Aryl tricyclic STING agonists and their uses

Abstract

The present specification discloses aryl-group tricyclic STING agonist compounds having the structure of formula (I) and methods for preparing the same. [Formula 1] JPEG2026507091000526.jpg103150

Description

[Technical Field]

[0001] The present disclosure is in the field of medicine, and specifically relates to STING agonist compounds and uses thereof. CROSS-REFERENCE TO RELATED APPLICATIONS This application is a national stage application of International Application No. PCT / CN2024 / 078291 filed on February 23, 2024, and is based on and claims priority to Chinese Patent Application No. 202310196685.0 filed on February 24, 2023, Chinese Patent Application No. 202311536799.1 filed on November 17, 2023, Chinese Patent Application No. 202311016692.4 filed on August 11, 2023, and Chinese Patent Application No. 202410178185.9 filed on February 8, 2024, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Currently, stimulator of interferon genes (STING) is the latest and most exciting immunotherapy target in drug development in the field of tumor immunotherapy. STING is a transmembrane protein that typically forms a dimer via binding at positions 152–173, maintaining an autoinhibitory state. Upon stimulation by specific ligands, it undergoes a molecular reconfiguration and becomes activated, recruiting TANK-binding kinase 1 in the cytoplasm and mediating the phosphorylation of IRF3 by TBK1, resulting in the production of interferon-β and various other cytokines. IFN-β production is a sign of STING activation. Innate immune signaling in the tumor microenvironment is a key step in the activation of tumor-specific T cells and the infiltration of tumor-infiltrating lymphocytes. Type I IFN plays a key role in the activation of tumor-activated T cells. STING induces the expression of type I interferon genes, playing a key role in the innate immune signaling pathway. STING agonists can activate immune stimulatory cells, including dendritic cells, to alter the tumor microenvironment and induce the generation of tumor-specific T cells. In murine experiments, the flavonoid vascular-disrupting agent DMXAA activated the mouse STING protein, inducing the production of IFN-β and other natural cytokines and effectively suppressing the growth of various solid tumors. However, when this drug was combined with standard chemotherapy in human non-small cell lung cancer clinical trials, no clear efficacy was observed. Although the human and mouse STING proteins share 81% similarity, the former gene encodes 379 amino acids, while the latter gene encodes 378 amino acids. Experiments subsequently demonstrated that DMXAA was unable to activate human STING. Other than cyclic dinucleotides, no other STING agonists have been discovered to directly activate mouse STING and human STING. Direct injection of CDN into B16 melanoma, CT26 rectal carcinoma, and 4T1 breast cancer tumors not only resulted in significant tumor suppression or tumor elimination, but also induced systemic, sustained antigen-specific T cell immunity and suppressed tumor growth at other sites in the animals without drug injection.ML RR-S2 CDA induces changes in the microenvironment of various solid tumors, effectively activating tumor-induced CD8+ T cells and resulting in sustained efficacy. In recent years, numerous studies and reports have demonstrated that the STING pathway is one of the leading signaling pathways that has been validated by numerous researchers for its ability to effectively initiate the body's innate immune system and induce the production of cytokines called interferons, making it crucial for innate immunity. The effective infiltration of lymphocytes into tumor tissue determines the success of immunotherapy. Because activation of this target pathway also promotes the infiltration and response of effector T cells in the tumor microenvironment, this target is becoming an important target in antitumor therapy, particularly in immunotherapy research. In multiple mouse inoculation models, it has been effective against a variety of intractable and metastatic solid tumors, not only eliminating directly injected tumors but also significantly suppressing tumor growth in other sites and preventing tumor development. Summary of the Invention [Problem to be solved by the invention]

[0003] Compounds that bind to and act as agonists of STING have been shown to induce type 1 interferon and other cytokines when incubated with human PBMCs. Compounds that induce human interferon can be used to treat a variety of conditions, including allergic diseases and other inflammatory diseases, such as allergic rhinitis and asthma, infectious diseases, neurodegenerative diseases, precancerous syndromes, and cancer, and can also be used as immunological compositions or vaccine adjuvants. Activating STING may be a potential method for treating diseases associated with the type 1 IFN pathway, including inflammatory, allergic, and autoimmune diseases, infectious diseases, cancer, and precancerous syndromes, or used as immunological compositions or vaccine adjuvants. [Means for solving the problem]

[0004] The present disclosure provides compounds having the structure of Formula I, or a pharmaceutically acceptable salt thereof: [ka] where R 1 is hydrogen, deuterium, halogen, cyano group, nitro group, -OR a , N.R. a R b , -SR a , a substituted or unsubstituted C1 to C6 alkyl group, a substituted or unsubstituted C2 to C6 alkenyl group, a substituted or unsubstituted C2 to C6 alkynyl group, a substituted or unsubstituted C1 to C6 alkoxy group, a substituted or unsubstituted saturated or unsaturated C3 to C 10 Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3-10 membered heterocycloalkyl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, substituted or unsubstituted C6-C 10 Aryl group, -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a represents where R 2 is hydrogen, deuterium, halogen, cyano group, nitro group, -OR a , N.R. a R b , -SR a , a substituted or unsubstituted C1 to C6 alkyl group, a substituted or unsubstituted C2 to C6 alkenyl group, a substituted or unsubstituted C2 to C6 alkynyl group, a substituted or unsubstituted C1 to C6 alkoxy group, a substituted or unsubstituted saturated or unsaturated C3 to C 10 Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3-10 membered heterocycloalkyl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, substituted or unsubstituted C6-C 10 Aryl group, -C(O)OR a , -C(O)R a , -C(O)NRa R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a represents Or R 1 and R 2 forms a 5- to 8-membered ring with the atom(s) bonded thereto, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; where R 3 is hydrogen, deuterium, halogen, cyano group, nitro group, -OR a , N.R. a R b , -SR a , a substituted or unsubstituted C1 to C6 alkyl group, a substituted or unsubstituted C2 to C6 alkenyl group, a substituted or unsubstituted C2 to C6 alkynyl group, a substituted or unsubstituted C1 to C6 alkoxy group, a substituted or unsubstituted saturated or unsaturated C3 to C 10 Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3-10 membered heterocycloalkyl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, substituted or unsubstituted C6-C 10 Aryl group, -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a represents Here, Z1 is -C1-C6 alkylene-, -C2-C6 alkenylene-, -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -(C0-C6 alkylene)-O-(C0-C6 alkylene)-, -(C0-C6 alkylene)-(3- to 6-membered heterocycloalkyl)-(C0-C6 alkylene)-, -(C0-C6 alkylene)-NR a -(C0-C6 alkylene)-, -(C0-C6 alkylene)-C(O)NR a -(C0-C6 alkylene)-, -(C0-C6 alkylene)-NR aC(O)-(C0-C6 alkylene)-, -(C0-C6 alkylene)-S(O)2NR a represents -(C0-C6 alkylene)-, and any one hydrogen atom in Z1 is selected from halogen, cyano group, -OR a , -SR a , -NR a R b , C1-C6 alkyl group, C1-C6 haloalkane, C3-C 10 or any one CH2 in Z1 is optionally substituted by 0 to 3 groups selected from a cycloalkyl group; [ka] or [ka] where R is replaced by s and R t forms a 3- to 6-membered ring with the C atom attached to it, where W represents S or Se; where V is the CR 3 or N, Here, X1 and X2 represent C or N. where Z2 is C(O)OR L , C(O)SR L , C(S)OR L , S(O)2R L represents where R L is hydrogen, deuterium, halogen, cyano group, nitro group, -OR a , N.R. a R b , -SR a , a substituted or unsubstituted C1 to C6 alkyl group, a substituted or unsubstituted C2 to C6 alkenyl group, a substituted or unsubstituted C2 to C6 alkynyl group, a substituted or unsubstituted C1 to C6 alkoxy group, a substituted or unsubstituted saturated or unsaturated C3 to C 10Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3-10 membered heterocycloalkyl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, substituted or unsubstituted C6-C 10 Aryl group, -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a represents wherein ring A represents a substituted or unsubstituted saturated or unsaturated 5- to 10-membered ring or a 5- to 10-membered heterocyclic ring; Here, the dashed lines represent single or double bonds. The above substituents defined as "substituted or unsubstituted" include deuterium, halogen, cyano group, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, nitro group, -OR a , N.R. a R b , -SR a , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a is optionally substituted with 0, 1, 2, or 3 substituents selected from where R a , R b are each independently hydrogen, deuterium, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a hydroxyl-substituted C1-C6 alkyl group, a C3-C 10 represents a cycloalkyl group, or R a and R b forms a 3- to 6-membered ring with the atom bonded thereto, and the ring may further optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S.

[0005] The present disclosure also discloses a compound having the structure of Formula I-1 below, or a pharmaceutically acceptable salt thereof: [ka] where R 1 , R 2 , W, V, X1, X2, Z2, ring A have the definitions for formula (I), where R 5 represents a C1 to C6 alkyl group, preferably a methyl group or an ethyl group, and the dashed line represents a single bond or a double bond.

[0006] Additionally, the present disclosure further provides a compound having the structure of Formula II below, or a pharmaceutically acceptable salt thereof: [ka] where R 1 is hydrogen, deuterium, halogen, cyano group, nitro group, -OR a , N.R. a R b , -SR a , a substituted or unsubstituted C1 to C6 alkyl group, a substituted or unsubstituted C2 to C6 alkenyl group, a substituted or unsubstituted C2 to C6 alkynyl group, a substituted or unsubstituted C1 to C6 alkoxy group, a substituted or unsubstituted saturated or unsaturated C3 to C 10 Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3-10 membered heterocycloalkyl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, substituted or unsubstituted C6-C 10 Aryl group, -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a represents where R 2 is hydrogen, deuterium, halogen, cyano group, nitro group, -ORa , N.R. a R b , -SR a , a substituted or unsubstituted C1 to C6 alkyl group, a substituted or unsubstituted C2 to C6 alkenyl group, a substituted or unsubstituted C2 to C6 alkynyl group, a substituted or unsubstituted C1 to C6 alkoxy group, a substituted or unsubstituted saturated or unsaturated C3 to C 10 Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3-10 membered heterocycloalkyl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, substituted or unsubstituted C6-C 10 Aryl group, -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a represents Or R 1 and R 2 forms a 5- to 8-membered ring with the atom(s) bonded thereto, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; where R 3 is hydrogen, deuterium, halogen, cyano group, nitro group, -OR a , N.R. a R b , -SR a , a substituted or unsubstituted C1 to C6 alkyl group, a substituted or unsubstituted C2 to C6 alkenyl group, a substituted or unsubstituted C2 to C6 alkynyl group, a substituted or unsubstituted C1 to C6 alkoxy group, a substituted or unsubstituted saturated or unsaturated C3 to C 10 Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3-10 membered heterocycloalkyl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, substituted or unsubstituted C6-C 10 Aryl group, -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NRa C(O)R a , -S(O)R a , -S(O)2R a represents where R 4 is hydrogen, deuterium, halogen, cyano group, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, nitro group, -OR a , N.R. a R b , -SR a , -C(O)OR a , -CO(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a represents Here, Z1 is -C1-C6 alkylene-, -C2-C6 alkenylene-, -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -(C0-C6 alkylene)-O-(C0-C6 alkylene)-, -(C0-C6 alkylene)-(3- to 6-membered heterocycloalkyl)-(C0-C6 alkylene)-, -(C0-C6 alkylene)-NR a -(C0-C6 alkylene)-, -(C0-C6 alkylene)-C(O)NR a -(C0-C6 alkylene)-, -(C0-C6 alkylene)-NR a C(O)-(C0-C6 alkylene)-, -(C0-C6 alkylene)-S(O)2NR a represents -(C0-C6 alkylene)-, and any one hydrogen atom in Z1 is selected from halogen, cyano group, -OR a , -SR a , -NR a R b , C1-C6 alkyl group, C1-C6 haloalkyl group, C3-C 10 or any one CH2 in Z1 is optionally substituted by 0 to 3 groups selected from a cycloalkyl group; [ka] or [ka] where R is replaced by s and R t forms a 3- to 6-membered ring with the C atom attached to it, where Z2 is C(O)OR L , C(O)SR L , C(S)OR L , S(O)2R L represents where R L is hydrogen, deuterium, halogen, cyano group, nitro group, -OR a , N.R. a R b , -SR a , a substituted or unsubstituted C1 to C6 alkyl group, a substituted or unsubstituted C2 to C6 alkenyl group, a substituted or unsubstituted C2 to C6 alkynyl group, a substituted or unsubstituted C1 to C6 alkoxy group, a substituted or unsubstituted saturated or unsaturated C3 to C 10 Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3-10 membered heterocycloalkyl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, substituted or unsubstituted C6-C 10 Aryl group, -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a represents where W represents S or Se; where V is the CR 3 or N, where X, Y, and M are each independently X , O, S or NR 5 represents wherein X1, X2 represent C or N, provided that at least one is C; where R X is hydrogen, deuterium, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 haloalkyl group, hydroxy C1-C6 alkyl group, halogen, cyano group, nitro group, -OR a , N.R. a R b , -SR a , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a represents where R 5 is hydrogen, deuterium, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 haloalkyl group, hydroxy C1-C6 alkyl group, halogen, cyano group, nitro group, -OR a , N.R. a R b , -SR a , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a represents where n is 0, 1, or 2, The above substituents defined as "substituted or unsubstituted" include halogen, cyano group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, nitro group, -OR a , N.R. a R b , -SR a , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R ais optionally substituted with 0, 1, 2, or 3 substituents selected from where R a , R b are each independently hydrogen, deuterium, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a hydroxyl-substituted C1-C6 alkyl group, a C3-C 10 represents a cycloalkyl group, or R a and R b forms a 3- to 6-membered ring with an atom bonded thereto, and the ring may further optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; Here, the dashed lines represent single or double bonds.

[0007] Additionally, the present disclosure further provides a compound having the structure of Formula II-2 below, or a pharmaceutically acceptable salt thereof: [ka] where R 1 , R 2 , X1, X2, X, Y, M, W, V, R4, n, Z2 have the definitions given above, where R 5 represents a C1 to C6 alkyl group, preferably a methyl group or an ethyl group, and the dashed line represents a single bond or a double bond.

[0008] In the preferred technical solutions of the above formula (I), formula (II), and formula (II-2) of the present disclosure, R 1 is hydrogen, deuterium, halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, hydroxy C1-C6 alkyl group, mercapto C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, hydroxy C2-C6 alkenyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, hydroxy C2-C6 alkenyl group, mercapto C2-C6 alkenyl group, C2-C6 alkynyl group, C2-C6 haloalkynyl group, hydroxy C2-C6 alkynyl group, mercapto C2-C6 alkynyl group, C3-C6 saturated or unsaturated cycloalkyl group, 3-6 membered saturated or unsaturated heterocycloalkyl group, cyano group, nitro group, -ORa , N.R. a R b , -SR a , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a Represents.

[0009] In the preferred technical solutions of the above formula (I), formula (II), and formula (II-2) of the present disclosure, R 1 is hydrogen, halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, hydroxy C1-C6 alkyl group, cyano group, nitro group, -OR a , N.R. a R b , -SR a , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a Represents.

[0010] In the preferred technical solutions of the above formula (I), formula (II), and formula (II-2) of the present disclosure, R 2 is hydrogen, deuterium, halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, hydroxy C1-C6 alkyl group, mercapto C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, hydroxy C2-C6 alkenyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, hydroxy C2-C6 alkenyl group, mercapto C2-C6 alkenyl group, C2-C6 alkynyl group, C2-C6 haloalkynyl group, hydroxy C2-C6 alkynyl group, mercapto C2-C6 alkynyl group, C3-C6 saturated or unsaturated cycloalkyl group, 3-6 membered saturated or unsaturated heterocycloalkyl group, cyano group, nitro group, -OR a , N.R. aR b , -SR a , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a Represents.

[0011] In the preferred technical solutions of the above formula (I), formula (II), and formula (II-2) of the present disclosure, R 2 is hydrogen, deuterium, halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, hydroxy C1-C6 alkyl group, cyano group, nitro group, -OR a , N.R. a R b , -SR a , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a Represents.

[0012] In the preferred technical solutions of the above formula (I), formula (II), and formula (II-2) of the present disclosure, R 1 and R 2 forms a 5- or 6-membered ring with the atom bonded thereto, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S.

[0013] In the preferred technical solutions of the above formula (I), formula (II), and formula (II-2) of the present disclosure, R 3 is hydrogen, deuterium, halogen, -OR a , a cyano group, a C1-C6 alkyl group, a hydroxy group-substituted C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C3-C6 cycloalkyl group.

[0014] In the preferred technical solutions of the above formula (I), formula (II), and formula (II-2) of the present disclosure, X, Y, and M are each independently O, S, or NR 5 or CR X Selected from.

[0015] In the preferred technical solutions of the above formula (I), formula (II), and formula (II-2) of the present disclosure, W represents S.

[0016] In the preferred technical solutions of the above formula (I), formula (II), and formula (II-2) of the present disclosure, R 4 is hydrogen, deuterium, halogen, -OR a , a cyano group, a C1-C6 alkyl group, a hydroxy group-substituted C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C3-C6 cycloalkyl group.

[0017] In the preferred technical solutions of the above formula (I), formula (II), and formula (II-2) of the present disclosure, Z1 represents -C1-C6 alkylene-, -C2-C6 alkenylene-, -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -(C0-C6 alkylene)-O-(C0-C6 alkylene)-, and any one hydrogen atom in Z1 is selected from halogen, cyano group, -OR a , -SR a , -NR a R b , C1-C6 alkyl group, C1-C6 haloalkyl group, C3-C 10 or any one CH2 in Z1 is optionally substituted by 0 to 3 groups selected from a cycloalkyl group; [ka] or [ka] where R is replaced by s and R t forms a 3- to 6-membered ring with the C atom attached to it.

[0018] In the preferred technical solutions of the above formula (I), formula (II), and formula (II-2) of the present disclosure, Z1 represents -C1-C6 alkylene- or -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, and any one hydrogen atom in Z1 is selected from halogen, cyano group, -OR a , -SR a , -NR a R b , C1-C6 alkyl group, C1-C6 haloalkyl group, C3-C 10 or any one CH2 in Z1 is optionally substituted by 0 to 3 groups selected from a cycloalkyl group; [ka] or [ka] where R is replaced by s and R t forms a 3- to 6-membered ring with the C atom attached to it.

[0019] In the preferred technical solutions of the above formula (I), formula (II), and formula (II-2) of the present disclosure, Z2 is C(O)OR L where R L represents hydrogen or a C1 to C6 alkyl group, and is preferably hydrogen.

[0020] In the preferred technical solutions of the above formula (I), formula (II), and formula (II-2) of the present disclosure, R a , R b each independently represents hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C3-C6 cycloalkyl group.

[0021] Additionally, the present disclosure further provides a compound having the structure of Formula II-3 below, or a pharmaceutically acceptable salt thereof: [ka] wherein Y represents CH or N; where R 1 , R 2 are each independently hydrogen, deuterium, halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, hydroxy C1-C6 alkyl group, cyano group, nitro group, -OR a , N.R. a R b , -SR a , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a or R 1 and R 2 forms a 5- to 6-membered saturated or unsaturated ring together with the atom(s) bonded thereto, and the ring may further optionally contain 0, 1, or 2 heteroatoms selected from O, S, and N; wherein Y represents CH or N; where R 4 represents hydrogen, deuterium, halogen, or a C1-C6 alkyl group, where R 5 represents a C1 to C6 alkyl group, preferably a methyl group or an ethyl group, where R a , R b each independently represents hydrogen or a C1 to C6 alkyl group.

[0022] In the preferred technical solution of the above formula (II-3) of the present disclosure, Y represents CH.

[0023] In the preferred technical solution of the above formula (II-3) of the present disclosure, Y represents N.

[0024] In the preferred technical solution of the above formula (II-3) of the present disclosure, R 1 represents hydrogen, deuterium, halogen, or a C1 to C6 alkyl group.

[0025] In the preferred technical solution of the above formula (II-3) of the present disclosure, R 2 is hydrogen, deuterium, halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, hydroxy C1-C6 alkyl group, cyano group, -OR a represents where R a represents hydrogen or a C1 to C6 alkyl group.

[0026] In the preferred technical solution of the above formula (II-3) of the present disclosure, R 2 represents hydrogen, halogen, a C1-C6 haloalkyl group, or a C1-C6 alkoxy group.

[0027] In the preferred technical solution of the above formula (II-3) of the present disclosure, R 4 represents hydrogen or a C1 to C6 alkyl group.

[0028] In the preferred technical solution of the above formula (II-3) of the present disclosure, R 5 represents a methyl group.

[0029] Additionally, the present disclosure further provides a compound having the structure of Formula III below, or a pharmaceutically acceptable salt thereof: [ka] where R 1 is hydrogen, deuterium, halogen, cyano group, nitro group, -OR a , N.R. a R b , -SR a , a substituted or unsubstituted C1 to C6 alkyl group, a substituted or unsubstituted C2 to C6 alkenyl group, a substituted or unsubstituted C2 to C6 alkynyl group, a substituted or unsubstituted C1 to C6 alkoxy group, a substituted or unsubstituted saturated or unsaturated C3 to C 10Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3-10 membered heterocycloalkyl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, substituted or unsubstituted C6-C 10 Aryl group, -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a represents where R 2 is hydrogen, deuterium, halogen, cyano group, nitro group, -OR a , N.R. a R b , -SR a , a substituted or unsubstituted C1 to C6 alkyl group, a substituted or unsubstituted C2 to C6 alkenyl group, a substituted or unsubstituted C2 to C6 alkynyl group, a substituted or unsubstituted C1 to C6 alkoxy group, a substituted or unsubstituted saturated or unsaturated C3 to C 10 Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3-10 membered heterocycloalkyl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, substituted or unsubstituted C6-C 10 Aryl group, -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a represents Or R 1 and R 2 forms a 5- to 8-membered ring with the atom(s) bonded thereto, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; where R 3 is hydrogen, deuterium, halogen, cyano group, nitro group, -OR a , N.R. a R b, -SR a , a substituted or unsubstituted C1 to C6 alkyl group, a substituted or unsubstituted C2 to C6 alkenyl group, a substituted or unsubstituted C2 to C6 alkynyl group, a substituted or unsubstituted C1 to C6 alkoxy group, a substituted or unsubstituted saturated or unsaturated C3 to C 10 Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3-10 membered heterocycloalkyl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, substituted or unsubstituted C6-C 10 Aryl group, -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a represents where R 4 is hydrogen, deuterium, halogen, cyano group, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, nitro group, -OR a , N.R. a R b , -SR a , -C(O)OR a , -CO(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a represents Here, Z1 is -C1-C6 alkylene-, -C2-C6 alkenylene-, -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -(C0-C6 alkylene)-O-(C0-C6 alkylene)-, -(C0-C6 alkylene)-(3- to 6-membered heterocycloalkyl)-(C0-C6 alkylene)-, -(C0-C6 alkylene)-NR a -(C0-C6 alkylene)-, -(C0-C6 alkylene)-C(O)NR a-(C0-C6 alkylene)-, -(C0-C6 alkylene)-NR a C(O)-(C0-C6 alkylene)-, -(C0-C6 alkylene)-S(O)2NR a represents -(C0-C6 alkylene)-, and any one hydrogen atom in Z1 is selected from halogen, cyano group, -OR a , -SR a , -NR a R b , C1-C6 alkyl group, C1-C6 haloalkyl group, C3-C 10 or any one CH2 in Z1 is optionally substituted by 0 to 3 groups selected from a cycloalkyl group; [ka] or [ka] where R is replaced by s and R t forms a 3- to 6-membered ring with the C atom attached to it, where Z2 is C(O)OR L , C(O)SR L , C(S)OR L , S(O)2R L represents where R L is hydrogen, deuterium, halogen, cyano group, nitro group, -OR a , N.R. a R b , -SR a , a substituted or unsubstituted C1 to C6 alkyl group, a substituted or unsubstituted C2 to C6 alkenyl group, a substituted or unsubstituted C2 to C6 alkynyl group, a substituted or unsubstituted C1 to C6 alkoxy group, a substituted or unsubstituted saturated or unsaturated C3 to C 10 Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3-10 membered heterocycloalkyl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, substituted or unsubstituted C6-C 10 Aryl group, -C(O)ORa , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a represents where W represents S or Se; where V is the CR 3 or N, where X, Y, M, and M1 are each independently CR X , O, S or NR 5 represents wherein X1, X2 represent C or N, provided that at least one is C; where R X is hydrogen, deuterium, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 haloalkyl group, hydroxy C1-C6 alkyl group, halogen, cyano group, nitro group, -OR a , N.R. a R b , -SR a , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a represents where R 5 is hydrogen, deuterium, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 haloalkyl group, hydroxy C1-C6 alkyl group, halogen, cyano group, nitro group, -OR a , N.R. a R b , -SR a , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a, -S(O)2R a represents where n is 0, 1, or 2, The above substituents defined as "substituted or unsubstituted" include deuterated groups, halogens, cyano groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, nitro groups, -OR a , N.R. a R b , -SR a , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a is optionally substituted with 0, 1, 2, or 3 substituents selected from where R a , R b are each independently hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a hydroxyl-substituted C1-C6 alkyl group, a C3-C 10 represents a cycloalkyl group, or R a and R b forms a 3- to 6-membered ring with an atom bonded thereto, and the ring may further optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; Here, the dashed lines represent single or double bonds.

[0030] Additionally, the present disclosure further provides a compound having the structure of Formula III-2 below, or a pharmaceutically acceptable salt thereof: [ka] where R 1 , R 2 , X1, X2, R 4 , R 5 , X, Y, M, M1, W, V, Z2, n have the definitions for formula (III), where the dashed line represents a single or double bond.

[0031] In the preferred technical solutions of the above formula (III) or formula (III-2) of the present disclosure, R 1 is hydrogen, halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, hydroxy C1-C6 alkyl group, mercapto C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, hydroxy C2-C6 alkenyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, hydroxy C2-C6 alkenyl group, mercapto C2-C6 alkenyl group, C2-C6 alkynyl group, C2-C6 haloalkynyl group, hydroxy C2-C6 alkynyl group, mercapto C2-C6 alkynyl group, C3-C6 saturated or unsaturated cycloalkyl group, 3-6 membered saturated or unsaturated heterocycloalkyl group, cyano group, nitro group, -OR a , N.R. a R b , -SR a , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a Represents.

[0032] In the preferred technical solutions of the above formula (III) or formula (III-2) of the present disclosure, R 1 is hydrogen, halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, hydroxy C1-C6 alkyl group, cyano group, nitro group, -OR a , N.R. a R b , -SR a , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a Represents.

[0033] In the preferred technical solutions of the above formula (III) or formula (III-2) of the present disclosure, R 2 is hydrogen, deuterium, halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, hydroxy C1-C6 alkyl group, mercapto C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, hydroxy C2-C6 alkenyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, hydroxy C2-C6 alkenyl group, mercapto C2-C6 alkenyl group, C2-C6 alkynyl group, C2-C6 haloalkynyl group, hydroxy C2-C6 alkynyl group, mercapto C2-C6 alkynyl group, C3-C6 saturated or unsaturated cycloalkyl group, 3-6 membered saturated or unsaturated heterocycloalkyl group, cyano group, nitro group, -OR a , N.R. a R b , -SR a , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a Represents.

[0034] In the preferred technical solutions of the above formula (III) or formula (III-2) of the present disclosure, R 2 is hydrogen, deuterium, halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, hydroxy C1-C6 alkyl group, cyano group, nitro group, -OR a , N.R. a R b , -SR a , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a C(O)R a , -S(O)R a , -S(O)2R a Represents.

[0035] In the preferred technical solutions of the above formula (III) or formula (III-2) of the present disclosure, R 1 and R 2 forms a 5- or 6-membered ring with the atom bonded thereto, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S.

[0036] In the preferred technical solutions of the above formula (III) or formula (III-2) of the present disclosure, R 3 is hydrogen, halogen, -OR a , a cyano group, a C1-C6 alkyl group, a hydroxy group-substituted C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C3-C6 cycloalkyl group.

[0037] In the preferred technical solutions of the above formula (III) or formula (III-2) of the present disclosure, X, Y, M, and M1 are each independently O, S, NR 5 or CR X Selected from.

[0038] In the preferred technical solutions of the above formula (III) or formula (III-2) of the present disclosure, R 4 is hydrogen, halogen, -OR a , a cyano group, a C1-C6 alkyl group, a hydroxy group-substituted C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C3-C6 cycloalkyl group.

[0039] In the preferred technical solutions of the above formula (III) or formula (III-2) of the present disclosure, Z1 represents -C1-C6 alkylene-, -C2-C6 alkenylene-, -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -(C0-C6 alkylene)-O-(C0-C6 alkylene)-, and any one hydrogen atom in Z1 is selected from halogen, cyano group, -OR a , -SR a , -NR a R b , C1-C6 alkyl group, C1-C6 haloalkyl group, C3-C 10or any one CH2 in Z1 is optionally substituted by 0 to 3 groups selected from a cycloalkyl group; [ka] or [ka] where R is replaced by s and R t forms a 3- to 6-membered ring with the C atom attached to it.

[0040] In the preferred technical solutions of the above formula (III) or formula (III-2) of the present disclosure, Z1 represents -C1-C6 alkylene- or -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, and any one hydrogen atom in Z1 is selected from halogen, cyano group, -OR a , -SR a , -NR a R b , C1-C6 alkyl group, C1-C6 haloalkyl group, C3-C 10 or any one CH2 in Z1 is optionally substituted by 0 to 3 groups selected from a cycloalkyl group; [ka] or [ka] where R is replaced by s and R t forms a 3- to 6-membered ring with the C atom attached to it.

[0041] In the preferred technical solutions of the above formula (III) or formula (III-2) of the present disclosure, Z2 is C(O)OR L where R Lrepresents hydrogen or a C1 to C6 alkyl group, and is preferably hydrogen.

[0042] In the preferred technical solutions of the above formula (III) or formula (III-2) of the present disclosure, R a , R b each independently represents hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C3-C6 cycloalkyl group.

[0043] In a preferred technical solution of the present disclosure, the compound of the present disclosure has the following structure: [Table 1] TIFF2026507091000551.tif230170 TIFF2026507091000552.tif227170 TIFF2026507091000553.tif220170 TIFF2026507091000554.tif229170 TIFF2026507091000555.tif238170 TIFF2026507091000556.tif103170

[0044] (Definition of terms) It should be particularly noted that when a "compound" having a specific structural formula is mentioned herein, it generally includes its stereoisomers, diastereomers, enantiomers, racemic mixtures, isotopic derivatives, and its alternative forms such as pharmaceutical salts, solvates, hydrates, etc. As is well known to those skilled in the art, salts, solvates, and hydrates of a compound are alternative forms of a compound, which can be converted into the compound under certain conditions. Therefore, it should be particularly noted that when a compound is mentioned herein, it generally includes its pharmaceutical salts, and further includes its solvates and hydrates.

[0045] Similarly, when a compound is referred to herein, its prodrugs, metabolites, and nitroxides are generally also included.

[0046] The medicinal salts or pharmaceutically acceptable salts described in the present disclosure can be prepared using inorganic or organic acids, and the term "medicinal salts" or "pharmaceutically acceptable salts" refers to salts that, within the scope of reasonable medical judgment, are suitable for use in contact with the tissues of humans and lower animals, are free of undue toxicity, irritation, allergic reactions, etc., and have a reasonable benefit / risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the present disclosure, or can be prepared by reacting the free base or free acid with a suitable reagent, as described below. For example, a free base can be reacted with a suitable acid. Furthermore, when the compounds of the present disclosure contain an acidic moiety, suitable medicinal salts include metal salts, such as alkali metal salts (e.g., sodium salts or potassium salts) and alkaline earth metal salts (e.g., calcium salts or magnesium salts). Examples of pharmaceutically acceptable non-toxic acid addition salts include salts formed by amino groups with inorganic acids (e.g., hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids) or organic acids (e.g., acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids), or salts formed by other methods known in the art, e.g., by ion exchange.

[0047] The pharmaceutical salts of the present disclosure can be prepared by conventional methods, for example, by dissolving the compound of the present disclosure in a water-miscible organic solvent (e.g., acetone, methanol, ethanol, and acetonitrile) and adding an excess amount of an aqueous solution of an organic or inorganic acid to precipitate the salt from the mixture, removing the solvent and any remaining free acid therefrom, and then separating the precipitated salt.

[0048] The precursors or metabolites referred to in the present disclosure may be precursors or metabolites known in the art, as long as they are converted into compounds by metabolism in the body. For example, a "prodrug" refers to a prodrug of a compound of the present disclosure that, within the scope of reasonable medical judgment, is suitable for use in contact with the tissues of humans and lower animals, does not produce undue toxicity, irritation, allergic reactions, etc., has a reasonable benefit / risk ratio, and is effective for the desired use. The term "prodrug" refers to a compound that is rapidly converted in the body to produce the parent compound of the above formula, for example, by metabolism in the body or N-demethylation of a compound of the present disclosure.

[0049] As used herein, the term "solvate" refers to a compound of the present disclosure physically associated with one or more solvent molecules (which may be organic or inorganic). Such physical associations include hydrogen bonding. In some cases, a solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvent molecules in a solvate may be present in an ordered and / or disordered arrangement. A solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. The term "solvate" covers solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are well known in the art.

[0050] In this disclosure, "stereoisomerism" is divided into conformational isomerism and configurational isomerism, and configurational isomerism is further divided into cis-trans isomerism and optical isomerism. Conformational isomerism refers to the phenomenon of stereoisomerism in which the spatial arrangement of each atom or group of atoms in an organic molecule with a specific configuration differs due to rotation or twisting of a carbon-carbon single bond. This is commonly seen in the structures of alkane and cycloalkane compounds, and examples of this include the chair and boat conformations in the cyclohexane structure. "Stereoisomer" refers to compounds of the present disclosure that contain one or more asymmetric centers and therefore may be racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and single diastereomers. Compounds of the present disclosure may also contain asymmetric centers, resulting in two optical isomers for each asymmetric center. All possible optical isomers, diastereomeric mixtures, and pure or partially pure compounds are within the scope of this disclosure. Compounds described in this disclosure may exist as tautomers with different hydrogen connection sites due to displacement of one or more double bonds. For example, a ketone and its enol form are ketone-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the present disclosure. All enantiomers, diastereomers, racemates, mesomers, cis-trans isomers, tautomers, geometric isomers, epiisomers, and mixtures thereof of the compounds of formula (I) are included in the present disclosure.

[0051] In the present disclosure, the term "isotopic derivative" refers to a molecule of the compound of the present invention that is labeled with an isotope. Generally, the isotope used for isotopic labeling is a hydrogen isotope ( 2 H and 3 H), carbon isotopes ( 11 C. 13 C and 14 C), chlorine isotopes ( 35 Cl and 37 Cl), fluorine isotopes ( 18 F), iodine isotopes ( 123 I and 125 I), nitrogen isotopes ( 13 N and 15 N), oxygen isotopes ( 15 O. 17 O and 18 O), sulfur isotopes ( 35These isotope-labeled compounds can be used to study the distribution of drug molecules in tissues. 2 H and carbon 13 C is widely used because it is easy to label and detect. Certain heavy isotopes (e.g., deuterium ( 2 H)) improves metabolic stability and extends half-life, thereby enabling both a reduction in dosage and ensuring efficacy. Isotopically labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, similar to the synthesis of non-isotopically labeled compounds.

[0052] The compounds or pharmaceutical compositions of the present disclosure can be formulated in any conventional manner into dosage forms for oral or parenteral administration (including intramuscular, intravenous and subcutaneous routes, intratumoral injection), such as tablets, granules, powders, capsules, syrups, emulsions, microemulsions, solutions or suspensions.

[0053] In this disclosure, exemplary embodiments are described to clarify other features of the disclosure, and the embodiments given are merely illustrative of the disclosure and not limiting, and the following examples are prepared, isolated, and characterized using the methods disclosed in the disclosure.

[0054] Unless otherwise stated, the terms used in this application (including the specification and claims) of this disclosure are defined as follows: It should be noted that in the specification and claims, the singular form "a" includes the plural unless clearly indicated otherwise. Conventional methods in the fields of mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are used unless otherwise indicated. In this application, the use of "or" or "and" refers to "and / or" unless otherwise indicated.

[0055] In the specification and claims, a given chemical formula or name includes all stereoisomers, optical isomers, and racemates in which such isomers exist. Unless otherwise specified, all chiral molecules (enantiomers and diastereomers) and racemates are included within the scope of the present disclosure. The compounds may also exist in various geometric isomers, such as C=C double bonds, C=N double bonds, and ring systems, and all such stable isomers are included within the present disclosure. The present disclosure describes cis- and trans- (or E- and Z-) geometric isomers of the disclosed compounds, which may be isolated as mixtures of isomers or as individual isomers. The disclosed compounds may be isolated by optical activity or as racemates. Methods for preparing the disclosed compounds and intermediates thereto are all considered part of this disclosure. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods (e.g., chromatography or fractional crystallization). Depending on the process conditions, the final products of the present disclosure may be obtained in free (neutral) form or as salts. Both these final products, in free form and as salts, are within the scope of the present disclosure. If necessary, compounds can be converted from one form to another. A free base or acid can be converted to a salt, a salt can be converted to the free compound or another salt, or a mixture of isomeric compounds of the present disclosure can be separated as a single isomer. The compounds of the present disclosure, in their free form and salts, can exist as various tautomers in which hydrogen atoms are transferred to other parts of the molecule, thereby rearranging the chemical bonds between the atoms of the molecule. It should be understood that all possible tautomeric forms are included in the present disclosure.

[0056] Unless otherwise defined, the substituents in the present disclosure are not related to one another and are defined independently, for example, R a (or R b ) are each independently defined by different substituents. Specifically, R a (or R b ) has one definition for one substituent, the same definition can be applied to other substituents as well. a (or R b) does not mean that they have the same definition. Specifically, for example (which is merely a list and is not exhaustive), NR a R b About R a (or R b ) is chosen to be hydrogen, then -C(O)-NR a R b In R a (or R b ) does not necessarily mean hydrogen.

[0057] Unless otherwise defined, when a substituent is described as being "optionally substituted with," the substituent includes, for example, alkyl, cycloalkyl, aryl, heterocyclic, halogen, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine (wherein the two amino substituents are selected from alkyl, aryl, and arylalkyl groups), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkyls and the like. The alkyl group is selected from a substituted or unsubstituted alkyl group, an aryl group, an arylalkyl group, a sulfonyl group, an arylsulfonyl group, an arylalkylsulfonyl group, a sulfonylamino group (e.g., -SO2NH2), a substituted sulfonylamino group, a nitro group, a cyano group, a carboxy group, a carbamoyl group (e.g., -CONH2), a substituted carbamoyl group (e.g., -CONH alkyl group, -CONH aryl group, -CONH arylalkyl group, or a group having two substituents on the nitrogen atom selected from an alkyl group, an aryl group, and an arylalkyl group), an alkoxycarbonyl group, an aryl group, a substituted aryl group, a guanidino group, a heterocyclic group (e.g., an indolyl group, an imidazolyl group, a furyl group, a thienyl group, a thiazolyl group, a pyrrolidinyl group, a pyridyl group, a pyrimidinyl group, a pyrrolidinyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, a homopiperazinyl group, etc.), and a substituted heterocyclic group.

[0058] As used herein, the term "alkyl group" or "alkylene group" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, a "C1-C6 alkyl group" refers to an alkyl group having from 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, and neopentyl groups.

[0059] The term "alkenyl group" refers to a straight or branched chain hydrocarbon group having one or more double bonds and generally having a length of 2 to 20 carbon atoms. For example, a "C2-C6 alkenyl group" contains 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.

[0060] The term "alkynyl group" refers to a straight or branched chain hydrocarbon group having one or more triple bonds and generally from 2 to 20 carbon atoms in length. For example, a "C2-C6 alkynyl group" contains from 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, and the like.

[0061] The term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. A "C1-C6 alkoxy (or alkyloxy)" is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy. Similarly, an "alkylthio" or "thioalkoxy" refers to an alkyl group, as defined above, with the specified number of carbon atoms connected via a sulfur bridge, e.g., methyl-S-, ethyl-S-.

[0062] The term "carbonyl group" refers to an organic functional group consisting of two atoms, carbon and oxygen, connected by a double bond (C=O).

[0063] The term "aryl group," by itself or, for example, as part of an "aralkyl group," "aralkoxy group," or "aryloxyalkyl group," refers to a monocyclic, bicyclic, or tricyclic ring system having a total of 5 to 12 ring atoms, wherein at least one ring in the ring system is aromatic and each ring in the ring system has 3 to 7 ring atoms. In some embodiments of the present invention, an "aryl group" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl groups. The term "aralkyl group" or "arylalkyl group" refers to an alkyl residue attached to an aromatic ring. Non-limiting examples include benzyl, phenethyl, and the like. A fused aryl group can be attached to another group at any suitable position on the cycloalkyl ring or aromatic ring. For example, a dashed line drawn through a ring system means that the bond can be attached to any suitable ring atom.

[0064] The term "cycloalkyl group" refers to a monocyclic or bicyclic alkyl group. Monocyclic alkyl groups refer to C3-C8 cyclic alkyl groups, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornanyl groups. Branched cycloalkyl groups, such as 1-methylcyclopropyl and 2-methylcyclopropyl, are also included within the definition of "cycloalkyl group." Bicyclic alkyl groups include bridged, spiro, and fused cycloalkyl groups.

[0065] The term "heterocycloalkyl group" refers to the above cycloalkyl group structure in which at least one ring carbon atom is replaced by a heteroatom selected from O, N, S, and Se.

[0066] The term "cycloalkenyl group" refers to a monocyclic or bicyclic cyclic alkenyl group. A monocyclic cyclic alkenyl group refers to a C3-C8 cyclic alkenyl group, including, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norbornenyl. Branched cycloalkenyl groups, such as 1-methylcyclopropenyl and 2-methylcyclopropenyl, are included in the definition of "cycloalkenyl group." A bicyclic cyclic alkenyl group includes bridged, spiro, or fused cyclic alkenyl groups.

[0067] "Halo" or "halogen" includes fluorine, chlorine, bromine, and iodine. "Haloalkyl group" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms and substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl groups. Examples of haloalkyl groups further include "fluoroalkyl groups," which are intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms and substituted with one or more fluorine atoms.

[0068] A "haloalkoxy group" or "haloalkyloxy group" refers to a haloalkyl group, as defined above, in which a specified number of carbon atoms are connected via an oxygen bridge. For example, a "C1-C6 haloalkoxy group" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, a "haloalkylthio group" or "thiohaloalkoxy group" refers to a haloalkyl group, as defined above, in which a specified number of carbon atoms are connected via a sulfur bridge, such as trifluoromethyl-S- and pentafluoroethyl-S-.

[0069] The term "C" is used in the context of this disclosure to refer to certain substituents. x1 ~C x2 " means that the number of carbon atoms in the substituent may be x1 to x2. For example, C0-C8 means that the group contains 0, 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, C1-C8 means that the group contains 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, C2-C8 means that the group contains 2, 3, 4, 5, 6, 7, or 8 carbon atoms, C3-C8 means that the group contains 3, 4, 5, 6, 7, or 8 carbon atoms, and C4-C8 means that the group contains C0-C6 means that the target group contains 0, 1, 2, 3, 4, 5, or 6 carbon atoms; C1-C6 means that the target group contains 1, 2, 3, 4, 5, or 6 carbon atoms; C2-C6 means that the target group contains 2, 3, 4, 5, or 6 carbon atoms; and C3-C6 means that the target group contains 3, 4, 5, or 6 carbon atoms.

[0070] In the present disclosure, the expression "x1-x2-membered ring" used when referring to a cyclic group (e.g., an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocycloalkyl group) means that the number of ring atoms in the group may be x1 to x2. For example, the 3- to 12-membered cyclic group may be a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, and the number of ring atoms may be 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In the case of a 3- to 6-membered ring, the cyclic group may be a 3-, 4-, 5-, or 6-membered ring, and the number of ring atoms may be 3, 4, 5, or 6. When it is a 3- to 8-membered ring, it means that the cyclic group may be a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, and the number of ring atoms may be 3, 4, 5, 6, 7, or 8; when it is a 3- to 9-membered ring, it means that the cyclic group may be a 3-, 4-, 5-, 6-, 7-, 8-, or 9-membered ring, and the number of ring atoms may be 3, 4, 5, 6, 7, 8, or 9; When it is a 4- to 7-membered ring, it means that the cyclic group may be a 4-, 5-, 6-, or 7-membered ring and may have 4, 5, 6, or 7 ring atoms; when it is a 5- to 8-membered ring, it means that the cyclic group may be a 5-, 6-, 7-, or 8-membered ring and may have 5, 6, 7, or 8 ring atoms; when it is a 5- to 12-membered ring, it means that the cyclic group may be a 5-, 6-, or The cyclic group may be a 7-, 8-, 9-, 10-, 11-, or 12-membered ring, and may have 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms. In the case of a 6- to 12-membered ring, the cyclic group may be a 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, and may have 6, 7, 8, 9, 10, 11, or 12 ring atoms. The ring atoms may be carbon atoms or heteroatoms, for example, heteroatoms selected from N, O, and S. When the ring is a heterocyclic ring, the heterocyclic ring may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more heteroatoms, for example, heteroatoms selected from N, O, and S.

[0071] In the context of the present disclosure, the one or more halogens can each be independently selected from fluorine, chlorine, bromine, and iodine.

[0072] The term "heteroaryl group" refers to a stable 3-, 4-, 5-, 6-, or 7-membered aromatic monocyclic or bicyclic ring, or a 7-, 8-, 9-, 10-, 11-, or 12-membered aromatic polyheterocyclic ring, fully or partially unsaturated, containing carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, including the polycyclic group below, in which a benzene ring is fused to any of the heterocyclic rings defined above. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituent, as defined). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic groups described herein can be substituted at carbon or nitrogen atoms, provided the resulting compound is stable. The nitrogen atom in the heterocyclic ring may optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. Preferably, the total number of S and O atoms in the heterocycle is 1 or less. [Brief explanation of the drawings]

[0073] [Figure 1] Pharmacodynamic evaluation of test articles of the present disclosure in a female Balb / c mouse tumor model subcutaneously implanted with the mouse colon cancer CT26 cell line. [Figure 2] Pharmacodynamic evaluation of another test article of the present disclosure in a female Balb / c mouse tumor model subcutaneously implanted with the murine colon cancer CT26 cell line. DETAILED DESCRIPTION OF THE INVENTION

[0074] The following preparation procedures and examples illustrate the present disclosure but are not intended to limit the disclosure in any way.

[0075] The features and advantages of the subject matter of the present disclosure will become more apparent from the detailed description of selected embodiments. It is understood that the disclosed and claimed subject matter can be modified in various aspects, and that none of these modifications depart from the scope of the claims. Accordingly, such descriptions should be regarded as illustrative in nature, rather than limiting. The entire scope of the subject matter of the present disclosure is set forth in the claims.

[0076] The present disclosure may be more readily understood by reference to the following examples, which are intended to be merely illustrative of the present disclosure and are not intended to limit the scope of the present disclosure.

[0077] Example 1 Synthesis of 4-(4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazol-7-yl)-4-oxobutyric acid (Example Compound 1) [ka] Step 1: Synthesis of ethyl 5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylate (Intermediate 2) [ka] The starting material, 2-bromo-5-hydroxy-4-methoxybenzaldehyde (25.0 g, 108.2 mmol) was dissolved in DMF (250 mL), followed by the addition of CuI (6.2 g, 32.5 mmol) and ethyl 2-mercaptoacetate (29.9 g, 248.9 mmol) and the mixture was cooled to 0 °C. To the mixture at 0 °C, K2CO3 (37.4 g, 270.5 mmol) was added. The reaction mixture was then sealed and stirred continuously at 80 °C under N2 protection for 3 h. The reaction mixture was cooled to room temperature and quenched by addition to ice water (2.5 kg) and then diluted with EtOAc (1000 mL). The resulting mixture was extracted with EtOAc (1000 mL), and the organic phase was washed with water (1000 mL) and brine (500 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether: EtOAc = 3:1) to give intermediate 2 as a yellow solid (20.0 g, 73%). 12 H 13 ESI MS of O4S [M+H] + :Calculated value 253.1, measured value 253.0.

[0078] Step 2: Synthesis of ethyl 5-hydroxy-6-methoxy-4-nitrobenzo[b]thiophene-2-carboxylate (intermediate 3) [ka] Intermediate 2 (3.0 g, 11.9 mmol) prepared in Step 1 was dissolved in AcOH (30 mL) and concentrated nitric acid (0.9 g, 14.3 mmol) was added dropwise. The reaction mixture was then sealed and stirred constantly at room temperature for 2 h. The reaction mixture was quenched by adding water (200 g). The resulting mixture was extracted with EtOAc (200 mL), and the organic phase was washed twice with water (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to obtain a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether: EtOAc = 3:1) to give intermediate 3 (3.1 g, 88%) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ 11.02(s,1H),8.04(s,1H),7.99(s,1H),4.34(q,J=7.1Hz,2H),3.98(s,3H),1.33(t,J=7.1Hz,3H).

[0079] Step 3: Synthesis of ethyl 4-amino-5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylate (Intermediate 4) [ka] Intermediate 3 (3.1 g, 10.4 mmol), iron powder (2.9 g, 52.1 mmol), and NH4Cl (2.8 g, 52.1 mmol) prepared in Step 2 were dissolved in THF (30 mL) and HO (10 mL), and the mixture was flushed with N2 three times. The reaction mixture was then sealed and constantly stirred under N2 protection at 50 °C for 2 h. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was diluted with EtOAc (200 mL) and washed with water (50 mL). The organic phase was collected, dried over Na2SO4, and concentrated in vacuo to give the crude product of Intermediate 4 (2.5 g, 90%) as a gray solid. 12 H 14 ESI MS of NO4S [M+H] + : Calculated value 268.1, measured value 268.1.

[0080] Step 4: Synthesis of ethyl 4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazole-7-carboxylate (Intermediate 5) [ka] Intermediate 4 (3.0 g, 11.2 mmol) prepared in Step 3 was dissolved in MeOH (10 mL) and trimethoxymethane (35.0 g, 336.6 mmol), and the reaction mixture was then stirred at 70 °C under N protection for 16 h. The reaction mixture was concentrated in vacuo to give a crude sample. Water (200 mL) was added to the residue, and the mixture was extracted three times with EtOAc (200 mL). The organic phase was collected, dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO, petroleum ether: EtOAc = 3:1) to give product 5 (1.7 g, 55%) as a white solid. 13 H 12 ESI MS of NO4S [M+H] + : Calculated value 278.0, actual value 278.1.

[0081] Step 5: Synthesis of 4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazole-7-carboxylic acid (Intermediate 6) [ka] Intermediate 5 (700.0 mg, 2.5 mmol) prepared in Step 4 was dissolved in THF (5 mL), MeOH (5 mL), and HO (2 mL), and NaOH (504.0 mg, 12.6 mmol) was added. The reaction mixture was then stirred at room temperature for 1 hour. The pH of the reaction mixture was adjusted to 4 and diluted with water (100 mL). The mixture was extracted three times with EtOAc (100 mL). The organic phases were collected, dried over NaSO, and concentrated in vacuo to give intermediate compound 6 (600.0 mg, 96%) as a yellow solid. 11 ESI MS of H8NO4S [M+H] + Calculated value: 250.0, Found value: 250.1. The reaction product was used in the next step without separation.

[0082] Step 6: Synthesis of N,4-dimethoxy-N-methylthieno[2',3':5,6]benzo[1,2-d]oxazole-7-carboxamide (Intermediate 7) [ka] Intermediate 5 (600.0 mg, 2.4 mmol) from Step 5, EDCI (923.0 mg, 4.8 mmol), N,O-dimethylhydroxylamine hydrochloride (281.8 mg, 2.9 mmol), and trimethylamine (730.8 mg, 7.2 mmol) were dissolved in DCM (20 mL) and the mixture was flushed with N three times. The reaction mixture was stirred at room temperature under N protection for 2 hours. The reaction mixture was quenched by adding water (100 g) and then diluted with EtOAc (100 mL). The resulting mixture was extracted with EtOAc (200 mL), and the organic phase was washed three times with water (100 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to obtain a crude sample. The crude product was further purified with petroleum ether: EtOAc = 1:1 to give the pure title intermediate compound 7 (250.0 mg, 36%) as a pale red solid. 13 H 13 ESI MS of N2O4S [M+H] + : Calculated value 293.1, measured value 293.1.

[0083] Step 7: Synthesis of 1-(4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazol-7-yl)ethan-1-one (Intermediate 8) [ka] Intermediate 7 (350.0 mg, 1.2 mmol) prepared in step 6 was dissolved in THF (10 mL), and a 1.0 M solution of methylchloromagnesium in THF (3.6 mL, 3.6 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding it to water (50 g) and then diluted with EtOAc (100 mL). The resulting mixture was extracted with EtOAc (100 mL), and the organic phase was then washed three times with water (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to obtain a crude sample. The crude product was further purified by slurry (petroleum ether: EtOAc = 3:1) to obtain the pure title intermediate compound 8 (240.0 mg, 81%) as a yellow solid. C 12 H 10ESI MS of NO3S [M+H] + : Calculated value 248.0, actual value 248.1.

[0084] Step 8: Synthesis of tert-butyl 4-(4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazol-7-yl)-4-oxobutyrate (Intermediate 9) [ka] Intermediate 8 (100.0 mg, 0.4 mmol) prepared in Step 7 and HMPA (217.4 mg, 1.2 mmol) were dissolved in anhydrous THF (5 mL), and the mixture was flushed with N three times. The reaction mixture was cooled to −78 °C in an ethanol-CO(s) bath under N protection. A 1 M solution of HMDSLi in THF (1.2 mL, 1.2 mmol) was then added dropwise and stirred at −78 °C for 30 min. tert-Butyl bromoacetate (276.1 mg, 1.4 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature under a N atmosphere for 30 min. The reaction mixture was quenched by addition to water (50 g) and then diluted with EtOAc (100 mL). The resulting mixture was extracted with EtOAc (100 mL), and the organic phase was washed three times with water (50 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by slurry (petroleum ether: EtOAc = 3:1) to give the pure title intermediate compound 9 as a white solid (100.0 mg, 68%). 18 H 20 ESI MS of NO5S [M+H] + : Calculated value 362.1, measured value 306.1.

[0085] Step 9: Synthesis of 4-(4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazol-7-yl)-4-oxobutyric acid [ka] Intermediate 9 (14.5 mg, 0.04 mmol) obtained in Step 8 was dissolved in TFA (40.0 mg, 0.35 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo to give a crude sample. The crude product was purified by reverse-phase HPLC (C 18 Further purification by column chromatography (50%-60% gradient of MeCN and water containing 0.1% TFA) gave the final product Example Compound 1 as a white solid (4.7 mg, 50%). 14 H 10 ESI MS [MH] of NO5S - :Calculated value 304.0, measured value 304.0. 1 H NMR(400MHz,DMSO-d6)δ 12.21(s,1H),8.93(s,1H),8.56(s,1H),7.79(s,1H),4.07(s,3H),3.38(t,J=6.3Hz,2H),2.60(t,J=6.3Hz,2H).

[0086] Example 2 Synthesis of 4-(4-methoxy-1,2-dihydrothieno[3,2-e]benzofuran-7-yl)-4-oxobutyric acid (Example Compound 2) [ka] Step 1: Synthesis of ethyl 5-hydroxy-6-methoxy-1-benzothiophene-2-carboxylate (Intermediate 3) [ka] 2-Bromo-5-hydroxy-4-methoxybenzaldehyde (6.0 g, 26.0 mmol) was dissolved in DMF (60 mL) and 2-thioethyl acetate (7.2 g, 59.7 mmol) and λ 1Copper iodide (1.5 g, 7.8 mmol) was added, and then the mixture was cooled to 0 °C and potassium carbonate (9.0 g, 64.9 mmol) was slowly added. The mixture was flushed with N2 three times, then the reaction mixture was sealed and constantly stirred under N2 protection at 80 °C for 2 h. The reaction mixture was quenched by adding ice water (600 g) to maintain the internal temperature below 20 °C. The resulting mixture was extracted with EtOAc (600 mL). The organic phase was then washed with water (400 mL), brine (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, 20% EtOAc-petroleum ether) to give Intermediate 3 (5.1 g, 78%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 9.38(s,1H),7.96(d,J=0.6Hz,1H),7.54(s,1H),7.31(s,1H),4.30(q,J=7.1Hz,2H),3.86(s,3H),1.31(t,J=7.1Hz,3H).

[0087] Step 2: Synthesis of ethyl 4-bromo-5-hydroxy-6-methoxy-1-benzothiophene-2-carboxylate (Intermediate 4) [ka] NBS (3.4 g, 19.0 mmol) was added to a solution of intermediate 3 (4.0 g, 15.9 mmol) in ethyl ester (50 mL) obtained in Step 1, and the mixture was flushed with N2 three times. The reaction mixture was then tightly sealed and constantly stirred under N2 protection at 0 °C for 1 h.

[0088] The reaction mixture was filtered and washed twice with water (50 mL), and the cake was collected and dried under vacuum to give the crude intermediate compound 4 as a brown solid (4.1 g, 78%). 12 H 12 ESI MS of BrO4S [M+H] + : Calculated value 332.2, actual value 333.0.

[0089] Step 3: Synthesis of ethyl 5-(acetyloxy)-4-bromo-6-methoxy-1-benzothiophene-2-carboxylate (intermediate 6) [ka] Intermediate compound 4 (3.6 g, 10.9 mmol) prepared in step 2 was added to acetyl chloride (2.6 g, 32.6 mmol) and triethylamine (3.3 g, 32.6 mmol), and the mixture was flushed with N three times. The reaction mixture was then sealed well and stirred constantly under N protection at room temperature for 1 h.

[0090] The reaction mixture was dried under reduced pressure. It was then diluted with EtOAc (200 mL) and washed with water (200 mL). The organic phase was collected, dried over Na2SO4, and concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, 30% EtOAc-petroleum ether) to give Intermediate 6 (3.5 g, 86%) as a white solid. 14 H 14 ESI MS of BrOS [M+H] + :Calculated value 374.2, actual value 375.0.

[0091] Step 4: Synthesis of ethyl 5-(acetyloxy)-6-methoxy-4-[2-(oxa-2-oxy)ethyl]-1-benzothiophene-2-carboxylate (Intermediate 8) [ka] To a solution of intermediate compound 6 (1.0 g, 2.7 mmol) prepared in Step 3 in toluene (10 mL) and HO (2 mL) was added potassium trifluoro[2-(oxa-2-oxy)ethyl]borate (3.2 g, 13.4 mmol), dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II) (1.0 g, 1.3 mmol), and cesium(1+) carbonate (1.8 g, 5.4 mmol). The mixture was then flushed with N three times. The reaction mixture was then sealed and stirred overnight at 100 °C under N protection. The reaction mixture was diluted with ice water (100 mL) and extracted twice with EtOAc (100 mL). The organic phase was collected, dried over NaSO, and concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, 30% EtOAc-petroleum ether) to give intermediate 8 as a yellow solid (0.4 g, 35%). 1 H NMR(400MHz,chloroform-d)δ 8.13(s,1H),7.22(s,1H),4.55(dd,J=4.4,2.7Hz,1H),4.39(t,J=7.1Hz,2H),3.89(s,3H),3.70(t,J= 7.0Hz,2H),3.16(t,J=7.1Hz,2H),2.55(t,J=6.9Hz,2H),2.36(s,3H),1.55-1.49(m,6H),1.40(s,3H).

[0092] Step 5: Synthesis of 5-hydroxy-6-methoxy-4-[2-(oxa-2-oxy)ethyl]-1-benzothiophene-2-carboxylic acid (Intermediate 9) [ka] Sodium hydroxide (946.0 mg, 23.7 mmol) was added to a solution of intermediate compound 8 (2.0 g, 4.7 mmol) prepared in Step 4 in tetrahydrofuran (10 mL), methanol (10 mL), and HO (5 mL), and the mixture was then stirred constantly at room temperature for 5 hours.

[0093] The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The pH of the aqueous phase was adjusted to 5-6 and extracted twice with EtOAc (100 mL). The organic phases were collected, dried over Na2SO4, and concentrated in vacuo to give crude intermediate 9 (1.5 g, 90%) as a yellow solid.

[0094] Step 6: Synthesis of methyl 5-hydroxy-4-(2-hydroxyethyl)-6-methoxy-1-benzothiophene-2-carboxylate (Intermediate 10) [ka] To a solution of intermediate compound 9 (1.5 g, 4.3 mmol) prepared in step 5 in methanol (20 mL) was added sulfuric acid (2 mL, 98%, 20.4 mmol). The mixture was then sealed tightly and stirred at 70 °C overnight. The reaction mixture was diluted with water (200 mL) and extracted twice with EtOAc (200 mL). The organic phases were collected, dried over Na2SO4, and concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, 30% EtOAc-petroleum ether) to give intermediate 10 (1.0 g, 83%) as a yellow solid. 13 H 15 ESI MS of O5S [M+H] + : Calculated value 283.3, actual value 283.0.

[0095] Step 7: Synthesis of methyl 4-methoxy-1,2-dihydrothieno[3,2-e]benzofuran-7-carboxylate (Intermediate 11) [ka] To a solution of intermediate compound 10 (1.2 g, 4.3 mmol) prepared in step 6 in tetrahydrofuran (50 mL) was added triphenylphosphine (2.2 g, 8.5 mmol). The mixture was then flushed with N2 three times and cooled to 0 °C, after which N-[(ethoxycarbonyl)imino]ethoxyformamide (1.5 g, 8.5 mmol) was added. The mixture was then flushed with N2 three times, after which the reaction mixture was well sealed and stirred constantly at room temperature under N2 protection for 2 h. The reaction mixture was diluted with water (100 mL) and extracted twice with EtOAc (100 mL). The organic phase was collected, dried over Na2SO4, and concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, 10% EtOAc-petroleum ether) to give intermediate 11 (1.0 g, 89%) as a yellow solid. 13 H 13 ESI MS of O4S [M+H] + : Calculated value 265.3, actual value 265.0.

[0096] Step 8: Synthesis of 4-methoxy-1,2-dihydrothieno[3,2-e]benzofuran-7-carboxylic acid (Intermediate 12) [ka] To a solution of intermediate compound 11 (1.0 g, 3.8 mmol) prepared in Step 6 in methanol (10 mL), THF (10 mL), and HO (5 mL) was added sodium hydroxide (756.0 mg, 18.9 mmol). The mixture was then stirred constantly at room temperature for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The pH of the aqueous phase was adjusted to 5-6 and extracted twice with EtOAc (100 mL). The organic phases were collected, dried over NaSO, and concentrated in vacuo to give the crude intermediate compound 12 (800.0 mg, 85%) as a yellow solid. 12 H 11 ESI MS of O4S [M+H] + : Calculated value 251.3, actual value 251.0.

[0097] Step 9: Synthesis of N,4-dimethoxy-N-methyl-1,2-dihydrothieno[3,2-e]benzofuran-7-carboxamide (Intermediate 14) [ka] To a solution of intermediate compound 12 (1.0 g, 4.0 mmol) prepared in Step 8 in dichloromethane (20 mL) was added sulfuryl chloride (2.4 g, 20.0 mmol). The reaction mixture was then sealed and stirred continuously at 50 °C for 1 h under N protection. The mixture was then concentrated in vacuo, and then a solution of methoxy(methyl)amine hydrochloride (2.0 g, 20.0 mmol) and triethylamine (2.0 g, 20.0 mmol) in THF (20 mL) and water (20 mL) was added. The mixture was then purged with N 3 times. The reaction mixture was then sealed in a sealed container and stirred continuously at room temperature under N protection for 2 h. The reaction mixture was diluted with ice water (100 mL) and extracted twice with EtOAc (100 mL). The organic phase was collected, dried over Na 2 SO 4 , and concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, 30% EtOAc-petroleum ether) to give a white solid product, Intermediate 14 (0.8 g, 68%). 14 H 16 ESI MS of NO4S [M+H] + : Calculated value 294.1, measured value 294.1.

[0098] Step 10: Synthesis of 1-(4-methoxy-1,2-dihydrothieno[3,2-e]benzofuran-7-yl)ethan-1-one (Intermediate 15) [ka] Intermediate compound 14 (100.0 mg, 0.3 mmol) prepared in step 9 was dissolved in THF (5 mL), and the mixture was flushed with N2 three times and cooled to 0 °C. Methylchloromagnesium (76.5 mg, 1.0 mmol) was then added. The reaction mixture was stirred at room temperature under N2 protection for 1 h. The reaction mixture was quenched by addition to water (100 g) and then diluted with EtOAc (100 mL). The resulting mixture was extracted with EtOAc (100 mL), and the organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by slurry (SiO2, 30% EtOAc-petroleum ether) to give pure intermediate compound 15 (60.0 mg, 71%) as a white solid. C 13 H 13 ESI MS of O3S [M+H] + :Calculated value 249.3, actual value 249.0.

[0099] Step 11: Synthesis of ethyl 4-(4-methoxy-1,2-dihydrothieno[3,2-e]benzofuran-7-yl)-4-oxobutyrate (Intermediate 17) [ka] Intermediate compound 15 (60.0 mg, 0.2 mmol) prepared in step 10 was dissolved in THF (5 mL), [bis(dimethylamino)phosphoryl]dimethylamine (129.9 mg, 0.7 mmol) was added, and the mixture was flushed with N2 three times and cooled to -78 °C. Lithium(1+) bis(trimethylsilyl)nitride (60.7 mg, 0.4 mmol) was then added to the reaction mixture, which was then constantly stirred under N2 protection at -78 °C for 30 min. Finally, ethyl 2-bromoacetate (60.5 mg, 0.4 mmol) was added, and the reaction mixture was then sealed and constantly stirred at room temperature under N2 protection for 2 h. The reaction mixture was quenched with ice water (100 g) and then diluted with EtOAc (100 mL). The resulting mixture was extracted with EtOAc (100 mL), and the organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a crude product of Intermediate 17 as a white solid (80.0 mg, 99%). 17 H 19ESI MS of O5S [M+H] + Calculated value 335.4, found value 335.1. No further purification was required and it was used in the next step.

[0100] Step 12: Synthesis of 4-(4-methoxy-1,2-dihydrothieno[3,2-e]benzofuran-7-yl)-4-oxobutyric acid (Example Compound 2) [ka] To a solution of intermediate compound 17 (80.0 mg, 0.2 mmol) prepared in step 11 in methanol (5 mL) and HO (1 mL) was added NaOH (47.9 mg, 1.2 mmol). The reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to 5-6 and diluted with water (100 mL). The mixture was extracted twice with EtOAc (100 mL). The organic phases were collected, dried over NaSO, and concentrated in vacuo to give a crude sample. The crude product was purified by reverse-phase HPLC (C 18 Further purification by column chromatography (40%-60% gradient of MeCN and water containing 0.1% TFA) gave the white solid product Example Compound 2 (25.0 mg, 34%). 15 H 15 ESI MS of O5S [M+H] + :Calculated value 307.33, actual value 307.0. 1 H NMR(400MHz,DMSO-d6)δ 12.17(s,1H),8.20(s,1H),7.49(s,1H),4.68(t,J=9.0Hz,2H),3.86(s,3H),3.46(t,J=9.0Hz,2H),3.28(t,J=6.4Hz,2H),2.59(t,J=6.4Hz,2H).

[0101] Example 3 Synthesis of 4-(5-methoxy-2,3-dihydrothieno[3',2':3,4]benzo[1,2-b][1,4]dioxin-8-yl)-4-oxobutyric acid (Example Compound 3) [ka] Step 1: Synthesis of ethyl 4-bromo-5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylate (Intermediate 2) [ka] Ethyl 5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylate (3.0 g, 11.9 mmol) was dissolved in acetonitrile (50 mL) and cooled to 0 °C. NBS (2539.7 mg, 14.3 mmol) was then slowly added, and the mixture was flushed with N three times. The reaction mixture was stirred at room temperature under N protection for 1 h. The reaction mixture was quenched by adding ice water (500 g) to maintain the internal temperature below 20 °C. The mixture was then filtered, and the cake was extracted with EA (500 mL). The organic phase was then washed with water (400 mL) and saturated brine (200 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to obtain a crude sample. PE (100 mL) was added to the crude product, and the mixture was stirred constantly at 25 °C for 1 h. The mixture was then filtered, and the cake was collected and dried in vacuo to obtain Intermediate 2 (3.0 g, 76%) as a light brown solid.

[0102] Step 2: Synthesis of ethyl 4-bromo-5-(2-hydroxyethoxy)-6-methoxybenzo[b]thiophene-2-carboxylate (Intermediate 3) [ka] Intermediate 2 (3.3 g, 10.0 mmol) prepared in Step 1 and 2-bromo-1-ol (2.5 g, 19.9 mmol) were dissolved in DMF (40 mL), K2CO3 (4.1 g, 29.9 mmol) was added, and the mixture was flushed with N2 three times. The reaction mixture was then sealed tightly and stirred continuously at 80 °C under N2 protection for 1 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was quenched by adding ice water (600 g), and the resulting mixture was extracted with EtOAc (400 mL). The organic phase was washed twice with water (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether: EtOAc = 5:1) to give intermediate 3 (1.8 g, 48%) as a yellow solid.

[0103] Step 3: Synthesis of ethyl 5-methoxy-2,3-dihydrothieno[3',2':3,4]benzo[1,2-b][1,4]dioxine-8-carboxylate (Intermediate 4) [ka] Intermediate 3 (1.8 g, 4.7 mmol), Pd(OAc) (319.5 mg, 1.4 mmol), CsCO (4.6 g, 14.2 mmol), and BINAP (1.5 g, 2.4 mmol) prepared in Step 2 were dissolved in toluene (20 mL), and the mixture was flushed with N three times. The reaction mixture was then sealed tightly and stirred continuously at 80 °C under N protection for 12 h. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was diluted with EtOAc (100 mL) and washed with water (200 mL). The organic phase was collected, dried over NaSO, and concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO, petroleum ether: EtOAc = 10:1) to give intermediate 4 (1.0 g, 72%) as a yellow solid.

[0104] Step 4: Synthesis of 5-methoxy-2,3-dihydrothieno[3',2':3,4]benzo[1,2-b][1,4]dioxine-8-carboxylic acid (Intermediate 5) [ka] Intermediate 4 (900 mg, 3.1 mmol) prepared in Step 3 was dissolved in EtOH (5 mL) and HO (3 mL), and NaOH (611.6 mg, 15.3 mmol) was added. The reaction mixture was then stirred at room temperature for 1 hour. The pH of the reaction mixture was adjusted to 4 and diluted with water (100 mL). The mixture was extracted three times with EtOAc (100 mL). The organic phases were collected, dried over NaSO, and concentrated in vacuo to give Intermediate 5 (580.0 mg, 71%) as a yellow solid.

[0105] Step 5: Synthesis of N,5-dimethoxy-N-methyl-2,3-dihydrothieno[3',2':3,4]benzo[1,2-b][1,4]dioxine-8-carboxamide [ka] Intermediate 5 (580 mg, 2.2 mmol) prepared in Step 4 was dissolved in SOCl (9.5 mL, 79.7 mmol), DMF (1.0 mL, 13.0 mmol), and DCM (10 mL) to obtain a solution. The reaction mixture was refluxed at 50 °C with stirring for 1 h. The reaction mixture was concentrated and dissolved in tetrahydrofuran (5 mL, 20.0%). To another 25 mL reaction flask, N,N-dimethylhydroxylamine hydrochloride (1062.3 mg, 10.9 mmol), triethylamine (2204.2 mg, 21.8 mmol), and tetrahydrofuran (10 mL) were added to dilute the sulfuryl chloride. The reaction mixture was added to the reaction flask and reacted at room temperature for 10 min. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with EtOAc (50 mL) and washed with water (100 mL). The organic phase was dried over NaSO and filtered. The filtrate was concentrated in vacuo to obtain a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether: EtOAc = 3:1) to give intermediate 6 as a yellow solid (600.0 mg, 89%). 14 H 15 ESI MS of NO5S [M+H]+ : Calculated value 310.34, actual value 309.99. 1 H NMR (400 MHz, chloroform-d) δ 8.17 (d, J = 0.8 Hz, 1H), 6.89 (s, 1H), 4.40 (dq, J = 3.5, 2.4, 1.7 Hz, 4H), 3.96 (s, 3H), 3.81 (s, 3H), 3.40 (s, 3H).

[0106] Step 6: Synthesis of 1-(5-methoxy-2,3-dihydrothieno[3',2':3,4]benzo[1,2-b][1,4]dioxin-8-yl)ethan-1-one [ka] Intermediate 6 prepared in step 5 was dissolved in THF (10 mL) to obtain a solution, which was then exchanged with N2 three times and cooled to 0 °C. Methylchloromagnesium (5.4 mL, 5.4 mmol) was added to the mixture, which was then stirred constantly at room temperature for 1 h. Water (50 mL) was added to quench the reaction mixture, which was then extracted with ethyl acetate (50 mL). The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to obtain a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether: EtOAc = 5:1) to obtain intermediate 7 (80.0 mg, 17%) as a white solid. C 13 H 12 ESI MS of N2O2S [M+H] + : Calculated value 261.31, actual value 261.0. 1 H NMR (400 MHz, chloroform-d) δ 7.91 (d, J = 0.7 Hz, 1H), 6.91 (s, 1H), 4.44-4.39 (m, 4H), 3.97 (s, 3H), 2.62 (s, 3H).

[0107] Step 7: Synthesis of ethyl 4-(5-methoxy-2,3-dihydrothieno[3',2':3,4]benzo[1,2-b][1,4]dioxin-8-yl)-4-oxobutyrate [ka] Intermediate 7 (80.0 mg, 0.3 mmol) prepared in Step 6 and HMPA (135.6 mg, 0.8 mmol) were dissolved in anhydrous THF (3 mL) to obtain a solution, and the mixture was flushed with N three times. The reaction mixture was cooled to -78 °C in an ethanol-CO(s) bath under N protection. HMDSLi (0.1 mL, 0.7 mmol) was then added dropwise and stirred at -40 °C for 1 h. The reaction mixture was then cooled to -78 °C, and ethyl 2-bromoacetate (75.8 mg, 0.5 mmol) was added dropwise and kept warm for 30 min. The reaction mixture was quenched by addition to water (50 g) and then diluted with EtOAc (100 mL). The resulting mixture was extracted with EtOAc (100 mL), and the organic phase was washed three times with water (50 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give intermediate compound 8 as a yellow solid (110 mg, 83%). 17 H 18 ESI MS of O6S [M+H] + Calculated value 351.4, Found value 351.0. No further purification was required and it was used in the next step.

[0108] Step 8: Synthesis of 4-(5-methoxy-2,3-dihydrothieno[3',2':3,4]benzo[1,2-b][1,4]dioxin-8-yl)-4-oxobutyric acid [ka] Intermediate 8 (108.6 mg, 0.3 mmol) prepared in step 7 was dissolved in ethanol (2 mL) and HO (2 mL), and then NaOH (62.0 mg, 1.6 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo to give a crude sample. The crude product was purified by reverse-phase HPLC (C 18 Further purification by column chromatography (50%-60% gradient of MeCN and water containing 0.1% FA) gave a white solid product, Example Compound 3 (26.0 mg, 26%). 1H NMR(400MHz,DMSO-d6)δ 12.02(s,1H),8.11(s,1H),7.23(s,1H),4.41(dd,J=5.4,2.6Hz,2H),4.32(dd,J= 5.4,2.6Hz,2H),3.85(s,3H),3.28-3.24(t,J=6.4Hz,2H),2.56(t,J=6.4Hz,2H). C 15 H 15 ESI MS of O6S [M+H] + :Calculated value 323.3, actual value 323.0.

[0109] Example 4 Synthesis of 4-(2-cyclopropyl-4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazol-7-yl)-4-oxobutyric acid (Example Compound 4) [ka] Step 1: Synthesis of ethyl 5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylate [ka] 2-Bromo-5-hydroxy-4-methoxybenzaldehyde (25.0 g, 108.2 mmol) was dissolved in DMF (250 mL), followed by the addition of ethyl 2-mercaptoacetate (29.9 g, 248.9 mmol), CuI (6.2 g, 32.5 mmol), and K2CO3 (37.4 g, 270.5 mmol). The reaction mixture was then sealed tightly and stirred continuously at 80 °C under N2 protection for 5 h. The reaction mixture was quenched by adding ice water (1000 g) to maintain the internal temperature below 20 °C, and then diluted with EtOAc (1000 mL). The resulting mixture was extracted with EtOAc (1000 mL), and the organic phase was washed twice with water (1000 mL), brine (1000 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, Hex) to give intermediate compound 3 (19.4 g, 71%). 12 H12 ESI MS of O4S [M+H] + :Calculated value 253.3, actual value 253.0.

[0110] Step 2: Synthesis of ethyl 5-hydroxy-6-methoxy-4-nitrobenzo[b]thiophene-2-carboxylate [ka] Intermediate compound 3 (19.4 g, 76.9 mmol) obtained in Step 1 was dissolved in EtOAc (200 mL) and HNO (7.3 g, 115.3 mmol) and slowly mixed at 25 °C. The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched by adding water (400 g). The resulting mixture was extracted with EtOAc (200 mL), and the organic phase was washed twice with water (400 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO, Hex) to give intermediate compound 4 (13.2 g, 57.7%). 1 H NMR(400MHz,DMSO-d6)δ 11.02(s,1H),8.04(s,1H),7.99(s,1H),4.34(q,J=7.1Hz,2H),3.98(s,3H),1.33(t,J=7.1Hz,3H).

[0111] Step 3: Synthesis of ethyl 4-amino-5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylate [ka] Intermediate compound 4 (5.0 g, 16.8 mmol), zinc (5.5 g, 84.1 mmol), and NH4Cl (4.5 g, 84.1 mmol) obtained in step 2 were dissolved in THF (100 mL) and HO (50 mL) to obtain a solution, which was then flushed with N2 three times. The reaction mixture was then sealed well and stirred at reflux under N2 protection for 1 h. The reaction mixture was cooled to room temperature and filtered through Celite. The cake was washed with THF (100 mL), and the filtrate was concentrated in vacuo to give the crude product of intermediate compound 5 as a yellow solid (4.2 g, 93.4%). 12 H 14 ESI MS of NO4S [M+H] + Calculated value 268.1, Found value 268.1. No further purification was required and it was used in the next step.

[0112] Step 4: Synthesis of ethyl 4-(cyclopropanecarboxamido)-5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylate [ka] Intermediate compound 5 obtained in step 3 was dissolved in THF (50 mL), followed by the addition of TEA (4.8 g, 47.1 mmol), and the mixture was flushed with N2 three times. The reaction mixture was cooled to 0 °C in an ice bath under N2 protection. Cyclopropanecarbonyl chloride (1.6 g, 15.7 mmol) was then added dropwise to the reaction mixture. The reaction mixture was then stirred at room temperature under N2 atmosphere for 1 h. The reaction mixture was concentrated in vacuo, maintaining the internal temperature below 20 °C, and concentrated with ice water (200 g), followed by dilution with EtOAc (100 mL). The resulting mixture was extracted with EtOAc (200 mL), and the organic phase was washed three times with water (100 mL), dried over Na2SO4, and filtered. The crude product was further purified by slurry (petroleum ether: EtOAc = 3:1) to give pure intermediate compound 7 (3.1 g, 58.8%) as a light tan solid. 16 H 17 ESI MS of NO5S [M+H] + :Calculated value 336.4, actual value 336.0.

[0113] Step 5: Synthesis of ethyl 2-cyclopropyl-4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazole-7-carboxylate (intermediate compound 8) [ka] A solution of ethyl 4-(cyclopropanecarboxamido)-5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylate (2.0 g, 6.0 mmol) in chloroform (20 mL) was flushed with N2 three times. Then, phosphoryl chloride (4.6 g, 29.8 mmol) was added to the reaction mixture. The reaction mixture was then stirred at 62 °C under N2 protection for 1 h. The reaction mixture was concentrated in vacuo to give a crude sample. Ice water (50 mL) was added to the residue, and the mixture was extracted with DCM (50 mL). The organic phase was then washed with water (100 mL), dried over Na2SO4, and filtered. The crude product was further purified by slurry (petroleum ether: EtOAc = 2:1) to give pure intermediate compound 8 (900 mg, 47.6%) as a pale white solid. 16 ESI MS of H5NO4S [M+H] + :Calculated value 318.4, actual value 318.0.

[0114] Step 6: Synthesis of 2-cyclopropyl-4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazole-7-carboxylic acid (intermediate compound 9) [ka] Intermediate compound 8 (500.0 mg, 1.6 mmol) obtained in step 5 was dissolved in EtOH (20 mL) and HO (10 mL), and then NaOH (189.1 mg, 4.7 mmol) was added. The reaction mixture was then stirred at 27 °C for 4 h. The pH of the reaction mixture was adjusted to 4 and diluted with water (100 mL). The mixture was extracted three times with EtOAc (100 mL). The organic phases were collected, dried over NaSO, and concentrated in vacuo to give intermediate compound 9 (460.0 mg, 96.3%) as a white solid. 14 H 11ESI MS of NO4S [M+H] + Calculated value 290.3, Found value 290.0. No further purification was required and it was used in the next step.

[0115] Step 7: Synthesis of 2-cyclopropyl-N,4-dimethoxy-N-methylthieno[2',3':5,6]benzo[1,2-d]oxazole-7-carboxamide (intermediate compound 11) [ka] Intermediate compound 11 (360.0 mg, 1.2 mmol) obtained in Step 6, EDCI (477.1 mg, 2.5 mmol), N,O-dimethylhydroxylamine hydrochloride (364.1 mg, 3.73 mmol), and trimethylamine (629.6 mg, 6.2 mmol) were dissolved in DCM (10 mL) and exchanged with N three times. The reaction mixture was stirred at 15 °C under N protection for 1 h. The reaction mixture was quenched by adding water (100 g) and then diluted with DCM (100 mL). The resulting mixture was extracted with DCM (200 mL), and the organic phase was washed three times with water (100 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by slurry (petroleum ether: EtOAc = 1:1) to give pure intermediate compound 11 (320 mg, 77.4%) as a white solid. 16 H 16 ESI MS of N2O4S [M+H] + :Calculated value 333.4, measured value 333.0.

[0116] Step 8: Synthesis of 1-(2-cyclopropyl-4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazol-7-yl)ethan-1-one (intermediate compound 12) [ka] Intermediate compound 11 (320.0 mg, 1.0 mmol) obtained in step 7 was dissolved in THF (6 mL), and a 1.0 M solution of methylchloromagnesium in THF (3.9 mL, 2.9 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 15 °C for 30 minutes. The reaction mixture was quenched by adding water (50 g) and then diluted with EtOAc (100 mL). The resulting mixture was extracted with EtOAc (100 mL), and the organic phase was washed three times with water (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to obtain a crude sample. The crude product was further purified by slurry (petroleum ether: EtOAc = 1:1) to obtain pure intermediate compound 12 (230.0 mg, 83.4%) as a white solid. C 15 H 13 ESI MS of NO3S [M+H] + : Calculated value 288.3, ​​actual value 288.0.

[0117] Step 9: Synthesis of tert-butyl 4-(2-cyclopropyl-4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazol-7-yl)-4-oxobutyrate (intermediate compound) [ka] Intermediate compound 12 (180.0 mg, 0.6 mmol) obtained in Step 8 and HMPA (392.9 mg, 2.2 mmol) were dissolved in anhydrous THF (2 mL) to obtain a solution, and the mixture was flushed with N three times. The reaction mixture was cooled to −78 °C in an ethanol-CO(s) bath under N protection. 1 M HMDSLi in THF (0.9 mL, 0.9 mmol) was then added dropwise and stirred at −40 °C for 1 h. The reaction mixture was cooled to −78 °C in an ethanol-CO(s) bath under N protection. tert-Butyl bromoacetate (244.4 mg, 1.25 mmol) was then added dropwise and stirred at room temperature under N atmosphere for 30 min. The reaction mixture was quenched by adding water (50 g) and then diluted with EtOAc (100 mL). The resulting mixture was extracted with EtOAc (100 mL), and then the organic phase was washed three times with water (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by slurry (petroleum ether: EtOAc = 10:1) to give pure intermediate compound 14 (140.0 mg, 55.4%) as a white solid. 21 H 23 ESI MS of NO5S [M+H] + : Calculated value 402.5, measured value 402.1.

[0118] Step 10: Synthesis of 4-(2-cyclopropyl-4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazol-7-yl)-4-oxobutyric acid (Example Compound 4) [ka] Intermediate compound 14 (140 mg, 0.35 mmol) obtained in step 9 was dissolved in TFA (380.1 mg, 3.5 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to give a crude sample. The crude product was purified by reverse phase HPLC (C 18 Further purification by column chromatography (50%-60% gradient of MeCN and water containing 0.1% TFA) gave the white solid product Example Compound 4. 17 H 15 ESI MS of NO5S [M+H]+ : Calculated value 346.4, actual value 346.1. 1 H NMR(400MHz,DMSO-d6)δ 12.35(s,1H),8.48(s,1H),7.66(s,1H),4.03(s,3H),3.35(t,J=6.3Hz,2H),2.59(t,J=6.3Hz,2H),2.38(tt,J=8.1,5.0Hz,1H),1.22(m,4H).

[0119] Example 5 Synthesis of 4-(2-isopropyl-4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazol-7-yl)-4-oxobutyric acid [ka] For the synthesis of ethyl 5-hydroxy-6-methoxy-4-nitrobenzo[b]thiophene-2-carboxylate (Intermediate 3), refer to the synthesis of Intermediate 3 in Example 4.

[0120] Step 3: Synthesis of ethyl 4-amino-5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylate (Intermediate 4) [ka] Intermediate compound 3 (1.0 g, 3.36 mmol), zinc (1.1 g, 16.8 mmol), and NH4Cl (0.9 g, 16.8 mmol) were dissolved in THF (10 mL) and HO (5 mL) and the mixture was flushed with N2 three times. The reaction mixture was then sealed well and stirred constantly under N2 protection at 70 °C for 3 h. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was diluted with EtOAc (50 mL) and washed with water (20 mL). The organic phase was collected, dried over Na2SO4, and concentrated in vacuo to give crude product 4 (850 mg, 94%) as a yellow solid. 12 H 14 ESI MS of NO4S [M+H] + Calculated value 268.1, Found value 268.1. No further purification was required and it was used in the next step.

[0121] Step 4: Synthesis of ethyl 2-isopropyl-4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazole-7-carboxylate (intermediate compound 5) [ka] Intermediate compound 4 (850.0 mg, 3.2 mmol) prepared in step 3 was dissolved in MeOH (10 mL) and 1,1,1-trimethoxy-2-methylpropane (2.36 g, 15.9 mmol). The reaction mixture was then stirred at 65 °C under N protection for 12 hours. The reaction mixture was concentrated in vacuo to give a crude sample. Water (200 mL) was added to the residue, and the mixture was extracted three times with EtOAc (200 mL). The organic phase was collected, dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (petroleum ether: EtOAc = 20:1) to give intermediate compound 5 (680 mg, 66%) as a yellow solid. 16 H 17 ESI MS of NO4S [M+H] + : Calculated value 320.1, measured value 319.9. 1 H NMR (400 MHz, chloroform-d) δ 8.44 (d, J = 0.8 Hz, 1H), 7.21 (s, 1H), 4.40 (q, J = 7.1 Hz, 2H), 4.09 (s, 3H), 3.35 (p, J = 7.0 Hz, 1H), 1.52 (s, 3H), 1.50 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H).

[0122] Step 5: Synthesis of 2-isopropyl-4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazole-7-carboxylic acid (Intermediate 6) [ka] To a solution of intermediate compound 5 (580.0 mg, 1.8 mmol) prepared in Step 4 in EtOH (10 mL) and HO (10 mL) was added NaOH (290.5 mg, 7.3 mmol). The reaction mixture was then stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to 4 and diluted with water (100 mL). The mixture was extracted three times with EtOAc (100 mL). The organic phases were collected, dried over NaSO, and concentrated in vacuo to give intermediate compound 6 (500.0 mg, 94%) as a yellow solid. 14 H 14 ESI MS of NO4S [M+H] + Calculated value 292.1, Found value 292.0. No further purification was required and it was used in the next step.

[0123] Step 6: Synthesis of 2-isopropyl-N,4-dimethoxy-N-methylthieno[2',3':5,6]benzo[1,2-d]oxazole-7-carboxamide (Intermediate 7) [ka] Intermediate compound 6 (500.0 mg, 1.7 mmol), EDCI (658.0 mg, 3.4 mmol), N,N-dimethylhydroxylamine hydrochloride (502.2 mg, 5.2 mmol), and trimethylamine (868.4 mg, 8.6 mmol) prepared in step 5 were dissolved in DCM (10 mL) to obtain a solution, and the mixture was flushed with N2 three times. The reaction mixture was stirred at room temperature under N2 protection for 12 hours. The reaction mixture was quenched by adding water (100 g) and then diluted with EtOAc (100 mL). The resulting mixture was extracted with EtOAc (200 mL), and the organic phase was washed three times with water (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to obtain a crude sample. The crude product was further purified by slurry (petroleum ether: EtOAc = 5:1) to obtain pure intermediate compound 7 (470 mg, 82%) as a white solid. C 16 H 19 ESI MS of N2O4S [M+H] + : Calculated value 335.1, measured value 335.1. 1H NMR (400 MHz, chloroform-d) δ 8.56 (s, 1H), 7.21 (s, 1H), 4.08 (s, 3H), 3.85 (s, 3H), 3.42 (s, 3H), 3.36 (p, J = 7.0 Hz, 1H), 1.51 (d, J = 7.0 Hz, 7H).

[0124] Step 7: Synthesis of 2-isopropyl-N,4-dimethoxy-N-methylthieno[2',3':5,6]benzo[1,2-d]oxazole-7-carboxamide (Intermediate 8) [ka] Intermediate compound 7 (370.0 mg, 1.11 mmol) prepared in step 6 was dissolved in THF (5 mL) and a 1.0 M solution of methylchloromagnesium in THF (0.25 mL, 3.33 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by adding water (50 g) and then diluted with EtOAc (100 mL). The resulting mixture was extracted with EtOAc (100 mL). The organic phase was then washed three times with water (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by slurry (petroleum ether: EtOAc = 10:1) to give pure intermediate compound 8 (150.0 mg, 47%) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 8.33 (s, 1H), 7.22 (s, 1H), 4.09 (s, 3H), 3.36 (p, J = 7.0 Hz, 1H), 2.67 (s, 3H), 1.52 (d, J = 7.0 Hz, 6H).

[0125] Step 8: Synthesis of tert-butyl 4-(2-isopropyl-4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazol-7-yl)-4-oxobutyrate (Intermediate 9) [ka] Intermediate compound 8 (50.0 mg, 0.2 mmol) prepared in Step 7 and HMPA (92.9 mg, 0.5 mmol) were dissolved in anhydrous THF (5 mL), and the mixture was flushed with N three times. The reaction mixture was cooled to -78 °C under N protection. A 1 M solution of HMDSLi in THF (0.26 mL, 1.6 mmol) was then added dropwise and stirred at -78 °C for 1 h. The reaction mixture was then added with tert-butyl bromoacetate (67.4 mg, 0.4 mmol) and stirred at room temperature under N for 30 min. The reaction mixture was quenched by addition to water (50 g) and then diluted with EtOAc (100 mL). The resulting mixture was extracted with EtOAc (100 mL), and the organic phase was washed three times with water (50 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample of intermediate compound 9 as a yellow solid (50.0 mg, 73%). 21 H 25 ESI MS of NO5S [M+H] + Calculated value: 404.2, Found value: 348.0. No further purification was required and it was used in the next step.

[0126] Step 9: Synthesis of 4-(2-isopropyl-4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazol-7-yl)-4-oxobutyric acid (Example Compound 5) [ka] Intermediate compound 9 (50.0 mg, 0.12 mmol) prepared in step 8 was dissolved in TFA (2 mL, 17.54 mmol) to obtain a solution. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to obtain a crude sample. The crude product was purified by reverse-phase HPLC (C 18 Further purification by column chromatography (50%-60% gradient of MeCN and water containing 0.1% TFA) gave the white solid product Example Compound 5 (16 mg, 38%). 17 H 18 ESI MS of NO5S [M+H] + :Calculated value 348.1, actual value 348.0. 1H NMR(400MHz,DMSO-d6)δ 12.13(s,1H),8.55(s,1H),7.71(s,1H),4.05(s,3H),3.37(td,J=6.5,3.4Hz,3H),2.60(t,J=6.3Hz,2H),1.44(s,3H),1.42(s,3H).

[0127] Example 6 Synthesis of 4-(4-methoxy-2-methylthieno[2',3':5,6]benzo[1,2-d]oxazol-7-yl)-4-oxobutyric acid (Example Compound 6) [ka] For the synthesis of ethyl 5-hydroxy-6-methoxy-4-nitrobenzo[b]thiophene-2-carboxylate (Intermediate 3), refer to the synthesis of Intermediate 3 in Example 4.

[0128] Step 3: Synthesis of ethyl 4-amino-5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylate (intermediate compound 4) [ka] Intermediate compound 3 (2.0 g, 6.7 mmol), zinc (2.2 g, 33.7 mmol), and NH4Cl (1.8 g, 33.7 mmol) were dissolved in THF (40 mL) and HO (20 mL), and the mixture was flushed with N2 three times. The reaction mixture was then sealed well and stirred continuously under N2 protection at 70 °C for 3 h. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was diluted with EtOAc (200 mL) and washed with water (50 mL). The organic phase was collected, dried over Na2SO4, and concentrated in vacuo to give crude product 4 (1.8 g, 80%) as a yellow solid. 12 H 14 ESI MS of NO4S [M+H] + Calculated value 268.1, Found value 268.0. No further purification was required and it was used in the next step.

[0129] Step 4: Synthesis of ethyl 4-methoxy-2-methylthieno[2',3':5,6]benzo[1,2-d]oxazole-7-carboxylate (intermediate compound 5) [ka] Intermediate compound 4 (1.8 g, 6.7 mmol) prepared in step 3 was dissolved in MeOH (36 mL) and 1,1,1-trimethoxyethane (5.0 g, 33.7 mmol). The reaction mixture was then stirred at 70 °C under N protection for 16 h. The reaction mixture was concentrated in vacuo to give a crude sample. Water (100 mL) was added to the residue, and the mixture was extracted three times with EtOAc (100 mL). The organic phase was collected, dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO, petroleum ether: EtOAc = 3:1) to give intermediate compound 5 (1.49 g, 76%) as a yellow solid product. 14 H 13 ESI MS of NO4S [M+H] + : Calculated value 292.1, measured value 292.0. 1 H NMR(400MHz, CDCl3)δ 8.40(s,1H),7.23(s,1H),4.43(q,J=7.1Hz,2H),4.11(s,3H),2.75(s,3H),1.44(t,J=7.1Hz,3H).

[0130] Step 5: Synthesis of 4-methoxy-2-methylthieno[2',3':5,6]benzo[1,2-d]oxazole-7-carboxylic acid (intermediate compound 6) [ka] To a solution of intermediate compound 5 prepared in step 4 in EtOH (40 mL) and HO (20 mL) was added NaOH (1.0 g, 25.6 mmol). The reaction mixture was then stirred at room temperature for 1 hour. The pH of the reaction mixture was adjusted to 4 and diluted with water (100 mL). The mixture was extracted three times with EtOAc (100 mL). The organic phases were collected, dried over NaSO, and concentrated in vacuo to give intermediate compound 6 (1.3 g, 97%) as a white solid. 12 H 10 ESI MS of NO4S [M+H] + Calculated value 264.0, Found value 264.0. No further purification was required and it was used in the next step.

[0131] Step 6: Synthesis of N,4-dimethoxy-N,2-dimethylthieno[2',3':5,6]benzo[1,2-d]oxazole-7-carboxamide (intermediate compound 7) [ka] A solution of intermediate compound 6 (1.3 g, 5.1 mmol), EDCI (2.0 g, 10.3 mmol), N,O-dimethylhydroxylamine hydrochloride (1.5 g, 15.4 mmol), and trimethylamine (2.6 g, 25.7 mmol) in DCM (20 mL) was flushed with N three times. The reaction mixture was stirred under N protection at room temperature for 2 hours. The reaction mixture was quenched by adding water (20 g) and then diluted with DCM (50 mL). The resulting mixture was extracted with DCM (50 mL), and the organic phase was washed three times with water (20 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by slurrying (dichloromethane: EtOAc = 20:1) to give the pure title intermediate compound 7 (700.0 mg, 45%) as a white solid. 14 H 15 ESI MS of N2O4S [M+H] + : Calculated value 307.1, measured value 307.0. 1H NMR (400MHz, CDCl3) δ 8.54 (s, 1H), 7.24 (s, 1H), 4.11 (s, 3H), 3.87 (s, 3H), 3.45 (s, 3H), 2.76 (s, 3H).

[0132] Step 7: Synthesis of 1-(4-methoxy-2-methylthieno[2',3':5,6]benzo[1,2-d]oxazol-7-yl)ethyl-1-one (intermediate compound 8) [ka] Intermediate compound 7 (600.0 mg, 2.0 mmol) prepared in step 6 was dissolved in THF (12 mL), and a 1.0 M solution of methylchloromagnesium in THF (6.0 mL, 6.0 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding it to water (10 g) and then diluted with EtOAc (20 mL). The resulting mixture was extracted with EtOAc (20 mL), and the organic phase was washed three times with water (10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by slurry (dichloromethane: EtOAc = 20:1) to give the pure title intermediate compound 8 (370.0 mg, 72%) as a white solid. C 13 H 12 ESI MS of NO3S [M+H] + :Calculated value 262.1, actual value 262.0. 1 H NMR (400MHz, CDCl3) δ 8.30 (s, 1H), 7.25 (s, 1H), 4.12 (s, 3H), 2.77 (s, 3H), 2.69 (s, 3H).

[0133] Step 8: Synthesis of tert-butyl 4-(4-methoxy-2-methylthieno[2',3':5,6]benzo[1,2-d]oxazol-7-yl)-4-oxobutyrate (intermediate compound 9) [ka] Intermediate compound 8 (100.0 mg, 0.4 mg) prepared in Step 7 and HMPA (205.7 mg, 1.2 mg) were dissolved in anhydrous THF (3 mL), and the mixture was exchanged with N three times. The reaction mixture was cooled to -78 °C under N protection. A 1 M solution of HMDSLi in THF (0.6 mL, 0.6 mmol) was then added dropwise and stirred at -78 °C for 30 minutes. The reaction mixture was then added to tert-butyl bromoacetate (149.3 mg, 0.8 mg) and stirred at room temperature under a N atmosphere for 30 minutes. The reaction mixture was quenched by addition to water (20 g) and then diluted with EtOAc (50 mL). The resulting mixture was extracted with EtOAc (50 mL), and the organic phase was washed three times with water (20 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give the crude product of intermediate compound 9 as a white solid (143.7 mg, 100%). 19 H 22 ESI MS of NO5S [M+H] + Calculated 376.1, found 378.1. No further purification was required and it was used in the next step.

[0134] Step 9: Synthesis of 4-(4-methoxy-2-methylthieno[2',3':5,6]benzo[1,2-d]oxazol-7-yl)-4-oxobutyric acid [ka] Intermediate compound 9 (143.7 mg, 0.4 mg) prepared in step 8 and trifluoroacetic acid (1 mL, 8.8 mg) were dissolved in DCM (2 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo to give a crude sample. The crude product was purified by reverse-phase HPLC (C 18 Further purification by column chromatography (30%-50% gradient of MeCN and water containing 0.1% TFA) gave a yellow solid product, Example Compound 6 (6.0 mg, 4.9%). 15 H 14 ESI MS of NO5S [M+H] + :Calculated value 320.1, actual value 320.0. 1H NMR(400MHz,DMSO-d6)δ 12.19(s,1H),8.50(s,1H),7.69(s,1H),4.04(s,3H),3.38-3.34(t,J=6.4,2H),2.70(s,3H),2.61(t,J=6.4Hz,2H).

[0135] Example 7 Synthesis of 4-(2-ethyl-4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazol-7-yl)-4-oxobutyric acid (Example Compound 7) [ka] For the synthesis of ethyl 5-hydroxy-6-methoxy-4-nitrobenzo[b]thiophene-2-carboxylate (Intermediate 3), refer to the synthesis of Intermediate 3 in Example 4.

[0136] Step 3: Synthesis of ethyl 4-amino-5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylate (intermediate compound 4) [ka] Intermediate compound 3 (1.0 g, 3.7 mmol), zinc (1.1 g, 16.8 mmol), and NH4Cl (0.9 g, 16.8 mmol) were dissolved in THF (8 mL) and HO (4 mL) to obtain a solution, and the mixture was exchanged with N2 three times. The reaction mixture was then well sealed and constantly stirred under N2 protection at 75 °C for 1 h. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was diluted with EtOAc (50 mL) and washed with water (30 mL). The organic phase was collected, dried over Na2SO4, and concentrated in vacuo to give crude product 4 (400 mg, 45%) as a gray solid. 12 H 14 ESI MS of NO4S [M+H] + :Calculated value 268.1, actual value 268.0.

[0137] Step 4: Synthesis of ethyl 2-ethyl-4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazole-7-carboxylate (intermediate compound 5) [ka] Intermediate compound 4 (400.0 mg, 1.5 mmol) prepared in step 3 was dissolved in MeOH (20 mL) and triethyl orthopropionate (1.0 g, 7.5 mmol). The reaction mixture was then stirred at 75 °C under N protection for 12 h. The reaction mixture was concentrated in vacuo to give a crude sample. Water (50 mL) was added to the residue, and the mixture was extracted three times with EtOAc (50 mL). The organic phase was collected, dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO, petroleum ether: EtOAc = 10:1) to give intermediate compound 5 (300.0 mg, 65%) as a white solid product. 15 H 16 ESI MS of NO4S [M+H] + :Calculated value 306.1, measured value 306.0.

[0138] Step 5: Synthesis of 2-ethyl-4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazole-7-carboxylic acid (intermediate compound 6) [ka] Intermediate compound 5 (700.0 mg, 2.3 mmol) prepared in step 4 was dissolved in MeOH (5 mL) and HO (5 mL), and NaOH (500.0 mg, 12.5 mmol) was added. The reaction mixture was then stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo, the pH of the mixture was adjusted to 4, and the residue was washed with water (20 mL) and filtered to obtain a cake. The cake was dried to obtain the title intermediate compound 6 (500.0 mg, 79%) as a white solid. 13 H 12 ESI MS of NO4S [M+H] + :Calculated value 278.0, measured value 278.0. 1H NMR(400MHz,DMSO-d6)δ 13.45(s,1H),8.11(s,1H),7.70(s,1H),4.03(s,3H),3.04(q,J=7.6Hz,2H),1.39(t,J=7.6Hz,3H).

[0139] Step 6: Synthesis of 2-ethyl-N,4-dimethoxy-N-methylthieno[2',3':5,6]benzo[1,2-d]oxazole-7-carboxamide (intermediate compound 7) [ka] Intermediate compound 6 (500.0 mg, 1.8 mmol), EDCI (691.3 mg, 3.6 mmol), N,O-dimethylhydroxylamine hydrochloride (527.6 mg, 5.4 mmol), and trimethylamine (912.3 mg, 9.0 mmol) prepared in Step 5 were dissolved in DCM (4 mL) and flushed with N2 three times. The reaction mixture was stirred at room temperature under N2 protection for 3 hours. The reaction mixture was quenched by addition to water (50 mL) and then diluted with EtOAc (50 mL). The resulting mixture was extracted with EtOAc (200 mL), and the organic phase was washed three times with water (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by slurry (petroleum ether: EtOAc = 3:1) to give the pure title intermediate compound 7 (300.0 mg, 52%) as a pale yellow oil. C 15 H 18 ESI MS of N2O4S [M+H] + : Calculated value 321.1, measured value 321.0.

[0140] Step 7: Synthesis of 1-(2-ethyl-4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazol-7-yl)ethan-1-one [ka] Intermediate compound 7 (300.0 mg, 0.9 mmol) prepared in step 6 was dissolved in THF (5 mL), and a 3.0 M solution of methylchloromagnesium in THF (0.9 mL, 2.7 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched by adding water (50 mL) and then diluted with EtOAc (100 mL). The resulting mixture was extracted with EtOAc (100 mL), and the organic phase was then washed three times with water (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to obtain a crude sample. The crude product was further purified by slurry (petroleum ether: EtOAc = 5:1) to obtain the pure title intermediate compound 8 (180.0 mg, 70%) as a white solid. C 14 H 14 ESI MS of NO3S [M+H] + : Calculated value 276.1, actual value 278.0.

[0141] Step 8: Synthesis of tert-butyl 4-(2-ethyl-4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazol-7-yl)-4-oxobutyrate [ka] Intermediate compound 8 (120.0 mg, 0.4 mmol) prepared in Step 7 and HMPA (273.3 mg, 1.5 mmol) were dissolved in anhydrous THF (2 mL), and the mixture was exchanged with N three times. The reaction mixture was cooled to -70 °C under N protection. A 1 M solution of HMDSLi in THF (1.7 mL, 1.7 mmol) was then added dropwise and stirred at -70 °C for 1 h. tert-Butyl bromoacetate (255.0 mg, 1.3 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature under a N atmosphere for 10 min. The reaction mixture was quenched by addition to water (50 mL) and then diluted with EtOAc (100 mL). The resulting mixture was extracted with EtOAc (100 mL), and the organic phase was washed three times with water (50 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by slurry (petroleum ether: EtOAc = 3:1) to give the pure title intermediate compound 9 as a yellow solid (25.0 mg, 15%). 20 H 24 ESI MS of NO5S [M+H] + : Calculated value 390.1, actual value 334.0.

[0142] Step 9: Synthesis of 4-(2-ethyl-4-methoxythieno[2',3':5,6]benzo[1,2-d]oxazol-7-yl)-4-oxobutyric acid (Example Compound 7) [ka] Intermediate compound 9 (30.0 mg, 0.08 mmol) prepared in step 8 was dissolved in TFA (2.0 mL, 17.5 mmol). The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated in vacuo to give a crude sample. The crude product was purified by reverse-phase HPLC (C 18 Further purification by column chromatography (45%-50% gradient of MeCN and water containing 0.1% TFA) gave the white solid product Example Compound 7 (2.2 mg, 13%). 16 H 16 ESI MS of NO5S [M+H] + :Calculated value 334.1, actual value 334.0. 1H NMR (400 MHz, methanol-d₄) δ 8.43 (s, 1H), 7.50 (s, 1H), 4.08 (s, 3H), 3.40 (t, J = 6.4 Hz, 2H), 3.08 (q, J = 7.6 Hz, 2H), 2.75 (t, J = 6.4 Hz, 2H), 1.50 (t, J = 7.6 Hz, 3H).

[0143] Example 8 Synthesis of 4-(4-methoxy-8-methylthieno[2,3:5,6]benzo[1,2-d]oxazol-7-yl)-4-oxobutyric acid

[0144] Example 9 Synthesis of 4-(2-amino-4-methoxy-8-methylthieno[2',3':5,6]benzo[1,2-d]oxazol-7-yl)-4-oxobutyric acid [ka] Step 1: Synthesis of 3-isopropoxy-4-methoxybenzaldehyde (Intermediate 2) [ka] 25g (164.31mmol, 1.0eq) of compound 1 was added to a 500mL one-neck flask protected with dry nitrogen, and 125mL of DMF was added to dissolve it. In an ice bath, 6.4g (262.9mmol, 1.6eq) of potassium carbonate and 30.3g (246.3mmol, 1.5eq) of 2-bromopropane were added, and the reaction was continued at 30°C for 24 hours. Sampling was performed. TLC showed that the reaction of the raw material was not complete. 10.1g (82.1mmol, 0.5eq) of 2-bromopropane was added, and the reaction was continued at 30°C for 24 hours. Sampling was performed. TLC showed that the reaction of the raw material was complete. The mixture was filtered, the DMF was concentrated, and the mixture was diluted with EA, washed with water, washed with brine, and dried over anhydrous sodium sulfate. TLC showed that the product was pure. The mixture was concentrated and suction filtered to obtain 30.3g of a pale orange oil. 11 H 15 ESI MS of O3 [M+H] +Calculated value: 195.2, Found value: 195.2 (M+1). Used directly in the next step. Next, 25 g was added to obtain intermediate compound 2 (28.5 g), a pale orange oil, which was used directly in the next step.

[0145] Step 2: Synthesis of 2-bromo-5-isopropoxy-4-methoxybenzaldehyde (Intermediate 3) [ka] 48.5 g (249.7 mmol, 1.0 eq) of intermediate compound 2 prepared in the previous step was added to a 500 mL three-neck flask protected with dry nitrogen, 100 mL of anhydrous DMF was added to dissolve the compound, and 66.66 g (347.56 mmol, 1.5 eq) of NBS was added. The reaction was allowed to proceed at 80 °C for 3 hours. TLC analysis indicated complete reaction of the starting material. The reaction was quenched with water, extracted with EA, and the EA phase was washed with water, 200 mL of 5% NaSO, brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and dry-loaded. The product was purified on a silica gel column using PE-EA as the mobile phase. The product was obtained with 5% EA and concentrated to give intermediate compound 3 (56 g) as a white solid. 11 H 14 ESI MS of BrO3 [M+H] + : Calculated value 273.1, measured value 273.1 (M+1).

[0146] Step 3: Synthesis of 1-(2-bromo-5-isopropoxy-4-methoxyphenyl)ethan-1-ol (Intermediate 4) [ka] 56 g (205.04 mmol, 1.0 eq) of intermediate compound 3 prepared in the previous step was protected with nitrogen and dissolved in 500 mL of anhydrous THF. 206 mL (615.12 mmol, 3.0 eq) of methylmagnesium bromide (3.0 M / L in 2-methyltetrahydrofuran) was added under ice bath conditions and the mixture was allowed to react at 0°C for 2 hours. After sampling, TLC showed that the reaction was complete. The mixture was quenched by slowly adding water dropwise, dissolved in EA, washed with water, washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column using PE-EA as a mobile phase. The product was obtained with 20% EA. The mixture was concentrated and suction filtered to give intermediate compound 4 (54.22 g) as a pale yellow oil.

[0147] Step 4: Synthesis of 1-(2-bromo-5-isopropoxy-4-methoxyphenyl)ethan-1-one (Intermediate 5) [ka] 54.22 g (187.5 mmol, 1.0 eq) of intermediate compound 4 prepared in the previous step was dissolved in 500 mL of anhydrous DCM under nitrogen protection. 87.5 g (206.2 mmol, 1.0 eq) of DMP was added in an ice bath and reacted at 0°C for 2 hours. TLC showed the reaction of the raw materials was complete. The product was directly dry loaded and purified on a silica gel column using PE-EA as the mobile phase. The product was obtained in 13%-16% EA. The product was concentrated to give intermediate compound 5 (30.22 g) as a white solid, which was used directly in the next step. 12 H 16 ESI MS of BrO3 [M+H] + : Calculated value 287.1, measured value 287.1 (M+1).

[0148] Step 5: Synthesis of ethyl 5-isopropoxy-6-methoxy-3-methylbenzo[b]thiophene-2-carboxylate (Intermediate 6) [ka] 11.27 g (35.77 mmol, 1.0 eq) of intermediate compound 5 prepared in the previous step was placed in a nitrogen-protected, dry, sealed tube and dissolved in 100 mL of anhydrous DMF. 14.8 g (107.3 mmol, 3.0 eq) of potassium carbonate and 6.45 g (53.65 mmol, 1.0 eq) of ethyl mercaptoacetate were added and the mixture was incubated at 90 °C overnight. The next day, a yellow solution was obtained. The reaction was quenched with water, diluted with EA, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. TLC showed a new spot. The product was purified on a silica gel column using PE-EA as the mobile phase and eluted with 4%-6% EA to give intermediate compound 6 (4.55 g) as a yellow solid. This was not very pure and was used directly in the next hydrolysis reaction.

[0149] Step 6: Synthesis of 5-isopropoxy-6-methoxy-3-methylbenzo[b]thiophene-2-carboxylic acid (Intermediate 7) [ka] 4.55 g (8.86 mmol, 1.0 eq) of the intermediate compound 6 (impure) prepared in the previous step was dissolved in 30 mL of 1,4-dioxane, 10 mL of water was added, and 3.72 g (88.6 mmol, 1.0 eq) of lithium hydroxide monohydrate was added. The mixture was allowed to react overnight at 30 °C. The next day, a sample was taken. TLC showed no starting material. The mixture was then directly treated, concentrated, and the organic solvent was removed. The mixture was diluted with water and extracted with EA. The EA phase was washed with water. The aqueous phases were combined and the pH was adjusted to 4 with 1N HCl. A large amount of white solid precipitated. The mixture was filtered, washed with water, dissolved in methanol, concentrated, and suction filtered to obtain intermediate compound 7 (2.0 g) as a white solid. 14 H 17 ESI MS of O4S [M+H] + : Calculated value 281.2, measured value 281.2 (M+1).

[0150] Step 7: Synthesis of 5-isopropoxy-6-methoxy-3-methylbenzothiophene (Intermediate 8) [ka] 2 g (7.14 mmol, 1.0 eq) of intermediate compound 7 prepared in the previous step was dissolved in 20 mL of anhydrous DMF under nitrogen protection, 4 g (28.57 mmol, 4.0 eq) of cuprous oxide was added, and the mixture was reacted at 140°C overnight. TLC showed that the reaction of the raw materials was complete, and the mixture was filtered, washed with EA, concentrated, and purified on a silica gel column using PE-EA as the mobile phase. The product was obtained with 0% PE-5% EA and concentrated to give 1.22 g of a colorless oil, which was then refrigerated and turned into a white solid, intermediate compound 8. 1 H NMR(400MHz,CDCl3)δ 7.32(s,1H),7.19(s,1H),6.93(d,J=1.0Hz,1H),4.62(hept,J=6.1Hz,1H),3.94(s,3H),2.40(d,J=1.0Hz,3H),1.44(s,3H),1.43(s,3H).

[0151] Step 8: Synthesis of ethyl 4-(5-hydroxy-6-methoxy-3-methylbenzo[b]thiophen-2-yl)-4-oxobutyrate (Intermediate 9) [ka] 540 mg (2.28 mmol, 1.0 eq) of intermediate compound 8 prepared in the previous step was protected with nitrogen and dissolved in 10 mL of anhydrous DCM. In an ice bath, 750 mg (4.56 mmol, 2.0 eq) of acid chloride was added dropwise, and 610 mg (4.56 mmol, 2.0 eq) of aluminum chloride was added. The reaction was continued for 30 minutes in an ice bath, and then at room temperature (15 °C) for 3 hours. 610 mg (4.56 mmol, 2.0 eq) of aluminum chloride was added. The mixture was added and reacted overnight at room temperature (15°C). The next day, TLC showed that the reaction of the raw material was complete, with one very pure new spot. Water was added to quench the reaction, and the mixture was extracted with EA. The EA phase was washed with water, then with brine, dried over anhydrous sodium sulfate, and concentrated. The mixture was purified on a silica gel column using PE-EA as the mobile phase. The product was obtained with 30% EA, and concentrated to give intermediate compound 9 (700 mg) as a white solid. 16 H 19 ESI MS of O5S [M+H] + Calculated value: 323.1, Found value: 451.3 (one acid chloride was also attached to the hydroxy group), 323.2 (M+1). TLC showed the same spot, which was directly used in the next step reaction.

[0152] Step 9: Synthesis of 4-(5-hydroxy-6-methoxy-3-methylbenzothiophen-2-yl)-4-oxobutyric acid (intermediate 10) [ka] 700 mg (2.17 mmol, 1.0 eq) of intermediate compound 9 prepared in the previous step was dissolved in 50 mL of 1,4-dioxane, 30 mL of water was added, and 911 mg (21.7 mmol, 10.0 eq) of lithium hydroxide monohydrate was added. The mixture was reacted at 35 °C for 5 hours, sampled, and TLC showed that the reaction of the raw materials was complete. The mixture was concentrated, the organic solvent was removed, and the mixture was diluted with water. The pH was adjusted to 4 with 1N HCl. A large amount of white solid precipitated, which was filtered, washed with water, dissolved in methanol, concentrated, and suction filtered to obtain intermediate compound 10 (600 mg) as a white solid. 14 H 15ESI MS of O5S [M+H] + : Calculated value 295.1, measured value 295.1 (M+1).

[0153] Step 10: Synthesis of 4-(5-hydroxy-6-methoxy-3-methyl-4-nitrobenzo[b]thiophen-2-yl)-4-oxobutyric acid (intermediate 11) [ka] 600 mg (2.04 mmol, 1.0 eq) of intermediate compound 10 prepared in the previous step was dissolved in 90 mL of EA. It was not completely dissolved, forming a white suspension. 30 drops of concentrated nitric acid were added in an ice bath, and the mixture was allowed to warm slowly to room temperature and react for 1 hour. A pale pink suspension was formed. MS monitoring revealed the reaction was not complete. A sample was taken at 2 hours, indicating the reaction was just about complete. The mixture was diluted with EA, washed with ice water and brine, dried over anhydrous magnesium sulfate, and concentrated at low temperature to give a red solid. The mixture was then directly dry-loaded and passed through a column. PE-EA was used as the mobile phase, and the product was obtained in 60% EA. A yellow solid, intermediate compound 11 (100 mg), was obtained. 14 H 14 ESI MS of NO7S [M+H] + Calculated 340.1, found 340.1 (M+1). Used directly in the next step reaction.

[0154] Step 11: Synthesis of 4-(4-amino-5-hydroxy-6-methoxy-3-methylbenzo[b]thiophen-2-yl)-4-oxobutyric acid (Intermediate 12) [ka] 100 mg (0.28 mmol, 1.0 eq) of the nitration product of the previous step, intermediate compound 11, was dissolved in 30 mL of methanol, 40 mg of palladium on carbon was added, and the hydrogenation reaction was carried out at 25 °C for 35 minutes. Sampling was performed, and TLC showed that the reaction of the raw material was complete. The mixture was filtered, concentrated at low temperature, and suction filtered to obtain intermediate compound 12 (87 mg) as a yellow solid. 14 H 16 ESI MS of NO5S [M+H] + Calculated 310.1, found 310.1 (M+1). Used directly in the next step reaction.

[0155] Step 12: Synthesis of 4-(4-methoxy-8-methylthieno[2,3:5,6]benzo[1,2-d]oxazol-7-yl)-4-oxobutyric acid (Example Compound 8) [ka] 60 mg (0.19 mmol, 1.0 eq) of the intermediate compound 12 obtained in the previous step was dissolved in 3 mL of methanol, and under nitrogen protection, 31 mg (0.97 mmol, 5 eq) of trimethoxymethane was added, and the mixture was reacted under microwave irradiation for 3 hours. The mixture was then directly treated, cooled, concentrated, and purified by preparative separation (column: C 18 , 10 μm, 20 × 250 mm, mobile phase: water (containing 0.1% formic acid) - acetonitrile, method: run with 10% acetonitrile for 5 minutes, increase the acetonitrile ratio from 10% to 90% within 30 minutes, run with 90% acetonitrile for 5 minutes, flow rate: 12 mL / min), obtain the product with 70% acetonitrile, freeze-dry and obtain Example Compound 8 (4.4 mg) as a yellow solid. C 15 H 14 ESI MS of NO5S [M+H] + :Calculated value 320.1, actual value 320.0. 1 H NMR(400MHz,DMSO)δ 12.19(s,1H),8.91(s,1H),7.72(s,1H),4.06(s,3H),3.25-3.20(m,2H),3.09(s,3H),2.61(t,J=6.2Hz,2H).

[0156] Step 13: Synthesis of 4-(2-amino-4-methoxy-8-methylthieno[2',3':5,6]benzo[1,2-d]oxazol-7-yl)-4-oxobutyric acid (Example Compound 9) [ka] 27 mg (0.087 mmol, 1.0 eq) of intermediate compound 12 in the synthesis of Example compound 8 was weighed out, and under nitrogen protection, 98 mg (0.611 mmol, 7 eq) of di(imidazol-1-yl)methanimine was added, and the mixture was reacted at room temperature for 2 hours, and then reacted overnight in a sealed tube at 70°C. The next day, the mixture was cooled, concentrated, dissolved in DMF, filtered, and purified using a preparative column (column: C 18 , 10 μm, 30 × 250 mm, mobile phase: water (containing 0.1% formic acid) - acetonitrile, method: run with 10% acetonitrile for 5 minutes, increase the acetonitrile ratio from 10% to 90% within 30 minutes, run with 90% acetonitrile for 5 minutes, flow rate: 20 mL / min), obtain the product with 57% acetonitrile, freeze-dry and obtain Example Compound 9 (7 mg) as a yellow solid. C 15 H 15 ESI MS of N2O5S [M+H] + : Calculated value 335.1, measured value 335.1. 1 H NMR(400MHz,DMSO)δ 12.16(s,1H),7.69(s,2H),7.29(s,1H),3.97(s,3H),3.17(t,J=6.2Hz,2H),3.01(s,3H),2.59(t,J=6.2Hz,2H).

[0157] Example 10 Synthesis of 4-(4-methoxy-8-methylthieno[2,3:5,6]benzo[1,2-d]oxazol-7-yl)-2-methyl-4-oxobutyric acid (Example Compound 10) [ka] Step 1: Synthesis of ethyl 4-chloro-2-methyl-4-oxobutyrate (Intermediate 2) [ka] 760 mg (4.18 mmol, 1.0 eq) of starting compound 1 was dissolved in 10 mL of anhydrous DCM under nitrogen protection. 2.5 mL (5.02 mmol, 1.2 eq) of oxalyl chloride (2.0 M / L in DCM) and 1 drop of anhydrous DMF were added dropwise under ice bath conditions. The mixture was then left in the ice bath for 30 minutes, slowly warmed to room temperature, and reacted for 2 hours. The solvent and excess oxalyl chloride were removed by concentration under nitrogen protection to give intermediate compound 2, which was used directly in the next step.

[0158] Step 2: Synthesis of ethyl 4-(5-hydroxy-6-methoxy-3-methylbenzo[b]thiophen-2-yl)-2-methyl-4-oxobutyrate (Intermediate 4) [ka] 760 mg (3.22 mmol, 1.0 eq) of intermediate compound 8 during the synthesis of example compound 8 was protected with nitrogen and dissolved in 5 mL of anhydrous DCM. In an ice bath, 5 mL of anhydrous DCM solution of intermediate compound 2 prepared in step 1 was added dropwise, and 860 mg (6.44 mmol, 2.0 eq) of aluminum chloride was added. The reaction was continued in an ice bath for 30 minutes, and then at room temperature for 3 hours. 860 mg (6.44 mmol, 2.0 eq) of aluminum chloride was added and the reaction was continued at room temperature. The reaction was allowed to proceed overnight, and the next day, TLC showed the reaction of the starting material was complete, with one very pure new spot. Water was added to quench the reaction, followed by extraction with EA. The EA phase was washed with water, then with brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column using PE-EA as the mobile phase. The product was obtained with 30% EA. TLC showed two spots with similar polarity, which were then concentrated to give intermediate compound 4 (800 mg) as a white solid. 17 H 20 ESI MS of O5S [M+H] + Calculated value: 337.1, Found value: 479.6 (one acid chloride was also attached to the hydroxy group), 337.1 (M+1). Used directly in the next step reaction.

[0159] Step 3: Synthesis of 4-(5-hydroxy-6-methoxy-3-methylbenzo[b]thiophen-2-yl)-2-methyl-4-oxobutyric acid (intermediate 5) [ka] 800 mg (2.38 mmol, 1.0 eq) of intermediate compound 14 prepared in step 2 was dissolved in 50 mL of 1,4-dioxane, 30 mL of water was added, and 1.0 g (23.8 mmol, 10.0 eq) of lithium hydroxide monohydrate was added. The mixture was reacted at 35 °C for 5 hours, sampled, and TLC showed that the reaction of the raw materials was complete. The mixture was concentrated, the organic solvent was removed, and the mixture was diluted with water. The pH was adjusted to 4 with 1N HCl. A large amount of white solid precipitated, which was filtered, washed with water, dissolved in methanol, concentrated, and suction filtered to obtain intermediate compound 5 (600 mg) as a white solid. 15 H 16 ESI MS of O5S [M+H] + : Calculated value 309.1, measured value 309.3 (M+1).

[0160] Step 4: Synthesis of 4-(5-hydroxy-6-methoxy-3-methyl-4-nitrobenzothiophen-2-yl)-2-methyl-4-oxobutyric acid (intermediate 6) [ka] 600 mg (1.94 mmol, 1.0 eq) of intermediate compound 15 prepared in the previous step was dissolved in 90 mL of EA. It was not completely dissolved, resulting in a white suspension. 30 drops of concentrated nitric acid were added in an ice bath, and the mixture was allowed to warm to room temperature for 1 hour. TLC showed the reaction of the raw material was complete. The mixture was diluted with EA, washed with ice water, washed with brine, dried over anhydrous magnesium sulfate, and concentrated at low temperature to give a red solid. This was then directly dry-loaded and passed through a column. Using PE-EA as the mobile phase, 100 mg of intermediate compound 6 (60% EA) was obtained as a yellow solid. 15 H16 ESI MS of NO7S [M+H] + Calculated 354.1, found 354.2 (M+1). Used directly in the next step reaction.

[0161] Step 5: Synthesis of 4-(4-amino-5-hydroxy-6-methoxy-3-methylbenzo[b]thiophen-2-yl)-2-methyl-4-oxobutyric acid (Intermediate 7) [ka] 100 mg (0.28 mmol, 1.0 eq) of the nitration product intermediate compound 16 from the previous step was dissolved in 30 mL of methanol, 40 mg of palladium on carbon was added, and the hydrogenation reaction was carried out at room temperature for 35 minutes. After sampling, TLC showed that the reaction of the raw material was complete. The mixture was filtered, concentrated at low temperature, and suction filtered to obtain intermediate compound 7 (65 mg) as a yellow solid. 15 H 18 ESI MS of NO5S [M+H] + Calculated 324.1, found 324.2 (M+1). Used directly in the next step reaction.

[0162] Step 6: Synthesis of 4-(4-methoxy-8-methylthieno[2,3:5,6]benzo[1,2-d]oxazol-7-yl)-2-methyl-4-oxobutyric acid (Example Compound 10) [ka] 36 mg (0.11 mmol, 1.0 eq) of the intermediate compound 7 obtained in the previous step was weighed out and dissolved in 6 mL of methanol under nitrogen protection. 118 mg (1.1 mmol, 10 eq) of trimethoxymethane was added, the reaction vessel was sealed, and the reaction was carried out for 6 hours. Sampling was carried out, and the reaction was monitored by liquid chromatography / mass spectrometry. The reaction of the raw material was completed. The mixture was cooled, concentrated, dissolved in DMF, filtered, and purified using a preparative column (column: C 18, 10 μm, 20 × 250 mm, mobile phase: water (containing 0.1% formic acid) - acetonitrile, method: run with 10% acetonitrile for 5 minutes, increase the acetonitrile ratio from 10% to 90% within 30 minutes, run with 90% acetonitrile for 5 minutes, flow rate: 12 mL / min), obtain the product with 70% acetonitrile, freeze-dry and obtain Example Compound 10 (5.7 mg) as a yellow solid. C 16 H 16 ESI MS of NO5S [M+H] + : Calculated value 334.3, measured value 334.2. 1 H NMR(400MHz,DMSO)δ 8.91(s,1H),7.72(d,J=8.6Hz,1H),4.06(s,3H),3.32(dd,J=17.5,8.3Hz,1H),3.08(d,J =5.3Hz,3H),3.07(d,J=2.8Hz,1H),2.91(dd,J=12.5,7.7Hz,1H),1.19(t,J=6.3Hz,3H).

[0163] Example 11 Synthesis of 4-(2-amino-4-methoxy-8-methylthieno[2',3':5,6]benzo[1,2-d]oxazol-7-yl)-2-methyl-4-oxobutyric acid (Example Compound 11) [ka] 27 mg (0.084 mmol, 1.0 eq) of intermediate compound 7 in the synthesis of Example compound 10 was weighed out, and under nitrogen protection, 2 mL of anhydrous THF was added and dissolved, and 27 mg (0.167 mmol, 2 eq) of di(imidazol-1-yl)methanimine was added, and the mixture was reacted at room temperature for 2 hours, and then reacted overnight in a sealed tube at 70°C. The next day, the mixture was cooled, concentrated, purified by fractionation, concentrated, dissolved in DMF, and purified by fractionation column (column: C 18, 10 μm, 20 × 250 mm, mobile phase: water (containing 0.1% formic acid) - acetonitrile, method: run with 10% acetonitrile for 5 minutes, increase the acetonitrile ratio from 10% to 90% within 30 minutes, run with 90% acetonitrile for 5 minutes, flow rate: 12 mL / min), obtain the product with 58% acetonitrile, freeze-dry and obtain Example Compound 11 (7 mg) as a yellow solid. C 16 H 17 ESI MS of N2O5S [M+H] + : Calculated value 349.1, measured value 349.1. 1 H NMR(400MHz,DMSO)δ 12.17(s,1H),7.69(s,2H),7.30(d,J=8.7Hz,1H),3.97(s,3H),3.30-3.22(m,1H),3.00( d,J=8.8Hz,3H),2.95-2.85(m,1H),2.75(dd,J=16.9,9.0Hz,1H),1.18(t,J=6.7Hz,3H).

[0164] Example 12 Synthesis of 4-(4-methoxythieno[2,3:5,6]benzo[1,2-d]oxazol-7-yl)-2-methyl-4-oxobutyric acid (Example Compound 12) [ka] Step 1: Synthesis of ethyl 6-methoxy-5-(methoxymethoxy)benzo[b]thiophene-2-carboxylate (Intermediate 2) [ka] Starting material 1 (5 g, 19.82 mmol) was dissolved in THF (80 mL), and NaH (1189.2 mg, 29.73 mmol) was added in an ice bath. The mixture was stirred for 30 minutes. Then, MOMBr (2972.05 mg, 23.78 mmol) was added in an ice bath. The mixture was allowed to warm to room temperature and stirred for 1 hour. TLC showed the starting material had completely reacted, and the reaction mixture was poured into ammonium chloride solution, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting solid was purified on a silica gel column (EA:PE = 0%-10%) to give intermediate compound 2 (5.2 g). The yield was 88.53%.

[0165] Step 2: Synthesis of 6-methoxy-5-(methoxymethoxy)benzo[b]thiophene-2-carboxylic acid (Intermediate 3) [ka] Intermediate compound 2 (5.2 g, 17.55 mmol) prepared in step 1 was dissolved in a tetrahydrofuran-water-methanol (2:1:1, 40 mL) mixed solvent, lithium hydroxide (1.1 g, 26.32 mmol) was added, and the mixture was allowed to react at room temperature for 18 hours. TLC showed the starting material had completely reacted, so the organic phase was concentrated and removed. The pH was adjusted to 4 with 1N aqueous hydrochloric acid, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give intermediate compound 3 (4.5 g) as a white solid. The yield was 95.57%.

[0166] Step 3: Synthesis of N,6-dimethoxy-5-methoxymethoxy-N-methylbenzothiophene-2-carboxamide (Intermediate 4) [ka] Intermediate compound 3 (3 g, 11.18 mmol) prepared in Step 2 was dissolved in DCM (30 mL) and N,O-dimethylhydroxylamine hydrochloride (1308.82 mg, 13.42 mmol), DIPEA (1878.7 mg, 14.54 mmol), and EDCI (3249.25 mg, 16.77 mmol) were added. The mixture was stirred at room temperature for 18 h under nitrogen protection. TLC showed the reaction of the starting materials was complete. The reaction mixture was added dropwise to ammonium chloride solution, extracted with EA, washed with brine, dried, concentrated, and purified on a silica gel column (EA:PE = 0%-30%) to give 2.3 g of a solid. The yield was 66.06%.

[0167] Step 4: Synthesis of dimethyl (2-(6-methoxy-5-(methoxymethoxy)benzo[b]thiophen-2-yl)-2-oxoethyl)phosphonate (Intermediate 5) [ka] Dimethyl methylphosphonate (1354.95 mg, 10.92 mmol) was dissolved in anhydrous THF (30 mL) and n-BuLi (2.5 M, 0.7 mL, 10.92 mmol) was added dropwise at -70 °C. After completion, the mixture was stirred at -70 °C for 1 hour. Then, intermediate 4 (1.7 g, 5.46 mmol) prepared in step 3 was dissolved in THF (5 mL) and added dropwise to the mixture at -70 °C. The mixture was stirred at -70 °C for 1 hour. TLC showed that most of the raw materials had reacted, so aqueous ammonium chloride solution was added dropwise to the mixture, which was then extracted three times with EA. The organic phase was washed with saturated brine, dried, concentrated, and purified on a silica gel column (EA:PE = 0%-100%) to obtain the solid intermediate compound. 5 (1.3 g) was obtained. The yield was 63.6%. 15 H 20 ESI MS of O7PS [M+H] + :Calculated value 375.15, actual value 375.

[0168] Step 5: Synthesis of methyl (E)-4-(6-methoxy-5-methoxymethoxy)benzo[b]thiophen-2-yl)-2-methyl-4-oxobut-2-enoate (Intermediate 6) [ka] Intermediate compound 5 (420 mg, 1.12 mmol) prepared in step 4 was dissolved in THF (10 mL). n-BuLi (2.5 M, 0.08 mL, 1.23 mmol) was slowly added at -20°C and stirred for 1 hour. Methyl pyruvate (125.99 mg, 1.23 mmol) was then dissolved in THF and added dropwise to the mixture. The mixture was stirred for 30 minutes, then the temperature was returned to room temperature and stirred for 1.5 hours. TLC indicated the reaction of the raw materials was complete. The reaction mixture was then added dropwise to an aqueous ammonium chloride solution and extracted three times with EA. The organic phase was washed with saturated brine, dried, concentrated, and purified on a silica gel column (EA:PE = 0%-50%) to give solid intermediate compound 6 (350 mg). The yield was 89.19%. 17 H 19 ESI MS of O6S [M+H] + :Calculated value 351.39, measured value 351.

[0169] Step 6: Synthesis of methyl 4-(6-methoxy-5-methoxymethoxy)benzo[b]thiophen-2-yl)-2-methyl-4-oxobutanoate (Intermediate 7) [ka] Intermediate compound 6 (300 mg, 0.86 mmol) prepared in step 5 was dissolved in ethyl acetate (10 mL), and Pd-C (91.52 mg, 0.09 mmol) was added. A hydrogen balloon was inserted, and the atmosphere was replaced with hydrogen. The reaction was allowed to proceed at room temperature for 2 hours. TLC showed that the reaction of the raw materials was complete. The reaction mixture was filtered, and the filtrate was concentrated and purified on a silica gel column (EA:PE = 0%-30%) to obtain intermediate compound 7 (130 mg) as a solid. The yield was 42.9%. 17 H 19 ESI MS of O6S [M+H] + :Calculated value 353.39, measured value 353. 1H NMR (400 MHz, chloroform-d) δ 7.86 (s, 1H), 7.59 (d, J = 2.5 Hz, 1H), 7.28 (s, 1H), 5.30 (s, 2H), 3.98 (s, 3H), 3.70 (s, 3H), 3.55 (s, 3H), 3.50-3.39 (m, 1H), 3.22-3.10 (m, 1H), 3.02 (dd, J = 16.8, 5.9 Hz, 1H), 1.29 (d, J = 7.2 Hz, 3H).

[0170] Step 7: Synthesis of methyl 4-(5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-2-methyl-4-oxobutyrate (Intermediate 8) [ka] Intermediate compound 7 (130 mg, 0.37 mmol) prepared in step 6 was dissolved in 2 M HCl-1,4-dioxane (2 M, 3 mL, 6 mmol) and stirred at room temperature for 2 h. TLC showed the reaction of the starting material was complete, and the reaction mixture was concentrated to give intermediate compound 8 (90 mg) as a solid in 78.38% yield.

[0171] Step 8: Synthesis of 4-(5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-2-methyl-4-oxobutyric acid (Intermediate 9) [ka] Intermediate compound 8 (90 mg, 0.29 mmol) prepared in step 7 was dissolved in a tetrahydrofuran-water-methanol (2:1:1, 4 mL) mixed solvent, lithium hydroxide (13.89 mg, 0.58 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours. TLC showed the reaction was complete, so the pH of the reaction mixture was adjusted to 3, extracted with EA, and the EA was washed with saturated brine, dried, and concentrated to give intermediate compound 9 (80 mg) as a solid. The yield was 93.73%.

[0172] Step 9: Synthesis of 4-(5-hydroxy-6-methoxy-4-nitrobenzo[b]thiophen-2-yl)-2-methyl-4-oxobutyric acid (Intermediate 10) [ka] Intermediate compound 9 (80 mg, 0.27 mmol) prepared in step 8 was dissolved in ethyl acetate (10 mL), concentrated nitric acid (75.98 mg, 0.82 mmol) was added in an ice bath, and the mixture was stirred at room temperature for 1.5 hours. TLC showed that the reaction of the starting material was complete. The reaction mixture was immediately poured into water, extracted with EA, and the organic phase was washed three times with saturated brine and concentrated at room temperature. The resulting solid was purified on a silica gel column (EA:PE = 0%-100%) to give intermediate compound 10 (45 mg) in a 49.12% yield.

[0173] Step 10: Synthesis of 4-(4-amino-5-hydroxy-6-methoxybenzothiophen-2-yl)-2-methyl-4-oxobutyric acid (intermediate 11) [ka] Intermediate 10 (45 mg, 0.13 mmol) prepared in step 9 was dissolved in methanol (5 mL), and Pd-C (31.93 mg, 0.03 mmol) was added. A hydrogen balloon was inserted, and the atmosphere was purged with hydrogen. The reaction was allowed to proceed at room temperature for 2 hours. TLC showed that the reaction of the starting materials was complete. The reaction mixture was filtered, and the filtrate was concentrated to give intermediate compound 11 (40 mg) as a solid. The yield was 99.47%.

[0174] Step 11: Synthesis of 4-(4-methoxythieno[2,3:5,6]benzo[1,2-d]oxazol-7-yl)-2-methyl-4-oxobutyric acid (Example Compound 12) [ka] Intermediate 11 prepared in step 10 was dissolved in methanol (40 mg, 0.13 mmol), trimethyl orthoformate (137.96 mg, 1.3 mmol) was added, and the mixture was reacted in a sealed tube at 70 °C for 5 hours. TLC showed that the reaction of the raw materials was complete. The reaction mixture was concentrated at room temperature, and the resulting solid was purified (column: C 18 , 10 μm, 20 × 250 mm, mobile phase: water (containing 0.1% formic acid) - acetonitrile, method: increasing the proportion of acetonitrile from 10% to 50% within 30 minutes), the product was obtained with 50% acetonitrile, and lyophilized to obtain Example Compound 12 as a white solid (8.5 mg, yield 20.48%). 15 H 14 ESI MS of NO5S [M+H] + :Calculated value 320.05, actual value 320.1. 1 H NMR(400MHz,DMSO-d6)δ 12.19(s,1H),8.92(s,1H),8.57(s,1H),7.78(s,1H),4.07(s,3H),3.53(dd,J=17.6,8.6Hz, 1H),3.20(dd,J=17.6,5.1Hz,1H),2.91(ddd,J=8.5,7.0,4.9Hz,1H),1.21(d,J=7.2Hz,3H).

[0175] Example 13 Synthesis of 4-(4-methoxythieno[3,2-e]benzofuran-7-yl)-4-oxobutyric acid (Example Compound 13) [ka] Step 1: Synthesis of 2-bromo-5-(2,2-diethoxyethoxy)-4-methoxybenzaldehyde (Intermediate 2) [ka] Compound 1 (5.0 g, 21.6 mmol) was dissolved in DMF (25 mL) to obtain a solution, followed by the addition of 2-bromo-1,1-diethoxypropane (5.1 g, 26.0 mmol) and K2CO3 (5.0 g, 36.2 mmol). The reaction mixture was then sealed tightly and stirred continuously at 110 °C for 3 h. The reaction mixture was cooled to room temperature and quenched by addition to ice water (200 mL), followed by dilution with EtOAc (200 mL). The resulting mixture was extracted with EtOAc (200 mL), and the organic phase was then washed with water (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give the crude intermediate compound 2 (7.0 g, 93%) as a light brown solid. 14 H 20 ESI MS of BrO5 [M+H] + : Calculated value 347.0, actual value 254.9. 1 H NMR(400MHz,DMSO-d6)δ 10.06(s,1H),7.39(s,1H),7.35(s,1H),4.80(t,J=5.1Hz,1H),4.01(d,J=5.1Hz ,2H),3.92(s,3H),3.71-3.64(m,2H),3.60-3.53(m,2H),1.13(t,J=7.0Hz,6H).

[0176] Step 2: Synthesis of ethyl 5-(2,2-diethoxyethoxy)-6-methoxybenzo[b]thiophene-2-carboxylate (Intermediate 3) [ka] Intermediate compound 2 (6.5 g, 18.7 mmol) prepared in Step 1 was dissolved in DMF (100 mL), followed by the addition of CuI (356.6 mg, 1.9 mmol) and ethyl mercaptoacetate (4.5 g, 37.4 mmol) and cooling to 0 °C. At 0 °C, K2CO3 (7.7 g, 56.2 mmol) was added to the mixture. The reaction mixture was then tightly sealed and constantly stirred at 60 °C under N2 protection for 2 h. The reaction mixture was cooled to room temperature and quenched by addition to ice water (500 mL) and then diluted with EtOAc (500 mL). The resulting mixture was extracted with EtOAc (500 mL), and the organic phase was washed with water (500 mL) and brine (500 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether: EtOAc = 10:1) to give intermediate compound 3 as a yellow solid product (3.5 g, 51%). 18 H 25 ESI MS of O6S [M+H] + : Calculated value 369.1, actual value 276.9. 1 H NMR(400MHz,DMSO-d6)δ 8.00(s,1H),7.62(s,1H),7.57(s,1H),4.87(s,1H),4.32(d,J=7.1Hz,2H),3.98(d,J=5.2Hz,2H),3 .87(s,3H),3.75-3.65(m,1H),3.61(d,J=6.9Hz,1H),1.33(t,J=7.1Hz,3H),1.15(t,J=7.0Hz,6H).

[0177] Step 3: Synthesis of ethyl 4-methoxythieno[3,2-e]benzofuran-7-carboxylate (Intermediate 4) [ka] To a toluene solution (5 mL) of intermediate compound 3 (500 mg, 1.4 mmol) prepared in step 2, PPA (3 mL) was added. The reaction mixture was stirred at 100 °C for 30 minutes. The reaction mixture was cooled to room temperature and quenched by adding ice water (50 mL) and then diluted with EtOAc (100 mL). The resulting mixture was extracted with EtOAc (100 mL). The organic phase was then washed twice with water (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to obtain a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether: EtOAc = 20:1) to obtain intermediate compound 4 (150 mg, 40%) as a white solid product. 14 H 13 ESI MS of O4S [M+H] + : Calculated value 277.1, measured value 276.9. 1 H NMR(400MHz,DMSO-d6)δ 8.47(s,1H),8.14(d,J=2.0Hz,1H),7.62(s,1H),7.51(d,J=2.1Hz,1H),4.36(q,J=7.1Hz,2H),4.03(s,3H),1.35(t,J=7.1Hz,3H).

[0178] Step 4: Synthesis of 4-methoxythieno[3,2-e]benzofuran-7-carboxylic acid (intermediate 5) [ka] Intermediate compound 4 (450.0 mg, 1.6 mmol) prepared in step 3 was dissolved in MeOH (10 mL) and HO (10 mL), and NaOH (232.6 mg, 5.8 mmol) was added. The reaction mixture was then stirred at 60 °C for 3 h, at which time LCMS indicated no more starting material. The pH of the reaction mixture was adjusted to 4 and diluted with water (100 mL). The mixture was extracted three times with EtOAc (100 mL). The organic phases were collected, dried over NaSO, and concentrated in vacuo to give the title intermediate compound 5 (400.0 mg, 99%) as a white solid. 12 ESI MS of H9O4S [M+H] +Calculated 248.1, found 247.9. No further purification was required and it was used in the next step.

[0179] Step 5: Synthesis of N,4-dimethoxy-N-methylthieno[3,2-e]benzofuran-7-carboxamide (Intermediate 6) [ka] Intermediate compound 5 (550.0 mg, 2.2 mmol), EDCI (849.4 mg, 4.4 mmol), N,O-dimethylhydroxylamine hydrochloride (648.3 mg, 6.7 mmol), and trimethylamine (1.1 g, 11.1 mmol) prepared in Step 4 were dissolved in DCM (10 mL) and the mixture was flushed with N three times. The reaction mixture was stirred at room temperature under N protection for 12 hours. The reaction mixture was quenched by addition to water (100 g) and then diluted with DCM (100 mL). The resulting mixture was extracted with DCM (200 mL), and the organic phase was washed three times with water (100 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by slurry (petroleum ether: EtOAc = 5:1) to give the pure title intermediate compound 6 (600.0 mg, 93%) as a pale red solid. 13 H 13 ESI MS of N2O4S [M+H] + : Calculated value 293.1, actual value 292.0. 1 H NMR (400 MHz, chloroform-d) δ 8.41 (s, 1H), 7.78 (d, J = 2.1 Hz, 1H), 7.21 (s, 1H), 7.11 (d, J = 2.1 Hz, 1H), 4.11 (s, 3H), 3.88 (s, 3H), 3.46 (s, 3H).

[0180] Step 6: Synthesis of 1-(4-methoxythieno[3,2-e]benzofuran-7-yl)ethan-1-one (Intermediate 7) [ka] Intermediate compound 6 (600.0 mg, 2.1 mmol) prepared in step 5 was dissolved in THF (10 mL), and a 1.0 M solution of methylchloromagnesium in THF (6.2 mL, 6.2 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched by adding it to water (50 g) and then diluted with EtOAc (100 mL). The resulting mixture was extracted with EtOAc (100 mL), and the organic phase was then washed three times with water (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to obtain a crude sample. The crude product was further purified by slurry (petroleum ether: EtOAc = 5:1) to obtain the pure title intermediate compound 7 (400.0 mg, 79%) as a white solid. C 13 H 11 ESI MS of O3S [M+H] + :Calculated value 247.0, measured value 247.0. 1 H NMR (400 MHz, chloroform-d) δ 8.09 (s, 1H), 7.78 (d, J = 2.1 Hz, 1H), 7.20 (s, 1H), 7.07 (d, J = 2.1 Hz, 1H), 4.10 (s, 3H), 2.68 (s, 3H).

[0181] Step 7: Synthesis of tert-butyl 4-(4-methoxythieno[3,2-e]benzofuran-7-yl)-4-oxobutyrate (Intermediate 8) [ka] Intermediate compound 7 (150.0 mg, 0.6 mmol) prepared in Step 6 and HMPA (382.0 mg, 2.1 mmol) were dissolved in anhydrous THF (3 mL), and the mixture was flushed with N three times. The reaction mixture was cooled to −78 °C under N protection. HMDSLi (152.9 mg, 0.9 mmol) was then added dropwise and stirred at −40 °C for 1 h. The reaction mixture was then cooled to −78 °C, and tert-butyl 2-bromoacetate (237.6 mg, 1.2 mmol) was added dropwise and stirred at −78 °C for 30 min. The reaction mixture was quenched by addition to water (50 g) and then diluted with EtOAc (100 mL). The resulting mixture was extracted with EtOAc (100 mL), and the organic phase was washed three times with water (50 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give the title intermediate compound 8 as a yellow solid (89.7 mg, 41%). 19 H 20 ESI MS of O5S [M-55H] + Calculated 360.1, found 304.9. No further purification was required and it was used in the next step.

[0182] Step 8: Synthesis of 4-(4-methoxythieno[3,2-e]benzofuran-7-yl)-4-oxobutyric acid (Example Compound 13) [ka] Intermediate compound 8 (219.0 mg, 0.6 mmol) prepared in step 7 was dissolved in DCM (2 mL) and TFA (698.0 mg, 6.1 mmol) to obtain a solution. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to obtain a crude sample. The crude product was purified by reverse-phase HPLC (C 18 Further purification by column chromatography (30%-50% gradient of MeCN and water containing 0.1% FA) gave the white solid product Example Compound 13. 15 H 13 ESI MS of O5S [M+H] + :Calculated value 305.0, measured value 305.0. 1H NMR(400MHz,DMSO-d6)δ 12.19(s,1H),8.68(s,1H),8.16(d,J=2.1Hz,1H),7.61(s,1H),7.45(d,J=2.0Hz,1H),4.04(s,3H),3.35(t,J=6.4Hz,2H),2.64(t,J=6.4Hz,2H).

[0183] Example 14 Synthesis of 4-(4-methoxy-8-methylthieno[3,2-e]benzofuran-7-yl)-4-oxobutyric acid (Example Compound 14) [ka] Step 1: Synthesis of 2-bromo-5-isopropoxy-4-methoxybenzaldehyde (Intermediate 2) [ka] 2-Bromo-5-hydroxy-4-methoxybenzaldehyde (10.0 g, 43.3 mmol) was dissolved in DMF (100 mL) to obtain a solution, followed by the addition of 2-bromopropane (8.0 g, 64.9 mmol) and K2CO3 (12 g, 86.6 mmol) at 25 °C. The reaction mixture was then tightly sealed and stirred continuously at 25 °C for 16 h. The reaction mixture was quenched by addition to water (2.0 kg) and then diluted with EtOAc (1000 mL). The resulting mixture was extracted with EtOAc (1000 mL), and the organic phase was washed with water (1000 mL) and brine (500 mL). The organic phase was collected, dried over Na2SO4, and concentrated in vacuo to give intermediate compound 2 (10.6 g, 90%) as a white solid. 11 H 13 ESI MS of BrO3 [M+H] + : Calculated value 274.1, measured value 272.9.

[0184] Step 2: Synthesis of 1-(2-bromo-5-isopropoxy-4-methoxyphenyl)ethan-1-ol (Intermediate 3) [ka] Intermediate compound 2 (10.6 g, 38.8 mmol) prepared in the previous step was dissolved in THF (110 mL), and the mixture was flushed with N2 three times. 3.0 M methylchloromagnesium in THF (12.9 mL, 38.8 mmol) was added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by addition of 1 M HCl (150 g) and then diluted with EtOAc (200 mL). The resulting mixture was extracted with EtOAc (100 mL), and the organic phase was then washed with water (100 mL) and brine (100 mL). The organic phase was collected, dried over Na2SO4, and concentrated in vacuo to give intermediate compound 3 (11 g, 98%) as a pale yellow solid as product 3. 12 H 17 ESI MS of BrO3 [M+H] + : Calculated value 290.2, actual value 270.9.

[0185] Step 3: Synthesis of 1-(2-bromo-5-isopropoxy-4-methoxyphenyl)ethan-1-one (Intermediate 4) [ka] Intermediate compound 3 (11 g, 38 mmol) prepared in the previous step was dissolved in DCM (150 mL) to obtain a solution. Dess-Martin periodinane (32.3 g, 76.1 mmol) was added to the reaction mixture in portions, and the mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by adding water (500 g). The resulting mixture was extracted with EtOAc (500 mL), and the organic phase was washed five times with water (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give intermediate compound 4 (7.8 g, 92%) as a white solid product. 15 H 19 ESI MS of O4S [M+H] + : Calculated value 295.1, actual value 295.0. 1H NMR(400MHz,CDCl3)δ 7.90(s,1H),7.26(s,1H),7.24(s,1H),4.57(hept,J=6.1Hz,1H),4.38(q,J=7.1Hz,2H),3.93(s,3H),1.40(dd,J=8.8,6.6Hz,9H).

[0186] Step 4: Ethyl 5-isopropoxy-6-methoxy-3-methylbenzo[b]thiophene-2-carboxylate (Intermediate 5) [ka] Intermediate compound 4 (10.0 g, 34.8 mmol) prepared in the previous step was dissolved in DMF (180 mL), followed by the addition of CuI (1.3 g, 7.0 mmol) and ethyl mercaptoacetate (8.4 g, 69.7 mmol) and cooling to 0 °C. To the mixture at 0 °C, K2CO3 (14.4 g, 104.5 mmol) was added. The reaction mixture was then tightly sealed and constantly stirred at 80 °C under N2 protection for 3 h. The reaction mixture was cooled to room temperature and quenched by addition to ice water (2.0 kg) and then diluted with EtOAc (1000 mL). The resulting mixture was extracted with EtOAc (1000 mL), and the organic phase was washed with water (1000 mL) and brine (500 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether: EtOAc = 10:1) to give the white solid product intermediate compound 5 (6.1 g, 57%). 16 H 21 ESI MS of O4S [M+H] + :Calculated value 309.1, measured value 309.0.

[0187] Step 5: Synthesis of 5-isopropoxy-6-methoxy-3-methylbenzo[b]thiophene-2-carboxylic acid (Intermediate 6) [ka] To the intermediate compound 5 (6.0 g, 20.4 mmol) prepared in the previous step, water (40 mL), EtOH (40 mL), and NaOH (2.4 g, 61.2 mmol) were added to obtain a solution. The reaction mixture was stirred at 40 °C for 3 h. The pH of the reaction mixture was adjusted to 6 and diluted with water (500 mL). The mixture was extracted twice with EtOAc (500 mL). The organic phases were collected, dried over NaSO, and concentrated in vacuo to give the crude intermediate compound 6 (4.1 g, 76%) as a pale white solid. 14 H 17 ESI MS of O4S [M+H] + Calculated value 281.1, Found value 281.0. No further purification was required and it was used in the next step.

[0188] Step 6: Synthesis of 5-isopropoxy-N,6-dimethoxy-N,3-dimethylbenzo[b]thiophene-2-carboxamide (Intermediate 7) [ka] To a solution of intermediate compound 6 (4.0 g, 14.3 mmol) prepared in the previous step in DCM (60 mL) was added dropwise sulfinyl chloride (8.5 g, 71.4 mmol) at room temperature. The reaction mixture was then refluxed at 50 °C for 1 h under N protection. The reaction mixture was concentrated in vacuo to give a light brown sample. The residue was diluted with DCM (10 mL) and quenched with water (2 mL) and THF (38 mL) to give N,O-dimethylhydroxylamine hydrochloride (4.2 g, 42.8 mmol) and EtN (7.2 g, 71.4 mmol). Water (200 mL) was then added and extracted three times with DCM (200 mL). The organic phase was collected, dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether: EtOAc = 5:1) to give a white solid product, intermediate compound 7 (4.4 g, 95%). 1H NMR (400 MHz, chloroform-d) δ 7.24 (s, 1H), 7.22 (s, 1H), 4.61 (hept, J = 6.1 Hz, 1H), 3.93 (s, 3H), 3.71 (s, 3H), 3.37 (s, 3H), 2.63 (s, 3H), 1.42 (d, J = 6.1 Hz, 6H).

[0189] Step 7: Synthesis of 1-(5-isopropoxy-6-methoxy-3-methylbenzo[b]thiophen-2-yl)ethan-1-one (Intermediate 8) [ka] To a solution of intermediate compound 7 (4.3 g, 13.3 mmol) prepared in the previous step in THF (50 mL) was added 3.0 M methylchloromagnesium in THF (13.3 mL, 39.9 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was quenched by adding water (100 g) and then diluted with EtOAc (200 mL). The resulting mixture was extracted with EtOAc (200 mL), and the organic phase was washed three times with water (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether: EtOAc = 10:1) to give the title compound, intermediate compound 8, as a white solid product (3.0 g, 81%). 1 H NMR (400 MHz, chloroform-d) δ 7.24 (s, 1H), 7.22 (s, 1H), 4.62 (hept, J = 6.2 Hz, 1H), 3.95 (s, 3H), 2.70 (d, J = 1.6 Hz, 3H), 2.59 (d, J = 1.5 Hz, 3H), 1.42 (d, J = 6.1 Hz, 6H).

[0190] Step 8: Synthesis of ethyl 4-(5-isopropoxy-6-methoxy-3-methylbenzo[b]thiophen-2-yl)-4-oxobutyrate (Intermediate 9) [ka] Intermediate compound 8 (2.9 g, 10.4 mmol) prepared in the previous step and HMPA (6.5 g, 36.5 mmol) were added to anhydrous THF (30 mL) to obtain a solution, and the reaction mixture was cooled to -78 °C under N protection. A 1 M solution of HMDSLi in THF (15.6 mL, 15.6 mmol) was then added dropwise and stirred at -40 °C for 1.5 h. After cooling to -78 °C, ethyl 2-bromoacetate (3.5 g, 20.8 mmol) was added dropwise to the reaction mixture, which was then stirred at -78 °C under N atmosphere for 30 min.

[0191] The reaction mixture was quenched by addition to water (100 g) and then diluted with EtOAc (200 mL). The resulting mixture was extracted with EtOAc (200 mL). The organic phase was then washed three times with water (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to obtain a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether: EtOAc = 10:1) to obtain the title compound, intermediate compound 9 (3.2 g, 84%) as a pale yellow solid. 1 H NMR(400MHz,chloroform-d)δ 7.24(s,1H),7.22(s,1H),4.61(h,J=6.0Hz,1H),4.17(q,J=7.1Hz,2H),3.95(s,3H),3.25(t,J =6.6Hz,2H),2.75(t,J=6.6Hz,2H),2.71(s,3H),1.42(d,J=6.1Hz,6H),1.27(t,J=7.1Hz,3H).

[0192] Step 9: Synthesis of ethyl 4-(5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutyrate (intermediate compound 10) [ka] Intermediate compound prepared in the previous step 9(3.0 g, 8.2 mmol) was added to DCM (30 mL) to obtain a solution, and AlCl (1.6 g, 12.4 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched by adding ice water (100 g) and then diluted with DCM (200 mL). The resulting mixture was extracted with DCM (200 mL), and the organic phase was washed twice with water (100 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to obtain a crude sample. The crude product was further purified by column chromatography (SiO, petroleum ether: EtOAc = 10:1) to obtain the title compound, intermediate compound 10 (2.1 g, 79%) as a yellow solid. 16 H 19 ESI MS of O5S [M+H] + :Calculated value 323.1, measured value 323.0.

[0193] Step 10: Synthesis of ethyl 4-(5-(2,2-diethoxyethoxy)-6-methoxy-3-methylbenzo[b]thiophen-2-yl)-4-oxobutyrate (Intermediate 11) [ka] Intermediate compound 10 (0.5 g, 1.6 mmol) prepared in the previous step was added to DMF (15 mL) to obtain a solution, followed by the addition of KI (51.5 mg, 0.3 mmol), 2-bromo-1,1-diethoxyethane (3.1 g, 15.5 mmol), and K2CO3 (1.1 g, 7.8 mmol). The reaction mixture was then sealed and stirred continuously at 110 °C for 4 h. The reaction mixture was cooled to room temperature and quenched by addition to ice water (200 mL) and then diluted with EtOAc (200 mL). The resulting mixture was extracted with EtOAc (200 mL), and the organic phase was washed with water (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to obtain a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether: EtOAc = 10:1) to give intermediate compound 11 (550 mg, 81%) as a yellow solid product. 1H NMR(400MHz,DMSO-d6)δ 7.58(s,1H),7.48(s,1H),4.87(t,J=5.1Hz,1H),4.10-4.04(m,4H),3.88(s,3H),3.71(dq,J=9.6,7.1Hz,2H),3.60( dq,J=9.6,7.0Hz,2H),3.22(dd,J=7.1,5.4Hz,2H),2.70(s,3H),2.65(t,J=6.2Hz,2H),1.18(dt,J=12.4,7.1Hz,9H).

[0194] Step 11: Synthesis of ethyl 4-(4-methoxy-8-methylthieno[3,2-e]benzofuran-7-yl)-4-oxobutyrate (Intermediate 12) [ka] Intermediate compound 11 (300 mg, 0.7 mmol) prepared in the previous step was added to toluene (3 mL) to obtain a solution, and PPA (557.6 mg, 6.8 mmol) was added. The reaction mixture was stirred at 110 °C for 30 min. The reaction mixture was cooled to room temperature and quenched by adding ice water (20 mL) and then diluted with EtOAc (50 mL). The resulting mixture was extracted with EtOAc (50 mL), and the organic phase was then washed three times with water (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to obtain a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether: EtOAc = 5:1) to obtain intermediate compound 12 (50 mg, 21%) as a white solid product. 18 H 19 ESI MS of O5S [M+H] + : Calculated value 347.1, measured value 347.1.

[0195] Step 12: Synthesis of 4-(4-methoxy-8-methylthieno[3,2-e]benzofuran-7-yl)-4-oxobutyric acid (Example Compound 14) [ka] To the intermediate compound 12 (50 mg, 0.1 mmol) prepared in the previous step, water (2 mL), ethanol (4 mL), and NaOH (28 mg, 0.7 mmol) were added to obtain a solution. The reaction mixture was stirred at room temperature for 30 minutes. The pH of the reaction mixture was adjusted to 5-6 and diluted with water (20 mL). The mixture was extracted three times with EtOAc (20 mL). The organic phases were collected, dried over Na2SO4, and concentrated in vacuo to obtain a crude sample. The crude product was purified by reverse-phase HPLC (C 18 Further purification by column chromatography (30%-50% gradient of MeCN and water containing 0.1% FA) gave a white solid product (8.9 mg, 19%). 16 H 15 ESI MS of O5S [M+H] + :Calculated value 319.1, measured value 319.0. 1 H NMR(400MHz,DMSO-d6)δ 12.20(s,1H),8.19(d,J=2.1Hz,1H),7.58(s,1H),7.51(d,J=2.1Hz,1H),4. 03(s,3H),3.20(dd,J=7.1,5.4Hz,2H),2.93(s,3H),2.60(t,J=6.2Hz,2H).

[0196] Example 15 Synthesis of 4-(4-methoxy-3-methyl-3H-thieno[3,2-e]indazol-7-yl)-4-oxobutyric acid (Example Compound 15) [ka] Step 1: Synthesis of 2-fluoro-4-methoxy-5-nitrobenzaldehyde (Intermediate 2) [ka] A solution of 2-fluoro-4-methoxybenzaldehyde (5.0 g, 32.4 mmol) in HSO (30 mL) was cooled to 0 °C, and then HNO (4 mL, 65%, 41.3 mmol) was slowly added. The reaction mixture was stirred at 0 °C for 2 min. The reaction mixture was quenched by adding ice water (500 g) while maintaining the internal temperature below 20 °C. The mixture was then filtered, and the cake was extracted with EA (500 mL). The organic phase was then washed with water (400 mL) and saturated brine (200 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a yellow solid intermediate compound 2, i.e., crude product 2, 2-fluoro-4-methoxy-5-nitrobenzaldehyde (6.0 g, 92.9%). ESI MS [M+H] of CHFNO + : Calculated value 200.14, actual value 200.1.

[0197] Step 2: Synthesis of ethyl 6-methoxy-5-nitro-1-benzothiophene-2-carboxylate (intermediate compound 4) [ka] To a solution of intermediate compound 2 (5.0 g, 25.1 mmol) prepared in the previous step and ethyl 2-thioacetate (4.5 g, 37.66 mmol) in DMF (50 mL) was added K2CO3 (6.9 g, 50.22 mmol), and the mixture was flushed with N2 three times. The reaction mixture was then sealed tightly and constantly stirred under N2 protection at 80 °C for 3 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was quenched by addition to ice water (600 g), and the resulting mixture was extracted with EtOAc (400 mL). The organic phase was washed twice with water (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. EtOAc (10 mL) and PE (100 mL) were added to the crude product, and the mixture was constantly stirred at 25 °C for 1 h, followed by filtration. The cake was dried under vacuum to give a yellow solid product 4, i.e., intermediate compound 4, ethyl 6-methoxy-5-nitro-1-benzothiophene-2-carboxylate (6.0 g, 85.0%). 12 H 11 ESI MS of NO5S [M+H]+ : Calculated value 282.28, actual value 282.0.

[0198] Step 3: Synthesis of ethyl 5-amino-6-methoxybenzo[b]thiophene-2-carboxylate (Intermediate 5) [ka] A solution of intermediate compound 4 (6.0 g, 21.33 mmol), zinc (7.0 g, 106.7 mmol), and NH4Cl (5.7 g, 106.7 mmol) prepared in the previous step in THF (50 mL) and HO (10 mL) was flushed with N2 three times. The reaction mixture was then sealed tightly and stirred continuously at 70 °C under N2 protection for 2 h. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was diluted with EtOAc (500 mL) and washed with water (200 mL). The organic phase was collected, dried over Na2SO4, and concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, 20% EtOAc-petroleum ether) to give intermediate compound 5 (5.0 g, 93.3%) as a yellow solid. 12 H 13 ESI MS of NO3S [M+H] + : Calculated value 252.3, actual value 252.1.

[0199] Step 4: Synthesis of ethyl 5-amino-4-bromo-6-methoxy-1-benzothiophene-2-carboxylate (Intermediate 6) [ka] Intermediate compound 5 (2.7 g, 10.74 mmol) prepared in the previous step was dissolved in acetonitrile (300 mL), and 1-bromopyrrolidine-2,5-dione (1.9 g, 10.7 mmol) was added. The reaction mixture was then stirred at room temperature for 2 minutes. The reaction mixture was diluted with water (300 mL) and extracted twice with EtOAc (500 mL). The organic phases were collected, dried over Na2SO4, and concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, 10% EtOAc-petroleum ether) to give intermediate compound 6 (2.9 g, 81.7%) as a yellow solid product. 12 H 12 ESI MS of BrNO3S [M+H] + : Calculated value 331.2, actual value 332.0.

[0200] Step 5: Synthesis of ethyl 5-amino-6-methoxy-4-methyl-1-benzothiophene-2-carboxylate (Intermediate 8) [ka] Intermediate compound prepared in the previous step 6 (2.6 g, 7.9 mmol), methylboronic acid (1.4 g, 23.6 mmol), sodium carbonate (2.5 g, 23.6 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.6 g, 0.79 mmol) were dissolved in 1,4-dioxane (50 mL) and water (10 mL) to give a solution, and the mixture was flushed with N three times. The reaction mixture was well sealed and stirred overnight at 100 °C under N protection.

[0201] The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with EtOAc (500 mL) and washed with water (200 mL). The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, 10% EtOAc-petroleum ether) to give intermediate compound 8 (1.7 g, 79.9%) as a yellow solid product. 13 H 15ESI MS of NO3S [M+H] + : Calculated value 266.33, actual value 266.2.

[0202] Step 6: Synthesis of ethyl 4-methoxy-3H-thieno[3,2-e]indazole-7-carboxylate (Intermediate 9) [ka] Sodium nitrite (0.5 g, 7.6 mmol) was added to a solution of intermediate compound 8 (1.7 g, 6.3 mmol) prepared in the previous step in hydrogen chloride (15 mL, 36%) at 0 °C to obtain a mixture. The reaction mixture was then stirred at 0 °C for 30 minutes. Sodium tetrafluoroborate (0.8 g, 7.6 mmol) was then added and stirred continuously at 0 °C for 30 minutes. The reaction mixture was filtered, and dichloromethane (20 mL) and potassium acetate (0.7 g, 7.6 mmol) were added to the cake. The reaction mixture was stirred continuously at room temperature for 1 hour. The reaction mixture was quenched by adding water (100 g). The resulting mixture was extracted with DCM (100 mL), and the organic phase was washed with water (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give the title intermediate compound 9 (1.3 g, 74.8%) as a yellow solid. 13 H 12 ESI MS of N2O3S [M+H] + Calculated 277.31, found 277.1. No further purification was required and it was used in the next step.

[0203] Step 7: Synthesis of ethyl 4-methoxy-3-methyl-3H-thieno[3,2-e]indazole-7-carboxylate (Intermediate 10) [ka] To a solution of intermediate compound 9 (1.3 g, 4.7 mmol) prepared in the previous step in DMF (15 mL) was added iodomethane (0.8 g, 5.7 mmol) and potassium carbonate (1.3 g, 9.4 mmol), and the mixture was then stirred constantly at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (200 mL) and washed three times with ice water (200 mL). The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, 30% EtOAc-petroleum ether) to give intermediate compound 10 (0.6 g, 44.0%) as a yellow solid product. 14 H 14 ESI MS of N2O3S [M+H] + : Calculated value 291.34, actual value 291.1.

[0204] Step 8: Synthesis of 4-methoxy-3-methyl-3H-thieno[3,2-e]indazole-7-carboxylic acid (Intermediate 11) [ka] To a solution of intermediate compound 10 (1.0 g, 3.4 mmol) prepared in the previous step in THF (10 mL), MeOH (10 mL), and HO (2 mL) was added NaOH (688 mg, 17.2 mmol). The reaction mixture was stirred at room temperature for 3 h. The pH of the reaction mixture was adjusted to 5-6 and diluted with water (100 mL). The mixture was extracted three times with EtOAc (100 mL). The organic phases were collected, dried over NaSO, and concentrated in vacuo to give the crude sample. The crude product was further purified by column chromatography (SiO, 10% MeOH-DCM, 1% AcOH) to give intermediate compound 11 as a yellow solid. 12 H 10 ESI MS of N2O3S [M+H] + :Calculated value 263.3, actual value 263.0.

[0205] Step 9: Synthesis of 4-{4-methoxy-3-methyl-3H-thieno[3,2-e]indazole-7-carbonyl}morpholine (Intermediate 13) [ka] To a solution of intermediate compound 11 (1.2 g, 4.6 mmol) prepared in the previous step in THF (20 mL) were added 4-methylmorpholine (2.3 g, 22.9 mmol) and 2-methylpropyl chloroformate (1.3 g, 9.2 mmol), and the mixture was flushed with N2 three times. The reaction mixture was tightly sealed and stirred continuously at room temperature for 1 h. Morpholine (2.0 g, 22.9 mmol) was added to the mixture, and the mixture was then stirred continuously at room temperature for 1 h.

[0206] The reaction mixture was diluted with EtOAc (200 mL) and washed twice with water (200 mL). The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, 30% EtOAc-petroleum ether) to give intermediate compound 13 (200 mg, 13.2%) as a yellow solid product. 16 H 17 ESI MS of N3O3S [M+H] + : Calculated value 332.39, measured value 332.1.

[0207] Step 10: Synthesis of 1-{4-methoxy-3-methyl-3H-thieno[3,2-e]indazol-7-yl}ethan-1-one (Intermediate 14) [ka] A solution of intermediate compound 13 (200.0 mg, 0.6 mmol) prepared in the previous step in THF (15 mL) was exchanged with N2 three times and cooled to 0 °C. Magnesium chloride dimethyl sulfide (134.6 mg, 1.8 mmol) was added to the mixture, which was then stirred constantly at room temperature for 1 h. Water (100 mL) was added to quench the reaction mixture, which was then extracted with ethyl acetate (100 mL). The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, 30% EtOAc-petroleum ether) to give intermediate compound 14 (57.0 mg, 36.5%) as a white solid product. 13 H 12 ESI MS of N2O2S [M+H] + : Calculated value 261.31, actual value 261.0.

[0208] Step 11: Synthesis of ethyl 4-(4-methoxy-3-methyl-3H-thieno[3,2-e]indazol-7-yl)-4-oxobutyrate (intermediate compound 16) [ka] Intermediate compound 14 (50.0 mg, 0.2 mmol) prepared in the previous step and HMPA (119.2 mg, 0.7 mmol) were dissolved in anhydrous THF (2 mL), and the mixture was exchanged with N three times. The reaction mixture was cooled to −78 °C in an ethanol-CO(s) bath under N protection. HMDSLi (47.7 mg, 0.3 mmol) was then added dropwise and stirred at −40 °C for 1.5 h. The reaction mixture was then cooled to −78 °C, and ethyl 2-bromoacetate (63.5 mg, 0.4 mmol) was added dropwise and stirred at −78 °C for 30 min. The reaction mixture was quenched by addition to water (50 g) and then diluted with EtOAc (100 mL). The resulting mixture was extracted with EtOAc (100 mL), and the organic phase was washed three times with water (50 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give the title compound, intermediate compound 16, as a yellow solid (30 mg, 45%). 17 H 18ESI MS of N2O4S [M+H] + Calculated 347.4, found 347.05. No further purification was required and it was used in the next step.

[0209] Step 12: Synthesis of 4-(4-methoxy-3-methyl-3H-thieno[3,2-e]indazol-7-yl)-4-oxobutyric acid (Example compound 15) [ka] Intermediate compound 1 prepared in the previous step 6 To a solution of (30.0 mg, 0.1 mmol) in EtOH (6 mL) and HO (2 mL) was added NaOH (18.0 mg, 0.5 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo to give a crude sample. The crude product was purified by reverse phase HPLC (C 18 Further purification by column chromatography (30%-50% gradient of MeCN and water containing 0.1% FA) gave the white solid product Example Compound 15 (8.9 mg, 31%). 15 H 14 ESI MS [M+H] for N2O4S: calculated 319.4, found 319.1. 1 H NMR(400MHz,DMSO-d6)δ 12.21(s,1H),8.68(s,1H),8.37(s,1H),7.50(s,1H),4.28(s,3H),4.05(s,3H),3.30(s,2H),2.63(t,J=6.5Hz,2H).

[0210] Example 16 Synthesis of 4-(4-methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-4-oxobutyric acid (Example Compound 16) [ka] Step 1: Synthesis of ethyl 5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylate (Intermediate 2) [ka] 2-Bromo-5-hydroxy-4-methoxybenzaldehyde (10.0 g, 43.3 mmol) was dissolved in DMF (100 mL) to obtain a solution, followed by the addition of CuI (2.5 g, 13.0 mmol) and ethyl 2-mercaptoacetate (12 g, 99.6 mmol) and cooling to 0 °C. To the mixture was added KCO (15 g, 108.2 mmol) at 0 °C. The reaction mixture was then well sealed and constantly stirred at 80 °C under N protection for 3 h.

[0211] The reaction mixture was cooled to room temperature and quenched by addition to ice water (2.0 kg), then diluted with EtOAc (1000 mL). The resulting mixture was extracted with EtOAc (1000 mL), and the organic phase was then washed with water (1000 mL) and brine (500 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether: EtOAc = 5:1) to give intermediate compound 2 (8.3 g, 76%) as a yellow solid product. 12 H 13 ESI MS of O4S [M+H] + :Calculated value 253.1, measured value 253.0.

[0212] Step 2: Synthesis of ethyl 5-isopropoxy-6-methoxybenzo[b]thiophene-2-carboxylate (Intermediate 3) [ka] Intermediate compound 2 (7.3 g, 28.9 mmol) prepared in the previous step was dissolved in DMF (70 mL), and K2CO3 (20.0 g, 144.7 mmol) and 2-bromopropane (10.7 g, 86.8 mmol) were added. The mixture was stirred at room temperature under N2 protection for 48 hours. The reaction mixture was quenched by adding water (500 g). The resulting mixture was extracted with EtOAc (500 mL), and the organic phase was washed five times with water (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give intermediate compound 3 (7.8 g, 92%) as a white solid product. 15 H 19 ESI MS of O4S [M+H] + : Calculated value 295.1, actual value 295.0. 1 H NMR(400MHz,CDCl3)δ 7.90(s,1H),7.26(s,1H),7.24(s,1H),4.57(hept,J=6.1Hz,1H),4.38(q,J=7.1Hz,2H),3.93(s,3H),1.40(dd,J=8.8,6.6Hz,9H).

[0213] Step 3: Synthesis of 5-isopropoxy-6-methoxybenzo[b]thiophene-2-carboxylic acid (Intermediate 4) [ka] Intermediate compound 3 (7.5 g, 25.5 mmol) prepared in the previous step was added to water (30 mL), ethanol (75 mL), and sodium hydroxide (6.1 g, 152.9 mmol) to give a solution, and the reaction mixture was stirred at 40° C. for 1 h.

[0214] The pH of the reaction mixture was adjusted to 2-4 and diluted with water (500 mL). The mixture was extracted three times with EtOAc (500 mL). The organic phases were collected, dried over Na2SO4, and concentrated in vacuo to give the crude pale yellow solid intermediate compound 4 (6.3 g, 93%). 13 H 15 ESI MS of O4S [M+H] + Calculated value 267.1, Found value 267.0. No further purification was required and it was used in the next step.

[0215] Step 4: Synthesis of 5-isopropoxy-N,6-dimethoxy-N-methylbenzo[b]thiophene-2-carboxamide (Intermediate 5) [ka] Intermediate compound prepared in the previous step 4 (7.0 g, 26.3 mmol) was dissolved in DCM (100 mL), and sulfinyl chloride (15.6 g, 131.5 mmol) was added dropwise at room temperature. The reaction mixture was then refluxed at 50 °C under N protection for 1 hour. The reaction mixture was concentrated in vacuo to give a light brown sample. The residue was diluted with THF (70 mL) and quenched to give an aqueous solution of N,O-dimethylhydroxylamine hydrochloride (7.7 g, 78.9 mmol) (7 mL), followed by the addition of water (200 mL) and extraction with DCM (200 mL) three times. The organic phase was collected, dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give intermediate compound 5 (7.3 g, 90%) as a light yellow solid product. 15 H 20 ESI MS of NO4S [M+H] + :Calculated value 310.1, actual value 310.0. 1 H NMR (400 MHz, CDCl) δ 8.06 (s, 1H), 7.29 (s, 1H), 7.24 (s, 1H), 4.58 (hept, J = 6.1 Hz, 1H), 3.93 (s, 3H), 3.81 (s, 3H), 3.40 (s, 3H), 1.41 (d, J = 6.1 Hz, 6H). No further purification was required and the product was used in the next step.

[0216] Step 5: Synthesis of 1-(5-isopropoxy-6-methoxybenzo[b]thiophen-2-yl)ethan-1-one (Intermediate 6) [ka] Intermediate compound 5 (6.9 g, 22.3 mmol) prepared in the previous step was dissolved in THF (70 mL), and 3.0 M methylchloromagnesium in THF (22.3 mL, 66.9 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding water (100 g) and then diluted with EtOAc (200 mL). The resulting mixture was extracted with EtOAc (200 mL), and the organic phase was washed three times with water (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to obtain a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether: EtOAc = 10:1) to obtain the title compound, intermediate compound 6 (5.1 g, 87%) as a white solid product. 14 H 17 ESI MS of O3S [M+H] + :Calculated value 265.1, actual value 265.0. 1 H NMR(400MHz, CDCl3)δ 7.80(s,1H),7.28(s,1H),7.25(s,1H),4.57(hept,J=6.1Hz,1H),3.94(s,3H),2.62(s,3H),1.42(d,J=6.1Hz,6H).

[0217] Step 6: Synthesis of ethyl 4-(5-isopropoxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutyrate (Intermediate 7) [ka] Intermediate compound 6 (4.6 g, 17.4 mmol) prepared in the previous step and HMPA (60.9 mg, 10.9 mmol) were dissolved in anhydrous THF (50 mL), and the mixture was flushed with N three times. The reaction mixture was cooled to −78 °C under N protection. A 1 M solution of HMDSLi in THF (26.1 mL, 26.1 mmol) was then added dropwise and stirred at −40 °C for 1 h. After cooling to −78 °C, ethyl 2-bromoacetate (5.8 g, 34.8 mmol) was added dropwise and stirred at −78 °C under N for 1 h. The reaction mixture was quenched by addition to water (100 g) and then diluted with EtOAc (200 mL). The resulting mixture was extracted with EtOAc (200 mL), and the organic phase was washed three times with water (100 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether: EtOAc = 10:1) to give the title compound, intermediate compound 7, as a white solid (5.1 g, 84%). 18 H 23 ESI MS of O5S [M+H] + :Calculated value 351.1, measured value 351.0. 1 H NMR(400MHz,CDCl3)δ 7.87(s,1H),7.28(s,1H),7.25(s,1H),4.58(hept,J=6.1Hz,1H),4.16(q,J=7.1Hz,2H),3.94(s ,3H),3.31(t,J=6.8Hz,2H),2.78(t,J=6.8Hz,2H),1.42(d,J=6.1Hz,6H),1.26(t,J=7.1Hz,4H).

[0218] Step 7: Synthesis of ethyl 4-(5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutyrate (Intermediate 8) [ka] To a solution of intermediate compound 7 (5.1 g, 14.6 mmol) prepared in the previous step in DCM (50 mL) was added AlCl (2.9 g, 21.8 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched by adding ice water (100 g) and then diluted with DCM (200 mL). The resulting mixture was extracted with DCM (200 mL), and the organic phase was washed twice with water (100 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO, petroleum ether: EtOAc = 3:1) to give the title compound, intermediate compound 8, as a white solid (3.7 g, 82%). 15 H 17 ESI MS of O5S [M+H] + :Calculated value 309.1, measured value 309.0. 1 H NMR(400MHz,DMSO)δ 9.37(s,1H),8.13(s,1H),7.49(s,1H),7.27(s,1H),4.01(q,J=7.1Hz,2H),3. 82(s,3H),3.24(t,J=6.4Hz,2H),2.60(t,J=6.4Hz,2H),1.13(t,J=7.1Hz,3H).

[0219] Step 8: Synthesis of ethyl 4-(5-((1,1-diethoxyprop-2-yl)oxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutyrate (Intermediate 9) [ka] Intermediate compound 8 (1.0 g, 3.2 mmol) prepared in the previous step was dissolved in DMF (30 mL), followed by the addition of KI (107.6 g, 0.7 mmol), 2-bromo-1,1-diethoxypropane (6.8 g, 32.4 mmol), and K2CO3 (2.2 g, 16.2 mmol). The reaction mixture was then sealed tightly and stirred continuously at 130 °C for 16 h. The reaction mixture was cooled to room temperature and quenched by addition to ice water (200 mL), followed by dilution with EtOAc (200 mL). The resulting mixture was extracted with EtOAc (200 mL), and the organic phase was then washed with water (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether: EtOAc = 3:1) to give intermediate compound 9 (250 mg, 18%) as a white solid product. 22 H 31 ESI MS of O7S [M+H] + : Calculated value 439.2, measured value 439.1.

[0220] Step 9: Ethyl 4-(4-methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-4-oxobutyrate (Intermediate 10) [ka] Intermediate compound 9 (100 mg, 0.2 mmol) prepared in the previous step was dissolved in toluene (2 mL) and PPA (1 mL) was added. The reaction mixture was stirred at 110 °C for 30 minutes. The reaction mixture was cooled to room temperature and quenched by adding ice water (20 mL) and then diluted with EtOAc (50 mL). The resulting mixture was extracted with EtOAc (50 mL). The organic phase was then washed twice with water (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether: EtOAc = 5:1) to give intermediate compound 10 (25 mg, 31%) as a white solid product. 18 H 19 ESI MS of O5S [M+H] +:Calculated value 347.1, measured value 347.0.

[0221] Step 10: Synthesis of 4-(4-methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-4-oxobutyric acid (Example Compound 16) [ka] To the intermediate compound 10 (25 mg, 0.07 mmol) prepared in the previous step, water (1 mL), EtOH (1 mL), and NaOH (14 mg, 0.4 mmol) were added to obtain a solution. The reaction mixture was stirred at room temperature for 1 h, at which time LCMS indicated no more starting material. The pH of the reaction mixture was adjusted to 3-4 and diluted with water (20 mL). The mixture was extracted three times with EtOAc (20 mL). The organic phases were collected, dried over Na2SO4, and concentrated in vacuo to obtain a crude sample. The crude product was purified by reverse-phase HPLC (C 18 Further purification by column chromatography (40%-60% gradient of MeCN and water containing 0.1% TFA) gave the white solid product Example Compound 16. 16 H 15 ESI MS of O5S [M+H] + :Calculated value 319.1, measured value 319.0. 1 H NMR(400MHz,DMSO-d6)δ 8.59(s,1H),7.51(s,1H),7.04(s,1H),4.00(s,3H),3.30(t,J=6.4Hz,2H),2.61(t,J=6.4Hz,2H),2.53(s,3H).

[0222] Example 17 Synthesis of 4-(4-methoxythieno[3,2-e]benzofuran-7-yl)-2-methyl-4-oxobutyric acid (Example Compound 17) [ka] Step 1: Synthesis of ethyl 5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylate (Intermediate 2) [ka] A solution of 2-bromo-5-hydroxy-4-methoxybenzaldehyde (20.0 g, 86.6 mmol), ethyl 2-mercaptoacetate (20.8 g, 173.1 mmol), and CuI (1.7 g, 8.7 mmol) dissolved in DMF (300 mL) and K2CO3 (35.9 g, 35.9 mmol) was added at 0 °C and the reaction mixture was then flushed with N2 three times. The reaction mixture was then sealed and constantly stirred under N2 protection at 60 °C for 2 h. The reaction mixture was cooled to room temperature, quenched with water (600 mL), and extracted three times with EtOAc (500 mL). The organic phase was washed three times with brine (200 mL), dried over Na2SO4, and concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether: EtOAc = 5:1) to give a white solid product, intermediate compound 2 (17 g, 78%). 12 H 13 ESI MS of NO4S [M+H] + :Calculated value 253.2, actual value 253.0.

[0223] Step 2: Synthesis of ethyl 5-isopropoxy-6-methoxybenzo[b]thiophene-2-carboxylate (Intermediate 3) [ka] A solution of intermediate compound 2 (10.0 g, 40.0 mmol) prepared in the previous step and 2-bromopropane (14.6 g, 118.9 mmol) in DMF (150 mL) and K2CO3 (16.4 g, 118.9 mmol) was added and reacted at 0 °C. The mixture was then flushed with N2 three times. The reaction mixture was sealed well and stirred continuously under N2 protection at 25 °C for 18 h. The reaction mixture was cooled to room temperature, quenched with water (400 mL), and extracted three times with EtOAc (300 mL). The organic phase was washed three times with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to give the crude intermediate compound 3 (12.0 g, 102%) as a brown solid. 15 H 19 ESI MS of NO4S [M+H]+ Calculated value 295.3, Found value 295.0. No further purification was required and it was used in the next step.

[0224] Step 3: Synthesis of dimethyl(2-(5-isopropoxy-6-methoxybenzo[b]thiophen-2-yl)-2-oxoethyl)phosphonate (Intermediate 4) [ka] To THF (30 mL) were added the intermediate compound 3 (3.0 g, 10.2 mmol) prepared in the previous step and dimethyl methylphosphonate (1.3 g, 10.2 mmol), and LDA (2.2 g, 20.4 mmol) was added slowly at -20 °C under N protection. The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was quenched with water (100 mL) and extracted three times with EtOAc (100 mL). The organic phase was dried over NaSO and concentrated in vacuo to obtain a crude sample. The crude product was further purified by column chromatography (SiO, EtOAc) to obtain the title compound, intermediate compound 4 (2.6 g, 69%) as a yellow solid. 16 H 22 ESI MS of NO6PS [M+H] + : Calculated value 373.3, actual value 373.1.

[0225] Step 4: Synthesis of methyl (E)-4-(5-isopropoxy-6-methoxybenzo[b]thiophen-2-yl)-2-methyl-4-oxobut-2-enoate (Intermediate 5) [ka] Intermediate compound 4 (2.7 g, 7.3 mmol) prepared in the previous step was dissolved in THF (35 mL), and n-BuLi (650.2 g, 10.2 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. Then, methyl 2-oxopropionate (1.1 g, 10.9 mmol) was added to the mixture, and the mixture was stirred at room temperature under N protection for 10 minutes. The reaction mixture was quenched by adding water (50 mL) and then diluted with EtOAc (50 mL) three times. The organic phase was then dried over Na SO and concentrated in vacuo to obtain a crude sample. The crude product was further purified by column chromatography (SiO, petroleum ether: EtOAc = 8:1) to obtain the title compound, intermediate compound 5 (1.5 g, 59%) as a yellow solid. 18 H 21 ESI MS of O5S [M+H] + : Calculated value 349.5, actual value 349.1.

[0226] Step 5: Synthesis of methyl 4-(5-isopropoxy-6-methoxybenzo[b]thiophen-2-yl)-2-methyl-4-oxobutyrate (Intermediate 6) [ka] To EA (30 mL) was added intermediate compound 5 (1.0 g, 2.9 mmol) prepared in the previous step and Pd—C (305.4 mg, 2.9 mmol) to obtain a solution. The mixture was then exchanged with H2 three times. The reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was filtered and concentrated in vacuo to give the crude intermediate compound 6 (1.0 g, 99%) as a yellow solid. 18 H 23 ESI MS of NO5 [M+H] + Calculated value 351.4, found value 351.1. No further purification was required and it was used in the next step.

[0227] Step 6: Synthesis of methyl 4-(5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-2-methyl-4-oxobutyrate (Intermediate 7) [ka] Intermediate compound 6 (350.0 mg, 1.0 mmol) prepared in the previous step and AlCl (266.4 mg, 2.0 mmol) were added to DCM (10 mL) to obtain a solution, which was then flushed with N three times. The reaction mixture was stirred at 40 °C for 4 h. The reaction mixture was quenched by addition to water (50 mL) and then extracted three times with EtOAc (50 mL). The organic phase was then dried over Na SO and concentrated in vacuo to give the crude intermediate compound 7 (250.0 mg, 81%) as a yellow solid. 15 H 17 ESI MS of O5S [M+H] + Calculated value 309.1, Found value 309.0. No further purification was required and it was used in the next step.

[0228] Step 7: Synthesis of methyl 4-(5-(2,2-diethoxyethoxy)-6-methoxybenzo[b]thiophen-2-yl)-2-methyl-4-oxobutyrate (Intermediate 8) [ka] Intermediate compound 7 (160.0 mg, 0.5 mmol), 2-bromo-1,1-diethoxyethane (122.7 mg, 0.6 mmol), and K2CO3 (119.8 mg, 0.87 mmol) prepared in the previous step were added to DMF (2.0 mL) to obtain a solution, which was then flushed with N2 three times. The reaction mixture was stirred at 110 °C for 4 h. The reaction mixture was cooled to room temperature, quenched with water (20 mL), and extracted three times with EtOAc (30 mL). The organic phase was washed three times with brine (30 mL), dried over Na2SO4, and concentrated in vacuo to give the crude intermediate compound 8 (150.0 mg, 68%) as a yellow oil. 21 H 29 ESI MS of O7S [M+H] + Calculated value 425.2, Found value 425.1. No further purification was required and it was used in the next step.

[0229] Step 8: Synthesis of methyl 4-(4-methoxythieno[3,2-e]benzofuran-7-yl)-2-methyl-4-oxobutyrate (intermediate compound 9) [ka] The intermediate compound 8 (190.0 mg, 0.5 mmol) prepared in the previous step and PPA (0.1 mL, 1.2 mmol) were added to toluene (2.0 mL) to obtain a solution, and the reaction mixture was stirred at 100° C. for 30 min.

[0230] The reaction mixture was diluted with EA (100 mL), and the EA layer was concentrated in vacuo to give a crude sample. The residue was further purified by column chromatography (SiO, petroleum ether: EtOAc = 3:1) to give the title compound, intermediate compound 9 (70.0 mg, 47%) as a yellow oil. 17 H 17 ESI MS of O5S [M+H] + : Calculated value 333.1, measured value 333.0.

[0231] Step 9: Synthesis of 4-(4-methoxythieno[3,2-e]benzofuran-7-yl)-2-methyl-4-oxobutyric acid (Example Compound 17) [ka] Intermediate compound 9 (60.0 mg, 0.18 mmol) prepared in the previous step and NaOH (72.0 mg, 1.8 mmol) were added to MeOH (5.0 mL) and HO (1.0 mL) to obtain a solution. The reaction mixture was stirred at 30 °C for 3 h. The reaction mixture was concentrated in vacuo to obtain a crude sample. The crude product was purified by reverse-phase HPLC (C 18 Further purification by column chromatography (40%-45% gradient of MeCN and water containing 0.1% FA) gave the white solid product Example Compound 17. 16 H 15 ESI MS of NO5S [M+H] + :Calculated value 319.1, measured value 319.0. 1H NMR(400MHz,DMSO-d6)δ 12.23(s,1H),8.69(s,1H),8.16(d,J=2.0Hz,1H),7.61(s,1H),7.44(d,J=2.1Hz,1H),4. 04(s,3H),3.52-3.42(m,1H),3.12(s,1H),2.94(q,J=7.1Hz,1H),1.21(d,J=7.2Hz,3H).

[0232] Example 18 Synthesis of 4-(4-methoxy-2,8-dimethylthieno[3,2-e]benzofuran-7-yl)-4-oxobutyric acid (Example Compound 18) [ka] Step 1: Synthesis of ethyl 4-(5-(2,2-diethoxyethoxy)-6-methoxy-1-benzothiophene)-2-ethyl-4-oxobutyrate (Intermediate 3) [ka] Ethyl 4-(5-hydroxy-6-methoxy-3-methylbenzo-1-thiophen-2-yl)-4-oxobutyrate (1.0 g, 3.1 mmol) was dissolved in DMF (15 mL) and 2-bromo-1,1-diethoxypropane (3.3 g, 15.5 mmol) was added. The mixture was then cooled to 0 °C, and potassium carbonate (2.1 g, 15.5 mmol) and potassium iodide (103.0 mg, 0.62 mmol) were slowly added. The mixture was flushed with N2 three times, and then the reaction mixture was sealed and stirred continuously under N2 protection at 130 °C for 12 h. The reaction mixture was quenched by adding ice water (600 g) while maintaining the internal temperature below 20 °C. The resulting mixture was extracted with EtOAc (600 mL). The organic phase was then washed with water (400 mL), brine (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample, which was further purified by column chromatography (SiO2, 20% EtOAc-petroleum ether) to give Intermediate 3 (260.0 mg, 18.5%) as a white solid. 1H NMR(400MHz,chloroform-d)δ 7.38(s,1H),7.21(s,1H),4.60(d,J=5.4Hz,1H),4.42(p,J=6.2Hz,1H),4.17(q,J=7.1Hz,4H),3.93(s,3H),3.24(t,J=6 .6Hz,3H),2.75(t,J=6.6Hz,3H),2.69(s,5H),1.40(d,J=6.5Hz,3H),1.28(dd,J=7.3,1.6Hz,3H),1.17(t,J=7.1Hz,3H).

[0233] Step 2: Synthesis of ethyl 4-(4-methoxy-2,8-dimethylthieno[3,2-e]benzofuran-7-yl)-4-oxobutyrate (Intermediate 4) [ka] Step 1: Methyl 4-(5-(2,2-diethoxyethoxy)-6-methoxy-1-benzothiophene)-2-ethyl-4-oxobutyrate (100.0 mg, 0.22 mmol) was dissolved in toluene (5 mL), polyphosphoric acid (18.10 mg, 0.22 mmol) was added, and the mixture was flushed with N three times. The reaction mixture was then sealed and constantly stirred under N protection at 80 °C for 15 min. The reaction mixture was quenched by adding ice water (60 g) to maintain the internal temperature below 20 °C. The resulting mixture was extracted with EtOAc (60 mL). The organic phase was then washed with water (40 mL), brine (20 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO, 20% EtOAc-petroleum ether) to give Intermediate 4 (40 mg, 50.2%) as a white solid. LCMS: C 19 H 20 ESI MS of O5S [M+H] + :Calculated value 361.4, actual value 361.06.

[0234] Step 3: Synthesis of 4-(4-methoxy-2,8-dimethylthieno[3,2-e]benzofuran-7-yl)-4-oxobutyric acid (Example Compound 18) [ka] Ethyl 4-(4-methoxy-2,8-dimethylthieno[3,2-e]benzofuran-7-yl)-4-oxobutyrate (40 mg, 0.11 mmol) was dissolved in methanol (5 mL). The mixture was then cooled to 0 °C, and a solution of sodium hydroxide (22.0 mg, 0.6 mmol) in water (5 mL) was slowly added. The mixture was flushed with N2 three times, and then the reaction mixture was sealed and constantly stirred under N2 protection at 25 °C for 12 h. The reaction was quenched with ice water, extracted with EA, and concentrated to give the crude product, which was then purified by prep-HPLC (column: Hanbang DAC-50, packing: Nanomicro UniHybrid 10-120 C). 18 The purified product was pumped into a 0.1% aqueous NH4HCO3 solution (mobile phase: acetonitrile) and eluted with 50% ACN to give the pure final product as a white solid (2.4 mg, 6.6%). LCMS: C 17 H 16 ESI MS of O5S [M+H] + : Calculated value 333.4, actual value 332.90. 1 H NMR(400MHz,DMSO-d6)δ 12.19(s,1H),7.49(s,1H),7.16(s,1H),4.01(s,3H),3.18(t,J=6.2Hz,2H),2.90(s,3H),2.59(t,J=6.2Hz,2H),2.53(s,3H).

[0235] Example 19 Synthesis of 4-(4-methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-2-methyl-4-oxobutyric acid (Example Compound 19) [ka] Step 1: Synthesis of ethyl 5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylate (Intermediate 2) [ka] 2-Bromo-5-hydroxy-4-methoxybenzaldehyde (50 g, 216.4 mmol) was dissolved in DMF (500 mL). Ethyl 2-mercaptoacetate (59.8 g, 497.7 mmol) and CuI (12.4 g, 64.9 mmol) were added. The temperature was kept at 0 °C. KCO (74.8 g, 541.0 mmol) was added, the mixture was purged with nitrogen, and the temperature was raised to 80 °C and stirred for 3 h. After the reaction was complete, the reaction mixture was cooled to room temperature, 5 L of water was added, and the mixture was extracted with 3 L of EA. The organic phase was washed twice with 3 L of water and then with 1 L of saturated brine. The organic phase was dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography (SiO, EA:petroleum ether = 3:1) to obtain intermediate 2 (46 g, 84%) as a yellow solid. C 12 H 13 ESI MS of O4S [M+H] + : Calculated value 253.29, actual value 253.0.

[0236] Step 2: Synthesis of ethyl 4-formyl-5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylate (Intermediate 3) [ka] HEXA (76.7 g, 547.0 mmol) was dissolved in TFA (460 mL) in an ice-water bath. Ethyl 5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylate (46 g, 182.3 mmol) was added, the mixture was purged with nitrogen, and the temperature was raised to 70 °C and stirred overnight. The reaction mixture was cooled to room temperature, 5 L of water was added, and the mixture was separated and extracted with 3 L of DCM. The aqueous phase was extracted twice with 2 L of DCM. The combined organic phase was extracted twice with 2 L of water, washed once with 2 L of saturated aqueous ammonium chloride, once with 2 L of 5% aqueous NaHCO, and finally with 2 L of purified water. The organic phase was dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was further purified by slurrying it in 100 mL of a mixed solvent (PE:EA = 1:1) and filtering. The cake was collected and spin-dried to give intermediate 3 (37 g, 72%) as a yellow solid. 13 H 13 ESI MS of O5S [M+H] + : Calculated value 281.3, actual value 281.0.

[0237] Step 3: Synthesis of ethyl 5-((1-(tert-butoxy)-1-oxoprop-2-yl)oxy)-4-formyl-6-methoxybenzo[b]thiophene-2-carboxylate (Intermediate 4) [ka] Ethyl 4-formyl-5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylate (27 g, 96.3 mmol) was dissolved in DMF (270 mL), and tert-butyl 2-propionate (24.2 g, 115.6 mmol) and K2CO3 (39.9 g, 289.0 mmol) were added. The mixture was purged with nitrogen, heated to 80 °C, and stirred for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered, and the filtrate was added with 3 L of water. The mixture was separated and extracted with 2 L of EA. The organic phase was washed twice with 3 L of water and once with 1 L of saturated brine. The organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. This was purified by slurrying (PE:EA = 10:1) to give Intermediate 4 (27 g, 69%) as a yellow solid. 20 H 25 ESI MS of O7S [M+Na] + : Calculated value 431.47, actual value 431.06.

[0238] Step 4: Synthesis of 2-((2-(ethoxycarbonyl)-4-formyl-6-methoxybenzo[b]thiophen-5-yl)oxy)propanoic acid (intermediate 5) [ka] Ethyl 5-((1-(tert-butoxy)-1-oxoprop-2-yl)oxy)-4-formyl-6-methoxybenzo[b]thiophene-2-carboxylate (38 g, 93.0 mmol) was dissolved in TFA (106.1 g, 930.3 mmol) and stirred at room temperature for 1 hour. After spotting and monitoring, the reaction mixture was completely mixed with 1 L of ice water, and the mixture was extracted with 1 L of DCM. The organic phase was washed twice with 1 L of water, once with 500 mL of saturated aqueous sodium bicarbonate and once with 500 mL of saturated brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was slurried with 100 mL of tert-butyl methyl ether, filtered, and the cake was spin-dried to obtain intermediate 5 (30 g, 92%) as a yellow solid. 16 H 17 ESI MS of O7S [M+H] +:Calculated value 353.36, actual value 353.05.

[0239] Step 5: Synthesis of ethyl 4-methoxy-2-methylthieno[3,2-e]benzofuran-7-carboxylate (Intermediate 6) [ka] 2-((2-(ethoxycarbonyl)-4-formyl-6-methoxybenzo[b]thiophen-5-yl)oxy)propanoic acid (27 g, 76.6 mmol) was dissolved in acetic anhydride (270 mL), and sodium acetate (27.9 g, 283.8 mmol) was added. The mixture was purged with nitrogen, heated to 130°C, and stirred for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, 2 L of water was added, and the mixture was separated and extracted with 2 L of EA. The organic phase was washed twice with 2 L of water and once with 1 L of saturated aqueous NaHCO3 solution. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography (SiO2, EA:petroleum ether = 1:60) to obtain intermediate 6 (20 g, 90%) as a yellow solid. 15 H 15 ESI MS of O4S [M+H] + : Calculated value 291.33, actual value 291.1.

[0240] Step 6: Synthesis of dimethyl (2-(4-methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-2-oxoethyl)phosphonate (Intermediate 7) [ka] Dimethyl methylphosphonate (7.7 g, 62.0 mmol) and ethyl 4-methoxy-2-methylthieno[3,2-e]benzofuran-7-carboxylate (18.0 g, 62.0 mmol) were dissolved in THF (180 mL), purged with nitrogen, and cooled to -78 °C. LDA (62 mL, 2 M) was added, and the mixture was slowly returned to room temperature and stirred for 3 hours. After the reaction was complete, 500 mL of water was added to the reaction mixture, followed by extraction with 500 mL of EA. The organic phase was washed once with 500 mL of brine and concentrated under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography (SiO2, EA only) to obtain intermediate 7 (16.0 g, 70%) as a yellow solid. 16 H 18 ESI MS [M+H] of O6PS + : Calculated value 369.34, measured value 369.1.

[0241] Step 7: Synthesis of methyl (E)-4-(4-methoxy-2-methylthieno[3,2-E]benzofuran-7-yl)-2-methyl-4-oxobut-2-enoate (Intermediate 8) [ka] Dimethyl (2-(4-methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-2-oxoethyl)phosphonate (23.0 g, 62.4 mmol) was dissolved in THF (500 mL), purged with nitrogen, and cooled to -78 °C. Further, n-butyllithium (25 mL, 2.5 M) was added and stirred for 30 minutes. Further, methyl 2-oxopropionate (6.4 g, 62.4 mmol) was added, and the mixture was returned to room temperature and stirred for 1 hour. After the reaction was complete, 300 mL of saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was separated and extracted with 500 mL of EA. The organic phase was washed once with 500 mL of brine and concentrated under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography (SiO2, PE:EA:DCM = 20:1:1) to obtain intermediate 8 (12 g, 56%) as a yellow solid. 18 H 17 ESI MS of O5S [M+H] +: Calculated value 345.38, actual value 345.1.

[0242] Step 8: Synthesis of methyl 4-(4-methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-2-methyl-4-oxobutyrate (Intermediate 9) [ka] Methyl (E)-4-(4-methoxy-2-methylthieno[3,2-E]benzofuran-7-yl)-2-methyl-4-oxobut-2-enoate (12 g, 34.9 mmol) was dissolved in EA (250 mL). Pd-C (1.2 g, 11.3 mmol) was added, the mixture was purged with hydrogen, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was poured onto diatomaceous earth, washed with 500 mL of EA, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography (SiO2, PE:EA:DCM = 20:1:1) to obtain intermediate 9 (6 g, 50%) as a yellow solid. 18 H 19 ESI MS of O5S [M+H] + : Calculated value 347.4, actual value 347.1.

[0243] Step 9: Synthesis of 4-(4-methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-2-methyl-4-oxobutyric acid (Example Compound 19) [ka] Methyl 4-(4-methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-2-methyl-4-oxobutyrate (6.5 g, 18.8 mmol) was dissolved in HO (20 mL), methanol (50 mL), and dichloromethane (50 mL). NaOH (7.5 g, 187.6 mmol) was added and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, 500 mL of water was added to the reaction mixture, the pH was adjusted to 4-5 with hydrochloric acid, and the mixture was extracted three times with 500 mL of DCM (adding any solids to the organic phase). The organic phase was concentrated under reduced pressure to obtain the crude product, which was then slurried with 10 mL of tert-butyl methyl ether, filtered, and the cake was collected and spin-dried to obtain Example Compound 19 (5.6 g, 90%) as a yellow solid. 17 H 17 ESI MS of O5S [M+H] + : Calculated value 333.37, measured value 333.1. 1 H NMR(400MHz,DMSO-d6)δ 12.22(s,1H),8.60(s,1H),7.50(s,1H),7.03(d,J=1.2Hz,1H),4.00(s,3H),3.45(dd,J=17.4,8.5Hz,1 H),3.13(dd,J=17.3,5.3Hz,1H),2.92(td,J=8.0,5.5Hz,1H),2.55-2.52(m,3H),1.20(d,J=7.2Hz,3H).

[0244] Example 20 Synthesis of 4-(4-methoxy-3H-thieno[3',2':3,4]benzo[1,2-d]imidazol-7-yl)-4-oxobutyric acid (Example Compound 20) [ka] Step 1: Synthesis of 2-fluoro-4-methoxy-5-nitrobenzaldehyde (Intermediate 1) [ka] 2-Fluoro-4-methoxybenzaldehyde (5.0 g, 32.4 mmol) was dissolved in H2SO4 (30 mL), and HNO3 (4 mL, 63.5 mmol) was added dropwise at 0 °C to 20 °C. The reaction mixture was then poured into ice water (100 mL) and extracted twice with EtOAc (200 mL). The organic phases were collected, dried over Na2SO4, and concentrated in vacuo to give the crude product of intermediate 2 as a yellow solid (6.0 g, 93%). ESI MS [M+H] of CHFNO4 + : Calculated value 200.1, actual value 200.1.

[0245] Step 2: Synthesis of ethyl 6-methoxy-5-nitrobenzo[b]thiophene-2-carboxylate (Intermediate 3) [ka] 2-Fluoro-4-methoxy-5-nitrobenzaldehyde (5.0 g, 25.1 mmol) was dissolved in DMF (50 mL), and ethyl 2-mercaptoacetate (4.5 g, 37.7 mmol) and K2CO3 (6.9 g, 50.2 mmol) were added. The mixture was then flushed with N2 three times. The reaction mixture was then sealed tightly and stirred continuously at 80 °C under N2 protection for 2 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was quenched by adding ice water (200 mL), extracted with EtOAc (300 mL), and washed three times with brine (300 mL). The organic phase was collected, dried over Na2SO4, and concentrated in vacuo to give the crude product. The crude product was slurried in petroleum ether:ethyl acetate = 10:1 to give Intermediate 3 (6.0 g, 85%) as a yellow solid. 12 H 12 ESI MS of NO5S [M+H] + : Calculated value 282.3, measured value 282.0

[0246] Step 3: Synthesis of ethyl 5-amino-6-methoxybenzo[b]thiophene-2-carboxylate (Intermediate 4) [ka] Ethyl 6-methoxy-5-nitrobenzo[b]thiophene-2-carboxylate (15.0 g, 53.3 mmol) was dissolved in THF (150 mL) and HO (75 mL), and Zn (17.4 g, 266.6 mmol) and NH4Cl (14.3 g, 266.7 mmol) were slowly added. The reaction mixture was flushed with N2 three times. The reaction mixture was then stirred at 70 °C under N2 protection for 2 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was quenched by adding water (100 mL) and extracted three times with EtOAc (200 mL). The organic phase was collected, dried over Na2SO4, and concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 3:1) to give the pure title intermediate 4 (11.0 g, 82%) as a pale yellow solid. 12 H 14 ESI MS of NO3S [M+H] + : Calculated value 252.3, actual value 252.1.

[0247] Step 4: Synthesis of ethyl 5-amino-4-bromo-6-methoxybenzo[b]thiophene-2-carboxylate (Intermediate 5) [ka] Ethyl 5-amino-6-methoxybenzo[b]thiophene-2-carboxylate (10.0 g, 39.8 mmol) was dissolved in MeCN (400 mL), and a solution of NBS (7.1 g, 39.8 mmol) in MeCN (100 mL) was slowly added at 0 °C. The reaction mixture was then constantly stirred at 25 °C under N protection for 10 minutes. The reaction mixture was quenched by addition to ice water (300 mL) and extracted three times with EtOAc (400 mL). The organic phase was collected, dried over NaSO, and concentrated in vacuo to give the crude product of Intermediate 5 (8.8 g, 67%) as a brown solid. 12 H 13 ESI MS of BrNO3S [M+H] + : Calculated value 331.2, measured value 331.9.

[0248] Step 5: Synthesis of ethyl 5-amino-4-(tert-butoxycarbonyl)amino-6-methoxybenzo[B]thiophene-2-carboxylate (Intermediate 6) [ka] Ethyl 5-amino-4-bromo-6-methoxybenzo[b]thiophene-2-carboxylate (8.8 g, 26.7 mmol) was dissolved in 1,4-dioxane (120 mL) and CsCO (17.4 g, 53.3 mmol), tert-butyl carbamate (4.7 g, 40.0 mmol), Xphos (2.5 g, 5.3 mmol), and PdCl(dba) (2.4 g, 2.7 mmol) were added. The reaction mixture was stirred at 100 °C under N protection for 4 h. The reaction mixture was then concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO, petroleum ether:ethyl acetate = 5:1) to give pure intermediate 6 (5.1 g, 52%) as a light brown solid. 1 H NMR(400MHz,chloroform-d)δ 7.89(d,J=0.9Hz,1H),7.09(s,1H),6.33(s,1H),4.38(q,J=7.1Hz,2H),4. 25(d,J=4.8Hz,2H),3.94(s,3H),1.53(s,9H),1.40(td,J=7.1,1.5Hz,3H).

[0249] Step 6: Synthesis of ethyl 4-methoxy-3H-thieno[3',2':3,4]benzo[1,2-d]imidazole-7-carboxylate (Intermediate 7) [ka] Ethyl 5-amino-4-((tert-butoxycarbonyl)amino)-6-methoxybenzo[b]thiophene-2-carboxylate (5.1 g, 13.9 mmol) was dissolved in formic acid (10 mL, 1.1 mol), and the reaction mixture was then stirred at 100 °C under N protection for 3 h. The reaction mixture was concentrated in vacuo and diluted with EtOAc (50 mL) and HO (50 mL). The pH of the reaction mixture was adjusted to 6, and the organic phase was washed three times with water (50 mL) and brine (50 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO, DCM:MeOH = 50:1) to give Intermediate 7 (2.2 g, 57%) as a white solid.

[0250] Step 7: Synthesis of ethyl 4-methoxy-3-((2-(trimethylsilyl)ethoxy)methyl-3H-thieno[3',2':3,4]benzo[1,2-d]imidazole-7-carboxylate (Intermediate 8) [ka] Ethyl 4-methoxy-3H-thieno[3',2':3,4]benzo[1,2-d]imidazole-7-carboxylate (950.0 mg, 3.4 mmol) was dissolved in THF (20 mL) and NaH (158.1 mg, 6.9 mmol) was added slowly at 0 °C under N protection. The mixture was stirred at 25 °C for 30 minutes. Then, SEMCl (1.1 g, 6.9 mmol) was added to the mixture and stirred at 25 °C for 1 hour. The reaction mixture was quenched by adding it to ice water (50 mL) and then extracted three times with EtOAc (50 mL). The organic phase was then washed twice with brine (50 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give the crude product of Intermediate 8 (1.1 g, 79%) as a brown solid. 19 H 27 ESI MS of N2O4SSi [M+H] + : Calculated value 407.6, measured value 407.1.

[0251] Step 8: Synthesis of 4-methoxy-3-(2-(trimethylsilyl)ethoxy)methyl-3H-thieno[3',2':3,4]benzo[1,2-d]imidazole-7-carboxylic acid (Intermediate 9) [ka] Ethyl 4-methoxy-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-thieno[3',2':3,4]benzo[1,2-d]imidazole-7-carboxylate (1.0 g, 2.5 mmol) was dissolved in HO (5 mL) and EtOH (20 mL), and NaOH (491.9 mg, 2.5 mmol) was added. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with EtOAc (50 mL) and HO (50 mL), and the pH of the reaction mixture was adjusted to 6. The mixture was then extracted three times with EtOAc (50 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo. The crude product was slurried in petroleum ether:ethyl acetate (5:1), the mixture was filtered, and the filtrate was concentrated in vacuo to give Intermediate 9 (850 mg, 91%) as a white solid. 17 H 23 ESI MS of N2O4SSi [M+H] + : Calculated value 379.5, actual value 379.1.

[0252] Step 9: Synthesis of N,4-dimethoxy-N-methyl-3-(2-(trimethylsilyl)ethoxy)methyl-3H-thieno[3',2':3,4]benzo[1,2-d]imidazole-7-carboxamide (Intermediate 10) [ka] 4-Methoxy-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-thieno[3',2':3,4]benzo[1,2-d]imidazole-7-carboxylic acid (800.0 mg, 2.1 mmol) was dissolved in DMF (10.0 mL), followed by the addition of HATU (1.6 g, 4.2 mmol), TEA (1.1 g, 10.6 mmol), and N,O-dimethylhydroxylamine hydrochloride (0.4 g, 4.2 mmol). The reaction mixture was stirred under N protection at 20 °C for 2 h. The reaction mixture was quenched by addition to ice water (50 mL), extracted three times with DCM (50 mL), washed three times with brine (100 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, DCM:MeOH=50:1) to give intermediate 10 as a yellow oil (650 mg, 73%). 19 H 28 ESI MS of N3O4SSi [M+H] + : Calculated value 422.6, measured value 422.1.

[0253] Step 10: Synthesis of 1-(4-methoxy-3-(2-(trimethylsilyl)ethoxy)methyl-3H-thieno[3',2':3,4]benzo[1,2-d]imidazol-7-yl)ethan-1-one (Intermediate 11) [ka] N,4-Dimethoxy-N-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-thieno[3',2':3,4]benzo[1,2-d]imidazole-7-carboxamide (600.0 mg, 1.4 mmol) was dissolved in anhydrous THF (6 mL), and methylmagnesium bromide (509.1 mg, 4.3 mmol) was added under N protection at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by adding to ice water (50 mL) and then diluted with EtOAc (50 mL). The resulting mixture was extracted three times with EtOAc (50 mL), washed three times with brine (100 mL), dried over Na SO , and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, DCM:MeOH=50:1) to give pure intermediate 11 as a yellow oil (380.0 mg, 71%). 18 H 25 ESI MS of N3O3SSi [M+H] + : Calculated value 377.6, actual value 377.1.

[0254] Step 11: Synthesis of tert-butyl 4-(4-methoxy-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-thieno[3',2':3,4]benzo[1,2-d]imidazol-7-yl)-4-oxobutyrate (Intermediate 12) [ka] 1-(4-Methoxy-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-thieno[3',2':3,4]benzo[1,2-d]imidazol-7-yl)ethan-1-one (100 mg, 0.3 mmol) and HMPA (166.6 mg, 1.0 mmol) were dissolved in anhydrous THF (4 mL). The mixture was exchanged with N three times. The reaction mixture was cooled to −78 °C in an ethanol-CO (s) bath under N protection. Then, a 1 M solution of HMDSLi in THF (0.4 mL, 0.4 mmol) was added dropwise and stirred at −40 °C for 1 hour. Then, tert-butyl 2-bromoacetate (103.6 mg, 0.5 mmol) was added to the reaction mixture at −78 °C and stirred at −78 °C for 30 minutes under N protection. The reaction mixture was quenched by addition to ice water (50 mL) and then diluted with EtOAc (50 mL). The resulting mixture was extracted with EtOAc (50 mL), and the organic phase was washed three times with brine (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give the crude product of Intermediate 12 as a yellow solid (100.0 mg, 75%). 24 H 35 ESI MS of N2O5SSi [M+H] + : Calculated value 491.7, measured value 491.1.

[0255] Step 12: Synthesis of 4-(4-methoxy-3H-thieno[3',2':3,4]benzo[1,2-d]imidazol-7-yl)-4-oxobutyric acid (Example Compound 20) [ka] tert-Butyl 4-(4-methoxy-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-thieno[3',2':3,4]benzo[1,2-d]imidazol-7-yl)-4-oxobutyrate (100.0 mg, 0.2 mmol) was dissolved in TFA (3.0 mL), and the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated in vacuo to give a crude sample. The crude product was purified by reverse-phase HPLC (C 18 Further purification by column chromatography (30%-60% MeCN and water with 0.1% TFA) gave a white solid product (9.0 mg, 15%).14 H 13 ESI MS of N2O4S [M+H] + :Calculated value 305.3, measured value 305.0. 1 H NMR (400MHz, DMSO-d6) δ 8.50 (s, 1H), 8.24 (s, 1H), 7.40 (s, 1H), 4.02 (s, 3H), 2.60 (t, J = 6.4Hz, 2H).

[0256] Example 21 Synthesis of ethyl 4-(4-methoxy-1-methyl-1H-thieno[3',2':3,4]benzo[1,2-d]imidazol-7-yl)-4-oxobutyrate (Example Compound 21) [ka] Step 1: Synthesis of ethyl 4-(4-methoxy-1-methyl-1H-thieno[3',2':3,4]benzo[1,2-d]imidazol-7-yl)-4-oxobutyrate (Example Compound 21) To a solution of ethyl 4-(4-methoxy-1-methyl-1H-thieno[3',2':3,4]benzo[1,2-d]imidazol-7-yl)-4-oxobutyrate (30.0 mg, 0.1 mmol) in ethanol (2 mL) and HO (2 mL) was added NaOH (18.0 mg, 0.5 mmol). The reaction mixture was then stirred at room temperature for 2 hours. After monitoring by LCMS, the reaction mixture was adjusted to pH 5 with HCl (1 mol / L) and then concentrated in vacuo to obtain a crude sample. The crude product was purified by reverse-phase HPLC (C 18 Further purification by column chromatography (30%-60% gradient of MeCN, water and water containing 0.1% TFA) gave Example Compound 21 as a white solid (5.0 mg, 17%). 15 H 15 ESI MS of N2O4S [M+H] + : Calculated value 319.4, measured value 319.1. 1H NMR(400MHz,DMSO-d6)δ 12.24(s,1H),8.62(s,1H),8.13(s,1H),7.38(s,1H),4.19(s,3H),4.00(s,3H),3.38(t,J=6.4Hz,2H),2.62(t,J=6.4Hz,2H).

[0257] Example 22 Synthesis of 4-(4-methoxy-3-methyl-3H-thieno[3,2]benzo[1,2-d]imidazol-7-yl)-4-oxobutyric acid (Example Compound 22) [ka] For the synthesis of ethyl 4-methoxy-3H-thieno[3′,2′:3,4]benzo[1,2-d]imidazole-7-carboxylate, see Example 20.

[0258] Step 7: Synthesis of ethyl 4-methoxy-3-methyl-3H-thieno[3',2':3,4]benzo[1,2-d]imidazole-7-carboxylate (Intermediate 8) [ka] Ethyl 4-methoxy-3H-thieno[3',2':3,4]benzo[1,2-d]imidazole-7-carboxylate (1.2 g, 4.3 mmol) was dissolved in DMF (20 mL), and MeI (0.9 g, 6.5 mmol) and K2CO3 (1.8 g, 13.0 mmol) were added. The reaction mixture was then sealed and stirred constantly at 20 °C for 1 h. The reaction mixture was quenched with water (100 mL), extracted with EtOAc (100 mL), and washed three times with brine (100 mL). The organic phase was collected, dried over Na2SO4, and concentrated in vacuo to give the crude product 8 (1.2 g, 95%) as a white solid. 14 H 15 ESI MS of N2O3S [M+H] + : Calculated value 291.3, measured value 291.1.

[0259] Step 8: Synthesis of 4-methoxy-3-methylthieno[3,2:3,4]benzo[1,2-d]imidazole-7-carboxylic acid (Intermediate 9) [ka] Ethyl 4-methoxy-3-methyl-3H-thieno[3',2':3,4]benzo[1,2-d]imidazole-7-carboxylate (1.2 g, 4.1 mmol) was dissolved in HO (20 mL) and EtOH (40 mL). NaOH (0.826 g, 20.7 mmol) was added, and the reaction mixture was then stirred constantly at 20 °C for 3 h. The reaction mixture was diluted with EtOAc (50 mL) and HO (50 mL), and the pH of the reaction mixture was adjusted to 6. The mixture was then extracted three times with EtOAc (100 mL), dried over NaSO, filtered, and the filtrate was concentrated in vacuo to give the crude product, intermediate 9, as a white solid (900 mg, 83%). 12 H 11 ESI MS of N2O3S [M+H] + :Calculated value 263.3, actual value 263.0.

[0260] Step 9: Synthesis of N,4-dimethoxy-N,3-dimethylthieno[3,2:3,4]benzo[1,2-d]imidazole-7-carboxamide (Intermediate 10) [ka] 4-Methoxy-3-methyl-3H-thieno[3',2':3,4]benzo[1,2-d]imidazole-7-carboxylic acid (1.0 g, 3.8 mmol) was dissolved in DMF (50 mL) and HATU (2.9 g, 7.6 mmol), TEA (1.9 g, 19.1 mmol), and N,O-dimethylhydroxylamine hydrochloride (0.7 g, 7.6 mmol) were added under a N atmosphere. The reaction mixture was stirred continuously at 20 °C for 1 h. The reaction mixture was quenched by adding ice water (200 mL), then extracted three times with DCM (200 mL), washed three times with brine (100 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO, 20% MeOH-DCM) to give intermediate 10 (1.0 g, 86%) as a yellow solid. 14 H 16 ESI MS of N3O3S [M+H] + : Calculated value 306.4, actual value 306.0.

[0261] Step 10: Synthesis of 1-(4-methoxy-3-methyl-3H-thieno[3,2:3,4]benzo[1,2-d]imidazol-7-yl)ethan-1-one (Intermediate 11) [ka] N,4-Dimethoxy-N,3-dimethyl-3H-thieno[3',2':3,4]benzo[1,2-d]imidazole-7-carboxamide (900.0 mg, 3.0 mmol) was dissolved in anhydrous THF (20 mL) and methylchloromagnesium (661.3 mg, 8.8 mmol) was added under N2 and 0°C conditions. The reaction mixture was stirred continuously at 25°C for 30 minutes. The reaction mixture was quenched by adding ice water (100 mL) and then diluted with EtOAc (100 mL). The resulting mixture was extracted three times with EtOAc (100 mL), washed three times with brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, 20% MeOH-DCM) to give Intermediate 11 (720.0 mg, 94%) as a yellow solid.13 H 13 ESI MS of N2O2S [M+H] + : Calculated value 261.3, actual value 261.0.

[0262] Step 11: Synthesis of ethyl 4-(4-methoxy-3-methyl-3H-thieno[3',2':3,4]benzo[1,2-d]imidazol-7-yl)-4-oxobutyrate (Intermediate 12) [ka] 1-(4-Methoxy-3-methyl-3H-thieno[3',2':3,4]benzo[1,2-d]imidazol-7-yl)ethan-1-one (800.0 mg, 3.1 mmol) was dissolved in anhydrous THF (50 mL) and HMPA (1.9 g, 10.8 mmol) was added under a N atmosphere. The reaction mixture was cooled to -78 °C in an ethanol-carbon dioxide bath under N protection, and then a 1 mol / L HMDSLi (4.6 mL, 4.6 mmol) solution in tetrahydrofuran was added dropwise and stirred at -40 °C for 1 hour. Ethyl 2-bromoacetate (1.0 g, 6.2 mmol) was then added to the reaction mixture at -78 °C and stirred at -78 °C for 30 minutes under N protection. The reaction mixture was quenched by adding ice water (50 mL) and then diluted with EtOAc (50 mL). The resulting mixture was extracted with EtOAc (100 mL), and the organic phase was washed three times with brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product of compound 12 was obtained as a yellow solid (800.0 mg, 75%). 17 H 19 ESI MS of N2O4S [M+H] + :Calculated value 347.4, actual value 347.0.

[0263] Step 12: Synthesis of 4-(4-methoxy-3-methyl-3H-thieno[3,2]benzo[1,2-d]imidazol-7-yl)-4-oxobutyric acid (Example Compound 22) [ka] Ethyl 4-(4-methoxy-3-methyl-3H-thieno[3',2':3,4]benzo[1,2-d]imidazol-7-yl)-4-oxobutyrate (80.0 mg, 0.2 mmol) was dissolved in HO (10 mL) and EtOH (10 mL), followed by the addition of NaOH (42.6 mg, 1.2 mmol). The reaction mixture was stirred at 50 °C for 2 h. The pH was adjusted to 5 with 1 mol / L hydrochloric acid solution and concentrated in vacuo to obtain a crude sample. The crude product was purified by reverse-phase HPLC (C 18 Further purification by column chromatography (30%-60% MeCN and water with 0.1% TFA) gave a white solid product (8.0 mg, 11%). 15 H 15 ESI MS of N2O4S [M+H] + :Calculated value 319.4, actual value 319.0. 1 H NMR(400MHz,DMSO-d6)δ 12.05(s,1H),8.49(s,1H),8.20(s,1H),7.44(s,1H),4.07(s,3H),4.02(s,3H),3.36(t,J=6.3Hz,2H),2.60(t,J=6.3Hz,2H).

[0264] Example 23 Synthesis of 4-(4-methoxy-2-methyl-2H-thieno[3,2-e]indazol-7-yl)-4-oxobutyric acid (Example Compound 23) [ka] For the synthesis of 4-methoxy-2-methyl-2H-thieno[3,2-e]indazole-7-carboxylic acid (intermediate 11), see Example 15.

[0265] Step 9: Synthesis of N,4-dimethoxy-N,3-dimethyl-3H-thieno[3,2-e]indazole-7-carboxamide (Intermediate 12) [ka] 4-Methoxy-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-thieno[3',2':3,4]benzo[1,2-d]imidazole-7-carboxylic acid (400.0 mg, 1.5 mmol) was dissolved in DMF (10.0 mL), and HATU (1.2 g, 3.1 mmol), TEA (0.8 g, 7.6 mmol), and N,O-dimethylhydroxylamine hydrochloride (0.3 g, 3.1 mol) were added. The reaction mixture was stirred at 25 °C for 1 h under nitrogen protection.

[0266] The reaction mixture was poured into water (50 mL) and then extracted three times with EtOAc (50 mL). The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was further purified by column chromatography (SiO2, petroleum ether: EtOAc = 3:1) to give compound 12 (300 mg, 64%) as a yellow solid. 14 H 16 ESI MS of N3O3S [M+H] + : Calculated value 306.4, measured value 306.1.

[0267] Step 10: Synthesis of 1-(4-methoxy-2-methyl-2H-thieno[3,2-e]indazol-7-yl)ethan-1-one (Intermediate 13) [ka] N,4-Dimethoxy-N,3-dimethyl-3H-thieno[3,2-e]indazole-7-carboxamide (300.0 mg, 1.0 mmol) was dissolved in THF (10 mL) and cooled to 0 °C under nitrogen protection. Methylchloromagnesium (367.4 mg, 4.9 mmol) was added to the reaction mixture and stirred continuously at room temperature for 1 h. The reaction was quenched by adding water (50 mL) and extracted twice with EtOAc (50 mL). The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was further purified by column chromatography (SiO2, petroleum ether: EtOAc = 3:1) to give intermediate 13 (250.0 mg, 98%) as a yellow solid. 13 H 13ESI MS of N2O2S [M+H] + : Calculated value 261.3, actual value 261.0.

[0268] Step 11: Synthesis of ethyl 4-(4-methoxy-2-methyl-2H-thieno[3,2-e]indazol-7-yl)-4-oxobutyrate (Intermediate 14) [ka] 1-(4-Methoxy-2-methyl-2H-thieno[3,2-e]indazol-7-yl)ethan-1-one (70.0 mg, 0.3 mmol) and HMPA (168.7 mg, 1.0 mmol) were dissolved in anhydrous THF (5 mL). The reaction mixture was cooled to -78 °C under N protection using a solid carbon dioxide-ethanol bath. HMDSLi (0.4 mL, 0.4 mmol, 1 M in THF) was then added dropwise and stirred at -45 °C for 1 h. The reaction mixture was then cooled to -78 °C, and 2-bromoethyl acetate (89.8 mg, 0.5 mmol) was added dropwise and stirred at -78 °C for 1 h. The reaction mixture was quenched with water (50 mL), extracted twice with EtOAc (50 mL), and the organic phase was dried over NaSO and filtered. The filtrate was concentrated under reduced pressure to give a crude product of Intermediate 14 as a yellow solid (90 mg, 96%). 17 H 19 ESI MS of N2O4S [M+H] + Calculated 347.4, found 347.0. Intermediate 14 was taken directly into the next step without purification.

[0269] Step 12: Synthesis of 4-(4-methoxy-2-methyl-2H-thieno[3,2-e]indazol-7-yl)-4-oxobutyric acid (Example Compound 23) [ka] To a solution of ethyl 4-(4-methoxy-2-methyl-2H-thieno[3,2-e]indazol-7-yl)-4-oxobutyrate (90.0 mg, 0.3 mmol) in MeOH (3 mL), THF (3 mL), and HO (1 mL) was added NaOH (52.0 mg, 1.3 mmol), and the reaction mixture was stirred at room temperature for 2 h.

[0270] The reaction mixture was added with 20 mL of EtOAc and 20 mL of H2O to adjust the pH to 5, and then extracted three times with 20 mL of EtOAc, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by reverse phase HPLC (C 18 Further purification by column chromatography (30%-50% gradient of MeCN and water containing 0.1% FA) gave a white solid product (18.0 mg, 22%). 15 H 15 ESI MS of N2O4S [M+H] + :Calculated value 319.4, actual value 319.0. 1 H NMR(400MHz,DMSO-d6)δ 12.19(s,1H),8.57(s,1H),8.55(s,1H),7.26(s,1H),4.19(s,3H),3.99(s,3H),3.29(t,J=6.5Hz,2H),2.62(t,J=6.4Hz,2H).

[0271] Example 24 Synthesis of 4-(4-methoxy-2,8-dimethylthieno[3,2-e]benzofuran-7-yl)-4-oxobutyric acid (Example Compound 24) [ka] Step 1: Synthesis of ethyl 4-formyl-5-hydroxy-6-methoxy-1-benzothiophene-2-carboxylate (Intermediate 2) [ka] Ethyl 5-hydroxy-6-methoxy-1-benzothiophene-2-carboxylate (4.2 g, 16.7 mmol) was dissolved in TFA (42 mL, 368.3 mmol), hexamethylenetetramine (11.7 g, 83.2 mmol) was added, and the mixture was flushed with N three times. The reaction mixture was then sealed and constantly stirred under N protection at 90 °C for 8 h. The reaction mixture was quenched by adding ice water (600 g) while maintaining the internal temperature below 20 °C. The resulting mixture was extracted with EtOAc (600 mL). The organic phase was then washed with water (400 mL), brine (200 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO, 20% EtOAc-petroleum ether) to give Intermediate 2 (4 g, 85.7%) as a white solid. LCMS: C 13 H 12 ESI MS of O5S [M+H] + : Calculated value 281.3, actual value 280.92.

[0272] Step 2: Synthesis of ethyl (E)-5-hydroxy-4-(hydroxyimino)methyl)-6-methoxy-1-benzothiophene-2-carboxylate (Intermediate 3) [ka] Ethyl 4-formyl-5-hydroxy-6-methoxy-1-benzothiophene-2-carboxylate (2.7 g, 9.6 mmol) was dissolved in ethanol (30 mL), sodium bicarbonate (1.1 g, 12.9 mmol) was added, and hydroxylamine hydrochloride (3.3 g, 48.2 mmol) was added. The mixture was flushed with N2 three times, then sealed and stirred continuously at 80 °C under N2 protection for 1 h. The reaction mixture was quenched by adding ice water (600 g) while maintaining the internal temperature below 20 °C. The resulting mixture was extracted with EtOAc (600 mL). The organic phase was then washed with water (400 mL), brine (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, 20% EtOAc-petroleum ether) to give Intermediate 3 (2.1 g, 84.0%) as a yellow solid. 13 H 13 ESI MS of NO5S [M+H] + : Calculated value 296.3, actual value 296.0.

[0273] Step 3: Synthesis of ethyl 4-methoxythieno[2',3':5,6]benzo[1,2-d]isoxazole-7-carboxylate [ka] Ethyl (E)-5-hydroxy-4-(hydroxyimino)methyl)-6-methoxy-1-benzothiophene-2-carboxylate (2.3 g, 7.62 mmol) was dissolved in THF (50 mL), followed by the addition of triphenylphosphine (6 g, 22.9 mmol). Diisopropyl azodicarboxylate (3.1 g, 15.2 mmol) was added under nitrogen protection in an ice-water bath. The mixture was flushed with N2 three times, and then the reaction mixture was sealed and stirred constantly under N2 protection at 25 °C for 12 hours. The reaction was quenched with ice water, extracted with EA, and concentrated to give the crude product, which was further purified by column chromatography (SiO2, 20% EtOAc-petroleum ether) to give intermediate 3 (1.35 g, 63.9%) as a yellow solid. 13 H 11ESI MS of NO4S [M+H] + : Calculated value 278.3, actual value 278.0.

[0274] Step 4: Synthesis of 4-methoxythieno[2',3':5,6]benzo[1,2-d]isoxazole-7-carboxylic acid [ka] Ethyl 4-methoxythieno[2',3':5,6]benzo[1,2-D]isoxazole-7-carboxylate (1.3 g, 4.7 mmol) was added to water (20 mL), ethanol (20 mL), and NaOH (187.5 mg, 4.7 mmol) to dissolve the ethyl 4-methoxythieno[2',3':5,6]benzo[1,2-D]isoxazole-7-carboxylate, resulting in a solution. The reaction mixture was stirred at room temperature for 2 hours, quenched with ice water, extracted with EA, and concentrated to give the crude product, which was further purified by column chromatography (SiO2, 20% EtOAc-petroleum ether) to give Intermediate 3 (1.1 g, 94%) as a yellow solid. 11 ESI MS of H7NO4S [MH] - : Calculated value 248.2, actual value 247.9.

[0275] Step 5: Synthesis of N,4-dimethoxy-N-methylthieno[2',3':5,6]benzo[1,2-d]isoxazole-7-carboxamide [ka] To a solution of ethyl (E)-5-hydroxy-4-(hydroxyimino)methyl)-6-methoxy-1-benzothiophene-2-carboxylate (2.3 g, 7.62 mmol) in DCM (15 mL), N,O-dimethylhydroxylamine hydrochloride (1.3 g, 12.9 mmol), triethylamine (2.2 g, 21.5 mmol), and EDCI (1.6 g, 8.6 mmol) were added. The reaction mixture was then reacted at 25 °C under N protection for 1 hour. The reaction was quenched with ice water, extracted with EA, and concentrated to obtain the crude product, which was further purified by column chromatography (SiO, 20% EtOAc-petroleum ether) to obtain intermediate 6 (330 mg, 26.0%) as a yellow solid. 13 H 12 ESI MS of N2O4S [M+H] + : Calculated value 293.3, actual value 293.1.

[0276] Step 6: Synthesis of 1-(4-methoxythieno[2',3':5,6]benzo[1,2-d]isoxazol-7-yl)ethan-1-one [ka] A solution of N,4-dimethoxy-N-methylthieno[2',3':5,6]benzo[1,2-d]isoxazole-7-carboxamide (300.0 mg, 1 mmol) in THF (3 mL) was flushed with N three times. The reaction mixture was cooled to 0 °C under N protection. Then, at 0 °C, 1.0 M methylchloromagnesium in THF (3.1 mL, 3.1 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by adding ice water (20 mL) and then diluted with EtOAc (20 mL). The resulting mixture was extracted with EtOAc (20 mL), and the organic phase was washed three times with water (20 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO, petroleum ether: EtOAc = 5:1) to give Intermediate 7 (180 mg, 71%) as a yellow solid. C 12 ESI MS of H9NO3S [MH]- : Calculated value 246.3, actual value 246.0.

[0277] Step 7: Synthesis of tert-butyl 4-(4-methoxythieno[2',3':5,6]benzo[1,2-d]isoxazol-7-yl)-4-oxobutyrate [ka] A solution of 1-(4-methoxythieno[2',3':5,6]benzo[1,2-d]isoxazol-7-yl)ethan-1-one (100.0 mg, 0.4 mmol) and HMPA (253.7 g, 1.4 mmol) in anhydrous THF (1 mL) was flushed with N three times. The reaction mixture was cooled to -78 °C under N protection. A 1 M solution of HMDSLi in THF (0.6 mL, 0.6 mmol) was then added dropwise and stirred at -78 °C for 30 min. tert-Butyl 2-bromoacetate (157.8 mg, 0.8 mmol) was then added to the reaction mixture and stirred at -78 °C under N for 2 h. LCMS indicated no more starting material. The pH of the reaction mixture was adjusted to 5 and diluted with water (20 mL) followed by EtOAc (20 mL). The organic phase was then washed with water (20 mL) and brine (20 mL), dried over Na2SO4, concentrated in vacuo, and filtered to give crude compound 8 (100.0 mg, 68%) as a yellow solid. 18 H 19 ESI MS of NO5S [M+H] + : Calculated value 362.4, actual value 306.0.

[0278] Step 8: Synthesis of 4-(4-methoxythieno[2',3':5,6]benzo[1,2-d]isoxazol-7-yl)-4-oxobutyric acid [ka] 1-(4-Methoxythieno[2',3':5,6]benzo[1,2-d]isoxazol-7-yl)ethan-1-one (100.0 mg, 0.28 mmol) was added to TFA (0.5 mL) to obtain a solution. The reaction mixture was stirred at 20 °C for 30 min. The reaction mixture was concentrated in vacuo to obtain a crude sample. The crude product was purified by reverse phase HPLC (C 18 Further purification by column, 30%-50% gradient of MeCN and water with 0.1% FA) gave a white solid product (16.8 mg, 19.65%). 1 H NMR(400MHz,DMSO-d6)δ 12.18(s,1H),11.03(s,1H),8.12(s,1H),7.95(s,1H),3.96(s,3H),3.36(t,J=6.4Hz,2H),2.59(t,J=6.4Hz,2H).

[0279] Example 25 Synthesis of 4-(4-methoxy-2-methyl-2H-thieno[3,2-e]indazol-7-yl)-4-oxobutyric acid (Example Compound 25) [ka] Step 1: Synthesis of 2-fluoro-4-methoxy-5-nitrobenzaldehyde (Intermediate 2) [ka] 2-Fluoro-4-methoxybenzaldehyde (5 g, 32.4 mmol) was dissolved in sulfuric acid (30 mL) and cooled to 0 °C. Nitric acid (4 mL, 63.5 mmol, 64%) was slowly added. During the dropwise addition, a severe exotherm occurred; the internal temperature was controlled to not exceed 20 °C. Upon completion, the reaction mixture was immediately monitored by spotting. The reaction mixture was added dropwise to ice water, filtered, and the cake was added with EA (500 mL) and water (500 mL). The organic phase was extracted by separation and dried over NaSO and filtered. The filtrate was concentrated under reduced pressure to give the crude product of intermediate 2 (6 g, 93%) as a yellow solid. ESI MS [M+H] of C8H7FNO4 + : Calculated value 200.14, actual value 200.0.

[0280] Step 2: Synthesis of ethyl 6-methoxy-5-nitrobenzo[b]thiophene-2-carboxylate (Intermediate 3) [ka] 2-Fluoro-4-methoxy-5-nitrobenzaldehyde (6 g, 30.1 mmol) was dissolved in DMF (60 mL) and cooled to 0 °C. Ethyl 2-thioacetate (5.4 g, 45.2 mmol) and potassium carbonate (8.3 g, 60.3 mmol) were added, and the mixture was stirred at 80 °C for 4 hours under nitrogen protection. The reaction mixture was cooled to room temperature, filtered, and the cake was washed with EA (600 mL). Ice water (600 mL) was added to the filtrate, followed by separation and extraction. The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by slurrying in a 10V mixed solvent (PE:EA = 10:1), filtered, and the cake was collected to obtain Intermediate 3 (7 g, 83%) as a yellow solid. 12 H 12 ESI MS of NO5S [M+H] + : Calculated value 282.28, actual value 282.0.

[0281] Step 3: Synthesis of ethyl 5-methoxy-6H-thieno[3,2-ethyl]indole-2-carboxylate (Intermediate 4) [ka] Ethyl 6-methoxy-5-nitrobenzo[b]thiophene-2-carboxylate (3 g, 10.7 mmol) was dissolved in anhydrous THF (50 mL) and cooled to -40 °C under nitrogen protection. Vinyl magnesium bromide (53 mL, 53.3 mmol, 1 M in THF) was added. Upon completion, the mixture was stirred for 1 hour, warmed to room temperature, and stirred overnight. The reaction mixture was quenched by adding water (500 mL), and EA (500 mL) was added. The mixture was separated and extracted. The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was further purified by column chromatography (SiO2, EtOAc:petroleum ether = 1:3) to give Intermediate 4 (500 mg, 17%) as a yellow liquid. 14 H 14 ESI MS of NO3S [M+H] + : Calculated value 276.32, actual value 276.1.

[0282] Step 4: Synthesis of ethyl 5-methoxy-6-methyl-6H-thieno[3,2-e]indole-2-carboxylate (Intermediate 5) [ka] Ethyl 5-methoxy-6H-thieno[3,2-ethyl]indole-2-carboxylate (400 mg, 1.5 mmol) was dissolved in THF (10 mL). Under nitrogen protection, sodium hydride (66.8 mg, 2.9 mmol) and iodomethane (247.5 mg, 1.7 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Ice water (50 mL) was added to the reaction mixture, and the mixture was separated and extracted with EA (50 mL). The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a crude product of intermediate 5 (400 mg, 95%) as a yellow solid. The crude product was directly used in the next step without purification. C 15 H 16 ESI MS of NO3S [M+H] + : Calculated value 290.35, actual value 290.1.

[0283] Step 5: Synthesis of 5-methoxy-6-methyl-6H-thieno[3,2-e]indole-2-carboxylic acid (Intermediate 6) [ka] Ethyl 5-methoxy-6-methyl-6H-thieno[3,2-e]indole-2-carboxylate (400 mg, 1.4 mmol) was dissolved in HO (2 mL) and methanol (10 mL). NaOH (276.5 mg, 6.9 mmol) was added and the mixture was stirred overnight at room temperature. The pH of the reaction mixture was adjusted to 5, and EA (100 mL) and water (100 mL) were added. The mixture was separated and extracted. The organic phase was dried over NaSO and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was further purified by column chromatography (SiO, DCM:MeOH = 20:1) to obtain Intermediate 6 (300 mg, 83%) as a yellow liquid. 13 H 12 ESI MS of NO3S [M+H] + : Calculated value 262.3, measured value 262.0

[0284] Step 6: Synthesis of N,5-dimethoxy-N,6-dimethyl-6H-thieno[3,2-e]indole-2-carboxamide (Intermediate 7) [ka] 5-Methoxy-6-methyl-6H-thieno[3,2-e]indole-2-carboxylic acid (300 mg, 1.2 mmol) was dissolved in DMF (10 mL), and HATU (387.1 mg, 2.3 mmol), triethylamine (580.9 mg, 5.7 mmol), and dimethylhydroxylamine hydrochloride (224.0 mg, 2.3 mmol) were added. The mixture was maintained at room temperature and stirred for 1 hour. Water (100 mL) was added to the reaction mixture, and the mixture was separated and extracted with EA (100 mL). The organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography (SiO2, PE:EA = 3:1) to obtain intermediate 7 (300 mg, 86%) as a yellow liquid. 15 H 17 ESI MS of N2O3S [M+H] +: Calculated value 305.36, measured value 305.1.

[0285] Step 7: Synthesis of 1-(5-methoxy-6-methyl-6H-thieno[3,2-e]indol-2-yl)ethan-1-one (Intermediate 8) [ka] N,5-Dimethoxy-N,6-dimethyl-6H-thieno[3,2-e]indole-2-carboxamide (300 mg, 1.0 mmol) was dissolved in THF (10 mL). Under nitrogen protection, methylchloromagnesium (222.1 mg, 3.0 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water (100 mL) was added to the reaction mixture, followed by separation and extraction with EA (100 mL). The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography (SiO2, PE:EA = 3:1) to obtain intermediate 8 (150 mg, 58%) as a yellow liquid. 14 H 14 ESI MS of NO2S [M+H] + : Calculated value 260.32, actual value 260.0.

[0286] Step 8: Synthesis of ethyl 4-(5-methoxy-6-methyl-6H-thieno[3,2-e]indol-2-yl)-4-oxobutyrate (Intermediate 9) [ka] 1-(5-Methoxy-6-methyl-6H-thieno[3,2-e]indol-2-yl)ethan-1-one (80 mg, 0.3 mmol) was dissolved in THF (5 mL), HMPA (193.5 mg, 1.1 mmol) was added, and the mixture was cooled to -78 °C under nitrogen protection. HMDSLi (154.9 mg, 0.9 mmol) was added, and the mixture was warmed to -40 °C and stirred for 2 hours. 2-Bromoethyl acetate (154.6 mg, 0.9 mmol) was added, and the mixture was stirred for 1 hour. Water (50 mL) was added to the reaction mixture, and the mixture was separated and extracted with EA (50 mL). The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the crude product of intermediate 9 as a yellow solid (80 mg, 75%). 18 H 19 ESI MS of NO4S [M+H] + : Calculated value 346.41, measured value 346.1.

[0287] Step 9: Synthesis of 4-(5-methoxy-6-methyl-6H-thieno[3,2-e]indol-2-yl)-4-oxobutyric acid (Example Compound 25) [ka] To a solution of ethyl 4-(5-methoxy-6-methyl-6H-thieno[3,2-e]indol-2-yl)-4-oxobutyrate (80.0 mg, 0.2 mmol) in MeOH (2 mL), THF (2 mL), and HO (1 mL) was added NaOH (46.0 mg, 1.2 mmol), and the reaction mixture was stirred at room temperature for 2 h.

[0288] The reaction mixture was added with 20 mL of EtOAc and 20 mL of H2O to adjust the pH to 5, and then extracted three times with 20 mL of EtOAc, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by reverse phase HPLC (C 18 Further purification by column chromatography (30%-50% gradient of MeCN and water containing 0.1% FA) gave a white solid product (2.0 mg, 3%). 16 H 16 ESI MS of NO4S [M+H] +: Calculated value 318.36, actual value 317.95. 1 H NMR(400MHz,DMSO-d6)δ 8.56(s,1H),7.33(d,J=3.0Hz,1H),7.25(s,1H),6.86(d,J=2.9Hz,1H),4.06(s,3H),3.99(s,3H),3.27(t,J=6.7Hz,2H),2.64(t,J=6.7Hz,2H).

[0289] Example 26 Synthesis of 4-(5-methoxy-7,8-dihydro-6H-indeno[5,4-b]thiophen-2-yl)-4-oxobutyric acid (Example Compound 26) [ka] Step 1: Synthesis of 5-bromo-2-fluoro-4-methoxybenzaldehyde (Intermediate 2) [ka] Potassium bromide (19.3 g, 162.2 mmol) was dissolved in HO (100 mL) and MeOH (25 mL), and bromine (10.4 g, 64.9 mmol) was added. The reaction mixture was then cooled to 0 °C. 2-Fluoro-4-methoxybenzaldehyde (5.0 g, 34.4 mmol) was dissolved in 20 mL of methanol and added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred at room temperature for 3 hours, and a solid precipitated from the reaction mixture. The reaction mixture was filtered, and water (500 mL) was added to wash the cake. The cake was concentrated in vacuo to give compound 2 (7.6 g, 93%) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 10.16 (s, 1H), 8.06 (d, J = 7.4 Hz, 1H), 6.68 (d, J = 11.9 Hz, 1H), 3.97 (s, 3H).

[0290] Step 2: Synthesis of ethyl 5-bromo-6-methoxybenzo[b]thiophene-2-carboxylate (Intermediate 3) [ka] 5-Bromo-2-fluoro-4-methoxybenzaldehyde (25.0 g, 108.2 mmol) was dissolved in THF (250 mL), and CsCO (14.0 g, 42.9 mmol) and ethyl 2-mercaptoacetate (2.8 g, 23.6 mmol) were added. The reaction mixture was then sealed and stirred overnight at 66 °C under N protection. The reaction mixture was cooled to room temperature and quenched by addition to ice water (1000 mL) and then diluted with EtOAc (1000 mL). The resulting mixture was extracted with EtOAc (1000 mL), and the organic phase was washed with water (1000 mL) and brine (1000 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO, petroleum ether:ethyl acetate = 3:1) to give product 3 (6.8 g, 83%) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 8.03 (s, 1H), 7.89 (s, 1H), 7.29 (s, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.98 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H).

[0291] Step 3: Synthesis of 5-bromo-6-methoxybenzo[b]thiophene-2-carboxylic acid (Intermediate 4) [ka] Ethyl 5-bromo-6-methoxybenzo[b]thiophene-2-carboxylate (5.6 g, 17.8 mmol) was dissolved in 50 mL of EtOAc and 50 mL of HO, and NaOH (2.1 g, 53.3 mmol) was added. The reaction mixture was stirred constantly at room temperature for 2 h. The pH of the reaction mixture was then adjusted to 6, diluted with 200 mL of water, and extracted twice with 200 mL of EtOAc. After drying over NaSO and filtration, the filtrate was concentrated in vacuo to give the product 4 (5.0 g, 98%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 8.26 (s, 1H), 7.98 (s, 1H), 7.79 (s, 1H), 3.93 (s, 3H).

[0292] Step 4: Synthesis of (5-bromo-6-methoxybenzothiophen-2-yl)(morpholinyl)methanone (Intermediate 5) [ka] 5-Bromo-6-methoxybenzo[b]thiophene-2-carboxylic acid (5.0 g, 17.4 mmol) was dissolved in DMF (100 mL), and HATU (13.2 g, 34.8 mmol) and morpholine (7.6 g, 87.1 mmol) were added. The reaction mixture was stirred continuously at room temperature for 1 hour. The reaction mixture was quenched by adding water (500 mL) and then diluted with EtOAc (500 mL). The resulting mixture was extracted three times with EtOAc (100 mL). The organic phase was washed twice with water (500 mL) and twice with brine (500 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to obtain a crude sample. The crude product was further purified by column chromatography (SiO, petroleum ether:ethyl acetate = 10:1) to give product 5 (6.0 g, 97%) as a white solid. 14 H 14 ESI MS of BrNO3S [M+H] + : Calculated value 357.2, actual values ​​355.9 and 357.9.

[0293] Step 5: Synthesis of ethyl (E)-3-(6-methoxy-2-(morpholine-4-carbonyl)benzo[b]thiophen-5-yl)acrylate (Intermediate 6) [ka] (5-Bromo-6-methoxybenzo[b]thiophen-2-yl)(morpholinyl)methanone (5.0 g, 14.0 mmol) was dissolved in DMF (100 mL) and palladium acetate (1.6 g, 7.0 mmol), triphenylphosphine (1.8 g, 7.0 mmol), ethyl acrylate (4.2 g, 42.1 mmol), and DIPEA (5.4 g, 42.1 mmol) were added. The reaction mixture was flushed with N2 three times, then well-sealed and stirred overnight at 90 °C under N2 protection. The reaction mixture was cooled to room temperature and quenched by addition to ice water (500 mL). The mixture was extracted with EtOAc (500 mL), and the organic phase was washed with water (500 mL) and brine (500 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether:ethyl acetate=3:1) to give product 6 as a yellow solid (5.0 g, 95%). 19 H 21 ESI MS of NO5S [M+H] + : Calculated value 376.4, actual value 376.1.

[0294] Step 6: Synthesis of ethyl 3-(6-methoxy-2-(morpholine-4-carbonyl)benzo[b]thiophen-5-yl)propanoate (compound 7) [ka] Ethyl (E)-3-(6-methoxy-2-(morpholine-4-carbonyl)benzo[b]thiophen-5-yl)acrylate (5.0 g, 13.3 mmol) was dissolved in EtOH (100 mL) and Pd—C (15.0 g, 141.0 mmol) was added. The mixture was exchanged with H2 three times. The reaction mixture was stirred at room temperature for 72 h. The reaction mixture was filtered, EtOAc (100 mL) was added, the cake was washed, and the filtrate was concentrated in vacuo to give crude product 7 (4.5 g, 90%) as a yellow solid. 19 H 23 ESI MS of NO5S [M+H] + : Calculated value 378.5, actual value 378.1.

[0295] Step 7: Synthesis of 3-(6-methoxy-2-morpholine-4-carbonyl)benzo[b]thiophen-5-yl)propanoic acid (Intermediate 8) [ka] Ethyl 3-(6-methoxy-2-(morpholine-4-carbonyl)benzo[b]thiophen-5-yl)propanoate (4.5 g, 11.9 mmol) was dissolved in EtOH (80 mL) and HO (20 mL), and sodium hydroxide (2.4 g, 59.6 mmol) was added. The reaction mixture was then stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to 5 and diluted with water (200 mL). The mixture was extracted with EtOAc (200 mL), and the organic phase was washed with water (200 mL) and brine (200 mL). The organic phase was collected, dried over NaSO, and concentrated in vacuo to give product 8 (3.8 g, 91%) as a white solid. 17 H 19 ESI MS of NO5S [M+H] + :Calculated value 350.4, actual value 350.0.

[0296] Step 8: Synthesis of 5-methoxy-2-morpholine-4-carbonyl-6,7-dihydro-8H-indeno[5,4-b]thiophen-8-one (Intermediate 9) [ka] 3-(6-Methoxy-2-(morpholine-4-carbonyl)benzo[b]thiophen-5-yl)propanoic acid (2.8 g, 8.0 mmol) was dissolved in PPA (28 mL). The mixture was flushed with N2 three times. The reaction mixture was stirred at 80 °C for 1 h. After that, the reaction mixture was cooled to room temperature and quenched by adding ice water (200 mL) and diluting with EtOAc (200 mL). The organic phase was washed with water (200 mL) and brine (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether:ethyl acetate=1:1) to give product 9 (1.5 g, 57%) as a white solid. C 17 H 17 ESI MS of NO4S [M+H] + : Calculated value 332.4, actual value 332.0.

[0297] Step 9: Synthesis of 8-hydroxy-5-methoxy-7,8-dihydro-6H-indeno[5,4-b]thiophen-2-yl)(morpholinyl)methanone (Intermediate 10) [ka] 5-Methoxy-2-(morpholine-4-carbonyl)-6,7-dihydro-8H-indeno[5,4-b]thiophen-8-one (1.5 g, 4.5 mmol) was dissolved in MeOH (20 mL). NaBH (856.2 mg, 22.6 mmol) was then added, and the reaction mixture was stirred at room temperature for 30 min. The mixture was flushed with N three times, and the reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was then diluted with water (100 mL), extracted with DCM (100 mL), and the organic phase was washed with water (100 mL) and brine (100 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give product 10 (1.2 g, 80%) as a white solid. 17 H 19 ESI MS of NO4S [M+H] + : Calculated value 334.4, actual value 334.0.

[0298] Step 10: Synthesis of 5-methoxy-7,8-dihydro-6H-indeno[5,4-b]thiophen-2-yl)(morpholinyl)methanone (Intermediate 11) [ka] 8-Hydroxy-5-methoxy-7,8-dihydro-6H-indeno[5,4-b]thiophen-2-yl)(morpholinyl)methanone (1.2 g, 3.6 mmol) was dissolved in DCM (24 mL). The mixture was flushed with N2 three times, and the reaction mixture was cooled to 0 °C under N2 protection. Triethylsilane (1.2 g, 10.8 mmol) and boron trifluoride diethyl etherate (47%) (1.6 g, 5.4 mmol) were then added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with methanol (5 mL) and diluted with water (50 mL). The mixture was extracted with DCM (50 mL), and the organic phase was washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether:ethyl acetate=5:1) to give a white solid product 11 (520 mg, 46%). 17 H 19 ESI MS of NO3S [M+H] + :Calculated value 318.4, actual value 318.0.

[0299] Step 11: Synthesis of 1-(5-methoxy-7,8-dihydro-6H-indeno[5,4-b]thiophen-2-yl)ethan-1-one (Intermediate 12) [ka] 5-Methoxy-7,8-dihydro-6H-indeno[5,4-b]thiophen-2-yl)(morpholinyl)methanone (510.0 mg, 1.6 mmol) was dissolved in THF (10 mL). The mixture was flushed with N2 three times, and the reaction mixture was cooled to 0 °C under N2 protection. Then, 1.0 M methylchloromagnesium in THF (4.8 mL, 4.8 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding to ice water (20 mL) and then diluted with EtOAc (20 mL). The resulting mixture was extracted with EtOAc (20 mL). The organic phase was then washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, petroleum ether:ethyl acetate=1:1) to give the product 12 as a yellow solid (330 mg, 83%). 1 H NMR(400MHz,DMSO-d6)δ 8.18(d,J=0.7Hz,1H),7.41(s,1H),3.87(s,3H),3.17(t,J=7.5Hz,2H),2.87(t,J=7.4Hz,2H),2.61(s,3H),2.15(p,J=7.5Hz,2H). C 14 H 14 ESI MS of O2S [M+H] + : Calculated value 247.3, actual value 247.0.

[0300] Step 12: Synthesis of ethyl 4-(5-methoxy-7,8-dihydro-6H-indeno[5,4-b]thiophen-2-yl)-4-oxobutyrate (Intermediate 13) [ka] 1-(5-Methoxy-7,8-dihydro-6H-indeno[5,4-b]thiophen-2-yl)ethan-1-one (100.0 mg, 0.4 mmol) and HMPA (254.6 mg, 1.4 mmol) were dissolved in anhydrous THF (2 mL). The mixture was exchanged with N three times. The reaction mixture was cooled to −78 °C in an ethanol-CO (s) bath under N protection. A 1 M solution of HMDSLi in THF (0.6 mL, 0.6 mmol) was then added dropwise and stirred at −40 °C for 1.5 h. The reaction mixture was then cooled to −78 °C, and 2-bromoethyl acetate (135.6 mg, 0.8 mmol) was added dropwise and stirred at −78 °C for 2 h under N protection. The reaction mixture was diluted with ice water (20 mL) and then with EtOAc (20 mL). The organic phase was then washed with water (20 mL) and brine (20 mL), dried over Na2SO4, concentrated in vacuo, and filtered to give crude product 13 as a yellow solid (80.0 mg, 59%). 18 H 20 ESI MS of O4S [M+H] + :Calculated value 333.4, measured value 333.0.

[0301] Step 13: Synthesis of 4-(5-methoxy-7,8-dihydro-6H-indeno[5,4-b]thiophen-2-yl)-4-oxobutyric acid (Example 26) [ka] Ethyl 4-(5-methoxy-7,8-dihydro-6H-indeno[5,4-b]thiophen-2-yl)-4-oxobutyrate (100 mg, 0.3 mmol) was dissolved in HO (2 mL) and EtOH (2 mL), and NaOH (60.2 mg, 1.5 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to 5-6 and concentrated in vacuo to obtain a crude sample. The crude product was purified by reverse-phase HPLC (C 18 Further purification by column chromatography (30%-60% MeCN and 0.1% FA in water) gave the product ZSSW2104140-01 as an off-white solid (26 mg, 28%). 1H NMR(400MHz,DMSO-d6)δ 12.00(s,1H),8.23(s,1H),7.41(s,1H),3.87(s,3H),3.29(t,J=6.4Hz,2H),3.18(t ,J=7.4Hz,2H),2.88(t,J=7.4Hz,2H),2.59(t,J=6.4Hz,2H),2.15(p,J=7.5Hz,2H). C 16 H 16 ESI MS of O4S [M+H] + : Calculated value 305.4, measured value 305.1.

[0302] Example 27 Synthesis of 4-(4-methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-2-methyl-4-oxobutyric acid (Example Compound 27) [ka] Steps 1 to 4 refer to Example 25.

[0303] Step 5: Synthesis of ethyl 5-tert-butoxyamido-4-bromo-6-methoxybenzo[b]thiophene-2-carboxylate (Intermediate 6) [ka] Ethyl 5-amino-4-bromo-6-methoxybenzo[b]thiophene-2-carboxylate (5 g, 15.14 mmol) was dissolved in DMF (50 mL), and di-tert-butyl dicarbonate (1.6 g, 75.7 mmol), 4-dimethylaminopyridine (1.8 g, 15.4 mmol), and triethylamine (9.1 mg, 90 mmol) were added. The mixture was stirred at 20 °C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched by adding water, and the mixture was separated and extracted with EA. The organic phase was washed twice with water and then with saturated brine. The organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography (SiO2, EA:petroleum ether = 5:1) to obtain Intermediate 6 (7.5 g, 94%) as a white solid.22 H 28 ESI MS [M+H] of BrNO7S + : Calculated value 531.4, measured value 331.8.

[0304] Step 6: Synthesis of 5-tert-butoxyamido-4-bromo-6-methoxybenzo[b]thiophene-2-carboxylic acid (Intermediate 7) [ka] Ethyl 5-tert-butoxyamido-4-bromo-6-methoxybenzo[b]thiophene-2-carboxylate (7.5 g, 14.14 mmol) and NaOH (3.9 g, 98.9 mmol) were dissolved in ethanol (75 mL) and water (75 mL) to obtain a solution, which was stirred at 25 °C for 1 h. After completion of the reaction, monitored by LCMS, the pH of the reaction mixture was adjusted to 3 and diluted with water (1 L). The mixture was extracted with EtOAc (1 L), and the organic phase was washed with water (1 L) and brine (100 mL). The organic phase was collected, dried over NaSO, and concentrated in vacuo to give the pure compound Intermediate 7 (6.5 g, 91.5%) as a white solid. 20 H 24 ESI MS [M+H] of BrNO4S + : Calculated value 503.3, measured value 303.3.

[0305] Step 7: Synthesis of 5-tert-butoxyamido-4-bromo-N,6-dimethoxy-N-methylbenzo[b]thiophene-2-carboxamide (Intermediate 8) [ka] To a solution of 5-tert-butoxyamido-4-bromo-6-methoxybenzo[b]thiophene-2-carboxylic acid (6.5 g, 12.94 mmol) and NaOH (3.9 g, 98.9 mmol) in DCM (75 mL) was added carbodiimide hydrochloride (4.9 g, 59 mmol), dimethylhydroxylamine hydrochloride (3.8 g, 38 mmol), and triethylamine (6.5 g, 64.5 mmol). The mixture was stirred at 30 °C for 2 h under nitrogen protection. After completion of the reaction, monitored by LCMS, the pH of the reaction mixture was adjusted to 3 and diluted with water (1 L). The mixture was extracted with EtOAc (1 L), and the organic phase was washed with water (1 L) and brine (100 mL). The organic phase was collected, dried over NaSO, and concentrated in vacuo to give pure compound Intermediate 8 (5.7 g, 81.5%) as a white solid. 22 H 29 ESI MS [M+H] of BrNOS + Calculated value 546.4, observed value 390.9. This is the fragment signal from the removal of the BOC group.

[0306] Step 8: Synthesis of 1-(5-tert-butoxyamido-4-bromo-6-methoxybenzo[b]thiophen-2-yl)ethan-1-one (Intermediate 9) [ka] 5-tert-Butoxyamido-4-bromo-N,6-dimethoxy-N-methylbenzo[b]thiophene-2-carboxamide (6.5 g, 12.94 mmol) was dissolved in THF (75 mL) to obtain a solution. Methylchloromagnesium (2.3 g, 31.3 mmol) was added under ice-water bath and stirred at 25 °C under nitrogen protection for 2 hours. The reaction was monitored by LCMS. Upon completion, the mixture was diluted with water (1 L). The mixture was extracted with EtOAc (1 L), and the organic phase was washed with water (1 L) and saturated ammonium chloride (100 mL). The organic phase was collected, dried over Na2SO4, and concentrated in vacuo to obtain the pure compound Intermediate 9 (4.24 g, 81%) as a white solid. 21 H 26 ESI MS of BrNO6S [M+H] +Calculated value 501.4, observed value 301.8. This is the fragment signal from the removal of the BOC group.

[0307] Step 9: Synthesis of 1-(5-amino-4-bromo-6-methoxybenzo[b]thiophen-2-yl)ethan-1-one (Intermediate 10) [ka] To a solution of 1-(5-tert-butoxyamido-4-bromo-6-methoxybenzo[b]thiophen-2-yl)ethan-1-one (4.24 g, 8.5 mmol) in DCM (75 mL) was added HCl (3.1 g, 87 mmol) and stirred at 25 °C for 16 h. After completion of the reaction, monitored by LCMS, the mixture was diluted with water (1 L) and the pH was adjusted to 7. The mixture was extracted with EtOAc (1 L), and the organic phase was washed with water (1 L) and saturated ammonium chloride (100 mL). The organic phase was collected, dried over NaSO, and concentrated in vacuo to give pure compound Intermediate 10 (2.2 g, 86%) as a white solid. 11 H 10 ESI MS of BrNO2S [M+H] + : Calculated value 301.2, measured value 301.8.

[0308] Step 10: Synthesis of N-(2-acetyl-4-bromo-6-methoxybenzo[b]thiophen-5-yl)carboxamide (Intermediate 11) [ka] To a solution of 1-(5-amino-4-bromo-6-methoxybenzo[b]thiophen-2-yl)ethan-1-one (1.2 g, 4 mmol) in DCM (100 mL), formic acid (1.8 g, 40 mmol) and acetoacetic acid ester (816 g, 8 mmol) were added and stirred at 25 °C for 3 hours. The reaction was monitored by LCMS and, upon completion, was filtered and the cake washed with dichloromethane to give pure compound Intermediate 11 as a white solid (1.2 g, 91%). 12 H 10ESI MS of BrNO3S [M+H] + : Calculated value 329.2, measured value 329.8.

[0309] Step 11: Synthesis of 1-(4-methoxythieno[3,2:3,4]benzo[1,2-d]oxazol-7-yl)ethan-1-one (Intermediate 12) [ka] To a solution of N-(2-acetyl-4-bromo-6-methoxybenzo[b]thiophen-5-yl)carboxamide (1.0 g, 3 mmol) in 1,4-dioxane (100 mL), methyldimethylamine ethylamine (288 mg, 3.08 mmol), CuI (290 mg, 1.52 mmol), and dicesium carbonate (1.4 g, 4.57 mmol) were added and stirred at 90 °C for 2 hours. The reaction was monitored by LCMS. Upon completion, the mixture was filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 2:1) to give the pure compound Intermediate 12 (300 mg, 40%) as a white solid. 12 ESI MS of H9NO3S [M+H] + : Calculated value 248.3, actual value 247.96. 1 H NMR (400MHz, DMSO) δ 8.81 (s, 1H), 8.52 (s, 1H), 7.63 (s, 1H), 4.04 (s, 3H), 2.67 (s, 3H).

[0310] Step 12: Synthesis of tert-butyl 4-(4-methoxythieno[3',2':3,4]benzo[1,2-d]oxazol-7-yl)-4-oxobutyrate (Intermediate 13) [ka] To a solution of 1-(4-methoxythieno[3,2:3,4]benzo[1,2-d]oxazol-7-yl)ethan-1-one (80 mg, 0.3 mmol) in THF (2 mL), HMPA (202 mg, 1.3 mmol) was added, cooled to -78 °C, and under nitrogen protection, HMDSLi (81 mg, 0.5 mmol) was added dropwise. The mixture was warmed to -40 °C and stirred for 1 h. The mixture was then cooled again to -78 °C and ethyl bromide (126 mg, 0.65 mmol) was added dropwise. The mixture was then stirred at -78 °C for 2 h. The reaction was monitored by LCMS, and upon completion, it was diluted with water (100 mL). The mixture was extracted with EtOAc (100 mL), and the organic phase was washed with water (100 mL) and brine (100 mL). The organic phase was collected, dried over Na2SO4, and concentrated in vacuo to give the pure compound Intermediate 13 as a white solid (100 mg, 41%). 22 H 28 ESI MS of O7S [M+H] + Calculated value 362.41, observed value 305.92. This is the signal from the removal of the tert-butyl group.

[0311] Step 13: Synthesis of 4-(4-methoxythieno[3',2':3,4]benzo[1,2-d]oxazol-7-yl)-4-oxobutyric acid (Example Compound 27) [ka] tert-Butyl 4-(4-methoxythieno[3',2':3,4]benzo[1,2-d]oxazol-7-yl)-4-oxobutyrate (100 mg, 0.28 mmol) was dissolved in trifluoroacetic acid (0.35 mg, 3.3 mmol) and the reaction mixture was stirred at room temperature for 30 minutes, at which time LCMS indicated the reaction was complete. The reaction mixture was concentrated in vacuo to give a crude sample. The crude product was purified by reverse-phase HPLC (C 18 Further purification by column chromatography (50%-60% gradient of MeCN and water with 0.1% TFA) gave the product as a white solid (25.5 mg, 30%). 14 H 11 ESI MS of NO5S [M+H] + : Calculated value 306.3, actual value 306.07.1 H NMR(400MHz,DMSO-d6)δ 8.81(s,1H),8.52(s,1H),7.64(s,1H),6.18(s,2H),4.04(s,3H),3.26(t,J=6.6Hz,2H),2.45(t,J=6.5Hz,2H).

[0312] Example 28 Synthesis of 2-ethyl-4-(4-methoxythieno[3,2-e]benzofuran-7-yl)-4-oxobutyric acid (Example Compound 28) [ka] Step 1: Synthesis of ethyl 5-hydroxy-6-methoxy-1-benzothiophene-2-carboxylate (Intermediate 3) [ka] 2-Bromo-5-hydroxy-4-methoxybenzaldehyde (6.0 g, 26.0 mmol) was dissolved in DMF (60 mL) and 2-thioethyl acetate (7.2 g, 59.7 mmol) and λ 1 Copper iodide (1.5 g, 7.8 mmol) was added, and then the mixture was cooled to 0 °C and potassium carbonate (9.0 g, 64.9 mmol) was slowly added. The mixture was flushed with N2 three times, then the reaction mixture was sealed and constantly stirred at 80 °C under N2 protection for 2 h. The reaction mixture was quenched by adding ice water (600 g) while maintaining the internal temperature below 20 °C. The resulting mixture was extracted with EtOAc (600 mL). The organic phase was then washed with water (400 mL), brine (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, 20% EtOAc-petroleum ether) to give Intermediate 3 (5.1 g, 78%) as a white solid. LCMS. 1H NMR(400MHz,DMSO-d6)δ 9.38(s,1H),7.96(d,J=0.6Hz,1H),7.54(s,1H),7.31(s,1H),4.30(q,J=7.1Hz,2H),3.86(s,3H),1.31(t,J=7.1Hz,3H).

[0313] Step 2: Synthesis of ethyl 5-isopropoxy-6-methoxy-1-benzothiophene-2-carboxylate (Intermediate 5) [ka] Ethyl 5-hydroxy-6-methoxy-1-benzothiophene-2-carboxylate (5.0 g, 22.0 mmol) was dissolved in DMF (60 mL) and isopropyl bromide (8.0 g, 64.9 mmol) was added. The mixture was then cooled to 0 °C and anhydrous potassium carbonate (15 g, 108.2 mmol) was slowly added. The mixture was flushed with N2 three times, after which the reaction mixture was sealed and constantly stirred under N2 protection at 45 °C for 12 h. The reaction mixture was quenched by adding ice water (600 g) while maintaining the internal temperature below 20 °C. The resulting mixture was extracted with EtOAc (600 mL). The organic phase was then washed with water (400 mL), brine (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, 20% EtOAc-petroleum ether) to give Intermediate 3 (5.1 g, 78%) as a white solid. 15 H 18 ESI MS of O4S [M+H] + : Calculated value 295.4, actual value 295.01.

[0314] Step 3: Synthesis of dimethyl (2-(5-isopropoxy-6-methoxy-1-benzothiophene)-2-oxoethyl)phosphonate (Intermediate 7) [ka] Ethyl 5-isopropoxy-6-methoxy-1-benzothiophene-2-carboxylate (5.15 g, 17.5 mmol) was dissolved in THF (50 mL), and the mixture was flushed with N three times. The reaction mixture was then sealed. The mixture was then cooled to -20 °C and LDA (3.8 g, 35.0 mmol) was slowly added dropwise. Upon completion, the mixture was stirred for 5 minutes, followed by the dropwise addition of dimethyl methylphosphonate (2.2 g, 17.5 mmol). The mixture was continuously stirred under N protection at 25 °C for 12 hours. The reaction mixture was quenched by adding ice water (600 g) to maintain the internal temperature below 20 °C. The resulting mixture was extracted with EtOAc (600 mL). The organic phase was then washed with water (400 mL), brine (200 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, 20% EtOAc-petroleum ether) to give Intermediate 7 as a white solid (6.0 g, 92.1%). LCMS: C 16 H 21 ESI MS [M+H] of O6PS + :Calculated value 373.4, actual value 373.05. 1 H NMR(400MHz,DMSO-d6)δ 8.28(s,1H),7.61(s,1H),7.51(s,1H),4.70-4.59(m,1H),3.92-3.83(m,5H),3.69(d,J=11.1Hz,6H),1.31(d,J=6.1Hz,6H).

[0315] Step 4: Synthesis of methyl 2-ethyl-4-(5-isopropoxy-6-methoxy-1-benzothiophene)-4-oxobut-2-enoate (Intermediate 9) [ka] Dimethyl 2-(5-isopropoxy-6-methoxy-1-benzothiophene)-2-oxoethyl)phosphonate (5.2 g, 13.83 mmol) was dissolved in THF (50 mL). The mixture was then cooled to -20 °C and LDA (1.5 g, 13.8 mmol) was slowly added dropwise. Upon completion, the mixture was stirred for 5 minutes, followed by the dropwise addition of methyl 2-oxobutyrate (1.6 g, 13.8 mmol). The mixture was continuously stirred at 25 °C under N protection for 1 hour. The reaction mixture was quenched by adding ice water (600 g) to maintain the internal temperature below 20 °C. The resulting mixture was extracted with EtOAc (600 mL). The organic phase was then washed with water (400 mL), brine (200 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, 20% EtOAc-petroleum ether) to give intermediate 3 as a white solid (4.5 g, 89.8%). LCMS: C 19 H 22 ESI MS of O5S [M+H] + :Calculated value 363.4, actual value 363.08. 1 H NMR(400MHz,DMSO-d6)δ 8.28(s,1H),7.61(s,1H),7.51(s,1H),4.70-4.59(m,1H),3.92-3.83(m,5H),3.69(d,J=11.1Hz,6H),1.31(d,J=6.1Hz,6H).

[0316] Step 5: Synthesis of methyl 2-ethyl-4-(5-isopropoxy-6-methoxy-1-benzothiophene)-4-oxobutyrate (Intermediate 10) [ka] Methyl 2-ethyl-4-(5-isopropoxy-6-methoxy-1-benzothiophene)-4-oxobut-2-enoate (4.5 g, 12.4 mmol) was dissolved in EA (50 mL), Pd—C (0.45 g, 1.24 mmol) and copper iodide (1.5 g, 7.8 mmol) were added, and the mixture was exchanged with H 3 times. After that, the reaction mixture was sealed and stirred constantly under H 2 protection at 25 °C for 12 h. The reaction mixture was filtered to remove remaining Pd—C. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO 2 , 20% EtOAc-petroleum ether) to give Intermediate 10 (2.4 g, 53.0%) as a white solid. LCMS: C 19 H 24 ESI MS of O5S [M+H] + :Calculated value 365.5, actual value 365.08.

[0317] Step 6: Synthesis of methyl 2-ethyl-4-(5-hydroxy-6-methoxy-1-benzothiophene)-4-oxobutyrate (Intermediate 11) [ka] Methyl 2-ethyl-4-(5-isopropoxy-6-methoxy-1-benzothiophene)-4-oxobutyrate (2.6 g, 7.1 mmol) was dissolved in DCM (30 mL), AlCl (0.95 g, 7.1 mmol) was added, and the mixture was flushed with N three times. The reaction mixture was then sealed and constantly stirred under N protection at 25 °C for 2 h. The reaction mixture was quenched by adding ice water (600 g) to maintain the internal temperature below 20 °C. The resulting mixture was extracted with EtOAc (600 mL). The organic phase was then washed with water (400 mL), brine (200 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO, 20% EtOAc-petroleum ether) to give Intermediate 11 (2.3 g, 99%) as a white solid. LCMS: C 16 H 18 ESI MS of O5S [M+H] +: Calculated value 323.4, actual value 322.99.

[0318] Step 7: Synthesis of methyl 4-(5-(2,2-diethoxyethoxy)-6-methoxy-1-benzothiophene)-2-ethyl-4-oxobutyrate (Intermediate 13) [ka] Methyl 2-ethyl-4-(5-hydroxy-6-methoxy-1-benzothiophene)-4-oxobutyrate (1.0 g, 3.1 mmol) was dissolved in DMF (10 mL) and 2-bromo-1,1-diethoxyethane (1.8 g, 9.3 mmol) was added. The mixture was then cooled to 0 °C and potassium carbonate (2.1 g, 15.5 mmol) was slowly added. The mixture was flushed with N2 three times, after which the reaction mixture was sealed and stirred continuously at 110 °C under N2 protection for 3 h. The reaction mixture was quenched by adding ice water (600 g) to maintain the internal temperature below 20 °C. The resulting mixture was extracted with EtOAc (600 mL). The organic phase was then washed with water (400 mL), brine (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, 20% EtOAc-petroleum ether) to give intermediate 13 as a white solid (1.3 g, 95.6%). LCMS: C 22 H 30 ESI MS of O7S [M+H] + : Calculated value 439.5, actual value 439.12.

[0319] Step 8: Synthesis of methyl 2-ethyl-4-(4-methoxythieno[3,2-e]benzofuran-7-yl)-4-oxobutyrate (Intermediate 14) [ka] Methyl 4-(5-(2,2-diethoxyethoxy)-6-methoxy-1-benzothiophene)-2-ethyl-4-oxobutyrate (500.0 mg, 1.1 mmol) was dissolved in toluene (15 mL), polyphosphoric acid (187.0 mg, 2.3 mmol) was added, and the mixture was flushed with N three times. The reaction mixture was then sealed and constantly stirred under N protection at 80 °C for 30 min. The reaction mixture was quenched by adding ice water (600 g) to maintain the internal temperature below 20 °C. The resulting mixture was extracted with EtOAc (600 mL). The organic phase was then washed with water (400 mL), brine (200 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO, 20% EtOAc-petroleum ether) to give Intermediate 14 (150 mg, 38%) as a white solid. LCMS: C 18 H 18 ESI MS of O5S [M+H] + :Calculated value 347.4, actual value 347.03.

[0320] Step 9: Synthesis of 2-ethyl-4-(4-methoxythieno[3,2-e]benzofuran-7-yl)-4-oxobutyric acid (Example Compound 28) [ka] Methyl 2-ethyl-4-(4-methoxythieno[3,2-e]benzofuran-7-yl)-4-oxobutyrate (150 mg, 0.43 mmol) was dissolved in methanol (5 mL). The mixture was then cooled to 0 °C and a solution of sodium hydroxide (44.4 mg, 1.1 mmol) in water (5 mL) was slowly added. The mixture was flushed with N2 three times, and then the reaction mixture was sealed and constantly stirred under N2 protection at 25 °C for 12 h. The reaction was quenched with ice water, extracted with EA, and concentrated to give the crude product, which was then purified by prep-HPLC (column: Hanbang DAC-50, packing: Nanomicro UniHybrid 10-120 C). 18The pure final product was obtained as a white solid (13.0 mg, 17%) by pumping in a 0.1% aqueous NH4HCO3 solution (mobile phase: acetonitrile) and eluting with 50% ACN. 17 H 16 ESI MS of O5S [M+H] + :Calculated value 332.4, actual value 333.00. 1 H NMR(400MHz,DMSO-d6)δ 8.65(s,1H),8.14(d,J=2.0Hz,1H),7.58(s,1H),7.44(d,J=2.0Hz,1H),4.02(s,3H),3.44(dd,J=16.9,8.9Hz,2H),3 .02(dd,J=16.9,5.1Hz,1H),2.74(dq,J=9.0,6.2Hz,1H),1.60(ddq,J=20.4,13.5,6.8Hz,2H),0.92(t,J=7.4Hz,3H).

[0321] Example 29 Synthesis of (R)-2-ethyl-4-(4-methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-4-oxobutyric acid (Example Compound 29) [ka] For the synthesis of dimethyl (2-(4-methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-2-oxoethyl)phosphonate (Intermediate 7), see Example 19.

[0322] Step 7: Synthesis of ethyl (E)-2-ethyl-4-(4-methoxy-2-methylthieno[3,2-E]benzofuran-7-yl)-4-oxobut-2-enoate (Intermediate 8) [ka] Dimethyl (2-(4-methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-2-oxoethyl)phosphonate (8.5 g, 23.1 mmol) was dissolved in THF (16 mL), purged with nitrogen, and cooled to -78 °C. Further, n-butyllithium (9.2 mL, 2.5 M) was added and stirred for 30 minutes. Further, methyl 2-oxopropionate (3.3 g, 25.4 mmol) was added, and the mixture was returned to room temperature and stirred for 1 hour. After the reaction was complete, 300 mL of saturated aqueous ammonium chloride was added to the reaction mixture, followed by separation and extraction with 200 mL of EA. The organic phase was washed once with 200 mL of brine and concentrated under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography (SiO2, PE:EA:DCM = 20:1:1) to obtain intermediate 8 (6.3 g, 73%) as a yellow solid. 20 H 21 ESI MS of O5S [M+H] + : Calculated value 373.43, actual value 373.1.

[0323] Step 8: Synthesis of ethyl 2-ethyl-4-(4-methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-4-oxobutyrate (Intermediate 9) [ka] Ethyl (E)-2-ethyl-4-(4-methoxy-2-methylthieno[3,2-E]benzofuran-7-yl)-4-oxobut-2-enoate (5.2 g, 14.0 mmol) was dissolved in EA (100 mL). Pd-C (0.5 g, 4.7 mmol) was added, the mixture was purged with hydrogen, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was poured onto diatomaceous earth, washed with 500 mL of EA, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography (SiO2, PE:EA:DCM = 20:1:1) to obtain intermediate 9 (5.0 g, 96%) as a yellow solid. 20 H 23 ESI MS of O5S [M+H] + : Calculated value 375.45, actual value 375.1.

[0324] Step 9: Synthesis of 2-ethyl-4-(4-methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-4-oxobutyric acid (Example Compound 29) [ka] Ethyl 2-ethyl-4-(4-methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-4-oxobutyrate (3.1 g, 8.3 mmol) was dissolved in HO (5 mL), methanol (10 mL), and dichloromethane (10 mL). NaOH (1.7 g, 41.4 mmol) was added and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, 200 mL of water was added to the reaction mixture, the pH was adjusted to 4-5 with hydrochloric acid, and 200 mL of DCM was added three times for extraction (solids were added to the organic phase). The organic phase was concentrated under reduced pressure to give the crude product. 10 mL of tert-butyl methyl ether was added to form a slurry, which was then filtered. The cake was collected and spin-dried to give a yellow solid (2.6 g, 91%). 18 H 19 ESI MS of O5S [M+H] + : Calculated value 347.4, actual value 347.1.

[0325] Example 30 Synthesis of 4-(5-methoxybenzo[1,2-b:4,3-b']dithiophen-2-yl)-4-oxobutyric acid (Example Compound 30) [ka] Step 1: Synthesis of ethyl 6-methoxy-5-((4-methoxybenzyl)thio)-1-benzothiophene-2-carboxylate (Intermediate 2) [ka] Ethyl 5-bromo-6-methoxy-1-benzothiophene-2-carboxylate (6.0 g, 19.0 mmol), Pd(dba) (1.7 g, 1.9 mmol), Xantphos (2.2 g, 3.8 mmol), 4-methoxythiophenol (8.8 g, 57.1 mmol), and DIPEA (7.4 g, 57.1 mmol) were dissolved in 1,4-dioxane (60 mL). The mixture was flushed with N three times, then the reaction mixture was sealed and stirred continuously under N protection at 100 °C for 16 h. The reaction mixture was quenched by adding ice water (600 g) while maintaining the internal temperature below 20 °C. The resulting mixture was extracted with EtOAc (600 mL). The organic phase was then washed with water (400 mL), brine (200 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (SiO2, 20% EtOAc-petroleum ether) to give Intermediate 2 as a white solid (6.2 g, 84%). 1 H NMR(400MHz,DMSO)δ 8.02(s,1H),7.89(s,1H),7.64(s,1H),7.37-7.28(m,2H),6.90-6.81(m,2H),4.3 2(q,J=7.1Hz,2H),4.15(s,2H),3.91(s,3H),3.71(s,3H),1.32(t,J=7.1Hz,3H).

[0326] Step 2: Synthesis of ethyl 5-mercapto-6-methoxy-1-benzothiophene-2-carboxylate (Intermediate 3) [ka] Ethyl 6-methoxy-5-((4-methoxybenzyl)thio)-1-benzothiophene-2-carboxylate (5.0 g, 12.9 mmol) was dissolved in TFA (50 mL) to obtain a solution. The reaction mixture was then sealed tightly and constantly stirred under N2 protection at 90 °C for 3 h. The reaction was monitored by LCMS. Upon completion of the reaction, the reaction mixture was cooled to room temperature and quenched by adding ice water (500 mL). The pH of the reaction mixture was then adjusted to 7 and extracted with EtOAc (500 mL). The resulting mixture was extracted with EtOAc (500 mL). The organic phase was then washed with water (500 mL) and brine (500 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to obtain a crude sample. The crude product was further purified by column chromatography (petroleum ether: EtOAc = 10:1) to obtain product 3 (3.0 g, 87%) as a white solid. 12 H 12 ESI MS of O3S2 [M+H] + : Calculated value 269.4, actual value 269.0.

[0327] Step 3: Synthesis of ethyl 5-((2,2-diethoxyethyl)thio)-6-methoxy-1-benzothiophene-2-carboxylate (Intermediate 4) [ka] Ethyl 5-mercapto-6-methoxy-1-benzothiophene-2-carboxylate (2.6 g, 9.7 mmol), 2-bromo-1,1-diethoxyethane (5.7 g, 29.1 mmol), and potassium carbonate (4.0 g, 29.1 mmol) were dissolved in DMF (26 mL). The mixture was flushed with N2 three times, then sealed and stirred continuously at 100 °C under N2 protection for 1 h. The reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched by adding ice water (200 g) to maintain the internal temperature below 20 °C. The resulting mixture was extracted with EtOAc (200 mL). The organic phase was washed with water (200 mL), brine (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude sample. The crude product was further purified by column chromatography (20% EtOAc-petroleum ether) to give Intermediate 4 as a white solid (3.0 g, 81%). 18 H 24 ESI MS of O5S2 [M+H] + : Calculated value 385.5, actual value 292.9.

[0328] Step 4: Synthesis of ethyl 5-methoxybenzo[1,2-b:4,3-b']dithiophene-2-carboxylate (Intermediate 5) [ka] Ethyl 5-((2,2-diethoxyethyl)thio)-6-methoxy-1-benzothiophene-2-carboxylate (3.2 g, 8.3 mmol) was dissolved in toluene (10 mL), followed by the addition of PPA (10 mL). Under N2 protection, the mixture was constantly stirred at 100 °C for 30 minutes. The reaction mixture was quenched by addition to ice water (600 g) and monitored by LCMS. Upon completion of the reaction, the reaction mixture was cooled to room temperature and quenched by addition to ice water (200 mL), followed by dilution with EtOAc (100 mL). The organic phase was then washed with water (100 mL) and brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to obtain a crude sample. The crude product was further purified by column chromatography (petroleum ether: EtOAc = 50:1) to obtain product 5 (1.2 g, 47%) as a white solid. 14 H 12 ESI MS of O3S2 [M+H] + : Calculated value 293.4, actual value 292.9.

[0329] Step 5: Synthesis of 5-methoxybenzo[1,2-b:4,3-b']dithiophene-2-carboxylic acid (Intermediate 6) [ka] To a solution of ethyl 5-methoxybenzo[1,2-b:4,3-b']dithiophene-2-carboxylate (1.4 g, 4.8 mmol) in ethanol (20 mL) and HO (10 mL) was added NaOH (574.6 mg, 14.4 mmol). The reaction mixture was then stirred at room temperature for 2 h. After completion of the reaction, monitored by LCMS, the pH of the reaction mixture was adjusted to 6 and diluted with water (100 mL). The mixture was extracted with EtOAc (100 mL), and the organic phase was washed with water (100 mL) and brine (100 mL). The organic phase was collected, dried over NaSO, and concentrated in vacuo to give compound 6 (1.2 g, 95%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.53(s,1H),8.06(d,J=5.3Hz,1H),7.95(d,J=5.3Hz,1H),7.61(s,1H),4.05(s,3H). C12 ESI MS of H8O3S2 [M+H] + : Calculated value 265.3, actual value 264.9.

[0330] Step 6: Synthesis of N,5-dimethoxy-N-methylbenzo[1,2-b:4,3-b']dithiophene-2-carboxamide (Intermediate 7) [ka] 5-Methoxybenzo[1,2-b:4,3-b']dithiophene-2-carboxylic acid (1.1 g, 4.2 mmol), N,O-dimethylhydroxylamine hydrochloride (8.1 g, 8.3 mmol), HATU (3.2 g, 8.3 mmol), and triethylamine (2.1 g, 20.8 mmol) were dissolved in DMF (20 mL) to obtain a solution, and the mixture was flushed with N2 three times. The reaction mixture was stirred at room temperature for 2 h. After monitoring by LCMS, the reaction mixture was quenched by adding ice water (200 mL) and then diluted with EtOAc (200 mL). The resulting mixture was extracted with EtOAc (200 mL), and the organic phase was washed twice with water (200 mL) and brine (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to obtain a crude sample. The crude product was further purified by column chromatography (petroleum ether: EtOAc = 20:1) to give the product 7 as a white solid (1.1 g, 86%). 14 H 13 ESI MS of NO3S2 [M+H] + : Calculated value 308.4, measured value 307.9.

[0331] Step 7: Synthesis of 1-(5-methoxybenzo[1,2-b:4,3-b']dithiophen-2-yl)ethan-1-one (Intermediate 8) [ka] N,5-Dimethoxy-N-methylbenzo[1,2-b:4,3-b']dithiophene-2-carboxamide (1.1 g, 3.6 mmol) was dissolved in THF (20 mL) to obtain a solution, and the mixture was flushed with N2 three times. The reaction mixture was cooled to 0 °C under N2 protection. Then, at 0 °C, 1.0 M methylchloromagnesium in THF (10.7 mL, 10.7 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched by adding ice water (200 mL) and then diluted with EtOAc (200 mL). The resulting mixture was extracted with EtOAc (200 mL), and the organic phase was washed with water (200 mL) and brine (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to obtain a crude sample. The crude product was further purified by column chromatography (petroleum ether: EtOAc = 3:1) to give compound 8 (900 mg, 96%) as an off-white solid. 13 H 10 ESI MS of O2S2 [M+H] + : Calculated value 263.4, measured value 262.9.

[0332] Step 8: Synthesis of ethyl 4-(5-methoxybenzo[1,2-b:4,3-b']dithiophen-2-yl)-4-oxobutyrate (Intermediate 9) [ka] 1-(5-Methoxybenzo[1,2-b:4,3-b']dithiophen-2-yl)ethan-1-one (100.0 mg, 0.4 mmol) and HMPA (239.1 mg, 1.3 mmol) were dissolved in anhydrous THF (2 mL) to obtain a solution, and the mixture was exchanged with N three times. The reaction mixture was cooled to −78 °C in an ethanol-solid carbon dioxide bath under N protection. A 1 M solution of HMDSLi in THF (0.6 mL, 0.6 mmol) was then added dropwise and stirred at −40 °C for 1.5 hours. After cooling to −78 °C, ethyl 2-bromoacetate (127.3 mg, 0.8 mmol) was added dropwise to the reaction mixture, which was then stirred at −78 °C for 2 hours. The reaction was monitored by LCMS and, upon completion, the reaction mixture was diluted with ice water (20 mL) and then with EtOAc (20 mL). The organic phase was then washed with water (20 mL) and brine (20 mL), dried over Na2SO4, concentrated in vacuo, and filtered to give compound 9 (80.0 mg, 60%) as a yellow solid. 17 H 16 ESI MS of O4S2 [M+H] + :Calculated value 349.4, actual value 349.0.

[0333] Step 9: Synthesis of 4-(5-methoxybenzo[1,2-b:4,3-b']dithiophen-2-yl)-4-oxobutyric acid (Example Compound 30) [ka] Ethyl 4-(5-methoxybenzo[1,2-b:4,3-b']dithiophen-2-yl)-4-oxobutyrate (80 mg, 0.23 mmol) was dissolved in HO (3 mL), ethanol (3 mL), and NaOH (27.6 mg, 0.7 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. Upon completion, the pH of the reaction mixture was adjusted to 5 and concentrated in vacuo to obtain a crude sample. The crude product was purified by reverse-phase HPLC (C 18 Further purification by column, 30%-60% gradient of MeCN and water with 0.1% FA) gave a white solid product (24 mg, 33%). 1H NMR (400 MHz, acetonitrile-d3) δ 8.52 (s, 1H), 7.85 (d, J = 5.3 Hz, 1H), 7.78 (d, J = 5.3 Hz, 1H), 7.40 (s, 1H), 4.07 (s, 3H), 3.37 (t, J = 6.5 Hz, 2H), 2.72 (t, J = 6.5 Hz, 2H). 15 H 12 ESI MS of O4S2 [M+H] + : Calculated value 321.4, measured value 320.9.

[0334] Example 31 Chiral separation of 4-(4-methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-2-methyl-4-oxobutyric acid (Example Compound 31) [ka] 4-(4-Methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-2-methyl-4-oxobutyric acid (2.8 g, 8.4 mmol) was added to a reaction flask containing ethyl acetate (420 mL, 100.0%), and 1-naphthylethan-1-amine (1.5 g, 8.7 mmol) was added. The mixture was heated to 75°C to clarify the reaction, then slowly cooled to room temperature and allowed to crystallize for 12 hours. White crystals precipitated, which were suction filtered and dried to give the product (R)-4-(4-methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-2-methyl-4-oxobutyric acid (2 g, 6.0 mmol, 71%) with a purity of 89%. (R)-4-(4-methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-2-methyl-4-oxobutyric acid (2 g, 6.0 mmol, 71%) with 89% purity was added to a reaction flask containing ethyl acetate (200 mL, 100.0%), heated to 75 °C for clarification, then slowly cooled to room temperature and allowed to crystallize for 12 hours. White crystals precipitated, and the crystals were suction filtered and dried. An appropriate amount of EA was added to clarify the crystals, and the amine was then liberated with 2 mol of dilute hydrochloric acid to give the product (R)-4-(4-methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-2-methyl-4-oxobutyric acid (0.6 g, 1.8 mmol, 30%) with a purity of 97%. 17 H 16 ESI MS of O5S [M+H] + : Calculated value 332.4, actual value 332.97. 1 H NMR(400MHz,DMSO-d6)δ 12.21(s,1H),8.59(s,1H),7.50(s,1H),7.02(s,1H),4.00(s,3H),3.45(dd,J=17.4,8.5Hz ,2H),3.13(dd,J=17.4,5.3Hz,1H),2.98-2.87(m,1H),2.53(s,3H),1.20(d,J=7.2Hz,3H).

[0335] Example 32 Chiral separation of 4-(4-methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-2-methyl-4-oxobutyric acid (Example Compound 32) [ka] 4-(4-Methoxy-2-methylthieno[3,2-e]benzofuran-7-yl)-2-methyl-4-oxobutyric acid (5 g, 15 mmol) was added to a reaction flask containing ethyl acetate (400 mL) and 1-naphthylethan-1-amine (2.58 g, 15.04 mmol). The mixture was heated to 75°C to clarify the reaction mixt...

Claims

1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 (where R １ is hydrogen, deuterium, halogen, cyano group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , substituted or unsubstituted C １ ~C ６ alkyl group, substituted or unsubstituted C ２ ~C ６ Alkenyl group, substituted or unsubstituted C ２ ~C ６ Alkynyl group, substituted or unsubstituted C １ ~C ６ Alkoxy group, substituted or unsubstituted saturated or unsaturated C ３ ~C １０ Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted 5- to 10-membered heteroaryl groups, substituted or unsubstituted C ６ ~C １０ Aryl group, —C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ represents Here, R ２ is hydrogen, deuterium, halogen, cyano group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , substituted or unsubstituted C １ ~C ６ alkyl group, substituted or unsubstituted C ２ ~C ６ Alkenyl group, substituted or unsubstituted C ２ ~C ６ Alkynyl group, substituted or unsubstituted C １ ~C ６ Alkoxy group, substituted or unsubstituted saturated or unsaturated C ３ ~C １０ Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted 5- to 10-membered heteroaryl groups, substituted or unsubstituted C ６ ~C １０ Aryl group, —C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ represents Or, R １ and R ２ forms a 5- to 8-membered ring with the atom(s) bonded thereto, said ring optionally containing 0, 1 or 2 heteroatoms selected from O, N and S; Here, R ３ is hydrogen, deuterium, halogen, cyano group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , substituted or unsubstituted C １ ~C ６ alkyl group, substituted or unsubstituted C ２ ~C ６ Alkenyl group, substituted or unsubstituted C ２ ~C ６ Alkynyl group, substituted or unsubstituted C １ ~C ６ Alkoxy group, substituted or unsubstituted saturated or unsaturated C ３ ~C １０ Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted 5- to 10-membered heteroaryl groups, substituted or unsubstituted C ６ ~C １０ Aryl group, —C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ represents Here, Z １ Ha-C １ ~C ６ Alkylene-, -C ２ ~C ６ Alkenylene-, -(C ０ ~C ６ alkylene)-(C ３ ~C ６ cycloalkyl)-(C ０ ~C ６ alkylene)-, -(C ０ ~C ６ alkylene)-O-(C ０ ~C ６ alkylene)-, -(C ０ ~C ６ alkylene)-(3- to 6-membered heterocycloalkyl)-(C ０ ~C ６ alkylene)-, -(C ０ ~C ６ alkylene)-NR ａ -(C ０ ~C ６ alkylene)-, -(C ０ ~C ６ alkylene)-C(O)NR ａ -(C ０ ~C ６ alkylene)-, -(C ０ ~C ６ alkylene)-NR ａ C(O)-(C ０ ~C ６ alkylene)-, -(C ０ ~C ６ alkylene)-S(O) ２ NR ａ -(C ０ ~C ６ alkylene)-, and the Z １ Any one hydrogen atom in ａ , -SR ａ , -NR ａ R ｂ , C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkanes, C ３ ~C １０ cycloalkyl groups, or Z １ Any one CH in ２ teeth, 【Chemistry 2】 or 【Transformation 3】 where R ｓ and R ｔ forms a 3- to 6-membered ring with the C atom bonded thereto, where W represents S or Se; where V is CR ３ or N, Here, X １ , X ２ represents C or N, Here, Z ２ is C(O)OR Ｌ , C(O)SR Ｌ , C(S) OR Ｌ , S(O) ２ R Ｌ represents Here, R Ｌ is hydrogen, deuterium, halogen, cyano group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , substituted or unsubstituted C １ ~C ６ alkyl group, substituted or unsubstituted C ２ ~C ６ Alkenyl group, substituted or unsubstituted C ２ ~C ６ Alkynyl group, substituted or unsubstituted C １ ~C ６ Alkoxy group, substituted or unsubstituted saturated or unsaturated C ３ ~C １０ Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted 5- to 10-membered heteroaryl groups, substituted or unsubstituted C ６ ~C １０ Aryl group, —C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ represents wherein ring A represents a substituted or unsubstituted saturated or unsaturated 5- to 10-membered ring or a 5- to 10-membered heterocyclic ring; Here, the dashed lines represent single or double bonds. The above substituents defined as "substituted or unsubstituted" include deuterated, halogenated, cyano, C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , -C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ is optionally substituted with 0, 1, 2, or 3 substituents selected from Here, R ａ , R ｂ are each independently hydrogen, deuterium, or C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, hydroxy group-substituted C １ ~C ６ Alkyl group, C ３ ~C １０ represents a cycloalkyl group, or R ａ and R ｂ forms a 3- to 6-membered ring with the atom(s) bonded thereto, and the ring may further optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S.

2. 2. The compound of claim 1, having the structure of Formula I-1 below, or a pharmaceutically acceptable salt thereof: 【Chemistry 4】 (where R １ , R ２ , W, V, X １ , X ２ , Z ２ , Ring A has the definition in claim 1, where R ５ is C １ ~C ６ represents an alkyl group, preferably a methyl group or an ethyl group, and the dashed line represents a single bond or a double bond.

3. 2. The compound of claim 1, having the structure of Formula II: or a pharmaceutically acceptable salt thereof. 【Transformation 5】 (where R １ is hydrogen, deuterium, halogen, cyano group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , substituted or unsubstituted C １ ~C ６ alkyl group, substituted or unsubstituted C ２ ~C ６ Alkenyl group, substituted or unsubstituted C ２ ~C ６ Alkynyl group, substituted or unsubstituted C １ ~C ６ Alkoxy group, substituted or unsubstituted saturated or unsaturated C ３ ~C １０ Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted 5- to 10-membered heteroaryl groups, substituted or unsubstituted C ６ ~C １０ Aryl group, —C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ represents Here, R ２ is hydrogen, deuterium, halogen, cyano group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , substituted or unsubstituted C １ ~C ６ alkyl group, substituted or unsubstituted C ２ ~C ６ Alkenyl group, substituted or unsubstituted C ２ ~C ６ Alkynyl group, substituted or unsubstituted C １ ~C ６ Alkoxy group, substituted or unsubstituted saturated or unsaturated C ３ ~C １０ Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted 5- to 10-membered heteroaryl groups, substituted or unsubstituted C ６ ~C １０ Aryl group, —C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ represents Or, R １ and R ２ forms a 5- to 8-membered ring with the atom(s) bonded thereto, said ring optionally containing 0, 1 or 2 heteroatoms selected from O, N and S; Here, R ３ is hydrogen, deuterium, halogen, cyano group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , substituted or unsubstituted C １ ~C ６ alkyl group, substituted or unsubstituted C ２ ~C ６ Alkenyl group, substituted or unsubstituted C ２ ~C ６ Alkynyl group, substituted or unsubstituted C １ ~C ６ Alkoxy group, substituted or unsubstituted saturated or unsaturated C ３ ~C １０ Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted 5- to 10-membered heteroaryl groups, substituted or unsubstituted C ６ ~C １０ Aryl group, —C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ represents Here, R ４ is hydrogen, deuterium, halogen, cyano group, C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , -C(O)OR ａ , —CO(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ represents Here, Z １ Ha-C １ ~C ６ Alkylene-, -C ２ ~C ６ Alkenylene-, -(C ０ ~C ６ alkylene)-(C ３ ~C ６ cycloalkyl)-(C ０ ~C ６ alkylene)-, -(C ０ ~C ６ alkylene)-O-(C ０ ~C ６ alkylene)-, -(C ０ ~C ６ alkylene)-(3- to 6-membered heterocycloalkyl)-(C ０ ~C ６ alkylene)-, -(C ０ ~C ６ alkylene)-NR ａ -(C ０ ~C ６ alkylene)-, -(C ０ ~C ６ alkylene)-C(O)NR ａ -(C ０ ~C ６ alkylene)-, -(C ０ ~C ６ alkylene)-NR ａ C(O)-(C ０ ~C ６ alkylene)-, -(C ０ ~C ６ alkylene)-S(O) ２ NR ａ -(C ０ ~C ６ alkylene)-, and the Z １ Any one hydrogen atom in ａ , -SR ａ , -NR ａ R ｂ , C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, C ３ ~C １０ cycloalkyl groups, or Z １ Any one CH in ２ teeth, 【Transformation 6】 or 【Transformation 7】 where R ｓ and R ｔ forms a 3- to 6-membered ring with the C atom bonded thereto, Here, Z ２ is C(O)OR Ｌ , C(O)SR Ｌ , C(S) OR Ｌ , S(O) ２ R Ｌ represents Here, R Ｌ is hydrogen, deuterium, halogen, cyano group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , substituted or unsubstituted C １ ~C ６ alkyl group, substituted or unsubstituted C ２ ~C ６ Alkenyl group, substituted or unsubstituted C ２ ~C ６ Alkynyl group, substituted or unsubstituted C １ ~C ６ Alkoxy group, substituted or unsubstituted saturated or unsaturated C ３ ~C １０ Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted 5- to 10-membered heteroaryl groups, substituted or unsubstituted C ６ ~C １０ Aryl group, —C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ represents where W represents S or Se; where V is CR ３ or N, Here, X, Y, and M are each independently CR Ｘ , O, S or NR ５ represents Here, X １ , X ２ represents C or N, provided that at least one is C; Here, R Ｘ are hydrogen, deuterium, and C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ Haloalkyl group, hydroxy C １ ~C ６ Alkyl group, halogen, cyano group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , -C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ represents Here, R ５ are hydrogen, deuterium, and C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ Haloalkyl group, hydroxy C １ ~C ６ Alkyl group, halogen, cyano group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , -C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ represents where n is 0, 1, or 2; The above substituents defined as "substituted or unsubstituted" include halogen, cyano group, C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , -C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ is optionally substituted with 0, 1, 2, or 3 substituents selected from Here, R ａ , R ｂ are each independently hydrogen, deuterium, or C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, hydroxy group-substituted C １ ~C ６ Alkyl group, C ３ ~C １０ represents a cycloalkyl group, or R ａ and R ｂ forms a 3- to 6-membered ring with the atom(s) bonded thereto, and the ring may further optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; Here, the dashed lines represent single or double bonds.

4. 4. The compound of claim 3, having the structure of Formula II-2: 【Transformation 8】 (where R １ , R ２ , X １ , X ２ ,X,Y,M,W,V,R ４ , n, Z ２ has the definition in claim 3, where R ５ is C １ ~C ６ represents an alkyl group, preferably a methyl group or an ethyl group, and the dashed line represents a single bond or a double bond.

5. R １ are hydrogen, deuterium, halogen, C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, hydroxy C １ ~C ６ Alkyl group, mercapto C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Haloalkenyl group, hydroxy C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Haloalkenyl group, hydroxy C ２ ~C ６ Alkenyl group, mercapto C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C ２ ~C ６ Haloalkynyl group, hydroxy C ２ ~C ６ Alkynyl group, mercapto C ２ ~C ６ Alkynyl group, C ３ ~C ６ saturated or unsaturated cycloalkyl group, 3- to 6-membered saturated or unsaturated heterocycloalkyl group, cyano group, nitro group, —OR ａ , N.R. ａ R ｂ , -SR ａ , -C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, which represents:

6. R １ is hydrogen, halogen, C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, hydroxy C １ ~C ６ Alkyl group, cyano group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , -C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ 6. The compound of claim 5, wherein:

7. R ２ are hydrogen, deuterium, halogen, C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, hydroxy C １ ~C ６ Alkyl group, mercapto C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Haloalkenyl group, hydroxy C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Haloalkenyl group, hydroxy C ２ ~C ６ Alkenyl group, mercapto C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C ２ ~C ６ Haloalkynyl group, hydroxy C ２ ~C ６ Alkynyl group, mercapto C ２ ~C ６ Alkynyl group, C ３ ~C ６ saturated or unsaturated cycloalkyl group, 3- to 6-membered saturated or unsaturated heterocycloalkyl group, cyano group, nitro group, —OR ａ , N.R. ａ R ｂ , -SR ａ , -C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, which represents:

8. R ２ are hydrogen, deuterium, halogen, C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, hydroxy C １ ~C ６ Alkyl group, cyano group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , -C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, which represents:

9. R １ and R ２ or a pharmaceutically acceptable salt thereof, according to claim 1 or 3, wherein:

10. R ３ is hydrogen, deuterium, halogen, -OR ａ , cyano group, C １ ~C ６ Alkyl group, hydroxy group substituted C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, C ３ ~C ６ 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, which represents a cycloalkyl group.

11. X, Y, and M each independently represent O, S, or NR. ５ or CR Ｘ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, selected from:

12. 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein W represents S.

13. R ４ is hydrogen, deuterium, halogen, -OR ａ , cyano group, C １ ~C ６ Alkyl group, hydroxy group substituted C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, C ３ ~C ６ 13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, which represents a cycloalkyl group.

14. Z １ Ha-C １ ~C ６ Alkylene-, -C ２ ~C ６ Alkenylene-, -(C ０ ~C ６ alkylene)-(C ３ ~C ６ cycloalkyl)-(C ０ ~C ６ alkylene)-, -(C ０ ~C ６ alkylene)-O-(C ０ ~C ６ alkylene)-, and the Z １ Any one hydrogen atom in ａ , -SR ａ , -NR ａ R ｂ , C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, C ３ ~C １０ cycloalkyl groups, or Z １ Any one CH in ２ teeth, 【Chemistry 9】 or 【Chemistry 10】 where R ｓ and R ｔ The compound according to any one of claims 1 to 13, wherein R 1 is a 3- to 6-membered ring with the C atom bonded thereto, or a pharmaceutically acceptable salt thereof.

15. Z １ Ha-C １ ~C ６ Alkylene- or -(C ０ ~C ６ alkylene)-(C ３ ~C ６ cycloalkyl)-(C ０ ~C ６ alkylene)-, and the Z １ Any one hydrogen atom in ａ , -SR ａ , -NR ａ R ｂ , C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, C ３ ~C １０ cycloalkyl groups, or Z １ Any one CH in ２ teeth, 【Chemistry 11】 or 【Chemistry 12】 where R ｓ and R ｔ The compound according to claim 14, wherein R 1 is a 3- to 6-membered ring with the C atom bonded thereto, or a pharmaceutically acceptable salt thereof.

16. Z ２ is C(O)OR Ｌ where R Ｌ is hydrogen or C １ ~C ６ 16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R represents an alkyl group, preferably hydrogen.

17. R ａ , R ｂ are each independently hydrogen, C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, C ３ ~C ６ 17. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, which represents a cycloalkyl group.

18. 5. The compound of claim 4, having the structure of Formula II-3: 【Chemistry 13】 (wherein Y represents CH or N, Here, R １ , R ２ are each independently hydrogen, deuterium, halogen, C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, hydroxy C １ ~C ６ Alkyl group, cyano group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , -C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ or R １ and R ２ forms a 5- to 6-membered saturated or unsaturated ring with the atom(s) attached thereto, which ring may further optionally contain 0, 1 or 2 heteroatoms selected from O, S and N; wherein Y represents CH or N; Here, R ４ are hydrogen, deuterium, halogen, C １ ~C ６ represents an alkyl group, Here, R ５ is C １ ~C ６ represents an alkyl group, preferably a methyl group or an ethyl group, Here, R ａ , R ｂ are each independently hydrogen or C １ ~C ６ represents an alkyl group.

19. 19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein Y represents CH.

20. 19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein Y represents N.

21. R １ are hydrogen, deuterium, halogen, C １ ~C ６ 20. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R represents an alkyl group.

22. R ２ are hydrogen, deuterium, halogen, C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, hydroxy C １ ~C ６ Alkyl group, cyano group, —OR ａ represents Here, R ａ is hydrogen or C １ ~C ６ 20. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R represents an alkyl group.

23. R ２ is hydrogen, halogen, C １ ~C ６ Haloalkyl group, C １ ~C ６ 19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, which represents an alkoxy group.

24. R ４ is hydrogen or C １ ~C ６ 20. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R represents an alkyl group.

25. R ５ 19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein represents a methyl group.

26. 10. The compound of claim 1, having the structure of Formula III: or a pharmaceutically acceptable salt thereof. 【Chemistry 14】 (where R １ is hydrogen, deuterium, halogen, cyano group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , substituted or unsubstituted C １ ~C ６ alkyl group, substituted or unsubstituted C ２ ~C ６ Alkenyl group, substituted or unsubstituted C ２ ~C ６ Alkynyl group, substituted or unsubstituted C １ ~C ６ Alkoxy group, substituted or unsubstituted saturated or unsaturated C ３ ~C １０ Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted 5- to 10-membered heteroaryl groups, substituted or unsubstituted C ６ ~C １０ Aryl group, —C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ represents Here, R ２ is hydrogen, deuterium, halogen, cyano group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , substituted or unsubstituted C １ ~C ６ alkyl group, substituted or unsubstituted C ２ ~C ６ Alkenyl group, substituted or unsubstituted C ２ ~C ６ Alkynyl group, substituted or unsubstituted C １ ~C ６ Alkoxy group, substituted or unsubstituted saturated or unsaturated C ３ ~C １０ Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted 5- to 10-membered heteroaryl groups, substituted or unsubstituted C ６ ~C １０ Aryl group, —C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ represents Or, R １ and R ２ forms a 5- to 8-membered ring with the atom(s) bonded thereto, said ring optionally containing 0, 1 or 2 heteroatoms selected from O, N and S; Here, R ３ is hydrogen, deuterium, halogen, cyano group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , substituted or unsubstituted C １ ~C ６ alkyl group, substituted or unsubstituted C ２ ~C ６ Alkenyl group, substituted or unsubstituted C ２ ~C ６ Alkynyl group, substituted or unsubstituted C １ ~C ６ Alkoxy group, substituted or unsubstituted saturated or unsaturated C ３ ~C １０ Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted 5- to 10-membered heteroaryl groups, substituted or unsubstituted C ６ ~C １０ Aryl group, —C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ represents Here, R ４ is hydrogen, deuterium, halogen, cyano group, C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , -C(O)OR ａ , —CO(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ represents Here, Z １ Ha-C １ ~C ６ Alkylene-, -C ２ ~C ６ Alkenylene-, -(C ０ ~C ６ alkylene)-(C ３ ~C ６ cycloalkyl)-(C ０ ~C ６ alkylene)-, -(C ０ ~C ６ alkylene)-O-(C ０ ~C ６ alkylene)-, -(C ０ ~C ６ alkylene)-(3- to 6-membered heterocycloalkyl)-(C ０ ~C ６ alkylene)-, -(C ０ ~C ６ alkylene)-NR ａ -(C ０ ~C ６ alkylene)-, -(C ０ ~C ６ alkylene)-C(O)NR ａ -(C ０ ~C ６ alkylene)-, -(C ０ ~C ６ alkylene)-NR ａ C(O)-(C ０ ~C ６ alkylene)-, -(C ０ ~C ６ alkylene)-S(O) ２ NR ａ -(C ０ ~C ６ alkylene)-, and the Z １ Any one hydrogen atom in ａ , -SR ａ , -NR ａ R ｂ , C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, C ３ ~C １０ cycloalkyl groups, or Z １ Any one CH in ２ teeth, 【Chemistry 15】 or 【Chemistry 16】 where R ｓ and R ｔ forms a 3- to 6-membered ring with the C atom bonded thereto, Here, Z ２ is C(O)OR Ｌ , C(O)SR Ｌ , C(S) OR Ｌ , S(O) ２ R Ｌ represents Here, R Ｌ is hydrogen, deuterium, halogen, cyano group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , substituted or unsubstituted C １ ~C ６ alkyl group, substituted or unsubstituted C ２ ~C ６ Alkenyl group, substituted or unsubstituted C ２ ~C ６ Alkynyl group, substituted or unsubstituted C １ ~C ６ Alkoxy group, substituted or unsubstituted saturated or unsaturated C ３ ~C １０ Cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted 5- to 10-membered heteroaryl groups, substituted or unsubstituted C ６ ~C １０ Aryl group, —C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ represents where W represents S or Se; where V is CR ３ or N, Here, X, Y, M, M １ are each independently CR Ｘ , O, S or NR ５ represents Here, X １ , X ２ represents C or N, provided that at least one is C; Here, R Ｘ are hydrogen, deuterium, and C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ Haloalkyl group, hydroxy C １ ~C ６ Alkyl group, halogen, cyano group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , -C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ represents Here, R ５ are hydrogen, deuterium, and C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ Haloalkyl group, hydroxy C １ ~C ６ Alkyl group, halogen, cyano group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , -C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ represents where n is 0, 1, or 2; The above substituents defined as "substituted or unsubstituted" include deuterated, halogenated, cyano, C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , -C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ is optionally substituted with 0, 1, 2, or 3 substituents selected from Here, R ａ , R ｂ are each independently hydrogen, C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, hydroxy group-substituted C １ ~C ６ Alkyl group, C ３ ~C １０ represents a cycloalkyl group, or R ａ and R ｂ forms a 3- to 6-membered ring with the atom(s) bonded thereto, and the ring may further optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; Here, the dashed lines represent single or double bonds.

27. 27. The compound of claim 26, having the structure of Formula III-2: 【Chemistry 17】 (where R １ , R ２ , X １ , X ２ , R ４ , R ５ , X, Y, M, M １ , W., V., Z. ２ , n has the definition in claim 26, where the dashed line represents a single or double bond.

28. R １ is hydrogen, halogen, C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, hydroxy C １ ~C ６ Alkyl group, mercapto C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Haloalkenyl group, hydroxy C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Haloalkenyl group, hydroxy C ２ ~C ６ Alkenyl group, mercapto C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C ２ ~C ６ Haloalkynyl group, hydroxy C ２ ~C ６ Alkynyl group, mercapto C ２ ~C ６ Alkynyl group, C ３ ~C ６ saturated or unsaturated cycloalkyl group, 3- to 6-membered saturated or unsaturated heterocycloalkyl group, cyano group, nitro group, —OR ａ , N.R. ａ R ｂ , -SR ａ , -C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ 28. The compound of claim 26 or 27, wherein:

29. R １ is hydrogen, halogen, C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, hydroxy C １ ~C ６ Alkyl group, cyano group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , -C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ 28. The compound of claim 26 or 27, wherein:

30. R ２ are hydrogen, deuterium, halogen, C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, hydroxy C １ ~C ６ Alkyl group, mercapto C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Haloalkenyl group, hydroxy C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Haloalkenyl group, hydroxy C ２ ~C ６ Alkenyl group, mercapto C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C ２ ~C ６ Haloalkynyl group, hydroxy C ２ ~C ６ Alkynyl group, mercapto C ２ ~C ６ Alkynyl group, C ３ ~C ６ saturated or unsaturated cycloalkyl group, 3- to 6-membered saturated or unsaturated heterocycloalkyl group, cyano group, nitro group, —OR ａ , N.R. ａ R ｂ , -SR ａ , -C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ 30. The compound according to any one of claims 26 to 29, wherein the compound represents: or a pharmaceutically acceptable salt thereof.

31. R ２ are hydrogen, deuterium, halogen, C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, hydroxy C １ ~C ６ Alkyl group, cyano group, nitro group, -OR ａ , N.R. ａ R ｂ , -SR ａ , -C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ C(O)R ａ , -S(O) ３ R ａ , -S(O) ２ R ａ The compound according to any one of claims 26 to 30, or a pharmaceutically acceptable salt thereof, which represents:

32. R １ and R ２ forms a 5- or 6-membered ring with the atom(s) bonded thereto, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S, or a pharmaceutically acceptable salt thereof.

33. R ３ is hydrogen, halogen, -OR ａ , cyano group, C １ ~C ６ Alkyl group, hydroxy group substituted C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, C ３ ~C ６ 33. A compound according to any one of claims 26 to 32, or a pharmaceutically acceptable salt thereof, which represents a cycloalkyl group.

34. X, Y, M, M １ are each independently O, S, or NR ５ or CR Ｘ The compound according to any one of claims 26 to 33, or a pharmaceutically acceptable salt thereof, selected from:

35. R ４ is hydrogen, halogen, -OR ａ , cyano group, C １ ~C ６ Alkyl group, hydroxy group substituted C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, C ３ ~C ６ 35. A compound according to any one of claims 26 to 34, or a pharmaceutically acceptable salt thereof, which represents a cycloalkyl group.

36. Z １ Ha-C １ ~C ６ Alkylene-, -C ２ ~C ６ Alkenylene-, -(C ０ ~C ６ alkylene)-(C ３ ~C ６ cycloalkyl)-(C ０ ~C ６ alkylene)-, -(C ０ ~C ６ alkylene)-O-(C ０ ~C ６ alkylene)-, and the Z １ Any one hydrogen atom in ａ , -SR ａ , -NR ａ R ｂ , C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, C ３ ~C １０ cycloalkyl groups, or Z １ Any one CH in ２ teeth, [Chemistry 18] or 【Chemistry 19】 where R ｓ and R ｔ The compound according to any one of claims 26 to 35, or a pharmaceutically acceptable salt thereof, wherein: forms a 3- to 6-membered ring with the C atom bonded thereto.

37. Z １ Ha-C １ ~C ６ Alkylene- or -(C ０ ~C ６ alkylene)-(C ３ ~C ６ cycloalkyl)-(C ０ ~C ６ alkylene)-, and the Z １ Any one hydrogen atom in ａ , -SR ａ , -NR ａ R ｂ , C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, C ３ ~C １０ cycloalkyl groups, or Z １ Any one CH in ２ teeth, 【Chemistry 20】 or 【Chemistry 21】 where R ｓ and R ｔ The compound according to claim 26, wherein R 1 is a 3- to 6-membered ring with the C atom bonded thereto, or a pharmaceutically acceptable salt thereof.

38. Z ２ is C(O)OR Ｌ where R Ｌ is hydrogen or C １ ~C ６ 38. The compound according to any one of claims 26 to 37, or a pharmaceutically acceptable salt thereof, wherein R represents an alkyl group, preferably hydrogen.

39. R ａ , R ｂ are each independently hydrogen, C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, C ３ ~C ６ 39. A compound according to any one of claims 26 to 38, or a pharmaceutically acceptable salt thereof, which represents a cycloalkyl group.

40. A compound having the structure: or a pharmaceutically acceptable salt thereof. Table 1

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