Compounds as SUMO-activating enzyme inhibitors

Abstract

A compound represented by general formula (1) and a preparation method thereof, and uses of the compound represented by general formula (1) and isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof as SAE inhibitors, the compound and the isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof can be used for preparing medicines for treating or preventing SAE protein related diseases. # imgabs0 #

Description

Compounds that act as inhibitors of SUMO-activating enzymes

[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. This application incorporates the entirety of the aforementioned Chinese patent applications. Technical Field

[0002] The present invention belongs to the field of medicinal chemistry, and more specifically, relates to a class of compounds having SAE protein inhibitory effects, as well as a preparation method thereof and the use of such compounds in preparing drugs for treating or preventing SAE-mediated related diseases. Background Art

[0003] Small ubiquitin-like modifiers (SUMOs) are ubiquitin-like proteins that are reversible intracellular post-translational modifiers of proteins. Mammalian cells express three SUMO family proteins: SUMO1, SUMO2, and SUMO3. SUMO2 and SUMO3 share approximately 95% amino acid sequence homology and primarily form oligomeric chains when modifying proteins. SUMO1 shares approximately 45% sequence homology with SUMO2 and SUMO3 and primarily modifies proteins as monomers. Target protein SUMOylation occurs through a three-step, enzyme-catalyzed reaction that activates, transfers, and ultimately attaches the SUMO protein to a lysine residue on the target protein. SAE (Sumo Activating Enzyme) catalyzes the first step. SAEs belong to a class of activating enzymes collectively known as E1s and are heterodimers formed by SAE1, SAE2, or UBA2. SAE uses 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. SUMO is then transferred from E1 to a SUMO-conjugating enzyme (collectively referred to as E2) via thioester exchange. Finally, under the action of a SUMO-specific E3 protein ligase, SUMO is ultimately transferred to a lysine residue on the target protein, forming an oligomeric chain. Protein SUMOylation affects its catalytic activity, intracellular localization, and protein-protein interactions. Recent studies have shown that protein SUMOylation plays an important role in various cellular signaling pathways, such as cell division and DNA repair, chromosome segregation, nuclear transport, gene transcription, and immune regulation. Overexpression of proteins involved in the SUMO signaling pathway is associated with poor prognosis in certain cancer patients. Knockdown of SAE has a synthetic lethal effect in certain MYC-overexpressing tumor cells. SUMOylation also modulates innate immune responses. Inhibition of SUMOylation can enhance the expression of type 1 interferon (IFN). In summary, there is an urgent need to study and discover compounds with good targeting activity against SAE.

[0004] Summary of the Invention

[0005] The present invention provides a compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0006] In the general formula (1):

[0007] Y is -O-, -CH2- or -N(H)-;

[0008] R a is -H, -F, -NH2 or -OH;

[0009] R a’ is -H or -F, and when R a When it is -NH2 or -OH, R a’ is -H;

[0010] R b is -H or (C1-C4)alkyl;

[0011] R c is -H or (C1-C4)alkyl;

[0012] R d is -H, halogen, -CF3 or (C1-C4) alkyl;

[0013] X 1 is C(H), C(F) or N;

[0014] X 2 is S or O;

[0015] X 3 C(R x3 ) or N;

[0016] R x3 is -H, halogen or -CH3;

[0017] X 4 S, O, C (R x41 )(R x41’ ) or N(R x42 );

[0018] R x42 is -H, (C1-C4)alkyl or (C3-C5)cycloalkyl;

[0019] R x41 and R x41’ Each independently 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;

[0020] R x411 and R x412 Each independently selected from -H, (C1-C4) alkyl or (C3-C5) cycloalkyl, or R on the same nitrogen atom x411and R x412 Together with the N atom to which they are attached, they can form a (3-6 membered) heterocycloalkyl group, wherein the (3-6 membered) heterocycloalkyl group may be optionally substituted by 1, 2, 3 or 4 of the following groups: -H or halogen;

[0021] R 3 and R 4 each independently optionally being -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 said (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 may each independently be optionally substituted with 1, 2, 3, or 4 of the following groups: -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)2NR 31 R 32 ; or R 3 and R 4 The carbon atoms to which they are attached can together form a (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group, wherein the (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group may be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, (C1-C6) alkyl or (C1-C6) alkoxy; or R 3 and adjacent R 5 The atoms to which they are attached can together form a (C3-C9) cycloalkyl group or a (3-11 membered) heterocycloalkyl group, wherein said (C3-C9) cycloalkyl group or (3-11 membered) heterocycloalkyl group can each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, (C1-C6) alkyl group or (C1-C6) alkoxy group; or when R3 and adjacent R 5 When both are absent, an intracyclic double bond is formed; or R 3 and R 4 Together they form an oxo group.

[0022] R 5 and R 6 each independently optionally being -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 said (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 may each independently be optionally substituted with 1, 2, 3, or 4 of the following groups: -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)2NR 31 R 32 ; or R 5 and R 6 The carbon atoms to which they are attached can together form a (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group, wherein the (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group may be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, (C1-C6) alkyl and (C1-C6) alkoxy; or R 5 and R 6 Together they form an oxo group.

[0023] Ring A is (C6-C10)aryl or (5-10 membered)heteroaryl;

[0024] Each R 1Each independently 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)2NR 31 R 32 wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl or (C3-C8)cycloalkyl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, -OH, -(CH2) r OR 31 、-(CH2) r NR 31 R 32 、-OR 31 、-NR 31 R 32 , -CN and (C1-C6) alkyl;

[0025] Ring B is (C5-C7)cycloalkyl or (5-7 membered)heterocycloalkyl;

[0026] Each R 2 Each independently 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 The carbon atoms to which they are attached can together form a (4-6 membered) heterocycloalkyl or (C3-C6) cycloalkyl group, wherein the (4-6 membered) heterocycloalkyl or (C3-C6) cycloalkyl group may be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, (C1-C6) alkyl and (C1-C6) alkoxy; or two R on the same carbon atom 2Together they form an oxo group.

[0027] R 31 and R 32 Each independently selected from -H, (C1-C4) alkyl or (C3-C5) cycloalkyl, or R on the same nitrogen atom 31 and R 32 Together with the N atom to which they are attached, they can form a (3-6 membered) heterocycloalkyl group, wherein the (3-6 membered) heterocycloalkyl group may be optionally substituted with 1, 2, 3 or 4 of the following groups: -H and halogen; and

[0028] n is an integer of 0, 1, 2, 3 or 4, m is an integer of 0, 1, 2, 3 or 4, r is an integer of 0, 1 or 2, and p is an integer of 0, 1 or 2.

[0029] In another preferred embodiment, in the general formula (1), Y is -O- or -N(H)-, preferably -O-.

[0030] In another preferred embodiment, wherein in the general formula (1), R d It is -H, -F, -CF3 or -CH3.

[0031] In another preferred embodiment, wherein in the general formula (1), R x42 is -H, (C1-C3)alkyl or (C3-C5)cycloalkyl.

[0032] In another preferred embodiment, wherein in the general formula (1), R x42 For -H,

[0033] In another preferred embodiment, wherein in the general formula (1), R x41 and R x41’ Each is independently selected from -H, -F, -OH, -OCH3, -N(CH3)2, -NH2, -CN, -CF3, -CH2CF3,

[0034] In another preferred embodiment, wherein in the general formula (1), R 3 and R 4Each is 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 the (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 Heterocycloalkyl or (5-6 membered)heteroaryl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -F, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2, -CN, -C(O)N(CH3)2, -NCH3C(O)CH3, -NHC(O)CH3, -NCH3S(O)2CH3, -NHS(O)2CH3, -SCH3, -S(O)2CH3, -S(O)2NH2 and -S(O)2N(CH3)2; or R 3 and R 4 The carbon atoms to which they are attached can together form a (4-6 membered) heterocycloalkyl or (C3-C4) cycloalkyl group, wherein the (4-6 membered) heterocycloalkyl or (C3-C4) cycloalkyl group can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, or -OCH3; or R 3 and adjacent R 5 The atoms to which they are attached can together form a (C3-C6) cycloalkyl group or a (3-6 membered) heterocycloalkyl group, wherein the (C3-C6) cycloalkyl group or the (3-6 membered) heterocycloalkyl group can each be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, or -OCH3; or when R 3 and adjacent R 5 When both are absent, an intracyclic double bond is formed; or R 3 and R 4 Together they form an oxo group.

[0035] In another preferred embodiment, wherein in the general formula (1), R 5 and R 6Each is 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 the (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 R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, 5 and R 6 The carbon atoms to which they are attached can together form a (4-6 membered) heterocycloalkyl or (C3-C4) cycloalkyl group, wherein the (4-6 membered) heterocycloalkyl or (C3-C4) cycloalkyl group can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, or -OCH3; or R 5 and R 6 Together they form an oxo group.

[0036] In another preferred embodiment, in the general formula (1), ring A is a phenyl group or a (5-6 membered) heteroaryl group.

[0037] In another preferred embodiment, in the general formula (1), ring A is phenyl, pyridyl, furyl, thienyl, thiazolyl, imidazolyl, or oxazolyl; preferably phenyl and pyridyl.

[0038] In another preferred embodiment, wherein in the general formula (1), ring A is:

[0039] In another preferred embodiment, wherein in the general formula (1), each R 1Each is independently selected from: -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, -NHS( -S(O)2CH3, -SCH3, -S(O)2CH3, -S(O)2NH2 and -S(O)2N(CH3)2, wherein the (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, (C2-C4)alkenyl, (C2-C4)alkynyl or (C3-C6)cycloalkyl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -F, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2, -NH2, -CN,

[0040] In another preferred embodiment, wherein in the general formula (1), each R 1 are independently: -H, -F, -Cl, -Br, -I, -OH, -NO2, -N(CH3)2, -NH2, -CH2OCH3, -CH2N(CH3)2, -CN, -C(O)N(CH3)2, -NCH3C(O)CH3, -NHC(O)CH3, -NCH3S(O)2CH3, -NHS(O)2CH3, -SCH3, -S(O)2CH3, -S(O)2NH2, -S(O)2N(CH3)2, -CF3, -CH2CF3, -OCH3, -OCH2CH3, -OCH(CH3)2,

[0041] In another preferred embodiment, in the general formula (1), ring B is a (C5-C6)cycloalkyl group or a (5-6 membered)heterocycloalkyl group.

[0042] In another preferred embodiment, in the general formula (1), ring B is a (C5-C6)cycloalkyl group or a (5-6 membered)heterocycloalkyl group containing one ring heteroatom independently selected from nitrogen, oxygen or sulfur.

[0043] In another preferred embodiment, wherein in the general formula (1), the structural unit for:

[0044] In another preferred embodiment, wherein in the general formula (1), the structural unit for:

[0045] In another preferred embodiment, wherein in the general formula (1), each R 2 Each independently selected from: -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 2 The carbon atoms to which they are attached can together form a (4-5 membered) heterocycloalkyl or (C3-C5) cycloalkyl, wherein the (4-5 membered) heterocycloalkyl or (C3-C5) cycloalkyl can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, and -OCH3; or two R on the same carbon atom 2 Together they form an oxo group.

[0046] In another preferred embodiment, wherein in the general formula (1), each R 2 Each independently selected from: -H, -F, -Cl, -Br, -I, -OH, -N(CH3)2, -NH2, -CN, -CF3, -CH2CF3, -OCH3, -OCH2CH3, -OCH(CH3)2,

[0047] In another preferred embodiment, wherein in the general formula (1), the structural unit for:

[0048] In another preferred embodiment, wherein in the general formula (1), the structural unit for:

[0049] In another preferred embodiment, wherein in the general formula (1), the structural unit for:

[0050] In another preferred embodiment, wherein the general formula (1) has a structure as shown in the general formula (1a):

[0051] Among them, 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 The definitions of m and n are as described above and are illustrated in the specific embodiments.

[0052] In another preferred embodiment, wherein the general formula (1) has a structure as shown in the general formula (2a):

[0053] Among them, 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 The definitions of m and n are as described above and are illustrated in the specific embodiments.

[0054] In another preferred embodiment, wherein the general formula (1) has a structure as shown in general formula (3a):

[0055] Among them, ring A, ring B, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R a 、R a’ 、R b 、R c 、X 1 、X 4 The definitions of m and n are as described above and are illustrated in the specific embodiments.

[0056] In another preferred embodiment, wherein the general formula (1) has a structure as shown in general formula (4a):

[0057] Among them, 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 The definitions of m and n are as described above and are illustrated in the specific embodiments.

[0058] In another preferred embodiment, wherein the general formula (1) has a structure as shown in general formula (5a):

[0059] Among them, ring A, ring B, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R b 、X 1 、X 4 The definitions of m and n are as described above and are illustrated in the specific embodiments.

[0060] In another preferred embodiment, wherein the general formula (1) has a structure as shown in general formula (6a):

[0061] Among them, ring A, ring B, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、X 4 The definitions of m and n are as described above and are illustrated in the specific embodiments.

[0062] In another preferred embodiment, wherein the general formula (1) has a structure as shown in general formula (7a) or (7b):

[0063] Among them, ring A, ring B, R 1 、R 2 、R 3 、R 4 、R 5 、R6 、X 4 The definitions of m and n are as described above and are illustrated in the specific embodiments.

[0064] In another specific embodiment of the present invention, the compound of formula (1) has one of the following structures:

[0065] Another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent and / or excipient, and a compound of the general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.

[0066] Another object of the present invention is to provide the use of the compound represented by general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition thereof, for preparing a medicament for treating, regulating or preventing a disease associated with an SAE protein. The disease is preferably cancer, and the cancer is a blood cancer or a solid tumor.

[0067] Another object of the present invention is to provide a method for treating, regulating or preventing diseases related to SAE proteins, comprising administering to a subject a therapeutically effective amount of a compound represented by the general formula (1) of the present invention, or its isomers, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical composition.

[0068] By synthesizing and carefully studying a variety of new compounds having SAE inhibitory effects, the inventors found that among the compounds of formula (1), the compounds unexpectedly have strong SAE inhibitory activity.

[0069] It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

[0070] Synthesis of compounds

[0071] The following specifically describes the preparation methods of the compound of general formula (1) of the present invention, but these specific methods do not constitute any limitation to the present invention.

[0072] The compounds of formula (1) described above can be synthesized using standard synthetic techniques or known techniques in combination with the methods described herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein may vary. The starting materials used in the synthesis of the compounds can be synthesized or obtained from commercial sources. The compounds described herein and other related compounds having different substituents can be synthesized using known techniques and starting materials, including those found 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), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed., (Wiley 1999). The general methods for the preparation of compounds can be modified by using appropriate reagents and conditions to introduce various groups into the formulae provided herein.

[0073] On the one hand, the compounds described herein are based on methods known in the art. However, the conditions of the method, such as reactants, solvents, bases, the amounts of the compounds used, reaction temperature, reaction time, etc. are not limited to the following explanations. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art. On the one hand, the present invention also provides a method for preparing the compound of the general formula (1), wherein the compound of the general formula (1) can be prepared using 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:

[0074] General reaction scheme 1

[0075] The embodiment of the compound of formula (1) can be prepared according to the general reaction scheme 1, wherein P is R b or hydroxyl protecting group, 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, X 4a represents O or S, and L represents O or NH. As shown in General Reaction Scheme 1, compound 1-1 and compound 1-2 undergo a substitution reaction to form an alcohol intermediate, which is further oxidized to produce ketone compound 1-3. Compound 1-3 and compound 1-4 undergo a substitution reaction to produce compound 1-5. Compound 1-5 further undergoes a substitution reaction with compound 1-6 to produce compound 1-7. In some cases, compound 1-7 is deprotected from the hydroxyl protecting group to produce compound 1-8. In some cases, compound 1-8 is subjected to chiral resolution to produce optical isomers 1-A and 1-B.

[0076] General reaction scheme 2

[0077] The embodiment of the compound of formula (1) can be prepared according to the general reaction scheme 2, wherein P is R b or a hydroxyl protecting group, P' is an amine protecting group, 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 and compound 2-2 undergo a substitution reaction to form an alcohol intermediate, which is further oxidized to produce ketone compound 2-3. Compound 2-3 and compound 2-4 undergo a substitution reaction to produce compound 2-5. Compound 2-5 further undergoes a substitution reaction with compound 2-6 to produce compound 2-7. In some cases, compound 2-7 is deprotected to produce compound 2-8. In some cases, compound 2-8 is subjected to chiral resolution to produce optical isomers 2-A and 2-B.

[0078] General reaction scheme 3

[0079] Embodiments of compounds of formula (1) can be prepared according to general reaction scheme 3, wherein R 1and 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 and nitromethane undergo condensation reaction to produce compound 3-2, compound 3-2 is reduced to produce amine 3-3, amine 3-3 and ketone 3-4 undergo condensation to produce compound 3-5, compound 3-5 undergoes cyclization reaction under acidic conditions to produce compound 3-6, compound 3-6 is demethylated to produce compound 3-7, compound 3-7 reacts with PhNTf2 to produce compound 3-8, compound 3-8 is reduced to produce compound 3-9, compound 3-9 is deformylated to produce compound 3-10, compound 3-10 is protected with (Boc)2O to produce compound 3-11, and compound 3-11 reacts with DMF under n-butyllithium conditions. Aldehyde 3-12 is obtained, and aldehyde 3-12 undergoes addition reaction with compound 3-13 under n-butyllithium conditions to obtain compound 3-14. Compound 3-14 is subjected to Dess-Martin oxidation or Swern oxidation to obtain ketone 3-15. Ketone 3-15 undergoes substitution reaction with compound 3-16 under alkaline conditions to produce compound 3-17. Compound 3-17 reacts with compound 3-18 to produce compound 3-19. Compound 3-19 is deprotected with TBAF to obtain compound 3-20. Compound 3-20 is deaminated under acidic conditions to obtain compound 3-21. In some cases, compound 3-21 is subjected to chiral resolution to obtain optical isomers 3-A and 3-B.

[0080] General reaction scheme 4

[0081] Embodiments of compounds of formula (1) can be prepared according to general reaction scheme 4, wherein 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 4, compound 4-1 and nitromethane undergo condensation reaction to produce compound 4-2, compound 4-2 is reduced to produce amine 4-3, amine 4-3 and ketone 4-4 undergo condensation to produce compound 4-5, compound 4-5 reacts with acetic anhydride to produce compound 4-6, compound 4-6 undergoes cyclization reaction under Pd catalysis to produce compound 4-7, compound 4-7 is deacetylated to produce compound 4-8, compound 4-8 is protected with (Boc)2O to produce compound 4-9, compound 4-9 undergoes hydrogenation reaction to produce compound 4-10, and compound 4-10 reacts with DMF under n-butyllithium to produce aldehyde 4 -11, aldehyde 4-11 undergoes 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 undergoes substitution reaction with compound 4-15 under alkaline conditions to produce compound 4-16, compound 4-16 reacts with compound 4-17 to produce compound 4-18, compound 4-18 is deprotected with TBAF to obtain compound 4-19, and compound 4-19 is deaminated under acidic conditions to obtain compound 4-20. In some cases, compound 4-20 is subjected to chiral resolution to obtain optical isomers 4-A and 4-B.

[0082] General Reaction Scheme 5

[0083] Embodiments of compounds of formula (1) can be prepared according to general reaction scheme 5, wherein 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 and nitromethane undergo condensation reaction to produce compound 5-2, compound 5-2 is reduced to produce amine 5-3, amine 5-3 and ketone 5-4 undergo condensation to produce compound 5-5, compound 5-5 reacts with acetic anhydride to produce compound 5-6, compound 5-6 undergoes cyclization reaction under Pd catalysis to produce compound 5-7, compound 5-7 is deacetylated to produce compound 5-8, compound 5-8 is protected with (Boc)2O to produce compound 5-9, compound 5-9 reacts with DMF under n-butyllithium to produce aldehyde 5-10, aldehyde 5-10 is reacted with DMF under n-butyllithium Under the condition of lithium, an addition reaction occurs with compound 5-11 to obtain compound 5-12, compound 5-12 is oxidized by Dess-Martin to obtain ketone 5-13, ketone 5-13 undergoes a substitution reaction with compound 5-14 under alkaline conditions to produce compound 5-15, compound 5-15 reacts with compound 5-16 to produce compound 5-17, compound 5-17 is deprotected with TBAF to obtain compound 5-18, compound 5-18 is deaminated under acidic conditions to obtain compound 5-19, and in some cases, compound 5-19 is subjected to chiral resolution to obtain optical isomers 5-A and 5-B.

[0084] General Reaction Scheme 6

[0085] Embodiments of compounds of formula (1) can be prepared according to general reaction scheme 6, wherein 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 6, compound 6-1 undergoes a condensation reaction with nitromethane to produce compound 6-2, compound 6-2 is reduced to produce amine 6-3, amine 6-3 is condensed with ketone 6-4 to produce compound 6-5, compound 6-5 reacts with acetic anhydride to produce compound 6-6, compound 6-6 undergoes a cyclization reaction under Pd-catalyzed conditions to produce compound 6-7, compound 6-7 is deacetylated to produce compound 6-8, compound 6-8 is protected with (Boc)2O to produce compound 6-9, compound 6-9 is oxidized with potassium osmate and sodium periodate to produce dialdehyde 6-10, dialdehyde 6-10 is reduced with sodium borohydride to produce diol 6-11, diol 6-11 undergoes a cyclization reaction under acidic conditions to produce compound 6-12, and compound 6-1 is protected with (Boc)2O. 2 to obtain compound 6-13, compound 6-13 reacts with DMF under n-butyllithium to obtain aldehyde 6-14, aldehyde 6-14 reacts with compound 6-15 under n-butyllithium to obtain compound 6-16, compound 6-16 is subjected to Dess-Martin oxidation or Swern oxidation to obtain ketone 6-17, ketone 6-17 and compound 6-18 undergo substitution reaction under alkaline conditions to obtain compound 6-19, compound 6-19 reacts with compound 6-20 to obtain compound 6-21, compound 6-21 is deprotected with TBAF to obtain compound 6-22, compound 6-22 is deaminated under acidic conditions to obtain compound 6-23, in some cases, compound 6-23 is subjected to chiral resolution to obtain optical isomers 6-A and 6-B.

[0086] General reaction scheme 7

[0087] Embodiments of compounds of formula (1) can be prepared according to general reaction scheme 7, wherein 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 and nitromethane undergo condensation reaction to produce compound 7-2, compound 7-2 is reduced to produce amine 7-3, amine 7-3 is condensed with ketone 7-4 to produce compound 7-5, compound 7-5 reacts with acetic anhydride to produce compound 7-6, compound 7-6 undergoes cyclization reaction under Pd catalysis to produce compound 7-7, compound 7-7 is deacetylated to produce compound 7-8, compound 7-8 is protected with (Boc)2O to produce compound 7-9, compound 7-9 is oxidized under potassium osmate and sodium periodate to produce dialdehyde 7-10, dialdehyde 7-10 undergoes reductive amination reaction to produce amine 7-11, compound 7-11 is catalyzed by n-butyl lithium. The aldehyde 7-12 is reacted with DMF, and the aldehyde 7-12 undergoes an addition reaction with the compound 7-13 under n-butyl lithium to obtain the compound 7-14. The compound 7-14 is subjected to Dess-Martin oxidation or Swern oxidation to obtain the ketone 7-15. The ketone 7-15 undergoes a substitution reaction with the compound 7-16 under alkaline conditions to produce the compound 7-17. The compound 7-17 reacts with the compound 7-18 to produce the compound 7-19. The compound 7-19 is deprotected with TBAF to obtain the compound 7-20. The compound 7-20 is deaminated under acidic conditions to obtain the compound 7-21. In some cases, the compound 7-21 is subjected to chiral resolution to obtain the optical isomers 7-A and 7-B.

[0088] Further forms of compounds

[0089] "Pharmaceutically acceptable" as used herein refers to a substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., a substance that does not cause undesirable biological effects or interact in a deleterious manner with any of its components when administered to a subject.

[0090] The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain specific aspects, pharmaceutically acceptable salts are obtained by reacting a compound of the formula with an acid or base, wherein the acid or base includes, but is not limited to, those found in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use 1. st Acids and Bases in Ed., (Wiley, 2002).

[0091] It should be understood that references to pharmaceutically acceptable salts include solvent-added forms or crystallized forms, particularly solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of compounds of formula (1) are conveniently prepared or formed according to the methods described herein. For example, hydrates of compounds of formula (1) are conveniently prepared by recrystallization from a mixed solvent of water / organic solvent, using organic solvents including, but not limited to, tetrahydrofuran, acetone, ethanol or methanol. In addition, the compounds mentioned herein can exist in unsolvated and solvated forms. In general, for the purposes of the compounds and methods provided herein, the solvated forms are considered to be equivalent to the unsolvated forms.

[0092] In other embodiments, the compound of formula (1) is prepared in different forms, including but not limited to, amorphous, crushed and nano-particle forms. In addition, the compound of formula (1) includes crystalline forms and can also be polymorphic. Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs generally have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystalline form to dominate.

[0093] In another aspect, compounds of formula (1) may have chiral centers and / or axial chirality and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers, and cis-trans isomers. Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially purified compounds are included within the scope of the present invention. The present invention is intended to include all such isomeric forms of these compounds.

[0094] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) and C-14( 14 C). For example, deuterated compounds can be formed by replacing hydrogen atoms with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs generally have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug half-life in vivo. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0095] Unless otherwise specified, any reference to an atom in the compounds of the present invention refers to its stable atomic isotope. Unless otherwise specified, when a position in a molecular structure is designated as "H" or "hydrogen," such position should be understood to have the natural abundance of the hydrogen isotope. Similarly, when a position is designated as "D" or "deuterium," such position should be understood to have a deuterium isotope abundance at least 3000 times its natural abundance (the natural abundance of the deuterium isotope is 0.015%).

[0096] More preferably, the deuterium atom abundance at each deuterated site of the deuterated compound of the present invention is at least 3500 times its natural abundance (52.2% deuterium atom enrichment). More preferably, it is at least 4500 times (67.5% deuterium atom enrichment). More preferably, it is at least 5000 times (75% deuterium atom enrichment). More preferably, it is at least 6000 times (90% deuterium atom enrichment). More preferably, it is at least 6333 times (95% deuterium atom enrichment). More preferably, it is at least 6466.7 times (97% deuterium atom enrichment). More preferably, it is at least 6600 times (99% deuterium atom enrichment). More preferably, it is at least 6633.3 times (99.5% deuterium atom enrichment).

[0097] the term

[0098] Unless otherwise indicated, the terms used in this application, including the specification and claims, are defined as follows. It should be noted that, throughout the specification and the appended claims, the singular forms "a," "an," and "an" include plural referents unless the context clearly indicates otherwise. Conventional methods, such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology, are employed unless otherwise indicated. Throughout this application, the use of "or" or "and" means "and / or," unless otherwise indicated.

[0099] Unless otherwise specified, "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 6 carbon atoms. Preferred are lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from CH3, CH3CH2, CF3, CHF2, CF3CH2, CF3(CH3)CH, i Pr, n Pr, i Bu, n Bu or t Bu.

[0100] Unless otherwise specified, "alkylene" refers to a divalent alkyl group as defined above. Examples of alkylene groups include, but are not limited to, methylene and ethylene.

[0101] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched groups of 1 to 14 carbon atoms. Preferred are lower alkenyl groups containing 1 to 4 carbon atoms, such as ethenyl, 1-propenyl, 1-butenyl, or 2-methylpropenyl. More preferred are lower alkenyl groups containing 1 to 2 carbon atoms.

[0102] Unless otherwise specified, "alkenylene" refers to a divalent alkenyl group as defined above.

[0103] Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight-chain and branched groups having 1 to 14 carbon atoms. Preferred are lower alkynyl groups having 1 to 4 carbon atoms, such as ethynyl, 1-propynyl, or 1-butynyl. More preferred are lower alkynyl groups having 1 to 2 carbon atoms.

[0104] Unless otherwise specified, "alkynylene" refers to a divalent alkynyl group as defined above.

[0105] 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, the cycloalkyl group has 3-10 ring carbon atoms (C 3-10 In some embodiments, a cycloalkyl group has 3-8 ring carbon atoms (C 3-8 In some embodiments, the cycloalkyl group has 3-7 ring carbon atoms (C 3-7 In some embodiments, the cycloalkyl group has 3-6 ring carbon atoms (C 3-6 In some embodiments, the cycloalkyl group has 4-6 ring carbon atoms (C 4-6 In some embodiments, the cycloalkyl group has 5-6 ring carbon atoms (C 5-6 In some embodiments, a cycloalkyl group has 5-10 ring carbon atoms (C 5-10Cycloalkyl). If the carbocyclic ring contains at least one double bond, the partially unsaturated cycloalkyl group may be referred to as a "cycloalkenyl group," or if the carbocyclic ring contains at least one triple bond, the partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl group." Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocycles. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is bicyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is tricyclic. The ring-forming carbon atoms of the cycloalkyl group may optionally be oxidized to form an oxo or thio group. Cycloalkyl groups also include cycloalkylene groups. In some embodiments, the cycloalkyl group contains 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl group contains 1 or 2 double bonds (partially unsaturated cycloalkyl groups). In some embodiments, the cycloalkyl group may be fused with an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocycloalkyl group. In some embodiments, the cycloalkyl group may be fused with an aryl group, a cycloalkyl group, and a heterocycloalkyl group. In some embodiments, cycloalkyl groups can be fused with aryl groups and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl groups and cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaryl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like.

[0106] Unless otherwise specified, "cycloalkylene" refers to a divalent cycloalkyl group as defined above.

[0107] Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the rest of the molecule through 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 groups, especially those substituted with one or more halogens. Preferred alkoxy groups are selected from OCH3, OCF3, CHF2O, CF3CH2O, i- PrO, n- PrO, i- BuO, n- BuO or t- BuO.

[0108] Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group. Aryl is monocyclic or polycyclic, for example, a monocyclic aryl ring fused to one or more carbocyclic aromatic groups. Examples of aryl include, but are not limited to, phenyl, naphthyl, and phenanthrenyl.

[0109] Unless otherwise specified, "aryloxy" refers to an aryl group bonded to the rest of the molecule through an ethereal oxygen atom. Examples of aryloxy groups include, but are not limited to, phenoxy and naphthoxy.

[0110] Unless otherwise specified, "arylene" refers to a divalent aromatic radical as defined above. Examples of arylene radicals include, but are not limited to, phenylene, naphthylene, and phenanthrenylene.

[0111] Unless otherwise specified, "heteroaryl" refers to a substituted or unsubstituted aromatic group containing one or more heteroatoms, preferably a 5-14 membered aromatic group containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, more preferably a 5-9 membered aromatic group containing 1-2 heteroatoms selected from oxygen, sulfur or nitrogen, the heteroatoms being independently selected from O, N or S, and the number of heteroatoms being preferably 1, 2 or 3. The heteroaryl group is monocyclic or polycyclic. The monocyclic heteroaryl group is preferably a 5-6 membered aromatic group containing 1-3 heteroatoms selected from oxygen, nitrogen or sulfur. More preferably, it is a 5-6 membered aromatic group containing 1-2 heteroatoms selected from oxygen, nitrogen or sulfur. More preferably, it is a 5-6 membered aromatic group containing 1 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 groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, 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,

[0112] Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl group as defined above.

[0113] Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen and selenium, preferably a saturated or partially unsaturated ring containing 1-4 heteroatoms selected from oxygen, sulfur or nitrogen, more preferably a saturated or partially unsaturated ring containing 1-2 heteroatoms selected from oxygen, sulfur or nitrogen. In some embodiments, heterocycloalkyl is a 5-8 membered non-aromatic ring containing ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen or sulfur (5-8 membered heterocycloalkyl). Heterocycloalkyl is a 5-6 membered non-aromatic ring containing ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen or sulfur (5-6 membered heterocycloalkyl). In some embodiments, 5-6 membered heterocycloalkyl contains 1-3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, 5-6 membered heterocycloalkyl contains 1-2 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, 5-6 membered heterocycloalkyl contains 1 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. If heterocycloalkyl contains at least one double bond, then partially unsaturated heterocycloalkyl can be referred to as "heterocycloalkenyl", or if heterocycloalkyl contains at least one triple bond, then partially unsaturated heterocycloalkyl can be referred to as "heterocycloalkynyl". Heterocycloalkyl can include monocyclic, bicyclic, spirocyclic or polycyclic (e.g., having two fused or bridged rings) ring systems. In certain embodiments, heterocycloalkyl is a monocyclic group having 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. The ring-forming carbon atoms and heteroatoms of heterocycloalkyl can be optionally oxidized to form oxo or thioxo or other oxidized bonds (e.g., C(O), S(O), C(S) or S(O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized. Heterocycloalkyl can be connected via ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, heterocycloalkyl contains 0 to 3 double bonds. In some embodiments, heterocycloalkyl contains 0 to 2 double bonds. The definition of heterocycloalkyl also includes a portion (also referred to as partially unsaturated heterocycle) of an aromatic ring having one or more fused to the heterocycloalkyl ring (i.e., sharing a key therewith), such as a benzo derivative of piperidine, morpholine, azacycloheptatriene or thienyl. The heterocycloalkyl containing a fused aromatic ring can be connected via any ring-forming atom, including the ring-forming atom of the fused aromatic ring.Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanediyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydro-1H-imidazole , 4-nitro-2-nitro-1-pyridine, 4 ...1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine,

[0114] Unless otherwise specified, "heterocycloalkylene" refers to a divalent heterocycloalkyl group as defined above.

[0115] Unless otherwise specified, "oxo" refers to =0; for example, a carbonyl group substituted with an oxo group is a "carbonyl group." "; the group formed by sulfur being replaced by an oxo group is called "sulfinyl" ", the group formed by sulfur being substituted by two oxo groups is called "sulfonyl" ”.

[0116] Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substituted") appearing before the name of a group indicates that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably substituted by F or Cl.

[0117] Unless otherwise specified, the term "substituted" refers to a substituent group other than one or more hydrogen atoms on a specified atom or group that is substituted by one or more hydrogen atoms, without exceeding the normal valence of the specified atom. For example, one or more hydrogen atoms of an alkyl, alkylene, alkenyl, alkynyl, hydroxyl or amido group can be substituted by one or more substituent groups. Wherein the substituent group includes but is not limited to alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxylate, cyano, guanidino, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclic radical, hydroxyl, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, mercaptan, thioketone or its combination. The definition of "substituted" does not include similar indefinite structures obtained by defining a substituent group having a further substituent group attached to infinity (for example, a substituted aryl group itself substituted by a substituted aryl group with a substituted alkyl group, which is further substituted by a substituted heteroalkyl group, etc.). Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, a substituted aryl group is continuously substituted by two other substituted aryls to an aryl group substituted by ((substituted aryl) substituted aryl). Similarly, the above definition does not include substitution patterns that are not allowed (for example, a methyl group substituted by 5 fluorines or a heteroaryl group with two adjacent oxygen ring atoms). This substitution pattern that is not allowed is well known to those skilled in the art. Whenever used to modify a chemical group, "substituted" can describe other chemical groups defined herein. For example, the term "substituted aryl" includes but is not limited to "alkyl aryl". Unless otherwise specified, if a group is described as optionally substituted, any substituent of the group itself is unsubstituted.

[0118] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0119] Unless otherwise specified, it will be understood that the word "comprise", or variations such as "comprises" or "comprising", imply the inclusion of a stated element or integer, or group of elements or integers, but not the exclusion of any other element or integer, or group of elements or integers.

[0120] The substituent "-O-CH2-O-" refers to the substituent in which two oxygen atoms are connected to two adjacent carbon atoms of a heterocycloalkyl, aryl or heteroaryl group, for example:

[0121] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a single bond.

[0122] When one of the variables is selected from a chemical bond, it means that the two groups it connects are directly connected. For example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0123] The term "membered ring" includes any cyclic structure. The term "membered" refers to the number of atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, and thiopyranyl are six-membered rings, while cyclopentyl, pyrrolyl, furanyl, and thiophenyl are five-membered rings.

[0124] The term "fragment" refers to a specific part or functional group of a molecule. A chemical fragment is generally considered to be a chemical entity contained in or attached to a molecule.

[0125] The term "isomer" means any tautomer, stereoisomer, atropisomer, isotopomer, enantiomer or diastereomer of any compound of the present invention. The compounds of the present invention may have one or more chiral centers or double bonds and therefore exist in stereoisomeric forms, for example, double bond isomers (i.e., E / Z geometric isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). Therefore, the compounds of the present invention encompass all corresponding stereoisomers, i.e., stereoisomerically pure (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) forms as well as enantiomers and stereoisomer mixtures, such as racemates. Enantiomeric and stereoisomeric mixtures of the compounds of the present invention can be separated into their component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high performance liquid chromatography, and crystallization of the compounds as chiral salt complexes or crystallization of the compounds in chiral solvents. Enantiomers and stereoisomers can also be obtained from stereoisomerically pure or enantiomerically pure intermediates, reagents and catalysts by well-known asymmetric synthetic methods.

[0126] The term "isotopomers" refers to different molecules whose structures differ only in one isotope but are otherwise identical.

[0127] The term "atropisomer" refers to a conformational stereoisomer produced when rotation about a single bond within a molecule is prevented or greatly slowed due to steric interactions with other parts of the molecule and the substituents at either end of the single bond are asymmetric, i.e., atropisomers do not require a stereocenter. When the barrier to rotation about the single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation of the individual isomers is permitted (LaPlante et al., J. Med. Chem. 2011, 54, 20, 7005), preferably by chiral resolution.

[0128] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond or straight dashed key

[0129] Unless otherwise stated, Indicates a single bond or a double bond.

[0130] Specific pharmaceutical and medical terms

[0131] The term "acceptable," as used herein, means that a prescribed ingredient or active ingredient has no undue adverse effect on health and well-being for the general purpose of treatment.

[0132] The terms "treat," "treatment," or "therapy" as used herein include alleviating, inhibiting, or ameliorating the symptoms of a disease or condition; inhibiting the development of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing a regression of a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating signs caused by a disease or symptom. As used herein, a compound or pharmaceutical composition, upon administration, can improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration. Whether the administration is fixed or temporary, continuous or intermittent, the circumstances attributable to or related to the administration can be explained.

[0133] "Active ingredient" refers to the compound of formula (1), as well as pharmaceutically acceptable inorganic or organic salts of the compound of formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and therefore appear in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. The asymmetric centers that may exist depend on the properties of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

[0134] The terms "compound," "composition," "agent," or "medicine or medicament" are used interchangeably herein and refer to a compound or composition that, when administered to a subject (human or animal), induces a desired pharmaceutical and / or physiological response through local and / or systemic action.

[0135] The term "administered," "administering," or "administration" as used herein refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound.

[0136] Although the numerical ranges and parameters used to define the broader scope of the present invention are approximate, the numerical values ​​of the specific examples are presented herein as precisely as possible. However, any numerical value inherently and inevitably contains standard deviations resulting from individual testing methods. As used herein, "about" generally refers to the actual value being within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the mean, as determined by one skilled in the art. Except in the experimental examples, or unless otherwise expressly indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe material amounts, time periods, temperatures, operating conditions, quantitative ratios, and the like) are to be understood as modified by the word "about." Therefore, unless otherwise indicated, the numerical parameters disclosed in this specification and the appended claims are approximate and may be modified as needed. At a minimum, these numerical parameters should be understood to include the number of significant digits indicated and to include normal rounding.

[0137] Unless otherwise defined in this specification, the scientific and technical terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, unless otherwise defined in this specification, singular terms used in this specification include the plural form of the term, and plural terms also include the singular form of the term, unless otherwise defined in the context.

[0138] Therapeutic uses

[0139] The compounds of formula (1) or pharmaceutical compositions of the present invention are generally useful for inhibiting SAE proteins and are therefore useful for treating one or more conditions associated with SAE protein activity. Therefore, in certain embodiments, the present invention provides a method for treating conditions mediated by SAE proteins, comprising administering a compound of formula (1) or a pharmaceutically acceptable composition thereof to a patient in need thereof.

[0140] In some embodiments, a method for treating cancer is provided, comprising administering to a subject in need thereof an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound of 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 syndrome) and solid tumors (cancers such as prostate, breast, lung, colon, pancreas, kidney, ovary and soft tissue cancer and osteosarcoma, as well as stromal tumors), preferably lung cancer, cervical cancer, colorectal 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.

[0141] Route of administration

[0142] The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into various formulations containing a safe and effective amount of the compounds of the present invention or their pharmaceutically acceptable salts and a pharmacologically acceptable excipient or carrier. "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 will be determined based on the patient's age, condition, and duration of treatment, among other factors.

[0143] "Pharmaceutically acceptable excipients or carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0144] The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.

[0145] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0146] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0147] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0148] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0149] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0150] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0151] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0152] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When using a pharmaceutical composition, a safe and effective amount of the compounds of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health status, all of which are within the skill of a skilled physician.

[0153] The features described above, or in the embodiments, may be combined in any combination. All features disclosed in this specification may be used in any combination, and each feature disclosed in this specification may be replaced by any alternative feature that serves the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the features disclosed are merely general examples of equivalent or similar features. DETAILED DESCRIPTION

[0154] The following description will elaborate on various specific aspects, characteristics, and advantages of the above-mentioned compounds, methods, and pharmaceutical compositions so that the present invention will be readily apparent. It should be understood that the following detailed description and examples describe specific embodiments and are provided for reference only. After reading the present description, those skilled in the art may make various changes or modifications to the present invention, and such equivalents are within the scope of the present invention.

[0155] In all embodiments, 1 H-NMR was recorded on a Varian Mercury 400 nuclear magnetic resonance instrument, and chemical shifts are expressed in δ (ppm). Silica gel used for separation was 200-300 mesh unless otherwise specified, and the eluent ratios were all by volume.

[0156] The present invention uses the following abbreviations: (Boc)2O represents di-tert-butyl dicarbonate; CDCl3 represents deuterated chloroform; (COCl)2 represents oxalyl chloride; Cs2CO3 represents cesium carbonate; EtOAc represents ethyl acetate; Hexane represents n-hexane; HPLC represents high performance liquid chromatography; MeCN represents acetonitrile; DCM represents dichloromethane; DIPEA represents diisopropylethylamine; Dioxane represents 1,4-dioxane; DME represents ethylene glycol dimethyl ether; DMF represents N,N-dimethylformamide; DMAP represents 4-(dimethylamino)pyridine; DMSO represents dimethyl sulfoxide; EtOH represents ethanol; hr represents hour; IPA represents isopropyl alcohol; =Biotage Isolera Prime rapid preparative liquid chromatograph; min = minute; K2CO3 = potassium carbonate; KOAc = potassium acetate; KOH = potassium hydroxide; K3PO4 = potassium phosphate; LiBH4 = lithium borohydride; LiHMDS = lithium bis(trimethylsilylamide); min = minute; MeOH = methanol; MeONa = sodium methoxide; MS = mass spectrometry; NaBH(OAc)3 = sodium triacetoxyborohydride; NaH = sodium hydrogen; n-BuLi = n-butyllithium; NMR = nuclear magnetic resonance; NIS = iodosuccinimide; PBST = phosphate buffered saline with Tween; Pd / C = palladium on carbon; Pd(PPh3)4 = tetrakistriphenylphosphine palladium; Pd(OAc2) = acetic acid Palladium; Pd(dppf)Cl2 stands for [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride; Pd(dtbpf)Cl2 stands for 1,1-bis(di-tert-butylphosphino)ferrocenepalladium dichloride; PE stands for petroleum ether; PFA stands for paraformaldehyde; PhNTf2 stands for N-phenylbis(trifluoromethylsulfonyl)imide; PPh3 stands for triphenylphosphine; TEA stands for triethylamine; TFA stands for trifluoroacetic acid; TMSCl stands for trimethylchlorosilane; TsOH stands for p-toluenesulfonic acid; XantPhos stands for 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; TfOH stands for trifluoromethanesulfonic acid; TLC stands for thin-layer chromatography; XPhos stands for 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0157] Example 1 Synthesis of Compound 1

[0158] Step 1: Synthesis of compound int_1-3:

[0159] Dissolve int_1-1 (2.8 g, 22.99 mmol) and int_1-2 (3.5 g, 22.99 mmol, 454.55 uL) in Ti(i-PrO)4 (20 mL). The atmosphere was purged with nitrogen three times. The mixture was heated to 80°C and stirred for 2 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature and used directly in the next reaction.

[0160] ESI-MS m / z:256[M+H] + .

[0161] Step 2: Synthesis of compound int_1-4:

[0162] At 0°C, HCOOH (78 mL) was slowly added dropwise to Ac2O (194 mL). After the addition was complete, the reaction mixture was allowed to react at 20°C for 0.5 hours. The int_1-3 solution obtained in step 1 was then cooled to -10°C, and the HOOCH and Ac2O mixture was slowly added dropwise to the int_1-3 solution, maintaining the temperature at -10°C. After the addition was complete, the reaction mixture was heated to 80°C and reacted for 2 hours. LC-MS monitoring indicated that the reaction was complete. The reaction mixture was used directly in the next reaction.

[0163] ESI-MS m / z:284[M+H] + .

[0164] Step 3: Synthesis of compound int_1-5:

[0165] At 70 ° C, TFA (316 mL) was slowly added to the int_1-4 solution obtained in step 2 over 1 hour, cooled to, and the mixture was stirred at 70 ° C for 3 hours. LC-MS monitoring showed that the reaction was complete. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was adjusted to a weak alkaline state with sodium bicarbonate aqueous solution (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 obtain a crude product, which was purified by column chromatography (SiO2, PE / EtOAc=4 / 1) to obtain a solid (3.5 g, yield: 48.6%).

[0166] ESI-MS m / z:284[M+H] + .

[0167] Step 4: Synthesis of compound int_1-6:

[0168] Int_1-5 (1.2 g, 4.23 mmol) was dissolved in THF (20 mL) and cooled to -30°C. Under nitrogen, n-BuLi (2.5 M, 3.38 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to react at -30°C for 2 hours. LC-MS monitoring indicated the reaction was complete. After the reaction mixture warmed to room temperature, saturated aqueous ammonium chloride (20 mL) was added to the reaction mixture. 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 a crude product, which was used directly in the next reaction.

[0169] ESI-MS m / z:256[M+H] + .

[0170] Step 5: Synthesis of compound int_1-7:

[0171] Int_1-6 (952 mg, 3.73 mmol) and (Boc)2O (1.22 g, 5.59 mmol, 1.28 mL) were dissolved in dioxane (20 mL). TEA (1.13 g, 11.18 mmol, 1.56 mL) was added to the reaction mixture at room temperature. The reaction mixture was heated to 90°C for 16 hours, monitored by LC-MS. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 4 / 1) to afford a solid (1.2 g, yield: 83.4%).

[0172] ESI-MS m / z:356[M+H] + .

[0173] Step 6: Synthesis of compound int_1-8:

[0174] Int_1-7 (1.1 g, 3.11 mmol) was dissolved in THF (25 mL) and cooled to -70°C. Under nitrogen, n-BuLi (2.5 M, 3.74 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to react at -70°C for 0.5 hours. DMF (682.55 mg, 9.34 mmol, 718.48 uL) was then added dropwise at -70°C. After the addition was complete, the reaction mixture was allowed to react at -60°C for 1.5 hours. LC-MS monitoring indicated the reaction was complete. Saturated ammonium chloride solution (20 mL) was slowly added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (30 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, which was then purified by column chromatography (SiO2, PE / EtOAc = 3 / 1) to obtain a solid (1.08 g, yield: 83.9%).

[0175] MS(ESI):384[M+H] + .

[0176] Step 7: Synthesis of compound int_1-10:

[0177] Int_1-9 (1.50 g, 6.26 mmol) was dissolved in THF (30 mL) and cooled to -70°C. Under nitrogen, n-BuLi (2.5 M, 5.01 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to react at -70°C for 1 hour. Then, a solution of int_1-8 (800 mg, 2.09 mmol) in THF (15 mL) was added dropwise at -70°C. After the addition was complete, the reaction mixture was allowed to react at -70°C for 1 hour and then warmed to room temperature for 16 hours. LC-MS monitoring indicated the reaction was complete. Saturated ammonium chloride solution (50 mL) was slowly added to the reaction mixture. 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, which was then purified by column chromatography (SiO2, PE / EtOAc = 2 / 1) to obtain a solid (600 mg, yield: 57.7%).

[0178] 1 H NMR(400MHz, CHLOROFORM-d)δ=9.07-9.02(m,1H),8.96-8.91(m,1H),7.19(d,J=4.4Hz,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=2.6,12.2Hz,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).

[0179] MS(ESI):498[M+H] + .

[0180] Step 8: Synthesis of compound int_1-11:

[0181] Int_1-10 (600 mg, 1.20 mmol) was dissolved in DCM (6 mL). Dess-Martin periodinane (766.46 mg, 1.81 mmol) was added to the reaction mixture at room temperature. The reaction mixture was allowed to react for 1 hour. LC-MS monitoring confirmed the completion of the reaction. Saturated aqueous sodium bicarbonate was slowly added to the reaction mixture 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, which was then purified by column chromatography (SiO2, PE / EtOAc = 3 / 1) to obtain a solid (550 mg, yield: 92%).

[0182] MS(ESI):496[M+H] + .

[0183] Step 9: Synthesis of compound int_1-13:

[0184] Int_1-11 (550 mg, 1.11 mmol) and int_1-12 (638.2 mg, 2.22 mmol) were dissolved in DMF (20 mL). KCO (766.25 mg, 5.54 mmol) was added to the reaction mixture at room temperature. The reaction mixture was allowed to react for 3 hours. LC-MS monitoring confirmed the completion of the reaction. Ice water (20 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (SiO, PE / EtOAc = 2 / 1) to obtain the product (700 mg, yield: 84.5%).

[0185] MS(ESI):747[M+H] + .

[0186] Step 10: Synthesis of compound int_1-15:

[0187] Int_1-13 (700 mg, 936.99 μmol) was dissolved in DMF (15 mL). Int_1-14 (216.52 mg, 1.87 mmol) was added to the reaction mixture at room temperature. The reaction mixture was allowed to react for 1 hour. LC-MS monitoring confirmed the completion of the reaction. Ice water (20 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 3 / 1) to obtain a solid (750 mg, yield: 96.9%).

[0188] MS(ESI):826[M+H] + .

[0189] Step 11: Synthesis of compound int_1-16:

[0190] Int_1-15 (750 mg, 907.83 μmol) was dissolved in THF (20 mL). TBAF (1 M, 1.82 mL) was added to the reaction mixture at room temperature and allowed to react for 4 hours. LC-MS monitoring confirmed the completion of the reaction. Water (15 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 1 / 1) to obtain a solid (500 mg, yield: 82.2%).

[0191] 1 H NMR (400MHz, CHLOROFORM-d) δ=8.63-8.49(m,3H),7.14-7.08(m,2H),7.04(d,J=2.1Hz,1H),7.03-6.97(m,1H),6.46(d,J=7.6Hz,1H),5.44(br s,2H),4.74-4.60(m,1H),4.37-4.12(m,4H),3.22-3.14(m,1H),3.01-2.8 8(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=5.1Hz,1H),2.09-1.99(m,2H),1.90(td,J=6.6,13.2Hz,2H),1.63(br d,J=13.9Hz,1H),1.44-1.32(m,1H),1.27-1.19(m,9H).

[0192] MS(ESI):670[M+H] + .

[0193] Step 12: Synthesis of Compound 1

[0194] 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 allowed to react for 5 minutes. LC-MS monitoring confirmed the completion of the reaction. The pH was adjusted to 8 by adding saturated sodium bicarbonate solution, followed by purification by preparative HPLC (column: Boston Prime C18 150*30 mm*5 μm; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 30%-50%, 9 min) to afford a solid (90 mg, yield: 35.2%).

[0195] 1 H NMR (400MHz, CHLOROFORM-d) δ = 8.61 (d, J = 3.8Hz, 1H), 8.58 (s, 1H), 8.50 (br t, J = 6.3Hz, 1H), 7.18-7.11 (m, 2H), 7.09 (br d,J=7.4Hz,1H),7.01(s,1H),6.78(br d,J=7.9Hz,1H),4.70(br d,J=6.4Hz,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=16.5Hz,1H),2.52(br s,1H),2.41-2.25(m,3H),2.15-1.90(m,5H),1.51-1.39(m,1H).

[0196] MS(ESI):570[M+H] + .

[0197] Example 2 Synthesis of Compound 2 and Compound 3

[0198] Compound 1 (0.09 g, 157 umol) was subjected to SFC chiral separation (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 60%, isocratic elution mode) to obtain compound 2 (30 mg) and compound 3 (30 mg).

[0199] Compound 2: 11H NMR (400 MHz, 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 (m, 1H), 2.30 - 2.21 (m, 1H), 2.20 - 2.09 (m, 2H), 2.06 - 1.97 (m, 2H), 1.92 - 1.79 (m, 1H), 1.40 (td, J = 9.0, 13.2 Hz, 1H).; MS (ESI): 570 [M+H] + .

[0200] Analysis of SFC retention time: 1.580 min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak IG-3 50x4.6 mm I.D., 3 um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 4 mL / min; Column temp.: 35 °C; ABPR: 1500 psi).

[0201] Compound 3: 1 1H NMR (400 MHz, 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 - 2.9 (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] + .

[0202] Analysis SFC retention time: 0.927min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak IG-3 50x4.6mm ID, 3um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 4mL / min; Column temp.:35℃; ABPR:1500psi).

[0203] Example 3 Synthesis of Compound 4

[0204] Step 1: Synthesis of compound int_4-2:

[0205] Int_4-1 (50.00 g, 293.10 mmol) and NH4OAc (51.96 g, 674.12 mmol) were dissolved in acetic acid (500 mL) and the atmosphere was replaced with nitrogen three times. Under nitrogen, CH3NO2 (46.52 g, 762.05 mmol, 41.16 mL) was added to the reaction solution. The reaction solution was heated to 100°C and stirred for 16 hours. LC-MS monitoring indicated 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 x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (60 g, yield: 95.8%), which was used directly in the next reaction.

[0206] 1 H NMR (400MHz, DMSO-d6) δ = 8.36 (d, J = 13.6Hz, 1H), 8.12 (d, J = 13.4Hz, 1H), 7.67 (d, J = 1.5Hz, 1H), 7.55 (d, J = 8.1Hz, 1H), 7.48-7.42 (m, 1H), 3.92 (s, 3H).

[0207] Step 2: Synthesis of compound int_4-3:

[0208] LiBH4 (20.39 g, 936.25 mmol) was dissolved in tetrahydrofuran (200 mL). Under nitrogen, TMSCl (203.43 g, 1.87 mol, 237.66 mL) was added to the reaction mixture at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. A solution of int_4-2 (20.00 g, 93.63 mmol) in tetrahydrofuran (200 mL) was slowly added dropwise over 15 minutes. The reaction mixture was heated to 75°C and the reaction was continued for 2 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to 0°C and quenched by the slow addition of 100 mL of methanol. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was adjusted to pH >7 with aqueous ammonia. The aqueous phase was extracted with ethyl acetate (300 mL x 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (15 g, yield: 86.3%), which was directly used in the next reaction.

[0209] 1 H NMR (400MHz, DMSO-d6) δ = 7.31 (d, J = 7.9Hz, 1H), 7.01 (d, J = 1.3Hz, 1H), 6.80 (dd, J = 1.7, 8.0Hz, 1H), 3.85 (s, 3H), 2.92-2.80 (m, 2H), 2.78-2.64 (m, 2H).

[0210] Step 3: Synthesis of compound int_4-4:

[0211] Dissolve int_4-3 (9.00 g, 48.48 mmol) and int_1-2 (8.12 g, 53.33 mmol) in Ti(i-PrO)4 (170 mL). Replace the atmosphere with nitrogen three times. Heat the mixture to 80°C and stir for 2 hours. LC-MS monitoring indicates the reaction is complete. Cool the reaction mixture to room temperature and use it directly in the next step.

[0212] ESI-MS m / z:320[M+H] + .

[0213] Step 4: Synthesis of compound int_4-5:

[0214] At -10°C, HCOOH (200 mL) was slowly added dropwise to Ac2O (500 mL). The reaction mixture was allowed to react at 20°C for 0.5 hours. The int_4-4 solution obtained in step 3 was then cooled to -10°C, and the HOOCH and Ac2O mixture was slowly added dropwise to the int_4-4 solution, maintaining the temperature at -10°C. After the addition was complete, the reaction mixture was heated to 70°C and reacted for 3 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was adjusted to pH >7 with saturated aqueous bicarbonate solution. The aqueous phase was extracted with ethyl acetate (500 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 1 / 1) to obtain a solid (2 g, yield: 10.6%).

[0215] 1 H NMR (400MHz, DMSO-d6) δ = 7.57 (s, 1H), 7.32 (d, J = 5.1Hz, 1H), 6.98 (s, 1H), 6.72 (s, 1H), 6. 24(d,J=5.3Hz,1H),4.40(td,J=3.9,12.9Hz,1H),3.85(s,3H),3.24-3.12(m,1H),2.93(br dd,J=3.7,7.9Hz,2H),2.89-2.79(m,2H),2.35(br dd,J=2.0,11.9Hz,1H),2.01-1.81(m,2H),1.70-1.53(m,1H).

[0216] ESI-MS m / z:348[M+H] + .

[0217] Step 5: Synthesis of compound int_4-6:

[0218] Int_4-5 (3.30 g, 9.49 mmol) was dissolved in dichloromethane (30 mL) and the atmosphere was replaced 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 to the reaction solution. The reaction solution was warmed to room temperature and allowed to react for 1 hour. LC-MS monitoring indicated 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 x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (2.8 g, yield: 88.4%), which was used directly in the next reaction.

[0219] 1H NMR (400MHz, DMSO-d6) δ = 10.36 (s, 1H), 7.72 (s, 1H), 7.48 (d, J = 5.1Hz, 1H), 6.91 (s, 1H), 6.79 (s, 1H), 6.41 (d, J = 5.3Hz, 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).

[0220] ESI-MS m / z:334[M+H] + .

[0221] Step 6: Synthesis of compound int_4-7:

[0222] 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 atmosphere was purged with nitrogen three times, and the reaction mixture was allowed to react at room temperature for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was slowly poured into 300 mL of ice water, and the aqueous phase was extracted with ethyl acetate (300 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 1 / 1) to obtain a solid (2.3 g, yield: 58.8%).

[0223] 1 H NMR (400MHz, DMSO-d6) δ=7.45-7.39(m,1H),7.36(d,J=5.3Hz,1H),7.31-7.24(m,1H),7.12(s,1H),6.28(d,J =5.3Hz,1H),4.51-4.38(m,1H),3.02-2.85(m,4H),2.42(td,J=2.0,12.0Hz,2H),2.06-1.94(m,1H),1.90(br d,J=13.8Hz,1H),1.94-1.83(m,1H),1.68-1.50(m,1H).

[0224] ESI-MS m / z:466[M+H] + .

[0225] Step 7: Synthesis of compound int_4-8:

[0226] 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 mixture was purged with hydrogen three times and allowed to react at room temperature for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was filtered to obtain a filtrate, which was then concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, PE / EtOAc = 1 / 1) to obtain a solid (0.64 g, yield: 40.7%).

[0227] 1 H NMR (400MHz, DMSO-d6) δ = 7.57 (s, 1H), 7.34 (d, J = 5.3Hz, 1H), 7.25 (d, J = 0.9 Hz,2H),6.76(s,1H),6.24(d,J=5.3Hz,1H),4.41(td,J=4.1,13.1Hz,1H),3 .25-3.13(m,1H),2.95(dd,J=3.9,7.8Hz,2H),2.86(dd,J=4.5,8.3Hz,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).

[0228] ESI-MS m / z:318[M+H] + .

[0229] Step 8: Synthesis of compound int_4-9:

[0230] Int_4-8 (0.64 g, 2.01 mmol) was dissolved in THF (10 mL) and cooled to -30°C. Under nitrogen, n-BuLi (2.5 M, 2.42 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to react at -30°C for 2 hours, then warmed to room temperature for 1 hour. LC-MS monitoring indicated the reaction was complete. Saturated aqueous ammonium chloride (10 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (0.5 g, yield: 85.6%), which was used directly in the next reaction.

[0231] ESI-MS m / z:290[M+H] + .

[0232] Step 9: Synthesis of compound int_4-10:

[0233] 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). TEA (523.71 mg, 5.18 mmol, 720.37 μL) was added to the reaction mixture at room temperature. The reaction mixture was heated to 80°C for 16 hours and monitored by LC-MS. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 10 / 1) to obtain a solid (0.11 g, yield: 16.3%).

[0234] 1 H NMR (400MHz, DMSO-d6) δ=7.33-7.23(m,3H),6.53(d,J=5.1Hz,1H),6.40(d,J=2.0Hz,1H),4.27(td,J =3.7,12.0Hz,1H),3.11(ddd,J=5.1,9.8,12.2Hz,1H),2.97-2.87(m,3H),2.75-2.63(m,2H),1.77(br d,J=13.2Hz,1H),1.65-1.49(m,2H),1.15(s,9H).

[0235] Step 10: Synthesis of compound int_4-11:

[0236] Int_4-10 (1.44 g, 3.693 mmol) was dissolved in THF (20 mL) and cooled to -75°C. Under nitrogen, n-BuLi (2.5 M, 4.43 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to react at -75°C for 1 hour. DMF (809 mg, 11.079 mmol) was then added dropwise at -75°C. After the addition was complete, the reaction mixture was allowed to react at -75°C for 1 hour. LC-MS monitoring indicated 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 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, which was then purified by column chromatography to obtain a solid (1.38 g, yield: 89.9%).

[0237] MS(ESI):418[M+H] + .

[0238] Step 11: Synthesis of compound int_4-12:

[0239] Int_1-9 (4.79 g, 19.911 mmol) was dissolved in THF (50 mL) and cooled to -75°C. Under nitrogen, n-BuLi (2.5 M, 16 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to react at -75°C for 1 hour. Then, a solution of int_4-11 (1.387 g, 3.319 mmol) in THF (25 mL) was added dropwise at -75°C. After the addition was complete, the reaction mixture was allowed to react at -75°C for 1 hour and then warmed to room temperature for 16 hours. LC-MS monitoring confirmed the completion of the reaction. Saturated ammonium chloride solution (200 mL) was slowly added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (200 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, which was then purified by column chromatography to obtain a solid (1.427 g, 80% yield).

[0240] MS(ESI):532[M+H] + .

[0241] Step 12: Synthesis of compound int_4-13:

[0242] Int_4-12 (1.427 g, 2.68 mmol) was dissolved in DCM (50 mL). Dess-Martin oxidant (1.36 g, 3.22 mmol) was added to the reaction mixture at room temperature. The reaction mixture was allowed to react for 1 hour. LC-MS monitoring confirmed the completion of the reaction. Saturated aqueous sodium bicarbonate was slowly added to the reaction mixture to adjust the pH to ~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 obtain the crude product, which was then purified by column chromatography to obtain a solid (1.324 g, 93% yield).

[0243] MS(ESI):530[M+H] + .

[0244] Step 13: Synthesis of compound int_4-14:

[0245] Int_4-13 (1.053 g, 1.985 mmol) and int_1-12 (628 mg, 2.184 mmol) were dissolved in DMF (10 mL). KCO (824 mg, 5.962 mmol) was added to the reaction mixture at room temperature and allowed to react for 3 hours. LC-MS monitoring confirmed the completion of the reaction. Ice water (100 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain the product (1.425 g, 91% yield).

[0246] MS(ESI):781[M+H] + .

[0247] Step 14: Synthesis of compound int_4-15:

[0248] Int_4-14 (1.425 g, 1.823 mmol) was dissolved in DMF (30 mL). Int_1-14 (421 mg, 3.647 mmol) was added to the reaction mixture at room temperature. The reaction mixture was allowed to react for 1 hour. LC-MS monitoring confirmed the completion of the reaction. Ice water (50 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain a solid (1.5 g, yield: 96.1%).

[0249] MS(ESI):860[M+H] + .

[0250] Step 15: Synthesis of compound int_4-16:

[0251] Int_4-15 (1.5 g, 1.742 mmol) was dissolved in THF (20 mL). TBAF (1 M, 3.6 mL) was added to the reaction mixture at room temperature and allowed to react for 4 hours. LC-MS monitoring confirmed the completion of the reaction. Water (50 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography to obtain a solid (1.1 g, yield: 90.1%).

[0252] MS(ESI):704[M+H] + .

[0253] Step 16: Synthesis of compound 4

[0254] Int_4-16 (1.28 g, 1.823 mmol) was dissolved in DCM (7 mL) at room temperature and TFA (7.8 mL) was added. The reaction mixture was allowed to react at room temperature for 5 minutes. LC-MS monitoring confirmed the completion of the reaction. The mixture was cooled to 0°C and the pH was adjusted to 8 by adding saturated aqueous sodium bicarbonate. 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, which was purified by preparative HPLC to afford a solid (897 mg, yield: 81.5%).

[0255] MS(ESI):604[M+H] + .

[0256] Example 4 Synthesis of Compound 5 and Compound 6

[0257] Compound 4 (100 mg, 0.165 mmol) was subjected to SFC chiral separation (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 60%, isocratic elution mode) to obtain compound 5 (45 mg) and compound 6 (40 mg).

[0258] Compound 5: 1 H NMR (400MHz, DMSO-d6) δ8.55(s,1H),8.50(s,1H),8.24(d,J=7.4Hz,1H),7.40(s,2H),7.14(d,J=2.6Hz,2H),6.95(s ,1H),6.76(d,J=1.9Hz,1H),4.85(d,J=4.6Hz,1H),4.64(h,J=7.9Hz,1H),4.06(dd,J=9.8,6.0Hz,1H),3.92(dt,J=8. 8,5.8Hz,2H),3.10–2.80(m,5H),2.67(d,J=19.0Hz,1H),2.35–2.14(m,2H),2.07(d,J=7.6Hz,2H),1.93(ddd,J=12.4 ,7.7,3.7Hz,1H),1.82(s,2H),1.72(ddd,J=13.1,8.6,6.6Hz,1H),1.22(dt,J=13.0,9.2Hz,1H).;MS(ESI):604[M+H] + .

[0259] Analysis SFC retention time: 1.659min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak IG-3 50x4.6mm ID, 3um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 4mL / min; Column temp.:35℃; ABPR:1500psi).

[0260] Compound 6: 1 H NMR (400MHz, DMSO-d6) δ8.54(s,1H),8.49(s,1H),8.22(d,J=7.5Hz,1H),7.41(s,2H),7.13(d,J=2.0Hz,2H),6.93(s,1H),6. 75(d,J=1.8Hz,1H),4.84(d,J=4.5Hz,1H),4.64(h,J=8.2Hz,1H),4.07(dd,J=9.7,6.0Hz,1H),4.00–3.80(m,2H),3.07–2.78 (m,5H),2.64(d,J=16.5Hz,1H),2.28(dt,J=12.5,7.6Hz,1H),2.22–2.13(m,1H),2.08(d,J=9.7Hz,2H), 1.90(ddd,J=11.9,7.5,3.8Hz,1H),1.85–1.63(m,3H),1.23(dt,J=12.8,9.2Hz,1H).;MS(ESI):604[M+H] + .

[0261] Analysis SFC retention time: 0.925min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak IG-3 50x4.6mm ID, 3um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 4mL / min; Column temp.:35℃; ABPR:1500psi).

[0262] Example 5 Synthesis of Compound 7

[0263] Step 1: Synthesis of compound int_7-2:

[0264] Int_7-1 (25.0 g, 162 mmol) and NH4OAc (28.8 g, 373 mmol) were dissolved in acetic acid (250 mL) and the atmosphere was replaced with nitrogen three times. Under nitrogen protection, CH3NO2 (25.7 g, 422 mmol, 22.8 mL) was added to the reaction solution. The reaction solution was heated to 100°C and stirred for 16 hours. LC-MS monitoring indicated 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 x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (50 g, yield: 78.2%), which was used directly in the next reaction.

[0265] 1 HNMR (400MHz, DMSO-d6) δ = 3.89 (s, 3H), 7.33 (dd, J = 11.25, 8.44Hz, 1H), 7.46 (ddd, J = 8.25, 4.59 ,1.96Hz,1H),7.72(dd,J=8.44,1.96Hz,1H),8.10(d,J=13.57Hz,1H),8.29(d,J=13.57Hz,1H).

[0266] Step 2: Synthesis of compound int_7-3:

[0267] LiBH4 (27.6 g, 1.27 mol) was dissolved in tetrahydrofuran (300 mL). Under nitrogen, TMSCl (276 g, 2.54 mol, 322 mL) was added to the reaction mixture at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. A solution of int_7-2 (25.0 g, 127 mmol) in tetrahydrofuran (250 mL) was slowly added dropwise over 30 minutes. The reaction mixture was heated to 75°C and the reaction continued for 2 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to 0°C and quenched by the slow addition of 600 mL of methanol. The organic phase was concentrated under reduced pressure to obtain the crude product. The pH of the crude product was adjusted to >7 with aqueous ammonia. The aqueous phase was extracted with ethyl acetate (500 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 (25 g), which was used directly in the next reaction.

[0268] ESI-MS m / z:170[M+H] + .

[0269] Step 3: Synthesis of compound int_7-4:

[0270] Dissolve int_7-3 (12.5 g, 73.9 mmol) and int_1-2 (11.8 g, 77.6 mmol) in Ti(i-PrO)4 (1130 mL). The atmosphere was purged with nitrogen three times. The mixture was heated to 80°C and stirred for 2 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature and used directly in the next step.

[0271] ESI-MS m / z:304[M+H] + .

[0272] Step 4: Synthesis of compound int_7-5:

[0273] At -10°C, HCOOH (400 mL) was slowly added dropwise to Ac2O (1000 mL). After the addition was complete, the reaction mixture was allowed to react at 20°C for 0.5 hours. The int_7-4 solution obtained in step 3 was then cooled to -10°C, and the HOOCH and Ac2O mixture was slowly added dropwise to the int_7-4 solution, maintaining the temperature at -10°C. After the addition was complete, the reaction mixture was heated to 80°C and reacted for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was adjusted to pH > 7 with saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with ethyl acetate (1000 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 3 / 2) to obtain a solid (1.5 g, yield: 5.05%).

[0274] 1 HNMR (400MHz, DMSO-d6) δ = 1.52-1.66 (m, 1H), 1.82-1.94 (m, 2H), 2.28-2.3 8(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=12.93,3.99Hz,1H),6.22(d,J=5.28Hz,1H),6.52(d,J=1 2.98Hz, 1H), 6.97 (d, J = 9.02Hz, 1H), 7.30 (d, J = 5.28Hz, 1H), 7.57 (s, 1H).

[0275] ESI-MS m / z:332[M+H] + .

[0276] Step 5: Synthesis of compound int_7-6:

[0277] Int_7-5 (4.00 g, 12.1 mmol) was dissolved in dichloromethane (40 mL) and the atmosphere was replaced 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 to the reaction solution. The reaction solution was warmed to room temperature and allowed to react for 1 hour. LC-MS monitoring indicated 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 x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (4.5 g, yield: 99.3%), which was used directly in the next reaction.

[0278] ESI-MS m / z:318[M+H] + .

[0279] Step 6: Synthesis of compound int_7-7:

[0280] 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 atmosphere was replaced with nitrogen three times, and the reaction mixture was allowed to react at room temperature for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was slowly poured into 200 mL of ice water, and the aqueous phase was extracted with ethyl acetate (200 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 2 / 1) to obtain a solid (4 g, yield: 62.8%).

[0281] 1 HNMR (400MHz, DMSO-d6) δ=1.52-1.67(m,1H),1.86-1.94(m,1H),1.99(s,1H),2.41(dt,J=11.83,2.01Hz,1H),2.91(br s,2H),2.94(br dd,J=8.03,3.85Hz,2H),3.18(ddd,J=13.20,10.45,4.95Hz,1H),4.40-4.49(m,1H),6.26(d,J=5 .28Hz, 1H), 6.98 (d, J = 11.66Hz, 1H), 7.35 (d, J = 5.28Hz, 1H), 7.56 (s, 1H), 7.60 (d, J = 7.70Hz, 1H).

[0282] ESI-MS m / z:450[M+H] + .

[0283] Step 7: Synthesis of compound int_7-8:

[0284] 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 replaced with hydrogen three times and allowed to react at room temperature under a hydrogen atmosphere (20.0 psi) for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was filtered to obtain a filtrate, which was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, PE / EtOAc = 1 / 1) to obtain a solid (2.2 g, yield: 81.2%).

[0285] 1 HNMR(400MHz, DMSO-d6)δ=1.53-1.67(m,1H),1.84-1.93(m,1H),1.98(td,J=13.45,2.69Hz,1H),2.35-2.43(m,1H),2.84(br dd,J=7.27,3.85Hz,2H),2.94(dd,J=8.01,3.97Hz,2H),3.19(dt,J=12.93,7.78Hz,1H),4.40(dt,J=13.02,4.07Hz,1H),6.22(d,J=5.26H z, 1H), 6.53 (dd, J = 10.51, 2.69Hz, 1H), 7.04 (td, J = 8.50, 2.69Hz, 1H), 7.25 (dd, J = 8.50, 6.05Hz, 1H), 7.32 (d, J = 5.26Hz, 1H), 7.59 (s, 1H).

[0286] ESI-MS m / z:302[M+H] + .

[0287] Step 8: Synthesis of compound int_7-9:

[0288] Int_7-8 (2.20 g, 7.30 mmol) was dissolved in THF (25 mL) and cooled to -78°C. Under nitrogen, n-BuLi (2.50 M, 8.76 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to react at -30°C for 2 hours, then warmed to room temperature for 0.5 hours. LC-MS monitoring indicated the reaction was complete. Saturated aqueous ammonium chloride (50 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (SiO2, DCM / MeOH = 95 / 5) to obtain a solid (1.4 g, yield: 56.1%).

[0289] 1 HNMR(400MHz, 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=5.28Hz,1H),6.45(dd,J=10.56,2.64Hz,1H),6.92(td,J=8.53,2.75Hz,1H),7.10(br s,1H),7.11-7.15(m,1H).

[0290] ESI-MS m / z:274[M+H] + .

[0291] Step 9: Synthesis of compound int_7-10:

[0292] 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). TEA (1.55 g, 15.4 mmol, 2.14 mL) was added to the reaction mixture at room temperature. The reaction mixture was heated to 80°C for 16 hours, monitored by LC-MS. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 4 / 1) to afford a solid (870 mg, 45.2% yield).

[0293] ESI-MS m / z:374[M+H] + .

[0294] Step 10: Synthesis of compound int_7-11:

[0295] Int_7-10 (900 mg, 2.41 mmol) was dissolved in THF (10 mL) and cooled to -70°C. Under nitrogen, n-BuLi (2.50 M, 2.89 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to react at -70°C for 0.5 hours. DMF (528 mg, 7.23 mmol, 556 μL) was then added dropwise at -70°C. After the addition was complete, the reaction mixture was allowed to react at -75°C for 1 hour. The reaction was monitored by LC-MS. Saturated ammonium chloride solution (25 mL) was slowly added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (30 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, which was then purified by column chromatography (SiO2, PE / EtOAc = 4 / 1) to obtain a solid (970 mg, yield: 95.9%).

[0296] 1 HNMR(400MHz,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=12.07,3.12Hz, 1H),4.40-4.49(m,1H),6.25(dd,J=10.45,2.63Hz,1H),6.90(td,J=8.25,2 .57Hz,1H),7.17(dd,J=8.07,5.87Hz,1H),7.27-7.28(m,1H),9.75(s,1H).

[0297] MS(ESI):402[M+H] + .

[0298] Step 11: Synthesis of compound int_7-12:

[0299] Int_1-9 (1.62 g, 6.72 mmol) was dissolved in THF (15 mL) and cooled to -75°C. Under nitrogen, n-BuLi (2.50 M, 5.38 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to react at -75°C for 1 hour. Then, a solution of int_7-11 (900 mg, 2.24 mmol) in THF (25 mL) was added dropwise at -75°C. After the addition was complete, the reaction mixture was allowed to react at -75°C for 1 hour and then warmed to room temperature for 16 hours. LC-MS monitoring indicated 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 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, which was then purified by column chromatography (SiO2, PE / EtOAc = 7 / 3) to obtain a solid (690 mg, yield: 59.7%).

[0300] 1 HNMR (400MHz, 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=8.47,6.05Hz,1H),8.93-8.97(m,1H).

[0301] MS(ESI):516[M+H] + .

[0302] Step 12: Synthesis of compound int_7-13:

[0303] Int_7-12 (640 mg, 1.24 mmol) was dissolved in DCM (10 mL). Dess-Martin periodinane (1.05 g, 2.48 mmol) was added to the reaction mixture at room temperature. The reaction mixture was allowed to react for 1 hour. LC-MS monitoring confirmed the completion of the reaction. Saturated aqueous sodium bicarbonate was slowly added to the reaction mixture 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, which was then purified by column chromatography (SiO2, PE / EtOAc = 10 / 1) to obtain a solid (630 mg, yield: 98.8%).

[0304] 1HNMR (400MHz, 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, 2 H), 4.17-4.26 (m, 1H), 6.22 (dd, J = 10.78, 2.64Hz, 1H), 7.05 (td, J = 8.47, 2.64Hz, 1H), 7.25-7.34 (m, 2H), 8.86 (s, 1H), 9.15 (s, 1H).

[0305] MS(ESI):514[M+H] + .

[0306] Step 13: Synthesis of compound int_7-14:

[0307] Int_7-13 (390 mg, 759 μmol) and int_1-12 (327 mg, 1.14 mmol) were dissolved in DMF (10 mL). KCO (524 mg, 3.79 mmol) was added to the reaction mixture at room temperature and allowed to react for 16 hours. LC-MS monitoring confirmed the completion of the reaction. Ice water (50 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (SiO, PE / EtOAc = 7 / 3) to obtain the product (350 mg, yield: 60.3%).

[0308] MS(ESI):765[M+H] + .

[0309] Step 14: Synthesis of compound int_7-15:

[0310] Int_7-14 (550 mg, 719 μmol) was dissolved in DMF (10 mL). Int_1-14 (249 mg, 2.16 mmol) was added to the reaction mixture at room temperature. The reaction mixture was allowed to react for 0.5 hours. LC-MS monitoring confirmed the completion of the reaction. Ice water (20 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography to obtain a solid (600 mg, yield: 98.9%).

[0311] MS(ESI):844[M+H] + .

[0312] Step 15: Synthesis of compound int_7-16:

[0313] Int_7-15 (550 mg, 652 μmol) was dissolved in THF (10 mL). TBAF (1.00 M, 652 μL) was added to the reaction mixture at room temperature and allowed to react for 16 hours. LC-MS monitoring confirmed the completion of the reaction. Water (20 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 4 / 1) to afford a solid (320 mg, yield: 58.6%).

[0314] 1 HNMR(400MHz,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=17.45,2.69Hz,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=10.88,2.13Hz,1H),7.05(td,J=8.32,2.25Hz,1H),7.22(s,1H),7.31(dd,J=8.07,6.19Hz,1H),7.43(d,J=5.13Hz,2H),8.26(br d,J=6.75Hz,1H),8.41(s,1H),8.57(s,1H).

[0315] MS(ESI):688[M+H] + .

[0316] Step 16: Synthesis of compound 7

[0317] Int_7-16 (200 mg, 291 μmol) was dissolved in DCM (5 mL) at room temperature and TFA (2 mL) was added. The reaction mixture was allowed to react at room temperature for 5 minutes. LC-MS monitoring confirmed the completion of the reaction. The mixture was cooled to 0°C, and the pH was adjusted to 8 by adding saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (20 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, which was purified by preparative HPLC (column: Phenomenex C1875 x 30 mm x 3 μm; mobile phase: [water (ammonia hydroxide)-ACN]; gradient: 38%-58% B over 9 min) to afford a solid (50 mg, yield: 29.3%).

[0318] 1 HNMR (400MHz, DMSO-d6) δ = 1.24 (dt, J = 8.71, 4.51Hz, 1H), 1.71-1.78 (m, 1H), 1.78-1.86 (m, 2H), 1.87-1.98 (m, 1H), 2.08 (br d, J = 8.56Hz, 2H), 2.17 (br dd,J=11.68,2.51Hz,1H),2.24-2.35(m,1H),2.61-2.68(m,1H),2.86(br dd,J=15.65,7.58Hz,1H),2.96(dt,J=8.56,4.28Hz,4H),3.30(s,1H),3.94(br dd,J=9.72,6.91Hz,2H),4.07(ddd,J=9.32,6.14,2.75Hz,1H),4.58-4.71(m,1H),4.87(dd,J=4.46,3.00Hz,1H),6.54(br d,J=9.41Hz,1H),6.90-6.97(m,2H),7.13(dd,J=8.38,6.17Hz,1H),7.43( d, J=2.57Hz, 2H), 8.22 (dd, J=7.40, 2.51Hz, 1H), 8.50 (s, 1H), 8.55 (s, 1H).

[0319] MS(ESI):588[M+H] + .

[0320] Example 6 Synthesis of Compound 8 and Compound 9

[0321] Compound 7 (50 mg, 0.085 mmol) was subjected to SFC chiral separation (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 50%, isocratic elution mode) to obtain compound 8 (22 mg) and compound 9 (14 mg).

[0322] Compound 8: 1 HNMR (400MHz, DMSO-d6) δ = 1.24 (dt, J = 12.65, 9.19Hz, 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=15.85Hz,1H),2.70-3.08(m,5H),3.30(s,1H),3.89-3.98(m,2H),4.08(dd,J=9.68,5.94Hz,1 H),4.60-4.70(m,1H),4.88(d,J=4.62Hz,1H),6.53(dd,J=10.34,2.64Hz,1H),6.90-6.96(m,2H), 7.13(dd,J=8.36,6.16Hz,1H),7.44(s,2H),8.22(d,J=7.48Hz,1H),8.50(s,1H),8.55(s,1H).;MS(ESI):588[M+H] + .

[0323] Analysis SFC retention time: 0.820min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak AD-3 50x4.6mm ID, 3um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 4mL / min; Column temp.:35℃; ABPR:1500psi).

[0324] Compound 9: 1HNMR (400MHz, DMSO-d6) δ = 1.23 (dt, J = 12.82, 9.33Hz, 1H), 1.69-1.86 (m, 3H), 1.88-1.98 (m, 1H), 2.08 (br d,J=6.38Hz,2H),2.16-2.33(m,2H),2.62-2.70(m,1H),2.77-3.08(m,5H),3.30(s,1 H),3.90-3.98(m,2H),4.07(dd,J=9.57,6.05Hz,1H),4.60-4.70(m,1H),4.88(d,J=4 .62Hz,1H),6.54(dd,J=10.23,2.53Hz,1H),6.91-6.97(m,2H),7.14(t,J=6.69Hz,1H ),7.43(s,2H),8.23(d,J=7.48Hz,1H),8.50(s,1H),8.56(s,1H).;MS(ESI):588[M+H] + .

[0325] Analysis SFC retention time: 0.636min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak AD-3 50x4.6mm ID, 3um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 4mL / min; Column temp.:35℃; ABPR:1500psi).

[0326] Example 7 Synthesis of Compound 19

[0327] Step 1: Synthesis of compound int_19-2:

[0328] Int_19-1 (50.0 g, 228 mmol) and NH₄OAc (40.4 g, 524 mmol) were dissolved in acetic acid (500 mL) and the atmosphere was replaced with nitrogen three times. Under nitrogen protection, CH₃NO₂ (36.2 g, 593 mmol, 32.0 mL) was added to the reaction solution. The reaction solution was heated to 100°C and stirred for 16 hours. LC-MS monitoring indicated 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 x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (50 g, yield: 83.6%), which was used directly in the next reaction.

[0329] 1 H NMR (400MHz, CHLOROFORM-d) δ = 8.35 (d, J = 13.6Hz, 1H), 7.73 (d, J = 2.0Hz, 1H), 7.58-7.51 (m, 2H), 7.40 (dd, J = 2.0, 8.4Hz, 1H).

[0330] Step 2: Synthesis of compound int_19-3:

[0331] LiBH4 (20.8 g, 952 mmol) was dissolved in tetrahydrofuran (300 mL). Under nitrogen, TMSCl (207 g, 1.90 mol, 242 mL) was added to the reaction mixture at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. A solution of int_19-2 (25.0 g, 95.2 mmol) in tetrahydrofuran (250 mL) was slowly added dropwise over 30 minutes. The reaction mixture was heated to 70°C and the reaction continued for 2 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to 0°C and quenched by the slow addition of 200 mL of methanol. The organic phase was concentrated under reduced pressure to obtain the crude product. The pH of the crude product was adjusted to >7 with aqueous ammonia. The aqueous phase was extracted with ethyl acetate (500 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 (20 g), which was used directly in the next reaction.

[0332] ESI-MS m / z:234[M+H] + .

[0333] ■

[0334] Step 3: Synthesis of compound int_19-5:

[0335] 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 atmosphere was replaced with nitrogen three times, and the mixture was heated to 90°C and stirred for 2 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product (23 g), which was used directly in the next reaction.

[0336] ESI-MS m / z:354[M+H] + .

[0337] Step 4: Synthesis of compound int_19-6:

[0338] Int_19-5 (23.0 g, 64.9 mmol), TEA (65.6 g, 648 mmol, 90.3 mL), and Ac2O (33.1 g, 324 mmol, 30.5 mL) were dissolved in dichloromethane (400 mL). The reaction mixture was incubated at 20°C under nitrogen for 2 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was adjusted to pH > 7 with saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with dichloromethane (500 mL x 3) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 3 / 1) to obtain a solid (20 g, yield: 77.7%).

[0339] 1 H NMR (400MHz, DMSO-d6) δ=1.09-1.17(m,1H),1.88(br d,J=7.00Hz,3H),2.82-2.96(m,2H),3.41-3.48(m,2H),3.80(br t,J=7.13Hz,2H),3.99(q,J=7.13Hz,1H),7.18–7.38(m,2H),7.43-7.54(m,1H),7.63(d,J=2.13Hz,1H).

[0340] Step 5: Synthesis of compound int_19-7:

[0341] Int_19-6 (20.0 g, 50.4 mmol), DIPEA (13.0 g, 101 mmol, 17.6 mL), ditert-butyl(cyclopentyl)phosphane, dichloropalladium, and iron (3.29 g, 5.04 mmol) were dissolved in 1,4-dioxane (300 mL). The atmosphere was purged with nitrogen three times, and the reaction mixture was heated to 110°C for 7 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature and slowly poured into 300 mL of ice water. The aqueous phase was extracted with ethyl acetate (300 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, which was then purified by column chromatography (SiO2, PE / EtOAc = 3 / 1) to obtain a solid (9.4 g, yield: 59%).

[0342] 1H NMR (400MHz, 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).

[0343] ESI-MS m / z:316[M+H] + .

[0344] Step 6: Synthesis of compound int_19-8:

[0345] Int_19-7 (9.40 g, 29.8 mmol) was dissolved in a mixture of n-butanol (15 mL) and water (5 mL). Sodium hydroxide (23.8 g, 595 mmol) was added to the reaction solution. The reaction mixture was heated to 100°C for 16 hours, then warmed to room temperature for 1 hour. LC-MS monitoring indicated the reaction was complete. Water (200 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (200 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 1 / 4) to obtain a solid (8 g, yield: 98.2%).

[0346] 1 H NMR (500MHz, 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 = 2.14Hz, 1H), 6.64 (dd, J = 5.57, 1.45Hz, 1H), 6.80 (d, J = 5.49Hz, 1H), 6.94 (d, J = 4.88Hz, 1H), 7.12-7.20 (m, 2H), 7.38 (dd, J = 4.81, 1.45Hz, 1H).

[0347] ESI-MS m / z:274[M+H] + .

[0348] Step 7: Synthesis of compound int_19-9:

[0349] 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). TEA (8.87 g, 87.7 mmol, 12.2 mL) was added to the reaction mixture at room temperature. Under nitrogen, the reaction mixture was allowed to react at room temperature for 16 hours. The reaction was monitored by LC-MS. The reaction mixture was slowly poured into 100 mL of ice water. The aqueous phase was extracted with dichloromethane (100 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, which was then purified by column chromatography (SiO2, PE / EtOAc = 3 / 1) to obtain a solid (8.9 g, yield: 81.5%).

[0350] 1 H NMR (400MHz, 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=5.50Hz,1H),6.85-6.95(m,1H),7.16-7.29(m,2H),7.41-7.49(m,1H).

[0351] Step 8: Synthesis of compound int_19-10:

[0352] 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 mixture was purged with nitrogen three times and allowed to react at room temperature for 2 hours. The reaction was monitored by LC-MS. The reaction mixture was slowly poured into 100 mL of ice water, and the aqueous phase was extracted with dichloromethane (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography to obtain a solid (2.6 g, yield: 96.2%).

[0353] ESI-MS m / z:406[M+H] + .

[0354] Step 9: Synthesis of compound int_19-11:

[0355] Int_19-10 (2.7 g, 6.686 mmol) was dissolved in a mixture of ethyl acetate (60 mL) and methanol (15 mL). Sodium borohydride (1.0 g, 26.744 mmol) was added to the reaction mixture. The reaction mixture was allowed to react at room temperature for 2 hours. The reaction was monitored by LC-MS. The reaction mixture was slowly poured into 100 mL of ice water. 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 obtain a crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 2 / 1) to obtain a solid (1.8 g, yield: 65.6%).

[0356] ESI-MS m / z:410[M+H] + .

[0357] Step 10: Synthesis of compound int_19-12:

[0358] Int_19-11 (1.2 g, 2.93 mmol) was dissolved in toluene (50 mL). p-Toluenesulfonic acid monohydrate (5.6 g, 29.3 mmol) was added to the reaction mixture. The reaction mixture was heated to 110°C for 1 hour. The reaction was monitored by LC-MS. The reaction mixture was cooled to room temperature and slowly poured into 50 mL of ice water. 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 a crude product, which was then purified by column chromatography to obtain a solid (310 mg, yield: 38.7%).

[0359] ESI-MS m / z:292[M+H] + .

[0360] Step 11: Synthesis of compound int_19-13:

[0361] Int_19-12 (1.87 g, 6.426 mmol) and (Boc)2O (2.1 g, 9.639 mmol) were dissolved in 1,4-dioxane (16 mL). TEA (973 mg, 9.639 mmol) was added to the reaction mixture at room temperature. Under nitrogen, the reaction mixture was heated to 80°C for 16 hours. The reaction was monitored by LC-MS. The reaction mixture was cooled to room temperature and the pH was adjusted to a weakly acidic state with 2M aqueous hydrochloric acid. 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 obtain the crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 2 / 1) to obtain a solid (1.6 g, yield: 63.5%).

[0362] ESI-MS m / z:392[M+H] + .

[0363] Step 12: Synthesis of compound int_19-14:

[0364] Int_19-13 (265 mg, 0.676 mmol) was dissolved in THF (10 mL) and cooled to -70°C. Under nitrogen, n-BuLi (2.5 M, 0.81 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to react at -70°C for 1 hour. DMF (148 mg, 2.028 mmol) was then added dropwise at -60°C. After the addition was complete, the reaction mixture was allowed to react at 70°C for 1 hour. The reaction was monitored by LC-MS. Saturated ammonium chloride solution (20 mL) was slowly added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (20 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, which was then purified by column chromatography (SiO2, PE / EtOAc = 5 / 1) to obtain a solid (170 mg, yield: 60.1%).

[0365] MS(ESI):420[M+H] + .

[0366] Step 13: Synthesis of compound int_19-15:

[0367] Int_1-9 (592 mg, 2.463 mmol) was dissolved in THF (10 mL) and cooled to -70°C. Under nitrogen, n-BuLi (2.5 M, 2 mL, 4.926 mmol) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to react at -70°C for 1 hour. Then, a solution of int_19-14 (170 mg, 0.411 mmol) in THF (1 mL) was added dropwise at -75°C. After the addition was complete, the reaction mixture was allowed to react at -75°C for 1 hour and then warmed to room temperature for 16 hours. LC-MS monitoring confirmed 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 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, which was then purified by column chromatography to obtain a solid (180 mg, yield: 81.2%).

[0368] MS(ESI):534[M+H] + .

[0369] Step 14: Synthesis of compound int_19-16:

[0370] Int_19-15 (180 mg, 0.337 mmol) was dissolved in DCM (15 mL). Dess-Martin periodinane (172 mg, 0.404 mmol) was added to the reaction mixture at room temperature and allowed to react for 1 hour. LC-MS monitoring confirmed the completion of the reaction. Saturated aqueous sodium bicarbonate was slowly added to the reaction mixture to adjust the pH to ~8. The aqueous phase was extracted with ethyl acetate (20 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, which was then purified by column chromatography (SiO2, PE / EtOAc = 2 / 1) to obtain a solid (156 mg, yield: 87.1%).

[0371] MS(ESI):532[M+H] + .

[0372] Step 15: Synthesis of compound int_19-17:

[0373] Int_19-16 (174 mg, 0.328 mmol) and int_1-12 (141 mg, 0.491 mmol) were dissolved in DMF (10 mL). KCO (138 mg, 1 mmol) was added to the reaction mixture at room temperature and allowed to react for 16 hours. LC-MS monitoring confirmed the completion of the reaction. Ice water (30 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (SiO, PE / EtOAc = 2 / 1) to obtain the product (230 mg, yield: 89.8%).

[0374] MS(ESI):783[M+H] + .

[0375] Step 16: Synthesis of compound int_19-18:

[0376] Int_19-17 (230 mg, 0.294 mmol) was dissolved in DMF (4 mL). Int_1-14 (67.8 mg, 0.587 mmol) was added to the reaction mixture at room temperature. The reaction mixture was allowed to react for 1 hour. LC-MS monitoring confirmed the completion of the reaction. Ice water (30 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain a solid (248 mg, 98% yield).

[0377] MS(ESI):862[M+H] + .

[0378] Step 17: Synthesis of compound int_19-19:

[0379] Int_19-18 (248 mg, 0.288 mmol) was dissolved in THF (4 mL). TBAF (1 M, 0.58 mL, 0.575 mmol) was added to the reaction mixture at room temperature and allowed to react for 16 hours. LC-MS monitoring confirmed the completion of the reaction. Water (30 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain a solid (183 mg, yield: 90.1%).

[0380] MS(ESI):706[M+H] + .

[0381] Step 18: Synthesis of compound 46:

[0382] Int_19-19 (172 mg, 0.244 mmol) was dissolved in dichloromethane (6 mL). TFA (1.5 mL) was added to the reaction mixture at room temperature and allowed to react for 10 minutes. LC-MS monitoring confirmed the completion of the reaction. Aqueous ammonia (1 mL) and water (10 mL) were added to the reaction mixture. 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 obtain the crude product, which was purified by preparative HPLC to yield a solid (65 mg, yield: 44.2%).

[0383] 1H NMR (400MHz, DMSO-d6) δ8.56(s,1H),8.49(s,1H),8.22(dd,J=7.5,4.3Hz,1H),7.42(d,J=3.7Hz,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=4.4Hz,1H),4.65(q,J=8.2Hz,1H),4.06(ddd,J=9.5,5. 4,2.2Hz,2H),3.93(dd,J=10.0,6.7Hz,2H),3.84(d,J=11.6Hz,1H),3.17–2.84(m,4H),2.70(d,J=16.2Hz,1H),2.28 (d,J=12.4Hz,1H),2.07(s,1H),1.89(s,1H),1.73(dt,J=13.7,7.6Hz,1H),1.30–1.19(m,1H),1.17(t,J=7.2Hz,1H).

[0384] MS(ESI):606[M+H] + .

[0385] Example 8 Synthesis of Compound 20 and Compound 21

[0386] Compound 19 (50 mg, 0.082 mmol) was subjected to SFC chiral separation (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 60%, isocratic elution mode) to give compound 20 (21 mg) and compound 21 (15 mg).

[0387] Compound 20: 11H 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] + .

[0388] SFC retention time: 1.910 min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak IG-3 50x4.6 mm I.D., 3 um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 4 mL / min; Column temp.: 35 °C; ABPR: 1500 psi).

[0389] Compound 21: 1H NMR (400MHz, DMSO-d6) δ8.58(s,1H),8.50(s,1H),8.21(d,J=7.5Hz,1H),7.44(s,2H),7.24–7.18(m,2H),7. 17(s,1H),6.90(d,J=1.9Hz,1H),5.07–4.94(m,2H),4.88(d,J=4.5Hz,1H),4.67(d,J=7.5Hz,1H),4.09(dd,J =9.6,6.0Hz,1H),4.02(d,J=11.3Hz,1H),3.99–3.89(m,2H),3.84(d,J=11.4Hz,1H),3.03(m,2H),2.88(m,2 H),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] + .

[0390] Analysis SFC retention time: 1.038min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak IG-3 50x4.6mm ID, 3um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 4mL / min; Column temp.:35℃; ABPR:1500psi).

[0391] Example 9 Synthesis of Compound 46

[0392] Step 1: Synthesis of compound int_46-1:

[0393] 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 replaced with hydrogen three times and allowed to react at room temperature under a hydrogen atmosphere (25 psi) for 16 hours. The reaction was monitored by LC-MS. The reaction solution was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, PE / EtOAc = 0 / 1) to obtain a solid (1.3 g, yield: 86.2%).

[0394] ESI-MS m / z:376[M+H] + .

[0395] Step 2: Synthesis of compound int_46-2:

[0396] Int_46-1 (0.30 g, 798 μmol) was dissolved in THF (10 mL) and cooled to -60°C. Under nitrogen, n-BuLi (2.50 M, 479 μL) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to react at -60°C for 1 hour. 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 hours. The reaction was monitored by LC-MS. Saturated ammonium chloride solution (100 mL) was slowly added to the reaction mixture. 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 obtain the crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 3 / 1) to obtain a solid (150 mg, yield: 46.5%).

[0397] MS(ESI):404[M+H] + .

[0398] Step 3: Synthesis of compound int_46-3:

[0399] Int_1-9 (4.79 g, 19.9 mmol) was dissolved in THF (50 mL) and cooled to -75°C. Under nitrogen, n-BuLi (2.5 M, 16 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to react at -75°C for 1 hour. Then, a solution of int_46-2 (1.3 g, 3.2 mmol) in THF (25 mL) was added dropwise at -75°C. After the addition was complete, the reaction mixture was allowed to react at -75°C for 1 hour and then warmed to room temperature for 16 hours. LC-MS monitoring confirmed the completion of the reaction. Saturated ammonium chloride solution (200 mL) was slowly added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (200 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, which was then purified by column chromatography to obtain a solid (1.15 g, yield: 69.6%).

[0400] MS(ESI):518[M+H] + .

[0401] Step 4: Synthesis of compound int_46-4:

[0402] Int_46-3 (0.200 g, 386 μmol) was dissolved in DCM (10 mL). Dess-Martin oxidant (327 mg, 772 μmol, 239 μL) was added to the reaction mixture at room temperature and allowed to react for 1 hour. LC-MS monitoring confirmed the completion of the reaction. Saturated aqueous sodium bicarbonate was slowly added to the reaction mixture to adjust the pH to ~8. The aqueous phase was extracted with ethyl acetate (30 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, which was then purified by column chromatography (SiO2, PE / EtOAc = 3 / 1) to obtain a solid (170 mg, yield: 85.3%).

[0403] 1 H NMR (400MHz, CHLOROFORM-d) δ = 9.10 (s, 1H), 8.71 (s, 1H), 7.12 (q, J = 8.0Hz, 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).

[0404] MS(ESI):516[M+H] + .

[0405] Step 5: Synthesis of compound int_46-5:

[0406] Int_46-4 (403 mg, 782 μmol) and int_1-12 (336 mg, 1.17 mmol) were dissolved in DMF (10 mL). K2CO3 (540 mg, 3.91 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 that 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 a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient) to obtain the product (0.5 g, yield: 83.3%).

[0407] MS(ESI):767[M+H] + .

[0408] Step 6: Synthesis of compound int_46-6:

[0409] Int_46-5 (0.500 g, 651 μmol) was dissolved in DMF (4 mL). Int_1-14 (150 mg, 1.30 mmol) was added to the reaction mixture at room temperature and allowed to react for 1 hour. LC-MS monitoring confirmed the completion of the reaction. Ice water (50 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain a solid (400 mg, yield: 72.5%).

[0410] MS(ESI):846[M+H] + .

[0411] Step 7: Synthesis of compound int_46-7:

[0412] Int_46-6 (0.400 g, 473 μmol) was dissolved in THF (4 mL). 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 that 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 a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient) to obtain a solid (170 mg, yield: 52.1%).

[0413] MS(ESI):690[M+H] + .

[0414] Step 8: Synthesis of compound 46:

[0415] Int_46-7 (0.17 g, 246 μmol) was added to TFA (0.500 mL) at room temperature, and the reaction mixture was allowed to react for 10 minutes. LC-MS monitoring confirmed the completion of the reaction. Aqueous ammonia (1 mL) and water (10 mL) were added to the reaction mixture, and the aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was purified by preparative HPLC (column: Boston Prime C18 150 x 30 mm x 5 μm; mobile phase: [water (ammonia hydroxide)-ACN]; gradient: 33% - 53% B over 16 min) to obtain a solid (35 mg, yield: 24.1%).

[0416] MS(ESI):590[M+H] + .

[0417] Example 10 Synthesis of Compound 47 and Compound 48

[0418] Compound 46 (50 mg, 84.7 μmol) was subjected to SFC chiral separation (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [CO2-EtOH (0.1% NH3H2O]; B%: 45%, isocratic elution mode) to give compound 47 (15 mg) and compound 48 (16 mg).

[0419] Compound 47: 11H NMR (400 MHz, 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] + .

[0420] Analytical SFC retention time: 0.758 min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak AD-3 50x4.6 mm I.D., 3 um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 4 mL / min; Column temp.: 35 °C; ABPR: 1500 psi).

[0421] Compound 48: 1H NMR (400MHz, DMSO-d6) δ = 8.57 (d, J = 10.8Hz, 2H), 8.18 (d, J = 7.5Hz, 1H), 7.45 (s, 2H), 7.23 (s, 1H), 7.18-7.12 (m,2H),6.77(d,J=1.8Hz,1H),4.88(d,J=4.5Hz,1H),4.76-4.55(m,1H),4.09(dd,J=6.0,9.7Hz,1H),3.96(br dd,J=7.0,9.8Hz,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] + .

[0422] Analysis SFC retention time: 0.545min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak AD-3 50x4.6mm ID, 3um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 4mL / min; Column temp.:35℃; ABPR:1500psi).

[0423] Example 11 Synthesis of Compound 49

[0424] Step 1: Synthesis of compound int_49-2:

[0425] Int_49-1 (59.0 g, 291 mmol) and NH₄OAc (51.52 g, 668.45 mmol) were dissolved in acetic acid (600 mL) and the atmosphere was replaced with nitrogen three times. Under nitrogen, CH₃NO₂ (46.1 g, 756 mmol, 40.9 mL) was added to the reaction solution. The reaction solution was heated to 100°C and stirred for 16 hours. LC-MS monitoring indicated 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 x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (60 g, yield: 83.9%), which was used directly in the next reaction.

[0426] Step 2: Synthesis of compound int_49-3:

[0427] LiBH4 (21.3 g, 975 mmol) was dissolved in tetrahydrofuran (300 mL). Under nitrogen, TMSCl (132.47 g, 1.22 mol, 154.75 mL) was added to the reaction mixture at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. A solution of int_49-2 (30 g, 122 mmol) in tetrahydrofuran (250 mL) was slowly added dropwise over 30 minutes. The reaction mixture was heated to 70°C and the reaction was continued for 2 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to 0°C and quenched by the slow addition of 200 mL of methanol. The organic phase was concentrated under reduced pressure to obtain the crude product. The pH of the crude product was adjusted to >7 with aqueous ammonia. The aqueous phase was extracted with ethyl acetate (500 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 (16 g, yield: 60.2%), which was used directly in the next reaction.

[0428] ESI-MS m / z:218[M+H] + .

[0429] Step 3: Synthesis of compound int_49-5:

[0430] 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 atmosphere was replaced with nitrogen three times, and the mixture was heated to 90°C and stirred for 2 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product (19 g, 93.7% yield), which was used directly in the next reaction.

[0431] ESI-MS m / z:338[M+H] + .

[0432] Step 4: Synthesis of compound int_49-6:

[0433] 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). The reaction mixture was incubated at 20°C under nitrogen for 2 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was adjusted to pH > 7 with saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with dichloromethane (500 mL x 3) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 3 / 1) to obtain a solid (9.2 g, yield: 43.1%).

[0434] Step 5: Synthesis of compound int_49-7:

[0435] Int_49-6 (7.10 g, 18.7 mmol), DIPEA (4.83 g, 37.3 mmol, 6.50 mL), ditert-butyl(cyclopentyl)phosphane, dichloropalladium, and iron (1.22 g, 1.87 mmol) were dissolved in 1,4-dioxane (100 mL). The atmosphere was purged with nitrogen three times, and the reaction mixture was heated to 110°C for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature and slowly poured into 200 mL of ice water. The aqueous phase was extracted with ethyl acetate (200 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, which was then purified by column chromatography (SiO2, PE / EtOAc = 2 / 1) to obtain a solid (4 g, yield: 71.6%).

[0436] ESI-MS m / z:300[M+H] + .

[0437] Step 6: Synthesis of compound int_49-8:

[0438] Int_49-7 (4.70 g, 15.7 mmol) was dissolved in a mixture of n-butanol (75 mL) and water (25 mL). Sodium hydroxide (12.6 g, 314 mmol) was added to the reaction mixture. The reaction mixture was heated to 100°C for 16 hours, then allowed to rise to room temperature for 1 hour. LC-MS monitoring indicated the reaction was complete. Water (100 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 1 / 4) to obtain a solid (4 g, yield: 99%).

[0439] ESI-MS m / z:258[M+H] + .

[0440] Step 7: Synthesis of compound int_49-9:

[0441] 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). TEA (4.72 g, 46.6 mmol, 6.49 mL) was added to the reaction mixture at room temperature. Under nitrogen, the reaction mixture was allowed to react at room temperature for 16 hours. The reaction was monitored by LC-MS. The reaction mixture was slowly poured into 100 mL of ice water. The aqueous phase was extracted with dichloromethane (100 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, which was then purified by column chromatography (SiO2, PE / EtOAc = 3 / 1) to obtain a solid (4 g, yield: 72%).

[0442] 1 H NMR (400MHz, DMSO-d6) δ = 1.05 (s, 9H), 2.80-2.98 (m, 2H), 3.65-3.85 (m, 2H), 6.14-6.26 (m, 1 H),6.41-6.55(m,1H),6.71(d,J=5.50Hz,1H),6.78-6.86(m,1H),6.88-7.00(m,1H),7.19(br dd,J=7.81,6.49Hz,1H),7.37(br d,J=4.62Hz,1H).

[0443] Step 8: Synthesis of compound int_49-10:

[0444] 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 replaced with hydrogen three times and allowed to react at room temperature under a hydrogen atmosphere (25 PSI) for 16 hours. The reaction was monitored by LC-MS. 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 column chromatography (SiO2, PE / EtOAc = 1 / 0 to 0 / 1) to obtain a solid (1.7 g, yield: 85%).

[0445] 1 H NMR (400MHz, 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=10.94,2.63Hz,1H),6.57(d,J=5.01Hz,1H),6.93-7.02(m,1H),7.19-7.28(m,1H),7.35(d,J=5.01Hz,1H).

[0446] ESI-MS m / z:360[M+H] + .

[0447] Step 9: Synthesis of compound int_49-11:

[0448] Int_49-10 (1.70 g, 4.73 mmol) was dissolved in THF (30 mL) and cooled to -60°C. Under nitrogen, n-BuLi (2.50 M, 2.84 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to react at -60°C for 1 hour. DMF (1.04 g, 14.2 mmol, 1.09 mL) was then added dropwise at -60°C. After the addition was complete, the reaction mixture was allowed to react at -60°C for 3 hours. LC-MS monitoring indicated the reaction was complete. Saturated ammonium chloride solution (100 mL) was slowly added to the reaction mixture. The aqueous phase was extracted with dichloromethane (100 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, which was then purified by column chromatography (SiO2, PE / EtOAc = 3 / 1) to obtain a solid (1.8 g, yield: 98.2%).

[0449] 1H NMR (400MHz, 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).

[0450] MS(ESI):388[M+H] + .

[0451] Step 10: Synthesis of compound int_49-12:

[0452] Int_1-9 (2.79 g, 11.6 mmol) was dissolved in THF (40 mL) and cooled to -70°C. Under nitrogen, n-BuLi (2.50 M, 9.29 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to react at -70°C for 1 hour. Then, a solution of int_49-11 (1.50 g, 3.87 mmol) in THF (20 mL) was added dropwise at -70°C. After the addition was complete, the reaction mixture was allowed to react at -70°C for 1 hour and then warmed to room temperature for 16 hours. LC-MS monitoring confirmed the completion of the reaction. Saturated ammonium chloride solution (200 mL) was slowly added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (200 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, which was then purified by column chromatography to obtain a solid (1.35 g, yield: 69.5%).

[0453] MS(ESI):502[M+H] + .

[0454] Step 11: Synthesis of compound int_49-13:

[0455] Int_49-12 (1.35 g, 2.69 mmol) was dissolved in DCM (25 mL). Dess-Martin periodinane (2.28 g, 5.38 mmol) was added to the reaction mixture at room temperature. The reaction mixture was allowed to react for 1 hour. LC-MS monitoring confirmed the completion of the reaction. Saturated aqueous sodium bicarbonate was slowly added to the reaction mixture to adjust the pH to ~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 obtain the crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 3 / 1) to obtain a solid (1 g, yield: 74.4%).

[0456] MS(ESI):500[M+H] + .

[0457] Step 12: Synthesis of compound int_49-14:

[0458] 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). 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 that 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 a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-80% Ethyl acetate / Petroleum ether gradient) to obtain the product (610 mg, yield: 67.7%).

[0459] MS(ESI):751[M+H] + .

[0460] Step 13: Synthesis of compound int_49-15:

[0461] Int_49-14 (610 mg, 812 μmol) was dissolved in DMF (20 mL). Int_1-14 (375 mg, 3.25 mmol) was added to the reaction mixture at room temperature. The reaction mixture was allowed to react for 1 hour. LC-MS monitoring confirmed the completion of the reaction. Ice water (50 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain a solid (670 mg, yield: 99.4%).

[0462] MS(ESI):830[M+H] + .

[0463] Step 14: Synthesis of compound int_49-16:

[0464] 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 showed that 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 a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-80% Ethyl acetate / Petroleum ether gradient) to obtain a solid (300 mg, yield: 55.2%).

[0465] 1H NMR (400MHz, 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).

[0466] MS(ESI):674[M+H] + .

[0467] Step 15: Synthesis of compound 49:

[0468] Int_49-16 (200 mg, 297 μmol) was added to TFA (0.5 mL) at room temperature, and the reaction mixture was allowed to react for 10 minutes. LC-MS monitoring confirmed the reaction was complete. Aqueous ammonia (1 mL) and water (30 mL) were added to the reaction mixture, and the aqueous phase was extracted with dichloromethane (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was purified by preparative HPLC (column: Boston Prime C18 150*30 mm x 5 μm; mobile phase: [water (ammonia hydroxide)-ACN]; gradient: 33%-53% B over 10 min) to obtain a solid (60 mg, yield: 35.2%).

[0469] MS(ESI):574[M+H] + .

[0470] Example 12 Synthesis of Compound 50 and Compound 51

[0471] Compound 49 (60 mg, 104 μmol) was subjected to SFC chiral separation (column: DAICEL CHIRALPAK IE (250 mm*30 mm, 10 um); mobile phase: [Heptane-EtOH (0.1% NH3H2O]; B%: 55%, isocratic elution mode) to give compound 50 (25 mg) and compound 51 (26 mg).

[0472] Compound 50: 1 H NMR(400MHz, 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),2.2 3-2.35(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),7.2 2-7.25(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] + .Analysis SFC retention time: 4.478min (Instrument: Shimadzu LC-20AD with PDA detector; Column: Chiralpak IE 100x4.6mm ID, 3um; Mobile phase: A: Hexane (0.1% DEA), B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 1mL / min; Column temp.:35℃).

[0473] Compound 51: 1H NMR(400MHz, 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),2.2 3-2.35(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),7.2 2-7.25(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] + .Analysis SFC retention time: 3.339min (Instrument: Shimadzu LC-20AD with PDA detector; Column: Chiralpak IE 100x4.6mm ID, 3um; Mobile phase: A: Hexane (0.1% DEA), B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 1mL / min; Column temp.:35℃).

[0474] Example 13 Synthesis of Compound 78

[0475] Step 1: Synthesis of compound int_78-1:

[0476] Int_78-1 (0.30 g, 798 μmol) was dissolved in THF (10 mL) and cooled to -60°C. Under nitrogen, n-BuLi (2.50 M, 479 μL) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to react at -60°C for 1 hour. 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 hours. The reaction was monitored by LC-MS. Saturated ammonium chloride solution (100 mL) was slowly added to the reaction mixture. 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 obtain the crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 2 / 1) to obtain a solid (140 mg, yield: 43.4%).

[0477] 1 H NMR (400MHz, 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=5.62Hz,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).

[0478] MS(ESI):402[M+H] + .

[0479] Step 2: Synthesis of compound int_78-2:

[0480] Int_1-9 (4.79 g, 19.9 mmol) was dissolved in THF (50 mL) and cooled to -75°C. Under nitrogen, n-BuLi (2.5 M, 16 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to react at -75°C for 1 hour. Then, a solution of int_78-1 (1.3 g, 3.2 mmol) in THF (25 mL) was added dropwise at -75°C. After the addition was complete, the reaction mixture was allowed to react at -75°C for 1 hour and then warmed to room temperature for 16 hours. LC-MS monitoring indicated the reaction was complete. Saturated ammonium chloride solution (200 mL) was slowly added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (200 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, which was then purified by column chromatography to obtain a solid (1.3 g, yield: 78.7%).

[0481] 1H NMR (400MHz, 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, 1 H),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).

[0482] MS(ESI):516[M+H] + .

[0483] Step 3: Synthesis of compound int_78-3:

[0484] Int_78-2 (1.60 g, 3.10 mmol) was dissolved in DCM (100 mL). Dess-Martin periodinane (2.63 g, 6.20 mmol) was added to the reaction mixture at room temperature. The reaction mixture was allowed to react for 1 hour. LC-MS monitoring confirmed the completion of the reaction. Saturated aqueous sodium bicarbonate was slowly added to the reaction mixture to adjust the pH to ~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 obtain the crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 2 / 1) to obtain a solid (0.9 g, yield: 56.5%).

[0485] MS(ESI):514[M+H] + .

[0486] Step 4: Synthesis of compound int_78-4:

[0487] 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). 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 that 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 a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient) to obtain the product (0.7 g, yield: 52.3%).

[0488] 1 H NMR(400MHz,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=7.68Hz,1H),6.57-6.61(m,2H) ,6.69(d,J=5.50Hz,1H),7.02(d,J=1.13Hz,2H),7.15(s,1H),7.86-8.06(m,1H),8.45(br dd,J=7.07,3.94Hz,1H),8.54(s,1H),8.59(s,1H).

[0489] MS(ESI):765[M+H] + .

[0490] Step 5: Synthesis of compound int_78-5:

[0491] Int_78-4 (0.70 g, 914 μmol) was dissolved in DMF (20 mL). Int_1-14 (423 mg, 3.66 mmol) was added to the reaction mixture at room temperature for 1 hour. LC-MS monitoring confirmed the completion of the reaction. Ice water (50 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain a solid (0.77 g, yield: 99.7%).

[0492] MS(ESI):844[M+H] + .

[0493] Step 6: Synthesis of compound int_78-6:

[0494] Int_78-5 (0.77 g, 912 μmol) was dissolved in THF (4 mL). 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 that 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 a crude product, which was then purified by column chromatography ( Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient) to obtain a solid (400 mg, yield: 63.8%).

[0495] MS(ESI):688[M+H] + .

[0496] Step 7: Synthesis of compound 78:

[0497] Int_78-6 (200 mg, 291 μmol) was added to TFA (0.500 mL) at room temperature, and the reaction mixture was allowed to react for 10 minutes. LC-MS monitoring confirmed the reaction was complete. Aqueous ammonia (1 mL) and water (10 mL) were added to the reaction mixture, and the aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (column: Boston Prime C18 150 x 30 mm x 5 μm; mobile phase: [water (ammonia hydroxide)-ACN]; gradient: 33% - 55% B over 10 min) to obtain a solid (90 mg, yield: 52.7%).

[0498] 1H NMR(400MHz, 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=12.38Hz,2H).

[0499] MS(ESI):588[M+H] + .

[0500] Example 14 Synthesis of Compound 175 and Compound 176

[0501] Compound 78 (100 mg, 170 μmol) was subjected to SFC chiral separation (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [CO2-EtOH (0.1% NH3H2O]; B%: 50%, isocratic elution mode) to give compound 175 (15 mg) and compound 176 (16 mg).

[0502] Compound 175: 11H 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] + .

[0503] Analysis of SFC retention time: 2.629 min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak AD-3 50x4.6 mm I.D., 3 um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Gradient: from 5% to 40% of B in 2 min and hold 40% for 1.2 min, then 5% of B for 0.8 min; Flow rate: 4 mL / min; Column temp.: 35 °C; ABPR: 1500 psi).

[0504] Compound 176: 1H NMR(400MHz, 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=12.38Hz,2H).;MS(ESI):588[M+H] + .

[0505] Analyze SFC retention time: 2.205min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak AD-3 50x4.6mm ID, 3um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Gradient: from 5% to 40% of B in 2min and hold 40% for 1.2min, then 5% of B for 0.8min; Flow rate: 4mL / min; Column temp.: 35℃; ABPR: 1500psi).

[0506] Example 15 Synthesis of Compound 91

[0507] Step 1: Synthesis of compound int_91-2:

[0508] Dissolve int_4-3 (9.00 g, 48.48 mmol) and int_91-1 (9.07 g, 53.33 mmol) in Ti(i-PrO)4 (170 mL). The atmosphere was purged with nitrogen three times. The mixture was heated to 80°C and stirred for 2 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature and used directly in the next reaction.

[0509] ESI-MS m / z:338[M+H]+ .

[0510] Step 2: Synthesis of compound int_91-3:

[0511] At -10°C, HCOOH (200 mL) was slowly added dropwise to Ac2O (500 mL). After the addition was complete, the reaction mixture was allowed to react at 20°C for 0.5 hours. The int_91-2 solution obtained in step 3 was then cooled to -10°C, and the HOOCH and Ac2O mixture was slowly added dropwise to the int_91-2 solution, maintaining the temperature at -10°C. After the addition was complete, the reaction mixture was heated to 70°C and reacted for 3 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was adjusted to pH >7 with saturated aqueous bicarbonate solution. The aqueous phase was extracted with ethyl acetate (500 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 1 / 1) to obtain a solid (2.3 g, yield: 11.7%).

[0512] 1 H NMR(400MHz,CHLOROFORM-d)δ7.91(s,1H),7.06(d,J=5.3Hz,1H),6.73(s,1H),6.70(s,1H),6.25(d,J=5.3Hz,1H),4.80–4.69(m, 1H),4.18(d,J=16.3Hz,1H),3.90(s,3H),3.71(dd,J=16.3,1.5Hz,1H),3.27–3.11(m,2H),3.06–2.97(m,2H),2.87–2.75(m,1H).

[0513] ESI-MS m / z:366[M+H] + .

[0514] Step 3: Synthesis of compound int_91-4:

[0515] Int_91-3 (3.50 g, 9.5 mmol) was dissolved in dichloromethane (30 mL) and the atmosphere was replaced with nitrogen three times. The reaction solution was cooled to 0°C and BBr3 (11.88 g, 47.43 mmol) was slowly added dropwise to the reaction solution. The reaction solution was warmed to room temperature and reacted for 1 hour. LC-MS monitoring indicated 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 x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (3 g, yield: 90.9%), which was used directly in the next reaction.

[0516] ESI-MS m / z:352[M+H] + .

[0517] Step 4: Synthesis of compound int_91-5:

[0518] 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 atmosphere was replaced with nitrogen three times, and the reaction mixture was allowed to react at room temperature for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was slowly poured into 300 mL of ice water, and the aqueous phase was extracted with ethyl acetate (300 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 1 / 1) to obtain a solid (2.9 g, yield: 70.7%).

[0519] ESI-MS m / z:484[M+H] + .

[0520] Step 5: Synthesis of compound int_91-6:

[0521] 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 mixture was purged with hydrogen three times and allowed to react at room temperature for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was filtered to obtain a filtrate, which was then concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, PE / EtOAc = 1 / 1) to obtain a solid (0.85 g, yield: 42.5%).

[0522] ESI-MS m / z:336[M+H] +.

[0523] Step 6: Synthesis of compound int_91-7:

[0524] Int_91-6 (0.85 g, 2.53 mmol) was dissolved in THF (10 mL) and cooled to -30°C. Under nitrogen, n-BuLi (2.5 M, 3.04 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to react at -30°C for 2 hours, then warmed to room temperature for 1 hour. LC-MS monitoring indicated the reaction was complete. Saturated aqueous ammonium chloride (10 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (0.71 g, yield: 91.2%), which was used directly in the next reaction.

[0525] 1 H NMR (400MHz, DMSO-d6) δ7.16(d,J=1.4Hz,2H),7.14(d,J=5.3Hz,1H),6.85(t,J=1.3Hz,1H),6.35(d,J=5.3Hz,1H),4.16(d,J=16. 1Hz,1H),3.69(dd,J=16.0,1.3Hz,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).

[0526] ESI-MS m / z:308[M+H] + .

[0527] Step 7: Synthesis of compound int_91-8:

[0528] Int_91-7 (0.71 g, 2.30 mmol) and (Boc)2O (1 g, 4.60 mmol) were dissolved in 1,4-dioxane (10 mL). TEA (581.8 mg, 5.75 mmol, 801.4 μL) was added to the reaction mixture at room temperature. The reaction mixture was heated to 80°C for 16 hours and monitored by LC-MS. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (SiO2, PE / EtOAc = 10 / 1) to obtain a solid (0.65 g, yield: 69.2%).

[0529] 1H NMR (400MHz, DMSO-d6) δ7.29(d,J=5.3Hz,1H),7.24(d,J=1.4Hz,2H),6.73(t,J=1.3Hz,1 H),6.53(d,J=5.3Hz,1H),4.23(dt,J=12.1,3.7Hz,1H),3.96(d,J=16.1Hz,1H),3.90(d, J=13.5Hz,1H),3.81(dd,J=16.1,1.5Hz,1H),3.15(td,J=12.0,3.2Hz,1H),2.98(ddd,J= 15.8, 11.7, 4.1Hz, 1H), 2.89 (dt, J = 15.5, 3.3Hz, 1H), 2.52 (d, J = 1.6Hz, 1H), 1.15 (s, 9H).

[0530] ESI-MS m / z:408[M+H] + .

[0531] Step 8: Synthesis of compound int_91-9:

[0532] Int_91-8 (1.5 g, 3.67 mmol) was dissolved in THF (20 mL) and cooled to -75°C. Under nitrogen, n-BuLi (2.5 M, 4.43 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to react at -75°C for 1 hour. DMF (809 mg, 11.08 mmol) was then added dropwise at -75°C. After the addition was complete, the reaction mixture was allowed to react at -75°C for 1 hour. The reaction was monitored by LC-MS. Saturated ammonium chloride solution (100 mL) was slowly added to the reaction mixture. 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 obtain the crude product, which was then purified by column chromatography to obtain a solid (1.25 g, yield: 78.1%).

[0533] MS(ESI):436[M+H] + .

[0534] Step 9: Synthesis of compound int_91-10:

[0535] Int_1-9 (4.8 g, 19.92 mmol) was dissolved in THF (50 mL) and cooled to -75°C. Under nitrogen, n-BuLi (2.5 M, 16 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to react at -75°C for 1 hour. Then, a solution of int_91-9 (1.45 g, 3.33 mmol) in THF (25 mL) was added dropwise at -75°C. After the addition was complete, the reaction mixture was allowed to react at -75°C for 1 hour and then warmed to room temperature for 16 hours. LC-MS monitoring indicated the reaction was complete. Saturated ammonium chloride solution (200 mL) was slowly added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (200 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, which was then purified by column chromatography to obtain a solid (1.51 g, yield: 82.5%).

[0536] MS(ESI):550[M+H] + .

[0537] Step 10: Synthesis of compound int_91-11:

[0538] Oxalyl chloride (413.7 mg, 3.26 mmol, 279 μL) was dissolved in dichloromethane (20 mL). Dimethyl sulfoxide (254.7 mg, 3.26 mmol, 231 μL) was slowly added dropwise to the reaction mixture at -78°C. The reaction mixture was allowed to react at -78°C for 0.5 h. Int_91-10 (1.5 g, 2.72 mmol) dissolved in DCM (10 mL) was then added dropwise to the reaction mixture. The reaction mixture was allowed to react at -78°C for another 0.5 h. Triethylamine (1.65 g, 16.32 mmol) was then added dropwise to the reaction mixture. The reaction mixture was allowed to react at -78°C for another 0.5 h, then slowly warmed to room temperature. LC-MS monitoring confirmed the completion of the reaction. Saturated aqueous sodium bicarbonate solution was slowly added to the reaction mixture to adjust the pH to ~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 obtain a crude product, which was purified by column chromatography to obtain a solid (1.38 g, yield: 92.6%).

[0539] MS(ESI):548[M+H] + .

[0540] Step 11: Synthesis of compound int_91-12:

[0541] 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). KCO (829.2 mg, 6.0 mmol) was added to the reaction mixture at room temperature and allowed to react for 3 hours. LC-MS monitoring confirmed the completion of the reaction. Ice water (100 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain the product (1.37 g, yield: 86.1%).

[0542] MS(ESI):799[M+H] + .

[0543] Step 12: Synthesis of compound int_91-13:

[0544] Int_91-12 (1.37 g, 1.71 mmol) was dissolved in DMF (30 mL). Int_1-14 (395.9 mg, 3.42 mmol) was added to the reaction mixture at room temperature. The reaction mixture was allowed to react for 1 hour. LC-MS monitoring confirmed the completion of the reaction. Ice water (50 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain a solid (1.3 g, yield: 86.6%).

[0545] MS(ESI):878[M+H] + .

[0546] Step 13: Synthesis of compound int_91-14:

[0547] Int_91-13 (1.58 g, 1.8 mmol) was dissolved in THF (20 mL). TBAF (1 M, 3.6 mL) was added to the reaction mixture at room temperature and allowed to react for 4 hours. LC-MS monitoring confirmed the completion of the reaction. Water (50 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain a solid (1.05 g, yield: 80.7%).

[0548] MS(ESI):722[M+H] + .

[0549] Step 14: Synthesis of Compound 91

[0550] Int_91-14 (1.05 g, 1.45 mmol) was dissolved in DCM (7 mL) at room temperature and TFA (7.8 mL) was added. The reaction mixture was allowed to react at room temperature for 5 minutes. LC-MS monitoring confirmed the completion of the reaction. The mixture was cooled to 0°C and the pH was adjusted to 8 by adding saturated aqueous sodium bicarbonate. 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, which was purified by preparative HPLC to yield a solid (862 mg, 95.3% yield).

[0551] 1 H NMR (400MHz, DMSO-d6) δ8.54(s,1H),8.38(d,J=1.2Hz,1H),8.20(d,J=7.4Hz,1H),7.41(d,J=2.2Hz, 2H),7.21–7.09(m,2H),7.00–6.92(m,2H),4.88(dd,J=4.6,3.0Hz,1H),4.63(h,J=8.0Hz,1H),4.27(d ,J=16.8Hz,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=15.9Hz,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).

[0552] MS(ESI):622[M+H] + .

[0553] Example 16 Synthesis of Compound 92 and Compound 93

[0554] Compound 91 (85 mg, 0.136 mmol) was subjected to SFC chiral separation to obtain compound 92 (27 mg) and compound 93 (29 mg).

[0555] Compound 92: 1H NMR (400MHz, DMSO-d6) δ8.54(s,1H),8.38(d,J=1.2Hz,1H),8.20(d,J=7.4Hz,1H),7.41(d,J=2.2Hz,2H),7.21–7.09(m,2H ),7.00–6.92(m,2H),4.88(dd,J=4.6,3.0Hz,1H),4.63(h,J=8.0Hz,1H),4.27(d,J=16.8Hz,1H),4.09–4.03(m,1H),3.97– 3.81(m,3H),3.31–3.16(m,3H),3.01(d,J=9.6Hz,2H),2.89(dt,J=16.0,7.1Hz,1H),2.67(d,J=15.9Hz,1H),2.25(dt,J=15. 4,7.7Hz,1H),2.07(d,J=7.4Hz,1H),1.93–1.83(m,1H),1.72(dt,J=15.2,6.6Hz,1H),1.32–1.18(m,1H).;MS(ESI):622[M+H] + .

[0556] Compound 93: 1 H NMR (400MHz, DMSO-d6) δ8.55(s,1H),8.38(d,J=1.2Hz,1H),8.21(d,J=7.4Hz,1H),7.42(d,J=2.2Hz,2H),7.21–7.09(m,2H) ,7.01–6.92(m,2H),4.89(dd,J=4.6,3.0Hz,1H),4.64(h,J=8.0Hz,1H),4.28(d,J=16.8Hz,1H),4.10–4.03(m,1H),3.97–3. 82(m,3H),3.32–3.16(m,3H),3.01(d,J=9.6Hz,2H),2.90(dt,J=16.0,7.1Hz,1H),2.67(d,J=15.9Hz,1H),2.26(dt,J=15.4 ,7.7Hz,1H),2.07(d,J=7.4Hz,1H),1.94–1.83(m,1H),1.73(dt,J=15.2,6.6Hz,1H),1.32–1.19(m,1H).;MS(ESI):622[M+H] + .

[0557] Example 17 Synthesis of Compound 112

[0558] Step 1: Synthesis of compound int_112-1:

[0559] Int_19-10 (2.5 g, 6.15 mmol) was dissolved in a mixed solvent of ethyl acetate (60 mL) and methanol (15 mL). 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 allowed to react at room temperature for 16 hours, monitored by LC-MS. 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 x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography to obtain a solid (2.1 g, yield: 84.3%).

[0560] ESI-MS m / z:405[M+H] + .

[0561] Step 2: Synthesis of compound int_112-2:

[0562] Int_112-1 (283.4 mg, 0.7 mmol) was dissolved in THF (10 mL) and cooled to -70°C. Under nitrogen, n-BuLi (2.5 M, 0.83 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to react at -70°C for 1 hour. DMF (153 mg, 2.1 mmol) was then added dropwise at -60°C. After the addition was complete, the reaction mixture was allowed to react at 70°C for 1 hour. The reaction was monitored by LC-MS. Saturated ammonium chloride solution (20 mL) was slowly added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (20 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, which was then purified by column chromatography to obtain a solid (169 mg, yield: 55.7%).

[0563] MS(ESI):433[M+H] + .

[0564] Step 3: Synthesis of compound int_112-3:

[0565] Int_1-9 (577 mg, 2.4 mmol) was dissolved in THF (10 mL) and cooled to -70°C. n-BuLi (2.5 M, 1.9 mL, 4.8 mmol) was slowly added dropwise to the reaction mixture under nitrogen. The reaction mixture was reacted at -70°C for 1 hour. Then, a solution of int_112-2 (173.1 mg, 0.4 mmol) in THF (1 mL) was added dropwise at -75°C. After the addition was complete, the reaction mixture was reacted at -75°C for 1 hour and then warmed to room temperature for 16 hours. LC-MS monitoring confirmed 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 obtain the crude product, which was purified by column chromatography to obtain a solid (162 mg, yield: 73.9%).

[0566] MS(ESI):547[M+H] + .

[0567] Step 4: Synthesis of compound int_112-4:

[0568] Oxalyl chloride (415 mg, 3.27 mmol, 280 μL) was dissolved in dichloromethane (20 mL). Dimethyl sulfoxide (254.75 mg, 3.27 mmol, 232 μL) was slowly added dropwise to the reaction mixture at -78°C. The reaction mixture was allowed to react at -78°C for 0.5 h. Int_112-3 (1.5 g, 2.73 mmol) dissolved in DCM (10 mL) was then added dropwise to the reaction mixture. The reaction mixture was allowed to react at -78°C for another 0.5 h. Triethylamine (1.65 g, 16.32 mmol) was then added dropwise to the reaction mixture. The reaction mixture was allowed to react at -78°C for another 0.5 h, then slowly warmed to room temperature. LC-MS monitoring confirmed the completion of the reaction. Saturated aqueous sodium bicarbonate solution was slowly added to the reaction mixture to adjust the pH to ~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 obtain a crude product, which was purified by column chromatography to obtain a solid (0.56 g, yield: 37.8%).

[0569] MS(ESI):545[M+H] + .

[0570] Step 5: Synthesis of compound int_112-5:

[0571] 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). KCO (207.3 mg, 1.5 mmol) was added to the reaction mixture at room temperature and allowed to react for 16 hours. LC-MS monitoring confirmed the completion of the reaction. Ice water (30 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain the product (237 mg, yield: 59.5%).

[0572] MS(ESI):796[M+H] + .

[0573] Step 6: Synthesis of compound int_112-6:

[0574] Int_112-5 (280 mg, 0.35 mmol) was dissolved in DMF (4 mL). Int_1-14 (80.8 mg, 0.7 mmol) was added to the reaction mixture at room temperature. The reaction mixture was allowed to react for 1 hour. LC-MS monitoring confirmed the completion of the reaction. Ice water (30 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography to obtain a solid (255 mg, yield: 83.3%).

[0575] MS(ESI):875[M+H] + .

[0576] Step 7: Synthesis of compound int_112-7:

[0577] Int_112-6 (255 mg, 0.29 mmol) was dissolved in THF (4 mL). TBAF (1 M, 0.58 mL, 0.58 mmol) was added to the reaction mixture at room temperature and allowed to react for 16 hours. LC-MS monitoring confirmed the completion of the reaction. Water (30 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain a solid (170 mg, yield: 81.3%).

[0578] MS(ESI):719[M+H] + .

[0579] Step 8: Synthesis of compound 112:

[0580] Int_112-7 (170 mg, 0.236 mmol) was dissolved in dichloromethane (6 mL). TFA (1.5 mL) was added to the reaction mixture at room temperature and allowed to react for 10 minutes. LC-MS monitoring confirmed the completion of the reaction. Aqueous ammonia (1 mL) and water (10 mL) were added to the reaction mixture. 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 obtain the crude product, which was purified by preparative HPLC to yield a solid (87 mg, yield: 59.5%).

[0581] MS(ESI):619[M+H] + .

[0582] Example 18 Synthesis of Compound 113 and Compound 114

[0583] Compound 112 (80 mg, 0.129 mmol) was subjected to SFC chiral separation (column: Phenomenex-Cellulose-2 (250 mm*30 mm, 10 um)); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; B%: 45%, isocratic elution mode) to give compound 113 (21 mg) and compound 114 (25 mg).

[0584] Compound 113: 1 H NMR (400MHz, DMSO-d6) δ8.57(s,1H),8.45(s,1H),8.20(d,J=7.5Hz,1H),7.44(s,2H),7.20(d,J=3.4Hz,2H),7.08 (s,1H),6.92(d,J=2.0Hz,1H),4.90(s,1H),4.66(q,J=8.2Hz,1H),4.08(dd,J=9.7,6.0Hz,1H),4.04–3.81(m,3H) ,3.72(d,J=16.2Hz,1H),3.17–2.87(m,4H),2.74(d,J=12.2Hz,2H),2.43(s,3H),2.27(dt,J=12.7,7.8Hz,1H),2. 09(d,J=7.6Hz,1H),1.94(ddd,J=11.9,7.4,3.7Hz,1H),1.83–1.67(m,1H),1.33–1.16(m,1H).;MS(ESI):619[M+H] + .

[0585] Analysis SFC retention time: 4.624min (Instrument: Waters UPCC with PDA Detector and QDa Detector; Column: Cellulose-2 100×4.6mm, ID, 3um; Mobile phase: A: CO2, B: Methanol (0.05% DEA); Isocratic: 50% B; Flow rate: 2.8mL / min; Column temp.:35℃; ABPR:1500psi).

[0586] Compound 114: 1 H NMR (400MHz, DMSO-d6) δ8.57(s,1H),8.44(s,1H),8.18(d,J=7.5Hz,1H),7.45(s,2H),7.18(d,J=2.8Hz,2H),7.08(s,1H),6.9 1(s,1H),4.89(d,J=4.3Hz,1H),4.66(q,J=8.0Hz,1H),4.08(dd,J=9.7,5.9Hz,1H),3.95(dd,J=9.9,6.9Hz,2H),3.84(d,J=16 .1Hz,1H),3.72(d,J=16.1Hz,1H),2.96(dd,J=36.7,25.1Hz,4H),2.71(dd,J=13.5,7.5Hz,2H),2.41(s,3H),2.29(dt,J=14.2 ,7.7Hz,1H),2.10(s,1H),1.97–1.84(m,1H),1.72(dt,J=13.3,7.4Hz,1H),1.26(dd,J=15.7,6.7Hz,1H).;MS(ESI):619[M+H] + .

[0587] Analysis SFC retention time: 3.796min (Instrument: Waters UPCC with PDA Detector and QDa Detector; Column: Cellulose-2 100×4.6mm, ID, 3um; Mobile phase: A: CO2, B: Methanol (0.05% DEA); Isocratic: 50% B; Flow rate: 2.8mL / min; Column temp.:35℃; ABPR:1500psi).

[0588] Example 19 Synthesis of Compound 172

[0589] Step 1: Synthesis of compound int_172-3:

[0590] Int_172-2 (2.22 g, 5.19 mmol) was dissolved in anhydrous THF (20 mL), replaced with nitrogen three times, and cooled to -10°C. LiHMDS (10.4 mL, 1 M) was added dropwise to the reaction mixture, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was then cooled to -10°C, and a solution of int_172-1 (1 g, 2.59 mmol) in anhydrous THF (10 mL) was added dropwise. The reaction mixture was slowly warmed to room temperature and allowed to react for 1 hour. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature and slowly poured into 50 mL of saturated ammonium chloride. 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, which was then purified by column chromatography (SiO2, PE / EtOAc = 3 / 1) to obtain a solid (298 mg, yield: 20%).

[0591] ESI-MS m / z:563[M+H] + .

[0592] Step 2: Synthesis of compound int_172-4:

[0593] Int_172-3 (298 mg, 0.529 mmol) and Pd(OH)2 (30 mg) were dissolved in ethanol (30 mL). The reaction solution was replaced with hydrogen three times and allowed to react at room temperature under a hydrogen atmosphere for 16 hours. The reaction was monitored by LC-MS. The reaction solution was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (290 mg, yield: 97.3%).

[0594] ESI-MS m / z:565[M+H] + .

[0595] Step 3: Synthesis of compound int_172-5:

[0596] Dissolve int_172-4 (310 mg, 0.529 mmol) in dichloromethane (10 mL) and add HCl / Dioxane (4 mL, 15.87 mmol). Stir the reaction at room temperature for 2 hours. LC-MS monitoring indicates the reaction is complete. Cool the reaction to room temperature and concentrate under reduced pressure to obtain the crude product, which is used directly in the next reaction.

[0597] ESI-MS m / z:209[M+H]+ .

[0598] Step 4: Synthesis of compound int_172-6:

[0599] 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). The reaction mixture was heated to 60°C for 4 hours. LC-MS monitoring confirmed the completion of the reaction. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain the product (59 mg, 44% yield).

[0600] MS(ESI):702[M+H] + .

[0601] Step 5: Synthesis of compound 172

[0602] Int_172-6 (59 mg, 0.084 mmol) was dissolved in DCM (1 mL) at room temperature and TFA (0.35 mL) was added. The reaction mixture was allowed to react at room temperature for 30 minutes. LC-MS monitoring confirmed the completion of the reaction. The mixture was cooled to 0°C and the pH was adjusted to 8 by the addition of triethylamine. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by preparative HPLC to afford a solid (26 mg, 51% yield).

[0603] 1 H NMR (400MHz, DMSO-d6) δ8.53 (s, 1H), 8.48 (d, J = 1.6 Hz, 1H), 8.21 (d, J = 7.5 Hz,1H),7.12(d,J=2.0Hz,2H),6.91(s,1H),6.74(s,1H),6.70(s,2H),4.78(t,J=4.6Hz ,1H),4.55(h,J=7.8Hz,1H),3.75(p,J=6.3Hz,1H),3.06–2.87(m,6H),2.87–2.79(m,1H ),2.63(dt,J=16.2,3.3Hz,1H),2.25(dt,J=12.9,7.3Hz,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=14.1,9.5,4.8Hz,1H).

[0604] MS(ESI):602[M+H] + .

[0605] Example 20 Synthesis of Compound 173 and Compound 174

[0606] 172 (100 mg, 0.166 mmol) was subjected to SFC chiral separation to give compound 173 (47 mg) and compound 174 (43 mg).

[0607] Compound 173: 1 H NMR (400MHz, DMSO-d6) δ8.53(s,1H),8.48(d,J=1.6Hz,1H),8.21(d,J=7.5Hz,1H),7.12(d,J=2.0Hz,2H),6.91 (s,1H),6.74(s,1H),6.70(s,2H),4.78(t,J=4.6Hz,1H),4.55(h,J=7.8Hz,1H),3.75(p,J=6.3Hz,1H),3.06–2. 87(m,6H),2.87–2.79(m,1H),2.63(dt,J=16.2,3.3Hz,1H),2.25(dt,J=12.9,7.3Hz,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=14.1,9.5,4.8Hz,1H).;MS(ESI):602[M+H] + .

[0608] Compound 174: 1 H NMR (400MHz, DMSO-d6) δ8.53(s,1H),8.48(d,J=1.6Hz,1H),8.21(d,J=7.5Hz,1H),7.12(d,J=2.0Hz,2H),6.91 (s,1H),6.74(s,1H),6.70(s,2H),4.78(t,J=4.6Hz,1H),4.55(h,J=7.8Hz,1H),3.75(p,J=6.3Hz,1H),3.06–2. 87(m,6H),2.87–2.79(m,1H),2.63(dt,J=16.2,3.3Hz,1H),2.25(dt,J=12.9,7.3Hz,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=14.1,9.5,4.8Hz,1H).;MS(ESI):602[M+H]+ .

[0609] Using the above synthesis method and different raw materials, the target compounds 10-18, 22-45, 52-77, 79-90, 94-111, 115-171 and 177-300 in Table 1 can be obtained.

[0610] Table 1

[0611] Biological Example 1 In vitro SAE inhibition activity test of the compounds of the present invention

[0612] Approximately 20,000 HCT116 cells / well were seeded into a 96-well black transparent bottom plate, with 90uL per well. Incubate overnight at 37°C for 24 hours. Dilute the test compound to 10 times the final concentration and add 10uL to the cell culture plate. Incubate at 37°C for 6 hours. Then rinse the cells, discard the culture medium, and wash the cells once with 200uL 0.1% PBST. Add 50uL 4% PFA to each well and fix at room temperature for 20 minutes, then wash 2-3 times with PBS, add 50uL 0.2% Triton X-100 to each well, let it stand at room temperature for 15 minutes, and wash 3 times with 0.1% PBST. Add 100uL 3% BSA (0.6g BSA + 20mL PBS) to each well and block at 37°C for 30 minutes. After blocking, remove the liquid and prepare the primary antibody (SUMO-2 / 3 (18H8) Rabbit mAb, 1:400 dilution) with 1% BSA. Add 30uL of diluted primary antibody to each well and incubate at 4°C overnight. Wash the cells 3 times with 200uL of 0.1% PBST. Then prepare FITC secondary antibody (Fluorescein (FITC)–conjugated Affinipure Goat Anti-Rabbit IgG (H+L), 1:300 dilution) with 1% BSA, add 40uL of diluted secondary antibody to each well, incubate at room temperature in the dark for 2 hours, and then wash 4 times with 0.1% PBST. Detect the sample fluorescence signal and compare it with the DMSO group to calculate the inhibition rate and IC 50 The results are shown in Table 2 below.

[0613] Table 2. Inhibitory activity of the compounds of the present invention against SAE (IC 50 ,nM)

[0614] Table 3. Inhibitory activity of the compounds of the present invention against SAE (IC 50 ,nM)

[0615] +++ indicates IC 50 Less than or equal to 50nM

[0616] ++ indicates IC 50 50nM to 200nM

[0617] + indicates IC 50 Greater than 200nM

[0618] TAK-981 is compound I-263a in WO2016004136A1, and its chemical structure is as follows:

[0619] It can be seen from the data in Table 2 and Table 3 that, compared with TAK-981, most of the compounds in the present invention have stronger inhibitory activity against SAE in the in vitro SAE activity inhibition experiment.

[0620] Biological Example 2 In vitro test of the killing activity of the compounds of the present invention on NK cells against tumor cells OVCAR3

[0621] Approximately 8,000 OVCAR3 cells / well and approximately 80,000 NK92MI cells / well were seeded into 96-well black clear cell culture plates, with 90 μL per well. The cells were incubated overnight at 37°C for 24 hours. The test compound was diluted to a 10-fold final concentration and 10 μL was added to the cell culture plate. The cells were incubated at 37°C for 48 hours. The OVCAR3 cell culture medium was discarded, and the OVCAR3 cells were stained with 1 μM calcein AM for 50 minutes. The cells were washed once with PBS, and 100 μL of culture medium was added. The NK92MI cells were mixed and then gently added to the OVCAR3 cells. After approximately 4 hours of co-incubation, the DMSO control group and the high-concentration drug group were photographed using PICO to observe the cytotoxicity of the NK92MI cells against the OVCAR3 cells. Co-incubation was terminated when a significant difference in cytotoxicity between the two groups was observed. The culture medium was discarded, and the cells were rinsed once with 100 μL of PBS. Add 100 μL of 4% PFA to each well and fix the cells at room temperature for 20 minutes. Rinse once with PBS and detect the fluorescence signal of the sample through the FITC channel of the microplate reader. Compare with the DMSO group and calculate the inhibition rate and IC 50 .

[0622] Biological Example 3 In vivo pharmacokinetic study of the compounds of the present invention

[0623] Female CD-1 mice aged 6 to 8 weeks were selected and the intravenous dose was 2 mg / Kg. The mice were fasted for at least 12 hours before administration, and food was resumed after administration. Water was freely available throughout the experiment. On the day of the experiment, the animals in the intravenous group were given a single injection of the corresponding compound through the tail vein, with a dosage of 0.2 mL / mouse. The sample collection time was: 0.083, 0.167, 0.5, 1, 2, 4, 8, and 24 hours. Approximately 150uL of whole blood (30uL of whole blood 1 / 3 was diluted with ultrapure water, and 120uL of whole blood was centrifuged to obtain plasma) was collected through the submandibular venous plexus at each time point for concentration determination by high performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). All animals were killed after the PK sample at the last time point was collected. Phoenix WinNonlin was used. TM Plasma concentrations were processed using a non-compartmental model using version 8.3 (Certara) pharmacokinetic software, and pharmacokinetic parameters were calculated using the linear-log trapezoidal method. The in vivo pharmacokinetic results are shown in Tables 4 and 5 below.

[0624] Table 4 In vivo pharmacokinetic evaluation results of the compounds of the present invention

[0625] Table 5 Plasma drug concentration and whole blood drug concentration of the compounds of the present invention

[0626] Biological Example 4 In vivo efficacy study - mouse MC38 subcutaneous transplant tumor model

[0627] Each C57BL / 6 mouse was subcutaneously inoculated with 1×10 6 MC38 cells, wait until the tumor grows to 100-200 mm 3 Tumor volumes were measured twice weekly and at the endpoint of dosing for the following treatments: vehicle, compound alone (intravenous injection, twice weekly), anti-PD-1 antibody alone (intravenous injection, once weekly), anti-VEGF antibody alone (intraperitoneal injection, once weekly), anti-PD-1 antibody (intravenous injection, once weekly) in combination with anti-VEGF antibody (intraperitoneal injection, once weekly), compound (intravenous injection, twice weekly) in combination with anti-PD-1 antibody (intravenous injection, once weekly), compound (intravenous injection, twice weekly) in combination with anti-VEGF antibody (intraperitoneal injection, once weekly), or compound (intravenous injection, twice weekly) in combination with anti-PD-1 antibody (intravenous injection, once weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly). Tumor growth inhibition rate (TGI) of the compound was calculated as 1-(tumor volume of the dosing group on day 20 - tumor volume of the dosing group on day 1) / (tumor volume of the vehicle control group on day 20 - tumor volume of the dosing group on day 1).

[0628] Biological Example 5 In vivo efficacy study - mouse MC38 subcutaneous transplant tumor model

[0629] Each C57BL / 6 mouse was subcutaneously inoculated with 1×10 6 MC38 cells, wait until the tumor grows to 50-80 mm 3Tumor volumes were measured twice weekly and at the endpoint of dosing for the following treatments: vehicle, compound alone (intravenous injection, twice weekly), anti-PD-1 antibody alone (intravenous injection, once weekly), anti-VEGF antibody alone (intraperitoneal injection, once weekly), combination of anti-PD-1 antibody (intravenous injection, once weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly), compound (intravenous injection, twice weekly) and anti-PD-1 antibody (intravenous injection, once weekly), compound (intravenous injection, twice weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly), or compound (intravenous injection, twice weekly) and anti-PD-1 antibody (intravenous injection, once weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly). Tumor growth inhibition rate (TGI) of the compound was calculated as 1-(tumor volume of the dosing group on day 20 - tumor volume of the dosing group on day 1) / (tumor volume of the vehicle control group on day 20 - tumor volume of the dosing group on day 1).

[0630] Biological Example 6 In vivo efficacy study - mouse MC38 subcutaneous transplant tumor model

[0631] Each C57BL / 6 mouse was subcutaneously inoculated with 1×10 6 MC38 cells were inoculated and dosed immediately after cell inoculation. Tumor volumes were measured twice weekly at the endpoint. Tumor growth inhibition (TGI) was calculated as 1-(tumor volume on day 20 of the treatment group - tumor volume on day 1 of the treatment group) / (tumor volume on day 20 of the vehicle control group - tumor volume on day 1 of the treatment group).

[0632] Biological Example 7 In vivo efficacy study - mouse CT26 subcutaneous transplant tumor model

[0633] Each BALB / c mouse was subcutaneously inoculated with 2×10 5 CT26 cells, wait until the tumor grows to 100-200 mm 3 Tumor volumes were measured twice weekly and at the endpoint of dosing for the following treatments: vehicle, compound alone (intravenous injection, twice weekly), anti-PD-1 antibody alone (intravenous injection, once weekly), anti-VEGF antibody alone (intraperitoneal injection, once weekly), combination of anti-PD-1 antibody (intravenous injection, once weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly), compound (intravenous injection, twice weekly) and anti-PD-1 antibody (intravenous injection, once weekly), compound (intravenous injection, twice weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly), or compound (intravenous injection, twice weekly) and anti-PD-1 antibody (intravenous injection, once weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly). Tumor growth inhibition rate (TGI) of the compound was calculated as 1-(tumor volume of the dosing group on day 20 - tumor volume of the dosing group on day 1) / (tumor volume of the vehicle control group on day 20 - tumor volume of the dosing group on day 1).

[0634] Biological Example 8 In Vivo Efficacy Study - Mouse CT26 Subcutaneous Transplant Tumor Model

[0635] Each BALB / c mouse was subcutaneously inoculated with 2×10 5 CT26 cells, wait until the tumor grows to 50-80 mm 3Tumor volumes were measured twice weekly and at the endpoint of dosing for the following treatments: vehicle, compound alone (intravenous injection, twice weekly), anti-PD-1 antibody alone (intravenous injection, once weekly), anti-VEGF antibody alone (intraperitoneal injection, once weekly), combination of anti-PD-1 antibody (intravenous injection, once weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly), compound (intravenous injection, twice weekly) and anti-PD-1 antibody (intravenous injection, once weekly), compound (intravenous injection, twice weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly), or compound (intravenous injection, twice weekly) and anti-PD-1 antibody (intravenous injection, once weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly). Tumor growth inhibition rate (TGI) of the compound was calculated as 1-(tumor volume of the dosing group on day 20 - tumor volume of the dosing group on day 1) / (tumor volume of the vehicle control group on day 20 - tumor volume of the dosing group on day 1).

[0636] Biological Example 9 In Vivo Efficacy Study - Mouse CT26 Subcutaneous Transplant Tumor Model

[0637] Each BALB / c mouse was subcutaneously inoculated with 2×10 5 CT26 cells were inoculated and dosed immediately after cell inoculation. Tumor volumes were measured twice weekly at the endpoint of dosing. Tumor growth inhibition (TGI) was calculated as 1-(tumor volume on day 20 of the treatment group - tumor volume on day 1 of the treatment group) / (tumor volume on day 20 of the vehicle control group - tumor volume on day 1 of the treatment group).

[0638] Biological Example 10 In vivo efficacy study - mouse A20 subcutaneous transplant tumor model

[0639] Each BALB / c mouse was subcutaneously inoculated with 2×10 6 A20 cells, wait until the tumor grows to 100-200mm 3 Tumor volumes were measured twice weekly and at the endpoint of dosing for the following treatments: vehicle, compound alone (intravenous injection, twice weekly), anti-PD-1 antibody alone (intravenous injection, once weekly), anti-VEGF antibody alone (intraperitoneal injection, once weekly), combination of anti-PD-1 antibody (intravenous injection, once weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly), compound (intravenous injection, twice weekly) and anti-PD-1 antibody (intravenous injection, once weekly), compound (intravenous injection, twice weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly), or compound (intravenous injection, twice weekly) and anti-PD-1 antibody (intravenous injection, once weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly). Tumor growth inhibition rate (TGI) of the compound was calculated as 1-(tumor volume of the dosing group on day 20 - tumor volume of the dosing group on day 1) / (tumor volume of the vehicle control group on day 20 - tumor volume of the dosing group on day 1).

[0640] Biological Example 11 In vivo efficacy study - mouse A20 subcutaneous transplant tumor model

[0641] Each BALB / c mouse was subcutaneously inoculated with 2×10 6 A20 cells, wait until the tumor grows to 50-80 mm 3Tumor volumes were measured twice weekly and at the endpoint of dosing for the following treatments: vehicle, compound alone (intravenous injection, twice weekly), anti-PD-1 antibody alone (intravenous injection, once weekly), anti-VEGF antibody alone (intraperitoneal injection, once weekly), combination of anti-PD-1 antibody (intravenous injection, once weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly), compound (intravenous injection, twice weekly) and anti-PD-1 antibody (intravenous injection, once weekly), compound (intravenous injection, twice weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly), or compound (intravenous injection, twice weekly) and anti-PD-1 antibody (intravenous injection, once weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly). Tumor growth inhibition rate (TGI) of the compound was calculated as 1-(tumor volume of the dosing group on day 20 - tumor volume of the dosing group on day 1) / (tumor volume of the vehicle control group on day 20 - tumor volume of the dosing group on day 1).

[0642] Biological Example 12 In vivo efficacy study - mouse A20 subcutaneous transplant tumor model

[0643] Each BALB / c mouse was subcutaneously inoculated with 2×10 6 A20 cells were inoculated and immediately dosed with the following: vehicle, compound alone (IV, twice weekly), anti-PD-1 antibody alone (IV, once weekly), anti-VEGF antibody alone (IP, once weekly), anti-PD-1 antibody (IV, once weekly) in combination with anti-VEGF antibody (IP, once weekly), compound (IV, twice weekly) in combination with anti-PD-1 antibody (IV, once weekly), compound (IV, twice weekly) in combination with anti-VEGF antibody (IP, once weekly), or compound (IV, twice weekly) in combination with anti-PD-1 antibody (IV, once weekly) and anti-VEGF antibody (IP, once weekly). Tumor volume was measured twice weekly and at the endpoint. Tumor growth inhibition (TGI) was calculated as 1 - (tumor volume of the treatment group on day 20 - tumor volume of the treatment group on day 1) / (tumor volume of the vehicle control group on day 20 - tumor volume of the treatment group on day 1).

[0644] Biological Example 13 In vivo efficacy study - mouse B16F10-OVA subcutaneous transplant tumor model

[0645] Fourteen days, eleven days, seven days, and four days before inoculation of B16F10-OVA cells, C57BL / 6 mice were administered vehicle, compound alone (intravenous injection), ovalbumin alone (intravenous injection), anti-PD-1 antibody alone (intravenous injection), anti-VEGF antibody alone (intraperitoneal injection), compound (intravenous injection) in combination with ovalbumin (intravenous injection), anti-PD-1 antibody (intravenous injection) and anti-VEGF antibody (intraperitoneal injection), compound (intravenous injection) in combination with anti-PD-1 antibody (intravenous injection), compound (intravenous injection) in combination with anti-VEGF antibody (intraperitoneal injection), compound (intravenous injection) in combination with anti-PD-1 antibody (intravenous injection) and ovalbumin (intravenous injection), compound (intravenous injection) in combination with anti-VEGF antibody (intraperitoneal injection) and ovalbumin (intravenous injection), compound (intravenous injection) in combination with anti-PD-1 Antibody (intravenous injection) and anti-VEGF antibody (intraperitoneal injection) were combined or compound (intravenous injection) was combined with anti-PD-1 antibody (intravenous injection), anti-VEGF antibody (intraperitoneal injection) and Ovalbumin (intravenous injection). Each C57BL / 6 mouse was subcutaneously inoculated with 0.3X10 6 B16F10-OVA cells were treated with the drug and tumor volumes were measured twice a week and at the end of the treatment. The tumor growth inhibition rate of the compound was calculated as follows: tumor growth inhibition rate (TGI) = 1-(tumor volume of the drug group on day 20 - tumor volume of the drug group on day 1) / (tumor volume of the vehicle control group on day 20 - tumor volume of the drug group on day 1).

[0646] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound represented by the general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates: In the 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 when R a When it is -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 C(R x3 ) or N; R x3 is -H, halogen or -CH3; X 4 S, O, C (R x41 )(R x41’ ) or N(R x42 ); R x42 is -H, (C1-C4)alkyl or (C3-C5)cycloalkyl; R x41 and R x41’ Each independently 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 Each independently selected from -H, (C1-C4) alkyl or (C3-C5) cycloalkyl, or R on the same nitrogen atom x411 and R x412 Together with the N atom to which they are attached, they can form a (3-6 membered) heterocycloalkyl group, wherein the (3-6 membered) heterocycloalkyl group may be optionally substituted by 1, 2, 3 or 4 of the following groups: -H or halogen; R 3 and R 4 each independently optionally being -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 said (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 may each independently be optionally substituted with 1, 2, 3, or 4 of the following groups: -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)2NR 31 R 32 ; or R 3 and R 4 The carbon atoms to which they are attached can together form a (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl, wherein the (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl can be optionally substituted by 1, 2, 3 or 4 substituted by: -H, halogen, (C1-C6)alkyl or (C1-C6)alkoxy; or R 3 and adjacent R 5 The atoms to which they are attached can together form a (C3-C9) cycloalkyl group or a (3-11 membered) heterocycloalkyl group, wherein said (C3-C9) cycloalkyl group or (3-11 membered) heterocycloalkyl group can each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, (C1-C6) alkyl group or (C1-C6) alkoxy group; or when R 3 and adjacent R 5 When both are absent, an intracyclic double bond is formed; or R 3 and R 4 Together they form an oxo group; R 5 and R 6 each independently optionally being -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 said (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 may each independently be optionally substituted with 1, 2, 3, or 4 of the following groups: -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)2NR 31 R 32 ; or R 5 and R 6 The carbon atoms to which they are attached can together form a (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group, wherein the (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group may be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, (C1-C6) alkyl and (C1-C6) alkoxy; or R 5 and R 6 Together they form an oxo group; Ring A is (C6-C10)aryl or (5-10 membered)heteroaryl; Each R 1 Each independently 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)2NR 31 R 32 wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl or (C3-C8)cycloalkyl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -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 Each independently 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 The carbon atoms to which they are attached can together form a (4-6 membered) heterocycloalkyl or (C3-C6) cycloalkyl group, wherein the (4-6 membered) heterocycloalkyl or (C3-C6) cycloalkyl group may be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, (C1-C6) alkyl and (C1-C6) alkoxy; or two R on the same carbon atom 2 Together they form an oxo group; R 31 and R 32 Each independently selected from -H, (C1-C4) alkyl or (C3-C5) cycloalkyl, or R on the same nitrogen atom 31 and R 32 Together with the N atom to which they are attached, they can form a (3-6 membered) heterocycloalkyl group, wherein the (3-6 membered) heterocycloalkyl group may be optionally substituted with 1, 2, 3 or 4 of the following groups: -H and halogen; and n is an integer of 0, 1, 2, 3 or 4, m is an integer of 0, 1, 2, 3 or 4, r is an integer of 0, 1 or 2, and p is an integer of 0, 1 or 2.

2. The compound according to claim 1 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R d It is -H, -F, -CF3 or -CH3.

3. The compound according to claim 1 or 2, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R x42 is -H, (C1-C3)alkyl or (C3-C5)cycloalkyl.

4. The compound according to claim 3 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R x42 For -H, 5. The compound according to any one of claims 1 to 4 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R x41 and R x41’ Each is independently selected from -H, -F, -OH, -OCH3, -N(CH3)2, -NH2, -CN, -CF3, -CH2CF3, 6. The compound according to any one of claims 1 to 5, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 3 and R 4 Each is 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 the (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 Heterocycloalkyl or (5-6 membered)heteroaryl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -F, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2, -CN, -C(O)N(CH3)2, -NCH3C(O)CH3, -NHC(O)CH3, -NCH3S(O)2CH3, -NHS(O)2CH3, -SCH3, -S(O)2CH3, -S(O)2NH2 and -S(O)2N(CH3)2; or R 3 and R 4 The carbon atoms to which they are attached can together form a (4-6 membered) heterocycloalkyl or (C3-C4) cycloalkyl group, wherein the (4-6 membered) heterocycloalkyl or (C3-C4) cycloalkyl group can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, or -OCH3; or R 3 and adjacent R 5 The atoms to which they are attached can together form a (C3-C6) cycloalkyl group or a (3-6 membered) heterocycloalkyl group, wherein the (C3-C6) cycloalkyl group or the (3-6 membered) heterocycloalkyl group can each be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, or -OCH3; or when R 3 and adjacent R 5 When both are absent, an intracyclic double bond is formed; or R 3 and R 4 Together they form an oxo group.

7. The compound according to any one of claims 1 to 6 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 5 and R 6 Each is 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 the (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 R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, 5 and R 6 The carbon atoms to which they are attached can together form a (4-6 membered) heterocycloalkyl or (C3-C4) cycloalkyl group, wherein the (4-6 membered) heterocycloalkyl or (C3-C4) cycloalkyl group can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, or -OCH3; or R 5 and R 6 Together they form an oxo group.

8. The compound according to any one of claims 1 to 7 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), ring A is a phenyl group or a (5-6 membered) heteroaryl group.

9. The compound according to claim 8 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), Ring A is:

10. The compound according to any one of claims 1 to 9 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 1 Each is independently selected from: -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, -NHS -H, -F, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2, -NH2, -CN, -H, -F, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2, -NH2, -CN, -H, -F, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2, -NH2, -CN, -H, -F, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2, -NH2, -CN, -H, -F, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2, -NH2, -CN, -H, -F, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2, -NH2, -CN, -H, -F, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2, - 11. The compound according to claim 10 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 1 are independently: -H, -F, -Cl, -Br, -I, -OH, -NO2, -N(CH3)2, -NH2, -CH2OCH3, -CH2N(CH3)2, -CN, -C(O)N(CH3)2, -NCH3C(O)CH3, -NHC(O)CH3, -NCH3S(O)2CH3, -NHS(O)2CH3, -SCH3, -S(O)2CH3, -S(O)2NH2, -S(O)2N(CH3)2, -CF3, -CH2CF3, -OCH3, -OCH2CH3, -OCH(CH3)2, 12. The compound according to any one of claims 1 to 11 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), ring B is a (C5-C6)cycloalkyl group or a (5-6 membered)heterocycloalkyl group.

13. The compound according to claim 12 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), the structural unit for:

14. The compound according to claim 12 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), the structural unit for:

15. The compound according to any one of claims 1 to 14, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 2 Each independently selected from: -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 2 The carbon atoms to which they are attached can together form a (4-5 membered) heterocycloalkyl or (C3-C5) cycloalkyl, wherein the (4-5 membered) heterocycloalkyl or (C3-C5) cycloalkyl can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, and -OCH3; or two R on the same carbon atom 2 Together they form an oxo group.

16. The compound according to claim 15 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 2 Each independently selected from: -H, -F, -Cl, -Br, -I, -OH, -N(CH3)2, -NH2, -CN, -CF3, -CH2CF3, -OCH3, -OCH2CH3, -OCH(CH3)2, 17. The compound according to any one of claims 1 to 16 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), the structural unit for:

18. The compound according to any one of claims 1 to 16 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), the structural unit for:

19. The compound according to any one of claims 1 to 16 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), the structural unit for:

20. The compound according to any one of claims 1 to 19, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound has one of the following structures:

21. The compound according to any one of claims 1 to 19, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound has one of the following structures:

22. The compound according to any one of claims 1 to 19, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound has one of the following structures:

23. A pharmaceutical composition, characterized in that It contains a pharmaceutically acceptable excipient or carrier, and the compound according to any one of claims 1 to 22 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.

24. Use of the compound according to any one of claims 1 to 22 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition according to claim 23, in the preparation of a medicament for treating SAE-mediated diseases.

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

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