mg, 0.13 mmol), DCM (3 mL), and DIEA (50 mg, 0.39 mmol) were added sequentially to a reaction flask. The reaction mixture was purged with nitrogen gas and cooled to 0 °C in an ice bath. A solution of compound A (37 mg, 0.14 mmol) in DCM (1 mL) was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred overnight. LC-MS showed the reaction was complete. Water was added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, and the crude product was evaporated in vacuo and purified on a thin-layer preparative plate to obtain 20 mg of product T-22. The yield was 29%.

[0246] LC-MS (ESI) m / z (M+H) + :528.2 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.51 (s, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.25~7.20 (m, 2H), 7.19-7.10 (m, 3H), 6.81 (d, J = 2.0 Hz, 1H), 6.12 (s, 1H), 4.69-4.59 (m, 2H), 4.43~4.35 (m, 2H), 3.96 (dd, J = 10.8 Hz, 8.8 Hz, 1H), 3.83 (s, 3H), 3.34-3.26 (m, 1H), 3.05-2.95 (m, 1H), 2.75-2.65 (m, 2H), 2.33 (s, 3H).

[0247] Example 23 Preparation of (R)-N-(3-(5-(azetidin-1-yl)pyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetamide (T-23) JPEG0007737734000057.jpg69170

[0248] Step 1: Preparation of (R)-N-(3-(5-bromopyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetamide (23-2)

[0249] Compound 20-3 (400 mg, 0.93 mmol), 23-1 (215 mg, 1.11 mmol), potassium carbonate (385 mg, 2.79 mmol), and DMF (10 mL) were added to a reaction flask. The reaction mixture was purged with nitrogen gas and heated to 100 °C and stirred for 4 h. LC-MS showed the reaction was complete. After cooling, water was added to the reaction mixture and extracted twice with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous Na2SO4, and the crude product obtained after vacuum evaporation was purified using a silica gel column to obtain 400 mg of product 23-2. The yield was 73%.

[0250] Step 2: Preparation of (R)-N-(3-(5-azetidin-1-yl)pyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetamide (T-23)

[0251] Compound 23-2 (120 mg, 0.20 mmol), azetidine (35 mg, 0.61 mmol), cesium carbonate (196 mg, 0.60 mmol), and 1,4-dioxane (3 mL) were added sequentially to a sealed glass tube. The air in the reaction system was purged with nitrogen gas. Xantphos (24 mg, 0.04 mmol) and Pd2(dba)3 (19 mg, 0.02 mmol) were then added, and the reaction mixture was purged with nitrogen gas again. The reaction mixture was heated to 100 °C and stirred for 8 h. LC-MS showed the reaction was complete. After cooling, water was added to the reaction system and extracted twice with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous Na2SO4, and evaporated in vacuo. The resulting crude product was purified on a silica gel column to obtain 20 mg of crude product, which was then purified on a thin-layer preparative plate to obtain 7 mg of product T-23. The yield was 6%.

[0252] LC-MS (ESI) m / z (M+H) + :564.5 1 H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H),7.83 (s, 2H), 7.25~7.20 (m, 2H), 7.16-7.09 (m, 3H), 6.77-6.72 (m, 1H), 6.69-6.62 (m, 2H), 6.11 (s, 1H), 4.55-4.42 (m, 2H), 4.33 (dd, J = 10.8, 2.4 Hz, 1H), 3.96-3.89 (m, 1H), 3.81 (s, 3H), 3.80-3.74 (m, 4H), 3.34-3.31 (m, 1H), 3.01-2.88 (m, 3H), 2.61-2.55 (m, 1H), 2.32 (s, 3H), 2.35-2.27 (m, 2H).

[0253] Example 24 Preparation of (R)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-morpholinopyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-oxamide (T-24) JPEG0007737734000058.jpg32170 Compound T-24 was synthesized in the same manner as in Example 23.

[0254] LC-MS (ESI) m / z (M+H) + :594.3 1 H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.24 (s, 2H), 7.25~7.20 (m, 2H), 7.16-7.09 (m, 3H), 6.78-6.73 (m, 1H), 6.70-6.62 (m, 2H), 6.11 (s, 1H), 4.61-4.49 (m, 2H), 4.34 (dd, J = 10.8, 2.4 Hz, 1H), 3.96-3.89 (m, 1H), 3.81 (s, 3H), 3.76-3.71 (m, 3H), 3.38-3.30 (m, 4H), 3.04-2.99 (m, 4H), 2.99-2.93 (m, 1H), 2.62-2.55 (m, 1H), 2.33 (s, 3H).

[0255] Example 25 Preparation of (R)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(10-fluoro-3-(5-fluoropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-oxamide (T-24) JPEG0007737734000059.jpg105170 Compound t-25 was synthesized in the same manner as in Example 3.

[0256] LC-MS (ESI) m / z (M+H) + :545.2 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.50 (s, 2H), 7.22~7.17 (m, 2H), 7.16-7.09 (m, 3H), 6.62 (dd, J = 15.2, 2.4 Hz, 1H), 6.55~6.52 (m, 1H), 6.12 (s, 1H), 4.26 (dd, J = 10.8 Hz, 2.4 Hz, 1H), 4.16 (dd, J = 13.2 Hz, 3.2 Hz, 1H), 4.08-4.01 (m, 1H), 3.99-3.93 (m, 1H), 3.83 (s, 3H), 3.69-3.61 (m, 1H), 3.61-3.52 (m, 1H), 3.40 (dd, J = 13.2Hz, 8.0 Hz, 1H), 3.22-3.14 (m, 1H), 2.98 (ddd, J = 11.2, 8.4, 2.8 Hz, 1H), 2.33 (s, 3H).

[0257] Examples 26-27: Preparation of compounds T-26-T-27 Using the preparation method of compound T-18, but using different raw materials (instead of 3-(hydroxymethyl)piperazine-1-carboxylic acid butyl ester (3-1), which is the raw material in Step 1 of Example 18, (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid and (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid butyl ester were used), compounds T-26 to T-27 were obtained. Their structural formulas, LC-MS, 1 H-NMR data are shown in Table 3.

[0258] Table 3: Structures, LC-MS and NMR of Examples 26-27 1 H-NMR data JPEG0007737734000060.jpg142170

[0259] Example 28 Preparation of (R)-N-(3-(1,3,5-triazin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetamide (T-28) JPEG0007737734000061.jpg68170

[0260] Step 1: Preparation of (R)-N-(3-(4,6-dichloro-1,3,5-triazin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetamide (28-2)

[0261] Compound 20-3 (100 mg, 0.232 mmol) and THF (10 mL) were added to a reaction flask, the reaction mixture was purged with nitrogen gas, and the mixture was cooled to -78 °C. A solution of compound 28-1 (85 mg, 0.461 mmol) and DIEA (90 mg, 0.696 mmol) in DMSO (2 mL) was added dropwise to the reaction mixture, and the reaction mixture was stirred at -78 °C for 4 h. LC-MS showed the reaction was complete. After quenching with a 4 M solution of hydrogen chloride in 1,4-dioxane (4 M in 1,4-dioxane), the reaction mixture was slowly returned to room temperature. The crude product obtained after vacuum evaporation was purified on a silica gel column to obtain 50 mg of product 28-2. The yield was 37%.

[0262] Step 2: Preparation of (R)-N-(3-(1,3,5-triazin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetamide (T-28)

[0263] Compound 28-2 (80 mg, 0.086 mmol), ethanol (6 mL), anhydrous sodium acetate (14 mg, 0.171 mmol), and Pd / C (20 mg) were added to a reaction flask, and the mixture was purged with hydrogen gas. The reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere. TLC showed that the reaction of the raw materials was complete. After filtration, the filtrate was evaporated under vacuum. The crude product was purified by thin-layer preparative plate to obtain 20 mg of product T-28. The yield was 45%.

[0264] LC-MS (ESI) m / z (M+H) + :510.5 1 H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.63 (s, 2H), 7.25~7.20 (m, 2H), 7.17-7.09 (m, 3H), 6.79-6.74 (m, 1H), 6.71-6.63 (m, 2H), 6.11 (s, 1H), 4.76-4.65 (m, 2H), 4.35 (dd, J = 10.8, 2.8 Hz, 1H), 3.94 (dd, J = 10.8, 8.8 Hz, 1H), 3.89-3.82 (m, 1H), 3.81 (s, 3H), 3.19-3.10 (m, 1H), 3.06-2.98 (m, 1H), 2.83-2.74 (m, 1H), 2.65-2.56 (m, 1H), 2.33 (s, 3H).

[0265] Example 29 Preparation of N-((R)-3-(5-((R)-1,2-hydroxyethyl)pyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazine[1,2-d][1,4]oxazin-8-yl)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetamide (T-29) JPEG0007737734000062.jpg53170

[0266] Step 1: Preparation of (R)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-formylpyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-oxoacetamide (29-2)

[0267] Compound 20-3 (150 mg, 0.35 mmol) and DMF (4 mL) were added to a reaction flask, followed by compound 29-1 (53 mg, 0.37 mmol) and 1,8-diazabicyclo-7-ene (61 mg, 0.40 mmol). The reaction mixture was stirred at room temperature for 4 hours. TLC monitoring showed the reaction was complete. Saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product obtained after vacuum evaporation was purified on a silica gel column to obtain 155 mg of the desired product 29-2. The yield was 83%.

[0268] Step 2: Preparation of (R)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-(3-(5-vinylpyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)acetamide (29-3)

[0269] Compound 29-2 (150 mg, 0.28 mmol), 1,4-dioxane (5 mL), and water (1 mL) were added to a reaction flask. Then, methyltriphenylphosphonium bromide (118 mg, 0.33 mmol) and potassium carbonate (46 mg, 0.33 mmol) were added. The mixture was heated to reflux at 100 °C overnight, and TLC monitoring indicated the reaction was complete. The solvent in the reaction system was spin-dried, water was added to the reaction system, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product obtained after vacuum evaporation was purified on a silica gel column to obtain 75 mg of the desired product 29-3. The yield was 50%.

[0270] Step 3: Preparation of N-((R)-3-(5-((R)-1,2-hydroxyethyl)pyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazine[1,2-d][1,4]oxazin-8-yl)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetamide (T-29)

[0271] To the reaction flask, tert-butanol (2 mL) and water (2 mL) were added, followed by the addition of AD-mix-β (218 mg, 0.28 mmol). The reaction mixture was cooled to 0 °C in an ice-water bath. A solution of compound 29-3 (75 mg, 0.14 mmol) in tert-butanol (1 mL) was slowly added dropwise, followed by the addition of potassium osmate dihydrate (77 mg, 0.21 mmol). The reaction mixture was stirred at 0 °C for 2 h, then allowed to warm to room temperature and react overnight. TLC monitoring indicated the reaction was complete. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and quenched with aqueous sodium sulfite solution. The reaction mixture was stirred for 10 min and extracted three times with ethyl acetate. The organic phases were combined, evaporated in vacuo, and the crude product was purified by thin-layer preparative plate to obtain 26 mg of the desired product t-29. The yield was 33%.

[0272] LC-MS (ESI) m / z (M+H) + :569.3 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.35 (s, 2H), 7.25~7.21 (m, 2H), 7.17-7.10 (m, 3H), 6.78-6.74 (m, 1H), 6.68 (dd, J = 8.8, 2.4 Hz, 1H), 6.65~6.62 (m, 1H), 6.11 (s, 1H), 5.28 (d, J = 4.4, 1H), 4.76 (t, J = 5.6 Hz, 1H), 4.74-4.62 (m, 2H), 4.48-4.42 (m, 1H), 4.36 (dd, J = 10.8, 2.4 Hz, 1H), 3.97-3.89 (m, 1H), 3.85-3.77 (m, 1H), 3.81 (s, 3H), 3.54-3.48 (m, 1H), 3.44-3.37 (m, 1H), 3.09-2.93 (m, 2H), 2.70-2.64 (m, 1H), 2.61-2.53 (m, 1H), 2.33 (s, 3H).

[0273] Example 30 Preparation of N-((R)-3-(5-((R)-2,3-dihydroxypropoxy)pyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazine[1,2-d][1,4]oxazin-8-yl)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetamide (T-30) JPEG0007737734000063.jpg72170

[0274] Step 1: Preparation of (S)-2-chloro-5-((2,2-dimethyl-1,3-diox-4-yl)methoxy)pyrimidine (30-3)

[0275] Compound 30-1 (100 mg, 0.77 mmol), 30-2 (260 mg, 0.91 mmol), potassium carbonate (157 mg, 1.14 mmol), and acetonitrile (5 mL) were added to a reaction flask, and the reaction mixture was heated to 80 °C and reacted overnight. TLC monitoring indicated that the reaction was complete. After spin-drying the solvent in the reaction mixture, water was added and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained after vacuum evaporation was purified using a silica gel column to obtain 119 mg of the desired product 30-3. The yield was 63%.

[0276] Step 2: Preparation of N-((R)-3-(5-((((s)-2,2-dimethyl-1,3-diox-4-yl)methoxy)pyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazine[1,2-d][1,4]oxazin-8-yl)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetamide (30-4)

[0277] Compound 30-3 (90 mg, 0.37 mmol), 20-3 (155 mg, 0.36 mmol), cesium carbonate (352 mg, 1.08 mmol), and toluene (5 mL) were added to a reaction flask and dissolved. The air in the reaction flask was purged with nitrogen gas. Tris(dibenzylideneacetone)dipalladium (37 mg, 0.04 mmol) and 4,5-bis-diphenylphosphine-9,9-dimethylthioxanthene (46 mg, 0.08 mmol) were then added, and the atmosphere was purged with nitrogen gas twice. The reaction system was heated to 80 °C and reacted overnight. TLC monitoring indicated the reaction was complete. Water was added to the reaction system, and the system was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the crude product was evaporated in vacuo and purified on a silica gel column to obtain 15 mg of the desired product 30-4. The yield was 6%.

[0278] Step 3: Preparation of N-((R)-3-(5-((R)-2,3-dihydroxypropoxy)pyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazine[1,2-d][1,4]oxazin-8-yl)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetamide (T-30)

[0279] Compound 30-4 (15 mg, 0.023 mmol) was added to a reaction flask, followed by dichloromethane (1 mL) and trifluoroacetic acid (1 mL) dropwise, and the mixture was allowed to react at room temperature overnight. TLC monitoring indicated the reaction was complete. The solvent in the reaction system was spin-dried, water was added to the reaction system, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The crude product was evaporated under vacuum and purified on a thin-layer preparative plate to obtain 5 mg of the desired product, T-30. The yield was 36%.

[0280] LC-MS (ESI) m / z (M+H) + :599.5 1 H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.25 (s, 2H), 7.25~7.20 (m, 2H), 7.16-7.10 (m, 3H), 6.77-6.74 (m, 1H), 6.67 (dd, J = 8.8, 2.4 Hz, 1H), 6.64-6.62 (m, 1H), 6.11 (s, 1H), 5.00 (d, J = 4.8, 1H), 4.70 (t, J = 5.6 Hz, 1H), 4.61-4.48 (m, 2H), 4.34 (dd, J = 10.8, 2.4Hz, 1H), 4.05-4.00 (m, 1H), 3.96-3.87 (m, 2H), 3.81 (s, 3H), 3.79-3.72 (m, 2H), 3.03-2.94 (m, 2H), 2.64-2.56 (m, 2H), 2.32 (s, 3H).

[0281] Example 31 Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-6-methyl-1,2,3,4,4a,5,6,7-octahydrobenzo[f]pyrazino[1,2-a][1,4]diazepin-9-yl)-2-oxoacetamide (T-31) JPEG0007737734000064.jpg101170

[0282] Step 1: Preparation of 3-(5-fluoropyrimidin-2-yl)-8-nitro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine (31-1)

[0283] Compound 21-5 (120 mg, 0.33 mmol) and THF (5 mL) were added to a reaction flask, followed by dropwise addition of borane in tetrahydrofuran (5 mL) and the reaction was allowed to proceed overnight at room temperature. TLC showed that the reaction of the raw materials was complete. Methanol (10 mL) was slowly added to the reaction mixture, and the mixture was heated to reflux overnight. The reaction mixture was then directly concentrated to dryness to give 105 mg of crude product 31-1. The yield was 91%.

[0284] Step 2: Preparation of 3-(5-fluoropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-amine (31-2)

[0285] Compound 31-1 (105 mg, 0.30 mmol) and 1,2-dichloroethane (5 mL) were added to a reaction flask. Then, aqueous formaldehyde solution (37%-40% in water, 245 mg, 3.02 mmol) and formic acid (10 mg, 0.22 mmol) were added and the reaction mixture was stirred at room temperature for 1 hour. Triacetoxyborohydride (318 mg, 1.50 mmol) was added and the reaction mixture was stirred at room temperature overnight. LC-MS showed the reaction of the starting material was complete. The reaction mixture was quenched by adding an appropriate amount of water, neutralized with saturated aqueous Na2CO3, and extracted three times with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, and evaporated in vacuo to give 100 mg of crude product 31-2. The yield was 92%.

[0286] Step 3: Preparation of 6-methyl-9-nitro-1,2,3,4,4a,5,6,7-octahydrobenzo[f]pyrazino[1,2-a][1,4]diazonium hydrochloride (31-3)

[0287] Compound 31-2 (100 mg, 0.28 mmol) and 1,4-dioxane (2 mL) were added to a reaction flask, followed by a 1,4-dioxane solution of hydrogen chloride (4 M in 1,4-dioxane, 2 mL). The reaction mixture was stirred at room temperature for 1 hour. TLC showed that the reaction of the raw materials was complete. After evaporating the reaction mixture under vacuum, 70 mg of crude product 31-3 was obtained, which was used directly in the next reaction without further purification.

[0288] Step 4: Preparation of 3-(5-fluoropyrimidin-2-yl)-6-methyl-9-nitro-1,2,3,4,4a,5,6,7-octahydrobenzo[f]pyrazine[1,2-a][1,4]diazepine (31-4)

[0289] Compound 31-3 (70 mg) and DMF (3 m) were added to a reaction flask, followed by 2-chloro-5-fluoropyrimidine (53 mg, 0.40 mmol) and potassium carbonate (110 mg, 0.80 mmol). The reaction mixture was heated to 100 °C and stirred overnight. LC-MS showed the reaction was complete. After cooling, water was added to the reaction mixture, which was then extracted three times with ethyl acetate and dried over anhydrous Na2SO4. The combined organic phases were washed with water and saturated brine. The crude product was evaporated under vacuum and purified on a silica gel column to give 67 mg of product 31-4. The yield for the two steps was 68%.

[0290] Step 5: Preparation of 3-(5-fluoropyrimidin-2-yl)-6-methyl-1,2,3,4,4a,5,6,7-octahydrobenzo[f]pyrazino[1,2-a][1,4]diaza-9-amine (31-5)

[0291] Compound 31-4 (67 mg, 0.19 mmol) and methanol (2 mL) were added to a reaction flask, followed by the addition of Pd / C (7 mg). The mixture was purged with hydrogen gas three times and stirred overnight at room temperature under a hydrogen atmosphere. TLC showed that the reaction of the raw materials was complete. The reaction mixture was filtered, and the filtrate was evaporated under vacuum and purified by thin-layer preparative plate to obtain 37 mg of product 31-5. The yield was 60%.

[0292] Step 6: Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-6-methyl-1,2,3,4,4a,5,6,7-octahydrobenzo[f]pyrazino[1,2-a][1,4]diazepin-9-yl)-2-oxoacetamide (T-31)

[0293] Compound 31-5 (37 mg, 0.11 mmol), DCM (2 mL), and EtN (22 mg, 0.22 mmol) were added to a reaction flask and cooled to 0 °C in an ice-water bath. A solution of compound A (35 mg, 0.13 mmol) in DCM (2 mL) was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 1 h. LC-MS analysis showed the reaction was complete. The reaction mixture was poured into water and extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous NaSO, and the crude product was evaporated in vacuo and purified on a thin-layer preparative plate to obtain 20 mg of product T-31. The yield was 32%.

[0294] LC-MS (ESI) m / z (M+H) + :554.3 1 H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.47 (s, 2H), 7.25~7.21 (m, 2H), 7.15~7.06 (m, 3H), 7.01 (dd, J = 8.8, 2.4 Hz, 1H), 6.91-6.88 (m, 1H), 6.81-6.77 (m, 1H), 6.10 (s, 1H), 4.18-4.10 (m, 2H), 3.82 (s, 3H), 3.82-3.75 (m, 1H), 3.52-3.35 (m, 3H), 3.35-3.25 (m, 2H), 3.13-3.05 (m, 1H), 2.65-2.55 (m, 2H), 2.32 (s, 3H), 2.26 (s, 3H).

[0295] Example 32 Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinolin-8-yl)-2-oxoacetamide (T-32) JPEG0007737734000065.jpg124170

[0296] Step 1: Preparation of 4-(2-fluoro-5-nitrophenyl)-4-hydroxybutyl-2-oic acid ethyl ester (32-2)

[0297] Diisopropylamine (6.6 g, 65.2 mmol) was added to a dry three-neck flask, which was then purged with nitrogen gas. Anhydrous THF (80 mL) was added, and the reaction mixture was cooled to approximately -10 °C. butyllithium (2.5 M in hexane, 26 mL, 65.0 mmol) was added dropwise and stirred at this temperature for 0.5 hours. The reaction mixture was then cooled to -78 °C, and a solution of ethyl propionate (6.4 g, 65.2 mmol) in anhydrous THF (300 mL) was added dropwise. During the dropwise addition, the reaction mixture was stirred at -78 °C for 1 hour. Next, a solution of compound 32-1 (10.0 g, 59.1 mmol) in anhydrous THF (50 mL) was added dropwise to the reaction mixture. During the dropwise addition, the reaction mixture was stirred at -78 °C for 0.5 hours. TLC showed the reaction was complete. 1M diluted hydrochloric acid solution was prepared and added directly to the reaction system at -78 °C to adjust the reaction system to acidity. Then, the reaction system was returned to room temperature, and an appropriate amount of water was added to the reaction system. The reaction system was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product after vacuum evaporation was purified on a silica gel column to obtain 6.3 g of product 32-2. The yield was 40%.

[0298] Step 2: Preparation of (E)-4-(2-fluoro-5-nitrophenyl)-4-ethyloxo-2-enoic acid ethyl ester (32-3)

[0299] Compound 32-2 (2.0 g, 7.5 mmol) and 1,4-dioxane (20 mL) were added to a reaction flask, followed by dropwise addition of EtN (1.9 g, 18.8 mmol). The reaction mixture was heated to 60 °C, stirred, and reacted for 2 h. TLC showed the reaction was complete. After evaporating the reaction mixture under vacuum, the crude product was purified on a silica gel column to obtain 1.8 g of product 32-3. The yield was 90%.

[0300] Step 3: Preparation of 8-nitro-2,3,4a,5-tetrahydro-1H-pyrazino[1,2-a]quinoline-4,6-dione (32-4)

[0301] Ethylenediamine (225 mg, 3.7 mmol) and ethylene glycol diethyl ether (5 mL) were added to a reaction flask and dissolved. The reaction mixture was cooled to 0 °C. 32-3 (1.0 g, 3.74 mol) was added dropwise to the reaction mixture and stirred at this temperature for 10 minutes. The mixture was then heated to 60 °C and stirred for 2 hours, at which point a solid was formed. TLC showed the reaction was complete. The mixture was filtered under suction, and the filter cake was washed several times with petroleum ether. The filter cake was dried under vacuum to obtain 440 mg of product 32-4. The yield was 45%.

[0302] Step 4: Preparation of 8-nitro-2,3,5,6-tetrahydro-1H-pyrazino[1,2-a]quinolin-4(4aH)-one (32-5)

[0303] Compound 32-4 (200 mg, 0.77 mmol) and trifluoroacetic acid (5 mL) were added to a reaction flask, followed by triethylsilane (1.2 mL). The reaction mixture was stirred at room temperature overnight. TLC showed the reaction was complete. Saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under vacuum to give 187 mg of crude product 32-5, which was used directly in the next reaction.

[0304] Step 5: Preparation of 8-nitro-2,3,4,4a,5,6-hexahydro-1H-pyrazino and [1,2-a]quinoline (32-6)

[0305] Compound 32-5 (187 mg) and anhydrous THF (5 mL) were added to a dry three-neck flask, followed by the addition of BHTHF (1 M in THF, 2.3 mL, 2.3 mmol). The reaction mixture was heated to 66 °C, stirred, and allowed to react overnight. TLC showed the reaction was complete. The reaction mixture was cooled to room temperature, quenched by the addition of methanol, and stirred for 0.5 h. An appropriate amount of water was added, followed by extraction three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product obtained after evaporation in vacuo was purified on a silica gel column to give 158 mg of product 32-6. The yield for the two steps was 88%.

[0306] Step 6: Preparation of 3-(5-fluoropyrimidin-2-yl)-8-nitro-2,3,4,4a,5,6-hexahydro-1H-pyrazino and [1,2-a]quinoline (32-7)

[0307] Compounds 32-6 (100 mg, 0.43 mmol) and DMF (3 mL) were added to a reaction flask, followed by the addition of 2-chloro-5-fluoropyrimidine (171 mg, 1.29 mmol) and potassium carbonate (178 mg, 1.29 mmol). The reaction mixture was heated to 100 °C, stirred, and reacted for 5 h. TLC showed the reaction was complete. The reaction mixture was quenched with an appropriate amount of water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was evaporated in vacuo and purified using a silica gel column to obtain 50 mg of product 32-7. The yield was 35%.

[0308] Step 7: Preparation of 3-(5-fluoropyrimidin-2-yl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinolin-8-amine (32-8)

[0309] Compound 32-7 (50 mg, 0.15 mmol) and methanol (3 mL) were added to a reaction flask. Pd / C (10 mg) was then added, and the mixture was purged with hydrogen gas. The reaction mixture was stirred under a hydrogen atmosphere for 3 hours. TLC showed the reaction was complete. The mixture was filtered with suction, and the filtrate was evaporated under vacuum. The resulting crude product was purified by thin-layer preparative plate to give 35 mg of product 32-8. The yield was 77%.

[0310] Step 8: Preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinolin-8-yl)-2-oxoacetamide (T-32)

[0311] Compound 32-8 (35 mg, 0.12 mmol), DCM (2 mL), and DIEA (47 mg, 0.36 mmol) were added to a reaction flask and cooled to 0 °C in an ice-water bath. A solution of compound A (31 mg, 0.12 mmol) in DCM (1 mL) was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 3 h. TLC showed that the reaction was complete. The reaction mixture was poured into water and extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, and the crude product after vacuum evaporation was purified using a thin-layer preparative plate to obtain 38 mg of product T-32. The yield was 62%.

[0312] LC-MS (ESI) m / z (M+H) + :525.2 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.49 (s, 2H), 7.26-7.21 (m, 2H), 7.18-7.11 (m, 3H), 6.86-6.81 (m, 1H), 6.75~6.69 (m, 2H), 6.10 (s, 1H), 4.60-4.48 (m, 2H), 3.90-3.83 (m, 1H), 3.81 (s, 3H), 3.12-3.03 (m, 1H), 2.93-2.85 (m, 1H), 2.80-2.58 (m, 4H), 2.32 (s, 3H), 2.00-1.90 (m, 1H), 1.72-1.60 (m, 1H).

[0313] Example 33 Preparation of (S)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(2-(5-fluoropyrimidin-2-yl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-8-yl)-2-oxoacetamide (T-33) JPEG0007737734000066.jpg154170

[0314] Step 1: Preparation of (S)-dihydroindole-2-carboxylic acid methyl ester (33-2)

[0315] Compound 33-1 (2.0 g, 12.3 mmol) and methanol (20 mL) were added to a dry three-neck flask and cooled to 0 °C in an ice bath. Thionyl chloride (2.9 g, 24.4 mmol) was then added dropwise, and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. TLC showed the reaction was complete. The solvent was removed by concentration under reduced pressure to obtain 2.1 g of crude product 33-2, which was used directly in the next reaction.

[0316] Step 2: Preparation of (S)-1-acetyldihydroindole-2-carboxylic acid methyl ester (33-3)

[0317] Compound 33-2 (2.1 g) and acetic anhydride (20 mL) were added to a reaction flask, and EtN (2.4 g, 23.7 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. TLC showed the reaction was complete. Ethyl acetate was added to the reaction mixture, which was then washed with saturated sodium bicarbonate solution and saturated citric acid solution. The organic phase was dried over anhydrous sodium sulfate, and the crude product was evaporated under vacuum and purified on a silica gel column to give 2.2 g of product 33-3. The yield for the two steps was 82%.

[0318] Step 3: Preparation of (S)-1-acetyl-5-nitroindole-2-carboxylic acid methyl ester (33-4)

[0319] Compound 33-3 (2.0 g, 9.1 mmol) and acetic anhydride (20 mL) were added to a dry three-neck flask and cooled to 0 °C in an ice bath. Fuming nitric acid (0.8 m, 17.9 mmol) was added dropwise to the reaction mixture. During the addition, the reaction temperature was controlled below 5 °C. After the addition was completed, the mixture was returned to room temperature and stirred for 2 hours. TLC showed that the reaction was complete. The reaction mixture was quenched by adding ice water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was evaporated in vacuo and purified on a silica gel column to obtain 892 mg of product 33-4. The yield was 37%.

[0320] Step 4: Preparation of (S)-5-nitrodihydroindole-2-carboxylic acid methyl ester (33-5)

[0321] Compound 33-4 (890 mg, 3.4 mmol) and 1 M dilute hydrochloric acid solution (25 mL) were added to a reaction flask, and the reaction mixture was heated to 100 °C and refluxed for 2 hours. The solvent was removed by concentration under reduced pressure, and the mixture was dissolved in methanol (25 mL) and cooled to 0 °C in an ice bath. Thionyl chloride (3 mL) was then added dropwise, and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. TLC showed the reaction was complete. The solvent was removed by concentration under reduced pressure, and the resulting crude product was purified on a silica gel column to obtain 711 mg of product 33-5. The yield was 95%.

[0322] Step 5: Preparation of (S)-N-(2-hydroxyethyl)-5-nitroindole-2-carboxamide (33-6)

[0323] Compound 33-5 (700 mg, 3.2 mmol) and methanol (10 mL) were added to a reaction flask, followed by the addition of ethanolamine (770 mg, 12.6 mmol) and EtN (1.3 g, 12.8 mmol). The reaction mixture was heated to 66 °C and stirred for 5 h. TLC showed the reaction was complete. An appropriate amount of water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The crude product was evaporated in vacuo and purified on a silica gel column to give 632 mg of product 33-6. The yield was 80%.

[0324] Step 6: Preparation of (S)-2-(((5-nitroindol-2-yl)methyl)amino)ethan-1-ol (33-7)

[0325] Compound 33-6 (400 mg, 1.6 mmol) and anhydrous THF (40 mL) were added to a dry three-neck flask, followed by BHTHF (1 M in THF, 4.0 mL, 4.0 mmol). The reaction mixture was heated to 66 °C, stirred, and reacted for 0.5 h. TLC showed the reaction was complete. The reaction mixture was cooled to room temperature and quenched by adding methanol. After stirring for 10 min, the reaction mixture was concentrated to dryness under reduced pressure. The resulting crude product was purified on a silica gel column to give 337 mg of product 33-7. The yield was 89%.

[0326] Step 7: Preparation of (S)-(2-hydroxyethyl)((5-nitroindol)-2-yl)methyl)carbamate (33-8)

[0327] Compound 33-7 (300 mg, 1.3 mmol) and methanol (5 mL) were added to a reaction flask, followed by the addition of butyl dicarbonate (330 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 1 hour. TLC showed the reaction was complete. The solvent was removed by concentration under reduced pressure, and the resulting crude product was purified on a silica gel column to obtain 404 mg of product 33-8. The yield was 95%.

[0328] Step 8: Preparation of (S)-2-((butoxycarbonyl)((5-nitroindol)-2-yl)methyl)amino) 4-methylbenzenesulfonic acid (33-9)

[0329] Compound 33-8 (400 mg, 1.2 mmol), DCM (5 mL), EtN (180 mg, 1.8 mmol), and then toluenesulfonyl chloride (339 mg, 1.8 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added to a reaction flask. The mixture was stirred at room temperature for 5 hours. TLC showed the reaction was complete. An appropriate amount of water was added to the reaction mixture, and the mixture was extracted three times with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under vacuum to give 580 mg of crude product 33-9, which was used directly in the next reaction.

[0330] Step 9: Preparation of (S)-8-nitro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylic acid butyl ester (33-10)

[0331] Compound 33-9 (580 mg, 1.2 mmol) and DMF (5 mL) were added to a reaction flask, followed by potassium carbonate (329 mg, 2.4 mmol). The reaction mixture was heated to 40 °C, stirred, and reacted for 0.5 h. TLC showed the reaction was complete. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, evaporated in vacuo, and purified on a silica gel column to give 140 mg of product 33-10. The yield for the two steps was 37%.

[0332] Step 10: Preparation of (S)-8-nitro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (33-11)

[0333] Compound 33-10 (140 mg, 0.44 mmol) and 1,4-dioxane (2 mL) were added to a reaction flask, followed by a solution of hydrogen chloride in 1,4-dioxane (4 M in 1,4-dioxane, 3 mL). The reaction mixture was stirred at room temperature for 2 hours. TLC showed the reaction was complete. After evaporating the reaction mixture under vacuum, 110 mg of crude product 33-11 was obtained, which was used directly in the next reaction without further purification.

[0334] Step 11: Preparation of (S)-2-(5-fluoropyrimidin-2-yl)-8-nitro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole (33-12)

[0335] Compound 33-11 (110 mg, 0.43 mmol), DMF (5 mL), and potassium carbonate (182 mg, 1.3 mmol) were added to a reaction flask, followed by 2-chloro-5-fluoropyrimidine (175 mg, 1.3 mmol). The reaction mixture was heated to 100 °C, stirred, and reacted for 5 hours. TLC showed the reaction was complete. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was evaporated in vacuo and purified on a silica gel column to give 117 mg of product 33-12. The yield for the two steps was 85%.

[0336] Step 12: Preparation of (S)-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-8-amine (33-13)

[0337] Compound 33-12 (60 mg, 0.19 mmol) and methanol (3 mL) were added to a reaction flask, followed by the addition of Pd / C (15 mg). The mixture was purged with hydrogen gas and the reaction mixture was stirred under a hydrogen atmosphere for 1 hour. TLC showed the reaction was complete. The mixture was filtered with suction, and the filtrate was evaporated under vacuum. The resulting crude product was purified by thin-layer preparative plate to obtain 50 mg of product 33-13. The yield was 92%.

[0338] Step 13: Preparation of (S)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(2-(5-fluoropyrimidin-2-yl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-8-yl)-2-oxoacetamide (T-33)

[0339] Compound 33-13 (50 mg, 0.18 mmol), DCM (2 mL), and DIEA (70 mg, 0.54 mmol) were added to a reaction flask and cooled to 0 °C in an ice-water bath. A solution of compound A (52 mg, 0.20 mmol) in DCM (1 mL) was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 1 h. TLC showed that the reaction was complete. The reaction mixture was poured into water and extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, and the crude product after vacuum evaporation was purified using a thin-layer preparative plate to obtain 53 mg of product T-33. The yield was 59%.

[0340] LC-MS (ESI) m / z (M+H) + :511.2 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.48 (s, 2H), 7.26-7.22 (m, 2H), 7.17-7.09 (m, 3H), 6.87-6.84 (m, 1H), 6.84-6.80 (m, 1H), 6.40 (d, J = 8.4 Hz, 1H), 6.10 (s, 1H), 4.68-4.62 (m, 1H), 4.60-4.53 (m, 1H), 3.82 (s, 3H), 3.67-3.61 (m, 1H), 3.39-3.30 (m, 1H), 3.01 (td, J = 12.8, 3.2 Hz, 1H), 2.95-2.85 (m, 2H), 2.78 (td, J = 12.0, 3.2 Hz, 1H), 2.56-2.52 (m, 1H), 2.32 (s, 3H).

[0341] Example 34 Preparation of (R)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(2-(5-fluoropyrimidin-2-yl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-8-yl)-2-oxoacetamide (T-34) JPEG0007737734000067.jpg27170

[0342] Compound T-34 was prepared using the method for preparing compound T-33, but using a different starting material ((R)-dihydroindole-2-carboxylic acid (34-1) was used instead of (S)-dihydroindole-2-carboxylic acid (33-1), which was the starting material in Step 1 of Example 33).

[0343] LC-MS (ESI) m / z (M+H) + :511.2 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.48 (s, 2H), 7.26-7.22 (m, 2H), 7.17-7.09 (m, 3H), 6.87-6.85 (m, 1H), 6.84-6.80 (m, 1H), 6.40 (d, J = 8.4 Hz, 1H), 6.10 (s, 1H), 4.68-4.61 (m, 1H), 4.60-4.53 (m, 1H), 3.82 (s, 3H), 3.67-3.61 (m, 1H), 3.39-3.30 (m, 1H), 3.05-2.96 (m, 1H), 2.94-2.85 (m, 2H), 2.83-2.74 (m, 1H), 2.56-2.53 (m, 1H), 2.32 (s, 3H).

[0344] Example 35 Preparation of (R)-2-(3-(2-fluorophenyl)-1,5-dimethyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl-2-oxamide (T-35) JPEG0007737734000068.jpg91170

[0345] Step 1: Preparation of (Z)-3-(2-fluorophenyl)-2-(hydroxyimino)-3-oxopropionate (35-2)

[0346] Compound 35-1 (1.0 g, 4.8 mmol) and glacial acetic acid (2 mL) were added to a reaction flask. Then, a solution prepared from sodium nitrite (493 mg, 7.1 mmol) and water (3 mL) was slowly added dropwise to the reaction system. The temperature was maintained between 0 and 10 °C during the addition. After the addition was completed, the reaction was stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. 2 mL of water was added, and the mixture was stirred for 1 hour. After suction filtration, the filter cake was washed with 2 mL of water. The resulting filter cake was dissolved in dichloromethane (2 mL), washed successively with water and saturated brine, dried over anhydrous Na2SO4, and evaporated in vacuo to obtain 1.0 g of product 35-2. The yield was 88%.

[0347] Step 2: Preparation of 3-(2-fluorophenyl)-5-methyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester (35-3)

[0348] A reaction flask was charged with zinc powder (863 mg, 13.2 mmol), anhydrous sodium acetate (902 mg, 11.0 mmol), ethyl acetoacetate (640 mg, 4.9 mmol), and glacial acetic acid (4 mL). The mixture was heated to 60 °C in an oil bath. A solution prepared from compound 35-2 (1.0 g, 4.2 mmol) and glacial acetic acid (6 mL) was added to the reaction mixture in three portions. After the dropwise addition, the mixture was heated to 70 °C and stirred for 3 hours. Zinc powder (431 mg, 6.6 mmol) was added, and the reaction was continued for 1 hour. TLC showed that the reaction of the raw materials was complete. The reaction mixture was cooled to room temperature, filtered under suction, and the filtrate was evaporated under vacuum. The residue was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous Na2SO4. The crude product obtained after evaporation under vacuum was purified on a silica gel column to obtain 1.2 g of product 35-3. The yield was 90%.

[0349] Step 3: Preparation of 3-(2-fluorophenyl)-1,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid (35-4)

[0350] A reaction flask was charged with sodium hydride (60% in mineral oil, 150 mg, 3.8 mmol) and THF (10 mL). A solution of compound 35-3 (600 mg, 1.9 mmol) in THF (10 mL) was slowly added dropwise at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. The mixture was then placed in an ice-water bath, and iodomethane (667 mg, 4.7 mmol) was slowly added. The reaction mixture was allowed to react at room temperature overnight. LC-MS analysis indicated the reaction was complete. The reaction mixture was quenched with an appropriate amount of water, the solvent was removed by vacuum evaporation, and a solution of ethanol (3 mL) and sodium hydroxide (752 mg, 18.8 mmol) in water (2.5 mL) was added. The reaction mixture was heated to 100 °C and refluxed for 18 h. LC-MS analysis indicated the reaction was complete. After removing the ethanol by vacuum evaporation, an appropriate amount of water was added, and the mixture was cooled in an ice-water bath. The pH of the solution was adjusted to 2 with concentrated hydrochloric acid and maintained at 10°C or below for 1 hour. Then, the mixture was filtered by suction. The filter cake was washed with water and petroleum ether in turn, and the resulting solid was dried in vacuum to obtain 480 mg of product 35-4. The yield was 92%.

[0351] Step 4: Preparation of 4-(2-fluorophenyl)-1,2-dimethyl-1H-pyrrole (35-5)

[0352] Compound 35-4 (300 mg, 1.1 mmol) and ethanolamine (2 mL) were added to a reaction flask, and the atmosphere was purged with nitrogen gas. The reaction mixture was heated to 175 °C and stirred for 3 hours. LC-MS analysis showed the reaction was complete. The reaction mixture was cooled to room temperature, and an appropriate amount of water was added. The mixture was extracted twice with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous Na2SO4, and evaporated under vacuum at below 40 °C. The crude product was purified with neutral alumina to give 109 mg of product 35-5. The yield was 53%.

[0353] Step 5: Preparation of 2-(3-(2-fluorophenyl)-1,5-dimethyl-1H-pyrrol-2-yl)-2-oxoacetyl chloride (35-6)

[0354] Compound 35-5 (26 mg, 0.14 mmol) and DCM (2 mL) were added to a reaction flask, and oxalyl chloride (20 mg, 0.15 mmol) was slowly added at 0 °C. After the addition was completed, the mixture was allowed to react at room temperature for 1 h. LC-MS showed the reaction was complete. Direct concentration under reduced pressure gave 38 mg of product 35-6, which was used directly in the next reaction without further treatment.

[0355] Step 6: Preparation of (R)-2-(3-(2-fluorophenyl)-1,5-dimethyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-oxamide (T-35)

[0356] Compound 5-6 (35 mg, 0.12 mmol), DCM (1 mL), and EtN (24 mg, 0.24 mmol) were added to a reaction flask and cooled to 0 °C in an ice-water bath. A solution of compound 35-6 (38 mg, 0.14 mmol) in DCM (1 mL) was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 1 h. TLC showed the reaction was complete. The reaction mixture was poured into water and extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous NaSO, and the crude product was evaporated in vacuo and purified using a thin-layer preparative plate to obtain 24 mg of product T-35. The yield was 38%.

[0357] LC-MS (ESI) m / z (M+H) + :545.2 1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.50 (s, 2H), 7.21-7.11 (m, 2H), 7.03~6.96 (m, 1H), 6.93 (td, J = 12.8, 3.2 Hz, 1H), 6.77-6.73 (m, 1H), 6.70-6.65 (m, 1H), 6.65~6.62 (m, 1H), 6.11 (s, 1H), 4.64-4.52 (m, 2H), 4.34 (dd, J = 10.8, 2.4 Hz, 1H), 3.92 (dd, J = 10.8, 8.8 Hz, 1H), 3.82 (s, 3H), 3.82-3.77 (m, 1H), 3.10-2.95 (m, 2H), 2.72-2.52 (m, 2H), 2.32 (s, 3H).

[0358] Example 36 Preparation of (R)-2-(3-(3-fluorophenyl)-1,5-dimethyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-oxamide (T-36) JPEG0007737734000069.jpg95170

[0359] Step 1: Preparation of (Z)-3-(3-fluorophenyl)-2-(hydroxyimino)-3-oxopropionate (36-2)

[0360] Compound 36-1 (1.0 g, 4.8 mmol) and glacial acetic acid (2 mL) were added to a reaction flask. Then, a solution prepared from sodium nitrite (493 mg, 7.1 mmol) and water (3 mL) was slowly added dropwise to the reaction system. The temperature was maintained between 0 and 10 °C during the addition. After the addition was completed, the reaction was stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. 2 mL of water was added, and the mixture was stirred for 1 hour. After suction filtration, the filter cake was washed with 2 mL of water. The resulting filter cake was dissolved in dichloromethane (2 mL), washed successively with water and saturated brine, dried over anhydrous Na2SO4, and evaporated under vacuum to obtain 1.1 g of product 36-2. The yield was 97%.

[0361] Step 2: Preparation of 3-(3-fluorophenyl)-5-methyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester (36-3)

[0362] A reaction flask was charged with zinc powder (896 mg, 13.7 mmol), anhydrous sodium acetate (935 mg, 11.4 mmol), ethyl acetoacetate (664 mg, 5.1 mmol), and glacial acetic acid (4 mL). The mixture was heated to 60 °C in an oil bath. A solution prepared from compound 36-2 (1.1 g, 4.6 mmol) and glacial acetic acid (6 mL) was added to the reaction mixture in three portions. After the dropwise addition, the temperature was raised to 70 °C and the mixture was stirred for 3 h. Zinc powder (447 mg, 6.8 mmol) was added and the reaction was continued for 1 h. TLC showed that the reaction of the raw materials was complete. The reaction mixture was cooled to room temperature and filtered under suction. The filtrate was evaporated under vacuum, and the residue was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous Na2SO4. The crude product obtained after evaporation under vacuum was purified on a silica gel column to obtain 1.2 g of product 36-3. The yield was 82%.

[0363] Step 3: Preparation of 3-(3-fluorophenyl)-1,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid (36-4)

[0364] Sodium hydride (60% in mineral oil, 150 mg, 3.8 mmol) and THF (10 mL) were added to the reaction flask, and a solution of compound 36-3 (600 mg, 1.9 mmol) in THF (10 mL) was slowly added dropwise at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 1 h, then placed in an ice-water bath. Iodomethane (667 mg, 4.7 mmol) was slowly added, and the reaction mixture was allowed to react at room temperature overnight. LC-MS analysis showed the reaction was complete. The reaction mixture was quenched with an appropriate amount of water, the solvent was removed by vacuum evaporation, ethanol (3 mL) and a solution of sodium hydroxide (752 mg, 18.8 mmol) in water (2.5 mL) were added, and the reaction mixture was heated to 100 °C and refluxed for 18 h. LC-MS analysis showed the reaction was complete. After removing the ethanol by vacuum evaporation, an appropriate amount of water was added, and the mixture was cooled in an ice-water bath. The pH of the solution was adjusted to 2 with concentrated hydrochloric acid, and the solution was kept below 10°C for 1 hour. Then, the mixture was filtered under suction. The filter cake was washed with water and petroleum ether in turn, and the resulting solid was dried under vacuum to obtain 500 mg of product 36-4. The yield was 96%.

[0365] Step 4: Preparation of 4-(3-fluorophenyl)-1,2-dimethyl-1H-pyrrole (36-5)

[0366] Compound 36-4 (300 mg, 1.1 mmol) and ethanolamine (2 mL) were added to a reaction flask, and the atmosphere was purged with nitrogen gas. The reaction mixture was heated to 175 °C, stirred, and reacted for 3 hours. LC-MS showed the reaction was complete. The reaction mixture was cooled to room temperature, and an appropriate amount of water was added. The mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous Na2SO4, and evaporated under vacuum at below 40 °C. The crude product was purified with neutral alumina to give 133 mg of product 36-5. The yield was 65%.

[0367] Step 5: Preparation of 2-(3-(3-fluorophenyl)-1,5-dimethyl-1H-pyrrol-2-yl)-2-oxoacetyl chloride (36-6)

[0368] Compound 36-5 (25 mg, 0.13 mmol) and DCM (2 mL) were added to a reaction flask, and oxalyl chloride (20 mg, 0.15 mmol) was added slowly at 0 °C. After the addition was completed, the mixture was allowed to react at room temperature for 1 h. LC-MS showed that the reaction was complete. Direct concentration under reduced pressure gave 36 mg of product 36-6, which was used directly in the next reaction without further treatment.

[0369] Step 6: Preparation of (R)-2-(3-(3-fluorophenyl)-1,5-dimethyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-oxamide (T-36)

[0370] Compound 5-6 (33 mg, 0.11 mmol), DCM (1 mL), and EtN (22 mg, 0.22 mmol) were added to a reaction flask and cooled to 0 °C in an ice-water bath. A solution of compound 36-6 (36 mg, 0.13 mmol) in DCM (1 mL) was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 1 h. TLC showed the reaction was complete. The reaction mixture was poured into water and extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous NaSO, and evaporated in vacuo. The crude product was purified on a thin-layer preparative plate to obtain 18 mg of product T-36. The yield was 30%.

[0371] LC-MS (ESI) m / z (M+H) + :545.2 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.49 (s, 2H), 7.18-7.11 (m, 1H), 7.06-6.97 (m, 2H), 6.96-6.89 (m, 1H), 6.79-6.74 (m, 1H), 6.73~6.65 (m, 2H), 6.14 (s, 1H), 4.65-4.52 (m, 2H), 4.34 (dd, J = 10.8, 2.4 Hz, 1H), 3.97-3.89 (m, 1H), 3.85-3.81 (m, 1H), 3.81 (s, 3H), 3.11-2.96 (m, 2H), 2.72-2.53 (m, 2H), 2.31 (s, 3H).

[0372] Example 37 Preparation of (R)-2-(3-(4-fluorophenyl)-1,5-dimethyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-oxamide (T-37) JPEG0007737734000070.jpg65170JPEG0007737734000071.jpg33170

[0373] Step 1: Preparation of (Z)-3-(4-fluorophenyl)-2-(hydroxyimino)-3-oxopropionate (37-2)

[0374] Compound 37-1 (1.4 g, 6.7 mmol) and glacial acetic acid (4 mL) were added to a reaction flask. Then, a solution prepared from sodium nitrite (1.9 g, 27.5 mmol) and water (6 mL) was slowly added dropwise to the reaction system. The temperature was maintained between 0 and 10 °C during the addition. After the addition was completed, the temperature was maintained between 0 and 10 °C and the reaction was stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. 4 mL of water was added, and the mixture was stirred for 1 hour. The mixture was then suction filtered and the filter cake was washed with 5 mL of water. The resulting filter cake was dissolved in dichloromethane (5 mL), washed successively with water and saturated brine, dried over anhydrous Na2SO4, and evaporated in vacuo to give 1.6 g of crude product 37-2.

[0375] Step 2: Preparation of 3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester (37-3)

[0376] A reaction flask was charged with zinc powder (1.3 g, 19.9 mmol), anhydrous sodium acetate (1.4 g, 17.1 mmol), ethyl acetate acetoacetate (1.1 g, 8.5 mmol), and glacial acetic acid (5 mL). The mixture was placed in an oil bath and heated to 60 °C. A solution prepared from compound 37-2 (1.6 g, 6.7 mmol) and glacial acetic acid (5 mL) was then added in three portions. After the addition was complete, the temperature was raised to 70 °C and the mixture was stirred for 3 hours. Zinc powder (661 mg, 10.1 mmol) was then added and the reaction was continued for 1 hour. TLC showed that the reaction of the raw materials was complete. The reaction mixture was cooled to room temperature and filtered under suction. The filtrate was evaporated under vacuum and dried over anhydrous Na2SO4. The residue was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine. The crude product after evaporation was purified on a silica gel column to obtain 1.2 g of product 37-3. The yield for the two steps was 56%.

[0377] Step 3: Preparation of 3-(4-fluorophenyl)-1,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid (37-4)

[0378] Sodium hydride (60% in mineral oil, 602 mg, 15.0 mmol) and THF (10 mL) were added to a reaction flask, and a solution of compound 37-3 (1.2 g, 3.8 mmol) in THF (10 mL) was slowly added dropwise at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. The mixture was then placed in an ice-water bath, and methyl iodide (2.7 g, 19.0 mmol) was slowly added. The reaction mixture was allowed to react at room temperature overnight. LC-MS analysis indicated the reaction was complete. The reaction mixture was quenched with an appropriate amount of water. After removing the solvent by vacuum evaporation, a solution of ethanol (10 mL) and sodium hydroxide (1.8 g, 45.0 mmol) in water (8 mL) was added. The reaction mixture was heated to 100 °C and refluxed for 18 h. LC-MS analysis indicated the reaction was complete. After removing the ethanol by evaporation under vacuum, an appropriate amount of water was added, and the mixture was cooled in an ice-water bath. The pH of the solution was adjusted to 2 with concentrated hydrochloric acid, and the solution was kept below 10°C and stirred for 1 hour. Then, the mixture was filtered under suction, and the filter cake was washed with water and petroleum ether in turn. The resulting solid was dried under vacuum to obtain 700 mg of product 37-4. The yield was 67%.

[0379] Step 4: Preparation of 4-(4-fluorophenyl)-1,2-dimethyl-1H-pyrrole (37-5)

[0380] Compound 37-4 (400 mg, 1.4 mmol) and ethanolamine (4 mL) were added to a reaction flask, and the atmosphere was purged with nitrogen gas. The reaction mixture was heated to 175 °C, stirred, and reacted for 3 hours. LC-MS showed the reaction was complete. The reaction mixture was cooled to room temperature, and an appropriate amount of water was added. The mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous Na2SO4, and the crude product was evaporated in vacuo and purified with neutral alumina to give 130 mg of product 37-5. The yield was 48%.

[0381] Step 5: Preparation of 2-(4-(2-fluorophenyl)-1,5-dimethyl-1H-pyrrol-2-yl)-2-oxoacetyl chloride (37-6)

[0382] Compound 37-5 (60 mg, 0.32 mmol) and DCM (2 mL) were added to a reaction flask, and oxalyl chloride (45 mg, 0.35 mmol) was added slowly at 0 °C. After the addition was completed, the mixture was allowed to react at room temperature for 1 h. LC-MS showed that the reaction was complete. Direct concentration under reduced pressure gave 88 mg of product 37-6, which was used directly in the next reaction without further treatment.

[0383] Step 6: Preparation of (R)-2-(4-(2-fluorophenyl)-1,5-dimethyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-oxamide (T-37)

[0384] Compound 5-6 (87 mg, 0.29 mmol), DCM (3 mL), and DIEA (112 mg, 0.87 mmol) were added to a reaction flask and cooled to 0 °C in an ice-water bath. A solution of compound 35-6 (88 mg, 0.31 mmol) in DCM (2 mL) was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 1 h. TLC showed the reaction was complete. The reaction mixture was poured into water and extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, and the crude product after vacuum evaporation was purified on a thin-layer preparative plate to obtain 80 mg of product T-37. The yield was 51%.

[0385] LC-MS (ESI) m / z (M+H) + :545.2 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.50 (s, 2H), 7.24-7.18 (m, 2H), 6.94-6.87 (m, 2H), 6.79-6.75 (m, 1H), 6.72~6.64 (m, 2H), 6..09 (s, 1H), 4.65-4.53 (m, 2H), 4.34 (dd, J = 10.8, 2.8 Hz, 1H), 3.93 (dd, J = 10.8, 8.8 Hz, 1H), 3.85-3.82 (m, 1H), 3.81 (s, 3H), 3.11-2.95 (m, 2H), 2.73-2.65 (m, 1H), 2.59 (dd, J = 12.0, 3.2 Hz, 1H), 2.31 (s, 3H).

[0386] Example 38 Preparation of (S)-2-(3-(2-fluorophenyl)-1,5-dimethyl-1H-pyrrol-2-yl)-N-(2-(5-fluoropyrimidin-2-yl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-8-yl)-2-oxoacetamide (T-38) JPEG0007737734000072.jpg42170

[0387] Step 1: Preparation of (S)-2-(3-(2-fluorophenyl)-1,5-dimethyl-1H-pyrrol-2-yl)-N-(2-(5-fluoropyrimidin-2-yl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-8-yl)-2-oxoacetamide (T-38)

[0388] A reaction flask was charged with compound 33-13 (57 mg, 0.20 mmol), DCM (2 mL), and DIEA (78 mg, 0.60 mmol). The mixture was cooled to 0 °C in an ice-water bath. A solution of compound 35-6 (62 mg, 0.22 mmol) in DCM (1 mL) was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 1 h. TLC showed the reaction was complete. The reaction mixture was poured into water and extracted twice with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, and the crude product was evaporated in vacuo and purified by thin-layer preparative plate to obtain 80 mg of product T-38. The yield was 76%.

[0389] LC-MS (ESI) m / z (M+H) + :529.2 1 H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.48 (s, 2H), 7.23-7.14 (m, 2H), 7.05~6.99 (m, 1H), 6.98-6.92 (m, 1H), 6.88-6.81 (m, 2H), 6.40 (d, J = 8.4 Hz, 1H), 6.11 (s, 1H), 4.68-4.62 (m, 1H), 4.60-4.53 (m, 1H), 3.84 (s, 3H), 3.67-3.61 (m, 1H), 3.40-3.33 (m, 1H), 3.06-2.97 (m, 1H), 2.95-2.85 (m, 2H), 2.84-2.75 (m, 1H), 2.57-2.52 (m, 1H), 2.33 (s, 3H).

[0390] Example 39 Preparation of 2-(3-(2-fluorophenyl)-1,5-dimethyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydro-7H-benzo[e]pyrazine[2,1-c][1,4]oxazolin-9-yl)-2-oxoacetamide (T-39) JPEG0007737734000073.jpg38170

[0391] Step 1: Preparation of 2-(3-(2-fluorophenyl)-1,5-dimethyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydro-7H-benzo[e]pyrazine[2,1-c][1,4]oxazolin-9-yl)-2-oxoacetamide (T-39)

[0392] Compound 18-6 (50 mg, 0.16 mmol), DCM (2 mL), and DIEA (62 mg, 0.48 mmol) were added to a reaction flask and cooled to 0 °C in an ice-water bath. A solution of compound 35-6 (50 mg, 0.18 mmol) in DCM (1 mL) was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 1 h. TLC showed the reaction was complete. The reaction mixture was poured into water and extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, and the crude product after vacuum evaporation was purified on a thin-layer preparative plate to obtain 65 mg of product T-39. The yield was 73%.

[0393] LC-MS (ESI) m / z (M+H) + :559.2 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.49 (s, 2H), 7.22~7.16 (m, 1H), 7.16-7.11 (m, 1H), 7.08 (dd, J = 8.8, 2.4 Hz, 1H), 7.03~6.97 (m, 1H), 6.96-6.90 (m, 2H), 6.87-6.83 (m, 1H), 6.12 (s, 1H), 4.66-4.61 (m, 1H), 4.47-4.42 (m, 1H), 4.18-4.09 (m, 2H), 3.85 (s, 3H), 3.73-3.67 (m, 1H), 3.64-3.53 (m, 2H), 3.40-3.41 (m, 1H), 3.33-3.28 (m, 2H), 2.99-2.92 (m, 1H), 2.32 (s, 3H).

[0394] Example 40 Preparation of 2-(3-(2-fluorophenyl)-1,5-dimethyl-1H-pyrrol-2-yl)-N-(8-(5-fluoropyrimidin-2-yl)-6,6a,7,8,9,10-hexahydropyrazino and [1,2-d]pyrido[3,2-b][1,4]oxazin-3-yl)-2-oxamide (T-40) JPEG0007737734000074.jpg43170

[0395] Step 1: Preparation of 2-(3-(2-fluorophenyl)-1,5-dimethyl-1H-pyrrol-2-yl)-N-(8-(5-fluoropyrimidin-2-yl)-6,6a,7,8,9,10-hexahydropyrazino and [1,2-d]pyrido and [3,2-b][1,4]oxazin-3-yl)-2-oxamide (T-40)

[0396] Compound 22-5 (50 mg, 0.17 mmol), DCM (4 mL), and DIEA (64 mg, 0.50 mmol) were added to a reaction flask and cooled to 0 °C in an ice-water bath. A solution of compound 35-6 (51 mg, 0.18 mmol) in DCM (1 mL) was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred overnight. LC-MS showed the reaction was complete. The reaction mixture was poured into water and extracted three times with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, and the crude product was evaporated in vacuo and purified on a thin-layer preparative plate to obtain 30 mg of product T-40. The yield was 33%.

[0397] LC-MS (ESI) m / z (M+H) + :546.2 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.51 (s, 2H), 7.62 (d, J = 2.0 Hz, 1H), 7.22~7.15 (m, 2H), 7.06-6.94 (m, 2H), 6.84 (d, J = 2.0 Hz, 1H), 6.13 (s, 1H), 4.70-4.59 (m, 2H), 4.43~4.36 (m, 2H), 4.01-3.93 (m, 1H), 3.85 (s, 3H), 3.33-3.26 (m, 1H), 3.05-2.95 (m, 1H), 2.76-2.65 (m, 2H), 2.34 (s, 3H).

[0398] Example 41 Preparation of (R)-2-(5-cyano-1-methyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-oxamide (T-41) JPEG0007737734000075.jpg101170

[0399] Step 1: Preparation of 4-bromo-1-methyl-1H-pyrrole-2-nitrile (41-2)

[0400] Compound 41-1 (500 mg, 4.7 mmol) and DMF (5 mL) were added to a reaction flask and cooled to 0 °C in an ice bath. A solution prepared from NBS (839 mg, 4.7 mmol) and DMF (5 mL) was slowly added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred overnight. LC-MS showed the reaction was complete. An appropriate amount of water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous Na2SO4, and filtered. The filtrate was evaporated under vacuum to give 700 mg of crude product 41-2, which was used directly in the next reaction.

[0401] Step 2: Preparation of 1-methyl-4-phenyl-1H-pyrrole-2-nitrile (41-3)

[0402] Compound 41-2 (700 mg, 3.8 mmol), phenylboronic acid (923 mg, 7.6 mmol), cesium fluoride (1.7 g, 11.2 mmol), and 1,4-dioxane / water (20 mL) were added to a reaction flask and purged with nitrogen. Pd(dppf)Cl2 (139 mg, 0.19 mmol) was then added, and the reaction mixture was heated to 100 °C, stirred, and reacted overnight. LC-MS showed the reaction was complete. An appropriate amount of water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed successively with water and saturated brine, dried over anhydrous Na2SO4, and filtered. The filtrate was evaporated under vacuum. The resulting crude product was purified on a silica gel column to give 470 mg of product 41-3. The yield for the two steps was 55%.

[0403] Step 3: Preparation of 5-bromo-1-methyl-4-phenyl-1H-pyrrole-2-nitrile (41-4)

[0404] Compound 41-3 (440 mg, 2.4 mmol) and DMF (5 mL) were added to a reaction flask and cooled to 0 °C in an ice bath. A solution prepared from NBS (429 mg, 2.4 mmol) and DMF (5 mL) was slowly added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred overnight. LC-MS showed the reaction was complete. An appropriate amount of water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous Na2SO4, and filtered. The filtrate was evaporated under vacuum. The resulting crude product was purified on a silica gel column to give 570 mg of product 41-4. The yield was 90%.

[0405] Step 4: Preparation of 2-(5-cyano-1-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxymethyl acetate (41-5)

[0406] Compound 41-4 (500 mg, 1.9 mmol) and anhydrous THF (25 mL) were added to a three-neck flask, purged with nitrogen, and the reaction mixture was cooled to -78 °C. A solution of n-BuLi (2.5 M in hexane, 0.8 mL, 2.0 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at -78 °C for 1 h. A solution prepared from methyl chloride (350 mg, 2.86 mmol) and anhydrous THF (5 mL) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at -78 °C for 4 h. Then, the mixture was slowly warmed to room temperature and stirred overnight. LC-MS showed the reaction was complete. The reaction mixture was quenched with saturated aqueous NH4Cl (5 mL) and extracted with ethyl acetate three times. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, and filtered. The filtrate was evaporated in vacuo to give a crude product, which was purified on a silica gel column to give 250 mg of product 41-5 in a 49% yield.

[0407] Step 5: Preparation of 2-(5-cyano-1-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetic acid (41-6)

[0408] Compound 41-5 (230 mg, 0.86 mmol) and methanol (3 mL) were added to a reaction flask. Then, a solution prepared from lithium hydroxide (103 mg, 4.3 mmol) and water (3 mL) was added to the reaction mixture. After the addition was complete, the reaction mixture was slowly heated to 40 °C and stirred overnight. LC-MS showed the reaction was complete. 2 M dilute hydrochloric acid was added dropwise to the reaction mixture to adjust the pH to 4. The reaction mixture was concentrated to dryness under reduced pressure. The resulting crude product was purified on a silica gel column to obtain 120 mg of product 41-6. The yield was 55%.

[0409] Step 6: Preparation of (R)-2-(5-cyano-1-methyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-oxamide (T-41)

[0410] Compound 41-6 (70 mg, 0.28 mmol), DCM (5 mL), and DMF (4 mg, 0.055 mmol) were added to a reaction flask, cooled to 0 °C, and a solution of oxalyl chloride (39 mg, 0.31 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred at 0 °C for 1 h. The solution prepared above was added dropwise to a reaction flask containing a solution of compound 5-6 (75 mg, 0.25 mmol) and DIEA (97 mg, 0.75 mmol) in DCM (2 mL) in an ice bath. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. TLC indicated the reaction was complete. The reaction was quenched with an appropriate amount of water, extracted with dichloromethane, dried over anhydrous Na2SO4, and the organic phase was washed with saturated brine. The crude product was evaporated in vacuo and purified on a silica gel column to obtain 70 mg of product T-41. The yield was 52%.

[0411] LC-MS (ESI) m / z (M+H) + :538.2 1 H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.51 (s, 2H), 7.30-7.20 (m, 6H), 6.82~6.78 (m, 1H), 6.76-6.72 (m, 1H), 670-6.68 (m, 1H), 4.65-4.53 (m, 2H), 4.34 (dd, J = 10.8, 2.8 Hz, 1H), 3.97 (s, 3H), 3.95-3.90 (m, 1H), 3.86-3.79 (m, 1H), 3.11-2.97 (m, 2H), 2.72-2.55 (m, 2H).

[0412] Test Example 1: Measurement of minimum inhibitory concentration (MIC) 1.1 Spore formation

[0413] A glycerol stock solution of Aspergillus fumigatus (ATCC MYA-4609 / AF 293 / CBS 101355) was used to create a new streak on Sabouraud-dextrose agar (SDA) and incubated at 35°C and 40-70% humidity for 72 hours. Other strains were the same as AF293. 1.2 Medium preparation

[0414] RPMI1640: One packet of RPMI1640 powder was dissolved in 1 L of purified water and mixed evenly. 0.165 M MOPS was added, the pH was adjusted to 7.0, and the mixture was filtered and sterilized through a 0.22 μm membrane. The mixture was then stored at 4°C for no more than 3 months. Physiological saline: 9 g of sodium chloride powder was dissolved in 1 L of purified water, mixed uniformly, sterilized under high pressure at 121°C for 30 minutes, and stored at room temperature (RT) for up to one week. 1.3 Preparation of test plates 1.3.1 Preparation of stock solutions Stock solutions of test and control compounds were dissolved in dimethyl sulfoxide to 12.8 mg / mL. 1.3.2 Preparation of 100x working solution

[0415] The highest concentration of each compound was 0.8 mg / mL (e.g., 150 μL of dimethyl sulfoxide + 10 μL of 12.8 mg / mL compound / control). Column 1 was loaded with 40 μL of compound, and columns 2-11 were loaded with 20 μL of dimethyl sulfoxide. 20 μL of compound was transferred from the first column to the second column, and the mixture was diluted. The above steps were repeated up to column 11 to obtain two-fold serial dilutions. 1.3.3 Preparation of test plates Using a multichannel pipette, 2 μL of the above two-fold serial dilutions was dispensed into each well of the corresponding test plate. 1.4 Creation of an inoculum

[0416] Five milliliters of saline was dropped onto an Aspergillus fumigatus SDA board. The spores on the surface of the plate were carefully wiped off with an L-shaped coated rod, and the resulting suspension was transferred to a sterile tube. After shaking to ensure uniform mixing, the test tube was left to stand for 5-10 minutes. The number of spores in the suspension was counted using a hemocytometer to check purity. The inoculum concentration was adjusted to 0.2-2.5 x 10. 4 The concentration was adjusted to 0.01 spores / mL. 1.5 Addition of fungi A multi-pass pipette was then used to dispense 198 μL of the diluted inoculum into each well of the corresponding test plate. 1.6 Incubation The culture was incubated at 35°C for 48 hours. 1.7 MIC measurement

[0417] For each sample, the lowest concentration that completely / significantly (e.g., 80% inhibition) inhibited visible fungal growth after incubation was recorded as the MIC. A magnifying glass was used to facilitate scoring. The 96-well microplates were photographed, and the optical density at 530 nm was read using an ELISA Spark (Tecan Spark). The positive control compound F901318 has the following structure: JPEG0007737734000076.jpg29170The MIC results for the compounds of the present invention are shown in Table 4.

[0418] Table 4: Compound MIC results JPEG0007737734000077.jpg40170JPEG0007737734000078.jpg221170

[0419] The compounds of the present invention exhibit potent inhibitory activity against Aspergillus fumigatus (ATCC MYA-4609 / AF 293 / CBS 101355, ATCC-204305) and Aspergillus fumigatus (ATCC 204304, ATCC MYA-1004) in tests measuring minimum inhibitory concentrations (MICs).

[0420] Test Example 2: Pharmacokinetics test Each compound was mixed with F901318 (10 mg / kg, 3 rats per group) and orally administered once to SD rats for pharmacokinetic studies. The test compound and F901318 were dissolved in 5% DMSO, 10% solute, and 85% saline, vortexed for 1-2 minutes, and sonicated for 5-10 minutes to prepare a clear, colorless drug delivery solution. Animals were fasted overnight prior to oral administration and re-fed 4 hours after administration. After oral administration, SD rats were subjected to retroorbital blood sampling for pharmacokinetic studies. Three whole blood samples were collected at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h post-dose. Three whole blood samples were collected at each time point, with a volume of approximately 0.2-0.3 ml. After collection, blood samples were immediately placed on ice and centrifuged within 15 minutes (centrifugation conditions: 8000 rpm, 1 minute, room temperature). The collected plasma was stored at -20°C until analysis. 20 μL of plasma sample was placed in a 0.5 μmL EP tube, and 200 μL of working internal standard solution was added (no internal standard was added to the blank to make up the same volume of solvent). The tube was then rotated and mixed for 3 minutes, centrifuged at 13500 rpm for 10 minutes, and 100 μL of the supernatant was taken and subjected to LC-MS / MS sample introduction analysis. Pharmacokinetic test results for some compounds of the present invention are shown in Table 5 below.

[0421] Table 5: Pharmacokinetic results of some compounds of the present invention JPEG0007737734000079.jpg134170Note: Cmax: maximum compound concentration, AUC: exposure, T1 / 2: half-life, Tmax: time to reach Cmax. The compounds of the present invention have better exposure and maximum compound concentrations than F901318 in pharmacokinetic studies.

[0422] Test Example 3: Liver microsome stability experiment

[0423] 1: To blanks T0, T5, T10, T20, T30, T60, and NCF60, 10 μL of test or reference working solution and 80 μL of microsomal working solution (liver microsomal protein concentration 0.5 mg / mL) were added. To the blank position of Blank60, only microsomal working solution was added. Samples other than T0 and NCF60, Blank60, T5, T10, T20, T30, and T60, were placed in a 37°C water bath and pre-incubated for approximately 10 minutes.

[0424] 2: 300 μL of stop solution (containing 200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile) was added to the TO sample, followed by 10 μL of NADPH regenerating solution.

[0425] 3: After the pre-incubation of Blank60, T5, T10, T20, T30, and T60 on the culture plate was completed, 10 μL of NADPH regenerating system processing solution was added to each sample well to start the reaction, and 10 μL of 100 mM potassium phosphate buffer was added to the NCF60 sample well.

[0426] 4: After incubation for an appropriate time (e.g., 5, 10, 20, 30, 60 minutes), the reaction was terminated by adding 300 μL of stop solution to each test and reference sample well on the Blak60, T5, T10, T20, T30, T60, and NCF60 plates.

[0427] 5: All sample plates were shaken well and centrifuged at 4000 rpm for 20 minutes, and 100 μL of the supernatant of each test or reference product was collected and diluted with 300 μL of pure water for use in LC-MSMS analysis.

[0428] 6: Data were analyzed and T1 / 2 and Cl were calculated based on first-order elimination kinetics. int(mic) The (μL / min / mg) values ​​were calculated. The equation for first order elimination kinetics is shown below: JPEG0007737734000080.jpg81170 Experimental results of the liver microsomal stability of some compounds of the present invention are shown in Table 6 below.

[0429] Table 6. Liver microsomal stability measurements of some compounds of the present invention Compared to JPEG0007737734000081.jpg103170F901318, some compounds of the present invention have better liver microsomal stability for two species, human and / or rat.

[0430] Test Example 5: Survival rate study of Aspergillus fumigatus bloodstream infection model in mice Experimental animals: male CD-1 mice, 6-8 weeks old, 10 per group;

[0431] Suppression of induced immunity: The day of infection was defined as day 0, and the mice were intraperitoneally injected with the corresponding doses of cyclophosphamide on days -4 (150 mg / kg), 1 (100 mg / kg), and 2 (100 mg / kg). Microbial pathogen: Aspergillus fumigatus ATCCMYA-4690 (AF293), Inoculum recovery conditions: SDA culture plate, 25°C incubator for at least 7 days, PBS + 0.1% polysorbate 20, counted by microscope, Inoculation level, inoculation route and inoculation volume: 3.60E+05 CFU / mouse, tail vein injection, injection volume 100μL / mouse. Treatment: 24 hours after infection, treatment was started. The test compound was dissolved in PEG400 (0.3 mg / m) and orally administered at 3 mg / kg, twice daily for 6 consecutive days, followed by 8-hour observation. The experimental results of the survival rate of Aspergillus fumigatus in mice are shown in Figure 1.

[0432] As can be seen from the experimental results, T-5, T-33, and F901318 play a role in extending the survival time of mice. At the same dose, the 7-day survival rate of T-33 is 40%, while the survival rates of the reference compounds F901318 and T-5 are both 0%. The in vivo effect of T-33 in this model was significantly better than that of F901318 and T-5.

[0433] Test Example 6: Survival rate experiment 2 in a mouse bloodstream infection model with Aspergillus fumigatus Experimental animals: male CD-1 mice, 6-8 weeks old, 10 per group;

[0434] Induction immunosuppression: The day of infection was defined as day 0, and the mice were intraperitoneally injected with the corresponding doses of cyclophosphamide on days -4 (150 mg / kg), 1 (100 mg / kg), and 2 (100 mg / kg). Microbial pathogen: Aspergillus fumigatus ATCCMYA-4690 (AF293), Inoculum recovery conditions: SDA culture plate, incubate at 25°C for at least 7 days, recover in PBS + 0.1% polysorbate 20, count under microscope, Inoculation level, inoculation route and inoculation volume: 3.90E+05 CFU / mouse, tail vein injection, injection volume: 100 μL / mouse. Treatment: Treatment began 24 hours after infection, and the test compounds were dissolved in PEG400 (0.3 mg / m) and orally administered at the corresponding doses, twice a day for 6 consecutive days, followed by an 8-hour observation period. The experimental results of the survival rate of Aspergillus fumigatus in mice are shown in Figure 2.

[0435] The experimental results showed that T-33, T-38, and F901318 all played a role in extending mouse survival. At a dose of 3 mg / kg (bid), the 7-day survival rate for T-33 was 30%, for T-38 it was 50%, and for the reference compound F901318 it was 0%. T-33 exhibited a dose-dependent relationship at three doses: 1 mg / kg, 3 mg / kg, and 10 mg / kg, with the mouse survival rate for T-33 reaching 80% at 10 mg / kg (bid). The in vivo efficacy of T-33 and T-38 in this model was significantly better than that of F901318.

[0436] While embodiments of the present invention have been illustrated and described, it should be understood that those skilled in the art can make various changes, modifications, substitutions and variations to these embodiments without departing from the principles and spirit of the present invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. having the structure shown in Formula II: Z １ is N or CR ８ is selected from Ring B is selected from a phenyl group, a naphthyl group, a substituted or unsubstituted 5- to 10-membered heteroaryl group, an unsubstituted 3- to 9-membered cycloalkyl group, and a substituted or unsubstituted 3- to 9-membered heterocycloalkyl group; Ring A is selected from the following substituted or unsubstituted groups: R ２ , R ３ , R ４ are hydrogen, halogen, nitro, cyano group, hydroxyl, and -NH ２ , independently selected from a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted 2- to 10-membered heteroalkyl group, a substituted or unsubstituted 3- to 12-membered cycloalkyl group, a substituted or unsubstituted C2-C10 alkenyl group, a substituted or unsubstituted C2-C10 alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, an acyl group, an ester group, an amide group, a sulfonyl group, a sulfonamide group, a boric acid group, a boric acid ester group, and a phosphoryl group; L is a single bond, O, S, S(=O), S(=O) ２ , C(=O), NR １０ , -(CR １１ R １２ ) n ５ -, -S(=O)n ６ NR １３ -, -NR １４ S(=O)n ７ NR １５ -, -C(=O)NR １６ -, -NR １７ C(=O)NR １８ -, C2-C4 alkenylene, C2-C4 alkynylene; n ５ is selected from 1, 2, 3, and 4, and n ６ , n ７ are independently selected from 0, 1, and 2, R １０ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ are each independently selected from hydrogen, acyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl group, substituted or unsubstituted 3- to 12-membered cycloalkyl group, and substituted or unsubstituted alkenyl group; R １１ , R １２ is independently selected at each occurrence from hydrogen, halogen, hydroxyl, C1-C10 alkyl; R ５ is selected from a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted 2- to 10-membered heteroalkyl group, a substituted or unsubstituted 3- to 12-membered cycloalkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; R ６ is selected from hydrogen, a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted 2- to 10-membered heteroalkyl group, a substituted or unsubstituted 3- to 12-membered cycloalkyl group, and a substituted or unsubstituted alkenyl group; R ７ When present, represents hydrogen, halogen, cyano group, ═O, hydroxy group, —NH ２ , a carboxyl group, a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted 2- to 10-membered heteroalkyl group, a substituted or unsubstituted 3- to 12-membered cycloalkyl group, a substituted or unsubstituted 3- to 12-membered cycloalkyl group, a substituted or unsubstituted C2-C10 alkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, an acyl group, an ester group, an amide group, a sulfonyl group, a sulfonamide group, a boric acid group, or a boric acid ester group; R ８ is hydrogen, halogen, nitro, cyano group, hydroxyl, -NH ２ , a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted 2- to 10-membered heteroalkyl group, a substituted or unsubstituted 3- to 12-membered cycloalkyl group, a substituted or unsubstituted C2-C10 alkenyl group, a substituted or unsubstituted C2-C10 alkynyl group, a substituted or unsubstituted phenyl, a substituted or unsubstituted 5- to 9-membered heteroaryl group, an acyl group, an ester group, an amide group, a sulfonyl group, a sulfonamide group, a boric acid group, a boric acid ester group, or a phosphoryl group; R １９ , R ２０ are each independently selected from hydrogen, halogen, cyano, carboxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl, substituted or unsubstituted 3- to 12-membered cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, acyl, ester, amide, sulfonyl, and sulfonamide; R ２４ are each independently selected from hydrogen, halogen, hydroxyl, a substituted or unsubstituted C1-C4 alkyl group, and a substituted or unsubstituted C1-C4 alkenyl group; R ２４ The substituents of are halogen, hydroxyl, -NH ２ , an ester group, an acyl group, a C1-C4 alkyl group, and a 3- to 6-membered cycloalkyl group; R ２５ , R ２６ , R ２７ , R ２８ represents, at each occurrence, hydrogen, halogen, cyano group, hydroxyl, -NH ２ , independently selected from a carboxyl group, a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted 2- to 10-membered heteroalkyl group, a substituted or unsubstituted 3- to 12-membered cycloalkyl group, a substituted or unsubstituted C2-C10 alkenyl group, an acyl group, an ester group, an amide group, a sulfonyl group, and a sulfonamide group; R ２ , R ３ , R ４ , R ５ , R ６ , R ７ The substituents of each of the groups are halogen, alkyl group, cycloalkyl group, heteroalkyl group, alkenyl group, alkynyl group, hydroxyl group, cyano group, -NH ２ , a carboxyl group, an acyl group, an ester group, an amide group, a phenyl group, a heteroaryl group, a sulfinyl group, a sulfonyl group, a sulfonamide group, and a sulfinamide group; R ８ , R １０ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２５ , R ２６ , R ２７ , R ２８ The substituents of each of the groups are halogen, alkyl group, cycloalkyl group, heteroalkyl group, heterocycloalkyl group, alkenyl group, alkynyl group, hydroxyl group, cyano group, -NH ２ , a carboxyl group, an acyl group, an ester group, an amide group, a phenyl group, a heteroaryl group, a sulfinyl group, a sulfonyl group, a sulfonamide group, and a sulfinamide group; n ２ is selected from 0, 1, 2, 3, 4, 5, and 6; ４ , n ９ is a compound selected from 1, 2, 3, or a tautomer, enantiomer, diastereomer, or mixture thereof, a pharmaceutically acceptable hydrate or salt thereof.

2. 2. The compound of claim 1, wherein ring A is selected from the following substituted or unsubstituted groups:

3. having a structure shown in Formula III or Formula IV: W １ is CH ２ , CHF, CF ２ are independently selected from W ２ is CH ２ , C.F. ２ are independently selected from R ８ represents hydrogen, halogen, cyano group, hydroxyl group, -NH ２ , a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted 2- to 5-membered alkoxyl group, a substituted or unsubstituted 2- to 5-membered nitrogen-containing heteroalkyl group, a substituted or unsubstituted 3- to 6-membered cycloalkyl group, a substituted or unsubstituted C2-C4 alkenyl group, an acyl group, an ester group, an amide group, a boric acid group, or a boric acid ester group, or a tautomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable hydrate or salt thereof according to claim 1.

4. R ８ are H, F, -OH, -B(OH) ２ 2. The compound of claim 1, wherein the compound is selected from the group consisting of:

5. R ２４ 2. The compound of claim 1, wherein is selected from hydrogen, halogen, or a tautomer, enantiomer, diastereomer, or mixture thereof, a pharmaceutically acceptable hydrate, or salt thereof.

6. R ２５ and R ２７ is independently selected at each occurrence from hydrogen, halogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted 2- to 6-membered heteroalkyl group, a substituted or unsubstituted 3- to 6-membered cycloalkyl group, an acyl group, and an ester group; R ２６ , R ２８ is H, or a tautomer, enantiomer, diastereomer, or mixture thereof, a pharmaceutically acceptable hydrate, or salt thereof.

7. R １９ , R ２０ , R ２５ , R ２６ , R ２７ , R ２８ and R are H, or a tautomer, enantiomer, diastereomer, or mixture thereof, a pharmaceutically acceptable hydrate, or a salt thereof.

8. The compound according to claim 1, wherein Ring B is selected from a substituted or unsubstituted 5- to 6-membered heteroaryl group, or a tautomer, enantiomer, diastereomer, or mixture thereof, a pharmaceutically acceptable hydrate, or a salt thereof.

9. 2. The compound according to claim 1, wherein ring B is selected from the group consisting of pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, thiadiazolyl, and oxadiazolyl groups, or a tautomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable hydrate or salt thereof.

10. R ２ , R ３ are each independently selected from hydrogen, a cyano group, a substituted or unsubstituted C1-C4 alkyl group, and a substituted or unsubstituted 2- to 5-membered heteroalkyl group; R ２ , R ３ are each independently selected from halogen, hydroxyl, C1-C4 alkyl, 3- to 6-membered cycloalkyl, 2- to 4-membered heteroalkyl, 3- to 6-membered heterocycloalkyl, and C2-C4 alkenyl; ４ are each selected from hydrogen and a methyl group; R ５ is selected from a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted 2- to 6-membered heteroalkyl group, a substituted or unsubstituted 3- to 6-membered cycloalkyl group, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted 5- to 6-membered heteroaryl group; R ５ The substituents of each of the groups are halogen, a C1 to C6 alkyl group, a 3 to 6-membered cycloalkyl group, a 2 to 6-membered heteroalkyl group, a 3 to 6-membered heterocycloalkyl group, a hydroxyl group, a cyano group, and —NH ２ , an acyl group, an ester group, an amide group, a sulfinyl group, a sulfonyl group, a sulfonamide group, and a sulfinamide group; R ７ is selected at each occurrence from hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C1-C6 alkyl, unsubstituted 2- to 7-membered heteroalkyl, substituted or unsubstituted 3- to 6-membered cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, acyl, ester, amide, sulfonyl, and sulfonamide; ７ The compound according to claim 1, wherein the heteroatom in the heteroalkyl group, heterocycloalkyl group, heteroaryl group, or heterohydrocarbon ring is selected from one or more of N, O, and S, or a tautomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable hydrate or salt thereof.

11. R ５ is selected from a substituted or unsubstituted tetrahydropyranyl group, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted pyridyl group, and a substituted or unsubstituted pyrimidinyl group; R ５ are each independently selected from halogen and a C1-C6 alkyl group; R ７ is independently selected at each occurrence from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 7-membered oxygen-containing heteroalkyl, substituted or unsubstituted 2- to 7-membered nitrogen-containing heteroalkyl, substituted or unsubstituted 3- to 6-membered cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and sulfonamide; R ７ The substituents of the formula (I) are halogen, C1-C6 alkyl group, 3- to 6-membered cycloalkyl group, 2- to 7-membered heteroalkyl group, 3- to 6-membered heterocycloalkyl group, hydroxy group, cyano group, -NH ２ , an acyl group, an ester group, an amide group, a sulfinyl group, a sulfonyl, a sulfonamide, a sulfinamide; n ２ is selected from 0, 1, 2, 3, 4, 5, or a tautomer, enantiomer, diastereomer, or mixture thereof, a pharmaceutically acceptable hydrate, or salt thereof.

12. R ７ represents, at each occurrence, hydrogen, halogen, cyano group, -OH, -N(CH ３ ) ２ , -N(CH ２ CH ３ ) ２ , -S(=O) ２ NH ２ , -CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , A morpholinyl group, a piperidinyl group, a piperazinyl group, an oxetanyl group, a pyrrolidinyl group, -(CH ２ ) n ８ -OH, -CH(OH)-CH ２ OH, -C(CH ３ ) ２ OH, -OCH ２ CH(OH)-CH ２ OH, -OCH ２ CH ２ OCH ３ , -OCH ２ CH ２ OCH ２ CH ３ , -OCH3, -OCH ２ CH ３ , -OCH(CH ３ ) ２ , -CF ３ , -CHF ２ , -CF ２ CF ３ n ８ is selected from 1, 2, 3, and 4, and n ２ is selected from 0, 1, 2, 3, or a tautomer, enantiomer, diastereomer, or mixture thereof, a pharmaceutically acceptable hydrate, or salt thereof.

13. R ７ is independently selected at each occurrence from F, —OCH3, —CF3, —CH3, —OH, and a cyano group; ２ is 1, R ５ is a substituted or unsubstituted phenyl group, R ５ or a tautomer, enantiomer, diastereomer, or mixture thereof, pharmaceutically acceptable hydrate, or salt thereof, wherein the substituents are selected from F, Cl, and C1-C4 alkyl groups.

14. R ４ 2. The compound of claim 1, or a tautomer, enantiomer, diastereomer, or mixture thereof, pharmaceutically acceptable hydrate, or salt thereof, wherein R is selected from hydrogen.

15. R ２ , R ３ are each independently selected from hydrogen, a cyano group, and a substituted or unsubstituted methyl group, or a tautomer, enantiomer, diastereomer, or mixture thereof, a pharmaceutically acceptable hydrate, or a salt thereof, according to claim 1.

16. R ６ is selected from hydrogen, fluorine-substituted or unsubstituted C1-C4 alkyl, or a tautomer, enantiomer, diastereomer, or mixture thereof, a pharmaceutically acceptable hydrate, or a salt thereof.

17. 2. The compound of claim 1, wherein the compound is selected from the following structures: or their R or S configurations: or a tautomer, enantiomer, diastereomer, or mixture thereof, a pharmaceutically acceptable hydrate, or salt.

18. 2. The compound of claim 1, wherein the compound is selected from the following structures: or a tautomer, enantiomer, diastereomer, or mixture thereof, a pharmaceutically acceptable hydrate, or salt thereof.

19. 10. Use of a compound of claim 1 in the preparation of a medicament for treating or preventing a fungal infection or a disease caused by a fungal infection.

20. The fungus Absidia, Acremonium, Alternaria, Aspergillus, Bipolaris, Blastomyces, Blumeria, Cladosporium, Coccidioides, Colletotricium, Curvularia, Encephalitozoon, Epicoccum, Epidermophyton, Exophiala, Exserohilum, Fusarium, The method of claim 19, characterized in that the organism is one or more selected from the group consisting of Histoplasma, Leptosphaeria, Microsporum, Mycosphaerella, Neurospora, Paecilomyces, Penicillium, Phytophthora, Plasmopara, Pneumocystis, Pyricularia, Pythium, Puccinia, Rhizoctonia, Rhizomucor, Scedosporium, Scopula riopsis, Trichophyton, Trichosporon, and Ustilago.

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