Compounds as SUMO-activating enzyme inhibitors

Abstract

The present invention discloses compounds as SUMO-activating enzyme inhibitors. Specifically, the present invention relates to a compound of general formula (1), its preparation method, and the use of the compound of general formula (1), its isomer, its crystalline form, its pharmaceutically acceptable salt, its hydrate, or its solvate as an SAE inhibitor. The disclosed compounds, and their isomers, their crystalline form, its pharmaceutically acceptable salt, its hydrate, or its solvate can be used in preparing medicaments for treating or preventing diseases associated with SAE proteins. [Case 1] TIFF2025534374000289.tif56168

Description

[Technical Field]

[0001] This application claims priority to Chinese Patent Application No. 202211212103.5, filed on September 30, 2022, and Chinese Patent Application No. 202311026791.0, filed on August 15, 2023, which are incorporated herein by reference in their entireties.

[0002] The present disclosure is in the field of pharmaceutical chemistry and, in particular, relates to a group of compounds having inhibitory activity against SAE proteins, methods for their preparation, and the use of such compounds in the preparation of medicaments for treating or preventing related diseases mediated by SAE. [Background technology]

[0003] Small ubiquitin-like modifiers (SUMOs) are a family of ubiquitin-like proteins that function as reversible post-translational modifiers in cells. Mammalian cells express three SUMO family proteins: SUMO1, SUMO2, and SUMO3. SUMO2 shares approximately 95% amino acid sequence identity with SUMO3 and primarily forms oligomeric chains during protein modification. SUMO1 shares approximately 45% sequence identity with SUMO2 and SUMO3 and primarily modifies proteins in its monomeric form. SUMOylation of target proteins involves three enzyme-catalyzed steps that activate, transfer, and ultimately conjugate SUMO proteins to lysine residues on target proteins. The first step is catalyzed by SAEs (SUMO-activating enzymes), a class of activating enzymes known as E1 enzymes, which function as heterodimers consisting of SAE1 and SAE2 / UBA2. SAEs use ATP to adenylate the C-terminal glycine residue of SUMO, forming a thioester intermediate between the C-terminal glycine of SUMO and a cysteine ​​residue in SAE2. The SUMO protein is then transferred from E1 to a SUMO-specific conjugating enzyme, collectively referred to as E2, via thioester bond exchange. Finally, through the action of SUMO-specific E3 protein ligases, the SUMO protein is finally conjugated to a lysine residue on a target protein, forming an oligomeric chain. Protein sumoylation affects catalytic activity, subcellular localization, and interactions with other proteins. Furthermore, recent studies have shown that protein sumoylation plays an important role in various cell signaling pathways, including cell division, DNA repair, chromosome segregation, nuclear transport, gene transcription, and immune regulation. Overexpression of proteins related to the SUMO signaling pathway is associated with poor prognosis in certain cancer patients. Knockdown of SAEs has shown synthetic lethality in certain MYC-overexpressing tumor cells. Furthermore, sumoylation can also regulate innate immune responses. Inhibition of sumoylation enhances the expression of type 1 interferon (IFN). In short, there is an urgent need to research and identify compounds with potent activity targeting SAE. Summary of the Invention [Problem to be solved by the invention]

[0004] There is an urgent need to research and identify compounds with potent activity that target SAEs. [Means for solving the problem]

[0005] (overview) The present disclosure provides a compound of general formula (1), or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof. [ka] (In general formula (1), Y is -O-, -CH2-, or -N(H)-; R a is -H, -F, -NH2, or -OH; R a’ is -H or -F, and R a If -NH2 or -OH, R a’ is -H; R b is —H or (C1-C4) alkyl; R c is —H or (C1-C4) alkyl; R d is -H, halogen, -CF3, or (C1-C4) alkyl; X 1 is C(H), C(F), or N; X 2 is S or O; X 3 is C(R x3 ) or N; R x3 is -H, halogen, or -CH3; X 4 is S, O, C(R x41 )(R x41’ ), or N(R x42 ) and; R x42is —H, (C1-C4) alkyl, or (C3-C5) cycloalkyl; R x41 and R x41’ are each independently selected from the group consisting of -H, halogen, -OH, -OR x411 , -N(R x411 )(R x412 ), —CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C9)cycloalkyl, or (C1-C6)alkoxy; R x411 and R x412 are each independently optionally -H, (C1-C4) alkyl, or (C3-C5) cycloalkyl, or R x411 and R x412 may, together with the N atom to which they are attached, form a (3- to 6-membered)heterocycloalkyl, wherein said (3- to 6-membered)heterocycloalkyl may be optionally substituted with 1, 2, 3, or 4 groups of —H or halogen; R 3 and R 4 are each independently optionally -H, -D, -OH, -NH2, -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C1-C6) alkoxy, (C6-C14) aryl, (3-11 membered) heterocycloalkyl, or (5-11 membered) heteroaryl, wherein the (C1-C6) alkyl, the (C1-C6) haloalkyl, the (C2-C6) alkenyl, the (C2-C6) alkynyl, the (C3-C9) cycloalkyl, the (C1-C6) alkoxy, the (C6-C14) aryl, the (3-11 membered) heterocycloalkyl, or the (5-11 membered) heteroaryl are each independently -H, halogen, -OH, -(CH2) r OR 31 , -(CH2) r NR 31 R 32 , -OR 31 , -NR 31 R 32 , -CN, -C(O)NR31 R 32 , -NR 32 C(O)R 31 , -NR 32 S(O)2R 31 , -S(O) p R 31 , and -S(O)NR 31 R 32 optionally substituted with 1, 2, 3, or 4 groups selected from the group consisting of: 3 and R 4 may, together with the carbon atoms to which they are attached, form a (4-7 membered) heterocycloalkyl or a (C3-C6) cycloalkyl, wherein said (4-7 membered) heterocycloalkyl or said (C3-C6) cycloalkyl is optionally substituted with one, two, three, or four of -H, halogen, (C1-C6) alkyl, or (C1-C6) alkoxy; or R 3 and adjacent R 5 may, together with the atoms to which they are attached, form a (C3-C9)cycloalkyl or a (3-11 membered)heterocycloalkyl, wherein said (C3-C9)cycloalkyl or said (3-11 membered)heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 groups selected from the group consisting of —H, halogen, (C1-C6)alkyl, and (C1-C6)alkoxy; or R 3 and adjacent R 5 If both are absent, an endocyclic double bond is formed; alternatively, R 3 and R 4 together form oxo; R 5 and R 6are each independently optionally -H, -D, -OH, -NH2, -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C1-C6) alkoxy, (C6-C14) aryl, (3-11 membered) heterocycloalkyl, or (5-11 membered) heteroaryl, wherein the (C1-C6) alkyl, the (C1-C6) haloalkyl, the (C2-C6) alkenyl, the (C2-C6) alkynyl, the (C3-C9) cycloalkyl, the (C1-C6) alkoxy, the (C6-C14) aryl, the (3-11 membered) heterocycloalkyl, or the (5-11 membered) heteroaryl are each independently -H, halogen, -OH, -(CH2) r OR 31 , -(CH2) r NR 31 R 32 , -OR 31 , -NR 31 R 32 , -CN, -C(O)NR 31 R 32 , -NR 32 C(O)R 31 , -NR 32 S(O)2R 31 , -S(O) p R 31 , and -S(O)NR 31 R 32 optionally substituted with 1, 2, 3, or 4 groups selected from the group consisting of: 5 and R 6 may together with the carbon atoms to which they are attached form a (4-7 membered) heterocycloalkyl or a (C3-C6) cycloalkyl, wherein said (4-7 membered) heterocycloalkyl or said (C3-C6) cycloalkyl is optionally substituted with one, two, three, or four of -H, halogen, (C1-C6) alkyl, and (C1-C6) alkoxy; or R 5 and R 6 together form oxo; Ring A is (C6-C10)aryl or (5-10 membered)heteroaryl; Each R 1 are independently optionally selected from -H, halogen, -OH, -NO2, -NR 31 R 32 , -(CH2) r OR 31 , -(CH2) r NR 31 R 32 , -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, -C(O)NR 31 R 32 , -NR 32 C(O)R 31 , -NR 32 S(O)2R 31 , -S(O) p R 31 , or -S(O)NR 31 R 32 wherein the (C1-C6) alkyl, the (C1-C6) haloalkyl, the (C1-C6) alkoxy, the (C2-C6) alkenyl, the (C2-C6) alkynyl, or the (C3-C8) cycloalkyl each independently represents -H, halogen, -OH, -(CH2) r OR 31 , -(CH2) r NR 31 R 32 , -OR 31 , -NR 31 R 32 , -CN, and (C1-C6) alkyl; Ring B is (C5-C7)cycloalkyl or (5-7 membered)heterocycloalkyl; Each R 2 are independently optionally selected from -H, halogen, -OH, -NR 31 R 32 , —CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C2-C6) alkenyl, (C2-C6) alkynyl, or (C3-C8) cycloalkyl; or two R on the same carbon atom 2may together with the carbon atoms to which they are attached form a (4-6 membered) heterocycloalkyl or a (C3-C6) cycloalkyl, wherein said (4-6 membered) heterocycloalkyl or said (C3-C6) cycloalkyl may be optionally substituted with 1, 2, 3, or 4 groups selected from -H, halogen, (C1-C6) alkyl, and (C1-C6) alkoxy; or two R on the same carbon atom 2 together form oxo; R 31 and R 32 are each independently optionally -H, (C1-C4) alkyl, or (C3-C5) cycloalkyl, or R 31 and R 32 may, together with the N atom to which they are attached, form a (3- to 6-membered) heterocycloalkyl, wherein said (3- to 6-membered) heterocycloalkyl may be optionally substituted with 1, 2, 3, or 4 groups selected from -H and halogen; and n is an integer selected from 0, 1, 2, 3, or 4; m is an integer selected from 0, 1, 2, 3, or 4; r is an integer selected from 0, 1, or 2; and p is an integer selected from 0, 1, or 2.

[0006] In another preferred embodiment, in general formula (1), Y is —O— or —N(H)—, preferably —O—.

[0007] In another preferred embodiment, in general formula (1), R d is -H, -F, -CF3, or -CH3.

[0008] In another preferred embodiment, in the general formula (1), R x42 is —H, (C1-C3) alkyl, or (C3-C5) cycloalkyl.

[0009] In another preferred embodiment, in the general formula (1), R x42 is -H, [ka] is.

[0010] In another preferred embodiment, in the general formula (1), R x41 and R x41’ are each independently optionally selected from the group consisting of -H, -F, -OH, -OCH3, -N(CH3)2, -NH2, -CN, [ka] , -CF3, -CH2CF3, [ka] is.

[0011] In another preferred embodiment, in the general formula (1), R 3 and R 4 are each independently optionally -H, -D, -OH, -NH2, -CN, (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C5) cycloalkyl, (C1-C3) alkoxy, phenyl, (4-6 membered) heterocycloalkyl, or (5-6 membered) heteroaryl, wherein said (C1-C3) alkyl, said (C1-C3) haloalkyl, said (C2-C4) alkenyl, said (C2-C4) alkynyl, said (C3-C5) cycloalkyl, said (C1-C3) alkoxy, The phenyl, the (4- to 6-membered)heterocycloalkyl, or the (5- to 6-membered)heteroaryl are each independently optionally substituted with one, two, three, or four of the following groups: -H, -F, -OH, -CHOCH, -CHN(CH), -OCH, -N(CH), -CN, -C(O)N(CH), -NCHC(O)CH, -NHC(O)CH, -NCHS(O)CH, -NHS(O)CH, -SCH, -S(O)CH, -S(O)NH, and -S(O)N(CH); or R 3 and R 4may form, together with the carbon atoms to which they are attached, a (4-6 membered) heterocycloalkyl or a (C3-C4) cycloalkyl, wherein said (4-6 membered) heterocycloalkyl or said (C3-C4) cycloalkyl is selected from the group consisting of -H, -F, [ka] or —OCH3; or R 3 and adjacent R 5 may form, together with the atoms to which they are bonded, a (C3-C6)cycloalkyl or a (3- to 6-membered)heterocycloalkyl, wherein the (C3-C6)cycloalkyl or the (3- to 6-membered)heterocycloalkyl each independently represents -H, -F, [ka] or —OCH3; or R 3 and adjacent R 5 If both are absent, an endocyclic double bond is formed; alternatively, R 3 and R 4 together form an oxo.

[0012] In another preferred embodiment, in general formula (1), R 5 and R 6are each independently optionally -H, -D, -OH, -NH2, -CN, (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C5) cycloalkyl, (C1-C3) alkoxy, phenyl, (4-6 membered) heterocycloalkyl, or (5-6 membered) heteroaryl, wherein said (C1-C3) alkyl, said (C1-C3) haloalkyl, said (C2-C4) alkenyl, said (C2-C4) alkynyl, said (C3-C5) cycloalkyl, said (C1-C3) alkoxy, The phenyl, the (4- to 6-membered)heterocycloalkyl, or the (5- to 6-membered)heteroaryl may each independently be optionally substituted with one, two, three, or four of the following groups: -H, -F, -OH, -CHOCH, -CHN(CH), -OCH, -N(CH), -NH, -CN, -C(O)N(CH), -NCHC(O)CH, -NHC(O)CH, -NCHS(O)CH, -NHS(O)CH, -SCH, -S(O)CH, -S(O)NH, and -S(O)N(CH); or R 5 and R 6 may form, together with the carbon atoms to which they are attached, a (4-6 membered) heterocycloalkyl or a (C3-C4) cycloalkyl, wherein said (4-6 membered) heterocycloalkyl or said (C3-C4) cycloalkyl is selected from the group consisting of -H, -F, [ka] or —OCH3; or R 5 and R 6 together form an oxo.

[0013] In another preferred embodiment, in general formula (1), ring A is phenyl or (5- to 6-membered) heteroaryl.

[0014] In another preferred embodiment, in general formula (1), ring A is phenyl, pyridinyl, furanyl, thienyl, thiazolyl, imidazolyl, or oxazolyl, preferably phenyl or pyridinyl.

[0015] In another preferred embodiment, in general formula (1), ring A is [ka] is.

[0016] In another preferred embodiment, in general formula (1), each R 1 are independently optionally selected from the group consisting of -H, -F, -Cl, -Br, -I, -OH, -NO2, -N(CH3)2, -NH2, -CH2OCH3, -CH2N(CH3)2, -CN, (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, -C(O)N(CH3)2, -NCH3C(O)CH3, -NHC(O)CH3, -NCH3S(O)2CH3, and -NHS(O) 2CH3, -SCH3, -S(O)2CH3, -S(O)2NH2, and -S(O)2N(CH3)2, wherein the (C1-C3) alkyl, the (C1-C3) haloalkyl, the (C1-C3) alkoxy, the (C2-C4) alkenyl, the (C2-C4) alkynyl, or the (C3-C6) cycloalkyl are each independently -H, -F, -OH, -CHOCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2, -NH2, -CN, [ka] and optionally substituted with 1, 2, 3, or 4 groups of:

[0017] In another preferred embodiment, in general formula (1), each R 1are independently -H, -F, -Cl, -Br, -I, -OH, -NO2, -N(CH3)2, -NH2, -CH2OCH3, -CH2N(CH3)2, -CN, -C(O)N(CH3)2, -N CH3C(O)CH3, -NHC(O)CH3, -NCH3S(O)2CH3, -NHS(O)2CH3, -SCH3, -S(O)2CH3, -S(O)2NH2, -S(O)2N(CH3)2, [ka] , -CF3, -CH2CF3, [ka] , -OCH3, -OCH2CH3, -OCH(CH3)2, [ka] is.

[0018] In another preferred embodiment, in general formula (1), ring B is (C5-C6)cycloalkyl or (5- to 6-membered)heterocycloalkyl.

[0019] In another preferred embodiment, in general formula (1), ring B is a (C5-C6)cycloalkyl or (5- to 6-membered)heterocycloalkyl containing one ring heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0020] In another preferred embodiment, in the general formula (1), the structural unit: [ka] teeth, [ka] is.

[0021] In another preferred embodiment, in the general formula (1), the structural unit: [ka] teeth, [ka] is.

[0022] In another preferred embodiment, in the general formula (1), each R 2 are independently, optionally, -H, -F, -Cl, -Br, -I, -OH, -N(CH3)2, -NH2, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, (C2-C4)alkenyl, (C2-C4)alkynyl, or (C3-C5)cycloalkyl; or two R on the same carbon atom are 2 may form, together with the carbon atoms to which they are attached, a (4- to 5-membered) heterocycloalkyl or a (C3-C5) cycloalkyl, wherein said (4- to 5-membered) heterocycloalkyl or said (C3-C5) cycloalkyl is selected from the group consisting of -H, -F, [ka] and -OCH; or two R on the same carbon atom 2 together form an oxo.

[0023] In another preferred embodiment, in the general formula (1), each R 2 are independently optionally selected from -H, -F, -Cl, -Br, -I, -OH, -N(CH3)2, -NH2, -CN, [ka] , -CF3, -CH2CF3, [ka] , -OCH3, -OCH2CH3, -OCH(CH3)2, [ka] is.

[0024] In another preferred embodiment, in the general formula (1), the structural unit: [ka] teeth, [ka] [ka] [ka] is.

[0025] In another preferred embodiment, in the general formula (1), the structural unit: [ka] teeth, [ka] is.

[0026] In another preferred embodiment, in the general formula (1), the structural unit: [ka] teeth, [ka] [ka] [ka] [ka] is.

[0027] In another preferred embodiment, in the general formula (1), the general formula (1) is represented by the general formula (1a): [ka] wherein ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , R a’ , R b , R c , R d , X 1 , X 2 , X 3 , X 4 , m, and n are as defined above and exemplified in the specific examples.

[0028] In another preferred embodiment, in the general formula (1), the general formula (1) is represented by general formula (2a): [ka] wherein ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , R a’ , R b , R c , R d , X 1 , X 4 , m, and n are as defined above and exemplified in the specific examples.

[0029] In another preferred embodiment, in the general formula (1), the general formula (1) is represented by the general formula (3a): [ka] wherein ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Ra , R a’ , R b , R c , X 1 , X 4 , m, and n are as defined above and exemplified in the specific examples.

[0030] In another preferred embodiment, in the general formula (1), the general formula (1) is represented by general formula (4a): [ka] wherein ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , R a’ , R b , X 1 , X 4 , m, and n are as defined above and exemplified in the specific examples.

[0031] In another preferred embodiment, in the general formula (1), the general formula (1) is represented by the general formula (5a): [ka] wherein ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R b , X 1 , X 4 , m, and n are as defined above and exemplified in the specific examples.

[0032] In another preferred embodiment, in the general formula (1), the general formula (1) is represented by the general formula (6a): [ka] wherein ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 4 , m, and n are as defined above and exemplified in the specific examples.

[0033] In another preferred embodiment, in the general formula (1), the general formula (1) is represented by the general formula (7a) or (7a): [ka] wherein ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 4 , m, and n are as defined above and exemplified in the specific examples.

[0034] In another particular embodiment of the present invention, the compound of general formula (1) has the following structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] It has one of the following.

[0035] Another object of the present disclosure is to provide a pharmaceutical composition containing a pharmaceutically acceptable carrier, diluent and / or excipient and, as an active ingredient, the compound of general formula (1) of the present disclosure or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.

[0036] Yet another object of the present disclosure is to provide use of a compound of general formula (1) of the present disclosure, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, or the above pharmaceutical composition, in the preparation of a medicament for treating, regulating or preventing a disease associated with an SAE protein, wherein the disease is preferably cancer, and the cancer is a blood cancer or a solid cancer.

[0037] Yet another object of the present disclosure further provides a method for treating, regulating, or preventing a disease associated with an SAE protein, the method comprising administering to a subject a therapeutically effective amount of a compound of general formula (1) of the present disclosure, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, or the pharmaceutical composition.

[0038] The present inventors have discovered, through synthesis and careful study of various novel compounds having inhibitory effects against SAE, that the compound of general formula (1) has surprisingly strong inhibitory activity against SAE.

[0039] It is to be understood that both the foregoing general description and the following detailed description of the present disclosure are exemplary and explanatory and are intended to provide further explanation of the present disclosure as claimed.

[0040] (Compound synthesis) Methods for preparing the compounds of general formula (1) of the present invention are specifically described below, but these specific methods do not limit the present disclosure in any way.

[0041] The compounds of formula (1) above can be synthesized using standard synthetic techniques, well-known techniques, in combination with the methods described herein. Furthermore, the solvents, temperatures, and other reaction conditions described herein may vary. Starting materials for the synthesis of the compounds may be obtained synthetically or commercially available. The compounds described herein and other related compounds with different substituents are described in March, ADVANCED ORGANIC CHEMISTRY, 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY, 4 th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., (Wiley 1999). General methods for preparing compounds can be modified by using appropriate reagents and conditions to introduce various groups into the molecular formulas described herein.

[0042] In one embodiment, the compounds described herein are prepared according to methods known in the art. However, the conditions of the methods, such as reactants, solvents, bases, amounts of compounds used, reaction temperatures, and reaction times, are not limited to those described below. In addition, the compounds of the present disclosure can be easily prepared by any combination of various synthetic methods described herein or known in the art, and such combinations can be easily determined by those skilled in the art to which this disclosure pertains. In one embodiment, the present disclosure further provides a method for preparing a compound of general formula (1), where the compound of general formula (1) can be prepared according to the following General Reaction Scheme 1, General Reaction Scheme 2, General Reaction Scheme 3, General Reaction Scheme 4, General Reaction Scheme 5, General Reaction Scheme 6, or General Reaction Scheme 7.

[0043] General Reaction Scheme 1 [ka]

[0044] Embodiments of compounds of general formula (1) can be prepared according to General Reaction Scheme 1, where P is R b or a hydroxyl protecting group, and ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , R a’ , R b , R c , R d , X 1 , X 2 , X 3 , m, and n are as defined above, H represents hydrogen, N represents nitrogen, O represents oxygen, Cl represents chlorine, and X 4arepresents O or S, and L represents O or NH. As shown in General Reaction Scheme 1, compound 1-1 is subjected to a substitution reaction with compound 1-2 to produce an alcohol intermediate, which is further oxidized to give ketone compound 1-3. Compound 1-3 is subjected to a substitution reaction with compound 1-4 to produce compound 1-5, compound 1-5 is subjected to a substitution reaction with compound 1-6 to produce compound 1-7, optionally, compound 1-7 is subjected to deprotection of the hydroxyl group to produce compound 1-8, and optionally, compound 1-8 is subjected to chiral resolution to give enantiomer 1-A and enantiomer 1-B.

[0045] General Reaction Scheme 2 [ka]

[0046] Embodiments of compounds of general formula (1) can be prepared according to General Reaction Scheme 2, where P is R b or a hydroxyl protecting group, P' is an amino protecting group, and ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , R a’ , R b , R c , R d , X 1 , X 2 , X 3 , m, and n are as defined above, H represents hydrogen, N represents nitrogen, O represents oxygen, Cl represents chlorine, and L represents O or NH. As shown in General Reaction Scheme 2, compound 2-1 is subjected to a substitution reaction with compound 2-2 to produce an alcohol intermediate, which is further oxidized to give ketone compound 2-3, compound 2-3 is subjected to a substitution reaction with compound 2-4 to produce compound 2-5, compound 2-5 is subjected to a substitution reaction with compound 2-6 to produce compound 2-7, optionally compound 2-7 is subjected to deprotection to produce compound 2-8, and optionally compound 2-8 is subjected to chiral resolution to give enantiomer 2-A and enantiomer 2-B.

[0047] General Reaction Scheme 3 [ka]

[0048] Embodiments of compounds of general formula (1) can be prepared according to General Reaction Scheme 3, where R 1 and n are as defined above, X represents O, S, or CH2, H represents hydrogen, N represents nitrogen, O represents oxygen, and Cl represents chlorine. As shown in General Reaction Scheme 3, compound 3-1 is condensed with nitromethane to produce compound 3-2, compound 3-2 is reduced to give amine 3-3, amine 3-3 is condensed with ketone 3-4 to give compound 3-5, compound 3-5 is cyclized under acidic conditions to produce compound 3-6, compound 3-6 is demethylated to give compound 3-7, compound 3-7 is reacted with PhNTf2 to give compound 3-8, compound 3-8 is reduced to give compound 3-9, compound 3-9 is formyl-deprotected to give compound 3-10, compound 3-10 is protected with (Boc)2O to give compound 3-11, and compound 3-11 is reacted with DMF under n-butyllithium conditions to give compound 3-12. to give aldehyde 3-12, which is then subjected to an addition reaction with compound 3-13 under n-butyllithium conditions to give compound 3-14, which is then subjected to Dess-Martin oxidation or Swern oxidation to give ketone 3-15, which is then subjected to a substitution reaction with compound 3-16 under alkaline conditions to give compound 3-17, which is then reacted with compound 3-18 to give compound 3-19, which is then deprotected with TBAF to give compound 3-20, which is then subjected to deprotection of the amino group under acidic conditions to give compound 3-21, and optionally, compound 3-21 is subjected to chiral resolution to give enantiomer 3-A and enantiomer 3-B.

[0049] General Reaction Scheme 4 [ka]

[0050] Embodiments of compounds of general formula (1) can be prepared according to General Reaction Scheme 4, where R 1 and n are as defined above, Y represents Br or I, H represents hydrogen, N represents nitrogen, O represents oxygen, and Cl represents chlorine. As shown in General Reaction Scheme 4, compound 4-1 is condensed with nitromethane to produce compound 4-2, compound 4-2 is reduced to produce amine 4-3, amine 4-3 is condensed with ketone 4-4 to produce compound 4-5, compound 4-5 is reacted with acetic anhydride to produce compound 4-6, compound 4-6 is cyclized under Pd catalysis to produce compound 4-7, compound 4-7 is deprotected with an acetyl group to produce compound 4-8, compound 4-8 is protected with (Boc)2O to produce compound 4-9, compound 4-9 is hydrogenated to produce compound 4-10, and compound 4-10 is reacted with DMF under n-butyllithium conditions to produce an aldehyde. Aldehyde 4-11 is obtained, and aldehyde 4-11 is subjected to an addition reaction with compound 4-12 under n-butyllithium conditions to obtain compound 4-13. Compound 4-13 is subjected to Dess-Martin oxidation to obtain ketone 4-14. Ketone 4-14 is subjected to a substitution reaction with compound 4-15 under alkaline conditions to obtain compound 4-16. Compound 4-16 is reacted with compound 4-17 to produce compound 4-18. Compound 4-18 is deprotected with TBAF to obtain compound 4-19. Compound 4-19 is subjected to deprotection of the amino group under acidic conditions to obtain compound 4-20. In some cases, compound 4-20 is subjected to chiral resolution to obtain optical isomer 4-A and optical isomer 4-B.

[0051] General Reaction Scheme 5 [ka]

[0052] Embodiments of compounds of general formula (1) can be prepared according to General Reaction Scheme 5, where R 1and n are as defined above, Y represents Br or I, H represents hydrogen, N represents nitrogen, O represents oxygen, and Cl represents chlorine. As shown in General Reaction Scheme 5, compound 5-1 is condensed with nitromethane to produce compound 5-2, compound 5-2 is reduced to produce amine 5-3, amine 5-3 is condensed with ketone 5-4 to produce compound 5-5, compound 5-5 is reacted with acetic anhydride to produce compound 5-6, compound 5-6 is cyclized under Pd catalysis to produce compound 5-7, compound 5-7 is deprotected with an acetyl group to produce compound 5-8, compound 5-8 is protected with (Boc)2O to produce compound 5-9, compound 5-9 is reacted with DMF under n-butyllithium conditions to produce aldehyde 5-10, and aldehyde 5-10 is subjected to an addition reaction with compound 5-11 under n-butyllithium conditions to give compound 5-12, compound 5-12 is subjected to Dess-Martin oxidation to give ketone 5-13, ketone 5-13 is subjected to a substitution reaction with compound 5-14 under alkaline conditions to give compound 5-15, compound 5-15 is reacted with compound 5-16 to give compound 5-17, compound 5-17 is deprotected with TBAF to give compound 5-18, compound 5-18 is subjected to deprotection of the amino group under acidic conditions to give compound 5-19, and optionally compound 5-19 is subjected to chiral resolution to give optical isomer 5-A and optical isomer 5-B.

[0053] General Reaction Scheme 6 [ka]

[0054] Embodiments of compounds of general formula (1) can be prepared according to General Reaction Scheme 6, where R 1and n is as defined above, Y represents Br or I, H represents hydrogen, N represents nitrogen, O represents oxygen, and Cl represents chlorine. As shown in General Reaction Scheme 6, compound 6-1 is condensed with nitromethane to give compound 6-2, compound 6-2 is reduced to give amine 6-3, amine 6-3 is condensed with ketone 6-4 to give compound 6-5, compound 6-5 is reacted with acetic anhydride to give compound 6-6, compound 6-6 is cyclized under Pd catalysis to give compound 6-7, compound 6-7 is deprotected with an acetyl group to give compound 6-8, compound 6-8 is protected with (Boc)2O to give compound 6-9, compound 6-9 is oxidized under potassium osmate and sodium periodate conditions to give dialdehyde 6-10, dialdehyde 6-10 is reduced with sodium borohydride to give diol 6-11, diol 6-11 is cyclized under acidic conditions to give compound 6-12, and compound 6 -12 is protected with (Boc)2O to give compound 6-13, compound 6-13 is reacted with DMF under n-butyllithium conditions to give aldehyde 6-14, aldehyde 6-14 is subjected to an addition reaction with compound 6-15 under n-butyllithium conditions to give compound 6-16, compound 6-16 is subjected to Dess-Martin oxidation or Swern oxidation to give ketone 6-17, ketone 6-17 is subjected to a substitution reaction with compound 6-18 under alkaline conditions to give compound 6-19, compound 6-19 is reacted with compound 6-20 to give compound 6-21, compound 6-21 is deprotected with TBAF to give compound 6-22, compound 6-22 is subjected to deprotection of the amino group under acidic conditions to give compound 6-23, and optionally compound 6-23 is subjected to chiral resolution to give enantiomer 6-A and enantiomer 6-B.

[0055] General Reaction Scheme 7 [ka]

[0056] Embodiments of compounds of general formula (1) can be prepared according to General Reaction Scheme 7, where R 1and n are as defined above, Y represents Br or I, Z represents -H, -OH, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C2-C6) alkenyl, (C2-C6) alkynyl, or (C3-C8) cycloalkyl, H represents hydrogen, N represents nitrogen, O represents oxygen, and Cl represents chlorine. As shown in General Reaction Scheme 7, compound 7-1 is condensed with nitromethane to give compound 7-2, compound 7-2 is reduced to give amine 7-3, amine 7-3 is condensed with ketone 7-4 to give compound 7-5, compound 7-5 is reacted with acetic anhydride to give compound 7-6, compound 7-6 is cyclized under Pd catalysis to give compound 7-7, compound 7-7 is deprotected with an acetyl group to give compound 7-8, compound 7-8 is protected with (Boc)2O to give compound 7-9, compound 7-9 is oxidized under potassium osmate and sodium periodate conditions to give dialdehyde 7-10, dialdehyde 7-10 is subjected to reductive amination to give amine 7-11, and compound 7-11 is oxidized to give dialdehyde 7-12. The aldehyde 7-12 is reacted with DMF under n-butyllithium conditions to give aldehyde 7-12, which is then subjected to an addition reaction with compound 7-13 under n-butyllithium conditions to give compound 7-14, which is then subjected to Dess-Martin oxidation or Swern oxidation to give ketone 7-15, which is then subjected to a substitution reaction with compound 7-16 under alkaline conditions to give compound 7-17, which is then reacted with compound 7-18 to give compound 7-19, which is then deprotected with TBAF to give compound 7-20, which is then subjected to deprotection of the amino group under acidic conditions to give compound 7-21, and optionally, compound 7-21 is subjected to chiral resolution to give enantiomer 7-A and enantiomer 7-B.

[0057] Further forms of the compound As used herein, the term "pharmaceutically acceptable" refers to a substance, such as a carrier or diluent, that does not cause a loss of biological activity or properties of a compound and is relatively non-toxic. For example, when administered to an individual, the substance does not cause undesired biological effects or adverse interactions with any of its components.

[0058] The term "pharmaceutically acceptable salt" refers to a form of a compound that does not significantly irritate the receiving organism or eliminate the biological activity and properties of the compound. In certain specific embodiments, the pharmaceutically acceptable salt is obtained by reacting a compound of the general formula with an acid or base, where the acid or base is selected from the group consisting of: Stahl and Wermuth, Handbook of Pharmaceutical Salts: properties, Selection, and Use, 1 st Ed., (Wiley, 2002), but are not limited to these.

[0059] It should be understood that pharmaceutically acceptable salts include solvent addition forms or crystalline forms, particularly solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are preferentially formed upon crystallization in pharmaceutically acceptable solvents such as water and ethanol. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is ethanol. Solvates of compounds of general formula (1) are conveniently prepared or formed according to the methods described herein. For example, hydrates of compounds of general formula (1) are conveniently prepared by recrystallization in a water / organic solvent mixture, where the organic solvent used includes, but is not limited to, tetrahydrofuran, acetone, ethanol, or methanol. Furthermore, the compounds described herein can exist in either unsolvated or solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0060] In other specific examples, the compound of general formula (1) is prepared in different forms, including, but not limited to, amorphous, pulverized, and nanoparticle forms. Furthermore, the compound of general formula (1) may be a polymorph, including crystalline forms. Polymorphs contain different lattice arrangements of the same elements of a compound. Polymorphs generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystalline forms, optical properties, electrical properties, stability, and solubility. Various factors, such as recrystallization solvents, crystallization rates, and storage temperatures, may result in a single predominant crystalline system.

[0061] In another embodiment, the compounds of general formula (1) may have chiral centers and / or axial asymmetry and therefore may exist in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds, single diastereomers, and cis-trans isomers. Each chiral center or axial asymmetry independently produces two optical isomers, and all possible optical isomers, diastereomeric mixtures, and pure or partially pure compounds are included within the scope of the present disclosure. The present disclosure is meant to include all such isomers of these compounds.

[0062] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain tritium ( 3 H), iodine-125( 125 I) and C-14( 14

[0013] The compounds may be labeled with radioactive isotopes such as CI (C). As another example, deuterium can be used to replace a hydrogen atom to form a deuterated compound. The bond formed between deuterium and carbon is stronger than the bond formed between normal hydrogen and carbon. Compared to non-deuterated drugs, deuterated drugs generally have advantages such as reduced toxicity and side effects, improved drug stability, enhanced efficacy, and prolonged in vivo drug half-life. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are within the scope of the present disclosure.

[0063] Unless otherwise specified, any atom of the compounds of the present disclosure refers to the isotope of the atom in the stable state of the compound.Unless otherwise specified, when a site in a molecular structure is selected as "H" or "hydrogen", it should be understood that the site has the natural abundance of hydrogen isotopes.Similarly, unless otherwise specified, when a site is selected as "D" or "deuterium", it should be understood that the site has a deuterium isotope abundance that is at least 3000 times the natural abundance (the natural abundance of deuterium isotopes is 0.015%).

[0064] More preferably, each deuterated site of a deuterated compound of the present disclosure has a deuterium atom abundance that is at least 3500 times its natural abundance (52.2% deuterium atom enrichment). More preferably, the deuterium atom abundance is at least 4500 times its natural abundance (67.5% deuterium atom enrichment). More preferably, the deuterium atom abundance is at least 5000 times its natural abundance (75% deuterium atom enrichment). More preferably, the deuterium atom abundance is at least 6000 times its natural abundance (90% deuterium atom enrichment). More preferably, the deuterium atom abundance is at least 6333 times its natural abundance (95% deuterium atom enrichment). More preferably, the deuterium atom abundance is at least 6466.7 times its natural abundance (97% deuterium atom enrichment). More preferably, the deuterium atom abundance is at least 6600 times its natural abundance (99% deuterium atom enrichment). More preferably, the deuterium atom abundance is at least 6633.3 times the natural abundance (deuterium atom enrichment 99.5%).

[0065] Explanation of terms Unless otherwise indicated, the terms used herein, including those set forth in the specification and claims, are defined as follows: It should be noted that, in this specification and the appended claims, the singular forms "a" and "an" include the plural reference unless otherwise indicated. Conventional methods of mass spectrometry, nuclear magnetic resonance spectroscopy, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed unless otherwise indicated. As used herein, "or" means "and / or" unless otherwise indicated.

[0066] Unless otherwise specified, "alkyl" refers to saturated aliphatic hydrocarbon groups with straight and branched chains containing 1 to 6 carbon atoms. Lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, or tert-butyl, are preferred. As used herein, "alkyl" includes unsubstituted alkyl and substituted alkyl, particularly alkyl substituted with one or more halogens. Preferred alkyls are CH3, CH3CH2, CF3, CHF2, CF3CH2, CF3(CH3)CH, i Pr, n Pr, i Bu, n Bu, or t Bu.

[0067] Unless otherwise specified, "alkylene" refers to a divalent alkyl as defined above. Examples of alkylene include, but are not limited to, methylene and ethylene.

[0068] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group having a carbon-carbon double bond, including straight-chain or branched groups containing 1 to 14 carbon atoms. Lower alkenyl groups containing 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl, or 2-methylpropenyl, are preferred. Lower alkenyl groups containing 1 to 2 carbon atoms are even more preferred.

[0069] Unless otherwise specified, "alkenylene" refers to a divalent alkenyl as defined above.

[0070] Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group having a carbon-carbon triple bond, including straight-chain and branched groups, containing 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms, such as ethynyl, 1-propynyl, or 1-butynyl, are preferred. Lower alkynyl groups containing 1 to 2 carbon atoms are even more preferred.

[0071] Unless otherwise specified, "alkynylene" refers to a divalent alkynyl as defined above.

[0072] Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), preferably containing 3 to 14 ring carbon atoms (C 3~14 In some embodiments, a cycloalkyl has 3 to 10 ring carbon atoms (C 3~10 In some embodiments, a cycloalkyl has 3 to 8 ring carbon atoms (C 3~8 In some embodiments, a cycloalkyl has 3 to 7 ring carbon atoms (C 3~7 In some embodiments, a cycloalkyl has 3 to 6 ring carbon atoms (C 3~6 In some embodiments, a cycloalkyl has 4 to 6 ring carbon atoms (C 4~6 In some embodiments, a cycloalkyl has 5 to 6 ring carbon atoms (C 5~6 In some embodiments, a cycloalkyl has 5 to 10 ring carbon atoms (C 5~10 cycloalkyl). In the case of cycloalkyl, a partially unsaturated cycloalkyl may be referred to as a "cycloalkenyl" if the carbocyclic ring contains at least one double bond, or a "cycloalkynyl" if the carbocyclic ring contains at least one triple bond. Cycloalkyls can include monocyclic or polycyclic groups (e.g., having 2, 3, or 4 fused rings) and spirocycles. In some embodiments, a cycloalkyl is monocyclic. In some embodiments, a cycloalkyl is bicyclic. In some embodiments, a cycloalkyl is monocyclic or bicyclic. In some embodiments, a cycloalkyl is tricyclic. Ring carbon atoms of a cycloalkyl can be optionally oxidized to form an oxo or thio group. Cycloalkyl further includes cycloalkylene. In some embodiments, a cycloalkyl contains zero, one, or two double bonds. In some embodiments, a cycloalkyl contains one or two double bonds (partially unsaturated cycloalkyl). In some embodiments, a cycloalkyl can be fused with an aryl, heteroaryl, cycloalkyl, and heterocycloalkyl. In some embodiments, cycloalkyls can be fused with aryls, cycloalkyls, and heterocycloalkyls. In some embodiments, cycloalkyls can be fused with aryls and heterocycloalkyls. In some embodiments, cycloalkyls can be fused with aryls and cycloalkyls. Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norcamphanyl, norpinanyl, norcarnyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, and the like.

[0073] Unless otherwise specified, "cycloalkylene" refers to a divalent cycloalkyl as defined above.

[0074] Unless otherwise specified, "alkoxy" refers to an alkyl group attached to the remainder of the molecule via an ether oxygen atom. Representative alkoxy groups are those having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy, particularly alkoxy substituted with one or more halogens. Preferred alkoxy are OCH3, OCF3, CHF2O, CF3CHO, i- PrO, n- PrO, i- BuO, n- BuO, and t- BuO.

[0075] Unless otherwise specified, "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon group. For example, a monocyclic aryl ring can be fused with one or more carbocyclic aromatic groups. Examples of aryl include, but are not limited to, phenyl, naphthyl, and phenanthryl.

[0076] Unless otherwise noted, "aryloxy" refers to an aryl group attached to the remainder of the molecule through an ether oxygen atom. Examples of aryloxy include, but are not limited to, phenoxy and naphthoxy.

[0077] Unless otherwise specified, "arylene" refers to a divalent aryl as defined above. Examples of arylene include, but are not limited to, phenylene, naphthylene, and phenanthrylene.

[0078] Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatom substitutions or an unsubstituted aromatic group, preferably a 5- to 14-membered aromatic group containing one to four heteroatoms selected from oxygen, sulfur, and nitrogen, and more preferably a 5- to 9-membered aromatic group containing one to two heteroatoms selected from oxygen, sulfur, or nitrogen. The heteroatoms are independently selected from O, N, or S, and the number of heteroatoms is preferably one, two, or three. Heteroaryls are monocyclic or polycyclic. Monocyclic heteroaryls are preferably 5- to 6-membered aromatic groups containing one to three heteroatoms selected from oxygen, nitrogen, or sulfur. More preferably, monocyclic heteroaryls are 5- to 6-membered aromatic groups containing one to two heteroatoms selected from oxygen, nitrogen, or sulfur. More preferably, monocyclic heteroaryls are 5- to 6-membered aromatic groups containing one heteroatom selected from oxygen, nitrogen, or sulfur. In some embodiments, the monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups.Examples of heteroaryl include pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridinyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, [ka] These include, but are not limited to:

[0079] Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl as defined above.

[0080] Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system that may optionally contain one or more alkenylene groups as part of the ring structure and has at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, and selenium. Heterocycloalkyls are preferably saturated or partially unsaturated rings containing 1 to 4 heteroatoms selected from oxygen, sulfur, or nitrogen, and more preferably saturated or partially unsaturated rings containing 1 to 2 heteroatoms selected from oxygen, sulfur, or nitrogen. In some embodiments, heterocycloalkyls are 5- to 8-membered non-aromatic rings containing ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, or sulfur (5- to 8-membered heterocycloalkyl). Heterocycloalkyls are 5- to 6-membered non-aromatic rings containing ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, or sulfur (5- to 6-membered heterocycloalkyl). In some embodiments, a 5- to 6-membered heterocycloalkyl contains 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocycloalkyl contains 1 to 2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocycloalkyl contains 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. A partially unsaturated heterocycloalkyl may be referred to as a "heterocycloalkenyl" when the heterocycloalkyl contains at least one double bond, and as a "heterocycloalkynyl" when the heterocycloalkyl contains at least one triple bond. A heterocycloalkyl can include monocyclic, bicyclic, spirocyclic, or polycyclic (e.g., having two fused or bridged rings) systems. In some embodiments, a heterocycloalkyl is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen.The ring carbon atoms and heteroatoms of a heterocycloalkyl may be optionally oxidized to form oxo or thio groups or other oxidized bonds (e.g., C(O), S(O), C(S), or S(O)2, and N-oxide, etc.), or the nitrogen atom may be quaternized. A heterocycloalkyl may be bonded through a ring carbon atom or a ring heteroatom. In some embodiments, a heterocycloalkyl contains 0 to 3 double bonds. In some embodiments, a heterocycloalkyl contains 0 to 2 double bonds. Also included within the definition of heterocycloalkyl are moieties having one or more aromatic rings fused (i.e., sharing bonds) to the heterocycloalkyl ring (also called partially unsaturated heterocycles), such as piperidine, morpholine, azepine, and benzo derivatives that are thienyl. A heterocycloalkyl containing a fused aromatic ring may be bonded through any ring atom, including a ring atom of the fused aromatic ring. Examples of heterocycloalkyl include azetidinyl, azepinyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydro-1H-imidazo[ 4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butyrolactam, valerolactam, imidazolidinonyl, hydantoinyl, dioxolanyl, phthalimidyl, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-oxide, piperazinyl, pyranyl, pyridonyl, 3-pyrrolinyl, thiopyranyl, pyronyl, tetrahydrothienyl, 2-azaspiro[3.3]heptanyl, indolinyl, [ka] These include, but are not limited to:

[0081] Unless otherwise specified, "heterocycloalkylene" means a divalent heterocycloalkyl as defined above.

[0082] Unless otherwise specified, "oxo" means =0. For example, the group formed when one carbon is replaced with oxo is called "carbonyl." [ka] and the group formed when sulfur is replaced by one oxo is "sulfinyl". [ka] and the group formed when sulfur is replaced by two oxo is "sulfonyl". [ka] is.

[0083] Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine, or iodine. The term "halo" (or "halogenated") before a group name indicates that the group is partially or fully halogenated, i.e., substituted by F, Cl, Br, or I, preferably F or Cl, in any combination.

[0084] Unless otherwise specified, the term "substituted" means that one or more hydrogen atoms on the specified atom or group are replaced with one or more non-hydrogen substituents, to the extent that the normal valence of the specified atom is not exceeded. For example, one or more hydrogen atoms of an alkyl, alkylene, alkenyl, alkynyl, hydroxy, amino, etc. may be replaced with one or more substituents. The substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxy, carboxylate, cyano, guanidino, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. The definition of "substituted" does not include similar indefinite structures obtained by defining a substituent with an infinite number of further substituents (e.g., a substituted aryl with a substituted alkyl is itself substituted with a substituted aryl, which is further substituted with a substituted heteroalkyl, etc.). Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl with two other substituted aryls is limited to a substituted aryl substituted with (substituted aryl substituted with (substituted aryl)). Similarly, the above definition does not include impermissible substitution patterns (e.g., methyl substituted with five fluorines or a heteroaryl with two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those of skill in the art. When used to modify a chemical group, "substituted" can refer to other chemical groups defined herein. For example, the term "substituted aryl" includes, but is not limited to, "alkylaryl." Unless otherwise specified, if a group is described as optionally substituted, the substituents on that group are not themselves substituted.

[0085] "Optional" or "optionally" means that the subsequently described event or circumstance may occur, but does not necessarily occur, and the description includes cases where the event or circumstance occurs and cases where it does not occur.

[0086] Unless otherwise stated, the word "comprise" or variations thereof, such as "comprises" or "comprising," will be understood to refer to the inclusion of the specified element or integer or group of elements or integers, but not to the exclusion of other elements or integers or groups of elements or integers.

[0087] The substituent "-O-CH2-O-" means that the two oxygen atoms in the substituent are bonded to two adjacent carbon atoms in a heterocycloalkyl, aryl, or heteroaryl, for example: [ka]

[0088] When the number of a linker group is 0, such as -(CH2)0-, it means that the linker group is a single bond.

[0089] When one of the variables is selected from a chemical bond, it means that the two groups linked by this variable are directly linked. For example, when L in XLY represents a chemical bond, it actually means that the structure is XY.

[0090] The term "membered ring" includes any cyclic structure. The term "membered" refers to the number of main chain atoms that form the ring. For example, cyclohexyl, pyridinyl, pyranyl, and thiopyranyl are six-membered rings, and cyclopentyl, pyrrolyl, furanyl, and thienyl are five-membered rings.

[0091] The term "moiety" refers to a specific portion or functional group of a molecule. A chemical moiety is generally considered to refer to a chemical substance contained in or attached to a molecule.

[0092] The term "isomer" refers to any tautomer, stereoisomer, atropisomer, isotopic isomer, enantiomer, or diastereomer of a compound of the present disclosure. The compounds of the present disclosure may have one or more asymmetric centers or double bonds and therefore exist in the form of stereoisomers, e.g., double bond isomers (i.e., E / Z geometric isomers), or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). Thus, the compounds of the present disclosure encompass all corresponding stereoisomers, i.e., stereoisomerically pure (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) forms, as well as mixtures of enantiomers and stereoisomers, e.g., racemates. Enantiomeric and stereoisomeric mixtures of the compounds of the present disclosure can be resolved into their constituent enantiomers or stereoisomers by well-known methods such as chiral gas chromatography and chiral high-performance liquid chromatography, as well as by crystallizing the compounds in the form of chiral salt complexes or in chiral solvents. Enantiomers and stereoisomers can also be obtained from stereomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods. The term "isotopomers" refers to distinct molecules that differ only by isotopic composition, but are otherwise identical in structure.

[0093] The term "atropisomer" refers to a conformational stereoisomer that occurs when rotation around a single bond within a molecule is hindered or extremely slowed by steric interactions with other parts of the molecule, and the substituents on both ends of the single bond are asymmetric, i.e., the atropisomer does not require a stereocenter. If the rotational hindrance around the single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation of individual isomers may be possible, preferably by chiral resolution methods (LaPlante et al., J. Med. Chem. 2011, 54, 20, 7005).

[0094] Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by a solid wedge bond. [ka] and wedge-shaped dashed bond [ka] and the relative configuration of the stereocenters is represented by a straight solid bond [ka] and straight dashed bond [ka] It is represented by the wavy line [ka] is a solid wedge connection [ka] or wedge-shaped dashed bond [ka] or a wavy line [ka] is a straight solid line connection [ka] or straight dashed bond [ka] Represents.

[0095] Unless otherwise indicated, single or double bonds are [ka] It is expressed by:

[0096] Specific pharmaceutical and medical terms The term "acceptable" as used herein means that the formulation or active ingredient does not have an excessive and deleterious effect on the health of the general subject to be treated.

[0097] As used herein, the terms "treatment," "course of treatment," and "treatment" include alleviating, inhibiting, or ameliorating a disease symptom or condition, inhibiting the development of complications, improving or preventing underlying metabolic syndrome, inhibiting the development of a disease or condition (e.g., controlling the progression of a disease or condition), alleviating a disease or condition, regressing a disease or condition, and alleviating complications caused by a disease or condition, or preventing or treating symptoms caused by a disease or condition. As used herein, a compound or pharmaceutical composition, when administered, can ameliorate a disease, symptom, or condition, and in particular, can improve the severity, delay the onset, slow the progression, or shorten the duration of a disease. Fixed or temporary administration, or continuous or intermittent administration, can result from or be associated with administration.

[0098] "Active ingredient" refers to compounds of general formula (1) and pharmaceutically acceptable inorganic or organic salts of compounds of general formula (1). The compounds of the present disclosure may contain one or more asymmetric centers (chiral centers or axial asymmetry) and therefore may exist in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds, and single diastereomers. The number of asymmetric centers that may be present depends on the nature of the various substituents on the molecule. Each such asymmetric center independently generates two optical isomers, and all possible optical isomers, diastereomeric mixtures, and pure or partially pure compounds are included within the scope of the present disclosure. The present disclosure is meant to include all such isomeric forms of these compounds.

[0099] As used herein, terms such as "compound," "composition," "drug," or "medicine or pharmaceutical agent" are used interchangeably and refer to any compound or composition that, when administered to an individual (human or animal), is capable of eliciting a desired pharmacological and / or physiological response through local and / or systemic action.

[0100] The terms "administered, administering, or administration" as used herein means direct administration of a compound or composition, or administration of a prodrug, derivative, analog, etc. of an active compound.

[0101] While the numerical ranges and parameters defining the broad scope of the present disclosure are approximations, the relevant values ​​set forth in specific embodiments are set forth herein as precisely as possible. However, any numerical value inherently contains standard deviations that necessarily result from certain testing methods. Herein, the term "about" generally means that the actual numerical value is within a particular numerical value or range ±10%, 5%, 1%, or 0.5%. Alternatively, the term "about" indicates that the actual numerical value falls within an acceptable standard error of the mean, as would be understood by one of ordinary skill in the art. Except in experimental examples or unless otherwise indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe amounts of substances, lengths of time, temperatures, operating conditions, proportions of amounts, etc.) are understood to be modified by the term "about." Thus, unless otherwise indicated, all numerical parameters set forth in this specification and the appended claims are approximations that may vary, if desired. At the very least, these numerical parameters should be construed as representing significant digits or as derived using conventional rounding rules.

[0102] Unless otherwise defined herein, scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Furthermore, as used herein, singular nouns include their plural forms, unless contradictory to the context, and plural nouns as used herein also include their singular forms.

[0103] therapeutic use The compounds of general formula (1) or pharmaceutical compositions of the present disclosure are generally useful for inhibiting SAE proteins and for treating one or more diseases associated with the activity of SAE proteins. Accordingly, in certain embodiments, the present invention provides a method for treating an SAE protein-mediated disease, the method comprising administering a compound of general formula (1) of the present disclosure or a pharmaceutically acceptable composition thereof to a patient in need thereof.

[0104] In some embodiments, a method of treating cancer is provided, comprising administering to an individual in need thereof an effective amount of any of the aforementioned pharmaceutical compositions containing a compound of general structural formula (1). In some embodiments, the cancer includes, but is not limited to, hematological malignancies (leukemia, lymphoma, myeloma including multiple myeloma, myelodysplastic syndrome, and myeloproliferative disorder), and solid tumors (carcinomas such as prostate cancer, breast cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, ovarian cancer, and soft tissue cancer, osteosarcoma, and stromal tumors), preferably lung cancer, cervical cancer, colon cancer, lymphoma, myeloma, leukemia, hepatocellular carcinoma, pancreatic cancer, kidney cancer, breast cancer, head and neck cancer, melanoma, prostate cancer, adrenal cancer, endometrial cancer, appendix cancer, and metastases of these cancers.

[0105] Route of administration The compounds of the present disclosure and their pharmaceutically acceptable salts can be prepared into various formulations containing a safe and effective amount of the compounds of the present disclosure or their pharmaceutically acceptable salts and a pharmaceutically acceptable excipient or carrier, where "safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the age, condition, course of treatment, and other specific conditions of the subject to be treated.

[0106] "Pharmaceutically acceptable excipient or carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be suitable for human use and have sufficient purity and low toxicity. "Compatible," as used herein, means that the components of the composition are capable of being intermixed with the compounds of the present disclosure without significantly reducing the pharmaceutical efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, or cellulose acetate), gelatin, talc, solid lubricants (e.g., stearic acid or magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, or olive oil), polyols (e.g., propylene glycol, glycerol, mannitol, or sorbitol), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0107] When administering the compounds of the present disclosure, they can be administered orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously) or topically.

[0108] Solid dosage forms for oral administration include capsules, tablets, pills, pulvises, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or the following ingredients: (a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants such as glycerol; (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retardants such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, and sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, said dosage forms may further comprise buffering agents.

[0109] Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials known in the art.These may contain opacifying agents, and the active compound or compounds in such compositions can be delayed in certain parts of the digestive tract.The examples of embedding components that can be used include polymeric materials and wax-based materials.If necessary, the active compound can be formed into microcapsules with one or more of the above-mentioned excipients.

[0110] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0111] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0112] In addition to the active compound, suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methylate, and agar-agar, or mixtures of these substances.

[0113] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0114] Dosage forms for topical administration of the compounds of the present disclosure include ointments, powders, patches, sprays, inhalants, etc. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier, and any preservatives, buffers, or propellants that may be required, as may be required.

[0115] The compounds of the present disclosure may be administered alone or in combination with other pharmaceutically acceptable compounds. When the pharmaceutical composition of the present invention is used, a safe and effective amount of the compound of the present disclosure is administered to the mammal (e.g., human) to be treated, where the administered amount is a pharmaceutically effective dose. For a 60 kg human, the daily dose is typically 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dose will take into account factors such as the route of administration and the patient's health condition, but these are well known to those skilled in the art.

[0116] The features described in this disclosure or the features described above in the embodiments can be combined in any way. All features disclosed herein can be used in any composition, and various features disclosed herein can be replaced with any alternative features that serve the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the features disclosed herein are merely generic examples of equivalent or similar features.

[0117] (Detailed explanation) Various specific aspects, features and advantages of the above compounds, methods and pharmaceutical compositions will be described in detail below, so that the contents of the present disclosure will be more clearly understood. It should be understood that the following detailed description and examples describe specific examples for reference only. After reading the description of the present disclosure, those skilled in the art can make various changes or modifications to the present invention, and such equivalents also fall within the scope of the present application as defined herein.

[0118] In all examples, 1 H-NMR spectra were recorded on a Varian Mercury 400 nuclear magnetic resonance spectrometer, and chemical shifts are expressed in ppm. Unless otherwise specified, 200-300 mesh silica gel was used for separation, and the ratio of eluents was expressed by volume.

[0119] The following abbreviations are used in this disclosure: (Boc)2O is di-tert-butyl dicarbonate; CDCl3 is deuterated chloroform; (COCl)2 is oxalyl chloride; Cs2CO3 is cesium carbonate; EtOAc is ethyl acetate; Hexane is n-hexane; HPLC is high performance liquid chromatography; MeCN is acetonitrile; DCM is dichloromethane; DIPEA is diisopropylethylamine; Dioxane is 1,4-dioxane; DME is glycol dimethyl ether; DMF is N,N-dimethylformamide; DMAP is 4-(dimethylamino)pyridine; DMSO is dimethyl sulfoxide; EtOH is ethanol; EA is ethyl acetate; h is hour; IPA is isopropanol; ISCO® is Biotage Isolera Prime flash preparative liquid chromatography; min is minutes; K2CO3 is potassium carbonate; KOAc is potassium acetate; KOH is potassium hydroxide; K3PO4 is potassium phosphate; LiBH4 is lithium borohydride; LiHMDS is lithium bis(trimethylsilyl)amide; min is minutes; MeOH is methanol; MeONa is sodium methoxide; MS is mass spectrometry; NaBH(OAc)3 is sodium triacetoxyborohydride; NaH is sodium hydrogen; n-BuLi is n-butyllithium; NMR is nuclear magnetic resonance; NIS is iodosuccinimide; PBST is phosphate-buffered saline with Tween; Pd / C is palladium on carbon; Pd(PPh3)4 is tetrakis(triphenylphosphine)palladium; Pd(OAc)2 is acetic acid Palladium; Pd(dppf)Cl2 is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(dtbpf)Cl2 is dichloro(1,1'-bis(di-tert-butylphosphino)ferrocene)palladium(II); PE is petroleum ether; PFA is paraformaldehyde; PhNTf2 is N-phenylbis(trifluoromethanesulfonimide); PPh3 is triphenylphosphine; TEA is triethylamine; TFA is trifluoroacetic acid; TMSCl is trimethylchlorosilane; TsOH is p-toluenesulfonic acid; XantPhos is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; TfOH is trifluoromethanesulfonic acid; TLC is thin-layer chromatography;and XPhos represents 2-dicyclohexylphosphonium-2',4',6'-triisopropylbiphenyl;

[0120] Example 1: Synthesis of Compound 1: [ka]

[0121] Step 1: Synthesis of compounds int_1-3: [ka]

[0122] Int_1-1 (2.8 g, 22.99 mmol) and int_1-2 (3.5 g, 22.99 mmol, 454.55 μL) were dissolved in Ti(i-PrO)4 (20 mL). The mixture was purged with nitrogen three times, heated to 80 °C, and stirred for 2 h. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature and used directly in the next step. ESI-MS m / z: 256 [M+H] + .

[0123] Step 2: Synthesis of compounds int_1-4: [ka]

[0124] HCOOH (78 mL) was slowly added dropwise to AcO (194 mL) at 0 °C. After the addition was complete, the reaction solution was reacted at 20 °C for 0.5 h. Next, the int_1-3 solution obtained in step 1 was cooled to -10 °C, and the above mixed solution of HOOCH and AcO was slowly added dropwise to the int_1-3 solution. The temperature was maintained at -10 °C during the addition. After the addition was complete, the reaction solution was warmed to 80 °C and reacted for 2 h. LC-MS monitoring indicated the completion of the reaction. The reaction solution was used directly in the next step. ESI-MS m / z: 284 [M+H] + .

[0125] Step 3: Synthesis of compounds int_1-5: [ka]

[0126] TFA (316 mL) was slowly added to the solution of int_1-4 obtained in Step 2 at 70 °C within 1 hour. The mixture was cooled, stirred at 70 °C, and reacted for 3 hours. LC-MS monitoring showed the completion of the reaction. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to give the crude product, which was then adjusted to a weakly basic pH with aqueous sodium bicarbonate (400 mL). The aqueous phase was extracted with ethyl acetate (300 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 4 / 1) to give a solid (3.5 g, yield: 48.6%). ESI-MS m / z: 284 [M+H] + .

[0127] Step 4: Synthesis of compounds int_1-6: [ka]

[0128] Int_1-5 (1.2 g, 4.23 mmol) was dissolved in THF (20 mL) and cooled to -30 °C. Under a nitrogen atmosphere, n-BuLi (2.5 M, 3.38 mL) was slowly added dropwise, and the reaction was allowed to proceed at -30 °C for 2 hours. LC-MS monitoring indicated the completion of the reaction. After the reaction solution was warmed to room temperature, saturated aqueous ammonium chloride solution (20 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product, which was used directly in the next step. ESI-MS m / z: 256 [M+H] + .

[0129] Step 5: Synthesis of compounds int_1-7: [ka]

[0130] int_1-6 (952 mg, 3.73 mmol) and (Boc)O (1.22 g, 5.59 mmol, 1.28 mL) were dissolved in dioxane (20 mL), and TEA (1.13 g, 11.18 mmol, 1.56 mL) was added to the reaction solution at room temperature. The reaction solution was heated to 90 °C and reacted for 16 h. LC-MS monitoring showed the reaction was complete. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (SiO, PE / EtOAc = 4 / 1) to obtain a solid (1.2 g, yield: 83.4%). ESI-MS m / z: 356 [M+H] + .

[0131] Step 6: Synthesis of compounds int_1-8: [ka]

[0132] int_1-7 (1.1 g, 3.11 mmol) was dissolved in THF (25 mL), and the mixture was cooled to -70 °C. Under a nitrogen atmosphere, n-BuLi (2.5 M, 3.74 mL) was slowly added dropwise and the mixture was allowed to react at -70 °C for 0.5 h. DMF (682.55 mg, 9.34 mmol, 718.48 μL) was then added dropwise at -70 °C. After the addition was completed, the reaction solution was allowed to react at -60 °C for 1.5 h. LC-MS monitoring showed the reaction was complete. Saturated ammonium chloride solution (20 mL) was slowly added to the reaction solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 3 / 1) to give a solid (1.08 g, yield: 83.9%). MS (ESI): 384 [M+H] +.

[0133] Step 7: Synthesis of compound int_1-10: [ka]

[0134] Int_1-9 (1.50 g, 6.26 mmol) was dissolved in THF (30 mL) and cooled to -70 °C. Under a nitrogen atmosphere, n-BuLi (2.5 M, 5.01 mL) was slowly added dropwise and the mixture was allowed to react at -70 °C for 1 hour. Next, a THF solution (15 mL) of int_1-8 (800 mg, 2.09 mmol) was added dropwise to the reaction solution at -70 °C. After the addition was complete, the mixture was allowed to react at -70 °C for 1 hour, then warmed to room temperature and allowed to react for 16 hours. LC-MS monitoring indicated the completion of the reaction. Saturated ammonium chloride solution (50 mL) was slowly added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 2 / 1) to give a solid (600 mg, yield: 57.7%). 1 H NMR (400MHz, CHLOROFORM-d) δ = 9.07 - 9.02 (m, 1H), 8.96 - 8.91 (m, 1H), 7.19 (d, J = 4.4 Hz, 2H), 7.12 - 7.03 (m, 1H), 6.60 - 6.50 (m, 2H), 6.24 - 6.15 (m, 1H), 4.47 - 4.36 (m, 1H), 3.21 (dt, J = 2.6, 12.2 Hz, 1H), 3.10 - 2.99 (m, 1H), 2.93 - 2.85 (m, 1H), 2.84 - 2.66 (m, 4H), 1.85 - 1.59 (m, 6H), 1.27 - 1.17 (m, 9H). MS (ESI): 498 [M+H] + .

[0135] Step 8: Synthesis of compound int_1-11: [ka]

[0136] int_1-10 (600 mg, 1.20 mmol) was dissolved in DCM (6 mL), and Dess-Martin oxidant (766.46 mg, 1.81 mmol) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 1 hour. LC-MS monitoring showed the reaction was complete. Saturated aqueous sodium bicarbonate solution was slowly added to the reaction solution to adjust the pH to approximately 8. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 3 / 1) to give a solid (550 mg, yield: 92%). MS (ESI): 496 [M+H] + .

[0137] Step 9: Synthesis of compound int_1-13: [ka]

[0138] int_1-11 (550 mg, 1.11 mmol) and int_1-12 (638.2 mg, 2.22 mmol) were dissolved in DMF (20 mL), and K2CO3 (766.25 mg, 5.54 mmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 3 hours. LC-MS monitoring showed the reaction was complete. Ice water (20 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 2 / 1) to give the product (700 mg, yield: 84.5%). MS (ESI): 747 [M+H] + .

[0139] Step 10: Synthesis of compound int_1-15: [ka]

[0140] Int_1-13 (700 mg, 936.99 μmol) was dissolved in DMF (15 mL), and int_1-14 (216.52 mg, 1.87 mmol) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 1 hour. LC-MS monitoring showed the reaction was complete. Ice water (20 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 3 / 1) to give a solid (750 mg, yield: 96.9%). MS (ESI): 826 [M+H] + .

[0141] Step 11: Synthesis of compound int_1-16: [ka]

[0142] int_1-15 (750 mg, 907.83 μmol) was dissolved in THF (20 mL), and TBAF (1 M, 1.82 mL) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 4 hours. LC-MS monitoring showed the reaction was complete. Water (15 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 1 / 1) to give a solid (500 mg, yield: 82.2%). 1H NMR (400MHz, CHLOROFORM-d) δ = 8.63 - 8.49 (m, 3H), 7.14 - 7.08 (m, 2H), 7.04 (d, J = 2.1 Hz, 1H), 7.03 - 6.97 (m, 1H), 6.46 (d, J = 7.6 Hz, 1H), 5.44 (br s, 2H), 4.74 - 4.60 (m, 1H), 4.37 - 4.12 (m, 4H), 3.22 - 3.14 (m, 1H), 3.01 - 2.88 (m, 2H), 2.87 - 2.77 (m, 2H), 2.75 - 2.64 (m, 1H), 2.49 - 2.39 (m, 1H), 2.23 (br d, J = 5.1 Hz, 1H), 2.09 - 1.99 (m, 2H), 1.90 (td, J = 6.6, 13.2 Hz, 2H), 1.63 (br d, J = 13.9 Hz, 1H), 1.44 - 1.32 (m, 1H), 1.27 - 1.19 (m, 9H). MS (ESI): 670 [M+H] + .

[0143] Step 12: Synthesis of Compound 1: [ka]

[0144] int_1-16 (300 mg, 447.89 μmol) was added to TFA (5.11 g, 44.79 mmol, 3.32 mL) at room temperature, and the reaction mixture was allowed to react for 5 min. LC-MS monitoring indicated the reaction was complete. The pH of the reaction mixture was adjusted to 8 with saturated aqueous sodium bicarbonate, and the reaction mixture was purified by preparative HPLC (column: Boston Prime C18 150 × 30 mm × 5 μm, mobile phase: [water (ammonium hydroxide v / v)-ACN], B%: 30%-50%, 9 min) to obtain a solid (90 mg, yield: 35.2%). 1H NMR (400MHz, CHLOROFORM-d) δ = 8.61 (d, J = 3.8 Hz, 1H), 8.58 (s, 1H), 8.50 (br t, J = 6.3 Hz, 1H), 7.18 - 7.11 (m, 2H), 7.09 (br d, J = 7.4 Hz, 1H), 7.01 (s, 1H), 6.78 (br d, J = 7.9 Hz, 1H), 4.70 (br d, J = 6.4 Hz, 1H), 4.36 (br s, 1H), 4.32 - 4.19 (m, 2H), 3.30 - 3.11 (m, 2H), 3.11 - 3.00 (m, 2H), 3.00 - 2.89 (m, 1H), 2.80 (br d, J = 16.5 Hz, 1H), 2.52 (br s, 1H), 2.41 - 2.25 (m, 3H), 2.15 - 1.90 (m, 5H), 1.51 - 1.39 (m, 1H). MS (ESI): 570 [M+H] + .

[0145] Example 2: Synthesis of Compound 2 and Compound 3 [ka]

[0146] Compound 1 (0.09 g, 157 μmol) was subjected to SFC chiral separation (column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3HO)]; B%: 60%, isocratic elution mode) to obtain compound 2 (30 mg) and compound 3 (30 mg). Compound 2: 1H NMR (400MHz, METHANOL-d4) δ = 8.53 (s, 1H), 8.50 (s, 1H), 7.15 (d, J = 4.0 Hz, 2H), 7.09 (dt, J = 3.7, 8.0 Hz, 1H), 7.03 (s, 1H), 6.83 (d, J = 7.9 Hz, 1H), 4.80 - 4.73 (m, 1H), 4.25 - 4.13 (m, 3H), 3.29 - 3.20 (m, 1H), 3.16 - 2.98 (m, 4H), 2.88 - 2.81 (m, 1H), 2.55 - 2.44 (m, 1H), 2.41 - 2.32 MS (ESI): 570 [M+H] + . SFC retention time analysis: 1.580 minutes (machine: Waters UPCC with PDA Detector, cartridge: Chiralpak IG-3 50x4.6 mm ID, 3 μm, mobile phase: A: CO2, B: Etanol (0.05% DEA), Iso Class: 40% B, flow rate: 4 mL / min, cartridge temperature: 35°C, ABPR: 1500 psi). Compound 3: 1HNMR (400MHz, CHLOROFORM-d) δ = 8.61 (s, 1H), 8.57 (s, 1H), 8.50 (br d, J = 7.3 Hz, 1H), 7.18 - 7.11 (m, 2H), 7.11 - 7.05 (m, 1H), 7.02 (s, 1H), 6.79 (d, J = 7.7 Hz, 1H), 4.78 - 4.65 (m, 1H), 4.36 (dd, J = 4.0, 10.1 Hz, 1H), 4.33 - 4.22 (m, 2H), 3.31 - 3.13 (m, 2H), 3.12 - 2.90 (m, 3H), 2.80 (br d, J = 16.5 Hz, 1H), 2.57 - 2.44 (m, 1H), 2.40 - 2.26 (m, 2H), 2.16 - 1.92 (m, 7H), 1.48 - 1.41 (m, 1H).; MS (ESI): 570 [M+H] + . SFC retention time analysis: 0.927 minutes (machine: Waters UPCC with PDA Detector, cartridge: Chiralpak IG-3 50x4.6 mm ID, 3 μm, mobile phase: A: CO2, B: Etanol (0.05% DEA), Iso Class: 40% B, flow rate: 4 mL / min, cartridge temperature: 35°C, ABPR: 1500 psi).

[0147] Example 3: Synthesis of Compound 4

change

[0148] ステップ1:Synthesis of compound int_4-2:

change

[0149] int_4-1 (50.00 g, 293.10 mmol) and NHOAc (51.96 g, 674.12 mmol) were dissolved in acetic acid (500 mL), and the mixture was purged with nitrogen three times. Under a nitrogen atmosphere, CHNO (46.52 g, 762.05 mmol, 41.16 mL) was added to the reaction solution, which was then heated to 100 °C and stirred for 16 h. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature and slowly poured into 1000 mL of ice water. The aqueous phase was extracted with ethyl acetate (800 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product (60 g, yield: 95.8%), which was used directly in the next step. 1 H NMR (400MHz, DMSO-d6) δ = 8.36 (d, J = 13.6 Hz, 1H), 8.12 (d, J = 13.4 Hz, 1H), 7.67 (d, J = 1.5 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.48 - 7.42 (m, 1H), 3.92 (s, 3H).

[0150] Step 2: Synthesis of compound int_4-3: [ka]

[0151] LiBH4 (20.39 g, 936.25 mmol) was dissolved in tetrahydrofuran (200 mL) and TMSCl (203.43 g, 1.87 mol, 237.66 mL) was added to the reaction solution at 0 °C under a nitrogen atmosphere. The reaction solution was stirred at 0 °C for 30 min, and a tetrahydrofuran solution (200 mL) of int_4-2 (20.00 g, 93.63 mmol) was slowly added dropwise to the reaction solution within 15 min. The reaction solution was warmed to 75 °C and reacted for an additional 2 h. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to 0 °C, and 100 mL of methanol was slowly added to quench the reaction. The organic phase was concentrated under reduced pressure to obtain the crude product, and the pH of the crude product was adjusted to >7 with aqueous ammonia. The aqueous phase was extracted with ethyl acetate (300 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product (15 g, yield: 86.3%), which was used directly in the next step. 1 H NMR (400MHz, DMSO-d6) δ = 7.31 (d, J = 7.9 Hz, 1H), 7.01 (d, J = 1.3 Hz, 1H), 6.80 (dd, J = 1.7, 8.0 Hz, 1H), 3.85 (s, 3H), 2.92 - 2.80 (m, 2H), 2.78 - 2.64 (m, 2H).

[0152] Step 3: Synthesis of compound int_4-4: [ka]

[0153] Int_4-3 (9.00 g, 48.48 mmol) and int_1-2 (8.12 g, 53.33 mmol) were dissolved in Ti(i-PrO)4 (170 mL). The mixture was purged with nitrogen three times, heated to 80 °C, and stirred for 2 h. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature and used directly in the next step. ESI-MS m / z: 320 [M+H] + .

[0154] Step 4: Synthesis of compound int_4-5: [ka]

[0155] HCOOH (200 mL) was slowly added dropwise to AcO (500 mL) at -10 °C. After the addition was complete, the reaction solution was reacted at 20 °C for 0.5 h. Next, the int_4-4 solution obtained in Step 3 was cooled to -10 °C, and the above-mentioned mixed solution of HOOCH and AcO was slowly added dropwise to the int_4-4 solution. The temperature was maintained at -10 °C during the addition. After the addition was complete, the reaction solution was warmed to 70 °C and reacted for 3 h. LC-MS monitoring indicated the completion of the reaction. The reaction solution was cooled to room temperature. The organic phase was concentrated under reduced pressure to obtain the crude product, and the pH of the crude product was adjusted to >7 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (500 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc=1 / 1) to give a solid (2 g, yield: 10.6%). 1 H NMR (400MHz, DMSO-d6) δ = 7.57 (s, 1H), 7.32 (d, J = 5.1 Hz, 1H), 6.98 (s, 1H), 6.72 (s, 1H), 6.24 (d, J = 5.3 Hz, 1H), 4.40 (td, J = 3.9, 12.9 Hz, 1H), 3.85 (s, 3H), 3.24 - 3.12 (m, 1H), 2.93 (br dd, J = 3.7, 7.9 Hz, 2H), 2.89 - 2.79 (m, 2H), 2.35 (br dd, J = 2.0, 11.9 Hz, 1H), 2.01 - 1.81 (m, 2H), 1.70 - 1.53 (m, 1H). ESI-MS m / z: 348 [M+H] + .

[0156] Step 5: Synthesis of compound int_4-6: [ka]

[0157] Int_4-5 (3.30 g, 9.49 mmol) was dissolved in dichloromethane (30 mL), and the mixture was purged with nitrogen three times. The reaction solution was cooled to 0 °C, and BBr3 (11.88 g, 47.43 mmol, 4.57 mL) was slowly added dropwise. The reaction solution was warmed to room temperature and reacted for 1 h. LC-MS monitoring showed the reaction was complete. The reaction solution was slowly poured into 300 mL of ice water, and the aqueous phase was extracted with ethyl acetate (300 mL × 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product (2.8 g, yield: 88.4%), which was used directly in the next step. 1 H NMR (400MHz, DMSO-d6) δ = 10.36 (s, 1H), 7.72 (s, 1H), 7.48 (d, J = 5.1 Hz, 1H), 6.91 (s, 1H), 6.79 (s, 1H), 6.41 (d, J = 5.3 Hz, 1H), 4.57 - 4.45 (m, 1H), 3.38 - 3.28 (m, 1H), 3.15 - 3.04 (m, 2H), 2.98 - 2.85 (m, 2H), 2.55 - 2.44 (m, 1H), 2.14 - 1.97 (m, 2H), 1.86 - 1.66 (m, 1H). ESI-MS m / z: 334 [M+H] + .

[0158] Step 6: Synthesis of compound int_4-7: [ka]

[0159] int_4-6 (2.80 g, 8.39 mmol), PhNTf2 (5.39 g, 15.10 mmol), and TEA (2.12 g, 20.97 mmol, 2.92 mL) were dissolved in dichloromethane (30 mL). The reaction solution was purged with nitrogen three times and reacted at room temperature for 16 h. LC-MS monitoring showed the reaction was complete. The reaction solution was slowly poured into 300 mL of ice water. The aqueous phase was extracted with ethyl acetate (300 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 1 / 1) to give a solid (2.3 g, yield: 58.8%). 1 H NMR (400MHz, DMSO-d6) δ = 7.45 - 7.39 (m, 1H), 7.36 (d, J = 5.3 Hz, 1H), 7.31 - 7.24 (m, 1H), 7.12 (s, 1H), 6.28 (d, J = 5.3 Hz, 1H), 4.51 - 4.38 (m, 1H), 3.02 - 2.85 (m, 4H), 2.42 (td, J = 2.0, 12.0 Hz, 2H), 2.06 - 1.94 (m, 1H), 1.90 (br d, J = 13.8 Hz, 1H), 1.94 - 1.83 (m, 1H), 1.68 - 1.50 (m, 1H). ESI-MS m / z: 466 [M+H] + .

[0160] Step 7: Synthesis of compound int_4-8: [ka]

[0161] Int_4-7 (2.30 g, 4.94 mmol), Pd / C (1.05 g, 10% purity), and TEA (2.00 g, 19.75 mmol, 2.75 mL) were dissolved in a mixture of methanol (21 mL) and tetrahydrofuran (7 mL). The reaction solution was purged with hydrogen three times and reacted at room temperature for 16 h. LC-MS monitoring showed the reaction was complete. The reaction solution was filtered to obtain the filtrate, which was then concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 1 / 1) to obtain a solid (0.64 g, yield: 40.7%). 1 H NMR (400MHz, DMSO-d6) δ = 7.57 (s, 1H), 7.34 (d, J = 5.3 Hz, 1H), 7.25 (d, J = 0.9 Hz, 2H), 6.76 (s, 1H), 6.24 (d, J = 5.3 Hz, 1H), 4.41 (td, J = 4.1, 13.1 Hz, 1H), 3.25 - 3.13 (m, 1H), 2.95 (dd, J = 3.9, 7.8 Hz, 2H), 2.86 (dd, J = 4.5, 8.3 Hz, 2H), 2.45 - 2.35 (m, 1H), 2.03 - 1.95 (m, 1H), 1.95 - 1.83 (m, 1H), 1.69 - 1.51 (m, 1H). ESI-MS m / z: 318 [M+H] + .

[0162] Step 8: Synthesis of compound int_4-9: [ka]

[0163] Int_4-8 (0.64 g, 2.01 mmol) was dissolved in THF (10 mL) and cooled to -30 °C. Under a nitrogen atmosphere, n-BuLi (2.5 M, 2.42 mL) was slowly added dropwise and the reaction was allowed to proceed at -30 °C for 2 hours. The reaction solution was then warmed to room temperature and allowed to proceed for 1 hour. LC-MS monitoring indicated the completion of the reaction. Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product (0.5 g, yield: 85.6%), which was used directly in the next step. ESI-MS m / z: 290 [M+H] + .

[0164] Step 9: Synthesis of compound int_4-10: [ka]

[0165] int_4-9 (0.50 g, 1.73 mmol) and (Boc)2O (828.34 mg, 3.80 mmol, 871.93 μL) were dissolved in 1,4-dioxane (10 mL), and TEA (523.71 mg, 5.18 mmol, 720.37 μL) was added to the reaction solution at room temperature. The reaction solution was heated to 80 °C and reacted for 16 h. LC-MS monitoring showed the reaction was complete. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 10 / 1) to obtain a solid (0.11 g, yield: 16.3%). 1H NMR (400MHz, DMSO-d6) δ = 7.33 - 7.23 (m, 3H), 6.53 (d, J = 5.1 Hz, 1H), 6.40 (d, J = 2.0 Hz, 1H), 4.27 (td, J = 3.7, 12.0 Hz, 1H), 3.11 (ddd, J = 5.1, 9.8, 12.2 Hz, 1H), 2.97 - 2.87 (m, 3H), 2.75 - 2.63 (m, 2H), 1.77 (br d, J = 13.2 Hz, 1H), 1.65 - 1.49 (m, 2H), 1.15 (s, 9H).

[0166] Step 10: Synthesis of compound int_4-11: [ka]

[0167] int_4-10 (1.44 g, 3.693 mmol) was dissolved in THF (20 mL), and the mixture was cooled to -75 °C. Under a nitrogen atmosphere, n-BuLi (2.5 M, 4.43 mL) was slowly added dropwise, and the mixture was allowed to react at -75 °C for 1 h. Next, DMF (809 mg, 11.079 mmol) was added dropwise at -75 °C. After the addition was completed, the mixture was allowed to react at -75 °C for 1 h. LC-MS monitoring showed the completion of the reaction. Saturated ammonium chloride solution (100 mL) was slowly added to the reaction solution. The aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography to obtain a solid (1.38 g, yield: 89.9%). MS (ESI): 418 [M+H] + .

[0168] Step 11: Synthesis of compound int_4-12: [ka]

[0169] Int_1-9 (4.79 g, 19.911 mmol) was dissolved in THF (50 mL) and cooled to -75 °C. Under a nitrogen atmosphere, n-BuLi (2.5 M, 16 mL) was slowly added dropwise to the reaction solution, and the mixture was allowed to react at -75 °C for 1 hour. Next, a THF solution (25 mL) of int_4-11 (1.387 g, 3.319 mmol) was added dropwise to the reaction solution at -75 °C. After the addition was complete, the mixture was allowed to react at -75 °C for 1 hour, then warmed to room temperature and allowed to react for 16 hours. LC-MS monitoring indicated the completion of the reaction. Saturated ammonium chloride solution (200 mL) was slowly added to the reaction solution. The aqueous phase was extracted with ethyl acetate (200 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography to obtain a solid (1.427 g, 80% yield). MS (ESI): 532 [M+H] + .

[0170] Step 12: Synthesis of compound int_4-13: [ka]

[0171] Int_4-12 (1.427 g, 2.68 mmol) was dissolved in DCM (50 mL), and Dess-Martin oxidant (1.36 g, 3.22 mmol) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 1 hour. LC-MS monitoring showed the reaction was complete. Saturated aqueous sodium bicarbonate solution was slowly added to the reaction solution to adjust the pH to approximately 8. The aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography to obtain a solid (1.324 g, yield: 93%). MS (ESI): 530 [M+H] + .

[0172] Step 13: Synthesis of compound int_4-14: [ka]

[0173] int_4-13 (1.053 g, 1.985 mmol) and int_1-12 (628 mg, 2.184 mmol) were dissolved in DMF (10 mL), and K2CO3 (824 mg, 5.962 mmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 3 hours. LC-MS monitoring showed the reaction was complete. Ice water (100 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography to give the product (1.425 g, yield: 91%). MS (ESI): 781 [M+H] + .

[0174] Step 14: Synthesis of compound int_4-15: [ka]

[0175] Int_4-14 (1.425 g, 1.823 mmol) was dissolved in DMF (30 mL), and int_1-14 (421 mg, 3.647 mmol) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 1 hour. LC-MS monitoring showed the reaction was complete. Ice water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography to obtain a solid (1.5 g, yield: 96.1%). MS (ESI): 860 [M+H] + .

[0176] Step 15: Synthesis of compound int_4-16: [ka]

[0177] Int_4-15 (1.5 g, 1.742 mmol) was dissolved in THF (20 mL), and TBAF (1 M, 3.6 mL) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 4 hours. LC-MS monitoring showed the reaction was complete. Water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography to obtain a solid (1.1 g, yield: 90.1%). MS (ESI): 704 [M+H] + .

[0178] Step 16: Synthesis of Compound 4 [ka]

[0179] Int_4-16 (1.28 g, 1.823 mmol) was dissolved in DCM (7 mL) at room temperature, and the mixture was added with TFA (7.8 mL). The reaction solution was allowed to react at room temperature for 5 minutes. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to 0 °C. Saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust the pH to 8. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC to obtain a solid (897 mg, yield: 81.5%). MS (ESI): 604 [M+H] + .

[0180] Example 4: Synthesis of Compound 5 and Compound 6 [ka]

[0181] Compound 4 (100 mg, 0.165 mmol) was isolated from SFC キラル (カラム: DAICEL CHIRALPAK IG (250mm×30mm, 10μm); mobile phase: [CO2-EtOH (0.1%NH3H2O)]; B%: 60%, アイソクラティック dissolves モード)にかけ, compound 5 (45mg) and compound 6 (40mg) are obtained. Compound 5: 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.50 (s, 1H), 8.24 (d, J = 7.4 Hz, 1H), 7.40 (s, 2H), 7.14 (d, J = 2.6 Hz, 2H), 6.95 (s, 1H), 6.76 (d, J = 1.9 Hz, 1H), 4.85 (d, J = 4.6 Hz, 1H), 4.64 (h, J = 7.9 Hz, 1H), 4.06 (dd, J = 9.8, 6.0 Hz, 1H), 3.92 (dt, J = 8.8, 5.8 Hz, 2H), 3.10 - 2.80 (m, 5H), 2.67 (d, J = 19.0 Hz, 1H), 2.35 - 2.14 (m, 2H), 2.07 (d, J = 7.6 Hz, 2H), 1.93 (ddd, J = 12.4, 7.7, 3.7 Hz, 1H), 1.82 (s, 2H), 1.72 (ddd, J = 13.1, 8.6, 6.6 Hz, 1H), 1.22 (dt, J = 13.0, 9.2 Hz, 1H).; MS (ESI): 604 [M+H] + . SFC retention time analysis: 1.659 minutes (machine: Waters UPCC with PDA Detector, cartridge: Chiralpak IG-3 50x4.6 mm ID, 3 μm, mobile phase: A: CO2, B: Etanol (0.05% DEA), Iso Class: 40% B, flow rate: 4 mL / min, cartridge temperature: 35°C, ABPR: 1500 psi). Compound 6: 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.49 (s, 1H), 8.22 (d, J = 7.5 Hz, 1H), 7.41 (s, 2H), 7.13 (d, J = 2.0 Hz, 2H), 6.93 (s, 1H), 6.75 (d, J = 1.8 Hz, 1H), 4.84 (d, J = 4.5 Hz, 1H), 4.64 (h, J = 8.2 Hz, 1H), 4.07 (dd, J = 9.7, 6.0 Hz, 1H), 4.00 - 3.80 (m, 2H), 3.07 - 2.78 (m, 5H), 2.64 (d, J = 16.5 Hz, 1H), 2.28 (dt, J = 12.5, 7.6 Hz, 1H), 2.22 - 2.13 (m, 1H), 2.08 (d, J = 9.7 Hz, 2H), 1.90 (ddd, J = 11.9, 7.5, 3.8 Hz, 1H), 1.85 - 1.63 (m, 3H), 1.23 (dt, J = 12.8, 9.2 Hz, 1H).; MS (ESI): 604 [M+H] + . SFC holding time analysis: 0.925 minutes (machine: Waters UPCC with PDA Detector, カラム: Chiralpak IG-3 50x4.6mm ID, 3um, mobile phase: A: CO2, B: エタノール (0.05% DEA), アイソクラティック: 40% B, flow rate: 4mL / min, temperature: 35℃, ABPR: 1500psi).

[0182] Example 5: Synthesis of Compound 7

change

[0183] ステップ1:Synthesis of compound int_7-2:

change

[0184] int_7-1 (25.0 g, 162 mmol) and NHOAc (28.8 g, 373 mmol) were dissolved in acetic acid (250 mL), and the mixture was purged with nitrogen three times. Under a nitrogen atmosphere, CHNO (25.7 g, 422 mmol, 22.8 mL) was added to the reaction solution, which was then heated to 100 °C and stirred for 16 h. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature and slowly poured into 1000 mL of ice water. The aqueous phase was extracted with ethyl acetate (800 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product (50 g, yield: 78.2%), which was used directly in the next step. 1 HNMR (400 MHz, DMSO-d6) δ = 3.89 (s, 3 H), 7.33 (dd, J = 11.25, 8.44 Hz, 1 H), 7.46 (ddd, J = 8.25, 4.59, 1.96 Hz, 1 H), 7.72 (dd, J = 8.44, 1.96 Hz, 1 H), 8.10 (d, J = 13.57 Hz, 1 H), 8.29 (d, J = 13.57 Hz, 1 H).

[0185] Step 2: Synthesis of compound int_7-3: [ka]

[0186] LiBH4 (27.6 g, 1.27 mol) was dissolved in tetrahydrofuran (300 mL), and TMSCl (276 g, 2.54 mol, 322 mL) was added to the reaction solution at 0 °C under a nitrogen atmosphere. The reaction solution was stirred at 0 °C for 30 min, and a tetrahydrofuran solution (250 mL) of int_7-2 (25.0 g, 127 mmol) was slowly added dropwise to the reaction solution within 30 min. The reaction solution was warmed to 75 °C and reacted for an additional 2 h. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to 0 °C, and 600 mL of methanol was slowly added to quench the reaction. The organic phase was concentrated under reduced pressure to give the crude product, which was adjusted to a pH greater than 7 with aqueous ammonia. The aqueous phase was extracted with ethyl acetate (500 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product (25 g), which was used directly in the next step. ESI-MS m / z: 170 [M+H] + .

[0187] Step 3: Synthesis of compound int_7-4: [ka]

[0188] Int_7-3 (12.5 g, 73.9 mmol) and int_1-2 (11.8 g, 77.6 mmol) were dissolved in Ti(i-PrO)4 (1130 mL). The mixture was purged with nitrogen three times, heated to 80 °C, and stirred for 2 h. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature and used directly in the next step. ESI-MS m / z: 304 [M+H] + .

[0189] Step 4: Synthesis of compound int_7-5: [ka]

[0190] HCOOH (400 mL) was slowly added dropwise to AcO (1000 mL) at -10 °C. After the addition was complete, the reaction solution was reacted at 20 °C for 0.5 h. Next, the int_7-4 solution obtained in Step 3 was cooled to -10 °C, and the above-mentioned mixed solution of HOOCH and AcO was slowly added dropwise to the int_7-4 solution. The temperature was maintained at -10 °C during the addition. After the addition was complete, the reaction solution was warmed to 80 °C and reacted for 16 h. LC-MS monitoring indicated the completion of the reaction. The reaction solution was cooled to room temperature. The organic phase was concentrated under reduced pressure to obtain the crude product, and the pH of the crude product was adjusted to >7 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (1000 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc=3 / 2) to give a solid (1.5 g, yield: 5.05%). 1 HNMR (400 MHz, DMSO-d6) δ = 1.52 - 1.66 (m, 1H), 1.82 - 1.94 (m, 2H), 2.28 - 2.38 (m, 1H), 2.78 - 2.86 (m, 2H), 2.89 - 2.97 (m, 2H), 3.10 - 3.22 (m, 1H), 3.82 (s, 3H), 4.40 (dt, J = 12.93, 3.99 Hz, 1H), 6.22 (d, J = 5.28 Hz, 1H), 6.52 (d, J = 12.98 Hz, 1H), 6.97 (d, J = 9.02 Hz, 1H), 7.30 (d, J = 5.28 Hz, 1H), 7.57 (s, 1H). ESI-MS m / z: 332 [M+H] + .

[0191] Step 5: Synthesis of compound int_7-6: [ka]

[0192] int_7-5 (4.00 g, 12.1 mmol) was dissolved in dichloromethane (40 mL), and the mixture was purged with nitrogen three times. The reaction solution was cooled to 0 °C, and BBr3 (15.1 g, 60.4 mmol, 5.81 mL) was slowly added dropwise. The reaction solution was warmed to room temperature and reacted for 1 h. LC-MS monitoring showed the reaction was complete. The reaction solution was slowly poured into 200 mL of ice water. The aqueous phase was extracted with ethyl acetate (200 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product (4.5 g, yield: 99.3%), which was used directly in the next step. ESI-MS m / z: 318 [M+H] + .

[0193] Step 6: Synthesis of compound int_7-7: [ka]

[0194] int_7-6 (4.50 g, 14.2 mmol), PhNTf2 (9.12 g, 25.5 mmol), and TEA (3.59 g, 35.5 mmol, 4.93 mL) were dissolved in dichloromethane (50 mL) at 0 °C. The reaction solution was purged with nitrogen three times and reacted at room temperature for 16 h. LC-MS monitoring showed the reaction was complete. The reaction solution was slowly poured into 200 mL of ice water. The aqueous phase was extracted with ethyl acetate (200 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 2 / 1) to give a solid (4 g, yield: 62.8%). 1HNMR (400 MHz, DMSO-d6) δ = 1.52 - 1.67 (m, 1H), 1.86 - 1.94 (m, 1H), 1.99 (s, 1H), 2.41 (dt, J = 11.83, 2.01 Hz, 1H), 2.91 (br s, 2H), 2.94 (br dd, J = 8.03, 3.85 Hz, 2H), 3.18 (ddd, J = 13.20, 10.45, 4.95 Hz, 1H), 4.40 - 4.49 (m, 1H), 6.26 (d, J = 5.28 Hz, 1H), 6.98 (d, J = 11.66 Hz, 1H), 7.35 (d, J = 5.28 Hz, 1H), 7.56 (s, 1H), 7.60 (d, J = 7.70 Hz, 1H). ESI-MS m / z: 450 [M+H] + .

[0195] Step 7: Synthesis of compound int_7-8: [ka]

[0196] int_7-7 (4.00 g, 8.90 mmol), Pd / C (1.00 g, 10.0% purity), and TEA (3.60 g, 35.6 mmol, 4.96 mL) were dissolved in methanol (80 mL). The reaction solution was purged with hydrogen three times and reacted under a hydrogen atmosphere (20.0 Psi) at room temperature for 16 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was filtered to obtain the filtrate, which was then concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 1 / 1) to obtain a solid (2.2 g, yield: 81.2%). 1HNMR (400 MHz, DMSO-d6) δ = 1.53 - 1.67 (m, 1H), 1.84 - 1.93 (m, 1H), 1.98 (td, J = 13.45, 2.69 Hz, 1H), 2.35 - 2.43 (m, 1H), 2.84 (br dd, J = 7.27, 3.85 Hz, 2H), 2.94 (dd, J = 8.01, 3.97 Hz, 2H), 3.19 (dt, J = 12.93, 7.78 Hz, 1H), 4.40 (dt, J = 13.02, 4.07 Hz, 1H), 6.22 (d, J = 5.26 Hz, 1H), 6.53 (dd, J = 10.51, 2.69 Hz, 1H), 7.04 (td, J = 8.50, 2.69 Hz, 1H), 7.25 (dd, J = 8.50, 6.05 Hz, 1H), 7.32 (d, J = 5.26 Hz, 1H), 7.59 (s, 1H). ESI-MS m / z: 302 [M+H] + .

[0197] Step 8: Synthesis of compounds int_7-9: [ka]

[0198] int_7-8 (2.20 g, 7.30 mmol) was dissolved in THF (25 mL) and cooled to -78 °C. Under a nitrogen atmosphere, n-BuLi (2.50 M, 8.76 mL) was slowly added dropwise and the reaction was allowed to proceed at -30 °C for 2 h. The reaction solution was then warmed to room temperature and allowed to proceed for 0.5 h. LC-MS monitoring indicated the completion of the reaction. Saturated aqueous ammonium chloride solution (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (SiO2, DCM / MeOH = 95 / 5) to obtain a solid (1.4 g, yield: 56.1%). 1HNMR (400 MHz, DMSO-d6) δ = 1.72 - 1.84 (m, 2H), 1.96 - 2.08 (m, 1H), 2.10 - 2.22 (m, 1H), 2.67 (br s, 1H), 2.75 - 2.90 (m, 4H), 2.95 - 3.00 (m, 2H), 6.34 (d, J = 5.28 Hz, 1H), 6.45 (dd, J = 10.56, 2.64 Hz, 1H), 6.92 (td, J = 8.53, 2.75 Hz, 1H), 7.10 (br s, 1H), 7.11 - 7.15 (m, 1H). ESI-MS m / z: 274 [M+H] + .

[0199] Step 9: Synthesis of compounds int_7-10: [ka]

[0200] int_7-9 (1.40 g, 5.12 mmol) and (Boc)2O (2.46 g, 11.3 mmol, 2.59 mL) were dissolved in 1,4-dioxane (15 mL), and TEA (1.55 g, 15.4 mmol, 2.14 mL) was added to the reaction solution at room temperature. The reaction solution was heated to 80 °C and reacted for 16 h. LC-MS monitoring showed the reaction was complete. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EAP = 4 / 1) to obtain a solid (870 mg, yield: 45.2%). ESI-MS m / z: 374 [M+H] + .

[0201] Step 10: Synthesis of compound int_7-11: [ka]

[0202] int_7-10 (900 mg, 2.41 mmol) was dissolved in THF (10 mL), and the mixture was cooled to -70 °C. Under a nitrogen atmosphere, n-BuLi (2.50 M, 2.89 mL) was slowly added dropwise to the reaction solution, and the mixture was allowed to react at -70 °C for 0.5 h. DMF (528 mg, 7.23 mmol, 556 μL) was then added dropwise at -70 °C. After the addition was complete, the mixture was allowed to react at -75 °C for 1 h. LC-MS monitoring showed the reaction was complete. Saturated ammonium chloride solution (25 mL) was slowly added to the reaction solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 4 / 1) to give a solid (970 mg, yield: 95.9%). 1 HNMR (400 MHz, CHLOROFORM-d) δ = 1.23 (s, 9H), 1.66 - 1.80 (m, 2H), 1.82 - 1.91 (m, 1H), 2.73 - 2.94 (m, 3H), 2.95 - 3.06 (m, 2H), 3.25 (td, J = 12.07, 3.12 Hz, 1H), 4.40 - 4.49 (m, 1H), 6.25 (dd, J = 10.45, 2.63 Hz, 1H), 6.90 (td, J = 8.25, 2.57 Hz, 1H), 7.17 (dd, J = 8.07, 5.87 Hz, 1H), 7.27 - 7.28 (m, 1H), 9.75 (s, 1H). MS (ESI): 402 [M+H] + .

[0203] Step 11: Synthesis of compound int_7-12: [ka]

[0204] Int_1-9 (1.62 g, 6.72 mmol) was dissolved in THF (15 mL), and the mixture was cooled to -75 °C. Under a nitrogen atmosphere, n-BuLi (2.50 M, 5.38 mL) was slowly added dropwise to the reaction solution, and the mixture was allowed to react at -75 °C for 1 hour. Next, a solution of int_7-11 (900 mg, 2.24 mmol) in THF (25 mL) was added dropwise to the reaction solution at -75 °C. After the addition was complete, the mixture was allowed to react at -75 °C for 1 hour, then warmed to room temperature and allowed to react for 16 hours. LC-MS monitoring indicated the completion of the reaction. Saturated ammonium chloride solution (100 mL) was slowly added to the reaction solution. The aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc=7 / 3) to give a solid (690 mg, yield: 59.7%). 1 HNMR (400 MHz, DMSO-d6) δ = 0.94 - 1.18 (m, 9H), 1.44 - 1.80 (m, 4H), 2.55 - 2.71 (m, 2H), 2.77 - 2.94 (m, 3H), 3.01 - 3.12 (m, 1H), 4.18 - 4.28 (m, 1H), 5.96 - 6.12 (m, 1H), 6.16 - 6.27 (m, 1H), 6.40 - 6.45 (m, 1H), 6.57 - 6.72 (m, 1H), 6.99 - 7.07 (m, 1H), 7.28 (br dd, J = 8.47, 6.05 Hz, 1H), 8.93 - 8.97 (m, 1H). MS (ESI): 516 [M+H] + .

[0205] Step 12: Synthesis of compound int_7-13: [ka]

[0206] int_7-12 (640 mg, 1.24 mmol) was dissolved in DCM (10 mL), and Dess-Martin oxidant (1.05 g, 2.48 mmol) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 1 hour. LC-MS monitoring showed the reaction was complete. Saturated aqueous sodium bicarbonate solution was slowly added to the reaction solution to adjust the pH to approximately 8. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 10 / 1) to give a solid (630 mg, yield: 98.8%). 1 HNMR (400 MHz, DMSO-d6) δ = 1.19 (s, 9H), 1.54 - 1.66 (m, 2H), 1.75 - 1.85 (m, 1H), 2.59 - 2.81 (m, 2H), 2.85 - 2.91 (m, 2H), 3.03 - 3.18 (m, 2H), 4.17 - 4.26 (m, 1H), 6.22 (dd, J = 10.78, 2.64 Hz, 1H), 7.05 (td, J = 8.47, 2.64 Hz, 1H), 7.25 - 7.34 (m, 2H), 8.86 (s, 1H), 9.15 (s, 1H). MS (ESI): 514 [M+H] + .

[0207] Step 13: Synthesis of compound int_7-14: [ka]

[0208] int_7-13 (390 mg, 759 μmol) and int_1-12 (327 mg, 1.14 mmol) were dissolved in DMF (10 mL), and K2CO3 (524 mg, 3.79 mmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 16 hours. LC-MS monitoring showed the reaction was complete. Ice water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / ethyl acetate = 7 / 3) to give the product (350 mg, yield: 60.3%). MS (ESI): 765 [M+H] + .

[0209] Step 14: Synthesis of compound int_7-15: [ka]

[0210] Int_7-14 (550 mg, 719 μmol) was dissolved in DMF (10 mL), and int_1-14 (249 mg, 2.16 mmol) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 0.5 hours. LC-MS monitoring indicated the reaction was complete. Ice water (20 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (20 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography to obtain a solid (600 mg, yield: 98.9%). MS (ESI): 844 [M+H] + .

[0211] Step 15: Synthesis of compound int_7-16: [ka]

[0212] int_7-15 (550 mg, 652 μmol) was dissolved in THF (10 mL), and TBAF (1.00 M, 652 μL) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 16 hours. LC-MS monitoring showed the reaction was complete. Water (20 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (20 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / ethyl acetate = 4 / 1) to give a solid (320 mg, yield: 58.6%). 1 HNMR (400 MHz, CHLOROFORM-d) δ = 1.23 (s, 9H), 1.51 - 1.96 (m, 6H), 2.03 - 2.16 (m, 1H), 2.16 - 2.37 (m, 1H), 2.63 - 2.71 (m, 1H), 2.79 (br s, 1H), 2.91 (br s, 2H), 3.05 (br dd, J = 17.45, 2.69 Hz, 1H), 3.89 - 3.98 (m, 2H), 4.06 - 4.11 (m, 1H), 4.20 - 4.28 (m, 1H), 4.62 - 4.72 (m, 1H), 4.84 - 4.90 (m, 1H), 6.23 (dd, J = 10.88, 2.13 Hz, 1H), 7.05 (td, J = 8.32, 2.25 Hz, 1H), 7.22 (s, 1H), 7.31 (dd, J = 8.07, 6.19 Hz, 1H), 7.43 (d, J = 5.13 Hz, 2H), 8.26 (br d, J = 6.75 Hz, 1H), 8.41 (s, 1H), 8.57 (s, 1H). MS (ESI): 688 [M+H] + .

[0213] Step 16: Synthesis of Compound 7 [ka]

[0214] int_7-16 (200 mg, 291 μmol) was dissolved in DCM (5 mL) at room temperature, and the mixture was added with TFA (2 mL). The reaction solution was allowed to react at room temperature for 5 minutes. LC-MS monitoring indicated the reaction was complete. The reaction solution was cooled to 0 °C. Saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust the pH to 8. The aqueous phase was extracted with ethyl acetate (20 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: Phenomenex C18 75 × 30 mm × 3 μm, mobile phase: [water (ammonium hydroxide)-ACN], gradient: 38% to 58% B over 9 minutes) to obtain a solid (50 mg, yield: 29.3%). 1 HNMR (400 MHz, DMSO-d6) δ = 1.24 (dt, J = 8.71, 4.51 Hz, 1H), 1.71 - 1.78 (m, 1H), 1.78 - 1.86 (m, 2H), 1.87 - 1.98 (m, 1H), 2.08 (br d, J = 8.56 Hz, 2H), 2.17 (br dd, J = 11.68, 2.51 Hz, 1H), 2.24 - 2.35 (m, 1H), 2.61 - 2.68 (m, 1H), 2.86 (br dd, J = 15.65, 7.58 Hz, 1H), 2.96 (dt, J = 8.56, 4.28 Hz, 4H), 3.30 (s, 1H), 3.94 (br dd, J = 9.72, 6.91 Hz, 2H), 4.07 (ddd, J = 9.32, 6.14, 2.75 Hz, 1H), 4.58 - 4.71 (m, 1H), 4.87 (dd, J = 4.46, 3.00 Hz, 1H), 6.54 (br d, J = 9.41 Hz, 1H), 6.90 - 6.97 (m, 2H), 7.13 (dd, J = 8.38, 6.17 Hz, 1H), 7.43 (d, J = 2.57 Hz, 2H), 8.22 (dd, J = 7.40, 2.51 Hz, 1H), 8.50 (s, 1H), 8.55 (s, 1H). MS (ESI): 588 [M+H]+ .

[0215] Example 6: Synthesis of Compound 8 and Compound 9 [ka]

[0216] Compound 7 (50 mg, 0.085 mmol) was subjected to SFC chiral separation (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3HO)]; B%: 50%, isocratic elution mode) to give compound 8 (22 mg) and compound 9 (14 mg). Compound 8: 1 HNMR (400 MHz, DMSO-d6) δ = 1.24 (dt, J = 12.65, 9.19 Hz, 1H), 1.68 - 1.85 (m, 3H), 1.85 - 1.96 (m, 1H), 2.02 - 2.14 (m, 2H), 2.14 - 2.34 (m, 2H), 2.64 (br d, J = 15.85 Hz, 1H), 2.70 - 3.08 (m, 5H), 3.30 (s, 1H), 3.89 - 3.98 (m, 2H), 4.08 (dd, J = 9.68, 5.94 Hz, 1H), 4.60 - 4.70 (m, 1H), 4.88 (d, J = 4.62 Hz, 1H), 6.53 (dd, J = 10.34, 2.64 Hz, 1H), 6.90 - 6.96 (m, 2H), 7.13 (dd, J = 8.36, 6.16 Hz, 1H), 7.44 (s, 2H), 8.22 (d, J = 7.48 Hz, 1H), 8.50 (s, 1H), 8.55 (s, 1H).; MS (ESI): 588 [M+H] + . SFC retention time analysis: 0.820 min (machine: Waters UPCC with PDA Detector, cartridge: Chiralpak AD-3 50 x 4.6 mm ID, 3 μm, mobile phase: A: CO 2 , B: Etanol (0.05% DEA), Iso Class: 40% B, flow rate: 4 mL / min, cartridge temperature: 35° C., ABPR: 1500 psi). Compound 9: 1 HNMR (400 MHz, DMSO-d6) δ = 1.23 (dt, J = 12.82, 9.33 Hz, 1H), 1.69 - 1.86 (m, 3H), 1.88 - 1.98 (m, 1H), 2.08 (br d, J = 6.38 Hz, 2H), 2.16 - 2.33 (m, 2H), 2.62 - 2.70 (m, 1H), 2.77 - 3.08 (m, 5H), 3.30 (s, 1H), 3.90 - 3.98 (m, 2H), 4.07 (dd, J = 9.57, 6.05 Hz, 1H), 4.60 - 4.70 (m, 1H), 4.88 (d, J = 4.62 Hz, 1H), 6.54 (dd, J = 10.23, 2.53 Hz, 1H), 6.91 - 6.97 (m, 2H), 7.14 (t, J = 6.69 Hz, 1H), 7.43 (s, 2H), 8.23 ​​(d, J = 7.48 Hz, 1H), 8.50 (s, 1H), 8.56 (s, 1H).; MS (ESI): 588 [M+H] + . SFC retention time analysis: 0.636 minutes (machine: Waters UPCC with PDA Detector, cartridge: Chiralpak AD-3 50x4.6 mm ID, 3 μm, mobile phase: A: CO2, B: Etanol (0.05% DEA), Iso Class: 40% B, flow rate: 4 mL / min, cartridge temperature: 35°C, ABPR: 1500 psi).

[0217] Example 7: Synthesis of Compound 19

change

[0218] Step 1: Synthesis of compound int_19-2: [ka]

[0219] int_19-1 (50.0 g, 228 mmol) and NHOAc (40.4 g, 524 mmol) were dissolved in acetic acid (500 mL), and the mixture was purged with nitrogen three times. Under a nitrogen atmosphere, CHNO (36.2 g, 593 mmol, 32.0 mL) was added to the reaction solution, which was then heated to 100 °C and stirred for 16 h. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature and slowly poured into 1000 mL of ice water. The aqueous phase was extracted with ethyl acetate (800 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product (50 g, yield: 83.6%), which was used directly in the next step. 1 H NMR (400MHz, CHLOROFORM-d) δ = 8.35 (d, J = 13.6 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.58 - 7.51 (m, 2H), 7.40 (dd, J = 2.0, 8.4 Hz, 1H).

[0220] Step 2: Synthesis of compound int_19-3: [ka]

[0221] LiBH4 (20.8 g, 952 mmol) was dissolved in tetrahydrofuran (300 mL), and TMSCl (207 g, 1.90 mol, 242 mL) was added to the reaction solution at 0 °C under a nitrogen atmosphere. The reaction solution was stirred at 0 °C for 30 min, and a solution of int_19-2 (25.0 g, 95.2 mmol) in tetrahydrofuran (250 mL) was slowly added dropwise to the reaction solution within 30 min. The reaction solution was warmed to 70 °C and reacted for an additional 2 h. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to 0 °C, and 200 mL of methanol was slowly added to quench the reaction. The organic phase was concentrated under reduced pressure to give the crude product, which was adjusted to a pH greater than 7 with aqueous ammonia. The aqueous phase was extracted with ethyl acetate (500 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product (20 g), which was used directly in the next step. ESI-MS m / z: 234 [M+H] + .

[0222] Step 3: Synthesis of compound int_19-5: [ka]

[0223] Int_19-3 (20.0 g, 85.3 mmol), int_19-4 (9.07 g, 65.6 mmol), and Ti(i-PrO)4 (37.3 g, 131 mmol) were dissolved in toluene (200 mL). The mixture was purged with nitrogen three times, heated to 90 °C, and stirred for 2 h. LC-MS monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give the crude product (23 g), which was used directly in the next step. ESI-MS m / z: 354 [M+H] + .

[0224] Step 4: Synthesis of compound int_19-6: [ka]

[0225] int_19-5 (23.0 g, 64.9 mmol), TEA (65.6 g, 648 mmol, 90.3 mL), and AcO (33.1 g, 324 mmol, 30.5 mL) were dissolved in dichloromethane (400 mL), and the reaction solution was reacted under a nitrogen atmosphere at 20 °C for 2 h. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature. The organic phase was concentrated under reduced pressure to give the crude product, which was then adjusted to a pH greater than 7 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with dichloromethane (500 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO, PE / ethyl acetate = 3 / 1) to give a solid (20 g, 77.7% yield). 1 H NMR (400 MHz, DMSO-d6) δ =1.09 - 1.17 (m, 1H), 1.88 (br d, J = 7.00 Hz, 3H), 2.82 - 2.96 (m, 2H), 3.41 - 3.48 (m, 2H), 3.80 (br t, J = 7.13 Hz, 2H), 3.99 (q, J = 7.13 Hz, 1H), 7.18 - 7.38 (m, 2H), 7.43 - 7.54 (m, 1H), 7.63 (d, J = 2.13 Hz, 1H).

[0226] Step 5: Synthesis of compound int_19-7: [ka]

[0227] int_19-6 (20.0 g, 50.4 mmol), DIPEA (13.0 g, 101 mmol, 17.6 mL), and di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; and iron (3.29 g, 5.04 mmol) were dissolved in 1,4-dioxane (300 mL). The reaction solution was purged with nitrogen three times and heated to 110 °C for 7 h. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature and slowly poured into 300 mL of ice water. The aqueous phase was extracted with ethyl acetate (300 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / ethyl acetate = 3 / 1) to give a solid (9.4 g, 59% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 1.69 - 1.96 (m, 3H), 2.91 - 3.01 (m, 2H), 3.35 (s, 11H), 3.73 - 3.86 (m, 1H), 3.89 - 3.99 (m, 1H), 6.40 - 6.47 (m, 1H), 6.49 - 6.60 (m, 1H), 6.77 - 6.85 (m, 1H), 6.87 - 6.94 (m, 1H), 7.15 - 7.21 (m, 1H), 7.23 - 7.31 (m, 1H), 7.39 - 7.49 (m, 1H). ESI-MS m / z: 316 [M+H] + .

[0228] Step 6: Synthesis of compound int_19-8: [ka]

[0229] Int_19-7 (9.40 g, 29.8 mmol) was dissolved in a mixture of n-butanol (15 mL) and water (5 mL), and sodium hydroxide (23.8 g, 595 mmol) was added to the reaction solution. The reaction solution was heated to 100 °C and reacted for 16 hours. The reaction solution was then warmed to room temperature and reacted for 1 hour. LC-MS monitoring showed the reaction was complete. Water (200 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (200 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EAP = 1 / 4) to obtain a solid (8 g, yield: 98.2%). 1 H NMR (500 MHz, DMSO-d6) δ = 1.99 (s, 1H), 2.94 - 3.00 (m, 1H), 3.08 - 3.17 (m, 1H), 3.19 - 3.27 (m, 1H), 3.36 - 3.43 (m, 1H), 6.44 (d, J = 2.14 Hz, 1H), 6.64 (dd, J = 5.57, 1.45 Hz, 1H), 6.80 (d, J = 5.49 Hz, 1H), 6.94 (d, J = 4.88 Hz, 1H), 7.12 - 7.20 (m, 2H), 7.38 (dd, J = 4.81, 1.45 Hz, 1H). ESI-MS m / z: 274 [M+H] + .

[0230] Step 7: Synthesis of compound int_19-9: [ka]

[0231] int_19-8 (8.00 g, 29.2 mmol) and (Boc)2O (9.57 g, 43.8 mmol, 10.1 mL) were dissolved in dichloromethane (90 mL), and TEA (8.87 g, 87.7 mmol, 12.2 mL) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 16 hours under a nitrogen atmosphere. LC-MS monitoring showed the reaction was complete. The reaction solution was slowly poured into 100 mL of ice water. The aqueous phase was extracted with dichloromethane (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 3 / 1) to give a solid (8.9 g, yield: 81.5%). 1 H NMR (400 MHz, DMSO-d6) δ = 1.13 (s, 9H), 2.88 - 3.06 (m, 2H), 3.72 - 3.91 (m, 2H), 6.47 - 6.63 (m, 2H), 6.79 (d, J = 5.50 Hz, 1H), 6.85 - 6.95 (m, 1H), 7.16 - 7.29 (m, 2H), 7.41 - 7.49 (m, 1H).

[0232] Step 8: Synthesis of compound int_19-10: [ka]

[0233] Int_19-9 (2.5 g, 6.686 mmol), sodium periodate (7.2 g, 33.431 mmol), and K2OsO4·2H2O (250 mg, 0.678 mmol) were dissolved in a mixture of tetrahydrofuran (250 mL) and water (125 mL). The reaction solution was purged with nitrogen three times and reacted at room temperature for 2 h. LC-MS monitoring showed the reaction was complete. The reaction solution was slowly poured into 100 mL of ice water. The aqueous phase was extracted with dichloromethane (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography to give a solid (2.6 g, yield: 96.2%). ESI-MS m / z: 406 [M+H] + .

[0234] Step 9: Synthesis of compound int_19-11: [ka]

[0235] int_19-10 (2.7 g, 6.686 mmol) was dissolved in a mixed solvent of ethyl acetate (60 mL) and methanol (15 mL), and sodium borohydride (1.0 g, 26.744 mmol) was added to the reaction solution. The reaction solution was allowed to react at room temperature for 2 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was slowly poured into 100 mL of ice water. The aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / ethyl acetate = 2 / 1) to obtain a solid (1.8 g, yield: 65.6%). ESI-MS m / z: 410 [M+H] + .

[0236] Step 10: Synthesis of compound int_19-12: [ka]

[0237] Int_19-11 (1.2 g, 2.93 mmol) was dissolved in toluene (50 mL), and p-toluenesulfonic acid monohydrate (5.6 g, 29.3 mmol) was added to the reaction solution. The reaction solution was heated to 110 °C and reacted for 1 h. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature and then slowly poured into 50 mL of ice water. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography to obtain a solid (310 mg, yield: 38.7%). ESI-MS m / z: 292 [M+H] + .

[0238] Step 11: Synthesis of compound int_19-13: [ka]

[0239] int_19-12 (1.87 g, 6.426 mmol) and (Boc)O (2.1 g, 9.639 mmol) were dissolved in 1,4-dioxane (16 mL), and TEA (973 mg, 9.639 mmol) was added to the reaction solution at room temperature. The reaction solution was heated to 80 °C and reacted for 16 h under a nitrogen atmosphere. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature and adjusted to a weakly acidic pH with 2 M aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO, PE / EtOAc = 2 / 1) to give a solid (1.6 g, yield: 63.5%). ESI-MS m / z: 392 [M+H] + .

[0240] Step 12: Synthesis of compound int_19-14: [ka]

[0241] int_19-13 (265 mg, 0.676 mmol) was dissolved in THF (10 mL), and the mixture was cooled to -70 °C. Under a nitrogen atmosphere, n-BuLi (2.5 M, 0.81 mL) was slowly added dropwise, and the reaction mixture was allowed to react at -70 °C for 1 h. Next, DMF (148 mg, 2.028 mmol) was added dropwise to the reaction mixture at -60 °C. After the addition was complete, the reaction mixture was allowed to react at 70 °C for 1 h. LC-MS monitoring showed the completion of the reaction. Saturated ammonium chloride solution (20 mL) was slowly added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (20 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 5 / 1) to give a solid (170 mg, yield: 60.1%). MS (ESI): 420 [M+H] + .

[0242] Step 13: Synthesis of compound int_19-15: [ka]

[0243] Int_1-9 (592 mg, 2.463 mmol) was dissolved in THF (10 mL) and cooled to -70 °C. Under a nitrogen atmosphere, n-BuLi (2.5 M, 2 mL, 4.926 mmol) was slowly added dropwise to the reaction solution and allowed to react at -70 °C for 1 h. Next, a solution of int_19-14 (170 mg, 0.411 mmol) in THF (1 mL) was added dropwise to the reaction solution at -75 °C. After the addition was complete, the reaction was allowed to react at -75 °C for 1 h, then warmed to room temperature and allowed to react for 16 h. LC-MS monitoring showed the reaction was complete. Saturated ammonium chloride solution (20 mL) was slowly added to the reaction solution. The aqueous phase was extracted with ethyl acetate (20 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography to obtain a solid (180 mg, yield: 81.2%). MS (ESI): 534 [M+H] + .

[0244] Step 14: Synthesis of compound int_19-16: [ka]

[0245] int_19-15 (180 mg, 0.337 mmol) was dissolved in DCM (15 mL), and Dess-Martin oxidant (172 mg, 0.404 mmol) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 1 hour. LC-MS monitoring showed the reaction was complete. Saturated aqueous sodium bicarbonate was slowly added to the reaction solution to adjust the pH to approximately 8. The aqueous phase was extracted with ethyl acetate (20 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / ethyl acetate = 2 / 1) to obtain a solid (156 mg, yield: 87.1%). MS (ESI): 532 [M+H] + .

[0246] Step 15: Synthesis of compound int_19-17: [ka]

[0247] int_19-16 (174 mg, 0.328 mmol) and int_1-12 (141 mg, 0.491 mmol) were dissolved in DMF (10 mL), and K2CO3 (138 mg, 1 mmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 16 hours. LC-MS monitoring showed the reaction was complete. Ice water (30 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 2 / 1) to give the product (230 mg, yield: 89.8%). MS (ESI): 783 [M+H] + .

[0248] Step 16: Synthesis of compound int_19-18: [ka]

[0249] Int_19-17 (230 mg, 0.294 mmol) was dissolved in DMF (4 mL), and int_1-14 (67.8 mg, 0.587 mmol) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 1 hour. LC-MS monitoring showed the reaction was complete. Ice water (30 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography to give a solid (248 mg, yield: 98%). MS (ESI): 862 [M+H] + .

[0250] Step 17: Synthesis of compound int_19-19: [ka]

[0251] Int_19-18 (248 mg, 0.288 mmol) was dissolved in THF (4 mL), and TBAF (1 M, 0.58 mL, 0.575 mmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 16 hours. LC-MS monitoring showed the reaction was complete. Water (30 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography to obtain a solid (183 mg, yield: 90.1%). MS (ESI): 706 [M+H] + .

[0252] Step 18: Synthesis of Compound 19: [ka]

[0253] int_19-19 (172 mg, 0.244 mmol) was dissolved in dichloromethane (6 mL), and TFA (1.5 mL) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 10 minutes. LC-MS monitoring showed the reaction was complete. Aqueous ammonia (1 mL) and water (10 mL) were added to the reaction solution. The aqueous phase was extracted with dichloromethane (10 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC to obtain a solid (65 mg, yield: 44.2%). 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.49 (s, 1H), 8.22 (dd, J = 7.5, 4.3 Hz, 1H), 7.42 (d, J = 3.7 Hz, 2H), 7.26 - 7.17 (m, 2H), 7.16 (s, 1H), 6.90 (s, 1H), 5.09 - 4.91 (m, 2H), 4.87 (t, J = 4.4 Hz, 1H), 4.65 (q, J = 8.2 Hz, 1H), 4.06 (ddd, J = 9.5, 5.4, 2.2 Hz, 2H), 3.93 (dd, J = 10.0, 6.7 Hz, 2H), 3.84 (d, J = 11.6 Hz, 1H), 3.17 - 2.84 (m, 4H), 2.70 (d, J = 16.2 Hz, 1H), 2.28 (d, J = 12.4 Hz, 1H), 2.07 (s, 1H), 1.89 (s, 1H), 1.73 (dt, J = 13.7, 7.6 Hz, 1H), 1.30 - 1.19 (m, 1H), 1.17 (t, J = 7.2 Hz, 1H). MS (ESI): 606 [M+H] + .

[0254] Example 8: Synthesis of Compound 20 and Compound 21 [ka]

[0255] Compound 19 (50 mg, 0.082 mmol) was subjected to SFC chiral separation (column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3HO)]; B%: 60%, isocratic elution mode) to give compound 20 (21 mg) and compound 21 (15 mg). Compound 20: 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.49 (s, 1H), 8.22 (dd, J = 7.5, 4.3 Hz, 1H), 7.42 (d, J = 3.7 Hz, 2H), 7.26 - 7.17 (m, 2H), 7.16 (s, 1H), 6.90 (s, 1H), 5.09 - 4.91 (m, 2H), 4.87 (t, J = 4.4 Hz, 1H), 4.65 (q, J = 8.2 Hz, 1H), 4.06 (ddd, J = 9.5, 5.4, 2.2 Hz, 2H), 3.93 (dd, J = 10.0, 6.7 Hz, 2H), 3.84 (d, J = 11.6 Hz, 1H), 3.17 - 2.84 (m, 4H), 2.70 (d, J = 16.2 Hz, 1H), 2.28 (d, J = 12.4 Hz, 1H), 2.07 (s, 1H), 1.89 (s, 1H), 1.73 (dt, J = 13.7, 7.6 Hz, 1H), 1.30 - 1.19 (m, 1H), 1.17 (t, J = 7.2 Hz, 1H); MS (ESI): 606 [M+H] + . SFC retention time analysis: 1.910 minutes (machine: WatersUPCC with PDA Detector, KIRAL: Chiralpak IG-3 50x4.6mm ID, 3um, mobile phase: A: CO2, B: エタノール (0.05% DEA), アイソクラティック: 40% B, flow rate: 4mL / min, カラム temperature: 35℃, ABPR: 1500psi). Compound 21: 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.50 (s, 1H), 8.21 (d, J = 7.5 Hz, 1H), 7.44 (s, 2H), 7.24 - 7.18 (m, 2H), 7.17 (s, 1H), 6.90 (d, J = 1.9 Hz, 1H), 5.07 - 4.94 (m, 2H), 4.88 (d, J = 4.5 Hz, 1H), 4.67 (d, J = 7.5 Hz, 1H), 4.09 (dd, J = 9.6, 6.0 Hz, 1H), 4.02 (d, J = 11.3 Hz, 1H), 3.99 - 3.89 (m, 2H), 3.84 (d, J = 11.4 Hz, 1H), 3.03 (m, 2H), 2.88 (m, 2H), 2.68 (m, 1H), 2.36 - 2.23 (m, 2H), 2.10 (m, 1H), 1.90 (m, 1H), 1.75 (m, 1H), 1.26 (m, 2H).; MS (ESI): 606 [M+H] + . SFC retention time analysis: 1.038 minutes (machine: WatersUPCC with PDA Detector, Kura: Chiralpak IG-3 50x4.6mm ID, 3um, mobile phase: A: CO2, B: Elastomer (0.05% DEA), アイソクラティック: 40% B, flow rate: 4mL / min, カラム temperature: 35℃, ABPR: 1500psi).

[0256] Example 9: Synthesis of compound 46

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[0257] ステップ1:Synthesis of compound int_46-1:

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[0258] Int_19-9 (1.50 g, 4.01 mmol) and Pd / C (1.50 g, 10% purity) were dissolved in methanol (20 mL). The reaction solution was purged with hydrogen three times and reacted under a hydrogen atmosphere (25 Psi) at room temperature for 16 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was filtered to obtain the filtrate, which was then concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 0 / 1) to obtain a solid (1.3 g, yield: 86.2%). ESI-MS m / z: 376 [M+H] + .

[0259] Step 2: Synthesis of compound int_46-2: [ka]

[0260] int_46-1 (0.30 g, 798 μmol) was dissolved in THF (10 mL) and cooled to -60 °C. Under a nitrogen atmosphere, n-BuLi (2.50 M, 479 μL) was slowly added dropwise and the reaction mixture was allowed to react at -60 °C for 1 h. DMF (175 mg, 2.39 mmol, 184 μL) was then added dropwise at -60 °C. After the addition was complete, the reaction mixture was allowed to react at -60 °C for 3 h. LC-MS monitoring showed the completion of the reaction. Saturated ammonium chloride solution (100 mL) was slowly added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 3 / 1) to give a solid (150 mg, yield: 46.5%). MS (ESI): 404 [M+H] + .

[0261] Step 3: Synthesis of compound int_46-3: [ka]

[0262] Int_1-9 (4.79 g, 19.9 mmol) was dissolved in THF (50 mL) and cooled to -75 °C. Under a nitrogen atmosphere, n-BuLi (2.5 M, 16 mL) was slowly added dropwise and the mixture was allowed to react at -75 °C for 1 hour. Next, a THF solution (25 mL) of int_46-2 (1.3 g, 3.2 mmol) was added dropwise to the reaction solution at -75 °C. After the addition was complete, the mixture was allowed to react at -75 °C for 1 hour, then warmed to room temperature and allowed to react for 16 hours. LC-MS monitoring showed the reaction was complete. Saturated ammonium chloride solution (200 mL) was slowly added to the reaction solution. The aqueous phase was extracted with ethyl acetate (200 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography to obtain a solid (1.15 g, 69.6% yield). MS (ESI): 518 [M+H] + .

[0263] Step 4: Synthesis of compound int_46-4: [ka]

[0264] Int_46-3 (0.200 g, 386 μmol) was dissolved in DCM (10 mL), and Dess-Martin oxidant (327 mg, 772 μmol, 239 μL) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 1 hour. LC-MS monitoring showed the reaction was complete. Saturated aqueous sodium bicarbonate solution was slowly added to the reaction solution to adjust the pH to approximately 8. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 3 / 1) to give a solid (170 mg, yield: 85.3%). 1H NMR (400MHz, CHLOROFORM-d) δ = 9.10 (s, 1H), 8.71 (s, 1H), 7.12 (q, J = 8.0 Hz, 2H), 6.86 (s, 1H), 6.58 - 6.50 (m, 1H), 3.94 - 3.84 (m, 1H), 3.75 - 3.63 (m, 1H), 3.34 - 3.11 (m, 3H), 2.92 - 2.84 (m, 2H), 2.77 - 2.68 (m, 1H), 1.24 - 1.11 (m, 3H), 0.96 - 0.81 (m, 2H). MS (ESI): 516 [M+H] + .

[0265] Step 5: Synthesis of compound int_46-5: [ka]

[0266] int_46-4 (403 mg, 782 μmol) and int_1-12 (336 mg, 1.17 mmol) were dissolved in DMF (10 mL), and K2CO3 (540 mg, 3.91 mmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 16 hours. LC-MS monitoring showed the reaction was complete. Ice water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (ISCO®; Silica Flash Column, eluent: 0-20% ethyl acetate / petroleum ether gradient) to obtain the product (0.5 g, yield: 83.3%). MS (ESI): 767 [M+H] + .

[0267] Step 6: Synthesis of compound int_46-6: [ka]

[0268] Int_46-5 (0.500 g, 651 μmol) was dissolved in DMF (4 mL), and int_1-14 (150 mg, 1.30 mmol) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 1 hour. LC-MS monitoring showed the reaction was complete. Ice water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography to give a solid (400 mg, yield: 72.5%). MS (ESI): 846 [M+H] + .

[0269] Step 7: Synthesis of compound int_46-7: [ka]

[0270] Int_46-6 (0.400 g, 473 μmol) was dissolved in THF (4 mL), and TBAF (1 M, 473 μL) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 16 hours. LC-MS monitoring indicated the reaction was complete. Water (30 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (ISCO®; Silica Flash Column, eluent: 0-100% ethyl acetate / petroleum ether gradient) to obtain a solid (170 mg, yield: 52.1%). MS (ESI): 690 [M+H] + .

[0271] Step 8: Synthesis of compound 46: [ka]

[0272] int_46-7 (0.17 g, 246 μmol) was added to TFA (0.500 mL) at room temperature, and the reaction solution was allowed to react at room temperature for 10 minutes. LC-MS monitoring indicated the reaction was complete. Aqueous ammonia (1 mL) and water (10 mL) were added to the reaction solution. The aqueous phase was extracted with dichloromethane (10 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: Boston Prime C18 150 × 30 mm × 5 μm, mobile phase: [water (ammonium hydroxide)-ACN], gradient: 33% to 53% B over 16 minutes) to give a solid (35 mg, yield: 24.1%). MS (ESI): 590 [M+H] + .

[0273] Example 10: Synthesis of Compound 47 and Compound 48 [ka]

[0274] Compound 46 (50 mg, 84.7 μmol) was subjected to SFC chiral separation (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3HO)]; B%: 45%, isocratic elution mode) to give compound 47 (15 mg) and compound 48 (16 mg). Compound 47: 1H NMR (400MHz, DMSO-d6) δ = 8.57 (d, J = 10.8 Hz, 2H), 8.18 (d, J = 7.5 Hz, 1H), 7.45 (s, 2H), 7.23 (s, 1H), 7.18 - 7.12 (m, 2H), 6.77 (d, J = 1.8 Hz, 1H), 4.88 (d, J = 4.5 Hz, 1H), 4.76 - 4.55 (m, 1H), 4.09 (dd, J = 6.0, 9.7 Hz, 1H), 3.96 (br dd, J = 7.0, 9.8 Hz, 2H), 3.16 - 3.03 (m, 3H), 3.01 - 2.90 (m, 1H), 2.88 - 2.79 (m, 1H), 2.72 - 2.71 (m, 2H), 2.65 - 2.63 (m, 1H), 2.31 - 2.21 (m, 1H), 2.10 (br s, 1H), 1.98 - 1.85 (m, 1H), 1.78 - 1.64 (m, 1H), 1.34 - 1.21 (m, 2H).; MS (ESI): 590 [M+H] + . SFC retention time analysis: 0.758 minutes (machine: Waters UPCC with PDA Detector, KIRAL: Chiralpak AD-3 50x4.6mm ID, 3um, mobile phase: A: CO2, B: エタノール (0.05% DEA), アイソクラティック: 40%B, flow rate: 4mL / min, カラム temperature: 35℃, ABPR: 1500psi). Compound 48: 1H NMR (400MHz, DMSO-d6) δ = 8.57 (d, J = 10.8 Hz, 2H), 8.18 (d, J = 7.5 Hz, 1H), 7.45 (s, 2H), 7.23 (s, 1H), 7.18 - 7.12 (m, 2H), 6.77 (d, J = 1.8 Hz, 1H), 4.88 (d, J = 4.5 Hz, 1H), 4.76 - 4.55 (m, 1H), 4.09 (dd, J = 6.0, 9.7 Hz, 1H), 3.96 (br dd, J = 7.0, 9.8 Hz, 2H), 3.16 - 3.03 (m, 3H), 3.01 - 2.90 (m, 1H), 2.88 - 2.79 (m, 1H), 2.70 - 2.58 (m, 3H), 2.31 - 2.21 (m, 1H), 2.10 (br s, 1H), 1.98 - 1.85 (m, 1H), 1.78 - 1.64 (m, 1H), 1.34 - 1.21 (m, 2H).; MS (ESI): 590 [M+H] + . SFC retention time analysis: 0.545 minutes (machine: Waters UPCC with PDA Detector, Kura: Chiralpak AD-3 50x4.6mm ID, 3um, mobile phase: A: CO2, B: Elastomer (0.05% DEA), アイソクラティック: 40%B, flow rate: 4mL / min, カラム temperature: 35℃, ABPR: 1500psi).

[0275] Example 11: Synthesis of Compound 49

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[0276] ステップ1:Synthesis of compound int_49-2:

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[0277] int_49-1 (59.0 g, 291 mmol) and NHOAc (51.52 g, 668.45 mmol) were dissolved in acetic acid (600 mL), and the mixture was purged with nitrogen three times. Under a nitrogen atmosphere, CHNO (46.1 g, 756 mmol, 40.9 mL) was added to the reaction solution, which was then heated to 100 °C and stirred for 16 h. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature and slowly poured into 1000 mL of ice water. The aqueous phase was extracted with ethyl acetate (1000 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product (60 g, yield: 83.9%), which was used directly in the next step.

[0278] Step 2: Synthesis of compound int_49-3: [ka]

[0279] LiBH4 (21.3 g, 975 mmol) was dissolved in tetrahydrofuran (300 mL) and TMSCl (132.47 g, 1.22 mol, 154.75 mL) was added to the reaction solution at 0 °C under a nitrogen atmosphere. The reaction solution was stirred at 0 °C for 30 min, and a solution of int_49-2 (30 g, 122 mmol) in tetrahydrofuran (250 mL) was slowly added dropwise to the reaction solution within 30 min. The reaction solution was warmed to 70 °C and reacted for an additional 2 h. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to 0 °C, and 200 mL of methanol was slowly added to quench the reaction. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then adjusted to a pH greater than 7 with aqueous ammonia. The aqueous phase was extracted with ethyl acetate (500 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product (16 g, yield: 60.2%), which was used directly in the next step. ESI-MS m / z: 218 [M+H] + .

[0280] Step 3: Synthesis of compound int_49-5: [ka]

[0281] Int_49-3 (17.0 g, 78.0 mmol), int_49-4 (8.00 g, 57.9 mmol), and Ti(i-PrO)4 (34.1 g, 120 mmol, 35.4 mL) were dissolved in toluene (200 mL). The mixture was purged with nitrogen three times, heated to 90 °C, and stirred for 2 h. LC-MS monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give the crude product (19 g, yield: 93.7%), which was used directly in the next step. ESI-MS m / z: 338 [M+H] + .

[0282] Step 4: Synthesis of compound int_49-6: [ka]

[0283] int_49-5 (19.0 g, 56.2 mmol), TEA (56.8 g, 562 mmol, 78.2 mL), and AcO (28.7 g, 281 mmol, 26.4 mL) were dissolved in dichloromethane (400 mL), and the reaction solution was reacted under a nitrogen atmosphere at 20 °C for 2 h. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature. The organic phase was concentrated under reduced pressure to give the crude product, which was then adjusted to a pH greater than 7 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with dichloromethane (500 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO, PE / EtOAc = 3 / 1) to give a solid (9.2 g, 43.1% yield).

[0284] Step 5: Synthesis of compound int_49-7: [ka]

[0285] int_49-6 (7.10 g, 18.7 mmol), DIPEA (4.83 g, 37.3 mmol, 6.50 mL), and di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (1.22 g, 1.87 mmol) were dissolved in 1,4-dioxane (100 mL). The reaction solution was purged with nitrogen three times and heated to 110 °C for 16 h. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature and then slowly poured into 200 mL of ice water. The aqueous phase was extracted with ethyl acetate (200 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 2 / 1) to give a solid (4 g, 71.6% yield). ESI-MS m / z: 300 [M+H] + .

[0286] Step 6: Synthesis of compound int_49-8: [ka]

[0287] Int_49-7 (4.70 g, 15.7 mmol) was dissolved in a mixture of n-butanol (75 mL) and water (25 mL), and sodium hydroxide (12.6 g, 314 mmol) was added to the reaction solution. The reaction solution was heated to 100 °C and reacted for 16 hours. The reaction solution was then warmed to room temperature and reacted for 1 hour. LC-MS monitoring showed the reaction was complete. Water (100 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 1 / 4) to obtain a solid (4 g, yield: 99%). ESI-MS m / z: 258 [M+H] + .

[0288] Step 7: Synthesis of compound int_49-9: [ka]

[0289] int_49-8 (4.00 g, 15.5 mmol) and (Boc)2O (5.09 g, 23.3 mmol, 5.36 mL) were dissolved in dichloromethane (45 mL), and TEA (4.72 g, 46.6 mmol, 6.49 mL) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 16 hours under a nitrogen atmosphere. LC-MS monitoring showed the reaction was complete. The reaction solution was slowly poured into 100 mL of ice water. The aqueous phase was extracted with dichloromethane (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 3 / 1) to give a solid (4 g, yield: 72%). 1 H NMR (400 MHz, DMSO-d6) δ = 1.05 (s, 9H), 2.80 - 2.98 (m, 2H), 3.65 - 3.85 (m, 2H), 6.14 - 6.26 (m, 1H), 6.41 - 6.55 (m, 1H), 6.71 (d, J = 5.50 Hz, 1H), 6.78 - 6.86 (m, 1H), 6.88 - 7.00 (m, 1H), 7.19 (br dd, J = 7.81, 6.49 Hz, 1H), 7.37 (br d, J = 4.62 Hz, 1H).

[0290] Step 8: Synthesis of compound int_49-10: [ka]

[0291] Int_46-9 (2.00 g, 5.60 mmol) and Pd / C (2.00 g, 10% purity) were dissolved in methanol (20 mL). The reaction solution was purged with hydrogen three times and reacted under a hydrogen atmosphere (25 Psi) at room temperature for 16 h. LC-MS monitoring showed the reaction was complete. The reaction solution was filtered to obtain the filtrate, which was then concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 1 / 0 to 0 / 1) to obtain a solid (1.7 g, yield: 85%). 1 H NMR (400 MHz, DMSO-d6) δ = 1.04 - 1.24 (m, 9H), 2.54 - 2.66 (m, 1H), 2.76 - 2.94 (m, 2H), 2.99 - 3.08 (m, 2H), 3.11 - 3.22 (m, 1H), 3.59 - 3.71 (m, 1H), 3.72 - 3.80 (m, 1H), 6.26 (dd, J = 10.94, 2.63 Hz, 1H), 6.57 (d, J = 5.01 Hz, 1H), 6.93 - 7.02 (m, 1H), 7.19 - 7.28 (m, 1H), 7.35 (d, J = 5.01 Hz, 1H). ESI-MS m / z: 360 [M+H] + .

[0292] Step 9: Synthesis of compound int_49-11: [ka]

[0293] int_49-10 (1.70 g, 4.73 mmol) was dissolved in THF (30 mL), and the mixture was cooled to -60 °C. Under a nitrogen atmosphere, n-BuLi (2.50 M, 2.84 mL) was slowly added dropwise, and the reaction was allowed to proceed at -60 °C for 1 h. DMF (1.04 g, 14.2 mmol, 1.09 mL) was then added dropwise at -60 °C. After the addition was complete, the reaction was allowed to proceed at -60 °C for 3 h. LC-MS monitoring showed the completion of the reaction. Saturated ammonium chloride solution (100 mL) was slowly added to the reaction solution. The aqueous phase was extracted with dichloromethane (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 3 / 1) to give a solid (1.8 g, yield: 98.2%). 1 H NMR (400 MHz, DMSO-d6) δ =1.15 - 1.20 (m, 9H), 2.65 - 2.76 (m, 1H), 2.79 - 2.99 (m, 2H), 3.05 - 3.16 (m, 2H), 3.16 - 3.26 (m, 1H), 3.59 - 3.71 (m, 1H), 3.72 - 3.80 (m, 1H), 6.30 - 6.42 (m, 1H), 6.94 - 7.09 (m, 1H), 7.21 - 7.35 (m, 1H), 7.47 - 7.64 (m, 1H), 9.68 - 9.74 (m, 1H). MS (ESI): 388 [M+H] + .

[0294] Step 10: Synthesis of compound int_49-12: [ka]

[0295] Int_1-9 (2.79 g, 11.6 mmol) was dissolved in THF (40 mL) and cooled to -70 °C. Under a nitrogen atmosphere, n-BuLi (2.50 M, 9.29 mL) was slowly added dropwise and the mixture was allowed to react at -70 °C for 1 hour. Next, a solution of int_49-11 (1.50 g, 3.87 mmol) in THF (20 mL) was added dropwise to the reaction solution at -70 °C. After the addition was complete, the mixture was allowed to react at -70 °C for 1 hour, then warmed to room temperature and allowed to react for 16 hours. LC-MS monitoring showed the reaction was complete. Saturated ammonium chloride solution (200 mL) was slowly added to the reaction solution. The aqueous phase was extracted with ethyl acetate (200 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography to obtain a solid (1.35 g, yield: 69.5%). MS (ESI): 502 [M+H] + .

[0296] Step 11: Synthesis of compound int_49-13: [ka]

[0297] int_49-12 (1.35 g, 2.69 mmol) was dissolved in DCM (25 mL), and Dess-Martin oxidant (2.28 g, 5.38 mmol) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 1 hour. LC-MS monitoring showed the reaction was complete. Saturated aqueous sodium bicarbonate solution was slowly added to the reaction solution to adjust the pH to approximately 8. The aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 3 / 1) to give a solid (1 g, yield: 74.4%). MS (ESI): 500 [M+H] + .

[0298] Step 12: Synthesis of compound int_49-14: [ka]

[0299] int_49-13 (0.60 g, 1.20 mmol) and int_1-12 (1.30 g, 4.52 mmol) were dissolved in DMF (20 mL), and K2CO3 (829 mg, 6.00 mmol) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 16 hours. LC-MS monitoring indicated the reaction was complete. Ice water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (ISCO®; Silica Flash Column, eluting with a 0-80% ethyl acetate / petroleum ether gradient) to obtain the product (610 mg, yield: 67.7%). MS (ESI): 751 [M+H] + .

[0300] Step 13: Synthesis of compound int_49-15: [ka]

[0301] Int_49-14 (610 mg, 812 μmol) was dissolved in DMF (20 mL), and int_1-14 (375 mg, 3.25 mmol) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 1 hour. LC-MS monitoring showed the reaction was complete. Ice water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography to give a solid (670 mg, yield: 99.4%). MS (ESI): 830 [M+H] + .

[0302] Step 14: Synthesis of compound int_49-16: [ka]

[0303] int_49-15 (670 mg, 807 μmol) was dissolved in THF (20 mL), and TBAF (1.00 M, 807 μL) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 16 hours. LC-MS monitoring indicated the reaction was complete. Water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (ISCO®; Silica Flash Column, eluting with a 0-80% ethyl acetate / petroleum ether gradient) to obtain a solid (300 mg, yield: 55.2%). 1 H NMR (400 MHz, DMSO-d6) δ = 1.23 - 1.26 (m, 9H), 1.69 - 1.84 (m, 1H), 1.88 - 1.96 (m, 1H), 2.05 - 2.17 (m, 1H), 2.20 - 2.37 (m, 1H), 2.62 - 2.71 (m, 1H), 2.77 - 2.88 (m, 1H), 2.91 (s, 1H), 3.07 - 3.17 (m, 1H), 3.18 - 3.26 (m, 2H), 3.64 - 3.83 (m, 2H), 3.90 - 4.01 (m, 2H), 4.01 - 4.06 (m, 1H), 4.06 - 4.13 (m, 1H), 4.63 - 4.73 (m, 1H), 4.82 - 4.94 (m, 1H), 6.30 - 6.42 (m, 1H), 6.94 - 7.06 (m, 1H), 7.22 - 7.29 (m, 1H), 7.36 - 7.40 (m, 1H), 7.42 - 7.48 (m, 2H), 8.16 - 8.28 (m, 1H), 8.44 - 8.49 (m, 1H), 8.57 - 8.62 (m, 1H). MS (ESI): 674 [M+H] + .

[0304] Step 15: Synthesis of compound 49: [ka]

[0305] Int_49-16 (200 mg, 297 μmol) was added to TFA (0.5 mL) at room temperature, and the reaction solution was allowed to react for 10 minutes. LC-MS monitoring indicated the reaction was complete. Aqueous ammonia (1 mL) and water (30 mL) were added to the reaction solution. The aqueous phase was extracted with dichloromethane (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (column: Boston Prime C18 150 × 30 mm × 5 μm, mobile phase: [water (ammonium hydroxide)-ACN], gradient: 33% to 53% B over 10 minutes) to give a solid (60 mg, yield: 35.2%). MS (ESI): 574 [M+H] + .

[0306] Example 12: Synthesis of Compound 50 and Compound 51 [ka]

[0307] Compound 49 (60 mg, 104 μmol) was subjected to SFC chiral separation (column: DAICEL CHIRALPAK IE (250 mm × 30 mm, 10 μm); mobile phase: [heptane-EtOH (0.1% NH3HO)]; B%: 55%, isocratic elution mode) to give compound 50 (25 mg) and compound 51 (26 mg). Compound 50: 1H NMR (400 MHz, DMSO-d6) δ = 1.19 - 1.32 (m, 2H), 1.69 - 1.81 (m, 1H), 1.87 - 2.00 (m, 1H), 2.03 - 2.16 (m, 1H), 2.23 - 2.35 (m, 1H), 2.35 - 2.91 (m, 4H), 2.92 - 3.03 (m, 1H), 3.04 - 3.18 (m, 3H), 3.90 - 4.00 (m, 2H), 4.05 - 4.12 (m, 1H), 4.63 - 4.72 (m, 1H), 4.85 - 4.91 (m, 1H), 6.50 - 6.58 (m, 1H), 6.92 - 7.00 (m, 1H), 7.11 - 7.18 (m, 1H), 7.22 - 7.25 (m, 1H), 7.41 - 7.47 (m, 2H), 8.14 - 8.20 (m, 1H), 8.57 (s, 1H), 8.58 - 8.61 (m, 1H).; MS (ESI): 574 [M+H] + . SFC retention time analysis: 4.478 points (machine: Shimadzu LC-20AD with PDA Detector, Kura: Chiralpak IE 100x4.6mm ID, 3um, mobile phase: A: Decontaminant (0.1%DEA), B: Decontaminant (0.05%DEA), Aconite: 40%B, flow rate: 1mL / min, temperature: 35℃). Compound 51: 1H NMR (400 MHz, DMSO-d6) δ = 1.19 - 1.32 (m, 2H), 1.69 - 1.81 (m, 1H), 1.87 - 2.00 (m, 1H), 2.03 - 2.16 (m, 1H), 2.23 - 2.35 (m, 1H), 2.35 - 2.91 (m, 4H), 2.92 - 3.03 (m, 1H), 3.04 - 3.18 (m, 3H), 3.90 - 4.00 (m, 2H), 4.05 - 4.12 (m, 1H), 4.63 - 4.72 (m, 1H), 4.85 - 4.91 (m, 1H), 6.50 - 6.58 (m, 1H), 6.92 - 7.00 (m, 1H), 7.11 - 7.18 (m, 1H), 7.22 - 7.25 (m, 1H), 7.41 - 7.47 (m, 2H), 8.14 - 8.20 (m, 1H), 8.57 (s, 1H), 8.58 - 8.61 (m, 1H).; MS (ESI): 574 [M+H] + . SFC retention time analysis: 3.339 minutes (machine: Shimadzu LC-20AD with PDA Detector, Kura: Chiralpak IE 100x4.6mm ID, 3um, mobile phase: A: Decontaminant (0.1%DEA), B: Decontaminant (0.05%DEA), Aconite: 40%B, flow rate: 1mL / min, temperature: 35℃).

[0308] Example 13: Synthesis of Compound 78

change

[0309] ステップ1:Synthesis of compound int_78-1:

change

[0310] int_78-1 (0.30 g, 798 μmol) was dissolved in THF (10 mL) and cooled to -60 °C. Under a nitrogen atmosphere, n-BuLi (2.50 M, 479 μL) was slowly added dropwise and the reaction mixture was allowed to react at -60 °C for 1 h. DMF (175 mg, 2.39 mmol, 184 μL) was then added dropwise at -60 °C. After the addition was complete, the reaction mixture was allowed to react at -60 °C for 3 h. LC-MS monitoring showed the reaction was complete. Saturated ammonium chloride solution (100 mL) was slowly added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 2 / 1) to give a solid (140 mg, yield: 43.4%). 1 H NMR (400 MHz, DMSO-d6) δ = 1.12 (s, 9H), 2.88 - 3.08 (m, 2H), 3.66 - 3.93 (m, 2H), 6.53 - 6.59 (m, 1H), 6.90 (d, J=5.62 Hz, 1H), 6.94 - 7.00 (m, 1H), 7.19 - 7.26 (m, 1H), 7.27 - 7.33 (m, 1H), 7.74 - 7.85 (m, 1H), 9.75 (s, 1H). MS (ESI): 402 [M+H] + .

[0311] Step 2: Synthesis of compound int_78-2: [ka]

[0312] Int_1-9 (4.79 g, 19.9 mmol) was dissolved in THF (50 mL), and the mixture was cooled to -75 °C. Under a nitrogen atmosphere, n-BuLi (2.5 M, 16 mL) was slowly added dropwise, and the reaction was allowed to proceed at -75 °C for 1 h. Next, a solution of int_78-1 (1.3 g, 3.2 mmol) in THF (25 mL) was added dropwise to the reaction solution at -75 °C. After the addition was complete, the reaction was allowed to proceed at -75 °C for 1 h, then warmed to room temperature and allowed to proceed for 16 h. LC-MS monitoring showed the completion of the reaction. Saturated ammonium chloride solution (200 mL) was slowly added to the reaction solution. The aqueous phase was extracted with ethyl acetate (200 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography to obtain a solid (1.3 g, 78.7% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 1.14 (s, 9H), 2.82 - 3.02 (m, 2H), 3.67 - 3.82 (m, 2H), 5.74 - 5.78 (m, 1H), 6.53 - 6.59 (m, 1H), 6.90 - 6.94 (m, 1H), 6.98 - 7.03 (m, 1H), 7.19 - 7.29 (m, 2H), 7.57 - 7.62 (m, 1H), 8.97 - 9.01 (m, 1H), 9.19 (s, 1H). MS (ESI): 516 [M+H] + .

[0313] Step 3: Synthesis of compound int_78-3: [ka]

[0314] int_78-2 (1.60 g, 3.10 mmol) was dissolved in DCM (100 mL), and Dess-Martin oxidant (2.63 g, 6.20 mmol) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 1 hour. LC-MS monitoring showed the reaction was complete. Saturated aqueous sodium bicarbonate was slowly added to the reaction solution to adjust the pH to approximately 8. The aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 2 / 1) to give a solid (0.9 g, yield: 56.5%). MS (ESI): 514 [M+H] + .

[0315] Step 4: Synthesis of compound int_78-4: [ka]

[0316] int_78-3 (0.90 g, 1.75 mmol) and int_1-12 (1.50 g, 5.22 mmol) were dissolved in DMF (20 mL), and K2CO3 (1.21 g, 8.75 mmol) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 16 hours. LC-MS monitoring indicated the reaction was complete. Ice water (100 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (ISCO®; Silica Flash Column, eluting with a 0-30% ethyl acetate / petroleum ether gradient) to obtain the product (0.7 g, yield: 52.3%). 1H NMR (400 MHz, CHLOROFORM-d) δ = 1.00 - 1.01 (m, 18H), 1.12 - 1.29 (m, 9H), 1.65 - 1.83 (m, 3H), 2.05 - 2.17 (m, 2H), 2.34 - 2.48 (m, 1H), 2.80 - 2.97 (m, 3H), 3.55 - 3.66 (m, 2H), 3.74 - 3.91 (m, 2H), 4.19 - 4.27 (m, 1H), 4.60 - 4.78 (m, 1H), 4.70 (sxt, J = 7.68 Hz, 1H), 6.57 - 6.61 (m, 2H), 6.69 (d, J = 5.50 Hz, 1H), 7.02 (d, J = 1.13 Hz, 2H), 7.15 (s, 1H), 7.86 - 8.06 (m, 1H), 8.45 (br dd, J = 7.07, 3.94 Hz, 1H), 8.54 (s, 1H), 8.59 (s, 1H). MS (ESI): 765 [M+H] + .

[0317] Step 5: Synthesis of compound int_78-5: [ka]

[0318] Int_78-4 (0.70 g, 914 μmol) was dissolved in DMF (20 mL), and int_1-14 (423 mg, 3.66 mmol) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 1 hour. LC-MS monitoring showed the reaction was complete. Ice water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography to give a solid (0.77 g, yield: 99.7%). MS (ESI): 844 [M+H] + .

[0319] Step 6: Synthesis of compound int_78-6: [ka]

[0320] int_78-5 (0.77 g, 912 μmol) was dissolved in THF (4 mL), and TBAF (1 M, 912 μL) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 16 hours. LC-MS monitoring indicated the reaction was complete. Water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (ISCO®; Silica Flash Column, eluent: 0-30% ethyl acetate / petroleum ether gradient) to obtain a solid (400 mg, yield: 63.8%). MS (ESI): 688 [M+H] + .

[0321] Step 7: Synthesis of compound 78: [ka]

[0322] int_78-6 (200 mg, 291 μmol) was added to TFA (0.500 mL) at room temperature, and the reaction solution was allowed to react for 10 minutes at room temperature. LC-MS monitoring indicated the reaction was complete. Aqueous ammonia (1 mL) and water (10 mL) were added to the reaction solution. The aqueous phase was extracted with dichloromethane (10 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: Boston Prime C18 150 x 30 mm x 5 μm, mobile phase: [water (ammonium hydroxide)-ACN], gradient: 33% to 55% B over 10 minutes) to give a solid (90 mg, yield: 52.7%). 1H NMR (400 MHz, DMSO-d6) δ =1.11 - 1.25 (m, 1H), 1.66 - 1.73 (m, 1H), 1.86 - 1.96 (m, 1H), 1.99 - 2.10 (m, 1H), 2.15 - 2.27 (m, 1H), 2.70 - 2.90 (m, 2H), 3.03 - 3.07 (m, 1H), 3.15 - 3.19 (m, 2H), 3.81 - 3.95 (m, 2H), 3.96 - 4.06 (m, 1H), 4.51 - 4.70 (m, 1H), 4.75 - 4.91 (m, 1H), 6.36 - 6.43 (m, 1H), 6.90 - 6.97 (m, 2H), 7.08 - 7.19 (m, 2H), 7.32 - 7.45 (m, 2H), 7.48 - 7.60 (m, 1H), 8.01 - 8.06 (m, 1H), 8.45 - 8.50 (m, 1H), 8.53 (br d, J = 12.38 Hz, 2H). MS (ESI): 588 [M+H] + .

[0323] Example 14: Synthesis of Compound 175 and Compound 176 [ka]

[0324] Compound 78 (100 mg, 170 μmol) was subjected to SFC chiral separation (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3HO)]; B%: 50%, isocratic elution mode) to give compound 175 (15 mg) and compound 176 (16 mg). Compound 175: 1H NMR (400 MHz, DMSO-d6) δ =1.11 - 1.25 (m, 1H), 1.66 - 1.73 (m, 1H), 1.86 - 1.96 (m, 1H), 1.99 - 2.10 (m, 1H), 2.15 - 2.27 (m, 1H), 2.70 - 2.90 (m, 2H), 3.03 - 3.07 (m, 1H), 3.15 - 3.19 (m, 2H), 3.81 - 3.95 (m, 2H), 3.96 - 4.06 (m, 1H), 4.51 - 4.70 (m, 1H), 4.75 - 4.91 (m, 1H), 6.36 - 6.43 (m, 1H), 6.90 - 6.97 (m, 2H), 7.08 - 7.19 (m, 2H), 7.32 - 7.45 (m, 2H), 7.48 - 7.60 (m, 1H), 8.01 - 8.06 (m, 1H), 8.45 - 8.50 (m, 1H), 8.53 (br d, J = 12.38 Hz, 2H).; MS (ESI): 588 [M+H] + . SFC retention time analysis: 2.629 min (Instrument: Waters UPCC with PDA Detector, Column: Chiralpak AD-3 50x4.6mm ID, 3um, Mobile phase: A: CO2, B: Ethanol (0.05% DEA), Gradient: 5% to 40% B in 2 min, hold at 40% for 1.2 min, then hold at 5% B for 0.8 min, Flow rate: 4mL / min, Column temperature: 35°C, ABPR: 1500psi). Compound 176: 1H NMR (400 MHz, DMSO-d6) δ =1.11 - 1.25 (m, 1H), 1.66 - 1.73 (m, 1H), 1.86 - 1.96 (m, 1H), 1.99 - 2.10 (m, 1H), 2.15 - 2.27 (m, 1H), 2.70 - 2.90 (m, 2H), 3.03 - 3.07 (m, 1H), 3.15 - 3.19 (m, 2H), 3.81 - 3.95 (m, 2H), 3.96 - 4.06 (m, 1H), 4.51 - 4.70 (m, 1H), 4.75 - 4.91 (m, 1H), 6.36 - 6.43 (m, 1H), 6.90 - 6.97 (m, 2H), 7.08 - 7.19 (m, 2H), 7.32 - 7.45 (m, 2H), 7.48 - 7.60 (m, 1H), 8.01 - 8.06 (m, 1H), 8.45 - 8.50 (m, 1H), 8.53 (br d, J = 12.38 Hz, 2H).; MS (ESI): 588 [M+H] + . SFC retention time analysis: 2.205 min (Instrument: Waters UPCC with PDA Detector, Column: Chiralpak AD-3 50x4.6mm ID, 3um, Mobile phase: A: CO2, B: Ethanol (0.05% DEA), Gradient: 5% to 40% B in 2 min, hold at 40% for 1.2 min, then hold at 5% B for 0.8 min, Flow rate: 4mL / min, Column temperature: 35°C, ABPR: 1500psi).

[0325] Example 15: Synthesis of Compound 91 [ka]

[0326] Step 1: Synthesis of compound int_91-2: [ka]

[0327] Int_4-3 (9.00 g, 48.48 mmol) and int_91-1 (9.07 g, 53.33 mmol) were dissolved in Ti(i-PrO)4 (170 mL). The mixture was purged with nitrogen three times, heated to 80 °C, and stirred for 2 h. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature and used directly in the next step. ESI-MS m / z: 338 [M+H] + .

[0328] Step 2: Synthesis of compound int_91-3: [ka]

[0329] HCOOH (200 mL) was slowly added dropwise to AcO (500 mL) at -10 °C. After the addition was complete, the reaction was allowed to proceed at 20 °C for 0.5 h. Next, the int_91-2 solution obtained in Step 3 was cooled to -10 °C, and the mixture of HOOCH and AcO described above was slowly added dropwise to the int_91-2 solution. The temperature was maintained at -10 °C during the addition. After the addition was complete, the reaction solution was warmed to 70 °C and reacted for 3 h. LC-MS monitoring indicated the completion of the reaction. The reaction solution was cooled to room temperature. The organic phase was concentrated under reduced pressure to obtain the crude product, and the pH of the crude product was adjusted to >7 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (500 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc=1 / 1) to give a solid (2.3 g, yield: 11.7%). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.91 (s, 1H), 7.06 (d, J = 5.3 Hz, 1H), 6.73 (s, 1H), 6.70 (s, 1H), 6.25 (d, J = 5.3 Hz, 1H), 4.80 - 4.69 (m, 1H), 4.18 (d, J = 16.3 Hz, 1H), 3.90 (s, 3H), 3.71 (dd, J = 16.3, 1.5 Hz, 1H), 3.27 - 3.11 (m, 2H), 3.06 - 2.97 (m, 2H), 2.87 - 2.75 (m, 1H). ESI-MS m / z: 366 [M+H] + .

[0330] Step 3: Synthesis of compound int_91-4: [ka]

[0331] int_91-3 (3.50 g, 9.5 mmol) was dissolved in dichloromethane (30 mL), and the mixture was purged with nitrogen three times. The reaction solution was cooled to 0 °C, and BBr3 (11.88 g, 47.43 mmol) was slowly added dropwise. The reaction solution was warmed to room temperature and reacted for 1 h. LC-MS monitoring showed the reaction was complete. The reaction solution was slowly poured into 300 mL of ice water, and the aqueous phase was extracted with ethyl acetate (300 mL × 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product (3 g, yield: 90.9%), which was used directly in the next step. ESI-MS m / z: 352 [M+H] + .

[0332] Step 4: Synthesis of compound int_91-5: [ka]

[0333] int_91-4 (3 g, 8.5 mmol), PhNTf2 (5.46 g, 15.3 mmol), and TEA (2.15 g, 21.25 mmol, 2.92 mL) were dissolved in dichloromethane (30 mL). The reaction solution was purged with nitrogen three times and reacted at room temperature for 16 h. LC-MS monitoring showed the reaction was complete. The reaction solution was slowly poured into 300 mL of ice water. The aqueous phase was extracted with ethyl acetate (300 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 1 / 1) to give a solid (2.9 g, yield: 70.7%). ESI-MS m / z: 484 [M+H] + .

[0334] Step 5: Synthesis of compound int_91-6: [ka]

[0335] Int_91-5 (2.9 g, 5.99 mmol), Pd / C (1.2 g, 10% purity), and TEA (2.42 g, 23.96 mmol, 3.33 mL) were dissolved in a mixture of methanol (25 mL) and tetrahydrofuran (10 mL). The reaction solution was purged with hydrogen three times and reacted at room temperature for 16 h. LC-MS monitoring showed the reaction was complete. The reaction solution was filtered to obtain the filtrate, which was then concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 1 / 1) to obtain a solid (0.85 g, yield: 42.5%). ESI-MS m / z: 336 [M+H] + .

[0336] Step 6: Synthesis of compound int_91-7: [ka]

[0337] Int_91-6 (0.85 g, 2.53 mmol) was dissolved in THF (10 mL), and the mixture was cooled to -30 °C. Under a nitrogen atmosphere, n-BuLi (2.5 M, 3.04 mL) was slowly added dropwise, and the reaction was allowed to proceed at -30 °C for 2 hours. The reaction solution was then warmed to room temperature and allowed to proceed for 1 hour. LC-MS monitoring indicated the completion of the reaction. Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product (0.71 g, yield: 91.2%), which was used directly in the next step. 1 H NMR (400 MHz, DMSO-d6) δ 7.16 (d, J = 1.4 Hz, 2H), 7.14 (d, J = 5.3 Hz, 1H), 6.85 (t, J = 1.3 Hz, 1H), 6.35 (d, J = 5.3 Hz, 1H), 4.16 (d, J = 16.1 Hz, 1H), 3.69 (dd, J = 16.0, 1.3 Hz, 1H), 3.25 - 3.11 (m, 2H), 2.98 (m, 2H), 2.88 (m, 1H), 2.74 (br, 1H), 2.68 (dt, J = 16.0, 3.5Hz, 1H). ESI-MS m / z: 308 [M+H] + .

[0338] Step 7: Synthesis of compound int_91-8: [ka]

[0339] int_91-7 (0.71 g, 2.30 mmol) and (Boc)O (1 g, 4.60 mmol) were dissolved in 1,4-dioxane (10 mL), and TEA (581.8 mg, 5.75 mmol, 801.4 μL) was added to the reaction solution at room temperature. The reaction solution was warmed to 80 °C and reacted for 16 h. LC-MS monitoring showed the reaction was complete. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (SiO, PE / ethyl acetate = 10 / 1) to obtain a solid (0.65 g, yield: 69.2%). 1 H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J = 5.3 Hz, 1H), 7.24 (d, J = 1.4 Hz, 2H), 6.73 (t, J = 1.3 Hz, 1H), 6.53 (d, J = 5.3 Hz, 1H), 4.23 (dt, J = 12.1, 3.7 Hz, 1H), 3.96 (d, J = 16.1 Hz, 1H), 3.90 (d, J = 13.5 Hz, 1H), 3.81 (dd, J = 16.1, 1.5 Hz, 1H), 3.15 (td, J = 12.0, 3.2 Hz, 1H), 2.98 (ddd, J = 15.8, 11.7, 4.1 Hz, 1H), 2.89 (dt, J = 15.5, 3.3 Hz, 1H), 2.52 (d, J = 1.6 Hz, 1H), 1.15 (s, 9H). ESI-MS m / z: 408 [M+H] + .

[0340] Step 8: Synthesis of compound int_91-9: [ka]

[0341] int_91-8 (1.5 g, 3.67 mmol) was dissolved in THF (20 mL), and the mixture was cooled to -75 °C. Under a nitrogen atmosphere, n-BuLi (2.5 M, 4.43 mL) was slowly added dropwise to the reaction solution, and the mixture was allowed to react at -75 °C for 1 h. Next, DMF (809 mg, 11.08 mmol) was added dropwise at -75 °C. After the addition was completed, the mixture was allowed to react at -75 °C for 1 h. LC-MS monitoring showed the completion of the reaction. Saturated ammonium chloride solution (100 mL) was slowly added to the reaction solution. The aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography to obtain a solid (1.25 g, yield: 78.1%). MS (ESI): 436 [M+H] + .

[0342] Step 9: Synthesis of compound int_91-10: [ka]

[0343] Int_1-9 (4.8 g, 19.92 mmol) was dissolved in THF (50 mL) and cooled to -75 °C. Under a nitrogen atmosphere, n-BuLi (2.5 M, 16 mL) was slowly added dropwise to the reaction solution, and the mixture was allowed to react at -75 °C for 1 hour. Next, a solution of int_91-9 (1.45 g, 3.33 mmol) in THF (25 mL) was added dropwise to the reaction solution at -75 °C. After the addition was complete, the mixture was allowed to react at -75 °C for 1 hour, then warmed to room temperature and allowed to react for 16 hours. LC-MS monitoring showed the reaction was complete. Saturated ammonium chloride solution (200 mL) was slowly added to the reaction solution. The aqueous phase was extracted with ethyl acetate (200 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography to obtain a solid (1.51 g, yield: 82.5%). MS (ESI): 550 [M+H] + .

[0344] Step 10: Synthesis of compound int_91-11: [ka]

[0345] Oxalyl chloride (413.7 mg, 3.26 mmol, 279 μL) was dissolved in dichloromethane (20 mL), and dimethyl sulfoxide (254.7 mg, 3.26 mmol, 231 μL) was slowly added dropwise to the reaction solution at −78°C. The reaction solution was allowed to react at −78°C for 0.5 hours. A DCM solution (10 mL) of int_91-10 (1.5 g, 2.72 mmol) was added dropwise to the reaction solution, and the reaction solution was allowed to react at −78°C for an additional 0.5 hours. Triethylamine (1.65 g, 16.32 mmol) was added dropwise to the reaction solution, and the reaction solution was allowed to react at −78°C for an additional 0.5 hours, after which it was slowly warmed to room temperature. LC-MS monitoring indicated the reaction was complete. A saturated aqueous solution of sodium bicarbonate was slowly added to the reaction solution to adjust the pH to approximately 8. The aqueous phase was extracted with ethyl acetate (100 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography to give a solid (1.38 g, yield 92.6%). MS (ESI): 548 [M+H] + .

[0346] Step 11: Synthesis of compound int_91-12: [ka]

[0347] int_91-11 (1.097 g, 2.0 mmol) and int_1-12 (632.5 mg, 2.2 mmol) were dissolved in DMF (10 mL), and K2CO3 (829.2 mg, 6.0 mmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 3 hours. LC-MS monitoring showed the reaction was complete. Ice water (100 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography to give the product (1.37 g, yield: 86.1%). MS (ESI): 799 [M+H] + .

[0348] Step 12: Synthesis of compound int_91-13: [ka]

[0349] Int_91-12 (1.37 g, 1.71 mmol) was dissolved in DMF (30 mL), and int_1-14 (395.9 mg, 3.42 mmol) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 1 hour. LC-MS monitoring showed the reaction was complete. Ice water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography to obtain a solid (1.3 g, yield: 86.6%). MS (ESI): 878 [M+H] + .

[0350] Step 13: Synthesis of compound int_91-14: [ka]

[0351] Int_91-13 (1.58 g, 1.8 mmol) was dissolved in THF (20 mL), and TBAF (1 M, 3.6 mL) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 4 hours. LC-MS monitoring showed the reaction was complete. Water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography to obtain a solid (1.05 g, yield: 80.7%). MS (ESI): 722 [M+H]+.

[0352] Step 14: Synthesis of Compound 91 [ka]

[0353] Int_91-14 (1.05 g, 1.45 mmol) was dissolved in DCM (7 mL) at room temperature, and the mixture was added with TFA (7.8 mL). The reaction solution was allowed to react at room temperature for 5 minutes. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to 0°C. Saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust the pH to 8. The aqueous phase was extracted with ethyl acetate (50 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC to obtain a solid (862 mg, yield: 95.3%). 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.38 (d, J = 1.2 Hz, 1H), 8.20 (d, J = 7.4 Hz, 1H), 7.41 (d, J = 2.2 Hz, 2H), 7.21 - 7.09 (m, 2H), 7.00 - 6.92 (m, 2H), 4.88 (dd, J = 4.6, 3.0 Hz, 1H), 4.63 (h, J = 8.0 Hz, 1H), 4.27 (d, J = 16.8 Hz, 1H), 4.09 - 4.03 (m, 1H), 3.97 - 3.81 (m, 3H), 3.31 - 3.16 (m, 3H), 3.01 (m, 2H), 2.89 (m, 1H), 2.67 (d, J = 15.9 Hz, 1H), 2.25 (m, 1H), 2.07 (m, 1H), 1.93 - 1.83 (m, 1H), 1.72 (m, 1H), 1.32 - 1.18 (m, 1H). MS (ESI): 622 [M+H] + .

[0354] Example 16: Synthesis of Compound 92 and Compound 93

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[0355] Compound 91 (85 mg, 0.136 mmol) was separated into SFC キラル and compound 92 (27 mg) was obtained. Compound 93 (29 mg) was obtained. Compound 92: 11H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.38 (d, J = 1.2 Hz, 1H), 8.20 (d, J = 7.4 Hz, 1H), 7.41 (d, J = 2.2 Hz, 2H), 7.21 - 7.09 (m, 2H), 7.00 - 6.92 (m, 2H), 4.88 (dd, J = 4.6, 3.0 Hz, 1H), 4.63 (h, J = 8.0 Hz, 1H), 4.27 (d, J = 16.8 Hz, 1H), 4.09 - 4.03 (m, 1H), 3.97 - 3.81 (m, 3H), 3.31 - 3.16 (m, 3H), 3.01 (d, J = 9.6 Hz, 2H), 2.89 (dt, J = 16.0, 7.1 Hz, 1H), 2.67 (d, J = 15.9 Hz, 1H), 2.25 (dt, J = 15.4, 7.7 Hz, 1H), 2.07 (d, J = 7.4 Hz, 1H), 1.93 - 1.83 (m, 1H), 1.72 (dt, J = 15.2, 6.6 Hz, 1H), 1.32 - 1.18 (m, 1H).; MS (ESI): 622 [M+H] + . Compound 93: 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.38 (d, J = 1.2 Hz, 1H), 8.21 (d, J = 7.4 Hz, 1H), 7.42 (d, J = 2.2 Hz, 2H), 7.21 - 7.09 (m, 2H), 7.01 - 6.92 (m, 2H), 4.89 (dd, J = 4.6, 3.0 Hz, 1H), 4.64 (h, J = 8.0 Hz, 1H), 4.28 (d, J = 16.8 Hz, 1H), 4.10 - 4.03 (m, 1H), 3.97 - 3.82 (m, 3H), 3.32 - 3.16 (m, 3H), 3.01 (d, J = 9.6 Hz, 2H), 2.90 (dt, J = 16.0, 7.1 Hz, 1H), 2.67 (d, J = 15.9 Hz, 1H), 2.26 (dt, J = 15.4, 7.7 Hz, 1H), 2.07 (d, J = 7.4 Hz, 1H), 1.94 - 1.83 (m, 1H), 1.73 (dt, J = 15.2, 6.6 Hz, 1H), 1.32 - 1.19 (m, 1H).; MS (ESI): 622 [M+H] + .

[0356] Example 17: Synthesis of Compound 112

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[0357] ステップ1:Synthesis of compound int_112-1:

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[0358] int_19-10 (2.5 g, 6.15 mmol) was dissolved in a mixed solvent of ethyl acetate (60 mL) and methanol (15 mL), and methylamine (573 mg, 18.45 mmol, 1.88 mL, 40% in MeOH) and sodium cyanoborohydride (1.53 g, 24.63 mmol) were added to the reaction solution. The reaction solution was reacted at room temperature for 16 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was slowly poured into 100 mL of ice water. The aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography to give a solid (2.1 g, yield: 84.3%). ESI-MS m / z: 405 [M+H] + .

[0359] Step 2: Synthesis of compound int_112-2: [ka]

[0360] int_112-1 (283.4 mg, 0.7 mmol) was dissolved in THF (10 mL) and cooled to -70 °C. Under a nitrogen atmosphere, n-BuLi (2.5 M, 0.83 mL) was slowly added dropwise and the mixture was allowed to react at -70 °C for 1 h. DMF (153 mg, 2.1 mmol) was then added dropwise at -60 °C. After the addition was completed, the reaction solution was allowed to react at 70 °C for 1 h. LC-MS monitoring showed the completion of the reaction. Saturated ammonium chloride solution (20 mL) was slowly added to the reaction solution. The aqueous phase was extracted with ethyl acetate (20 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography to obtain a solid (169 mg, yield: 55.7%). MS (ESI): 433 [M+H] + .

[0361] Step 3: Synthesis of compound int_112-3: [ka]

[0362] Int_1-9 (577 mg, 2.4 mmol) was dissolved in THF (10 mL) and cooled to -70 °C. Under a nitrogen atmosphere, n-BuLi (2.5 M, 1.9 mL, 4.8 mmol) was slowly added dropwise to the reaction solution and allowed to react at -70 °C for 1 h. Next, a solution of int_112-2 (173.1 mg, 0.4 mmol) in THF (1 mL) was added dropwise to the reaction solution at -75 °C. After the addition was complete, the reaction was allowed to proceed at -75 °C for 1 h, then warmed to room temperature and allowed to proceed for 16 h. LC-MS monitoring showed the completion of the reaction. Saturated ammonium chloride solution (20 mL) was slowly added to the reaction solution. The aqueous phase was extracted with ethyl acetate (20 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography to obtain a solid (162 mg, yield: 73.9%). MS (ESI): 547 [M+H] + .

[0363] Step 4: Synthesis of compound int_112-4: [ka]

[0364] Oxalyl chloride (415 mg, 3.27 mmol, 280 μL) was dissolved in dichloromethane (20 mL), and dimethyl sulfoxide (254.75 mg, 3.27 mmol, 232 μL) was slowly added dropwise to the reaction solution at −78°C. The reaction solution was allowed to react at −78°C for 0.5 hours. A DCM solution (10 mL) of int_112-3 (1.5 g, 2.73 mmol) was added dropwise to the reaction solution, and the reaction solution was allowed to react at −78°C for an additional 0.5 hours. Triethylamine (1.65 g, 16.32 mmol) was added dropwise to the reaction solution, and the reaction solution was allowed to react at −78°C for an additional 0.5 hours, after which it was slowly warmed to room temperature. LC-MS monitoring indicated the reaction was complete. A saturated aqueous solution of sodium bicarbonate was slowly added to the reaction solution to adjust the pH to approximately 8. The aqueous phase was extracted with ethyl acetate (100 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography to give a solid (0.56 g, yield 37.8%). MS (ESI): 545 [M+H] + .

[0365] Step 5: Synthesis of compound int_112-5: [ka]

[0366] int_112-4 (272.7 mg, 0.5 mmol) and int_1-12 (172.5 mg, 0.6 mmol) were dissolved in DMF (10 mL), and K2CO3 (207.3 mg, 1.5 mmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 16 hours. LC-MS monitoring showed the reaction was complete. Ice water (30 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography to give the product (237 mg, yield: 59.5%). MS (ESI): 796 [M+H] + .

[0367] Step 6: Synthesis of compound int_112-6: [ka]

[0368] Int_112-5 (280 mg, 0.35 mmol) was dissolved in DMF (4 mL), and int_1-14 (80.8 mg, 0.7 mmol) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 1 hour. LC-MS monitoring showed the reaction was complete. Ice water (30 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography to give a solid (255 mg, yield: 83.3%). MS (ESI): 875 [M+H] + .

[0369] Step 7: Synthesis of compound int_112-7: [ka]

[0370] Int_112-6 (255 mg, 0.29 mmol) was dissolved in THF (4 mL), and TBAF (1 M, 0.58 mL, 0.58 mmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 16 hours. LC-MS monitoring showed the reaction was complete. Water (30 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography to obtain a solid (170 mg, yield: 81.3%). MS (ESI): 719 [M+H] + .

[0371] Step 8: Synthesis of compound 112: [ka]

[0372] Int_112-7 (170 mg, 0.236 mmol) was dissolved in dichloromethane (6 mL), and TFA (1.5 mL) was added to the reaction solution at room temperature. The reaction solution was allowed to react at room temperature for 10 minutes. LC-MS monitoring showed the reaction was complete. Aqueous ammonia (1 mL) and water (10 mL) were added to the reaction solution. The aqueous phase was extracted with dichloromethane (10 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give a solid (87 mg, yield: 59.5%). MS (ESI): 619 [M+H] + .

[0373] Example 18: Synthesis of Compound 113 and Compound 114 [ka]

[0374] Compound 112 (80 mg, 0.129 mmol) was subjected to SFC chiral separation (column: Phenomenex-Cellulose-2 (250 mm × 30 mm, 10 μm)), mobile phase: [CO2-MeOH (0.1% NH3HO)], B%: 45%, isocratic elution mode) to give compound 113 (21 mg) and compound 114 (25 mg). Compound 113: 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.45 (s, 1H), 8.20 (d, J = 7.5 Hz, 1H), 7.44 (s, 2H), 7.20 (d, J = 3.4 Hz, 2H), 7.08 (s, 1H), 6.92 (d, J = 2.0 Hz, 1H), 4.90 (s, 1H), 4.66 (q, J = 8.2 Hz, 1H), 4.08 (dd, J = 9.7, 6.0 Hz, 1H), 4.04 - 3.81 (m, 3H), 3.72 (d, J = 16.2 Hz, 1H), 3.17 - 2.87 (m, 4H), 2.74 (d, J = 12.2 Hz, 2H), 2.43 (s, 3H), 2.27 (dt, J = 12.7, 7.8 Hz, 1H), 2.09 (d, J = 7.6 Hz, 1H), 1.94 (ddd, J = 11.9, 7.4, 3.7 Hz, 1H), 1.83 - 1.67 (m, 1H), 1.33 - 1.16 (m, 1H).; MS (ESI): 619 [M+H] + . SFC retention time analysis: 4.624 points (machine: Waters UPCC with PDA Detector and QDa Detector, Kura: Cellulose-2100×4.6mm ID, 3um, mobile phase: A: CO2, B: メタノール (0.05% DEA), アイソクラティック: 50% B, flow rate: 2.8mL / min, temperature: 35℃, ABPR: 1500psi). Compound 114: 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.44 (s, 1H), 8.18 (d, J = 7.5 Hz, 1H), 7.45 (s, 2H), 7.18 (d, J = 2.8 Hz, 2H), 7.08 (s, 1H), 6.91 (s, 1H), 4.89 (d, J = 4.3 Hz, 1H), 4.66 (q, J = 8.0 Hz, 1H), 4.08 (dd, J = 9.7, 5.9 Hz, 1H), 3.95 (dd, J = 9.9, 6.9 Hz, 2H), 3.84 (d, J = 16.1 Hz, 1H), 3.72 (d, J = 16.1 Hz, 1H), 2.96 (dd, J = 36.7, 25.1 Hz, 4H), 2.71 (dd, J = 13.5, 7.5 Hz, 2H), 2.41 (s, 3H), 2.29 (dt, J = 14.2, 7.7 Hz, 1H), 2.10 (s, 1H), 1.97 - 1.84 (m, 1H), 1.72 (dt, J = 13.3, 7.4 Hz, 1H), 1.26 (dd, J = 15.7, 6.7 Hz, 1H).; MS (ESI): 619 [M+H] + . SFC retention time analysis: 3.796 minutes (machine: Waters UPCC with PDA Detector and QDa Detector, Kura: Cellulose-2100×4.6mm ID, 3um, mobile phase: A: CO2, B: メタノール (0.05% DEA), アイソクラティック: 50% B, flow rate: 2.8mL / min, temperature: 35℃, ABPR: 1500psi).

[0375] Example 19: Synthesis of Compound 172

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[0376] ステップ1:Synthesis of compound int_172-3:

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[0377] Int_172-2 (2.22 g, 5.19 mmol) was dissolved in anhydrous THF (20 mL), purged with nitrogen three times, and then cooled to -10 °C. LiHMDS (10.4 mL, 1 M) was added dropwise to the reaction solution. After the addition was complete, the reaction solution was allowed to react at room temperature for 1 hour. The reaction solution was cooled to -10 °C, and a solution of int_172-1 (1 g, 2.59 mmol) in anhydrous THF (10 mL) was added dropwise to the reaction solution. The reaction solution was slowly warmed to room temperature and allowed to react for 1 hour. LC-MS monitoring indicated the completion of the reaction. The reaction solution was cooled to room temperature and slowly poured into 50 mL of saturated aqueous ammonium chloride solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 3 / 1) to give a solid (298 mg, yield: 20%). ESI-MS m / z: 563 [M+H] + .

[0378] Step 2: Synthesis of compound int_172-4: [ka]

[0379] Int_172-3 (298 mg, 0.529 mmol) and Pd(OH) (30 mg) were dissolved in ethanol (30 mL). The reaction solution was purged with hydrogen three times and reacted under a hydrogen atmosphere at room temperature for 16 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was filtered to obtain a filtrate, which was then concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography to obtain a solid (290 mg, yield: 97.3%). ESI-MS m / z: 565 [M+H] + .

[0380] Step 3: Synthesis of compound int_172-5: [ka]

[0381] Int_172-4 (310 mg, 0.529 mmol) was dissolved in dichloromethane (10 mL) and HCl / Diox (4 mL, 15.87 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give the crude product, which was used directly in the next step. ESI-MS m / z: 209 [M+H] + .

[0382] Step 4: Synthesis of compound int_172-6: [ka]

[0383] int_172-5 (110 mg, 0.529 mmol), DIPEA (136 mg, 1.056 mmol), and int_4-13 (100 mg, 0.176 mmol) were dissolved in acetonitrile (10 mL), and the reaction solution was heated to 60 °C and reacted for 4 h. LC-MS monitoring showed the reaction was complete. The reaction solution was concentrated under reduced pressure to give the crude product, which was purified by preparative column chromatography to give the product (59 mg, yield: 44%). MS (ESI): 702 [M+H] + .

[0384] Step 5: Synthesis of compound int172: [ka]

[0385] Int_172-6 (59 mg, 0.084 mmol) was dissolved in DCM (1 mL) at room temperature, and the mixture was added with TFA (0.35 mL). The reaction solution was reacted at room temperature for 30 minutes. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to 0 °C, and triethylamine was added to adjust the pH to 8. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC to obtain a solid (26 mg, yield: 51%). 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.48 (d, J = 1.6 Hz, 1H), 8.21 (d, J = 7.5 Hz, 1H), 7.12 (d, J = 2.0 Hz, 2H), 6.91 (s, 1H), 6.74 (s, 1H), 6.70 (s, 2H), 4.78 (t, J = 4.6 Hz, 1H), 4.55 (h, J = 7.8 Hz, 1H), 3.75 (p, J = 6.3 Hz, 1H), 3.06 - 2.87 (m, 6H), 2.87 - 2.79 (m, 1H), 2.63 (dt, J = 16.2, 3.3 Hz, 1H), 2.25 (dt, J = 12.9, 7.3 Hz, 1H), 2.20 - 2.12 (m, 1H), 2.11 - 1.99 (m, 1H), 1.95 - 1.58 (m, 7H), 1.27 - 1.19 (m, 1H), 1.10 (dtd, J = 14.1, 9.5, 4.8 Hz, 1H). MS (ESI): 602 [M+H] + .

[0386] Example 20: Synthesis of Compound 173 and Compound 174 [ka]

[0387] Compound 172 (100 mg, 0.166 mmol) was subjected to SFC chiral resolution to give compound 173 (47 mg) and compound 174 (43 mg). Compound 173: 11H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.48 (d, J = 1.6 Hz, 1H), 8.21 (d, J = 7.5 Hz, 1H), 7.12 (d, J = 2.0 Hz, 2H), 6.91 (s, 1H), 6.74 (s, 1H), 6.70 (s, 2H), 4.78 (t, J = 4.6 Hz, 1H), 4.55 (h, J = 7.8 Hz, 1H), 3.75 (p, J = 6.3 Hz, 1H), 3.06 - 2.87 (m, 6H), 2.87 - 2.79 (m, 1H), 2.63 (dt, J = 16.2, 3.3 Hz, 1H), 2.25 (dt, J = 12.9, 7.3 Hz, 1H), 2.20 - 2.12 (m, 1H), 2.11 - 1.99 (m, 1H), 1.95 - 1.58 (m, 7H), 1.27 - 1.19 (m, 1H), 1.10 (dtd, J = 14.1, 9.5, 4.8 Hz, 1H).; MS (ESI): 602 [M+H] + . Compound 174: 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.48 (d, J = 1.6 Hz, 1H), 8.21 (d, J = 7.5 Hz, 1H), 7.12 (d, J = 2.0 Hz, 2H), 6.91 (s, 1H), 6.74 (s, 1H), 6.70 (s, 2H), 4.78 (t, J = 4.6 Hz, 1H), 4.55 (h, J = 7.8 Hz, 1H), 3.75 (p, J = 6.3 Hz, 1H), 3.06 - 2.87 (m, 6H), 2.87 - 2.79 (m, 1H), 2.63 (dt, J = 16.2, 3.3 Hz, 1H), 2.25 (dt, J = 12.9, 7.3 Hz, 1H), 2.20 - 2.12 (m, 1H), 2.11 - 1.99 (m, 1H), 1.95 - 1.58 (m, 7H), 1.27 - 1.19 (m, 1H), 1.10 (dtd, J = 14.1, 9.5, 4.8 Hz, 1H).; MS (ESI): 602 [M+H] + .

[0388] By changing the starting materials and using the above synthesis method, the target compounds 10-18, 22-45, 52-77, 79-90, 94-111, 115-171, and 177-300 in Table 1 were obtained.

[0389] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18]

[0390] Biological Example 1: In Vitro Inhibitory Activity Assay of Compounds of the Present Disclosure Against SAE HCT116 cells were seeded at approximately 20,000 cells / well, 90 μL per well, into a 96-well black, clear-bottom plate. The cells were incubated overnight at 37°C for 24 hours. Test compounds were diluted 10-fold to the final concentration, and 10 μL of the diluted compound was added to each well of the cell culture plate. After incubating the mixture at 37°C for 6 hours, the cells were gently washed, the medium was discarded, and the cells were washed once with 200 μL of 0.1% PBST. 50 μL of 4% PFA was added to each well, and the cells were fixed at room temperature for 20 minutes, followed by washing two to three times with PBS. 50 μL of 0.2% Triton X-100 was added to each well, and the cells were incubated at room temperature for 15 minutes, followed by washing three times with 0.1% PBST. 100 μL of 3% BSA (0.6 g BSA + 20 mL PBS) was added to each well, and the mixture was blocked at 37°C for 30 minutes. After blocking, the liquid was removed, and the primary antibody (SUMO-2 / 3 (18H8) Rabbit mAb, diluted 1:400) was prepared in 1% BSA. 30 μL of the diluted primary antibody was added to each well, and the mixture was incubated overnight at 4°C. The cells were washed three times with 200 μL of 0.1% PBST. FITC secondary antibody (Fluorescein (FITC)-conjugated Affinipure Goat Anti-Rabbit IgG (H+L), diluted 1:300) was further prepared in 1% BSA, and 40 μL of the diluted secondary antibody was added to each well. The mixture was incubated at room temperature in the dark for 2 hours, and the cells were washed four times with 0.1% PBST. The fluorescent signal of the samples was detected and compared with the DMSO group to determine the inhibition rate and IC 50 The results are shown in Table 2 below.

[0391] [Table 2]

[0392] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0393] +++ is IC 50 indicates that the concentration is 50 nM or less. ++ is IC 50 indicates that the concentration is 50nM to 200nM. + is IC 50 indicates that the concentration is greater than 200 nM.

[0394] TAK-981 is compound I-263a in WO 2016004136A1 and has the following chemical structure:

[0395] [ka]

[0396] As can be seen from the data in Tables 2 and 3, compared to TAK-981, most of the compounds of the present disclosure have stronger inhibitory activity against SAE in the in vitro inhibitory activity assay against SAE.

[0397] Biological Example 2: Assay of compounds of the present disclosure to enhance the in vitro killing activity of NK cells against tumor cells OVCAR3 OVCAR3 cells and NK92MI cells were seeded separately into a 96-well black transparent cell culture plate at approximately 8,000 / well and 80,000 / well, respectively, at 90 μL / well. The cells were incubated overnight at 37°C for 24 hours. Test compounds were diluted 10-fold to the final concentration, and 10 μL of the diluted compound was added to each well of the cell culture plate. The cells were incubated at 37°C for 48 hours, after which the OVCAR3 cell culture medium was discarded. OVCAR3 cells were stained with 1 μM Calcein AM for 50 minutes, washed once with PBS, and then 100 μL of culture medium was added. NK92MI cells were mixed well and gently added to the OVCAR3 cells. After approximately 4 hours of co-culture, the DMSO control group and the high-concentration drug group were photographed with a PICO microscope to observe the killing of OVCAR3 cells by NK92MI cells. When a significant difference in killing activity was observed between the two groups, the co-culture was discontinued. The culture medium was discarded, and the cells were gently washed once with 100 μL of PBS. 100 μL of 4% PFA was added to each well, and the cells were fixed at room temperature for 20 minutes, followed by gentle washing once with PBS. 100 μL of 4% PFA was added to each well, and the cells were fixed at room temperature for 20 minutes, followed by gentle washing once with PBS. The fluorescent signals of the samples were detected in the FITC channel of a microplate reader. The fluorescent signals were compared with the DMSO group to determine the inhibition rate and IC 50 was calculated.

[0398] Biological Example 3: In vivo pharmacokinetic studies of compounds of the present disclosure Six- to eight-week-old CD-1 female mice were intravenously administered 2 mg / kg of the compound. Mice were fasted for at least 12 hours before administration, and were allowed food after administration and water ad libitum throughout the experiment. On the day of the experiment, animals in the intravenous administration group received a single injection of the corresponding compound via the tail vein at 0.2 mL per animal. Sample collection times were 0.083, 0.167, 0.5, 1, 2, 4, 8, and 24 hours. Approximately 150 μL of whole blood was collected from the submandibular venous plexus at each time point (30 μL of whole blood was diluted 1:3 with ultrapure water, and 120 μL of whole blood was centrifuged to obtain plasma) and used for concentration measurement by high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). After the final PK sample was collected, all animals were sacrificed. Plasma concentrations were treated using a non-compartmental model in the pharmacokinetic software Phoenix WinNonlin™ version 8.3 (Certara), and pharmacokinetic parameters were calculated using the log-linear trapezoidal method. The in vivo pharmacokinetic results are shown in Tables 4 and 5 below.

[0399] [Table 4]

[0400] [Table 5]

[0401] Biological Example 4: In vivo Pharmacodynamic Studies - Mouse MC38 Subcutaneous Xenograft Tumor Model Each C57BL / 6 mouse received 1 × 10 MC38 cells. 6 The tumor was subcutaneously injected and grew to 100-200 mm 3At the time of tumor growth, tumors were administered with vehicle alone (intravenous injection twice weekly), the compound alone (intravenous injection twice weekly), anti-PD-1 antibody alone (intravenous injection once weekly), anti-VEGF antibody alone (intraperitoneal injection once weekly), a combination of anti-PD-1 antibody (intravenous injection once weekly) and anti-VEGF antibody (intraperitoneal injection once weekly), the compound (intravenous injection twice weekly) and anti-PD-1 antibody (intravenous injection once weekly), the compound (intravenous injection twice weekly) and anti-VEGF antibody (intraperitoneal injection once weekly), or the compound (intravenous injection twice weekly), anti-PD-1 antibody (intravenous injection once weekly) and anti-VEGF antibody (intraperitoneal injection once weekly). Tumor volumes were measured twice weekly and at the end of treatment. The tumor growth inhibition rate of the compound was calculated as follows: Tumor growth inhibition rate (TGI) = 1 - (tumor volume of treatment group on day 20 - tumor volume of treatment group on day 1) / (tumor volume of vehicle control group on day 20 - tumor volume of treatment group on day 1).

[0402] Biological Example 5: In vivo Pharmacodynamic Studies - Mouse MC38 Subcutaneous Xenograft Tumor Model Each C57BL / 6 mouse received 1 × 10 MC38 cells. 6 The tumor was subcutaneously injected and grew to 50-80 mm 3 At the time of tumor growth, tumors were administered with vehicle alone (intravenous injection twice weekly), the compound alone (intravenous injection twice weekly), anti-PD-1 antibody alone (intravenous injection once weekly), anti-VEGF antibody alone (intraperitoneal injection once weekly), a combination of anti-PD-1 antibody (intravenous injection once weekly) and anti-VEGF antibody (intraperitoneal injection once weekly), the compound (intravenous injection twice weekly) and anti-PD-1 antibody (intravenous injection once weekly), the compound (intravenous injection twice weekly) and anti-VEGF antibody (intraperitoneal injection once weekly), or the compound (intravenous injection twice weekly), anti-PD-1 antibody (intravenous injection once weekly) and anti-VEGF antibody (intraperitoneal injection once weekly). Tumor volumes were measured twice weekly and at the end of treatment. The tumor growth inhibition rate of the compound was calculated as follows: Tumor growth inhibition rate (TGI) = 1 - (tumor volume of treatment group on day 20 - tumor volume of treatment group on day 1) / (tumor volume of vehicle control group on day 20 - tumor volume of treatment group on day 1).

[0403] Biological Example 6: In vivo Pharmacodynamic Studies - Mouse MC38 Subcutaneous Xenograft Tumor Model Each C57BL / 6 mouse received 1 × 10 MC38 cells. 6 Mice were subcutaneously inoculated with the cells and treated immediately after cell inoculation. The following treatments were administered: vehicle alone (intravenous injection twice weekly), compound alone (intravenous injection twice weekly), anti-PD-1 antibody alone (intravenous injection once weekly), anti-VEGF antibody alone (intraperitoneal injection once weekly), a combination of anti-PD-1 antibody (intravenous injection once weekly) and anti-VEGF antibody (intraperitoneal injection once weekly), the compound (intravenous injection twice weekly) and anti-PD-1 antibody (intravenous injection once weekly), the compound (intravenous injection twice weekly) and anti-VEGF antibody (intraperitoneal injection once weekly), or the compound (intravenous injection twice weekly), anti-PD-1 antibody (intravenous injection once weekly) and anti-VEGF antibody (intraperitoneal injection once weekly). Tumor volumes were measured twice weekly and at the end of treatment. The tumor growth inhibition rate of the compound was calculated as follows: Tumor growth inhibition rate (TGI) = 1 - (tumor volume of treatment group on day 20 - tumor volume of treatment group on day 1) / (tumor volume of vehicle control group on day 20 - tumor volume of treatment group on day 1).

[0404] Biological Example 7: In vivo Pharmacodynamic Studies - Mouse CT26 Subcutaneous Xenograft Tumor Model Each BALB / c mouse received 2 × 10 CT26 cells. 5 The tumor was subcutaneously injected and grew to 100-200 mm 3At the time of tumor growth, tumors were treated with vehicle alone (intravenous injection twice weekly), compound alone (intravenous injection twice weekly), anti-PD-1 antibody alone (intravenous injection once weekly), anti-VEGF antibody alone (intraperitoneal injection once weekly), a combination of anti-PD-1 antibody (intravenous injection once weekly) and anti-VEGF antibody (intraperitoneal injection once weekly), the compound (intravenous injection twice weekly) and anti-PD-1 antibody (intravenous injection once weekly), the compound (intravenous injection twice weekly) and anti-VEGF antibody (intraperitoneal injection once weekly), or the compound (intravenous injection twice weekly), anti-PD-1 antibody (intravenous injection once weekly) and anti-VEGF antibody (intraperitoneal injection once weekly). Tumor volumes were measured twice weekly and at the end of treatment. The tumor growth inhibition rate of the compound was calculated as follows: Tumor growth inhibition rate (TGI) = 1 - (tumor volume of treatment group on day 20 - tumor volume of treatment group on day 1) / (tumor volume of vehicle control group on day 20 - tumor volume of treatment group on day 1).

[0405] Biological Example 8: In vivo Pharmacodynamic Studies - Mouse CT26 Subcutaneous Xenograft Tumor Model Each BALB / c mouse received 2 × 10 CT26 cells. 5 The tumor was subcutaneously injected and grew to 50-80 mm 3 At the time of tumor growth, tumors were treated with vehicle alone (intravenous injection twice weekly), compound alone (intravenous injection twice weekly), anti-PD-1 antibody alone (intravenous injection once weekly), anti-VEGF antibody alone (intraperitoneal injection once weekly), a combination of anti-PD-1 antibody (intravenous injection once weekly) and anti-VEGF antibody (intraperitoneal injection once weekly), the compound (intravenous injection twice weekly) and anti-PD-1 antibody (intravenous injection once weekly), the compound (intravenous injection twice weekly) and anti-VEGF antibody (intraperitoneal injection once weekly), or the compound (intravenous injection twice weekly), anti-PD-1 antibody (intravenous injection once weekly) and anti-VEGF antibody (intraperitoneal injection once weekly). Tumor volumes were measured twice weekly and at the end of treatment. The tumor growth inhibition rate of the compound was calculated as follows: Tumor growth inhibition rate (TGI) = 1 - (tumor volume of treatment group on day 20 - tumor volume of treatment group on day 1) / (tumor volume of vehicle control group on day 20 - tumor volume of treatment group on day 1).

[0406] Biological Example 9: In vivo Pharmacodynamics Study - Mouse CT26 Subcutaneous Xenograft Tumor Model Each BALB / c mouse received 2 × 10 CT26 cells. 5 Mice were subcutaneously inoculated with the cells and treated immediately after cell inoculation. The following treatments were administered: vehicle alone (intravenous injection twice weekly), compound alone (intravenous injection twice weekly), anti-PD-1 antibody alone (intravenous injection once weekly), anti-VEGF antibody alone (intraperitoneal injection once weekly), a combination of anti-PD-1 antibody (intravenous injection once weekly) and anti-VEGF antibody (intraperitoneal injection once weekly), the compound (intravenous injection twice weekly) and anti-PD-1 antibody (intravenous injection once weekly), the compound (intravenous injection twice weekly) and anti-VEGF antibody (intraperitoneal injection once weekly), or the compound (intravenous injection twice weekly), anti-PD-1 antibody (intravenous injection once weekly) and anti-VEGF antibody (intraperitoneal injection once weekly). Tumor volumes were measured twice weekly and at the end of treatment. The tumor growth inhibition rate of the compound was calculated as follows: Tumor growth inhibition rate (TGI) = 1 - (tumor volume of treatment group on day 20 - tumor volume of treatment group on day 1) / (tumor volume of vehicle control group on day 20 - tumor volume of treatment group on day 1).

[0407] Biological Example 10: In vivo Pharmacodynamic Studies - Mouse A20 Subcutaneous Xenograft Tumor Model Each BALB / c mouse received 2 × 10 A20 cells. 6 The tumor was subcutaneously injected and grew to 100-200 mm 3At the time of tumor growth, tumors were treated with vehicle alone (intravenous injection twice weekly), compound alone (intravenous injection twice weekly), anti-PD-1 antibody alone (intravenous injection once weekly), anti-VEGF antibody alone (intraperitoneal injection once weekly), a combination of anti-PD-1 antibody (intravenous injection once weekly) and anti-VEGF antibody (intraperitoneal injection once weekly), the compound (intravenous injection twice weekly) and anti-PD-1 antibody (intravenous injection once weekly), the compound (intravenous injection twice weekly) and anti-VEGF antibody (intraperitoneal injection once weekly), or the compound (intravenous injection twice weekly), anti-PD-1 antibody (intravenous injection once weekly) and anti-VEGF antibody (intraperitoneal injection once weekly). Tumor volumes were measured twice weekly and at the end of treatment. The tumor growth inhibition rate of the compound was calculated as follows: Tumor growth inhibition rate (TGI) = 1 - (tumor volume of treatment group on day 20 - tumor volume of treatment group on day 1) / (tumor volume of vehicle control group on day 20 - tumor volume of treatment group on day 1).

[0408] Biological Example 11: In vivo Pharmacodynamic Studies - Mouse A20 Subcutaneous Xenograft Tumor Model Each BALB / c mouse received 2 × 10 A20 cells. 6 The tumor was subcutaneously injected and grew to 50-80 mm 3 At the time of tumor growth, tumors were treated with vehicle alone (intravenous injection twice weekly), compound alone (intravenous injection twice weekly), anti-PD-1 antibody alone (intravenous injection once weekly), anti-VEGF antibody alone (intraperitoneal injection once weekly), a combination of anti-PD-1 antibody (intravenous injection once weekly) and anti-VEGF antibody (intraperitoneal injection once weekly), the compound (intravenous injection twice weekly) and anti-PD-1 antibody (intravenous injection once weekly), the compound (intravenous injection twice weekly) and anti-VEGF antibody (intraperitoneal injection once weekly), or the compound (intravenous injection twice weekly), anti-PD-1 antibody (intravenous injection once weekly) and anti-VEGF antibody (intraperitoneal injection once weekly). Tumor volumes were measured twice weekly and at the end of treatment. The tumor growth inhibition rate of the compound was calculated as follows: Tumor growth inhibition rate (TGI) = 1 - (tumor volume of treatment group on day 20 - tumor volume of treatment group on day 1) / (tumor volume of vehicle control group on day 20 - tumor volume of treatment group on day 1).

[0409] Biological Example 12: In vivo Pharmacodynamic Studies - Mouse A20 Subcutaneous Xenograft Tumor Model Each BALB / c mouse received 2 × 10 A20 cells. 6 Mice were subcutaneously inoculated with the cells and treated immediately after cell inoculation. The following treatments were administered: vehicle alone (intravenous injection twice weekly), compound alone (intravenous injection twice weekly), anti-PD-1 antibody alone (intravenous injection once weekly), anti-VEGF antibody alone (intraperitoneal injection once weekly), a combination of anti-PD-1 antibody (intravenous injection once weekly) and anti-VEGF antibody (intraperitoneal injection once weekly), the compound (intravenous injection twice weekly) and anti-PD-1 antibody (intravenous injection once weekly), the compound (intravenous injection twice weekly) and anti-VEGF antibody (intraperitoneal injection once weekly), or the compound (intravenous injection twice weekly), anti-PD-1 antibody (intravenous injection once weekly) and anti-VEGF antibody (intraperitoneal injection once weekly). Tumor volumes were measured twice weekly and at the end of treatment. The tumor growth inhibition rate of the compound was calculated as follows: Tumor growth inhibition rate (TGI) = 1 - (tumor volume of treatment group on day 20 - tumor volume of treatment group on day 1) / (tumor volume of vehicle control group on day 20 - tumor volume of treatment group on day 1).

[0410] Biological Example 13: In vivo Pharmacodynamics Study - Mouse B16F10-OVA Subcutaneous Xenograft Tumor Model On days 14, 11, 7, and 4 before inoculation with B16F10-OVA cells, each C57BL / 6 mouse was administered with the vehicle alone (intravenous injection), the compound alone (intravenous injection), ovalbumin alone (intravenous injection), an anti-PD-1 antibody alone (intravenous injection), an anti-VEGF antibody alone (intraperitoneal injection), the compound (intravenous injection) in combination with ovalbumin (intravenous injection), an anti-PD-1 antibody (intravenous injection) and an anti-VEGF antibody (intraperitoneal injection), the compound (intravenous injection) in combination with an anti-PD-1 antibody (intravenous injection) and an anti-VEGF antibody (intraperitoneal injection), the compound (intravenous injection) in combination with an anti-PD-1 antibody (intravenous injection), the compound (intravenous injection) The following combinations were administered to C57BL / 6 mice: a combination of this compound (intravenous injection), an anti-PD-1 antibody (intravenous injection), and an anti-VEGF antibody (intraperitoneal injection); a combination of this compound (intravenous injection), an anti-PD-1 antibody (intravenous injection), and ovalbumin (intravenous injection); a combination of this compound (intravenous injection), an anti-VEGF antibody (intraperitoneal injection), and ovalbumin (intravenous injection); a combination of this compound (intravenous injection), an anti-PD-1 antibody (intravenous injection), and an anti-VEGF antibody (intraperitoneal injection); and a combination of this compound (intravenous injection), an anti-PD-1 antibody (intravenous injection), an anti-VEGF antibody (intraperitoneal injection), and ovalbumin (intravenous injection). 6 B16F10-OVA cells were subcutaneously inoculated, and tumor volumes were measured twice a week and at the end of administration. The tumor growth inhibition rate of the compound was calculated as follows: TGI = 1 - (tumor volume on day 20 in the treatment group - tumor volume on day 1 in the treatment group) / (tumor volume on day 20 in the vehicle control group - tumor volume on day 1 in the treatment group).

[0411] Although specific embodiments of the present disclosure have been described above, it will be understood by those skilled in the art that these embodiments are merely examples and that many changes or modifications can be made to these embodiments without departing from the principles and spirit of the present disclosure. Therefore, the scope of protection of the present disclosure is defined by the appended claims.

Claims

1. A compound of general formula (1), or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof. 【Chemical 1】 (In general formula (1), Y is —O—, —CH ２ - or -N(H)-; R ａ is -H, -F, -NH ２ or —OH; R ａ’ is —H or —F, and R ａ Ga-NH ２ or in the case of —OH, R ａ’ is —H; R ｂ is —H or (C1-C4) alkyl; R ｃ is —H or (C1-C4) alkyl; R ｄ is -H, halogen, -CF ３ or (C1-C4) alkyl; X １ is C(H), C(F), or N; X ２ is S or O; X ３ is C(R ｘ３ ) or N; R ｘ３ is —H, halogen, or —CH ３ and X ４ is S, O, C(R ｘ４１ ) (R ｘ４１’ ), or N(R ｘ４２ ) and R ｘ４２ is —H, (C1-C4) alkyl, or (C3-C5) cycloalkyl; R ｘ４１ and R ｘ４１’ are each independently optionally selected from -H, halogen, -OH, -OR ｘ４１１ , -N(R ｘ４１１ ) (R ｘ４１２ ), —CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C9)cycloalkyl, or (C1-C6)alkoxy; R ｘ４１１ and R ｘ４１２ are each independently optionally —H, (C1-C4) alkyl, or (C3-C5) cycloalkyl, or R ｘ４１１ and R ｘ４１２ may, together with the N atom to which they are attached, form a (3- to 6-membered) heterocycloalkyl, wherein said (3- to 6-membered) heterocycloalkyl may be optionally substituted with 1, 2, 3, or 4 groups of —H or halogen; R ３ and R ４ are each independently optionally selected from -H, -D, -OH, -NH ２ , —CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C1-C6) alkoxy, (C6-C14) aryl, (3- to 11-membered) heterocycloalkyl, or (5- to 11-membered) heteroaryl, wherein the (C1-C6) alkyl, the (C1-C6) haloalkyl, the (C2-C6) alkenyl, the (C2-C6) alkynyl, the (C3-C9) cycloalkyl, the (C1-C6) alkoxy, the (C6-C14) aryl, the (3- to 11-membered) heterocycloalkyl, or the (5- to 11-membered) heteroaryl are each independently —H, halogen, —OH, —(CH ２ ) ｒ OR ３１ , -(CH ２ ) ｒ NR ３１ R ３２ , -OR ３１ , -NR ３１ R ３２ , -CN, -C(O)NR ３１ R ３２ , -NR ３２ C(O)R ３１ , -NR ３２ S (O) ２ R ３１ , -S(O) ｐ R ３１ , and -S(O) ２ NR ３１ R ３２ optionally substituted with one, two, three, or four groups selected from the group consisting of ３ and R ４ may, together with the carbon atoms to which they are attached, form a (4- to 7-membered) heterocycloalkyl or a (C3-C6) cycloalkyl, wherein said (4- to 7-membered) heterocycloalkyl or said (C3-C6) cycloalkyl is optionally substituted with 1, 2, 3, or 4 groups of —H, halogen, (C1-C6) alkyl, or (C1-C6) alkoxy; or R ３ and adjacent R ５ may, together with the atoms to which they are attached, form a (C3-C9)cycloalkyl or a (3- to 11-membered)heterocycloalkyl, wherein said (C3-C9)cycloalkyl or said (3- to 11-membered)heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 groups of —H, halogen, (C1-C6)alkyl, or (C1-C6)alkoxy; or R ３ and adjacent R ５ When both are absent, an endocyclic double bond is formed; or when R ３ and R ４ together form oxo; R ５ and R ６ are each independently optionally selected from -H, -D, -OH, -NH ２ , —CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C1-C6) alkoxy, (C6-C14) aryl, (3- to 11-membered) heterocycloalkyl, or (5- to 11-membered) heteroaryl, wherein the (C1-C6) alkyl, the (C1-C6) haloalkyl, the (C2-C6) alkenyl, the (C2-C6) alkynyl, the (C3-C9) cycloalkyl, the (C1-C6) alkoxy, the (C6-C14) aryl, the (3- to 11-membered) heterocycloalkyl, or the (5- to 11-membered) heteroaryl are each independently —H, halogen, —OH, —(CH ２ ) ｒ OR ３１ , -(CH ２ ) ｒ NR ３１ R ３２ , -OR ３１ , -NR ３１ R ３２ , -CN, -C(O)NR ３１ R ３２ , -NR ３２ C(O)R ３１ , -NR ３２ S (O) ２ R ３１ , -S(O) ｐ R ３１ , and -S(O) ２ NR ３１ R ３２ optionally substituted with one, two, three, or four groups selected from the group consisting of ５ and R ６ may, together with the carbon atoms to which they are attached, form a (4-7 membered) heterocycloalkyl or a (C3-C6) cycloalkyl, wherein said (4-7 membered) heterocycloalkyl or said (C3-C6) cycloalkyl is optionally substituted with one, two, three, or four of —H, halogen, (C1-C6) alkyl, and (C1-C6) alkoxy; or R ５ and R ６ together form oxo; Ring A is a (C6-C10)aryl or (5-10 membered)heteroaryl; Each R １ are independently optionally selected from -H, halogen, -OH, -NO ２ , -NR ３１ R ３２ , -(CH ２ ) ｒ OR ３１ , -(CH ２ ) ｒ NR ３１ R ３２ , —CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, —C(O)NR ３１ R ３２ , -NR ３２ C(O)R ３１ , -NR ３２ S (O) ２ R ３１ , -S(O) ｐ R ３１ , or -S(O) ２ NR ３１ R ３２ wherein the (C1-C6) alkyl, the (C1-C6) haloalkyl, the (C1-C6) alkoxy, the (C2-C6) alkenyl, the (C2-C6) alkynyl, or the (C3-C8) cycloalkyl are each independently —H, halogen, —OH, —(CH ２ ) ｒ OR ３１ , -(CH ２ ) ｒ NR ３１ R ３２ , -OR ３１ , -NR ３１ R ３２ , —CN, and (C1-C6) alkyl; Ring B is (C5-C7)cycloalkyl or (5-7 membered)heterocycloalkyl; Each R ２ are independently optionally selected from -H, halogen, -OH, -NR ３１ R ３２ , —CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C2-C6) alkenyl, (C2-C6) alkynyl, or (C3-C8) cycloalkyl; or two R on the same carbon atom. ２ may together with the carbon atoms to which they are attached form a (4-6 membered) heterocycloalkyl or a (C3-C6) cycloalkyl, wherein said (4-6 membered) heterocycloalkyl or said (C3-C6) cycloalkyl may be optionally substituted with 1, 2, 3, or 4 groups selected from —H, halogen, (C1-C6) alkyl, and (C1-C6) alkoxy; or two R on the same carbon atom ２ together form oxo; R ３１ and R ３２ are each independently optionally —H, (C1-C4) alkyl, or (C3-C5) cycloalkyl, or R ３１ and R ３２ may, together with the N atom to which they are attached, form a (3- to 6-membered) heterocycloalkyl, wherein said (3- to 6-membered) heterocycloalkyl may be optionally substituted with 1, 2, 3, or 4 groups selected from —H and halogen; and n is an integer selected from 0, 1, 2, 3, or 4; m is an integer selected from 0, 1, 2, 3, or 4; r is an integer selected from 0, 1, or 2; and p is an integer selected from 0, 1, or 2.

2. In the general formula (1), R ｄ -H, -F, -CF ３ , or -CH ３ 2. The compound according to claim 1, wherein:

3. In the general formula (1), R ｘ４２ is —H, (C1-C3) alkyl, or (C3-C5) cycloalkyl, or an isomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof according to claim 1 or 2.

4. In the general formula (1), R ｘ４２ But, -H, 【Chemistry 2】 4. The compound according to claim 3, wherein:

5. In the general formula (1), R ｘ４１ and R ｘ４１’ each independently optionally represents —H, —F, —OH, —OCH ３ , -N(CH ３ ) ２ , -NH ２ , -CN, 【Chemistry 3】 、-CF ３ 、-CH ２ CF ３ 、 【Chemistry 4】 5. The compound according to any one of claims 1 to 4, wherein:

6. In the general formula (1), R ３ and R ４ each independently optionally represents —H, —D, —OH, —NH ２ , —CN, (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C5) cycloalkyl, (C1-C3) alkoxy, phenyl, (4-6 membered) heterocycloalkyl, or (5-6 membered) heteroaryl, wherein said (C1-C3) alkyl, said (C1-C3) haloalkyl, said (C2-C4) alkenyl, said (C2-C4) alkynyl, said (C3-C5) cycloalkyl, said (C1-C3) alkoxy, said phenyl, said (4-6 membered) heterocycloalkyl, or said (5-6 membered) heteroaryl are each independently optionally selected from —H, —F, —OH, —CH ２ OCH ３ , -CH ２ N (CH ３ ) ２ , -OCH ３ , -N(CH ３ ) ２ , -CN, -C(O)N(CH ３ ) ２ , -NCH ３ C(O)CH ３ , -NHC(O)CH ３ , -NCH ３ S (O) ２ CH ３ , -NHS(O) ２ CH ３ , -SCH ３ , -S(O) ２ CH ３ , -S(O) ２ NH ２ , and -S(O) ２ N (CH ３ ) ２ or optionally substituted with one, two, three, or four groups selected from R ３ and R ４ may together with the carbon atoms to which they are attached form a (4- to 6-membered) heterocycloalkyl or a (C3-C4) cycloalkyl, wherein said (4- to 6-membered) heterocycloalkyl or said (C3-C4) cycloalkyl is -H, -F, 【Chemistry 5】 , or -OCH ３ or R ３ and adjacent R ５ together with the atoms to which they are attached may form a (C3-C6)cycloalkyl or a (3- to 6-membered)heterocycloalkyl, wherein said (C3-C6)cycloalkyl or said (3- to 6-membered)heterocycloalkyl are each independently -H, -F, 【Chemistry 6】 , or -OCH ３ or R ３ and adjacent R ５ When both are absent, an endocyclic double bond is formed; alternatively, R ３ and R ４ and R are independently selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 6

7. In the general formula (1), R ５ and R ６ each independently optionally represents —H, —D, —OH, —NH ２ , —CN, (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C5) cycloalkyl, (C1-C3) alkoxy, phenyl, (4-6 membered) heterocycloalkyl, or (5-6 membered) heteroaryl, wherein the (C1-C3) alkyl, the (C1-C3) haloalkyl, the (C2-C4) alkenyl, the (C2-C4) alkynyl, the (C3-C5) cycloalkyl, the (C1-C3) alkoxy, the phenyl, the (4-6 membered) heterocycloalkyl, or the (5-6 membered) heteroaryl are each independently —H, —F, —OH, —CH ２ OCH ３ , -CH ２ N (CH ３ ) ２ , -OCH ３ , -N(CH ３ ) ２ , -NH ２ , -CN, -C(O)N(CH ３ ) ２ , -NCH ３ C(O)CH ３ , -NHC(O)CH ３ , -NCH ３ S (O) ２ CH ３ , -NHS(O) ２ CH ３ , -SCH ３ , -S(O) ２ CH ３ , -S(O) ２ NH ２ , and -S(O) ２ N (CH ３ ) ２ or optionally substituted with one, two, three, or four groups selected from R ５ and R ６ may together with the carbon atoms to which they are attached form a (4- to 6-membered) heterocycloalkyl or a (C3-C4) cycloalkyl, wherein said (4- to 6-membered) heterocycloalkyl or said (C3-C4) cycloalkyl is selected from the group consisting of -H, -F, 【Chemistry 7】 or -OCH ３ or R ５ and R ６ and R are independently selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 6

8. The compound according to any one of claims 1 to 7, wherein, in general formula (1), ring A is phenyl or (5- to 6-membered) heteroaryl, or an isomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof.

9. In the general formula (1), ring A is 【Chemistry 8】 9. The compound according to claim 8, wherein:

10. In general formula (1), each R １ are independently optionally selected from —H, —F, —Cl, —Br, —I, —OH, —NO ２ , -N(CH ３ ) ２ , -NH ２ , -CH ２ OCH ３ , -CH ２ N (CH ３ ) ２ , —CN, (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, —C(O)N(CH ３ ) ２ , -NCH ３ C(O)CH ３ , -NHC(O)CH ３ , -NCH ３ S (O) ２ CH ３ , -NHS(O) ２ CH ３ , -SCH ３ , -S(O) ２ CH ３ , -S(O) ２ NH ２ , and -S(O) ２ N (CH ３ ) ２ wherein the (C1-C3) alkyl, the (C1-C3) haloalkyl, the (C1-C3) alkoxy, the (C2-C4) alkenyl, the (C2-C4) alkynyl, or the (C3-C6) cycloalkyl is each independently —H, —F, —OH, —CH ２ OCH ３ , -CH ２ N (CH ３ ) ２ , -OCH ３ , -N(CH ３ ) ２ , -NH ２ , -CN, 【Chemistry 9】 or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, optionally substituted with 1, 2, 3, or 4 groups selected from the group consisting of:

11. In the general formula (1), each R １ are independently —H, —F, —Cl, —Br, —I, —OH, or —NO ２ , -N(CH ３ ) ２ , -NH ２ , -CH ２ OCH ３ , -CH ２ N (CH ３ ) ２ , -CN, -C(O)N(CH ３ ) ２ , -NCH ３ C(O)CH ３ , -NHC(O)CH ３ , -NCH ３ S (O) ２ CH ３ , -NHS(O) ２ CH ３ , -SCH ３ , -S(O) ２ CH ３ , -S(O) ２ NH ２ , -S(O) ２ N (CH ３ ) ２ , 【Chemistry 10】 、-CF ３ 、-CH ２ CF ３ 、 【Chemistry 11】 ,-OCH ３ 、-OCH ２ CH ３ ,-OCH(CH ３ ) ２ 、 【Chemistry 12】 11. The compound according to claim 10, wherein:

12. The compound according to any one of claims 1 to 11, wherein, in the general formula (1), ring B is (C5-C6)cycloalkyl or (5- to 6-membered)heterocycloalkyl, or an isomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof.

13. In the general formula (1), the structural unit: 【Chemistry 13】 but, 【Chemistry 14】 13. The compound according to claim 12, wherein:

14. In the general formula (1), the structural unit: 【Chemistry 15】 but, 【Chemistry 16】 13. The compound according to claim 12, wherein:

15. In the general formula (1), each R ２ are independently optionally selected from -H, -F, -Cl, -Br, -I, -OH, -N(CH ３ ) ２ , -NH ２ , —CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, (C2-C4)alkenyl, (C2-C4)alkynyl, or (C3-C5)cycloalkyl; or two R on the same carbon atom. ２ may together with the carbon atoms to which they are attached form a (4- to 5-membered) heterocycloalkyl or a (C3-C5) cycloalkyl, wherein said (4- to 5-membered) heterocycloalkyl or said (C3-C5) cycloalkyl is selected from the group consisting of -H, -F, 【Chemistry 17】 and -OCH ３ or two R on the same carbon atom; ２ and R are independently selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 3

16. In the general formula (1), each R ２ are independently optionally selected from -H, -F, -Cl, -Br, -I, -OH, -N(CH ３ ) ２ , -NH ２ , -CN, 【Chemistry 18】 、-CF ３ 、-CH ２ CF ３ 、 【Chemistry 19】 、-OCH ３ 、-OCH ２ CH ３ ,-OCH(CH ３ ) ２ 、 【Chemistry 20】 16. The compound according to claim 15, wherein:

17. In the general formula (1), the structural unit: 【Chemical 21】 but, 【Chemistry 22-1】 【Chemistry 22-2】 【Chemistry 22-3】 17. The compound according to any one of claims 1 to 16, wherein:

18. In the general formula (1), the structural unit: 【Chemical 23】 but, 【Chemistry 24】 17. The compound according to any one of claims 1 to 16, wherein:

19. In the general formula (1), the structural unit: 【Chemistry 25】 but, 【Chemistry 26-1】 【Chemistry 26-2】 【Chemistry 26-3】 【Chemistry 26-4】 17. The compound according to any one of claims 1 to 16, wherein:

20. The compound has the following structure: 【Chemistry 27-1】 【Chemistry 27-2】 【Chemistry 27-3】 【Chemistry 27-4】 20. The compound of claim 1, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, having one of the following formula:

21. The compound has the following structure: 【Chemical Formula 28】 20. The compound of claim 1, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, having one of the following formula:

22. The compound has the following structure: 【Chemistry 29-1】 【Chemistry 29-2】 【Chemistry 29-3】 【Chemistry 29-4】 【Chemistry 29-5】 【Chemistry 29-6】 【Chemistry 29-7】 【Chemistry 29-8】 【Chemistry 29-9】 【Chemistry 29-10】 20. The compound of claim 1, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, having one of the following formula:

23. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and, as an active ingredient, a compound according to any one of claims 1 to 22 or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.

24. Use of a compound described in any one of claims 1 to 22, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, or a pharmaceutical composition described in claim 23, in the preparation of a medicament for treating a related disease mediated by an SAE protein.

25. 25. The use according to claim 24, wherein the disease is cancer, and the cancer is a blood cancer or a solid cancer.

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