Novel non-fluorinated quinolone compounds and their use

Abstract

The present invention relates to novel non-fluorinated quinolone compounds and their uses, and more particularly to compounds of formula (II) and pharma- ceutically acceptable salts thereof: JPEG2024541618000079.jpg34170

Description

[Technical Field]

[0001] This application claims priority over CN202111444560.2 dated November 30, 2021, and CN202210864782.8 dated July 21, 2022.

[0002] The present invention relates to novel non-fluorinated quinolone compounds and their uses, and more specifically to the compound represented by formula (II) and its pharmaceutically acceptable salts. [Background technology]

[0003] Quinolone antibiotics emerged in the 1960s and, after decades of development, have undergone continuous updates and improvements, leading to widespread clinical application. Quinolone antibiotics have a broad antibacterial spectrum, strong antibacterial activity, are easy to administer, and do not cross-resist with other commonly used antibiotics. These characteristics have led to their rapid adoption in clinical practice, and they are now one of the most important commonly used drugs worldwide. Further modification and research into this class of drugs have revealed that they also possess many other biological activities, such as antitumor, antiviral, and anti-inflammatory properties.

[0004] Acne is a skin disease that affects more than 85% of humans. It typically occurs on the face, neck, and upper torso. While acne development is multifactorial, the skin's commensal bacteria (Propionibacterium acnes) play a major role in the formation of acne lesions. It is a type of infection of the hair follicle sebaceous glands and oil glands of the skin. Furthermore, Propionibacterium acnes can trigger various cytokines (e.g., IL-6, IL-8, and IL-12) by activating Toll-like receptor 2 (TLR2) on intrinsic immune cells, and can stimulate the expression of chemokines that are recruited by other host immune cells.

[0005] Among the antibiotics for treating acne, erythromycin and clindamycin are the most widely applied. However, due to their long-term and extensive use, drug resistance has become increasingly serious, and there is an urgent need for new antibiotics that can be used in the treatment of acne. In recent years, many patents and articles have reported that quinolone drugs have good anti - Propionibacterium acnes activity and anti - inflammatory activity. Therefore, the research on new - generation quinolone drugs for treating acne has important value both theoretically and economically.

Summary of the Invention

Problems to be Solved by the Invention

[0006] The present invention provides a compound represented by formula (II), a stereoisomer or a pharmaceutically acceptable salt thereof. JPEG0007892060000001.jpg44170T1 is N, NH, CR1, and N + R1(A - ) is selected from T2 is selected from N and CR2, A - is F - , Cl - , Br - , I - , OH - , and HCO3 - and is selected from X is selected from -C(R7R8)- and -C(R7R8)-C(R7R8)-, Y is selected from -O-, -S-, -NH-, and -C(R7R8)-, Z is selected from -C(R7R8)-, or -Y-Z- is selected from -C(R9)=C(R9)-, R1 is selected from H, F, Cl, Br, I, -OH, -NH2, -CN, and -CH3, R2 is selected from H, F, Cl, Br, I, -OH, -NH2, -CN, and C 1~3 alkyl, where the C 1~3 alkyl is optionally substituted with 1, 2 or 3 R a s. R3 is H, F, Cl, Br, I, =O, -OH, -NH2, -CN, -NHC(=NH)NH2, C 1~3 Alkyl, C 1~3 Alkylamino, and C 1~3 Selected from alkoxy, where C 1~3 Alkyl, C 1~3 Alkylamino, and C 1~3 Each alkoxy can independently contain any 1, 2, or 3 R b Replaced by, or, R1 and R3, together with the atom they link, form a 5-6 member heterocycloalkyl, 5-6 member heterocyclinyl, or 5-6 member heteroaryl, where each of the 5-6 member heterocycloalkyl, 5-6 member heterocyclinyl, and 5-6 member heteroaryl can independently have 1, 2, 3, or 4 R c Replaced by, R4 is H, C 1~3 Alkyl, C 3~6 Selected from cycloalkyl, phenyl, and 5-6 member heteroaryl, where the C 1~3 Alkyl, C 3~6 Cycloalkyls, phenyls, and 5-6 member heteroaryls each independently optionally have 1, 2, 3, or 4 R groups. d Replaced by, R5 is selected from H, F, Cl, Br, I, -OH, -NH2, and -CN. R6 is selected from H, F, Cl, Br, I, -OH, -NH2, and -CN. Each of R7, R8, and R9 is independently selected from H, F, Cl, Br, I, -OH, -NH2, and -CN. Each R a Each of these is independently selected from F, Cl, Br, I, -OH, -NH2, and -CN. Each R b These are F, Cl, Br, I, -OH, -NH2, -CN, and C, respectively, independently. 1~3 Alkoxy, C 3~6 Selected from cycloalkyl, 3-6 member heterocycloalkyl, 5-6 member heteroaryl, and phenyl, where the C1~3 Alkoxy, C 3~6 Cycloalkyls, 3-6 membered heterocycloalkyls, 5-6 membered heteroaryls, and phenyls can each be independently substituted with 1, 2, 3, or 4 R atoms. Each R c Each of these is independently selected from F, Cl, Br, I, -OH, -NH2, -CN, and -CH3. Each R d Each of these is independently selected from F, Cl, Br, I, -OH, -NH2, and -CN. Each R is independently F, Cl, Br, I, -OH, -NH2, -NO2, -CN, -ONHC(=NH)NH2, and C 1~3 Selected from alkyl groups, In the aforementioned 5-6 member heterocycloalkyl, 3-6 member heterocycloalkyl, 5-6 member heterocyclyl, and 5-6 member heteroaryl compounds, "hetero" represents one, two, three, or four heteroatoms or heteroatomic groups independently selected from O, NH, S, and N.

[0007] The present invention provides a compound represented by formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. JPEG0007892060000002.jpg55170T1 is selected from N and CR1. T2 is selected from N and CR2. X is selected from -C(R7R8)- and -C(R7R8)-C(R7R8)-, Y is selected from -O-, -S-, -NH-, and -C(R7R8)-. Z is selected from -C(R7R8)-, or, -YZ- is selected from -C(R9)=C(R9)-, R1 is selected from H, F, Cl, Br, I, -OH, -NH2, and -CN. R2 consists of H, F, Cl, Br, I, -OH, -NH2, -CN, and C 1~3 Selected from alkyl, where C 1~3 Alkyl can optionally have 1, 2, or 3 R a Replaced by, R3 consists of H, F, Cl, Br, I, =O, -OH, -NH2, -CN, and C. 1~3 Alkyl, C 1~3 Alkylamino, and C 1~3 Selected from alkoxy, where C 1~3 Alkyl, C 1~3 Alkylamino, and C 1~3 Each alkoxy can independently contain any 1, 2, or 3 R b Replaced by, or, R1 and R3, together with the carbon atoms they link to, form a 5-6 member heterocycloalkyl, a 5-6 member heterocyclinyl, and a 5-6 member heteroaryl, where each of these 5-6 member heterocycloalkyl, 5-6 member heterocyclinyl, and 5-6 member heteroaryl groups can independently have 1, 2, 3, or 4 R c Replaced by, R4 is H, C 1~3 Alkyl, C 3~6 Selected from cycloalkyl, phenyl, and 5-6 member heteroaryl, where the C 1~3 Alkyl, C 3~6 Cycloalkyls, phenyls, and 5-6 member heteroaryls each independently optionally have 1, 2, 3, or 4 R groups. d Replaced by, R5 is selected from H, F, Cl, Br, I, -OH, -NH2, and -CN. R6 is selected from H, F, Cl, Br, I, -OH, -NH2, and -CN. Each of R7, R8, and R9 is independently selected from H, F, Cl, Br, I, -OH, -NH2, and -CN. R a Each of these is independently selected from F, Cl, Br, I, -OH, -NH2, and -CN. R b These are F, Cl, Br, I, -OH, -NH2, -CN, and C, respectively, independently. 3~6 Selected from cycloalkyl, 3-6 member heterocycloalkyl, and phenyl, where C 3~6Cycloalkyls, 3-6 membered heterocycloalkyls, and phenyls can each be independently substituted with 1, 2, 3, or 4 R atoms. R c Each of these is independently selected from F, Cl, Br, I, -OH, -NH2, and -CN. R d Each of these is independently selected from F, Cl, Br, I, -OH, -NH2, and -CN. R is independently selected from F, Cl, Br, I, -OH, -NH2, and -CN. In the aforementioned 5-6 member heterocycloalkyl, 3-6 member heterocycloalkyl, 5-6 member heterocyclyl, and 5-6 member heteroaryl compounds, "hetero" represents one, two, three, or four heteroatoms or heteroatomic groups independently selected from -O-, -NH-, -S-, and -N-.

[0008] The present invention provides a compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. JPEG0007892060000003.jpg35170 (however, T1 is selected from N and CR1. T2 is selected from N and CR2. X is selected from -C(R7R8)- and -C(R7R8)-C(R7R8)-, Y is selected from -O- and -C(R7R8)-, Z is selected from -C(R7R8)-, or, -YZ- is selected from -C(R9)=C(R9)-, R1 is selected from H, F, Cl, Br, I, -OH, -NH2, and -CN. R2 consists of H, F, Cl, Br, I, -OH, -NH2, -CN, and C 1~3 Selected from alkyl, where C 1~3 Alkyl can optionally have 1, 2, or 3 R a Replaced by, R3 consists of H, F, Cl, Br, I, -OH, -NH2, -CN, and C. 1~3 Alkylamino, and C 1~3Selected from alkoxy, where C 1~3 Alkylamino, and C 1~3 Each alkoxy can independently contain any 1, 2, or 3 R b Replaced by, or, R1 and R3, together with the carbon atoms they link to, form a 5-6 member heterocycloalkyl, a 5-6 member heterocyclyl, and a 5-6 member heteroaryl, where each of the 5-6 member heterocyclyl and 5-6 member heteroaryl groups can independently have 1, 2, 3, or 4 R 3, or 4 R1, 2, 3, 3, or 4 R1, 2, 3, 3, or 4 R1, 2, 3, 3, 4, 3, 4, 3, 4, 4, 5, 6, 4, 5, 6 c Replaced by, R4 is H, C 1~3 Alkyl, C 3~6 Selected from cycloalkyl, phenyl, and 5-6 member heteroaryl, where the C 1~3 Alkyl, C 3~6 Cycloalkyls, phenyls, and 5-6 member heteroaryls each independently optionally have 1, 2, 3, or 4 R groups. d Replaced by, R5 is selected from H, F, Cl, Br, I, -OH, -NH2, and -CN. R6 is selected from H, F, Cl, Br, I, -OH, -NH2, and -CN. Each of R7, R8, and R9 is independently selected from H, F, Cl, Br, I, -OH, -NH2, and -CN. R a Each of these is independently selected from F, Cl, Br, I, -OH, -NH2, and -CN. R b Each of these is independently selected from F, Cl, Br, I, -OH, -NH2, and -CN. R c Each of these is independently selected from F, Cl, Br, I, -OH, -NH2, and -CN. R d Each of these is independently selected from F, Cl, Br, I, -OH, -NH2, and -CN. In the aforementioned 5-6 member heterocycloalkyl, 5-6 member heterocyclyl, and 5-6 member heteroaryl compounds, the "hetero" represents, respectively, one, two, three, or four heteroatoms or heteroatomic groups independently selected from -O-, -NH-, -S-, and -N-.

[0009] JPEG0007892060000004.jpg11170

[0010] In some embodiments of the present invention, T1 is selected from N, and the other variables are as defined in the present invention.

[0011] In some embodiments of the present invention, T1 is selected from CH, and the other variables are as defined in the present invention.

[0012] In some embodiments of the present invention, T1 is selected from NH, and the other variables are as defined in the present invention.

[0013] In some embodiments of the present invention, T1 is N + R1(A - ) are selected from, and the other variables are as defined in this invention.

[0014] In some embodiments of the present invention, T1 is N + R1(Cl - ) are selected from, and the other variables are as defined in this invention.

[0015] In some embodiments of the present invention, T2 is selected from N, and the other variables are as defined in the present invention.

[0016] In some embodiments of the present invention, T2 is selected from CH, and the other variables are as defined in the present invention.

[0017] In some embodiments of the present invention, A - is, F - Cl - , Br - , and I -The variables are selected from the above, and the other variables are as defined in this invention.

[0018] In some embodiments of the present invention, A - Cl - The variables are selected from the above, and the other variables are as defined in this invention.

[0019] In some embodiments of the present invention, X is selected from -CH2-, and the other variables are as defined in the present invention.

[0020] In some embodiments of the present invention, Y is selected from -O-, and the other variables are as defined in the present invention.

[0021] In some embodiments of the present invention, Y is selected from -CH2-, and the other variables are as defined in the present invention.

[0022] In some embodiments of the present invention, Z is selected from -CH2-, and the other variables are as defined in the present invention.

[0023] In some embodiments of the present invention, -YZ- is selected from -CH=CH-, and the other variables are as defined in the present invention.

[0024] In some embodiments of the present invention, each of the above R is independently selected from -NO2, -ONHC(=NH)NH2, and -CH3, and the other variables are as defined in the present invention.

[0025] In some embodiments of the present invention, each of the above R b Each of these is independently selected from F, Cl, Br, -OH, -NH2, -OCH2CH3, cyclobutyl, oxetanyl, oxolanyl, azetidinyl, a five-membered heteroaryl, and phenyl, where -OCH2CH3, cyclobutyl, oxetanyl, oxolanyl, azetidinyl, a five-membered heteroaryl, and phenyl are each independently optionally substituted with 1, 2, 3, or 4 Rs, and R and other variables are as defined in the present invention.

[0026] In some forms of the present invention, each of the above Rs b is independently selected from F, Cl, Br, -OH, -NH2, cyclobutyl, oxetanyl, azetidinyl, and phenyl, where the cyclobutyl, oxetanyl, azetidinyl, and phenyl are each independently optionally substituted with 1, 2, 3, or 4 Rs, and R and other variables are as defined in the present invention.

[0027] In some forms of the present invention, each of the above Rs b is independently selected from F, Cl, Br, -OH, -NH2, -OCH2CH3, cyclobutyl, oxetanyl, 1,3-dioxane, azetidinyl, imidazolyl, and phenyl, where the -OCH2CH3, cyclobutyl, oxetanyl, 1,3-dioxane, azetidinyl, imidazolyl, and phenyl are each independently optionally substituted with 1, 2, 3, or 4 Rs, and R and other variables are as defined in the present invention.

[0028] JPEG0007892060000005.jpg41170

[0029] JPEG0007892060000006.jpg38170

[0030] JPEG0007892060000007.jpg31170

[0031] JPEG0007892060000008.jpg22170​​​​​​​​​​​​​

[0034] In some embodiments of the present invention, each of the above R d Each of these is independently selected from F, Cl, Br, and -NH2, and the other variables are as defined in this invention.

[0035] In some embodiments of the present invention, each of the above R d These are independently selected from F and -NH2, and the other variables are as defined in this invention.

[0036] In some embodiments of the present invention, R1 is selected from H, and the other variables are as defined in the present invention.

[0037] In some embodiments of the present invention, R2 is selected from H and -CH3, and the other variables are as defined in the present invention.

[0038] In some embodiments of the present invention, R2 is selected from H, and the other variables are as defined in the present invention.

[0039] In some embodiments of the present invention, R3 is selected from H, F, Cl, Br, =O, -OH, -NH2, -CN, -NHC(=NH)NH2, -CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -NHCH2CH2CH3, -N(CH3)CH2CH3, and -OCH3, where -NHC(=NH)NH2, -CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -NHCH2CH2CH3, -N(CH3)CH2CH3, and -OCH3 are each independently of any 1, 2, or 3 R b Replaced with R b And other variables are as defined in this invention.

[0040] In some embodiments of the present invention, the above R3 is selected from H, F, Cl, Br, =O, -OH, -NH2, -CN, -CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -NHCH2CH2CH3, and -OCH3, where the -CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -NHCH2CH2CH3, and -OCH3 are each independently optionally substituted with 1, 2, or 3 Rs b and the other variables are as defined in the present invention. b

[0041] In some embodiments of the present invention, the above R3 is selected from H, F, Cl, Br, -OH, -NH2, -CN, -NHCH3, -N(CH3)2, -NCH2CH3, and -OCH3, where the NHCH3, -N(CH3)2, -NCH2CH3, and -OCH3 are each independently optionally substituted with 1, 2, or 3 Rs b and the other variables are as defined in the present invention. b

[0042] JPEG0007892060000009.jpg65170

[0043] JPEG0007892060000010.jpg41170

[0044] <00***0435>In some embodiments of the present invention, the above R3 is selected from -NH2, -NHCH3, -N(CH3)2, -NCH2CH3, -NCH2CH2OH, and -OCH3, and the other variables are as defined in the present invention.

[0045] In some embodiments of the present invention, the above R4 is selected from C 3~6 cycloalkyl, where the C 3~6 cycloalkyl is optionally substituted with 1, 2, 3, or 4 Rs d and the other variables are as defined in the present invention.

[0046] ​In some embodiments of the present invention, R4 is selected from H, -CH2CH3, cyclopropyl, phenyl, and pyridyl, where -CH2CH3, cyclopropyl, phenyl, and pyridyl are each independently of any 1, 2, 3, or 4 R d It is replaced by and the other variables are as defined in this invention.

[0047] JPEG0007892060000011.jpg56170

[0048] JPEG0007892060000012.jpg17170

[0049] In some embodiments of the present invention, R5 and R6 are independently selected from H and F, respectively, and the other variables are as defined in the present invention.

[0050] In some embodiments of the present invention, R6 is selected from H and F, and the other variables are as defined in the present invention.

[0051] In some embodiments of the present invention, R5 and R6 are each independently selected from H, and the other variables are as defined in the present invention.

[0052] In some embodiments of the present invention, each of the above R7, R8, and R9 is independently selected from H, and the other variables are as defined in the present invention.

[0053] JPEG0007892060000013.jpg34170

[0054] JPEG0007892060000014.jpg31170

[0055] JPEG0007892060000015.jpg34170

[0056] JPEG0007892060000016.jpg31170

[0057] JPEG0007892060000017.jpg45170

[0058] JPEG0007892060000018.jpg30170

[0059] JPEG0007892060000019.jpg31170

[0060] JPEG0007892060000020.jpg20170

[0061] JPEG0007892060000021.jpg50170

[0062] JPEG0007892060000022.jpg45170

[0063] In some embodiments of the present invention, the above-mentioned compounds have structures represented by formulas (II-3), (II-4), (II-5), and (II-6). JPEG0007892060000023.jpg67170 (wherein T1, T2, and R3 are as defined in this invention.)

[0064] In some embodiments of the present invention, the above-mentioned compounds have structures represented by formulas (II-3A), (II-3B), (II-3C), (II-3D), (II-3E), (II-5A), and (II-6A). JPEG0007892060000024.jpg96170 (however, A - (R1, R2, and R3 are as defined in this invention.)

[0065] The present invention also includes forms in which the above variables are combined in any way.

[0066] The present invention also provides compounds, stereoisomers, or pharmaceutically acceptable salts thereof represented by the following formula. JPEG0007892060000025.jpg217170JPEG0007892060000026.jpg144170

[0067] The present invention also provides compounds, stereoisomers, or pharmaceutically acceptable salts thereof represented by the following formula. JPEG0007892060000027.jpg87170

[0068] The present invention also provides the use of the above-mentioned compounds, stereoisomers, or pharmaceutically acceptable salts thereof in the manufacture of antibacterial and anti-inflammatory drugs.

[0069] In some embodiments of the present invention, the above use is preferably in the manufacture of a drug for treating acne.

[0070] The present invention also provides the use of the above-mentioned compound, stereoisomer, or pharmaceutically acceptable salt thereof in the manufacture of a drug for treating acne.

[0071] The present invention also provides biological experimental methods for the above-mentioned compounds.

[0072] Experimental Method 1: Experiment to induce a THP-1 cell inflammation model using Propionibacterium acnes Experimental Objective We will construct a Propionibacterium acnes-induced THP-1 cell inflammation model. Laboratory consumables Strain: Propionibacterium acnes ATCC 6919; Medium: brucella agar (containing 5% LHB + 5 μg / ml Hemin + 1 μg / ml Vitamin K1); Cells: THP-1 ATCC TIB-202; Medium: RPMI1640 (gibco 22400-089) + 10% heat-inactivated FBS + 1 × GlutaMAX (100 × GlutaMAX: gibco 3050-061). Experimental Program a) Manufacturing of inflammatory irritants i. Inoculate Propionibacterium acnes ATCC 6919 in glycerin tubes into brucella agar (containing 5% LHB + 5 μg / mL hemin + 1 μg / mL vitamin K1) and culture anaerobically at 37°C for 48 hours. II. Take a sample of the plate culture and suspend it in PBS, then count the bacteria to 3 × 10⁻⁶ 9 Adjust the concentration to cfu / mL. Then, inactivate in a water bath at 80°C for 30 minutes. CFU counting should be performed before and after bacterial inactivation. iii. Package the inactivated bacterial suspension in individual packets and store in a refrigerator at 80°C until use. b) Production of cell THP-1 i. Cell resuscitation and culture: THP-1 cells, cryopreserved in liquid nitrogen, are resuscitated in RPMI1640 (containing 10% FBS and 1×glutamax). After one passage, they are ready for experimental use. ii. Cell inoculation: 2×10 5 Individual cells (190 μL, 1.1 × 10⁻⁶) 6 The solution (cfu / mL) was inoculated into a 96-well flat-bottom plate and stored until use. c) Induced stimulation of cells i. 8 μL of heat-inactivated Propionibacterium acnes (2 concentrations: 3 × 10⁻¹⁰) 9 cfu / mL (high concentration), 6×10 8 Cells are stimulated using cfu / mL (low concentration) to induce inflammatory cytokines, and two parallel tests are performed. After 1 hour of induction, the test plates are set to 37°C and cultured for 24, 48, and 72 hours. PBS is used as a negative control. After culturing, the test plates are centrifuged (4000 RPM, 5 min), and the supernatant is collected. Store at -80°C until use. d) Enzyme-linked immunosorbent assay i. Detect the cytokine IL-8 level in the cell supernatant according to the instructions for the Human CXCL8 / IL-8 Quantikine ELISA Kit (R&D-D8000C). ii. Detect the cytokine IL-6 level in the cell supernatant according to the instructions for the Human IL-6 Quantikine ELISA Kit (R&D-D6050).

[0073] Technical effects The present invention provides a novel non-fluorinated quinolone antibiotic that acts on a dual target of DNA gyrase and TLR-MD2, synthesizing the compound represented by formula (I) and its pharmaceutically acceptable salts by a simple manufacturing method, thereby treating acne caused by Propionibacterium acnes and solving the problem of drug resistance to Propionibacterium acnes. Definition and Description

[0074] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. Unless otherwise defined, specific terms and phrases should not be considered uncertain or ambiguous, but should be understood in their general sense. Where a trade name is used herein, it is intended to refer to the corresponding product or its active ingredient.

[0075] As used herein, the term “pharmaceutically acceptable” means, within the bounds of reliable medical judgment, a compound, material, composition and / or dosage form suitable for contact use with human and animal tissues in a reasonable benefit-to-risk ratio without excessive toxicity, irritation, anaphylaxis, or other problems or complications.

[0076] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention prepared from a compound found in the present invention having a specific substituent and a relatively harmless acid or base. If a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. If a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting such compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain compounds of the present invention contain both basic and acidic functional groups and can consequently be converted into either a base or an acid addition salt. The present invention also envisions any N-cationic quaternary ammonium salt formed from a compound having an N group. + R1(A -) indicates that the heteroatom N is a positive ion of the quaternary ammonium salt, where A is F - Cl - , Br - , I - , OH - , HCO3 - HSO3 - HSO4 - NO3 - , - , BrO - I3 - ClO3 - ClO4 - , HCOO - CH3COO - H2PO4 - And so on.

[0077] The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing an acid group or a base by conventional chemical methods. Generally, such salts are produced by reacting these compounds in the form of a free acid or base with a stoichiometrically appropriate base or acid in water or an organic solvent, or in a mixture thereof.

[0078] In addition to the salt form, the compounds according to the present invention also exist in the form of prodrugs. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions and are converted into the compounds of the present invention. Furthermore, the prodrugs can be converted into the compounds of the present invention in the biological environment by chemical or biochemical methods.

[0079] Some of the compounds of the present invention may exist in the form of non-solvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the non-solvated forms and are included within the scope of the present invention.

[0080] Unless otherwise specified, the term "treatment" is intended to mean all processes that may slow, interrupt, suppress, or halt the progression of a disease, but not necessarily that all symptoms will be resolved.

[0081] The compounds of the present invention may have specific geometric isomers or stereoisomers. The present invention envisions all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures such as concentrated mixtures of enantiomers or diastereomers, all of which fall within the scope of the present invention. Substituents such as alkyl groups may further contain chiral carbon atoms. All of these isomers and mixtures thereof are included within the scope of the present invention.

[0082] Unless otherwise specified, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0083] Unless otherwise specified, the terms "cis-trans isomer" or "geometric isomer" refer to the fact that the single bonds of the double bonds or ring-forming carbon atoms cannot rotate freely.

[0084] Unless otherwise specified, the term "diastereomer" refers to stereoisomers in which a molecule has two or more chiral centers and the molecules are in a non-mirror image relationship.

[0085] Unless otherwise specified, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0086] JPEG0007892060000028.jpg22170

[0087] The compounds of the present invention may include specific ones. Unless otherwise specified, the terms “tautomer” or “tautomer form” mean that different functional isomers are in dynamic equilibrium at room temperature and rapidly convert to each other. When tautomerism is possible (e.g., in solution), chemical equilibrium of tautomers can be achieved. For example, prototropic tautomers (also called prototropic tautomers) include interconversions by proton transfer, such as ketone-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions involving the rearrangement of some bonding electrons. A specific example of ketone-enol tautomerization is the interconversion between tautomers of pentane-2,4-dione and 4-hydroxypenta-3-en-2-one.

[0088] Unless otherwise specified, the terms "rich in one isomer," "isomer-enriched," "rich in one enantiomer," or "enantiomer-enriched" mean that the content of one of these isomers or enantiomers is less than 100%, and that the content of that isomer or enantiomer is 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or 99.9% or more.

[0089] Unless otherwise specified, the terms "isomer excess" or "enantiomer excess" refer to the difference in the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is present at 90% and the other isomer or enantiomer is present at 10%, the excess amount (ee value) of the isomer or enantiomer is 80%.

[0090] The optically active (R)- and (S)-isomers, as well as the D and L isomers, can be produced by chiral synthesis, chiral reagents, or other prior art. To obtain one enantiomer of the compound of the present invention, it can be produced by asymmetric synthesis or by the inductive action of a chiral auxiliary agent, where the resulting diastereomer mixture is separated and the auxiliary groups are cleaved to provide the pure desired enantiomer. Furthermore, if the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a salt of the diastereomer is formed with a suitable optically active acid or base, and the diastereomer is divided by a conventionally known method and recovered to obtain the pure enantiomer. In addition, the separation of enantiomers and diastereomers is generally achieved by using chromatography with a chiral stationary phase and optionally combined with a chemical induction method (e.g., production of carbamate salts from amines).

[0091] The compounds of the present invention may contain non-natural ratio atomic isotopes on one or more atoms constituting the compound. For example, tritium ( 3 H), Iodine-125( 125 I) or C-14 ( 14 The compound may be labeled with a radioactive isotope such as C). Alternatively, for example, hydrogen may be substituted with deuterium to form a deuterated drug. The bond composed of deuterium and carbon is more robust than the bond composed of ordinary hydrogen and carbon, and deuterated drugs have advantages over non-deuterated drugs, such as reduced toxicity and side effects, improved drug stability, enhanced therapeutic effect, and a longer biological half-life. Conversions of all isotopes of the compound of the present invention, with or without radioactivity, are included within the scope of the present invention.

[0092] "Optional" or "optional" means that the events or conditions described below may occur but do not necessarily occur, and this description includes cases in which such events or conditions occur and cases in which they do not occur.

[0093] JPEG0007892060000029.jpg48170

[0094] The term "optionally substituted" means, unless otherwise specified, that substitution may or may not occur, and the type and number of substituents may be arbitrary as long as chemically feasible.

[0095] If any variable (e.g., R) appears one or more times in the composition or structure of a compound, its definition is independent for each instance. Therefore, for example, if a group is substituted with 0 to 2 Rs, that group may be substituted with up to 2 Rs, and in each case, the Rs have independent choices. Furthermore, combinations of substituents and / or their variants are only permissible if such combinations produce a stable compound.

[0096] When the number of linking groups is 0, for example -(CRR)0-, it indicates that this linking group is a single bond.

[0097] If one variable is selected from a single bond, it indicates that the two groups connected by it are directly linked. For example, if L in ALZ represents a single bond, it indicates that the structure is essentially AZ.

[0098] If a substituent is missing, it indicates that the substituent is not present. For example, if X is missing in AX, it indicates that the structure is essentially A.

[0099] If it is not indicated which atoms a listed substituent is linked to, the substituent may be linked to any of the atoms, for example, pyridyl may be linked as a substituent via any carbon atom on the pyridine ring.

[0100] JPEG0007892060000030.jpg167170

[0101] Unless otherwise specified, the term "alkyl" refers to a linear or branched saturated hydrocarbon group, either by itself or as part of another substituent. The alkyl group is C 1~6 Alkyl or C 1~3 It may be alkyl. The alkyl is optionally substituted with one or more groups from among oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclooxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0102] Unless otherwise specified, "C 1~3 The term "alkyl" refers to a linear or branched saturated hydrocarbon group having 1 to 3 carbon atoms. 1~3 C 1~2 and C 2~3 It contains alkyl groups, which may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1~3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), and propyl (including n-propyl and isopropyl).

[0103] Unless otherwise specified, the term "alkoxy" refers to an alkyl group linked to the rest of the molecule via one oxygen atom. The alkoxy is C 1~6 Alkoxy or C 1~3 It may also be an alkoxy. The alkoxy is optionally substituted with one or more groups of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclooxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0104] Unless otherwise specified, "C 1~3 The term "alkoxy" refers to an alkyl group having 1 to 3 carbon atoms linked to the rest of the molecule via one oxygen atom. 1~3 Alkoxy is C 1~2 , C 2~3 , including C3 and C2 alkoxys. 1~3 Examples of alkoxys include, but are not limited to, methoxy, ethoxy, and propoxy (including n-propoxy and isopropoxy).

[0105] Unless otherwise specified, "C 1~3 The term "alkylamino" refers to an alkyl group having 1 to 3 carbon atoms linked to the rest of the molecule via an amino acid. 1~3 Alkylamino is C 1~2 , including C3 and C2 alkylaminos. 1~3 Examples of alkylaminos include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, and -NHCH2(CH3)2.

[0106] Unless otherwise specified, the term "halo" or "halogen" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, either by itself or as part of another substituent.

[0107] The term "cycloalkyl" refers to a carbon ring that is fully saturated and can exist as a monocycle, a bridging ring, or a spirocycle. Unless otherwise indicated, this carbon ring is typically a 3- to 12-membered ring. Non-limiting examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, and adamantyl. The cycloalkyl is C 3~6It may also be a cycloalkyl. The cycloalkyl is optionally substituted with one or more groups from among oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclooxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0108] Unless otherwise specified, "C 3~6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group having 3 to 6 carbon atoms, and can be monocyclic or bicyclic. 3~6 Cycloalkyl is C 3~5 , C 4~5 and C 5~6 It includes cycloalkyls, which may be monovalent, divalent, or polyvalent. 3~6 Examples of cycloalkyl compounds include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0109] The term "heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocycle, bridging ring, or spirocycle. Unless otherwise indicated, this heterocycle is typically a 3- to 12-membered ring containing 1-3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen. Non-limiting examples of heterocyclyls include, but are not limited to, oxyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, and tetrahydrothienyl. The heterocyclyl is optionally substituted with one or more groups from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclooxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0110] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocycle, a bridging ring, or a spirocycle. Unless otherwise indicated, this heterocycle is typically a 4- to 12-membered ring containing 1-3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen. Non-limiting examples of 4-membered heterocycloalkyls include, but are not limited to, azetidinyl, oxetanyl, and tibutanyl. Examples of 5-membered heterocycloalkyls include, but are not limited to, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl. Examples of 6-membered heterocycloalkyls include, but are not limited to, piperidinyl, tetrahydropyranil, tetrahydrothiopyranil, morpholinil, piperazinyl, 1,4-thiooxanil, 1,4-dioxanil, thiomorpholinil, 1,3-dithianil, and 1,4-dithianil. Examples of 7-membered heterocycloalkyls include, but are not limited to, azepanil, oxeptanil, and thiepanil. The heterocycloalkyls may be 4- to 6-membered heterocycloalkyls, or monocyclic heterocycloalkyls having 5 or 6 ring atoms. The heterocycloalkyl group is optionally substituted with one or more groups from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclooxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0111] Unless otherwise specified, the term "3-6 membered heterocycloalkyl" means, by itself or in combination with other terms, a saturated cyclic group consisting of 3 to 6 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized (i.e., C(O), NO, and S(O)). p (where p is 1 or 2). This includes monocyclic and bicyclic systems, with bicyclic systems including spiro rings, fused rings, and bridging rings. Furthermore, for these "3-6 membered heterocycloalkyls," the heteroatom may occupy a linking position between the heterocycloalkyl and the rest of the molecule. Examples of the 3-6 membered heterocycloalkyls include 4-6 membered, 5-6 membered, 4-membered, 5-membered, and 6-membered heterocycloalkyls. Examples of 3- to 6-membered heterocycloalkyls include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranil (including tetrahydrofuran-2-yl, etc.), tetrahydropyranil, piperidinyl (including 1-piperidyl, 2-piperidyl, and 3-piperidyl, etc.), piperazinyl (including 1-piperadinyl and 2-piperadinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiadinyl, or hexahydropyridazinyl.

[0112] Unless otherwise specified, the term "5-6 membered heterocycloalkyl" means, by itself or in combination with other terms, a saturated cyclic group consisting of 5-6 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the nitrogen atom may be optionally quaternized, and the carbon, nitrogen, and sulfur atoms may be optionally oxidized (i.e., C(O), NO, and S(O)). p(where p is 1 or 2). This includes monocyclic and bicyclic systems, with the bicyclic systems including spiro rings, fused rings, and bridging rings. Furthermore, for these "5-6 membered heterocycloalkyls," the heteroatom may occupy a linking position between the heterocycloalkyl and the rest of the molecule. The aforementioned 5-6 membered heterocycloalkyls include 5-membered heterocycloalkyls and 6-membered heterocycloalkyls. Examples of 5-6 member heterocycloalkyls include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranil (including tetrahydrofuran-2-yl, etc.), tetrahydropyranil, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanil, dithianil, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiadinyl, and hexahydropyridazinyl.

[0113] Unless otherwise specified, the term “5-6 membered heterocycloalkenyl” means, by itself or in combination with other terms, a partially unsaturated cyclic group consisting of 5-6 ring atoms, each containing at least one carbon-carbon double bond, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur atoms may optionally be oxidized (i.e., C(O), NO, and S(O)). p (where p is 1 or 2). This includes monocyclic and bicyclic systems, the bicyclic system including spiro rings, fused rings, and bridging rings, and all rings in this system are non-aromatic. Furthermore, for this "5-6 member heterocycloalkenyl," the heteroatom may occupy a linking position between the heterocycloalkenyl and the rest of the molecule. The aforementioned 5-6 member heterocycloalkenyl includes 5-member heterocycloalkenyls, 6-member heterocycloalkenyls, etc. JPEG0007892060000031.jpg33170

[0114] The term "heteroaryl" refers to a monocyclic or fused polycyclic system having at least one ring atom selected from N, O, and S, with the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryls have a single 4- to 8-membered ring, particularly a 5- to 8-membered ring, or multiple fused rings containing 6- to 14, particularly 6- to 10, ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc. The heteroaryl may also be a 5- to 6-membered heteroaryl. The heteroaryl is optionally substituted with one or more groups from the following: hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclooxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0115] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" of this invention are interchangeable. The term "5-6 membered heteroaryl" means a monocyclic group consisting of 5-6 ring atoms and having a conjugated π-electron system, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. Here, the nitrogen atom may be optionally quaternized, and the carbon, nitrogen, and sulfur atoms may be optionally oxidized (i.e., C(O), NO, and S(O)).p (where p is 1 or 2). The 5- to 6-membered heteroaryl may be linked to the rest of the molecule via heteroatoms or carbon atoms. The 5- to 6-membered heteroaryl includes 5-membered and 6-membered heteroaryls. Examples of the 5- to 6-membered heteroaryl include pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrrolyl and 3-pyrrolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4- This includes, but is not limited to, triazolyl, tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, etc.), thiazolyl (2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0116] Unless otherwise specified, the terms "5-membered heteroaromatic ring" and "5-membered heteroaromatic ring" in this invention are interchangeable, and the term "5-membered heteroaryl" means a monocyclic group consisting of five ring atoms having a conjugated π-electron system, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. Here, the nitrogen atom may be optionally quaternized, and the carbon, nitrogen, and sulfur atoms may be optionally oxidized (i.e., C(O), NO, and S(O)). p(where p is 1 or 2). The five-membered heteroaryl may be linked to the rest of the molecule via heteroatoms or carbon atoms. Examples of the five-membered heteroaryl include pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrrolyl and 3-pyrrolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), and triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3 This includes, but is not limited to, triazolyl (including 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl), tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl), furyl (including 2-furyl and 3-furyl), and thienyl (including 2-thienyl and 3-thienyl).

[0117] Unless otherwise specified, C n~n+m or C n ~C n+m It contains any of the n~n+m carbon atoms, for example, C 1~12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 It includes and also includes any of the ranges n to n+m, for example, C 1~12 C 1~3 , C 1~6 , C 1~9 , C 3~6 , C 3~9 , C 3~12 , C 6~9 , C 6~12 , and C 9~12This includes, for example, n-membered to n+m-membered rings, where the number of atoms on the ring is n to n+m. For example, 3- to 12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also include any number in the range of n to n+m. For example, 3- to 12-membered rings include 3- to 6-membered, 3- to 9-membered, 5- to 6-membered, 5- to 7-membered, 6- to 7-membered, 6- to 8-membered, and 6- to 10-membered rings.

[0118] The term "leaving group" refers to a functional group or atom that can be substituted for another functional group or atom by a substitution reaction (e.g., a nucleophilic substitution reaction). Examples of typical leaving groups include triflates; chlorine, bromine, iodine; sulfonate groups such as mesylates, tosylates, p-bromobenzenesulfonate, and p-toluenesulfonate; and acyloxy groups such as acetoxy and trifluoroacetoxy.

[0119] The term "protecting group" includes, but is not limited to, "amino protecting groups," "hydroxy protecting groups," or "mercapto protecting groups." The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino acid. Typical amino protecting groups include, but are not limited to, formyl; acyls, e.g., alkanoyls (acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyls, e.g., tert-butoxycarbonyl (Boc); arylmethoxycarbonyls, e.g., benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyls, e.g., benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyls, e.g., trimethylsilyl (TMS), 2-(trimethylsilyl)ethoxymethyl (SEM), and tert-butyldimethylsilyl (TBS). The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions of hydroxyls. Typical hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl, and tert-butyl; acyl groups such as alkanoyl (acetyl, etc.); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (diphenylmethyl, DPM); and silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS).

[0120] The compounds of the present invention can be produced by a variety of synthesis methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed in combination with other chemical synthesis methods, and equivalent alternative forms well known to those skilled in the art. Preferred embodiments include, but are not limited to, embodiments of the present invention.

[0121] The structure of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art, and if the present invention relates to the absolute configuration of a compound, the absolute configuration can be verified by means of the prior art to those skilled in the art. For example, in single-crystal X-ray diffraction (SXRD), diffraction intensity data can be collected from a cultured single crystal using a Bruker D8 venture diffractometer, the light source is CuKα emission, the scanning method is φ / ω scanning, and after collecting the relevant data, the absolute configuration can be verified by further analyzing the crystal structure using a direct method (Shelxs97).

[0122] The solvent used in this invention is commercially available.

[0123] This invention adopts the following abbreviations: DMAP represents 4-dimethylaminopyridine. DMSO represents dimethyl sulfoxide. CFU represents colony-forming unit. DCM represents dichloromethane. DMF represents N,N-dimethylformamide. DME represents ethylene glycol dimethyl ether. TFA represents trifluoroacetic acid. Boc2O represents di-t-butyl dicarbonate. NaOH represents sodium hydroxide. NaH represents sodium hydride. NBS represents N-bromosuccinimide. TBSCl represents tert-butyldimethylchlorosilane. HPLC represents high-pressure liquid chromatography. LCMS represents liquid chromatography-mass spectrometry. SBE-β-CD represents sulfobutyl ether β-cyclodextrin. PBS represents phosphate buffer.

[0124] Compounds are named according to the common naming conventions of the field or using ChemDraw® software, and commercially available compounds are named according to the supplier catalog. [Modes for carrying out the invention]

[0125] The present invention will be described in detail below with reference to examples, but this does not mean that there are any unfavorable limitations to the present invention. The compounds of the present invention can be produced by a variety of synthesis methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed in combination with other chemical synthesis methods, and equivalent alternative forms well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention. It will be obvious to those skilled in the art that various modifications and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0126] JPEG0007892060000032.jpg165170 Step 1: Preparation of Compound 1-2 Compound 1-1 (5.00 g, 23.14 mmol) was dissolved in thionyl chloride (65.13 g, 547.43 mmol, 39.71 mL). The mixture was stirred under reflux for 2 hours. Thionyl chloride was removed by vacuum concentration, and then methanol (50 mL) was added. The mixture was stirred at 65°C for 1 hour. Methanol was removed by vacuum concentration, and then the reaction mixture was quenched with aqueous sodium carbonate (50 mL). The mixture was extracted with ethyl acetate (50 mL x 2), the separated organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain compound 1-2. LCMS (ESI) m / z: 229.9 / 231.9 (M+1). Step 2: Preparation of Compounds 1-3 Compound 1-2 (15g, 65.20 mmol), cyclopropylboric acid (11.20g, 130.4 mmol), copper acetate (23.68g, 130.40 mmol), 2,2'-bipyridine (20.37g, 130.40 mmol), and sodium carbonate (20.73g, 195.60 mmol) were mixed with dichloromethane (240 mL), substituted three times with O2, and then the mixture was stirred at 15-25°C in an oxygen atmosphere for 12 hours. The reaction mixture was filtered, water (200 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (100 mL x 2). The separated organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to obtain compound 1-3. LCMS (ESI) m / z: 270.0 / 272.0 (M+1). Step 3: Preparation of Compounds 1-4 Compounds 1-3 (1.8 g, 6.66 mmol), diphenylphosphine ferrocene palladium dichloride (487.59 mg, 666.37 μmol), bis(pinacolato)diborone (2.03 g, 8.00 mmol), and potassium acetate (1.96 g, 19.99 mmol) were mixed with dioxane (30 mL), replaced three times with N2, and then the mixture was stirred at 100 °C under a nitrogen atmosphere for 4 hours. Water (20 mL) was added to quench the reaction mixture, extracted with ethyl acetate (20 mL x 3), washed the separated organic layer with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-4. LCMS (ESI) m / z: 318.2 (M+1). Step 4: Preparation of Compounds 1-6 Compound 1-5 (6.00 g, 25.97 mmol) was dissolved in dichloromethane (120 mL), and (Boc)2O (14.17 g, 64.92 mmol) and DMAP (317.26 mg, 2.60 mmol) were added. The mixture was then stirred at 15-25°C for 2 hours. The reaction solution was washed with saturated sodium bicarbonate aqueous solution (50 mL) and saturated brine (50 mL), respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-6. LCMS (ESI) m / z: 431.0 / 433.0 (M+1). Step 5: Preparation of Compounds 1-7 Potassium carbonate (9.61 g, 69.56 mmol) was added to a methanol (45 mL) solution of compound 1-6 (10.00 g, 23.19 mmol). The mixture was stirred at 15-25°C for 2 hours. Methanol was removed by vacuum concentration, and then the reaction mixture was quenched with water (50 mL). The mixture was extracted with ethyl acetate (50 mL x 2), the separated organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 0-2 / 1) to obtain compound 1-7. 1 H NMR (400 MHz, CDCl3) δ = 8.02 - 7.95 (m, 1H) 7.93 - 7.86 (m, 1H) 7.41 (br s, 1H) , 3.97 (s, 3H) , 1.51 (s, 9H). Step 6: Preparation of Compounds 1-8 Compound 1-7 (5.70 g, 17.21 mmol) was dissolved in acetone (85 mL), and methyl iodide (2.93 g, 20.65 mmol) and cesium carbonate (16.85 g, 51.64 mmol) were added. The mixture was then stirred at 15-25°C for 3 hours. Water (50 mL) was added to quench the reaction mixture, and it was extracted with ethyl acetate (50 mL x 2). The separated organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-8. LCMS (ESI) m / z: 344.9 / 446.9 (M+1). Step 7: Preparation of Compounds 1-9 Compound 1-8 (1.8 g, 5.21 mmol), Compound 1-4 (2.1 g, 6.62 mmol), sodium carbonate (1.11 g, 10.43 mmol), diphenylphosphineferrocenepalladium dichloride (381.55 mg, 521.45 μmol), 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (214.07 mg, 521.45 μmol), and palladium acetate (58.54 mg, 260.73 μmol) were mixed with tetrahydrofuran (30 mL) and water (6 mL), and the mixture was replaced three times with N2. The mixture was then stirred at 60-65°C under a nitrogen atmosphere for 10 hours. Water (50 mL) was added to quench the reaction mixture, and it was extracted with ethyl acetate (30 mL x 3). The separated organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to obtain compounds 1-9. LCMS (ESI) m / z: 456.1 (M+1). Step 8: Preparation of Compounds 1-10 At 0°C, compound 1-9 (0.50 g, 1.10 mmol) was dissolved in tetrahydrofuran (20 mL), and lithium aluminum tetrahydrogen (166.63 mg, 4.39 mmol) was added. The mixture was then stirred at 0°C for 2 hours. Water (1 mL) was added to quench the reaction mixture, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-10. LCMS (ESI) m / z: 300.2 (M+1). Step 9: Preparation of Compounds 1-11 Compound 1-10 (0.30 g, 1.00 mmol) was dissolved in water (10 mL), and concentrated sulfuric acid (18.4 g, 183.85 mmol) was added. The mixture was then stirred at 60°C for 12 hours. The reaction mixture was quenched with saturated sodium carbonate aqueous solution (100 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-11. LCMS (ESI) m / z: 282.1 (M+1). Step 10: Preparation of Compounds 1-12 Compound 1-11 (0.26 g, 924.11 μmol) and diethyl 2-(ethoxymethylene)malonate (0.20 g, 924.11 μmol) were dissolved in toluene (5 mL) and substituted three times with nitrogen. The mixture was stirred at 110 °C for 10 hours. The reaction mixture was concentrated under reduced pressure to obtain compound 1-12. LCMS (ESI) m / z: 452.1 (M+1). Step 11: Preparation of Compounds 1-13 Compound 1-12 (0.12 g, 265.77 μmol) was dissolved in polyphosphate (1.00 g). The mixture was then stirred at 90°C for 2 hours. Water (100 mL) was added to quench the reaction mixture, and the pH was adjusted to 8-9 with potassium carbonate. The mixture was then extracted with dichloromethane (20 mL x 4), the separated organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-13. LCMS (ESI) m / z: 406.1 (M+1). Step 12: Preparation of the hydrochloride salt of compound 1 Compound 1-13 (0.05 g, 123.32 μmol) was dissolved in tetrahydrofuran (1 mL), ethanol (1 mL), and water (0.5 mL), and sodium hydroxide (14.80 mg, 369.96 μmol) was added. The mixture was then stirred at 15-25°C for 2 hours. The reaction mixture was adjusted to pH 5-6 with 1 M hydrochloric acid, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: YMC Triart 30 × 150 mm × 7 μm; mobile phase: 0.05% aqueous hydrochloric acid solution and acetonitrile; gradient: acetonitrile 12%-32%) to obtain the hydrochloride salt of compound 1. 1 H NMR (400 MHz, CD3OD) δ = 9.08 (s, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.39 - 8.28 (m, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 9.4 Hz, 1H), 4.89 - 4.88 (m, 4H), 4.51 - 4.39 (m, 1H),3.18 (s, 3H), 1.50 - 1.44 (m, 2H), 1.09 - 1.03 (m, 2H). LCMS (ESI) m / z: 378.1 (M+1).

[0127] JPEG0007892060000033.jpg134170 Step 1: Preparation of Compound 2-2 Compound 2-1 (1.00 g, 4.33 mmol) was dissolved in dichloromethane (20 mL), and Boc2O (2.36 g, 10.82 mmol) and DMAP (52.88 mg, 432.81 μmol) were added. The mixture was stirred at 20-25°C for 2 hours. The reaction mixture was washed sequentially with saturated sodium bicarbonate (50 mL) and saturated saline solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 2-2. LCMS (ESI) m / z: 374.9 (M-56+1). Step 2: Preparation of Compounds 2-3 Potassium carbonate (1.44 g, 10.43 mmol) was added to a methanol (20 mL) solution of compound 2-2 (1.50 g, 3.48 mmol). The mixture was stirred at 20-25°C for 2 hours. The crude product was stirred in a mixed solvent (petroleum ether / ethyl acetate = 1 / 1) and filtered to obtain compound 2-3. 1 ¹H NMR (400 MHz, CDCl3) yielded δ values ​​of 8.47 (s, 1H), 8.33 (s, 1H), 7.68 (br s, 1H), 3.98 (s, 3H), and 1.56 (s, 9H). LCMS (ESI) m / z: 275.0 (M-56+1). Step 3: Preparation of Compounds 2-4 To a solution of compound 2-3 (5.3 g, 16.00 mmol) in acetone (80 mL), cesium carbonate (15.64 g, 48.01 mmol) and methyl iodide (2.73 g, 19.21 mmol) were added. The mixture was stirred at 20-25°C for 3 hours. After filtration, the mixture was concentrated under reduced pressure to obtain the crude product. Compound 2-4 was obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 300 / 1 to 100 / 1). LCMS (ESI) m / z: 289.0 (M-56+1). Step 4: Preparation of Compounds 2-5 Compound 2-4 (0.1 g, 289.70 μmol) was dissolved in tetrahydrofuran (2 mL) and water (0.4 mL). Compound 1-4 (91.89 mg, 289.70 μmol), 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (23.79 mg, 57.94 μmol), sodium carbonate (61.41 mg, 579.39 μmol), and palladium acetate (6.50 mg, 28.97 μmol) were added, and the mixture was purged with nitrogen three times. The temperature was raised to 70°C and stirred for 22 hours. The mixture was filtered and concentrated under reduced pressure to obtain the crude compound. Compound 2-5 was obtained by thin-layer chromatography (petroleum ether / ethyl acetate = 5 / 1). LCMS (ESI) m / z: 456.1 (M+1). Step 5: Preparation of Compounds 2-6 At 0°C, lithium aluminum tetrahydrogen (316.63 mg, 8.34 mmol) was added to a solution of compound 2-5 (950 mg, 2.09 mmol) in tetrahydrofuran (20 mL), and the mixture was stirred at 0-10°C for 2 hours. The reaction mixture was quenched with water (0.33 mL), 15% sodium hydroxide (0.33 mL), and water (1 mL), added to anhydrous sodium sulfate, dried, filtered, and concentrated to obtain compound 2-6. LCMS (ESI) m / z: 344.2 (M-56+1). Step 6: Preparation of Compounds 2-7 Compound 2-6 (500 mg, 1.67 mmol) was dissolved in 10 mL of 50% aqueous sulfuric acid solution, and the mixture was heated to 60°C and stirred for 12 hours. The reaction mixture was diluted with water (10 mL), the pH was adjusted to 9 with sodium carbonate, and the mixture was extracted with ethyl acetate (20 mL). The compound was purified by thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 2-7. LC-MS (ESI) m / z: 282.2 (M+1). Step 7: Preparation of Compounds 2-8 At 25°C, compound 2-7 (90.00 mg, 319.88 μmol) and diethyl 2-(ethoxymethylene)malonate (83.00 mg, 383.86 μmol) were dissolved in toluene (5 mL), and the temperature was raised to 110°C and stirred for 14 hours. The mixture was concentrated to obtain compound 2-8. LCMS (ESI) m / z: 452.3 (M+1). Step 8: Preparation of trifluoroacetate salts of compounds 2-9 Compound 2-8 (0.15 g, 332.22 μmol) was dissolved in polyphosphate (88.59 μmol) solution, heated to 90°C, and stirred for 2 hours. The solution was filtered, and the filtrate was separated and purified by HPLC (column: Shim-pack C18 150*25 mm*10 μm; mobile phase: 0.05% trifluoroacetic acid aqueous solution - acetonitrile; gradient: acetonitrile: 12%~42%) to obtain the trifluoroacetate salt of compound 2-9. LCMS (ESI) m / z: 406.3 (M+1). Step 9: Preparation of trifluoroacetate of compound 2 At 25°C, sodium hydroxide (2.96 mg, 73.99 μmol) was added to a solution of trifluoroacetate of compound 2-9 (6 mg, 14.80 μmol) in methanol (0.3 mL) and water (0.1 mL). The mixture was stirred at 25°C for 2 hours, filtered, and the filtrate was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: 0.05% trifluoroacetate aqueous solution - acetonitrile; gradient: acetonitrile: 12%~42%) to obtain trifluoroacetate of compound 2. 1 H NMR (400 MHz, CD3OD+D2O) δ = 9.15 (s, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.31 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.23 (s, 1H), 3.37 (s, 1H), 3.32 (s, 4H), 3.14 (s, 3H), 2.72 (s, 1H), 2.09 (s, 2H), 1.58 - 1.44 (m, 2H), 1.06 (br d, J = 2.3 Hz, 2H). LCMS (ESI) m / z:378.2 (M+1).

[0128] JPEG0007892060000034.jpg100170 Step 1: Preparation of Compound 3-2 Compound 3-1 (5.00 g, 23.69 mmol) was dissolved in t-butyl alcohol (60 mL) and water (60 mL), and potassium permanganate (18.72 g, 118.45 mmol) was added. The mixture was then stirred at 80°C for 6 hours. The reaction solution was cooled to room temperature, filtered, washed with water (20 mL) and methyl t-butyl ether (50 mL), respectively, and the aqueous phase was separated. The pH was adjusted to 4 with 1 M hydrochloric acid, and the mixture was concentrated under reduced pressure to obtain compound 3-2. LCMS (ESI) m / z: 241.0 / 243.0 (M+1). Step 2: Preparation of Compound 3-3 To a methanol (100 mL) solution of compound 3-2 (5 g, 20.74 mmol), thionyl chloride (4.94 g, 41.49 mmol) was added dropwise. The mixture was stirred at 70°C for 12 hours. Then, water (30 mL) was added to quench the reaction mixture, and methanol was removed by vacuum concentration. Extraction was performed with ethyl acetate (50 mL), and the separated organic layers were washed with water (50 mL), then with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain compound 3-3. LCMS (ESI) m / z: 255.1 / 257.1 (M+1). Step 3: Preparation of Compounds 3-4 Compound 3-3 (1.00 g, 3.92 mmol) was dissolved in DMF (20 mL), and sodium hydride (235.21 mg, 5.88 mmol, 60% purity) was added at 0°C. The mixture was stirred at 0°C for 1 hour. Then, 2-(trimethylsilyl)ethoxymethyl chloride (980.45 mg, 5.88 mmol) was added, and the mixture was stirred at 20-30°C for 2 hours. The reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (20 mL x 2), and the separated organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain compound 3-4. LCMS (ESI) m / z: 515.1 / 517.1 (M+1). Step 4: Preparation of Compounds 3-5 Compounds 3-4 (0.19 g, 493.09 μmol), 1-4 (187.68 mg, 591.70 μmol), sodium carbonate (130.66 mg, 1.23 μmol), and diphenylphosphine ferrocene palladium dichloride (36.08 mg, 49.31 μmol) were mixed with dioxane (4 mL) and water (1 mL). The mixture was then stirred at 115°C under microwave conditions for 1 hour. Water (30 mL) was added to quench the reaction mixture, and it was extracted with ethyl acetate (30 mL x 2). The separated organic layer was washed with 20 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain compound 3-5. LCMS (ESI) m / z: 496.3 (M+1). Step 5: Preparation of Compounds 3-6 At 0°C, compound 3-5 (0.55 g, 1.11 mmol) was dissolved in tetrahydrofuran (50 mL), and lithium aluminum tetrahydrogen (168.45 mg, 4.44 mmol) was added. The mixture was then stirred at 0°C for 2 hours. Water (4 mL) was added to quench the reaction mixture, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 3-6. LCMS (ESI) m / z: 440.2 (M+1). Step 6: Preparation of Compounds 3-7 Compound 3-6 (0.45 g, 1.02 mmol) was dissolved in water (5 mL), and concentrated sulfuric acid (9.2 g, 91.93 mmol) was added. The mixture was then stirred at 60°C for 12 hours. The reaction mixture was quenched with aqueous sodium carbonate solution (100 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 3-7. LCMS (ESI) m / z: 292.0 (M+1). Step 7: Preparation of Compounds 3-8 Compound 3-7 (0.2 g, 686.47 μmol) and diethyl 2-(ethoxymethylene)malonate (178.12 mg, 823.76 μmol) were dissolved in N-methylpyrrolidone (4 mL), degassed, and substituted with nitrogen three times. The mixture was stirred at 110°C for 16 hours. Water (30 mL) was added to quench the reaction mixture, and it was extracted with ethyl acetate (30 mL x 2). The separated organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to obtain compound 3-8. LCMS (ESI) m / z: 462.1 (M+1). Step 8: Preparation of Compounds 3-9 Compound 3-8 (0.12 g, 260.02 μmol) was dissolved in polyphosphate (5.00 g). The mixture was then stirred at 80°C for 4 hours. The reaction mixture was quenched with saturated sodium carbonate aqueous solution (100 mL), extracted with ethyl acetate (30 mL x 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 3-9. LCMS (ESI) m / z: 416.3 (M+1). Step 9: Preparation of Compound 3 Compound 3-9 (0.02 g, 48.14 μmol) was dissolved in methanol (3 mL) and water (1 mL), and lithium hydroxide monohydrate (4.04 mg, 96.28 μmol) was added. The mixture was then stirred at 20-30°C for 1 hour. The reaction mixture was adjusted to pH 5-6 with 1 M hydrochloric acid, and then concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150 × 25 mm × 10 μm; mobile phase: 0.225% formic acid aqueous solution - acetonitrile; gradient: acetonitrile: 8%-38%) to obtain compound 3. 1H NMR (400 MHz, DMSO-d6) δ = 8.91 (s, 1H), 8.57 - 8.46 (m, 1H), 8.40 (s, 1H), 8.09 - 7.76 (m, 3H), 4.67 - 4.46 (m, 4H), 3.98 - 3.98 (m, 1H), 1.39 - 1.29 (m, 2H), 1.08 - 1.01 (m, 2H). LCMS (ESI) m / z: 388.1 (M+1).

[0129] JPEG0007892060000035.jpg116170 Step 1: Preparation of Compound 4-2 Compound 4-1 (10.00 g, 48.20 mmol) was dissolved in dichloromethane (200 mL), and (Boc)2O (26.30 g, 120.51 mmol, 27.69 mL) and DMAP (588.90 mg, 4.82 mmol) were added. The mixture was then stirred at 15-25°C for 2 hours. The reaction solutions were washed with saturated sodium bicarbonate aqueous solution (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 4-2. LCMS (ESI) m / z: 250.9 / 252.9 (M-100-56+1). Step 2: Preparation of Compound 4-3 Potassium carbonate (20.34 g, 147.17 mmol) was added to a methanol (100 mL) solution of compound 4-2 (20.00 g, 49.06 mmol). The mixture was stirred at 20-30°C for 2 hours. Methanol was removed by vacuum concentration, and then the reaction mixture was quenched with water (100 mL) and ethyl acetate (50 mL). The mixture was filtered, and filter cake 1 was collected. The filtrate was extracted with ethyl acetate (30 mL x 2), the separated organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Ethyl acetate (15 mL) was added to the resulting crude product, stirred, and filtered to collect filter cake 2. The two filter cakes were combined and dried to obtain compound 4-3. LCMS (ESI) m / z: 250.9 / 252.9 (M-56+1). Step 3: Preparation of Compound 4-4 Compound 4-3 (13.2 g, 42.92 mmol) was dissolved in DMF (100 mL), and methyl iodide (7.31 g, 51.50 mmol) and cesium carbonate (41.95 g, 128.75 mmol) were added. The mixture was then stirred at 20-30°C for 3 hours. Water (200 mL) was added to quench the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 2). The separated organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 4-4. LCMS (ESI) m / z: 264.9 / 266.9 (M-56+1). Step 4: Preparation of Compounds 4-5 Compound 4-4 (4.94 g, 14.93 mmol), allyl tributyltin (4 g, 12.44 mmol), cesium fluoride (4.53 g, 29.85 mmol), and tetrakistriphenylphosphine palladium (1.15 g, 995.03 μmol) were mixed with dioxane (40 mL), substituted three times with N2, and then the mixture was stirred at 70°C under a nitrogen atmosphere for 5 hours. Potassium fluoride aqueous solution (50 mL) was added to quench the reaction mixture, stirred for 1 hour, then filtered, and the filtrate was extracted with ethyl acetate (50 mL x 3). The separated organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to obtain compound 4-5. LCMS (ESI) m / z: 227.1 / 229.1 (M-56+1). Step 5: Preparation of Compounds 4-7 Compound 4-6 (1.00 g, 3.27 mmol) was dissolved in chloroform (10 mL), and N-bromosuccinimide (698.53 mg, 3.92 mmol) and azobisisobutyronitrile (53.71 mg, 0.33 mmol) were added. The mixture was stirred at 80°C for 16 hours. The reaction mixture was then concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1 to 1 / 2) to obtain compound 4-7. 1H NMR (400 MHz, CD3OD) δ ppm= 8.90 (s, 1 H), 8.36 (d, J = 8.75 Hz, 1 H), 7.61 (d, J = 8.76 Hz, 1 H), 4.32 - 4.41 (m, 3 H), 2.71 (s, 2 H), 1.40 (t, J = 7.07 Hz, 7 H). JPEG0007892060000036.jpg38170 Step 7: Preparation of Compounds 4-9 Methyltriphenylphosphine bromide (2.85 g, 7.98 mmol) was dissolved in tetrahydrofuran (80 mL), and then potassium tert-butoxide (1 M, 7.98 mL) was added at 0°C. The mixture was stirred at 15-25°C for 0.5 hours. Compound 4-8 (1.7 g, 5.32 mmol) was then added, and the mixture was stirred at 15-25°C for 2 hours. The reaction mixture was quenched with water (200 mL), extracted with ethyl acetate (50 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain compound 4-9. LCMS (ESI) m / z: 318.1 (M+1). Step 8: Preparation of Compounds 4-10 Compound 4-9 (1.5 g, 4.72 mmol), 2-di-t-butylphosphino-2',4',6'-triisopropylbiphenyl (225.03 mg, 472.05 μmol), tricyclohexylphosphine (132.38 mg, 472.05 μmol), bis(pinacolato)diborone (1.80 g, 7.08 mmol), potassium acetate (926.53 mg, 9.44 mmol), and tris(dibenzylideneacetone)dipalladium (432.26 mg, 472.05 μmol) were mixed with dioxane (10 mL), replaced three times with N2, and then the mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain compounds 4-10. LCMS (ESI) m / z: 410.3 (M+1). Step 9: Preparation of Compound 4-11 Compound 4-10 (0.5 g, 1.22 mmol), Compound 4-5 (345.44 mg, 1.12 mmol), potassium carbonate (337.68 g, 2.44 mmol), 2-di-t-butylphosphino-2',4',6'-triisopropylbiphenyl (58.24 mg, 122.17 μmol), tricyclohexylphosphine (34.26 mg, 122.17 μmol), and tris(dibenzylideneacetone)dipalladium (111.87 mg, 122.17 μmol) were mixed with dioxane (10 mL) and water (2 mL), replaced three times with N2, and then the mixture was stirred at 100 °C under a nitrogen atmosphere for 1.5 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 40 mm × 15 μm; mobile phase: 0.225% formic acid aqueous solution - acetonitrile; gradient: acetonitrile: 57%~87%) to obtain compound 4-11. LCMS (ESI) m / z: 530.2 (M+1). 1 H NMR (400 MHz, CDCl3) δ = 8.70 (s, 1H), 8.47 (d, J = 8.3 Hz, 1H), 8.13 - 8.06 (m, 1H), 7.66 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.92 - 6.81 (m, 1H), 5.75 (tdd, J = 6.6, 10.2, 16.9 Hz, 1H), 5.34 - 5.26 (m, 1H), 5.09 - 4.83 (m, 1H), 4.43 (q, J = 7.0 Hz, 2H), 3.84 - 3.74 (m, 1H), 3.45 (s, 3H), 3.18 - 3.00 (m, 2H), 1.58 - 1.55 (m, 9H), 1.44 (t, J = 7.1 Hz, 3H), 1.30 - 1.24 (m, 3H), 1.15 - 1.08 (m, 2H), 0.91 - 0.84 (m, 2H). Step 10: Preparation of Compounds 4-12 Compound 4-11 (0.04 g, 75.53 μmol) was dissolved in dichloromethane (2 mL), and Hoveyda-Grubbs second-generation catalyst (4.73 mg, 7.55 μmol) was added. The mixture was then stirred at 40°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to obtain compound 4-12. LCMS (ESI) m / z: 502.3 (M+1). Step 11: Preparation of Compounds 4-13 Compound 4-12 (0.05 g, 99.69 μmol) was dissolved in dioxane (0.5 mL), and hydrochloric acid / dioxane solution (4 M, 0.5 mL) was added. The mixture was then stirred at 10-20°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain compound 4-13. LC-MS (ESI) m / z: 402.2 (M+1). Step 12: Preparation of Compound 4 Compound 4-13 (0.04 g, 99.64 μmol) was dissolved in methanol (1 mL) and water (0.2 mL), and sodium hydroxide (7.97 mg, 199.27 μmol) was added. The mixture was then stirred at 10-20°C for 2 hours. The reaction mixture was adjusted to pH 5-6 with acetic acid, and then concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: 0.225% formic acid aqueous solution - acetonitrile; gradient: acetonitrile: 4-34%) to obtain compound 4. 1H NMR (400 MHz, DMSO-d6) δ = 15.09 (s, 1H), 8.89 (s, 1H), 8.38 (s, 1H), 8.28 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 9.8 Hz, 1H), 6.86 (br d, J = 4.9 Hz, 1H), 6.39 (s, 1H), 6.16 (td, J = 7.1, 9.8 Hz, 1H), 4.37 (br t, J = 4.4 Hz, 1H), 3.45 - 3.39 (m, 2H), 2.83 (d, J = 4.9 Hz, 3H), A value of 1.28 - 0.77 (m, 4H) was obtained. LCMS (ESI) m / z: 374.1 (M+1).

[0130] JPEG0007892060000037.jpg100170 Step 1: Preparation of Compound 5-2 Silver carbonate (5.41 g, 19.61 mmol) was added to a toluene (50 mL) solution of compound 5-1 (3.50 g, 15.08 mmol) and methyl iodide (3.21 g, 22.63 mmol, 1.41 mL). The mixture was stirred at 100°C for 1.5 hours. The mixture was then cooled to room temperature, diluted with ethyl acetate (50 mL), filtered, and the mother liquor was concentrated to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to obtain compound 5-2. LCMS (ESI) m / z: 246 / 248 (M+1); 1 H NMR (400 MHz, CDCl3) δ= 8.37 (s,1 H),7.10 (s,1 H),3.97 (s,3 H),3.95 (s,3 H). Step 2: Preparation of Compound 5-3 At 0°C, lithium aluminum tetrahydrofuran (466.61 mg, 12.29 mmol) was added in batches to a 40 mL solution of 5-2 (2.75 g, 11.18 mmol) in tetrahydrofuran. The mixture was stirred at 0°C for 0.5 hours. At 0°C, sodium sulfate decahydrate (5.00 g) was added to quench the reaction mixture, and the mixture was then filtered. The resulting mother liquor was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1~3 / 1) to obtain compound 5-3. LCMS (ESI) m / z: 218 / 220 (M+1). Step 3: Preparation of Compounds 5-4 At 0°C, sodium hydride (238.46 mg, 5.96 mmol, 60% purity) was added to a solution of compound 5-3 (1.00 g, 4.59 mmol) in tetrahydrofuran (15 mL), followed by compound 4-7 (1.76 g, 4.59 mmol), and the mixture was stirred at 0°C for 3.5 hours. The reaction was quenched with 15 mL of saturated ammonium chloride aqueous solution and extracted with ethyl acetate (15 mL x 2). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1 to 1 / 1) to obtain compound 5-4. LCMS (ESI) m / z: 521 / 523 (M+1). Step 4: Preparation of Compound 5-5 Compound 5-4 (0.1 g, 0.19 mmol), bis(pinacolato)diborone (97.33 mg, 0.38 mmol), potassium acetate (37.62 g, 0.38 mmol), and bis(triphenylphosphine)palladium(II) dichloride (14.02 mg, 19.16 μmol) were mixed with ethylene glycol dimethyl ether (2 mL), replaced three times with N2, and then the mixture was stirred at 80°C under a nitrogen atmosphere for 16 hours. Further, bis(triphenylphosphine)palladium(II) dichloride (14.02 mg, 19.16 μmol), sodium carbonate (40.62 mg, 0.38 mmol), and water (0.2 mL) were added to the reaction mixture, and then the mixture was stirred at 80°C under a nitrogen atmosphere for 20 hours. The reaction mixture was concentrated under reduced pressure, the solvent was removed, and the residue was obtained. The compound 5-5 was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1 to 0 / 1). LCMS (ESI) m / z: 407 (M+1). Step 5: Preparation of Compound 5 At 20°C, lithium hydroxide monohydrate (10.32 mg, 246.04 μmol) was added to a solution of compound 5-5 (25 mg, 61.51 μmol) in methanol (1 mL) and water (0.25 mL). The mixture was stirred at 20°C for 3 hours and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex C1875 × 30 mm × 3 μm; mobile phase: 0.225% formic acid aqueous solution - acetonitrile; gradient: acetonitrile: 32%~62%) to obtain compound 5. LCMS (ESI) m / z: 309 (M+1); 1 H NMR (400 MHz, DMSO-d6) δ= 8.88 - 8.97 (m, 1 H), 8.61 - 8.68 (m, 1 H), 8.44 - 8.53 (m, 1 H), 7.90 - 8.01 (m, 1 H), 7.10 - 7.17 (m, 1 H), 4.66 - 4.78 (m, 2 H), 4.44 - 4.59 (m, 3 H), 3.95 - 4.02 (m, 3 H), 1.30 - 1.38 (m, 2 H), 1.04 (br d, J = 8.19 Hz, 2 H).

[0131] JPEG0007892060000038.jpg119170 Step 1: Preparation of Compound 6-2 Compound 6-1 (1.72 g, 13.86 mmol) was dissolved in acetonitrile (17.2 mL), and NBS (2.47 g, 13.86 mmol) was added at 0-20°C. The mixture was stirred under a nitrogen atmosphere for 3 hours. Water (20 mL) was added to the reaction mixture to quench it, and ethyl acetate (20 mL) was added to dilute it. After dilution, the mixture was extracted with ethyl acetate (20 mL x 2), the mixed organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain compound 6-2. LCMS (ESI) m / z: 203.05 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ = 7.87 (s, 1H), 6.67 (s, 1H), 6.11 (s, 2H), 5.46 (t, J = 5.6 Hz, 1H), 4.35 (d, J = 5.6 Hz, 2H). Step 2: Preparation of Compound 6-3 Compound 6-2 (30 g, 147.76 mmol) and imidazole (15.09 g, 221.64 mmol) were dissolved in DMF (250 mL) solution. Then, TBSCl (33.40 g, 221.64 mmol, 27.16 mL) was dissolved in DMF (50 mL) and slowly added dropwise to the reaction mixture over 20 minutes at 25°C, and the mixture was stirred at 25°C for 3 hours. After diluting the reaction mixture with water (100 mL), it was extracted with ethyl acetate (50 mL x 2). The mixed organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was stirred with petroleum ether (100 mL), filtered, and the filter cake was collected and dried to obtain compound 6-3. LCMS (ESI) m / z: 319.1 (M+1). Step 3: Preparation of Compound 6-4 Compound 6-3 (3g, 9.45 mmol) was dissolved in DMF (30 mL) and NaH (1.51 g, 37.82 mmol) and methyl iodide (6.71 g, 47.27 mmol, 2.94 mL) were added sequentially. The mixture was stirred at 0°C for 5 hours. The reaction solution was quenched with saturated ammonium chloride solution (50 mL), diluted with water (20 mL), extracted with ethyl acetate (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound 6-4 was obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1). LCMS (ESI) m / z: 346.9 (M+1). Step 4: Preparation of Compounds 6-5 To a solution of compound 6-4 (1.92 g, 5.56 mmol) in dichloromethane (20 mL), triethylamine hydrofluoride (4.48 g, 27.80 mmol, 4.53 mL) was added and the mixture was stirred at 25°C under a nitrogen atmosphere for 2 hours. After diluting the reaction mixture with water (5 mL), it was extracted with ethyl acetate (5 mL x 2), washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1~5 / 1) to obtain compound 6-5. 1 H NMR (400 MHz, DMSO-d6) δ = 8.09 (s, 1H), 6.83 (s, 1H), 4.44 (s, 2H), 3.05 (s, 6H). Step 5: Preparation of Compound 6-6 At 0°C, a solution of compound 6-5 (0.95 g, 4.11 mmol) in DMF (10 mL) was sequentially mixed with sodium hydride (328.88 mg, 8.22 mmol, 60% purity) and compound 4-7 (1.58 g, 4.11 mmol), and the mixture was stirred for 6 hours. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL), diluted with water (10 mL), extracted with ethyl acetate (10 mL x 2), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1~1 / 2) to obtain compound 6-6. 1 H NMR (400 MHz, DMSO-d6) δ = 8.60 (s, 1H), 8.14 (d, J = 8.6 Hz, 1H), 8.02 (s, 1H), 7.57 (d, J = 8.7 Hz, 1H), 6.51 (s, 1H), 5.39 (s, 2H), 4.44 (s, 2H), 4.24 (q, J = 7.1 Hz, 3H), 2.94 (s, 6H), 1.29 (t, J = 7.1 Hz, 3H), 1.17 (br d, J = 7.1 Hz, 3H), 0.90 - 0.85 (m, 2H). Step 6: Preparation of Compounds 6-7 At room temperature, compound 6-6 (0.5 g, 934.88 μmol), bis(pinacolato)diborone (712.20 mg, 2.80 mmol), potassium pivalate (327.73 mg, 2.34 mmol), and tetrakistriphenylphosphine palladium (108.03 mg, 93.49 μmol) were dissolved in ethylene glycol dimethyl ether (5 mL), and the mixture was heated to 90°C and stirred for 18 hours. After diluting the reaction mixture with water (10 mL), it was extracted with ethyl acetate (20 mL), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1~1 / 1) to obtain compound 6-7. LCMS (ESI) m / z: 582.3 (M+1). Step 7: Preparation of trifluoroacetate salts of compounds 6-8 Compounds 6-7 (390 mg, 670.23 μmol), potassium carbonate (231.58 mg, 1.68 mmol), tetrakistriphenylphosphine palladium (24.71 mg, 67.02 μmol), and 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (63.90 mg, 134.05 μmol) were dissolved in water (0.4 mL) and ethylene glycol dimethyl ether (4 mL), and the mixture was heated to 90°C and stirred for 15 hours. After diluting the reaction mixture with water (5 mL), it was extracted with ethyl acetate (5 mL x 2), the mixed organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100*25mm*4μm; mobile phase: 0.05% trifluoroacetic acid aqueous solution - acetonitrile; gradient: acetonitrile: 24%~44%) to obtain trifluoroacetic acid salts of compounds 6-8. LCMS (ESI) m / z: 420.2 (M+1). Step 8: Preparation of Compound 6 and Compound 6 Hydrochloride Method 1: At 0°C, sodium hydroxide (14.30 mg, 357.59 μmol) was added to a mixed solution of compound 6-8 (30 mg, 71.52 μmol) in methanol (0.6 mL) and water (0.3 mL), and the mixture was stirred at 20°C under a nitrogen atmosphere for 15 hours. The mixture was filtered, and the filtrate was separated and purified by HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: 10 mM ammonium bicarbonate aqueous solution - acetonitrile; gradient: acetonitrile: 24%~54%) to obtain compound 6. LCMS (ESI) m / z: 392.1 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ = 8.90 (s, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.41 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 4.77 (br s, 2H), 4.56 - 4.52 (m, 2H), 3.91 - 4.02 (m, 1H), 3.15 (s, 6H), 1.22-1.45 (m, 4H). Method 2: At 0°C, an aqueous solution (10 mL) of sodium hydroxide (600.76 mg, 15.02 mmol) was added to methanol (20 mL) containing compound 6-8 (0.63 g, 1.50 mmol), and the mixture was stirred at 20-30°C for 15 hours. The mixture was filtered, and the filter cake was collected to obtain the crude product. At room temperature, the crude product was added to a mixed solution of hydrochloric acid (12 M, 122.63 μL) and aqueous solution (4 mL), and the mixture was stirred for 16 hours. After filtering the reaction mixture, the filter cake was collected, dried, and the hydrochloride salt of compound 6 was obtained. LCMS (ESI) m / z: 392.1 (M+1).

[0132] JPEG0007892060000039.jpg156170 Step 1: Preparation of Compound 7-2 At 0°C, sodium hydride (322.22 mg, 8.06 mmol) was added to a solution of compound 7-1 (0.50 g, 4.03 mmol) in DMF (5 mL). After 10 minutes, compound 4-7 was added to the reaction mixture and stirred for 6 hours. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (10 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound 7-2 was obtained by silica gel column chromatography (dichloromethane / methanol = 100 / 3). LCMS (ESI) m / z: 428.2 (M+1). Step 2: Preparation of Compound 7-3 At 0°C, bromosuccinimide (0.61 g, 3.41 mmol) was added to a solution of compound 7-2 (1.46 g, 3.41 mmol) in dichloromethane (20 mL), and the mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated, diluted with water (10 mL), extracted with dichloromethane (10 mL x 2), washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. Compound 7-3 was obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0~100 / 3). LCMS (ESI) m / z: 508.1 (M+1). Step 3: Preparation of Compound 7-4 Compound 7-3 (390.85 mg, 771.24 μmol) was dissolved in 6 mL of dichloromethane, to which Boc2O (0.42 mg, 1.93 mmol, 0.44 mL) and 4-dimethylaminopyridine (9.42 mg, 77.12 μmol) were added, and the mixture was stirred at 20-25°C for 2 hours. After diluting the reaction mixture with water (5 mL), it was extracted with dichloromethane (5 mL x 2), the mixed organic phase was washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7-4. LCMS (ESI) m / z: 708.1 (M+1). Step 4: Preparation of Compounds 7-5 To a solution of compound 7-4 (0.05 g, 70.72 μmol) in ethylene glycol dimethyl ether (1 mL), bis(pinacolato)diborone (35.92 mg, 141.44 μmol), potassium pivalate (24.79 mg, 176.80 μmol), and tetrakistriphenylphosphine palladium (2.61 mg, 7.07 μmol) were sequentially added, and the mixture was stirred at 90°C for 15 hours. The crude reaction solution of compound 7-5 was obtained and used directly in the next step. LCMS (ESI) m / z: 672.3 (M+1). Step 5: Preparation of Compounds 7-6 Crude compound 7-5 (47.52 mg, 70.72 μmol), potassium carbonate (24.44 mg, 176.80 μmol), tetrakistriphenylphosphine palladium (2.61 mg, 7.07 μmol), and 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (6.74 mg, 14.14 μmol) were dissolved in water (0.1 mL) and ethylene glycol dimethyl ether (1 mL). The mixture was purged with nitrogen three times, and the temperature was raised to 90°C and stirred for 15 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain compound 7-6. LCMS (ESI) m / z: 592.2 (M+1). Step 6: Preparation of trifluoroacetate of compound 7-7 and compound 7-7 To a solution of compound 7-6 (41.84 mg, 70.72 μmol) in dichloromethane (1 mL), trifluoroacetic acid (821.20 mg, 7.20 mmol, 533.25 μL) was added and the mixture was stirred for 2 hours. The mixture was divided into multiple batches for post-treatment. Method 1: The reaction mixture was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 7-7. Method 2: The reaction mixture was concentrated under reduced pressure to obtain the crude product, the pH was adjusted to 8.0 with saturated sodium carbonate solution, and after extraction with dichloromethane, the organic phase was added and concentrated under reduced pressure to obtain compound 7-7. LCMS (ESI) m / z: 392.1 (M+1). Step 7: Preparation of trifluoroacetate and hydrochloride of compound 7 Method 1: At 0°C, sodium hydroxide (26.52 mg, 662.97 μmol) was added to a solution of crude compound 7-7 (25.95 mg, 66.30 μmol) in methanol (1 mL) and water (0.5 mL), and the mixture was stirred under a nitrogen atmosphere at 20°C for 15 hours. The mixture was concentrated under reduced pressure to obtain the crude compound, which was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100*25 mm*4 μm; mobile phase: 0.05% trifluoroacetic acid aqueous solution - acetonitrile; gradient: acetonitrile: 17%~37%) to obtain the trifluoroacetate of compound 7. LCMS (ESI) m / z: 364.1 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ = 8.90 (s, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.41 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 6.91 (s, 1H), 4.77 (br s, 2H), 4.51 (s, 3H), 1.32 (br d, J = 6.4 Hz, 2H), 1.02 (br s, 2H). Method 2: At room temperature, an aqueous solution (5 mL) of sodium hydroxide (102.18 mg, 2.55 mmol) was added to a methanol (10 mL) solution of crude compound 7-7 (1 g, 2.55 mmol), and the mixture was stirred at 20-50°C for 36 hours. The mixture was filtered, and the filter cake was collected to obtain the crude compound. Hydrochloric acid (12 M, 2 mL) was added to an aqueous solution (4 mL) of the crude compound, and the mixture was stirred for 16 hours. After filtering the reaction mixture, the filter cake was collected and dried to obtain the hydrochloride salt of compound 7. LCMS (ESI) m / z: 364.1 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ = 8.91 (s, 1H), 8.49 (d, J = 8.3 Hz, 1H), 8.42 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.05 (s, 1H), 4.81 (s, 2H), 4.55 (s, 2H), 4.52 - 4.43 (m, 1H), 1.36 - 1.28 (m, 2H), 1.07 - 0.99 (m, 2H).

[0133] JPEG0007892060000040.jpg181170 Step 1: Preparation of Compound 8-2 At 20°C, compound 8-1 (1.00 g, 5.39 mmol) and N-methylbenzylamine (979.32 mg, 8.08 mmol, 1.04 mL) were dissolved in dioxane (20 mL). Cesium carbonate (5.27 g, 16.16 mmol) and chloro[(tri-t-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (276.07 mg, 538.77 μmol) were added, and the mixture was stirred at 90°C for 16 hours. The compound was filtered and concentrated, and subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 30 / 1) to obtain compound 8-2. LCMS (ESI) m / z: 271.2 (M+1). 1 H NMR (400 MHz, CDCl3) δ = 8.15 (d, J = 5.0 Hz, 1H), 7.32 - 7.23 (m, 4H), 7.21 - 7.12 (m, 2H), 4.27 (s, 2H), 3.84 (s, 3H), 2.67 (s, 3H), 2.42 (s, 3H). Step 2: Preparation of Compound 8-3 Compound 8-2 (200 mg, 739.85 μmol) was dissolved in tetrahydrofuran solution (3 mL), and lithium aluminum tetrahydrogen (33.70 mg, 887.82 μmol) was added at 0°C. The mixture was stirred at 0-25°C for 2 hours, and water (0.034 mL) and 15% aqueous sodium hydroxide solution (0.034 mL) were added to the reaction mixture, followed by the addition of water (0.10 mL) to quench the reaction. Anhydrous magnesium sulfate was added, and the mixture was filtered and concentrated to obtain the crude compound. The crude compound was subjected to silica gel column chromatography (petroleum ether / ethyl acetate: 3 / 1) to obtain compound 8-3. LCMS (ESI) m / z: 243.1 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ = 8.09 (d, J = 5.0 Hz, 1H), 7.33 (d, J = 4.6 Hz, 4H), 7.28 - 7.20 (m, 1H), 7.08 (d, J = 5.0 Hz, 1H), 5.29 (t, J = 5.4 Hz, 1H), 4.50 (d, J = 5.4 Hz, 2H), 4.22 (s, 2H), 2.63 (s, 3H), 2.19 (s, 3H). Step 3: Preparation of Compound 8-4 Compound 8-3 (800 mg, 3.30 mmol) was dissolved in a mixed solvent of ethanol (3 mL) and acetic acid (3 mL). Then, 80 mg Pd / C (10% purity) was added. A hydrogen balloon was placed in the reaction flask, and the system was purged three times to fill it with hydrogen. The reaction was carried out with stirring at 15-25°C for 3 hours. The reaction mixture was filtered and concentrated. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (25 mL x 2). The organic phase was washed with water (15 mL x 2), then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 8-4. LCMS (ESI) m / z: 153.1 (M+1) Step 4: Preparation of Compound 8-5 Compound 8-4 (156 mg, 1.03 mmol) was dissolved in DMF (1 mL), and the mixture was stirred for 0.5 hours at 0-5°C with NaH (82.00 mg, 2.05 mmol, 60% purity). Then, compound 4-7 (413.99 mg, 1.08 mmol) was added and the mixture was stirred at 0-5°C for 3 hours to react. The reaction was quenched with saturated ammonium chloride aqueous solution (1 mL), water (50 mL) was added, and the mixture was extracted with ethyl acetate (25 mL x 2). The organic phase was washed with saturated brine (25 mL x 2), filtered, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain crude compound 8-5. LCMS (ESI) m / z: 456.1 (M+1). Step 5: Preparation of trifluoroacetate of compound 8-6 Compound 8-5 (330 mg, 723.79 μmol) was dissolved in DCM (3 mL), and N-bromosuccinimide (128.82 mg, 723.79 μmol) was added at 0°C. The mixture was stirred at 0-5°C for 1 hour. The solution was concentrated, and the crude product was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100*25 mm*4 μm; mobile phase: 0.05% trifluoroacetic acid aqueous solution - acetonitrile; gradient: acetonitrile: 32%~52%) to obtain the trifluoroacetate salt of compound 8-6. LCMS (ESI) m / z: 536.0 (M+1). Step 6: Preparation of Compounds 8-7 The trifluoroacetate salt of compound 8-6 (90 mg, 168.28 μmol) and bis(pinacolato)diborone (85.46 mg, 336.56 μmol) were dissolved in ethylene glycol dimethyl ether (5 mL). Then, potassium pivalate (47.19 mg, 336.56 μmol) and tetrakistriphenylphosphine palladium (19.45 mg, 16.83 μmol) were added, the mixture was purged with nitrogen three times, and stirred at 90°C for 12 hours to obtain a crude reaction solution containing compound 8-7, which was used directly in the next step. LCMS (ESI) m / z: 582.5 (M+1). Step 7: Preparation of Compound 8-8 A crude reaction solution containing compound 8-7 (97.9 mg, 168.24 μmol) was added to a solution of potassium carbonate (46.51 mg, 336.49 μmol), tetrakistriphenylphosphine palladium (19.44 mg, 16.82 μmol), and 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (16.04 mg, 33.65 μmol) dissolved in ethylene glycol dimethyl ether (2 mL) and water (0.2 mL). The mixture was reacted at 90°C for 2 hours. The solution was concentrated, diluted with saturated saline (30 mL), extracted with ethyl acetate (30 mL x 2), the organic phase was washed with saturated saline (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 8-8. LCMS (ESI) m / z: 420.2 (M+1). Step 8: Preparation of trifluoroacetate of compound 8 Compound 8-8 (95 mg, 226.48 μmol) was dissolved in methanol (3 mL), then water (1 mL) and NaOH (54.35 mg, 1.36 mmol) were added, and the mixture was stirred and reacted at 15-20°C for 12 hours. The mixture was filtered and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: 0.05% trifluoroacetic acid aqueous solution - acetonitrile; gradient: acetonitrile: 13%~33%) to obtain the trifluoroacetate of compound 8. LCMS (ESI) m / z: 392.1 (M+1). 1 H NMR (400 MHz, CD3OD) δ = 9.09 (s, 1H), 8.64 (d, J = 8.3 Hz, 1H), 8.15 (s, 1H), 7.85 (d, J = 8.3 Hz, 1H), 4.99 - 4.95 (s, 2H), 4.80 - 4.75 (s, 2H), 4.45 (tt, J = 3.5, 7.0 Hz, 1H), 3.21 (s, 3H), 2.42 (s, 3H), 1.52 - 1.45 (m, 2H), 1.12 - 1.03 (m, 2H).

[0134] JPEG0007892060000041.jpg172170 Step 1: Preparation of Compound 9-2 Compound 9-1 (2 g, 13.06 mmol) was added to a mixed solvent of ethanol (125 mL) and dichloromethane (20 mL), then NaBH4 (1.51 g, 39.97 mmol) was added, and the mixture was stirred at 15-20°C for 12 hours. The reaction mixture was filtered and concentrated, and acetone (20 mL) was added to the filtrate under ice bath. Then, 2 M dilute hydrochloric acid was added until no more bubbles were generated, and saturated sodium bicarbonate solution was added to adjust the pH to 8. The mixture was filtered, the filtrate was concentrated, ethanol (50 mL) was added, and the mixture was stirred at 15-20°C for 0.5 hours. The mixture was filtered and concentrated, and the filtrate was used to obtain compound 9-2. 1 H NMR (400 MHz, DMSO-d6) δ = 8.20 (d, J = 4.9 Hz, 1H), 6.66 (d, J = 5.0 Hz, 1H), 6.50 (br s, 2H), 5.75 - 5.00 (br s, 1H), 4.30(s, 2H). Step 2: Preparation of Compound 9-3 Compound 9-2 (0.87 g, 4.17 mmol) was dissolved in DMF (10 mL), NaH (667.47 mg, 16.69 mmol) was added at 0°C, and the mixture was stirred for 0.5 hours. Then, compound 4-7 (1.60 g, 4.17 mmol) was added, and the mixture was stirred at 0-5°C for 3 hours. Saturated saline (100 mL) was added and the mixture was quenched. The mixture was dried over sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 9-3. LCMS (ESI) m / z: 429.1 (M+1). Step 3: Preparation of Compound 9-4 Compound 9-3 (0.55 g, 1.28 mmol) was dissolved in DCM (5 mL), and NBS (228.25 mg, 1.28 mmol) was added at 0°C. The mixture was stirred and reacted for 1 hour. Compound 9-4 was obtained by silica gel flash column chromatography (dichloromethane / methanol = 50 / 1). LCMS (ESI) m / z: 508.9 (M+1). Step 4: Preparation of Compound 9-5 Compound 9-4 (0.8 g, 1.58 mmol), Boc2O (1.20 g, 5.51 mmol, 1.27 mL), and DMAP (19.25 mg, 157.55 μmol) were dissolved in DCM (3 mL) and reacted with stirring at 10-25°C for 12 hours. The reaction mixture was concentrated and subjected to silica gel flash column chromatography (dichloromethane / methanol = 50 / 1) to obtain compound 9-5. LCMS (ESI) m / z: 709.2 (M+1). Step 5: Preparation of Compound 9-6 Compound 9-5 (100 mg, 141.24 μmol), bis(pinacolato)diborone (71.73 mg, 282.49 μmol), tetrakistriphenylphosphine palladium (16.32 mg, 14.12 μmol), and potassium pivalate (39.61 mg, 282.49 μmol) were added to DME (2 mL), stirred at 90°C for 12 hours, cooled to room temperature, and potassium carbonate (39.02 mg, 282.35 μmol), tetrakistriphenylphosphine palladium (16.32 mg, 14.12 μmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (13.46 mg, 28.24 μmol), and H2O (0.2 mL) were added. The mixture was reacted at 90°C for 2 hours. The reaction mixture was concentrated to obtain compound 9-6. LCMS (ESI) m / z: 593.3 (M+1). Step 6: Preparation of Compound 9-7 Compound 9-6 (83 mg, 140.05 μmol) was added to a mixed solvent of MeOH (1 mL) and H2O (3 mL), and sodium hydroxide (33.61 mg, 840.31 μmol) was added. The mixture was stirred at 15-20°C for 12 hours to allow the reaction to proceed. The reaction solution was concentrated to obtain compound 9-7. LCMS (ESI) m / z: 565.4 (M+1). Step 7: Preparation of trifluoroacetate of compound 9 Compound 9-7 (79 mg, 139.93 μmol) was added to a mixed solvent of DCM (1 mL) and TFA (770.00 mg, 6.75 mmol) and reacted by stirring at 15-20°C for 6 hours. The reaction mixture was concentrated, and the crude product was dissolved in a mixed solvent of DMF (5 mL) and TFA (200 μL). Separation and purification were performed by preparative HPLC (column: Phenomenex Synergi Polar-RP 100*25 mm*4 μm; mobile phase: [0.05% trifluoroacetic acid aqueous solution - acetonitrile; gradient: acetonitrile: 30%~50%]), MeOH (1 mL) was added, and the mixture was stirred at 15-20°C for 1 hour. The mixture was filtered, the filter cake was rinsed with MeOH (0.5 mL), and dried under reduced pressure to obtain the trifluoroacetate of compound 9. LCMS (ESI) m / z: 365.1 (M+1).

[0135] JPEG0007892060000042.jpg126170 Step 1: Preparation of trifluoroacetate of compound 10-1 At 0°C, compound 5-bromo-2-methylpyridine-4-methanol (525.28 mg, 2.60 mmol) was dissolved in DMF (10 mL), and NaH (415.96 mg, 10.40 mmol, 60% purity) was slowly added, and the reaction was allowed to proceed for 0.5 hours. Then, at 0°C, compound 4-7 (1 g, 2.60 mmol) was added, and the mixture was stirred at 0°C for 1 hour. At 0°C, the reaction mixture was added to saturated ammonium chloride aqueous solution (20 mL) and quenched, diluted with water (20 mL), extracted with ethyl acetate (90 mL), the organic layer was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: Phenomenex Luna 150×40mm×15μm; mobile phase: 0.05% trifluoroacetic acid aqueous solution and acetonitrile; proportion of acetonitrile in the mobile phase: 21%~51%) to obtain the trifluoroacetate of compound 10-1. LCMS (ESI) m / z: 507.1 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm 0.81 - 0.92 (m, 2 H) 1.17 (br d, J=6.24 Hz, 3 H) 1.26 (t, J=7.09 Hz, 3 H) 2.42 (s, 3 H) 4.22 (d, J=7.09 Hz, 3 H) 4.54 (s, 2 H) 5.49 (s, 2 H) 7.35 (s, 1 H) 7.42 (d, J=8.68 Hz, 1 H) 8.13 (d, J=8.68 Hz, 1 H) 8.47 (s, 1 H) 8.71 (s, 1 H). Step 2: Preparation of trifluoroacetate of compound 10-2 252 mg, 498.23 μmol, trifluoroacetate of compound 10-1, bis(pinacorato)diborone (253.04 mg, 996.47 μmol), potassium pivalate (139.72 mg, 996.47 μmol), and triphenylphosphine palladium (36.74 mg, 99.65 μmol) were mixed in 3 mL of DMF, degassed, and purged three times with nitrogen. The mixture was stirred at 120°C under a nitrogen atmosphere for 16 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (column: 3_Phenomenex Luna 75 × 30 mm × 3 μm; mobile phase: 0.05% trifluoroacetic acid aqueous solution - acetonitrile; gradient: acetonitrile: 15%~35%) to obtain trifluoroacetate of compound 10-2. LCMS (ESI) m / z: 391.2 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.94 (br s, 2 H) 1.25 - 1.33 (m, 5 H) 2.65 (s, 3 H) 4.20 - 4.39 (m, 3 H) 4.57 (s, 2 H) 4.66 (s, 2 H) 7.65 (s, 1 H) 7.83 (d, J=8.31 ​​Hz, 1 H) 8.38 (d, J=8.19 Hz, 1 H) 8.67 (s, 1 H) 8.94 (s, 1 H). Step 3: Preparation of the sodium salt of compound 10 Under room temperature conditions, a solution of 10-2 trifluoroacetate (50 mg, 128.06 μmol) in anhydrous methanol (0.6 mL) was mixed with a solution of sodium hydroxide (51.22 mg, 1.28 mmol) in aqueous solution (0.3 mL). The mixture was stirred at 20°C for 3 hours. The mixture was concentrated under reduced pressure to obtain the crude product. DMF (1 mL) was added to the crude product and stirred for 1 hour. The mixture was filtered, and the filter cake was collected to obtain the sodium salt of compound 10. LCMS (ESI) m / z: 363.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (br s, 2 H) 1.34 (br d, J=6.85 Hz, 3 H) 2.62 (s, 3 H) 4.48 - 4.59 (m, 3 H) 4.69 (br s, 2 H) 7.54 (s, 1 H) 8.01 (d, J=8.31 ​​Hz, 1 H) 8.52 (d, J=8.31 ​​Hz, 1 H) 8.91 (d, J=10.03 Hz, 2 H) 14.84 (s, 1 H).

[0136] JPEG0007892060000043.jpg124170 Step 1: Preparation of trifluoroacetate of compound 11-1 At 0°C, compound 3-bromopyridine-4-methanol (2.44 g, 12.98 mmol) was dissolved in DMF (30 mL), and NaH (2.08 g, 51.91 mmol, 60% purity) was slowly added, and the reaction was allowed to proceed for 0.5 hours. Then, at 0°C, compound 4-7 (4.99 g, 12.98 mmol) was added, and the mixture was stirred at 0°C for 1 hour. At 0°C, the reaction mixture was added to saturated ammonium chloride aqueous solution (100 mL) and quenched, diluted with water (50 mL), extracted with dichloromethane (150 mL), the organic layer was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: Waters Xbridge 250×80mm×15μm; mobile phase: 10 mmol / L trifluoroacetic acid aqueous solution and acetonitrile; gradient: acetonitrile 40%~70%) to obtain the trifluoroacetic acid salt of compound 11-1. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.13 - 1.25 (m, 7 H) 4.39 (s, 2 H) 4.46 (br s, 1 H) 4.54 (s, 2 H) 5.46 (s, 2 H) 7.55 (d, J=8.63 Hz, 1 H) 7.62 (d, J=8.63 Hz, 1 H) 8.11 (dd, J=8.57, 5.19 Hz, 2 H) 8.60 (s, 1 H) 8.77 (s, 1 H). Step 2: Preparation of trifluoroacetate of compound 11-2 100 mg, 203.35 μmol, trifluoroacetate of compound 11-1, bis(pinacorato)diborone (103.28 mg, 406.70 μmol), potassium pivalate (57.03 mg, 406.70 μmol), and triphenylphosphine palladium (15.00 mg, 40.67 μmol) were mixed in 1 mL of DMF, degassed, and purged three times with nitrogen. The mixture was stirred at 120°C under a nitrogen atmosphere for 16 hours. After filtration, the filtrate was separated and purified by HPLC (column: 3_Phenomenex Luna 75 × 30 mm × 3 μm; mobile phase: 0.05% trifluoroacetate aqueous solution and acetonitrile; gradient: acetonitrile 16%~36%) to obtain trifluoroacetate of compound 11-2. LCMS (ESI) m / z: 377.1 (M+1). Step 3: Manufacturing of Compound 11 Under room temperature conditions, a solution of 10 mg (26.57 μmol) of trifluoroacetate 11-2 in anhydrous methanol (0.6 mL) was mixed with a solution of sodium hydroxide (10.63 mg, 265.67 μmol) in aqueous solution (0.3 mL). The mixture was stirred at 20°C for 3 hours. After filtration, the filtrate was separated and purified by HPLC (column: 3_Phenomenex Luna 75 × 30 mm × 3 μm; mobile phase: 0.05% trifluoroacetate aqueous solution - acetonitrile; gradient: acetonitrile: 15%~35%) to obtain trifluoroacetate of compound 11. LCMS (ESI) m / z: 349.0 (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 0.98 - 1.11 (m, 2 H) 1.22 - 1.27 (m, 2 H) 4.22 (dt, J=7.21, 3.48 Hz, 1 H) 4.59 (s, 2 H) 4.75 (br s, 2 H) 7.48 (d, J=5.14 Hz, 1 H) 7.83 (d, J=8.31 ​​Hz, 1 H) 8.70 (d, J=8.19 Hz, 1 H) 8.83 (d, J=4.89 Hz, 1 H) 9.00 (d, J=5.87 Hz, 2 H) 14.54 (br d, J=3.55 Hz, 1 H).

[0137] JPEG0007892060000044.jpg84170 Step 1: Preparation of trifluoroacetate of compound 12-1 and compound 12-1 At room temperature, a solution of trifluoroacetate of compound 7-7 (0.12 g, 306.58 μmol), (t-butyldimethylsilyloxy)acetaldehyde (106.88 mg, 613.15 μmol), dichloromethane (3 mL), and ethanol (1.5 mL) was prepared. Acetic acid (27.61 mg, 459.87 μmol) was added, the mixture was heated to 40°C and stirred for 1 hour, then cooled to room temperature. Sodium borohydride cyanohydride (57.80 mg, 919.73 μmol) was added, and the mixture was reacted at 40°C for another 1 hour. The mixture was then divided into multiple batches for post-treatment. Method 1: The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (column: 3_Phenomenex Luna C18 70*30mm*3μm; mobile phase: 0.05% trifluoroacetic acid aqueous solution and acetonitrile; gradient: acetonitrile 37%~57%) to obtain the trifluoroacetate of compound 12-1. Method 2: The reaction mixture was concentrated under reduced pressure, the crude product was adjusted to pH=8.0 with saturated sodium carbonate solution, extracted with dichloromethane, and then combined with the organic phase and concentrated under reduced pressure to obtain compound 12-1. LCMS (ESI) m / z: 436.2 (M+1). Step 2: Preparation of trifluoroacetate and hydrochloride of compound 12 Method 1: At room temperature, an aqueous solution of sodium hydroxide (55.11 mg, 1.38 mmol) (0.3 mL) was added to methanol (0.6 mL) containing compound 12-1 (0.06 g, 137.78 μmol), and the mixture was stirred at room temperature for 3 hours. The mixture was filtered, and the filtrate was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100*25 mm*4 μm; mobile phase: 0.05% trifluoroacetic acid aqueous solution - acetonitrile; gradient: acetonitrile: 20%~40%) to obtain the trifluoroacetate of compound 12. LCMS (ESI) m / z: 408.2 (M+1). Method 2: At room temperature, an aqueous solution (10 mL) of sodium hydroxide (918.54 mg, 22.96 mmol) was added to a methanol (20 mL) solution of Compound 12-1 (1 g, 2.30 mmol), and the mixture was stirred at 20 - 50 °C for 36 hours. It was filtered, and the filter cake was collected to obtain the crude product. Hydrochloric acid (12 M, 2 mL) was added to an aqueous solution (4 mL) of this crude product (100 mg, 245.45 μmol), and the mixture was stirred for 16 hours. The reaction solution was filtered, and the filter cake was collected and dried to obtain the hydrochloride salt of Compound 12. LCMS (ESI) m / z: 408.1 (M+1). 1 H NMR (400 MHz, CD3OD) δ ppm 9.08 (s, 1 H), 8.63 (d, J=8.44 Hz, 1 H), 8.31 (s, 1 H), 7.85 (d, J=8.31 Hz, 1 H), 7.18 (s, 1 H), 4.96 (br s, 2 H), 4.64 (s, 2 H), 4.41 - 4.48 (m, 1 H), 3.87 (t, J=5.20 Hz, 2 H), 3.63 (t, J=5.32 Hz, 2 H), 1.44 - 1.51 (m, 2 H), 1.05 - 1.11 (m, 2 H).

[0138] JPEG0007892060000045.jpg83170 Step 1: Preparation of the trifluoroacetate salt of Compound 13-1 At room temperature, acetic acid (4.60 mg, 76.64 μmol) was added to a dichloromethane (1 mL) and ethanol (0.5 mL) solution of Compound 7-7 (0.02 g, 51.10 μmol) and propionaldehyde (4.45 mg, 76.64 μmol). After heating to 40 °C and stirring for 1 hour, the temperature was lowered to room temperature, and sodium cyanoborohydride (9.63 mg, 153.29 μmol) was added, followed by reacting at 40 °C for 1 hr. After concentrating the reaction solution under reduced pressure, it was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100*25mm*4μm; mobile phase: 0.05% aqueous trifluoroacetic acid - acetonitrile; gradient: acetonitrile: 28% - 48%) to obtain the trifluoroacetate salt of Compound 13-1. LCMS (ESI) m / z: 434.2 (M+1). Step 2: Preparation of trifluoroacetate of Compound 13 At room temperature, a solution of sodium hydroxide (5.07 mg, 126.87 μmol) in water (0.25 mL) was added to trifluoroacetate of Compound 13-1 (11 mg, 25.37 μmol) in methanol (0.5 mL), and the mixture was stirred at room temperature for 16 hours. After filtration, the filtrate was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100*25mm*4μm; mobile phase: 0.05% aqueous trifluoroacetic acid - acetonitrile; gradient: acetonitrile: 20% - 40%) to obtain trifluoroacetate of Compound 13. LCMS (ESI) m / z: 406.2 (M+1).

[0139] JPEG0007892060000046.jpg80170 Step 1: Preparation of Compound 14-1 At room temperature, acetic acid (3.38 mg, 76.65 μmol) was added to a solution of trifluoroacetate of Compound 7-7 (0.02 g, 51.10 μmol), acetaldehyde (3.38 mg, 76.65 μmol) in dichloromethane (1 mL) and ethanol (0.5 mL). The temperature was raised to 30 °C and the mixture was stirred for 1 hour, then cooled to room temperature and sodium cyanoborohydride (9.63 mg, 153.29 μmol) was added, and the reaction was further carried out at 30 °C for 1 hr. The reaction solution was concentrated under reduced pressure to obtain Compound 3-9. LCMS (ESI) m / z: 420.1 (M+1). Step 2: Preparation of trifluoroacetate of Compound 14 At room temperature, an aqueous solution of sodium hydroxide (10.22 mg, 255.56 μmol) in water (0.5 mL) was added to Compound 14-1 (21.44 mg, 51.11 μmol) in methanol (1 mL), and the mixture was stirred at 30 °C for 16 hours. After filtration, the filtrate was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100*25mm*4μm; mobile phase: 0.05% aqueous trifluoroacetic acid - acetonitrile; gradient: acetonitrile: 23% - 43%) to obtain trifluoroacetate of Compound 14. LCMS (ESI) m / z: 392.1 (M+1).

[0140] JPEG0007892060000047.jpg78170 Step 1: Preparation of Compound 15-1 At room temperature, a solution of compound 7-7 trifluoroacetate (0.03 g, 76.64 μmol), benzaldehyde (16.27 mg, 153.29 μmol), dichloromethane (1 mL), and ethanol (0.5 mL) was prepared. Acetic acid (6.90 mg, 114.97 μmol) was added, the mixture was heated to 30°C and stirred for 1 hour, then cooled to room temperature. Sodium borohydride cyanohydride (9.63 mg, 153.29 μmol) was added, and the mixture was reacted at 50°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain crude compound 15-1. LCMS (ESI) m / z: 482.3 (M+1). Step 2: Preparation of trifluoroacetate of compound 15 At room temperature, an aqueous solution of sodium hydroxide (24.92 mg, 623.00 μmol) (1 mL) was added to methanol (2 mL) containing compound 15-1 (60 mg, 124.60 μmol), and the mixture was stirred at 30°C for 15 hours. The mixture was filtered, and the filtrate was separated and purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100*25 mm*4 μm; mobile phase: 0.05% trifluoroacetic acid aqueous solution - acetonitrile; gradient: acetonitrile: 32%~52%) to obtain trifluoroacetic acid of compound 15. LCMS (ESI) m / z: 454.2 (M+1). 1H NMR (400 MHz, CD3OD) δ = 9.08 (s, 1H), 8.64 (d, J = 8.3 Hz, 1H), 8.31 (s, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.54 - 7.34 (m, 6H), 7.26 (s, 1H), 4.98 (s, 2H), 4.72 (s, 2H), 4.65 (s, 2H), 4.44 (td, J = 3.5, 7.2 Hz, 1H), 1.47 (br d, J = 6.5 Hz, 2H), 1.08 (br d, J = 2.6 Hz, 2H).

[0141] JPEG0007892060000048.jpg80170 Step 1: Preparation of Compound 16-1 At room temperature, a solution of trifluoroacetate of compound 7-7 (0.1 g, 255.48 μmol), cyclobutylformaldehyde (42.98 mg, 510.96 μmol), dichloromethane (10 mL), and methanol (5 mL) was prepared. Acetic acid (23.01 mg, 383.22 μmol) was added, the mixture was heated to 40°C, and stirred for 1 hour. After cooling to room temperature, pyridineborane (71.23 mg, 766.44 μmol) was added, and the reaction was continued at 40°C for 40 hours. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL), extracted with dichloromethane (10 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 16-1. LCMS (ESI) m / z: 460.2 (M+1). Step 2: Preparation of trifluoroacetate of compound 16 At room temperature, an aqueous solution of sodium hydroxide (24.92 mg, 623.00 μmol) (0.6 mL) was added to methanol (1.2 mL) containing compound 16-1 (120 mg, 250.69 μmol), and the mixture was stirred at 40°C for 16 hours. The mixture was filtered, and the filtrate was separated and purified by HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: 0.05% trifluoroacetic acid aqueous solution - acetonitrile; gradient: acetonitrile: 29%~49%) to obtain the trifluoroacetate of compound 16. LCMS (ESI) m / z: 432.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ = 8.89 (s, 1H), 8.45 (d, J = 8.3 Hz, 1H), 8.37 (s, 1H), 7.88 (d, J = 8.5 Hz, 1H), 6.97 (br s, 1H), 4.77 (br s, 2H), 4.51 (s, 2H), 4.48 (br d, J = 3.6 Hz, 1H), 3.43 (br d, J = 7.1 Hz, 2H), 2.68 - 2.59 (m, 1H), 2.18 - 2.00 (m, 2H), 1.95 - 1.84 (m, 2H), 1.83 - 1.68 (m, 2H), 1.32 (br d, J = 6.6 Hz, 2H), 1.02 (br s, 2H).

[0142] JPEG0007892060000049.jpg81170 Step 1: Preparation of Compound 17-1 At room temperature, a solution of compound 7-7 trifluoroacetate (0.1 g, 255.48 μmol), oxa-3-cyclobutylformaldehyde (43.99 mg, 510.96 μmol), dichloromethane (10 mL), and methanol (5 mL) was mixed with acetic acid (23.01 mg, 383.22 μmol). The mixture was heated to 40°C and stirred for 1 hour. After cooling to room temperature, pyridineborane (71.23 mg, 766.44 μmol) was added, and the reaction was continued at 40°C for 40 hours. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL), extracted with dichloromethane (10 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 17-1. LCMS (ESI) m / z: 462.2 (M+1). Step 2: Preparation of trifluoroacetate of compound 17 At room temperature, an aqueous solution of sodium hydroxide (8.67 mg, 216.68 μmol) (0.5 mL) was added to methanol (1 mL) containing compound 17-1 (10 mg, 21.67 μmol), and the mixture was stirred at 40°C for 16 hours. The mixture was filtered, and the filtrate was separated and purified by HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: 0.05% trifluoroacetic acid aqueous solution - acetonitrile; gradient: acetonitrile: 11%~31%) to obtain the trifluoroacetate of compound 17. LCMS (ESI) m / z: 434.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ = 9.68 (br d, J = 1.1 Hz, 1H), 8.93 (s, 1H), 8.54 (d, J = 2.2 Hz, 1H), 7.92 - 7.83 (m, 1H), 7.16 (s, 1H), 4.91 - 4.81 (m, 2H), 4.58 (br d, J = 1.3 Hz, 3H), 4.53 - 4.43 (m, 2H), 4.22 - 4.19 (m, 1H), 3.58 (br dd, J = 3.2, 6.9 Hz, 2H), 3.54 - 3.46 (m, 1H), 1.33 - 1.33 (m, 1H), 1.31 (br d, J = 7.6 Hz, 1H), 1.03 (br s, 2H).

[0143] JPEG0007892060000050.jpg74170 Step 1: Preparation of Compound 18-1 At 20°C, the trifluoroacetate salt of compound 7-7 (20 mg, 51.10 μmol) and N-Boc-3-formylazetidine (14.20 mg, 76.64 μmol) were dissolved in dichloromethane (1 mL) and water (0.5 mL). Glacial acetic acid (4.60 mg, 76.64 μmol) was added, and the mixture was stirred at 50°C for 16 hours. At room temperature, sodium borohydride cyanohydride (9.63 mg, 153.29 μmol) was added, and the mixture was stirred at 20°C for 5 hours, then the temperature was raised to 50°C and the mixture was stirred for 16 hours. The mixture was filtered and concentrated under reduced pressure to obtain compound 18-1. LCMS (ESI) m / z: 561.4 (M+1). Step 2: Preparation of trifluoroacetate of compound 18-2 At 20°C, compound 18-1 (80 mg, 142.69 μmol) was dissolved in methanol (2 mL), and sodium hydroxide solution (28.54 mg of sodium hydroxide dissolved in 1 mL of water) was added. The mixture was stirred at 20°C for 16 hours. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100*25 mm*4 μm; mobile phase: 0.05% trifluoroacetic acid aqueous solution - acetonitrile; gradient: acetonitrile: 32%~52%) to obtain the trifluoroacetate salt of compound 18-2. LCMS (ESI) m / z: 533.3 (M+1). Step 3: Preparation of trifluoroacetate of compound 18 At 20°C, trifluoroacetate of compound 18-2 (42 mg, 78.86 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (616.00 mg, 5.40 mmol) was slowly added. The mixture was stirred at 20°C for 2 hours. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C18, 70*30 mm*3 μm; mobile phase: 0.05% trifluoroacetic acid aqueous solution - acetonitrile; gradient: acetonitrile: 5%~25%) to obtain trifluoroacetate of compound 18. LCMS (ESI) m / z: 433.2 (M+1). 1 H NMR (400 MHz, CD3OD) δ ppm 1.02 - 1.15 (m, 2 H) 1.23 - 1.40 (m, 2 H) 1.42 - 1.54 (m, 2 H) 3.17 - 3.28 (m, 2 H) 3.51 (br dd, J=13.27, 8.25 Hz, 2 H) 3.70 - 4.07 (m, 2 H) 4.43 (td, J=7.27, 3.91 Hz, 1 H) 4.62 - 4.69 (m, 2 H) 5.01 (br s, 2 H) 7.20 (s, 1 H) 7.84 (br d, J=8.44 Hz, 1 H) 8.33 (br s, 1 H) 8.54 - 8.72 (m, 1 H) 9.07 (br d, J=5.99 Hz, 1 H).

[0144] JPEG0007892060000051.jpg84170 Step 1: Preparation of trifluoroacetate of compound 19-1 At room temperature, trifluoroacetate of compound 7-7 (55 mg, 140.51 μmol) and N-(2-oxycarbonylethyl)carbamate t-butyl ester (22.37 mg, 140.51 μmol) were dissolved in dichloromethane (1 mL) and methanol (0.5 mL). Glacial acetic acid (16.88 mg, 281.03 μmol) was added, and the mixture was stirred at 50°C for 3 hours. At 20°C, sodium borohydride (26.49 mg, 421.54 μmol) was added, and the mixture was stirred at 20°C for 1 hour, then the temperature was raised to 50°C and the mixture was stirred for 16 hours. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C18, 75 × 30 mm × 3 μm; mobile phase: 0.05% trifluoroacetic acid aqueous solution and acetonitrile; proportion of acetonitrile in the mobile phase: 25%~45%) to obtain the trifluoroacetate of compound 19-1. LCMS (ESI) m / z: 535.3 (M+1). Step 2: Preparation of trifluoroacetic acid of compound 19-2 At room temperature, 22 mg (41.15 μmol) of compound 19-1 trifluoroacetate was dissolved in 1 mL of dichloromethane, and trifluoroacetic acid (469.22 mg, 4.12 mmol) was added. The mixture was stirred at 20°C for 2 hours. The mixture was concentrated under reduced pressure to obtain the trifluoroacetate of compound 19-2. LC-MS (ESI) m / z: 435.1 (M+1). Step 3: Preparation of trifluoroacetate of compound 19 At room temperature, 17.8 mg (40.97 μmol) of the trifluoroacetate of compound 19-2 was dissolved in methanol (1 mL), and sodium hydroxide solution (8.19 mg dissolved in 0.5 mL of water) was added. The mixture was stirred at 20°C for 16 hours. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C18, 75 × 30 mm × 3 μm; mobile phase: 0.05% trifluoroacetate aqueous solution - acetonitrile; gradient: acetonitrile: 10%~30%) to obtain the trifluoroacetate of compound 19. LCMS (ESI) m / z: 407.1 (M+1). 1 H NMR (400 MHz, CD3OD) δ ppm 0.90 - 1.01 (m, 2 H) 1.36 (br d, J=6.97 Hz, 2 H) 3.13 (t, J=5.69 Hz, 2 H) 3.64 (t, J=5.69 Hz, 2 H) 4.27 - 4.36 (m, 1 H) 4.44 (s, 2 H) 4.72 - 4.75 (m, 2 H) 6.69 (s, 1 H) 7.73 (d, J=8.44 Hz, 1 H) 8.37 (s, 1 H) 8.46 (d, J=8.44 Hz, 1 H) 8.94 (s, 1 H).

[0145] JPEG0007892060000052.jpg72170 Step 1: Preparation of Compound 20-1 At room temperature, compound 4-11 (15 mg, 29.91 μmol) was dissolved in methanol (2 mL), wet Pd / C (10 mg, 50% water content) was added, and the mixture was stirred at 10-15°C under a hydrogen (15 Psi) atmosphere for 2 hours. The mixture was filtered and concentrated under reduced pressure to obtain compound 20-1. LCMS (ESI) m / z: 504.2 (M+1). Step 2: Preparation of the hydrochloride salt of compound 20-2 At room temperature, compound 20-1 (16 mg, 28.59 μmol) was dissolved in methanol (1 mL) and water (0.5 mL), sodium hydroxide (6.86 mg, 171.57 μmol) was added, and the mixture was stirred at 10-15°C for 5 hours. The reaction mixture was adjusted to pH 1-2 with 1 M hydrochloric acid aqueous solution, concentrated, and the hydrochloride salt of compound 20-2 was obtained. LCMS (ESI) m / z: 476.1 (M+1). Step 3: Preparation of trifluoroacetate of compound 20 At room temperature, the hydrochloride salt of compound 20-2 (14 mg, 29.44 μmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at 25-30°C for 1 hour. The mixture was concentrated, and the residue was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: 0.05% trifluoroacetic acid aqueous solution - acetonitrile; gradient: acetonitrile: 18%~38%) to obtain the trifluoroacetate salt of compound 20. LCMS (ESI) m / z: 376.0 (M+1). 1 H NMR (400 MHz, CDCl3) δ = 14.51 (s, 1H), 10.22 (s, 1H), 9.01 (s, 1H), 8.51 (s, 1H), 7.85 (s, 1H), 7.43 (m, 1H), 6.68 (s, 1H), 3.13 (s, 3H), 2.74 (s, 2H), 2.39 (s, 2H), 1.36 - 1.31 (m, 2H), 1.14 (s, 2H).

[0146] JPEG0007892060000053.jpg47170 Step 1: Preparation of Compound 21 Compound 5-5 (105 mg, 258.35 μmol) was added to hydrobromic acid (12 mL, 40% aqueous solution) and stirred at 110°C for 8 hours. The mixture was concentrated, and the residue was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100*25 mm*4 μm; mobile phase: 0.05% trifluoroacetic acid aqueous solution - acetonitrile; gradient: acetonitrile: 29%~49%) to obtain compound 21. LCMS (ESI) m / z: 365.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ = 8.88 (s, 1H), 8.42-8.40 (m, 1H), 7.92 (s, 1H), 7.84-7.82 (m, 1H), 6.60 (s, 1H), 4.84 (s, 1H), 4.44 (s, 1H), 1.32 - 1.30 (m, 2H), 1.00 (s, 2H).

[0147] JPEG0007892060000054.jpg81170 Step 1: Preparation of Compound 22-1 At room temperature, compound 7-7 (70.00 mg, 178.84 μmol) and (R)-(+)-2,2-dimethyl-1,3-dioxo-4-aldehyde pentane (46.55 mg, 357.67 μmol) were dissolved in anhydrous dichloromethane (4 mL) and anhydrous methanol (2 mL). Then, at 20-30°C, acetic acid (16.11 mg, 268.25 μmol) was added, and the reaction mixture was heated to 40°C and stirred for 1 hour. After that, the temperature was lowered to 20-30°C, pyridineborane (49.86 mg, 536.51 μmol) was added, and the temperature was raised to 40°C and stirred for 16 hours to react. The mixture was concentrated, 10 mL of dichloromethane was added, and the mixture was sequentially washed with saturated sodium bicarbonate (10 mL * 2) and brine (10 mL), dried, and concentrated to obtain compound 22-1. LCMS (ESI) m / z: 506.1 (M+1). Step 2: Preparation of trifluoroacetate of compound 22 At room temperature, a solution of compound 22-1 (35.00 mg, 69.23 μmol) in ethanol (1.5 mL) and water (1.0 mL) was mixed with concentrated hydrochloric acid (0.5 mL), and the reaction mixture was stirred at 40°C for 22 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: YMC Triart C18 150*25 mm*5 μm; mobile phase: 0.05% trifluoroacetic acid aqueous solution and acetonitrile; acetonitrile content in mobile phase: 11%~31%, 10 min) to obtain the trifluoroacetate salt of compound 22.

[0148] JPEG0007892060000055.jpg87170 Step 1: Preparation of Compound 2-9 At room temperature, compound 2-9 (50 mg, 123.32 μmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). After cooling the reaction solution to 0 °C, under nitrogen protection, sodium hydride (5.43 mg, 135.65 μmol) and difluoroethyl triflate (29.04 mg, 135.65 μmol) were added sequentially. The reaction solution was stirred at 25 °C for 1 hour. Compound 23-1 was obtained without post-treatment of the reaction solution. LCMS (ESI) m / z: 470.2 (M + 1). Step 2: Preparation of trifluoroacetate of compound 23 At room temperature, a solution of compound 23-1 (57 mg, 121.41 μmol) in anhydrous N,N-dimethylformamide (3 mL) was added to a solution of sodium hydroxide (4.86 mg, 121.41 μmol) in water (1 mL), and the reaction solution was stirred at 25 °C for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. Purification by preparative HPLC (column: YMC Triart C18 150*25mm*5μm; mobile phase: 0.05% aqueous trifluoroacetic acid solution and acetonitrile; the proportion of acetonitrile in the mobile phase was 39% - 59%, 10 min) gave the trifluoroacetate of compound 23. LCMS (ESI) m / z: 442.1 (M + 1). 1 H NMR (400 MHz, DMSO-d6) δ ppm 14.83 - 15.13 (m, 1 H), 8.85 - 8.94 (m, 1 H), 8.54 - 8.62 (m, 1 H), 8.41 - 8.48 (m, 1 H), 7.88 - 7.99 (m, 1 H), 6.99 - 7.07 (m, 1 H), 6.06 - 6.48 (m, 1 H), 4.65 - 4.74 (m, 2 H), 4.52 - 4.56 (m, 2 H), 4.45 - 4.50 (m, 1 H), 4.05 - 4.18 (m, 2 H), 3.13 - 3.24 (m, 3 H), 1.28 - 1.38 (m, 2 H), 0.96 - 1.07 (m, 2 H).

[0149] JPEG0007892060000056.jpg48170 Step 1: Preparation of compound 24 At 0°C, sodium hydride (39.46 mg, 986.57 μmol) was added to a solution of compound 2-9 (0.10 g, 246.64.5 μmol) in DMF (4 mL). After 10 minutes, compound 1-fluoro-2-iodoethane (85.81 mg, 493.28 μmol) was added to the reaction mixture and stirred for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL), extracted with dichloromethane (10 mL x 2), washed with saturated saline solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: YMC Triart 30*150 mm*7 μm; mobile phase: aqueous hydrochloric acid and acetonitrile; acetonitrile content in mobile phase: 13%~33%, 10 min) to obtain compound 24. LCMS (ESI) m / z: 404.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ = 8.93 (s, 1H), 8.83 (s, 1H), 8.54 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H), 4.83 (br s, 2H), 4.80 - 4.72 (m, 2H), 4.60 (s, 2H), 4.51 - 4.44 (m, 1H), 4.09 - 4.01 (m, 2H), 3.20 - 3.18 (m, 3H), 1.32 (br d, J = 6.5 Hz, 2H), 1.04 (br s, 2H).

[0150] JPEG0007892060000057.jpg51170 Step 1: Preparation of Compound 25 At 0°C, sodium hydride (1.58 mg, 39.56 μmol) was added to a solution of compound 22-1 (0.02 g, 39.56 mmol) in DMF (2 mL). After 10 minutes, methyl iodide (39.56 μmol, 2.46 μL) was added to the reaction mixture and stirred for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL), extracted with dichloromethane (10 mL x 2), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: Waters Xbridge 150 x 25 mm x 5 μm; mobile phase: 0.05% aqueous ammonium bicarbonate solution and acetonitrile; acetonitrile content in mobile phase: 29%~59%, 9 min) to obtain compound 25. LCMS (ESI) m / z: 492.2 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ = 8.88 (s, 1H), 8.54 (s, 1H), 8.44 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 6.93 (s, 1H), 4.70 (br d, J = 1.5 Hz, 2H), 4.52 (s, 2H), 4.48 (br dd, J = 2.9, 5.8 Hz, 1H), 4.42 - 4.32 (m, 2H), 3.92 - 3.84 (m, 1H), 3.79 - 3.65 (m, 2H), 3.18 (s, 3H), 1.39 (s, 3H), 1.36 - 1.31 (m, 2H), 1.28 (s, 3H), 1.26 - 1.22 (m, 2H).

[0151] JPEG0007892060000058.jpg49170 Step 1: Preparation of Compound 26 At room temperature, an aqueous solution of sodium hydroxide (15.82 mg, 395.60 μmol) (0.5 mL) was added to methanol (1 mL) containing compound 22-1 (20.00 mg, 39.56 μmol), and the mixture was stirred at 40°C for 16 hours. The mixture was filtered, and the filtrate was separated and purified by preparative HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: 0.05% aqueous ammonium bicarbonate solution and acetonitrile; acetonitrile content in mobile phase: 25%~55%, 10 min) to obtain compound 26. LCMS (ESI) m / z: 478.3 (M+1). 1 H NMR (400 MHz, CD3OD) δ ppm 8.83 (br s, 1 H),8.51 (br d, J=8.31 ​​Hz, 1 H),8.37 (m, 1 H),7.69 (m, 1 H),6.72 (s, 1 H),4.56 - 4.68 (m, 2 H),4.51 (s, 2 H),4.36 - 4.44 (m, 1 H),4.25 - 4.34 (m, 1 H),4.13 (dd, J=8.25, 6.30 Hz, 1 H),3.79 (dd, J=8.38, 6.30 Hz, 1 H),3.60 (dd, J=8.19, 5.62 Hz, 2 H),1.45 (s, 3 H),1.41 (br d, J=6.72 Hz, 2 H), 1.37 (s, 3 H), 1.01 (br s, 2 H).

[0152] JPEG0007892060000059.jpg73170 Step 1: Preparation of Compound 27-1 At room temperature, compound 7-7 (50 mg, 127.74 μmol) was dissolved in anhydrous dichloromethane (5 mL). N,N-di(tert-butoxycarbonyl)thiourea (42.36 mg, 153.29 μmol), triethylamine (38.78 mg, 383.22 μmol), and copper chloride (20.61 mg, 153.29 μmol) were added sequentially, and the reaction mixture was stirred at 20°C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain compound 27-1. LCMS (ESI) m / z: 634.3 (M+1). Step 2: Preparation of trifluoroacetate of compound 27 At room temperature, compound 27-1 (80 mg, 126.24 μmol) was dissolved in ethanol (3 mL) and water (2 mL). 12 M hydrochloric acid (12 M, 2 mL) was added to the reaction mixture, and the mixture was stirred at 80°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100*25 mm*4 μm; mobile phase: 0.05% trifluoroacetic acid aqueous solution and acetonitrile; acetonitrile content in mobile phase: 18%~48%, 9 min) to obtain the trifluoroacetate salt of compound 27. LCMS (ESI) m / z: 406.2 (M+1).

[0153] JPEG0007892060000060.jpg120170 Step 1: Preparation of Compound 28-2 At 0°C, compound 28-1 (1 g, 4.55 mmol) was dissolved in DCM (10 mL), and slowly added to water (10 mL) containing sodium hydroxide (182.12 mg, 4.55 mmol). The reaction was carried out for 5 hours at a temperature of 0-25°C. After diluting the reaction mixture with water (20 mL), it was extracted with dichloromethane (60 mL), the organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 28-2. LCMS (ESI) m / z: 184.1 (M+1). Step 2: Preparation of Compound 28-3 Compound 28-2 (19.50 mg, 106.45 μmol) and Compound 7-7 (50 mg, 127.74 μmol) were dissolved in acetonitrile (1 mL), then calcium triflate (15.00 mg, 40.67 μmol) was added. The mixture was stirred at 45°C for 16 hours and monitored. The reactants were found not to have reacted completely. The reaction mixture was heated to 60°C and the reaction was sustained for 16 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (column: YMC Triart C18 150*25 mm*5 μm; mobile phase: [0.01% hydrochloric acid aqueous solution and acetonitrile; proportion of acetonitrile in mobile phase: 16%~46%, 8.5 min]) to obtain Compound 28-3. LCMS (ESI) m / z: 575.3 (M+1). Step 3: Preparation of trifluoroacetate of compound 28 Under room temperature conditions, a solution of compound 28-3 (20 mg, 34.81 μmol) in anhydrous methanol (1 mL) was mixed with a solution of sodium hydroxide (6.96 mg, 174.04 μmol) in aqueous solution (0.5 mL). The mixture was stirred at 25°C for 2 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100*25 mm*4 μm; mobile phase: 0.05% trifluoroacetic acid aqueous solution and acetonitrile; acetonitrile content in mobile phase: 15%~45%, 9 min) to obtain the trifluoroacetate of compound 28. LCMS (ESI) m / z: 547.3 (M+1).

[0154] JPEG0007892060000061.jpg81170 Step 1: Preparation of Compound 29-2 At room temperature, compound 7-7 (50 mg, 127.74 μmol) and compound 29-1 (92.33 mg, 255.48 μmol) were dissolved in methanol (2 mL) and dichloromethane (4 mL), respectively. Then, acetic acid (11.5 mg, 191.61 μmol) was added, and the mixture was stirred at 40°C for 1 hour. The temperature was reduced to 10-20°C, pyridineborane (35.61 mg, 383.22 μmol) was added, and the mixture was stirred at 40°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain compound 29-2. LCMS (ESI) m / z: 737.4 (M+1). Step 2: Preparation of the hydrochloride salt of compound 29 At room temperature, compound 29-2 (94 mg, 127.58 μmol) was dissolved in water (2 mL) and methanol (3 mL), concentrated hydrochloric acid (1.02 g, 10 mmol) was added, and the mixture was stirred at 50-55°C for 16 hours. The reaction mixture was purified by preparative HPLC (column: YMC Triart C18 150*25 mm*5 μm; mobile phase: 0.01% aqueous hydrochloric acid solution and acetonitrile; acetonitrile content in mobile phase: 9%-29%, 10 min) to obtain the hydrochloride salt of compound 29. LCMS (ESI) m / z: 509.2 (M+1). Biological evaluation

[0155] Experimental Example 1: Detection of the Minimum Inhibitory Bacteriostatic Concentration (MIC) 1) Manufacturing of compound matrix On the day of the experiment, the compound in the flask was dissolved in 100% DMSO to a mother liquor concentration of 0.4 mg / mL. If the mother liquor is not used on the day, it should be stored at -80°C. In a 96-microplate (bottom V), the compound mother liquor and standard antibiotic were gradient diluted 2-fold using the corresponding solvent to sequentially obtain 100× working solutions (wells 1-7). The compound concentrations were 400, 200, 100, 50, 25, 12.5, 6.25, and 3.125 μg / mL. 100% DMSO was used as a growth control (well 8). This is the compound matrix. 2) Manufacturing of the inoculum One day before the experiment, aerobic bacteria (Staphylococcus epidermidis) from a -80°C frozen tube were streaked onto MHA (Cation-adjusted Mueller-Hinton agar) plates. These were then placed in a 35+ / -2°C incubator and cultured aerobically for 18-24 hours. Two days prior to the experiment, anaerobic bacteria (Propionibacterium acnes) in a -80°C frozen tube were streaked onto MBA (Brucella Agar + 5% (v / v) defibroused sheep blood + 5 μg / mL Hemin + 1 μg / mL Vitamin K1) plates and incubated in an anaerobic incubator at 35 ± 2°C for 42-48 hours. On the day of the experiment, the plate was removed, the clones on the plate were taken out and suspended in physiological saline, and then the turbidity of the bacterial suspension was adjusted to OD600 = 0.2 using a turbidimeter. This bacterial suspension was 1.0~2.0 × 10⁶ 8 It contains CFU / mL. Next, the bacterial suspension with adjusted turbidity is mixed with the test medium, and for aerobic bacteria, it is ~5 × 10⁻⁶. 5 CFU / mL; for anaerobic bacteria, ~1 × 10 6 The solution was diluted to the appropriate concentration of CFU / mL. This is the inoculum. 3) Detection of the minimum bacteriostatic concentration (MIC) Two μl of 100× high-concentration working solution, serially diluted 2-fold from the compound matrix (prepared in Step 1), was transferred to a round-bottom 96-well plate. Then, 198 μL of bacterial inoculum (prepared in Step 2) was added to each well to obtain an MIC test plate. Therefore, the final test concentrations of the compound were 4, 2, 1, 0.5, 0.25, 0.125, 0.06, and 0.03 μg / mL. The total volume per well of the test plate was 200 μL, and it contained 1% DMSO, ~5×10⁶. 5 Aerobic bacteria at CFU / mL, and ~1 × 10⁻⁶ 6 Contains anaerobic bacteria at CFU / mL. All test plates for aerobic bacteria were cultured aerobically at 35+ / -2°C for 16-20 hours, and all test plates for anaerobic bacteria were cultured in an anaerobic incubator at 35+ / -2°C for 48 hours. Note: For anaerobic bacteria, both the bacterial suspension preparation in Step 2 and the bacterial suspension inoculation in Step 3 are performed on an anaerobic workstation. 4) Reading the minimum bacteriostatic concentration (MIC) After culturing, visual inspection of the test plates revealed that the drug concentration in the wells that completely or significantly inhibited bacterial growth was the lowest bacteriostatic concentration. 5) The experimental results are shown in Table 1. JPEG0007892060000062.jpg247170

[0156] Experimental Example 2: Pharmacokinetic Evaluation of Compounds 1) Experimental materials CD-1 mouse (male, Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.) 2) Experimental Procedure The pharmacokinetic characteristics of the compound were tested in rodents after intravenous and oral administration using a standard protocol. For the experiment, the candidate compound was formulated into a clarified solution and administered once intravenously and orally to mice. The solvent used for both intravenous and oral administration was a mixed solvent of 10% DMSO + 90% (20% SBE-β-CD). Four male CD-1 mice were used in this project. Two mice were intravenously administered a dose of 1 mg / kg, and plasma samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The other two mice were orally administered a dose of 2 mg / kg, and plasma samples were collected at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. After blood sample collection, the samples were placed on ice, and the plasma was centrifuged within 1 hour (centrifugation conditions: 6000g, 3 minutes, 2-8°C). Plasma samples were stored in a -80°C refrigerator before analysis. Blood concentrations were quantitatively analyzed using LC-MS / MS analysis, and the peak concentration (C) was determined. max ), clearance (CL), half-life (T 1 / 2 ), tissue distribution (Vdss), area under the drug-time curve (AUC) 0~last Pharmacokinetic parameters such as bioavailability (F) were calculated. 3) The experimental conclusions are shown in Table 4. JPEG0007892060000063.jpg51170 Experimental conclusion: The compounds of the present invention have good pharmacokinetic properties, including good oral bioavailability and oral exposure.

[0157] Experimental Example 3: Study of the pharmacokinetic effects of compounds in the body 1) Experimental materials Experimental strain: Propionibacterium acnes ATCC 6919 (Beijing Baiou Boyei Biotechnology Co., Ltd.) Experimental animal: Balb / C mouse (Zhejiang Wetong Lihua Experimental Animal Technology Co., Ltd.) 2) Experimental method 1. Building an acne model Balb / C mice were divided into groups and numbered, and incubated for one week. On the model creation day, Propionibacterium acnes was collected, the OD600 was measured using a microplate reader, and diluted to OD600=1 in BHI medium (approximately 5 × 10⁻¹). 8(CFU / mL), centrifuge and discard the supernatant, then refrozen in PBS for 1 × 10⁶ times. 8 The solution was diluted to CFU / mL. After starting the model, mice were anesthetized using a small animal anesthesia machine, and the gas volume and isoflurane volume of the machine were adjusted. Mice were placed in an anesthesia induction chamber and anesthesia was induced. Once there were no clear signs of activity, the mice were removed, and their toes were grasped with forceps or hemostatic forceps to perform a toe-pinching reaction test. If there was no reaction such as recoiling or pain, surgery was performed. After anesthesia, the mice were fixed on a mouse board, and anesthesia was maintained by adjusting the gas volume or isoflurane volume (isoflurane induction volume 3%~4%, anesthesia maintenance volume 1%~2%, air flow rate: 300~500 mL / min). Blank control group: 20 μL of PBS was injected into the skin of the left ear of each mouse. Model group, target drug group: 20 μL of Propionibacterium acnes PBS suspension was injected into the skin of the left ear of each mouse. Propionibacterium acnes was injected and administered to mice in each group 4, 20, 28, and 44 hours later, according to the administration method and dosage described in Table 5. Forty-eight hours after injecting Propionibacterium acnes, ear photographs were taken of each group of mice at the end of the experiment. The thickness of the left auricle was measured with calipers, and tissue homogenation was performed on the left ear to detect the amount of bacteria carried in the ear and the levels of IL-6 and IL-8 (since mice do not express IL-8, the functional homolog CXCL1 / KC was detected). 2. Preparation of medications The drugs measured were compounds 6, 7, and 12, all of which were hydrochloride salts. Compounds 6, 7, and 12 that appeared in this experiment were all prepared by adding the drug to DMSO with a 40% DMSO + 60% glycerin solvent, heating it to 100°C in a water bath, and then adding glycerin to obtain a bright yellow viscous solution. 3. The method of administration and dosage are shown in Table 5 below. JPEG0007892060000064.jpg125170 Administration area: The left ear is designated as the ear to be injected with Propionibacterium acnes. Administration timing: 4, 20, 28, and 44 hours after Propionibacterium acnes injection, for a total of 4 doses. 4. Model Creation Method Compounds 6, 7, and 12, as well as the model group, were anesthetized using a small animal anesthesia machine and isoflurane in Balb / C mice. After immobilization on an anesthesia maintenance platform, 1 × 10¹⁶ units were injected into the left ear skin of the model group and the target drug group mice using a 1 mL sterile syringe. 8 The group was injected with 20 μL of CFU / mL propionibacterium acnes PBS suspension, while the blank control group was injected with an equal volume of 1×PBS. 5. Detection Indicators Rough photography: Rough photographs were taken of the mouse ears 48 hours after injection with Propionibacterium acnes. Auricle thickness measurement: 48 hours after injecting mice with Propionibacterium acnes, the auricle thickness was measured using calipers. Detection of bacterial load in the ear: 48 hours after injection of Propionibacterium acnes, the left ear of a mouse was homogenized with 1 mL of PBS. Three 200 μL samples of the homogenate were taken, and each was diluted with 800 μL of PBS. 100 μL of each diluted homogenate was taken and diluted 10-fold. This procedure was repeated to create a total of five gradient dilutions. The homogenates from each gradient were spread onto BHI solid medium and incubated at 37°C in an anaerobic environment for 48 hours, after which the number of colonies was counted. Mouse BCA protein detection: 48 hours after injection of Propionibacterium acnes, the left ear of mice was homogenized in 1 mL of PBS using a BCA protein concentration measurement kit. A dilution factor equivalent to a 1:9 mass-to-volume homogenate was calculated, and 1500 g was centrifuged for 10 minutes. Each sample group was diluted 10-fold with PBS. 20 μL of sample was taken and added to a 96-well plate. 200 μL of BCA working solution was added to each well, and the plate was incubated at 37°C for 15–30 minutes. A562 was measured using a microplate reader, a calibration curve was created, and BCA concentrations were calculated. This yielded the levels of IL-6 and CXCL1. 3) The experimental conclusions are shown in Tables 6, 7, and 8. JPEG0007892060000065.jpg44170 After injecting Propionibacterium acnes, the thickness of the auricle of each group of mice was measured using a digital caliper 48 hours later. Results are shown as Mean ± SD. * p<0.05, ** p<0.01, *** p<0.001 means that compared to the blank control group, # p<0.05, ## p<0.01, ### If p < 0.001, we compare it with the set of models. JPEG0007892060000066.jpg44170 After injecting Propionibacterium acnes, left ear tissue was collected 48 hours later, and the amount of bacteria carried was detected. Results are shown as Mean ± SD. * p<0.05, ** p<0.01, *** If p < 0.001, we compare it with the set of models. The left ear of mice in the blank control group showed no change. Clear erythema was observed in the left ear of mice in the acne model group. Treatment with compound 6, compound 7, and compound 12 resulted in some reduction of erythema in the left ear of the mice, and their condition improved. Table 6 shows that the thickness of the left auricle was significantly increased in the acne model group compared to the control group (p<0.001). After topical treatment with compound 6, compound 7, and compound 12, the thickness of the left auricle of the mice was significantly decreased in all cases (p<0.05), with the decrease being most pronounced after treatment with compound 7. As shown in Table 7, when treated with compound 6, compound 7, and compound 12, the amount of bacteria in the left ear of mice significantly decreased in all cases (p<0.001). Among these, the amount of bacteria in the left ear of mice decreased most significantly after treatment with compound 7. JPEG0007892060000067.jpg44170 After injecting Propionibacterium acnes, the thickness of the auricle of each group of mice was measured using a digital caliper 48 hours later. The results are shown as Mean ± SD. * p<0.05, ** p<0.01, *** p<0.001 means that compared to the blank control group,# p<0.05, ## p<0.01, ### If p < 0.001, we compare it with the set of models. Table 8 shows that the levels of IL-6 and CXCL1 in the left ear tissue of mice in the acne model group were significantly increased compared to the blank control group (p<0.001). When treated with compound 6, compound 7, and compound 12, the levels of IL-6 and CXCL1 in the left ear tissue of mice were significantly decreased in all cases (p<0.001). Among these, compound 7 showed the highest efficacy after treatment. 4) Experimental conclusions This specification describes animal experiments on the effects of various drugs on the pathology of acne model mice, establishing both an acne model and an immunosuppressed mouse acne model. It demonstrates that the test drugs improve the pathology of acne model mice and lower IL-6 and CXCL-1 levels in lesional tissue. The main research findings are as follows: Compounds 6, 7, and 12 can all improve the thickness of the infected ear in acne model mice, reduce the symptoms of erythrocytosis, decrease the amount of bacteria carried in the infected ear, inhibit the growth of Propionibacterium acnes, and reduce the content of the inflammatory factors IL-6 and CXCL-1 in the infected ear of acne model mice.

Claims

1. The compound represented by formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof. T １ N, NH, CR １ , and N ＋ R １ (A － ) are selected from, T ２ N and CR ２ Selected from, A － is selected from F － , Cl － , Br － , I － , OH － , and HCO ３ － and is selected from X is -C(R ７ R ８ ) - and Y is -O-, -S-, -NH-, and -C(R ７ R ８ ) - Selected from, Z is -C(R ７ R ８ ) - Selected from, or, -Y-Z- is -C(R ９ ) = C(R ９ ) - Selected from, R １ is H, F, Cl, Br, I, -OH, -NH ２ , and -CN and -CH ３ Selected from, R ２ is H, F, Cl, Br, I, -OH, -NH ２ , -CN, and C １～３ Selected from alkyl, where C １～３ Alkyl can optionally have 1, 2, or 3 R ａ Replaced by, R ３ is H, F, Cl, Br, I, =O, -OH, -NH ２ , -CN, -NHC(=NH)NH ２ , C １～３ Alkyl, C １～３ Alkylamino, and C １～３ Selected from alkoxy, where -NHC(=NH)NH ２ , C １～３ Alkyl, C １～３ Alkylamino, and C １～３ Each alkoxy can independently contain any one, two, or three R atoms. ｂ Replaced by, Or, R １ and R ３ These, together with the linked atoms, form a 5-6 member heterocycloalkyl, 5-6 member heterocyclyl, or 5-6 member heteroaryl, where each of the 5-6 member heterocycloalkyl, 5-6 member heterocyclyl, and 5-6 member heteroaryl can independently have 1, 2, 3, or 4 R atoms. ｃ Replaced by, R ４ teeth, It is a group represented by, R ５ H is, R ６ H is, R ７ H is, R ８ H is, R ９ is H, F, Cl, Br, I, -OH, -NH ２ Selected from , and -CN, Each R ａ These are F, Cl, Br, I, -OH, and -NH, respectively, independently. ２ Selected from , and -CN, Each R ｂ These are F, Cl, Br, I, -OH, and -NH, respectively, independently. ２ ,-CN,C １～３ Alkoxy, C ３～６ Selected from cycloalkyl, 3-6 member heterocycloalkyl, 5-6 member heteroaryl, and phenyl, where the C １～３ Alkoxy, C ３～６ Cycloalkyls, 3-6 membered heterocycloalkyls, 5-6 membered heteroaryls, and phenyls are each independently and optionally substituted with 1, 2, 3, or 4 R atoms. Each R ｃ These are F, Cl, Br, I, -OH, and -NH, respectively, independently. ２ -CN and -CH ３ Selected from, Each R is independently F, Cl, Br, I, -OH, -NH ２ , -NO ２ , -CN, -ONHC(=NH)NH ２ , and C １～３ Selected from alkyl groups, In the aforementioned 5-6 member heterocycloalkyl, 3-6 member heterocycloalkyl, 5-6 member heterocyclyl, and 5-6 member heteroaryl compounds, "hetero" represents one, two, three, or four heteroatoms or heteroatomic groups independently selected from O, NH, S, and N.

2. Each R is independent of -NO ２ , -ONHC(=NH)NH ２ , and -CH ３ A compound, stereoisomer, or pharmaceutically acceptable salt thereof, selected from the compounds, stereoisomers, or pharmaceutically acceptable salts thereof described in claim 1.

3. Each R ｂ These are F, Cl, Br, -OH, and -NH, respectively, independently. ２ , -OCH ２ CH ３ Selected from cyclobutyl, oxetanyl, oxolanyl, azetidinyl, 5-membered heteroaryl, and phenyl, where the -OCH ２ CH ３ The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein cyclobutyl, oxetanyl, oxolanil, azetidinyl, a five-membered heteroaryl, and phenyl are each independently optionally substituted with 1, 2, 3, or 4 R groups.

4.

5. Each R ｃ Each of them is independent of -CH ３ A compound, stereoisomer, or pharmaceutically acceptable salt thereof, selected from the compounds, stereoisomers, or pharmaceutically acceptable salts thereof described in claim 1.

6. R １ is a compound, stereoisomer, or pharmaceutically acceptable salt thereof, selected from H.

7. R ２ H and -CH ３ A compound, stereoisomer, or pharmaceutically acceptable salt thereof, selected from the compounds, stereoisomers, or pharmaceutically acceptable salts thereof described in claim 1.

8. R ３ is selected from H, F, Cl, Br, =O, -OH, -NH ２ , -CN, -NH C(=NH)NH ２ , -CH ３ , -NHCH ３ , -N(CH ３ ) ２ , -NHCH ２ CH ３ , -NHCH ２ CH ２ CH ３ , -N(CH ３ )CH ２ CH ３ , and -OCH ３ , wherein the -NH C(=NH)NH ２ , -CH ３ , -NHCH ３ , -N(CH ３ ) ２ , -NHCH ２ CH ３ , -NHCH ２ CH ２ CH ３ , -N(CH ３ )CH ２ CH ３ , and -OCH ３ are each independently optionally substituted with 1, 2 or 3 R ｂ groups, a compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1.

9.

10. R ９ is a compound, stereoisomer, or pharmaceutically acceptable salt thereof, selected from H.

11.

12.

13. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1, having the structure represented by formula (II-2). (However, Y, Z, T) １ , T ２ (and R3 is as defined in claim 1.)

14. The compound, stereoisomer, or pharmaceutically acceptable salt thereof represented by the following formula.

15. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 14, wherein the compound is represented by the following formula.

16. Use of a compound, stereoisomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 15 in the manufacture of antibacterial and anti-inflammatory drugs.

17. The use according to claim 16, which is the use in a drug for treating acne.

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