Novel compounds useful as sting agonists and uses thereof

Abstract

This invention provides compounds of general formulas I, II, III, IV, and V that can be used as inducers of type I interferon production, particularly as STING activators, and their pharmaceutically acceptable salts. Methods for synthesizing these compounds, compositions comprising these compounds, and uses of these compounds are also provided.

Description

[Technical Field]

[0001] This invention relates to compounds and derivatives thereof that can be used as STING (interferon gene stimulator) agonists activating the STING pathway. The invention also relates to compositions comprising such compounds, methods for synthesizing such compounds, and the use of such compounds in inducing immune responses, inducing STING-dependent type I interferon production, and / or treating cell proliferation disorders as cancer. [Previous Technology]

[0002] This application claims rights to PCT application No. PCT / CN2021 / 083783 filed on March 30, 2021; PCT application No. PCT / CN2021 / 090945 filed on April 29, 2021; PCT application No. PCT / CN2021 / 111479 filed on August 9, 2021; and PCT application No. PCT / CN2021 / 1289 filed on November 5, 2021. 42. The rights of PCT application No. PCT / CN2021 / 130097 filed on November 11, 2021; PCT application No. PCT / CN2021 / 138806 filed on December 16, 2021; PCT application No. PCT / CN2021 / 143043 filed on December 30, 2021; and PCT application No. PCT / CN2022 / 071548 filed on January 12, 2022. The entire contents of the above applications are incorporated herein by reference.

[0003] The immune system has evolved to recognize and eliminate different types of threats to maintain the host's homeostasis. It is generally divided into two main categories: adaptive and innate. The adaptive immune system is specifically designed to recognize foreign antigens that are not naturally expressed in the host and to generate an anti-antigen response through the synergistic action of many leukocyte subsets. A characteristic of adaptive immune responses is their ability to provide "memory" or durable immunity against encountered antigens. Although this specific and lasting effect is crucial for the host's health and survival, adaptive immune responses require time to produce a full response.

[0004] The innate immune system compensates for this time delay by acting swiftly and specifically in response to various signals of aggression or danger. It provides the first line of defense against bacteria, viruses, parasites, and other infectious threats, but also responds strongly to certain danger signals associated with cell or tissue damage. The innate immune system lacks antigen specificity but does respond to a variety of effector mechanisms. Opsonization, phagocytosis, complement system activation, and the production of soluble bioactive substances such as cytokines or chemokines are all mechanisms by which the innate immune system mediates its responses. By responding to these damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) mentioned above, the innate immune system can provide broad protection against a wide range of threats to the host.

[0005] These PAMPs and DAMPs include free cytoplasmic DNA and RNA. It has recently been demonstrated that the primary sensor for cytoplasmic DNA is cGAS (circular GMP-AMP synthase). Upon recognition of cytoplasmic DNA, cGAS catalyzes the production of the cyclic dinucleotide 2'3'-cGAMP, an atypical second messenger that binds tightly to the ER transmembrane adaptor protein STING. cGAMP-bound STING undergoes a conformational change, translocating to the perinuclear compartment and inducing the activation of key transcription factors IRF-3 and NF-κB. This leads to a strong induction of type I interferon and the production of pro-inflammatory cytokines such as IL-6, TNF-α, and IFN-γ.

[0006] The importance of type I interferons and pro-inflammatory cytokines to various cells of the immune system has been well established. In particular, these molecules strongly enhance T cell activation by increasing the ability of dendritic cells and macrophages to take up, process, present, and cross-present antigens to T cells. The T cell stimulatory capacity of these antigen-presenting cells is enhanced by the upregulation of key co-stimulatory molecules (such as CD80 or CD86). Finally, type I interferons can rapidly bind to their homologous receptors and trigger the activation of interferon-responsive genes, thereby greatly contributing to the activation of adaptive immune cells.

[0007] From a therapeutic perspective, type I interferon has antiviral activity by directly inhibiting the replication of human hepatitis B virus and hepatitis C virus and stimulating the immune response to virus-infected cells. Compounds that can induce the production of type I interferon can be used in vaccines as adjuvants to enhance the specific immune response to antigens by reducing the dosage and expanding the immune response while minimizing side effects.

[0008] Furthermore, interferon and compounds that induce interferon production have potential applications in the treatment of human cancers. Such molecules could potentially serve as anticancer agents with multiple active pathways. Interferon can directly inhibit the proliferation of human tumor cells and can synergize with a variety of approved chemotherapeutic agents. Type I interferon can significantly enhance antitumor immune responses by inducing the activation of adaptive and innate immune cells. Finally, interferon can inhibit tumor invasion by regulating the expression of enzymes involved in tissue remodeling.

[0009] Given the potential of type I interferon and compounds that induce type I interferon as antiviral and anticancer agents, there remains a need for new agents that can induce effective type I interferon production. Increasing data indicate that the cGAS-STING cytoplasmic DNA sensing pathway has a significant ability to induce type I interferon, and the development of STING activators is rapidly gaining importance in the field of antitumor therapy.

[0010] Therefore, there remains a need in the art to develop compounds with novel structures, good biological activity, and high drugability, as well as methods for preventing or treating diseases and conditions such as cancer. The compounds of the present invention meet this need. [Summary of the Invention]

[0011] This invention relates to novel compounds used as STING agonists and for treating cell proliferation disorders. The invention includes compounds as shown in general formula (I), general formula (II), general formula (III), general formula (IV), and general formula (V), and pharmaceutically acceptable salts thereof. These compounds and their pharmaceutically acceptable salts can be used as agents for inducing immune responses, inducing STING-dependent type I interferon production, and / or treating cell proliferation disorders.

[0012] This invention relates to compounds represented by general formulas I, II, III, IV, V, or pharmaceutically acceptable salts thereof: IIIIIIIVV wherein each W is independently selected from C1 or N; each R1 is independently selected from H, deuterium, halogen, OR6, N(R6)2, COOR6, C(O)N(R6)2, CN, or C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted and / or not substituted by one or more of deuterium, halogen, OR6, N(R6)2, COOR6, or C(O)N(R6)2; R2 and R3 are independently selected from the group consisting of: O-(C1-C4 alkylene or haloalkylene), C1-C5 alkylene or haloalkylene, N(R6)-(C1-C4 alkylene or haloalkylene), -Ta-C1-C6 alkyl-Tb-, -Ta-N(Rs)-Tb, -Ta-O-Tb, -Ta-PEGn-O-Tb, -Ta-SS-Tb, -Ta-SSS-Tb, -Ta-N(Rs)-N(Rs)-Tb-, -Ta-C2-C6 alkenyl-Tb-, -Ta-C2-C6 alkynyl-Tb-, -Ta-C(=O)-Tb-, -Ta-C(=CH2)-Tb-, -Ta-C(=O)-C(=O)- Tb-, -Ta-C(=O)-(C1-C6 alkyl)-C(=O)-Tb-, -Ta-C(=O)-(C3-C12 cycloalkyl)-C(=O)-Tb-, -Ta-C(=O)-(C1-C6 alkyl)-(C3-C12 cycloalkyl)-(C1-C6 alkyl)-C(=O)-Tb-, -Ta-C(=O)-(3- to 12-membered heterocyclic alkyl)-C(=O)-Tb-, -Ta-C(=O)-(C1-C6 alkyl)-(3- -Ta-(C1-C6 alkyl)-C(=O)-Tb-, -Ta-C(=S)-Tb-, -Ta-S(=O)2-Tb-, -Ta-S(=O)-Tb-, -Ta-P(=O)(-ORs)-Tb-, -Ta-(C3-C12 cycloalkyl)-Tb-, -Ta-(C6-C12 aryl)-Tb-, -Ta-(3-to-12-membered heterocyclic alkyl)-Tb-, or -Ta-(5- (to 12-membered heteroaryl)-Tb-; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-to 12-membered heterocycloalkyl or 5-to 12-membered heteroaryl is optionally substituted or unsubstituted by one or more deuterium, halogen, -ORs, -N(Rs)2, or -C(=O)ORs; PEGn is (-OCH2CH2-)n, n = 1-8;Each Ta and Tb is independently absent, -N(Rs)-, -O-, C1-C6 alkyl, -N(Rs)-(C1-C6 alkyl)-, -(C1-C6 alkyl)-N(Rs)-, -N(RS)-(C1-C6 alkyl)-N(Rs)-, -O-(C1-C6 alkyl)-, -(C1-C6 alkyl)-O-, or -O-(C1-C6 alkyl)-O-; wherein the C1-C6 alkyl is optionally substituted with one or more halogens or not substituted; and each Rs is independently H, deuterium, or C1-C6 alkyl, wherein the C1-C6 alkyl may optionally be substituted with one or more halogens; Each R4 is independently selected from the group consisting of: H; deuterium; halogen; CN; OR6; N(R6)2; COOR6; C(O)N(R6)2; SO2R6; C1-C6 alkyl; C1-C6 haloalkyl; C1-C6 alkyl substituted with OR6; C2-C6 alkenyl; C2-C6 haloalkenyl; C2-C6 alkenyl substituted with OR6; C2-C6 ynyl; C2-C6 haloalkynyl; C2-C6 ynyl substituted with OR6; C3-C6 cycloalkyl; and heterocycles comprising 1-2 members selected from the O, S, and N(R6) ring members, ranging from 3- to 6-membered. Each R6 is independently selected from -H, deuterium, halogen, -NH2, -CN, -OH, -N3, -NO2, carboxyl, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, -C6-10 aryl, -C5-10 heteroaryl, C3-10 heterocyclic, or C3-10 carbocyclic; and each group may be independently and optionally substituted or unsubstituted by deuterium, halogen, -NH2, CN, -OH, -NO2, carbonyl, =O, oxo, carboxyl, C1-6 alkoxy, or C1-6 alkyl; and each heteroaryl and each heterocyclic contains at least one heteroatom selected from N, O, or S; each X1 is independently selected from the group consisting of: C=O, -CH2-, -CHF-, and -CF2-; Each X2 is independently selected from (C(R8)2)(1-3), NR8(C(R8)2)(1-3), -NH(C(R8)2)(1-3), –N(C1-6 alkyl)(C(R8)2)(1-3) or –N(C1-6 haloalkyl)(C(R8)2)(1-3); wherein each R8 is independently selected from the group consisting of: H, deuterium, halogen, C1-C6 alkyl, CN, OR6, N(R6)2, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl substituted with OR6, and C1-C6 alkyl substituted with N(R6)2; optionally, two R8s located on different carbon atoms may form a 3- to 6-membered fused ring together with the atoms they are attached to; optionally, two R8s located on one carbon atom may form a 3- to 6-membered spiro ring together with the atoms they are attached to;Each X3 is independently selected from the group consisting of: COOR6, C(O)SR6, C(S)OR6, SO2R6, C(O)N(R9)2, CN; each R9 is independently selected from H, deuterium, COOR6, SO2R6, (CH2)1-3-C(=O)OR6, OR6, SR6, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, O(C1-C6 alkyl), O(C6-C10 aryl), O(C1-C6 alkyl)-OR6, S(C1-C6 alkyl), S(C6-C10 aryl), S(=O)2R6, S(=O)2OR6, P(=O)(R6)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl. C3-C8 cycloalkyl, C6-C10 aryl, 3-8 membered heterocycloalkyl, or 3-10 membered heteroaryl.

[0013] In some embodiments of Formula I, the following groups are selected independently: , , or; and the following groups are selected independently: , , , , , or.

[0014] In some embodiments of Formula I, the following groups are independently selected: , , , , , , , , , , or; and the following groups are independently selected: , , , , , , , , , , , , , , , , , or.

[0015] In some embodiments of Formula I, the compound is as shown in Formula I-1: I-1.

[0016] In some embodiments of Formula II, the following groups are selected independently: , , , or; and the following groups are selected independently: , , , , , , or.

[0017] In some embodiments of Formula II, the following groups are independently selected: , , , , , , , , , , , , or; and the following groups are independently selected: , , , , , , , , , , , , , , , , or.

[0018] In some embodiments of Formula III, the following groups are selected independently: , , , , , , , or; and the following groups are selected independently: , , , or.

[0019] In some embodiments of Formula III, the following groups are independently selected: , , , , , , , , , , , , , , , , , , , or; and the following groups are independently selected: , , , , or.

[0020] In some embodiments of Formula IV, the following groups are selected independently: , , , or; and the following groups are selected independently: , , , , , or.

[0021] In some embodiments of Formula IV, the following groups are independently selected: , , , ; , , , , , , or; and the following groups are independently selected: , , , , , , , , , or.

[0022] In some embodiments of formula V, the following groups are selected independently: , , or; and the following groups are selected independently: , , , , , , or.

[0023] In some embodiments of formula V, the following groups are independently selected: , , , , , or; and the following groups are independently selected: , , , , , , , , , , or.

[0024] In some embodiments of formula I, I-1, II, III, IV or V, each W is independently CR1.

[0025] In some embodiments of formula I, I-1, II, III, IV or V, each W is independently CH or CF.

[0026] In some embodiments of formulas I, I-1, II, III, IV or V, each W is independently N.

[0027] In some embodiments of formula I, I-1, II, III, IV or V, each R1 is independently selected from H, deuterium, halogen, OR6, N(R6)2, COOR6, C(O)N(R6)2, CN or C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted or not substituted by one or more deuterium, halogen, OR6, N(R6)2, COOR6, or C(O)N(R6)2.

[0028] In some embodiments of formula I, I-1, II, III, IV or V, each R1 is independently selected from the group consisting of: H, deuterium, halogen, C1-C3 alkyl, CN and C1-C3 haloalkyl.

[0029] In some embodiments of formula I, I-1, II, III, IV or V, each R1 is independently selected from the group consisting of H, deuterium, halogen, CN and C1-C3 alkyl.

[0030] In some embodiments of formula I, I-1, II, III, IV or V, each R1 is independently selected from the group consisting of H, deuterium, F, Cl, Br, CN and methyl.

[0031] In some embodiments, each R1 is independently hydrogen or halogen.

[0032] In some embodiments, each R1 is independently hydrogen or F.

[0033] In some embodiments, each R1 is independently hydrogen or CN.

[0034] In some embodiments, each R1 is independently deuterium.

[0035] In some embodiments of formula I, I-1, II, III, IV, or V, R2 and R3 are independently selected from -Ta-C1-C6 alkyl-Tb-, -Ta-N(Rs)-Tb, -Ta-O-Tb, -Ta-PEGn-O-Tb, -Ta-SS-Tb, -Ta-SSS-Tb, -Ta-N(Rs)-N(Rs)-Tb-, -Ta-C2-C6 alkenyl-Tb-, -Ta-C2-C6 alkynyl-Tb-, -Ta-C(=O)-Tb-, -Ta-C(=CH2)-Tb-, -Ta-C(=O)-C(=O)- Tb-, -Ta-C(=O)-(C1-C6 alkyl)-C(=O)-Tb-, -Ta-C(=O)-(C3-C12 cycloalkyl)-C(=O)-Tb-, -Ta-C(=O)-(C1-C6 alkyl)-(C3-C12 cycloalkyl)-(C1-C6 alkyl)-C(=O)-Tb-, -Ta-C(=O)-(3-to-12-membered heterocyclic alkyl)-C(=O)-Tb-, -Ta-C(=O)-(C1-C6 alkyl)-(3-to-12-membered heterocyclic alkyl)-(C1-C6 alkyl)-C(= -Ta-C(=S)-Tb-, -Ta-S(=O)2-Tb-, -Ta-S(=O)-Tb-, -Ta-P(=O)(-ORs)-Tb-, -Ta-(C3-C12 cycloalkyl)-Tb-, -Ta-(C6-C12 aryl)-Tb-, -Ta-(3-to-12-membered heterocyclic alkyl)-Tb-, or -Ta-(5-to-12-membered heteroaryl)-Tb-, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-to-12-membered heterocyclic alkyl, or 5-to-12-membered heteroaryl are optionally substituted or not substituted by one or more deuterium, halogen, -ORs, -N(Rs)2, or -C(=O)ORs.

[0036] In some embodiments of formula I, I-1, II, III, IV, or V, R2 and R3 are independently selected from -Ta-C1-C6 alkyl-Tb-, -Ta-N(Rs)-Tb, -Ta-O-Tb, -Ta-PEGn-O-Tb, -Ta-SS-Tb, -Ta-SSS-Tb, -Ta-N(Rs)-N(Rs)-Tb-, -Ta-C2-C6 alkenyl-Tb-, -Ta-C2-C6 alkynyl-Tb-, -Ta-C(=O)-Tb-, -Ta-C(=CH2)-Tb-, -Ta-C(=O)-C(=O)- Tb-, -Ta-C(=O)-(C1-C6 alkyl)-C(=O)-Tb-, -Ta-C(=O)-(C3-C12 cycloalkyl)-C(=O)-Tb-, -Ta-C(=O)-(C1-C6 alkyl)-(C3-C12 cycloalkyl)-(C1-C6 alkyl)-C(=O)-Tb-, -Ta-C(=O)-(3-to-12-membered heterocyclic alkyl)-C(=O)-Tb-, -Ta-C(=O)-(C1-C6 alkyl)-(3-to-12-membered heterocyclic alkyl)-(C1-C6 alkyl)-C(=O)-Tb-, -Ta-C(=S)-Tb-, -Ta-S(=O)2-T b-, -Ta-S(=O)-Tb-, -Ta-P(=O)(-ORs)-Tb-, -Ta-(C3-C12 cycloalkyl)-Tb-, -Ta-(C6-C12 aryl)-Tb-, -Ta-(3-to-12-membered heterocyclic alkyl)-Tb-, or -Ta-(5-to-12-membered heteroaryl)-Tb-; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-to-12-membered heterocyclic alkyl, or 5-to-12-membered heteroaryl is optionally substituted or not substituted by one or more halogens, -ORs, -N(Rs)2, or -C(=O)ORs.In -Ta-(C3-C12 cycloalkyl)-Tb- or -Ta-(3-to-12-membered heterocycloalkyl)-Tb-, the C3-C12 cycloalkyl or 3-to-12-membered heterocycloalkyl is connected to Ta and Tb respectively through different atoms on the C3-C12 cycloalkyl or 3-to-12-membered heterocycloalkyl; PEGn is (-OCH2CH2-)n, n = 1-8; each Ta and Tb is independently absent, -N(Rs)-, -O-, C1-C6 alkyl, -N(Rs)-(C1-C6 alkyl)-, -(C1-C6 alkyl)-N(Rs)-, -N(RS)-(C1-C6 alkyl)-N(Rs)-, -O-(C1-C6 alkyl)-, -(C1-C6 alkyl)-O-, or -O- (C1-C6 alkyl)-O-, wherein the C1-C6 alkyl group is optionally substituted with or unsubstituted with one or more halogens; and each Rs is independently H, deuterium, or a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted with or unsubstituted with one or more halogens.

[0037] In some embodiments of formula I, I-1, II, III, IV, or V, R2 and R3 are independently selected from -Ta-C1-C6 alkyl-Tb-, -Ta-N(Rs)-Tb, -Ta-O-Tb, -Ta-PEGn-O-Tb, -Ta-SS-Tb, -Ta-SSS-Tb, -Ta-N(Rs)-N(Rs)-Tb-, -Ta-C2-C6 alkenyl-Tb-, -Ta-C2-C6 ynyl-Tb-, -Ta-C(=O)-Tb-, -Ta-C(=CH2)-Tb-, -Ta-C(=O)-C(=O)-Tb-, -Ta-C(=S)-Tb-, -Ta-S(=O)2-Tb-, -Ta-S(=O)-Tb-, -Ta-P(=O)(-ORs)-Tb-, -Ta-(C3-C12 cycloalkyl)-Tb-, -Ta-(C6-C12 aryl)-Tb-, -Ta-(3- to 12-membered heterocycloalkyl)-Tb-, or -Ta-(5- (to 12-membered heteroaryl)-Tb-; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-to 12-membered heterocycloalkyl, or 5- or 12-membered heteroaryl is optionally substituted or not substituted by one or more deuterium, halogen, -ORs, -N(Rs)2, or C(=O)ORs.

[0038] In some embodiments of formula I, I-1, II, III, IV or V, R2 and R3 are independently selected from -Ta-C1-C6 alkyl-Tb-, -Ta-N(Rs)-Tb, -Ta-O-Tb, -Ta-PEGn-O-Tb, -Ta-SS-Tb, -Ta-SSS-Tb, -Ta-N(Rs)-N(Rs)-Tb-, -Ta-C2-C6 alkenyl-Tb-, -Ta-C2-C6 alkynyl-Tb-, -Ta-C(=O)-Tb-, -Ta-C(=CH2)-Tb-, -Ta-C(=O)-C(=O)- Tb-, -Ta-C(=S)-Tb-, -Ta-S(=O)2-Tb-, -Ta-S(=O)-Tb-, -Ta-P(=O)(-ORs)-Tb-, -Ta-(C3-C12 cycloalkyl)-Tb-, -Ta-(C6-C12 aryl)-Tb-, -Ta-(3- to 12-membered heterocycloalkyl)-Tb-, or -Ta-(5- to 12-membered heteroaryl)-Tb-; wherein the C1-C6 alkyl The PEGn is optionally associated with one or more halogens, -ORs, -N(Rs)2, or -C(=O)ORs; and the C3-C12 cycloalkyl or 3- to 12-membered heterocyclic alkyl is connected to Ta and Tb through different atoms on the C3-C12 cycloalkyl or 3- to 12-membered heterocyclic alkyl; PEGn is (-OCH2CH2-)n, n=1-8;

[0039] Each Ta and Tb is independently absent, -N(Rs)-, -O-, C1-C6 alkyl, -N(Rs)-(C1-C6 alkyl)-, -(C1-C6 alkyl)-N(Rs)-, -N(RS)-(C1-C6 alkyl)-N(Rs)-, -O-(C1-C6 alkyl)-, -(C1-C6 alkyl)-O-, or -O-(C1-C6 alkyl)-O-, wherein the C1-C6 alkyl is optionally substituted with one or more halogens; and each Rs is independently H, deuterium, or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogens.

[0040] In some embodiments of formula I, I-1, II, III, IV, or V, R2 and R3 are independently selected from O-(C1-C4 alkylene or haloalkylene)-C2-C6 alkenyl, C1-C5 alkylene or haloalkylene, (C1-C4 alkylene or haloalkylene)-N(R6), and N(R6)-(C1-C4 alkylene or haloalkylene)- C2-C6 alkenyl, -C0-6alkyl-NH-C0-6alkyl-, -C0-6alkyl-N(C1-6alkyl)-C0-6alkyl-, -C0-6alkyl-O-C0-6alkyl-, -C0-6alkyl-PEGn-O-C0-6alkyl, -C0-6alkyl-SS-C0-6alkyl, -C0-6alkyl-SSS-C0-6alkyl, -C0-6alkyl-C2-C6 alkenyl-C0-6alkyl-, -C0-6alkyl-C2-C6 ynyl- C0-6alkyl-, -C0-6alkyl-C(=O)-C0-6alkyl-, -C0-6alkyl-C(=CH2)-C0-6alkyl-, -C0-6alkyl-C(=O)-C(=O)-C0-6alkyl-, -C0-6alkyl-C(=S)-C0-6alkyl-, -C0-6alkyl-S(=O)2-C0-6alkyl-, -C0-6alkyl-S(=O)-C0-6alkyl-, -C0-6alkyl-P(=O)(-OH)-C0-6alkyl-, -C0-6alkyl-C3-C12cycloalkyl-C0-6alkyl-, -C0-6alkyl-C6-C12aryl-C0-6alkyl-, -C0-6alkyl-(3- to 12-membered heterocyclic)-C0-6alkyl-, -C0-6alkyl-(5- to 12-membered heterocyclic)-C0-6alkyl- -C0-6alkyl-, -C0-6alkyl-O-(5- to 12-membered heteroaryl)-O-C0-6alkyl-, -C0-6alkyl-OC(=O)-NH-C0-6alkyl-, -C0-6alkyl-OC(=O)-C0-6alkyl-, -C0-6alkyl-NH-C(=O)-C0-6alkyl-, -OC(=O)-O-, -NH-C(=O)-NH-, or -NH-C(=S)-NH-; wherein the C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3- to 12-membered heterocycloalkyl, or 5- to 12-membered heteroaryl is optionally substituted or not substituted by one or more deuterium, halogen, -ORs, -N(Rs)2, or -C(=O)ORs.

[0041] In some embodiments of formula I, I-1, II, III, IV, or V, R2 and R3 are independently selected from -Ta-C2-C6 alkenyl-Tb-, -Ta-C(=O)-Tb-, -Ta-PEGn-O-Tb, -Ta-SS-Tb, -Ta-SSS-Tb, -Ta-C(=CH2)-Tb-, or -Ta-(C6-C12 aryl)-Tb-; wherein the C2-C6 alkenyl or C6-C12 aryl is optionally substituted or unsubstituted by one or more halogens, -ORs, -N(Rs)2, or -C(=O)ORs; PEGn is (-OCH2CH2-)n, n = 1-8; each Ta and Tb is independently -N(Rs)-, -O-, -(C1-C6 alkyl)-O-, or -O-( (C1-C6 alkyl)-O-; wherein the C1-C6 alkyl group is optionally substituted with one or more halogens; each Rs is independently H, deuterium or C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally substituted with one or more halogens or not substituted.

[0042] In some embodiments of formulas I, I-1, II, III, IV or V, R2-R3 are selected from: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) （20） （21） （22） （23） （24） （25） （26） （27） （28） （29） （30） （31） （32） （33） （34） （35） （36） （37） （38） （39） （40） （41） （42） （43） （44） （45） （46） （47） （48） （49） （50） （51） （52） （53） （54） （55） （56） （57） （58） （59） （60） （61） （62） （63） （64） （65） （66） （67） （68） （69） （70） （71） （72） （73） （74） （75） （76） （77） （78） （79） （80） （81） （82） （83） （84） （85） (86) (87) (88) (89) (90) (91) (92) (93) Wherein: each R5 is independently -OR7, NR7 or -C(O)OR7; each R7 is independently hydrogen, deuterium or C1-2 alkyl; and each R10 is independently hydrogen, deuterium, C1-2 alkyl or halogen.

[0043] In some embodiments, each R7 is independently hydrogen, deuterium, or methyl.

[0044] In some embodiments, each R10 is independently hydrogen, deuterium, methyl or fluorine.

[0045] In some embodiments, one R10 is hydrogen and the other R10 is methyl or fluorine.

[0046] In some embodiments, one R10 is deuterium and the other R10 is methyl or fluorine.

[0047] In some embodiments of formula I, I-1, II, III, IV or V, R2-R3 are selected from -(CH2)2-8-, -O(CH2)1-7-, -O(CH2)1-6O-, OCH2CH(CH3)CH2O-, -OCH(CH3)CH2CH(CH3)O-, -NH(CH2)1-7-, -(CH2)1-6NH(CH2)1-6-, -(CH2)1-6N(CH3)(CH2)1-6-, -NH(CH2)1-6O-, -NH -CO-NH-, -N(CH3)CO-NH-,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,or.

[0048] In some embodiments of formula I, I-1, II, III, IV or V, R2-R3 are selected from -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -O(CH2)2-, -O(CH2)3-, -O(CH2)4-, -O(CH2)2O-, -O(CH2)3O-, -O(CH2)4O-, -OCH2CH(CH3)CH2O-, -OCH(CH3)CH2CH(CH3)O-, , -O(CH2)4O-, -O(CH2)5O-, -NH(CH2)2-, -NH(CH2)3-, -NH(CH2)4-, -(CH2)2NH-, -(CH2)3NH-, -(CH2)4NH-, -CH2NHCH2-, -CH2N(CH3)CH2-, -NH(CH2)3O-, -NH-CO-NH-,,,,,, or -N(CH3)CONH-.

[0049] In some embodiments of formula I, I-1, II, III or IV, each R4 is independently selected from the group consisting of: H, deuterium, F, Cl, Br, I, CN, OR6, N(R6)2, COOR6, C(O)N(R6)2, SO2R6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted with OR6, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkenyl substituted with OR6, C2-C6 ynyl, C2-C6 haloynyl, C2-C6 ynyl substituted with OR6, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclic groups containing 1 to 2 ring atoms selected from O, S or N(R6).

[0050] In some embodiments of formula I, I-1, II, III or IV, each R4 is independently selected from the group consisting of: H, deuterium, F, Cl, Br, I, OH, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl, OC1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 alkynyl, and N(R6)2.

[0051] In some embodiments of formula I, I-1, II, III or IV, each R4 is independently selected from the group consisting of: H, deuterium, Br, Cl, OH, CH3, CH2CH3, CH=CH2, C≡CH, OCH3, OCFH2, OCF2H, OCF3, and N(R6)2.

[0052] In some embodiments of formula I, I-1, II, III or IV, each R4 independently consists of the group consisting of: H, deuterium, Br, OH, CH3, CH2CH3, CH=CH2, C≡CH, OCH3, NH2 and NHCH3.

[0053] In some embodiments of formula I, I-1, II, III, IV, or V, each R6 is independently selected from the group consisting of: -H, deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N3, -NO2, carboxyl, C1-C3 alkyl, C1-C3 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, 6-aryl, 7-aryl, 8-aryl, 5-heteroaryl, 6-heteroaryl, 7-heteroaryl, 8 -Hyperaryl, 5-Hypercyclic, 6-Hypercyclic, 7-Hypercyclic, 8-Hypercyclic, 5-Carbocyclic, 6-Carbocyclic, 7-Carbocyclic, or 8-Carbocyclic; and each R6 may be independently and optionally substituted with or unsubstituted by deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -NO2, carbonyl, =O, oxo, carboxyl, C1-C3 alkoxy, or C1-C3 alkyl; and each heteroaryl and each heterocyclic group contains one or two heteroatoms selected from N, O, or S.

[0054] In some embodiments of formula I, I-1, II, III, IV, or V, each R6 is independently selected from the group consisting of: H, deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N3, -NO2, carboxyl, methyl, ethyl, propyl, isopropylmethoxy, ethoxy, propoxy, isopropoxy, vinyl, 6-aryl, 5-heteroaryl, 6-heteroaryl, 5- The heterocyclic group is a 6-membered heterocyclic group, a 5-membered carbocyclic group, or a 6-membered carbocyclic group; and each R6 is independently and optionally substituted or unsubstituted by deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -NO2, carbonyl, =O, oxo, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy; and each heteroaryl and each heterocyclic group contains one or two heteroatoms selected from N, O, or S.

[0055] In some embodiments of formula I, I-1, II, III, IV or V, each R6 is independently selected from the group consisting of: H, deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH2F, -CHF2, and -CF3.

[0056] In some embodiments of formula I, I-1, II, III, IV or V, each X1 is independently selected from the group consisting of: C=O, -CH2-, -CHF-, and -CF2-.

[0057] In some embodiments of formula I, I-1, II, III, IV or V, each X1 is selected from the group consisting of: C=O and -CH2-.

[0058] In some embodiments of formula I, I-1, II, III, IV or V, each X1 is C=O.

[0059] In some embodiments of formula I, I-1, II, III, IV or V, each X2 is independently selected from (C(R8)2)(1-3), wherein each R8 is independently selected from the group consisting of: H, deuterium, halogen, C1-C6 alkyl, CN, OR6, N(R6)2, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl substituted with OR6, and C1-C6 alkyl substituted with N(R6)2; optionally, two R8s located on one carbon atom may form a 3- to 6-membered fused ring together with the atom to which they are attached; optionally, two R8s located on different carbon atoms may form a 3- to 6-membered spiro ring together with the atom to which they are attached.

[0060] In some embodiments, each X2 is independently -(C(R8)2)1-3-, wherein each R8 is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, CN, OR6, N(R6)2, or C3-C6 cycloalkyl; the C1-C6 alkyl is optionally substituted or not substituted by one or more halogens, OR6, or N(R6)2.

[0061] In some embodiments, each X2 is independently -(C(R8)2)1-3-, wherein at least two R8s together with the atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl.

[0062] In some embodiments, each X2 is independently -C(R8)1-3-.

[0063] In some embodiments, each X2 is independently -(CH2)1-3-.

[0064] In some embodiments, each X2 is independently -C(R8)2-.

[0065] In some embodiments, each X2 is independently -CH2-.

[0066] In some embodiments, each X2 is independently -C(R8)2C(R8)2-.

[0067] In some embodiments, each X2 is independently -CH2CH2-.

[0068] In some embodiments, each X2 is independently -C(R8)2C(R8)2C(R8)2-.

[0069] In some embodiments, each X2 is independently -CH2CH2CH2-.

[0070] In some embodiments of formula I, I-1, II, III, IV or V, each X2 is CH2CHR8, and R8 is selected from the group consisting of: H, deuterium, C1-C3 alkyl, C1-C3 alkyl substituted with OH, C1-C3 alkyl substituted with OC1-C3 alkyl, and C3-C6 cycloalkyl.

[0071] In some embodiments of formula I, I-1, II, III, IV or V, each X2 is CH2CHR8, and R8 is selected from the group consisting of: H, deuterium, CH3, CH2OH, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2OCH3, and cyclopropyl.

[0072] In some embodiments of formula I, I-1, II, III, IV or V, each X2 is CHR8CHR8, and each R8 is independently selected from the group consisting of: H, deuterium, C1-C3 alkyl, C1-C3 alkyl substituted with OH, C1-C3 alkyl substituted with OC1-C3 alkyl, and C3-C6 cycloalkyl; optionally, the two R8s located on different carbon atoms together with the atoms to which they are attached form a 3- to 6-membered fused ring.

[0073] In some embodiments of formula I, I-1, II, III, IV or V, each X2 is CHR8CHR8, and each R8 is independently selected from the group consisting of H, deuterium and C1-C3 alkyl; optionally, the two R8s located on different carbon atoms together with the atoms to which they are attached form a 3- to 6-membered fused ring.

[0074] In some embodiments of formula I, I-1, II, III, IV or V, each X2 is CH2C(R8)2, and each R8 is independently selected from the group consisting of: H, deuterium, C1-C3 alkyl, C1-C3 alkyl substituted with OH, C1-C3 alkyl substituted with OC1-C3 alkyl, and C3-C6 cycloalkyl; optionally, the two R8s located on a carbon atom together with the atoms to which they are attached form a 3- to 6-membered spirocycle.

[0075] In some embodiments of formula I, I-1, II, III, IV or V, each X2 is CH2C(R8)2, each R8 is independently selected from the group consisting of H, deuterium and C1-C3 alkyl; and optionally, the two R8s located on a carbon atom together with the atoms to which they are attached form a 3- to 6-membered spirocycle.

[0076] In some embodiments of formula I, I-1, II, III, IV or V, each X3 is independently selected from the group consisting of: COOR6, C(O)SR6, C(S)OR6, SO2R6, C(O)N(R9)2, and CN.

[0077] In some embodiments of formula I, I-1, II, III, IV or V, each X3 is independently selected from the group consisting of: COOR6, SO2R6, C(O)N(R9), and CN.

[0078] In some embodiments of formula I, I-1, II, III, IV or V, each X3 is independently selected from the group consisting of: COOR6, C(O)N(R9)2, and CN.

[0079] In some embodiments of formula I, I-1, II, III, IV or V, each X3 is independently selected from the group consisting of: COOH, COOCH3, CONH2, CONH-SO2-N(CH3)2, CONH-SO2-CH3, and CN.

[0080] In some embodiments of formula I, I-1, II, III, IV or V, each R9 is independently selected from the group consisting of: H, deuterium, COOR6, and SO2R6.

[0081] In some embodiments of formula I, I-1, II, III, IV or V, each R9 is independently H or deuterium, preferably H.

[0082] In some embodiments, compounds of formula IV, such as those represented by general formulas Ia, IIa, IIIa, IVa or Va: Ia IIa IIIa IVa VA or pharmaceutically acceptable salts thereof.

[0083] In some embodiments, compounds of formula IV, such as those represented by general formulas Ib, IIb, IIIb, or IVb: Ib IIb IIIb IVb or pharmaceutically acceptable salts thereof.

[0084] In some embodiments, compounds of formula IV, such as those represented by general formulas Ic, IIc, IIIc, IVc or Vc: Ic IIc IIIc IVc Vc or pharmaceutically acceptable salts thereof.

[0085] In some embodiments, each heterocycle (base) and each carbide (base) as defined herein comprises a heterocycle or carbide formed by a monocyclic ring, a spirocyclic ring, a bridged ring, a fused ring, and various combinations of spirocyclic rings, bridged rings and / or fused rings.

[0086] In some embodiments of the foregoing general formula as defined herein, the compound is selected from the compounds shown in Table 1 and their pharmaceutically acceptable salts.

[0087] In some embodiments of the foregoing general formula as defined herein, the compound is selected from the compounds shown in Table 1. Table 1 1. 4-(5-(3-((2-(3-carboxypropyl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid 2. 4-(5-(3-((2-(3-carboxypropyl)-4-chloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid 3. 4-(5-(3-((2-(3-carboxypropyl)-4-chloro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-4-oxobutyric acid 4. 4-(5-(3-((2-(3-carboxypropyl)-4-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-4-oxobutyric acid 5. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyrate sodium salt 6. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyrate sodium 7. Sodium 4-(5-(3-((2-(3-carboxypropyl)-6-hydroxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate 8. Sodium 4-(5-(3-((2-(3-carboxypropyl)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxythiopheno[3,2-b]pyridin-2-yl)-4-oxobutyrate 9. 4-(5-(3-((6-bromo-2-(3-carboxypropyl)benzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid 10. 4-(5-(3-((2-(3-carboxypropyl)-4-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid 11. 4-(5-(3-((6-(3-carboxypropyl)-3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propoxy)-6-methoxythiopheno[3,2-b]pyridin-2-yl)-4-oxobutyric acid 12. 4-(5-(3-((2-(4-ethoxy-4-oxobutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid 13. Sodium 4-(5-(3-((2-(3-carboxypropionic acid)-5-methoxythiopheno[2,3-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate 14. 4-(5-(3-((2-(3-carboxypropyl)-4-chloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid 15. 4-(5-(3-((2-(3-carboxypropyl)-5-methoxythiopheno[3,2-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid 16. 4-(5-((2-(((2-(3-carboxypropyl)-4-chloro-6-methoxyisoindoline-5-yl)oxy)methyl)allyl)oxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid 17. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 18. 4-(5-(3-((2-((2-carboxyethyl)aminomethyl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid 19. 4-(5-((2-(((2-(3-carboxypropyl)-6-methoxybenzo[b]thiophene-5-yl)oxy)methyl)allyl)oxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid 20. 4-(5-(3-((2-(3-carboxypropyl)-4-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid twenty one. trans-2-(5-(3-((2-(3-carboxypropionic acid)-4-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-carbonyl)cyclopropane-1-carboxylic acid twenty two. 4-(5-(3-((2-(3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid twenty three. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid twenty four. (S)-4-(5-(3-((2-(3-carboxypropyl)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 25. (S)-4-(5-(3-((2-(3-carboxypropyl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 26. (S)-4-(5-(2-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)ethoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 27. (S)-4-(5-(4-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)butoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 28. (S)-4-(5-((5-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)pentyl)oxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 29. (S)-4-(5-(4-(2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)butoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 30. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)amino)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 31. (S)-4-(5-(4-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)amino)butyl)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 32. (S)-4-(5-(4-(2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)butyl)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 33. (S)-4-(5-(5-(2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)pentyl)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 34. (2S)-4-(5-((4-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)pentane-2-yl)oxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 35. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)-2,2-dimethylpropoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 36. (S)-4-(5-((1-(((2-(((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)methyl)cyclopropyl)methoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 37. 4-(5-(3-((2-(3-carboxypropionic acid)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2,2-dimethyl-4-oxobutyric acid 38. 4-(5-(3-((2-(3-carboxypropionic acid)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2,2-dimethyl-4-oxobutyric acid 39. 4-(5-(3-((2-(3-carboxy-3-methylbutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2,2-dimethyl-4-oxobutyric acid 40. (S)-4-(5-((4-(2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)butyl)amino)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 41. (S)-4-(5-((3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propyl)amino)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 42. (S)-4-(5-(4-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)butyl)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 43. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 44. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 45. (S)-4-(5-(3-((4-bromo-2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 46. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[d]thiazolyl-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 47. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-hydroxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 48. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 49. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-dichloro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 50. (2S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxy-3-methylisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 51. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 52. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 53. (S)-4-(5-(3-((4-bromo-2-((S)-3-carboxybutyryl)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 54. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-hydroxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 55. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 56. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-chloro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 57. (S)-4-(5-(3-((7-bromo-2-((S)-3-carboxybutyryl)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 58. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 59. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-7-chloro-4-fluoro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 60. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-dichloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 61. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 62. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 63. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-chloro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 64. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-7-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 65. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-7-chloro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 66. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-7-chloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-7-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 67. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-7-chloro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 68. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-7-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 69. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-7-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-7-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 70. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 71. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-7-chloro-4-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 72. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-4,7-dichloro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 73. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-7-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-7-chloro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 74. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-dichloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-7-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 75. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-7-chloro-4-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-7-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 76. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-chloro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 77. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-4-chloro-7-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-chloro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 78. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-fluoro-6-hydroxyisoindoline-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 79. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-6-hydroxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 80. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-6-hydroxyisoindoline-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 81. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-6-hydroxyisoindoline-5-yl)oxy)propoxy)-4-chloro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 82. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-5-hydroxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 83. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-7-fluoro-6-hydroxyisoindoline-5-yl)oxy)propoxy)-7-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 84. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-7-chloro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-5-hydroxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 85. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-7-chloro-6-hydroxyisoindoline-5-yl)oxy)propoxy)-7-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 86. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-4-chloro-7-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 87. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-7-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-chloro-7-fluoro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 88. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4,7-difluoro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 89. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-7-chloro-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 90. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-dichloro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4,7-difluoro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 91. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-dichloro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-chloro-7-fluoro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 92. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-7-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-7-chloro-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 93. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-dichloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-4-chloro-7-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 94. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-7-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-7-chloro-4-fluoro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 95. (2S,2'S)-4,4'-(7,8,11,13,17,18-hexahydro-6H,12H,16H-thieno[2'',3'':4',5']benzo[1',2':9,10][1,4,8,11]tetraoxylatetetraaza[2,3-f]isoindoline-2,12-diacyl)bis(2-methyl-4-oxobutyric acid) 96. (S)-4-(6-methoxy-5-(3-((6-methoxy-2-((S)-3-methyl-4-(methylsulfonamide)-4-oxobutyryl)isoindololin-5-yl)oxy)propoxy)benzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 97. (S)-4-(5-(3-((2-((S)-4-((N,N-dimethylaminosulfonyl)amino)-3-methyl-4-oxobutyryl)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 98. (S)-4-(5-(3-((2-(3-cyanopropionic acid)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 99. 4-(5-(3-((2-(3-cyanopropionic acid)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyronitrile 100. (S)-4-(5-(3-((2-(3-cyanopropionic acid)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 101. (1R,2R)-2-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-carbonyl)cyclobutane-1-carboxylic acid 102. (1R,2R)-2-(5-(3-((2-((1R,2R)-2-carboxycyclobutane-1-carbonyl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-carbonyl)cyclobutane-1-carboxylic acid 103. (1R,2R)-2-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-carbonyl)cyclobutane-1-carboxylic acid 104. (1R,2R)-2-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-carbonyl)cyclopropane-1-carboxylic acid 105. (1R,2R)-2-(5-(3-((2-((1R,2R)-2-carboxycyclopropane-1-carbonyl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-carbonyl)cyclopropane-1-carboxylic acid 106. (1R,2R)-2-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-carbonyl)cyclopropane-1-carboxylic acid 107. (S)-N-(N,N-dimethylaminosulfonylurea)-4-(5-(3-((2-((S)-4-((N,N-dimethylaminosulfonylurea)amino)-3-methyl-4-oxobutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyramine 108. (S)-4-(5-(3-((2-((S)-4-((N,N-dimethylaminosulfonyl)amino)-3-methyl-4-oxobutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 109. (S)-4-(6-methoxy-5-(3-((6-methoxy-2-((S)-3-methyl-4-(methylsulfonyl)-4-oxobutyryl)isoindolin-5-yl)oxy)propoxy)benzo[b]thiophene-2-yl)-2-methyl-N-(methylsulfonyl)-4-oxobutyrylamine 110. (S)-4-(5-methoxy-6-(3-((6-methoxy-2-((S)-3-methyl-4-(methylsulfonamide)-4-oxobutyryl)benzo[b]thiophene-5-yl)oxy)propoxy)isoindolin-2-yl)-2-methyl-4-oxobutyric acid 111. (S)-4-(4-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 112. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-4-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 113. (S)-4-(4-(4-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)butyl)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 114. (S)-4-(4-(4-(2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)butoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 115. (S)-4-(5-(4-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-4-yl)oxy)butyl)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 116. (S)-4-(5-(4-(2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-4-yl)butoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 117. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methylbenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 118. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-ethylbenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 119. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-vinylbenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 120. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-ethynylbenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 121. (S)-4-(5-(3-((6-amino-2-((S)-3-carboxybutyryl)benzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 122. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-(methylamino)benzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 123. (S)-4-(5-(3-((6-bromo-2-((S)-3-carboxybutyryl)benzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 124. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methylisoindoline-2-yl)-2-methyl-4-oxobutyric acid 125. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-ethylisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 126. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-vinylisoindoline-2-yl)-2-methyl-4-oxobutyric acid 127. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-ethynylisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 128. (S)-4-(5-(3-((6-amino-2-((S)-3-carboxybutyryl)isoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 129. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-(methylamino)isoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 130. (S)-4-(5-(3-((6-bromo-2-((S)-3-carboxybutyryl)isoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 131. (S)-4-(5-(3-((6-((S)-3-carboxybutyryl)-3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 132. (S)-4-(5-(3-((6-((S)-3-carboxybutyryl)-3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 133. (S)-4-(5-(3-((6-((S)-3-carboxybutyryl)-3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propoxy)-4-chloro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 134. (S)-4-(5-(3-((6-((S)-3-carboxybutyryl)-3-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propoxy)-6-methoxythienolo[3,2-b]pyridin-2-yl)-2-methyl-4-oxobutyric acid 135. (S)-4-(5-(3-((6-((S)-3-carboxybutyryl)-3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propoxy)-6-hydroxythienolo[3,2-b]pyridin-2-yl)-2-methyl-4-oxobutyric acid 136. (S)-4-(5-(3-((6-((S)-3-carboxybutyryl)-3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propoxy)-6-methoxythienolo[3,2-b]pyridin-2-yl)-2-methyl-4-oxobutyric acid 137. (S)-4-(5-(3-((6-((S)-3-carboxybutyryl)-4-fluoro-3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propoxy)-6-methoxythienolo[3,2-b]pyridin-2-yl)-2-methyl-4-oxobutyric acid 138. (S)-4-(5-(3-((6-((S)-3-carboxybutyryl)-4-chloro-3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propoxy)-6-methoxythienolo[3,2-b]pyridin-2-yl)-2-methyl-4-oxobutyric acid 139. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxythiopheno[3,2-b]pyridin-2-yl)-2-methyl-4-oxobutyric acid 140. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxythiopheno[3,2-b]pyridin-2-yl)-2-methyl-4-oxobutyric acid 141. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxythiopheno[3,2-b]pyridin-2-yl)-2-methyl-4-oxobutyric acid 142. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-dichloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxythiopheno[3,2-b]pyridin-2-yl)-2-methyl-4-oxobutyric acid 143. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-7-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxythiopheno[3,2-b]pyridin-2-yl)-2-methyl-4-oxobutyric acid 144. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxythiopheno[3,2-b]pyridin-2-yl)-2-methyl-4-oxobutyric acid 145. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-hydroxyisoindoline-5-yl)oxy)propoxy)-6-methoxythiopheno[3,2-b]pyridin-2-yl)-2-methyl-4-oxobutyric acid 146. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-fluoro-6-hydroxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 147. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-6-hydroxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 148. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-4-fluoro-6-hydroxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 149. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-6-hydroxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-chloro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 150. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-6-hydroxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 151. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-7-fluoro-6-hydroxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 152. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-7-chloro-6-hydroxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 153. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-7-chloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-7-fluoro-6-hydroxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 154. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-7-chloro-6-hydroxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 155. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-7-fluoro-6-hydroxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 156. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-7-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-7-fluoro-6-hydroxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 157. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-hydroxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 158. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-7-chloro-4-fluoro-6-hydroxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 159. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-4,7-dichloro-6-hydroxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 160. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-5-methoxybenzo[b]thiophene-6-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 161. 4-(5-(3-((2-(3-carboxypropionic acid)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxythieno[2,3-b]pyridin-2-yl)-4-oxobutyric acid 162. 4-(5-(3-((2-(4-((((4R,5R)-5-hydroxy-1,2-dithiacan-4-yl)oxy)-4-oxobutyryl)-6-methoxythiopheno[2,3-b]pyridin-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid 163. 4-(5-(3-((6-(3-carboxypropyl)-3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid 164. 4-(2-(3-((2-(4-((((4R,5R)-5-hydroxy-1,2-dithiacan-4-yl)oxy)-4-oxobutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-3-methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxobutyric acid 165. 4-(5-(3-((6-(3-carboxypropyl)-2-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid 166. 4-(3-(3-((2-(4-((((4R,5R)-5-hydroxy-1,2-dithiacan-4-yl)oxy)-4-oxobutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-2-methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxobutyric acid 167. 4-(2-(3-((2-(4-((((4R,5R)-5-hydroxy-1,2-dithiacan-4-yl)oxy)-4-oxobutyryl)-6-methoxythiopheno[3,2-b]pyridin-5-yl)oxy)propoxy)-3-methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxobutyric acid 168. 4-(5-(3-((2-(3-carboxypropionic acid)-5-methoxythiopheno[2,3-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid 169. (S)-4-(5-(3-((2-(3-carboxypropyl)-5-methoxythio[2,3-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-2-methyl-4-oxobutyric acid 170. (S)-4-(6-(3-((2-(3-carboxypropyl)-6-methoxyisoindolin-5-yl)oxy)propoxy)-5-methoxythieno[2,3-b]pyridin-2-yl)-2-methyl-4-oxobutyric acid 171. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-5-methoxythiopheno[2,3-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 172. 4-(5-(3-((2-(4-((((4R,5R)-5-hydroxy-1,2-dithiacan-4-yl)oxy)-4-oxobutyric)-5-methoxythiopheno[2,3-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid

[0088] In some embodiments, the compound is an isotopic derivative of any of the compounds of the general formula disclosed herein (e.g., an isotopically labeled compound).

[0089] In some embodiments, the compound is any of the compounds described in Table 1, as well as its prodrugs and pharmaceutically acceptable salt isotopic derivatives thereof.

[0090] In some embodiments, the compound is any of the compounds described in Table 1 and isotopic derivatives of pharmaceutically acceptable salts thereof.

[0091] In some embodiments, the compound is a prodrug of the compound described in Table 1 and an isotopic derivative of a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, the isotope derivative is a deuterium-labeled compound.

[0093] In some embodiments, the compound is any of the compounds described in Table 1, as well as its prodrug and a deuterated compound of a pharmaceutically acceptable salt.

[0094] In some embodiments, the compound is any of the compounds described in Table 1 and deuterated compounds of pharmaceutically acceptable salts thereof.

[0095] In some embodiments, the compound is any of the prodrugs described in Table 1 and deuterated compounds of pharmaceutically acceptable salts thereof.

[0096] Preparation Method

[0097] The compounds of the present invention can be prepared using various methods well known to those skilled in the art of organic synthesis, using the methods described below or variations thereof. All references cited herein are incorporated herein by reference in their entirety.

[0098] The synthetic methods described below are intended as examples of the invention and not to limit the subject matter of the invention and the scope of the claimed compounds to these examples. If the preparation of the starting compound is not described, it is commercially available or can be prepared similarly according to known compounds or methods described herein. Any general formula compound described herein can be synthesized with reference to the methods shown in the following schemes. As shown herein, the final compound is a product whose structural formula is identical to that described in any general formula herein. It is understood that any compound in the general formula can be prepared by appropriately selecting reagents with suitable alternatives. Solvents, temperatures, pressures, and other reaction conditions can be readily selected by those skilled in the art to which this invention pertains. Protecting groups are operated according to standard methods of organic synthesis (TW Green and PGM Wuts (1999), Protecting Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons). These groups are removed at specific stages of compound synthesis, and the methods used are obvious to those skilled in the art to which this invention pertains.

[0099] For example, suitable protecting groups for amino or alkylamino groups are, for example, acetyl, alkyl, such as acetyl; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, or tributoxycarbonyl; arylmethoxycarbonyl, such as benzyloxycarbonyl, or aryl, such as benzoyl. The deprotection conditions for the above protecting groups necessarily vary depending on the choice of protecting group. Therefore, for example, acetyl, such as alkyl, alkoxycarbonyl, or aryl can be removed by hydrolysis using a suitable base such as an alkali metal hydroxide (e.g., lithium hydroxide or sodium hydroxide). Alternatively, acetyl, such as tributoxycarbonyl, can be removed by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl, such as benzyloxycarbonyl, can be removed, for example, by hydrogenation on a catalyst such as palladium on carbon, or by treatment with a Lewis acid such as boron trifluoroacetate. Suitable alternative protecting groups for primary amine groups are, for example, phthalic acid, which can be removed by treatment with alkylamines (e.g., dimethylaminopropylamine) or with hydrazine.

[0100] Suitable protecting groups for the hydroxyl group are, for example, acetyl, such as alkyl, such as acetyl; aryl, such as benzoyl; or arylmethyl, such as benzyl. The deprotection conditions for the above protecting groups necessarily vary depending on the choice of protecting group. Therefore, for example, acetyl, such as alkyl or aryl, can be removed by hydrolysis with a suitable base such as an alkali metal hydroxide (e.g., lithium, sodium hydroxide, or ammonia). Alternatively, for example, arylmethyl (e.g., benzyl) can be removed by hydrogenation on a catalyst such as palladium on carbon.

[0101] Suitable protecting groups for carboxyl groups are, for example, esterification groups, such as methyl or ethyl groups, which can be removed by hydrolysis with a base (e.g., sodium hydroxide) or, for example, by hydrolysis of a third butyl group; or, for example, the third butyl group can be removed by treatment with an acid, such as an organic acid (e.g., trifluoroacetic acid), or by hydrogenation with a catalyst such as palladium / carbon.

[0102] Once a compound of the present disclosure has been synthesized by any of the methods defined herein, the method may further include the following additional steps: (i) removing any protecting groups present; (ii) converting a compound of the present invention into another compound of the present invention; (iii) forming a pharmaceutically acceptable salt thereof and its hydrate; and / or (iv) forming its prodrug.

[0103] For ease of illustration, synthetic routes 1 and 2 provide general synthetic methods for preparing the compounds described herein. For a more detailed description of each reaction step, see the examples below. Those skilled in the art will understand that other synthetic routes can be used to synthesize the compounds. Furthermore, according to the present invention, many compounds obtained by the methods described below can be further modified using conventional chemical methods well known to those skilled in the art.

[0104] Synthetic routes 1 and 2 describe the general routes for the compounds of the present invention, wherein the groups or functional groups such as W, R1, X1, X2, X3, R2, R3 and R4 as defined herein can be converted into the desired final substituents.

[0105] In the following methods and schemes, LG represents a leaving group, which can be a halide or trifluoromethanesulfonate group. Variables included in the methods and schemes have the meanings provided; exemplary catalysts are defined in abbreviations (hereinafter).

[0106] Synthetic Route 1: Under CDI, MgCl2, and alkaline conditions, B6 reacts with tributyl malonate to generate B7. In the presence of LDA or K2CO3, B7 reacts with H6 to generate B8. B8 reacts with TFA to give B1. A′1 and H1 undergo a substitution reaction under alkaline conditions to give A2. A2 and B1 undergo a substitution reaction under alkaline conditions to give D.

[0107] Synthetic Route 2: B3 reacts with tributyl malonate under CDI, MgCl2, and alkaline conditions to generate B4. B4 reacts with H6 under alkaline conditions to generate B5. B5 reacts with TFA to remove tributyl malonate, yielding B2. A4 reacts with H2 in the presence of NaH to generate A3. A3 reacts with B2 in the presence of a palladium catalyst to generate D.

[0108] The present invention also provides a pharmaceutical composition comprising at least one therapeutically effective amount of a compound of formula I, II, III, IV or V of the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. Furthermore, in the pharmaceutical composition, the weight ratio of the compound of formula I, II, III, IV or V or a pharmaceutically acceptable salt thereof to the excipient is in the range of about 0.0001 to about 10.

[0109] The pharmaceutical composition of the present invention may contain at least one other active agent, which may be selected from STING agonist compounds, antiviral compounds, antigens, adjuvants, CTLA-4 and PD-1 pathway antagonists and other immunomodulators, lipids, liposomes as additional active agents, peptides, anticancer agents and chemotherapeutic agents, etc.

[0110] The present invention also provides the use of at least one compound of the general formula shown in Formula I, II, III, IV or V above, or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, for the preparation of a medicament.

[0111] In some embodiments, the drug is used to induce an immune response in a subject, induce STING-dependent type I interferon production, induce STING-dependent cytokine production, or treat cell proliferation disorders.

[0112] In some embodiments, the cell proliferative disease is cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis, or eye disease.

[0113] The present invention provides at least one compound of formula I, II, III, IV or V or a pharmaceutically acceptable salt thereof, and / or the above-described pharmaceutical compositions for therapeutic purposes.

[0114] The present invention provides at least one compound of formula I, II, III, IV or V or a pharmaceutically acceptable salt thereof, and / or the above pharmaceutical composition, for use in subjects to induce immune responses, induce STING-dependent type I interferon production, induce STING-dependent cytokine production, or treat cell proliferative diseases.

[0115] In some embodiments, the cell proliferative disease is cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis, or eye disease.

[0116] The present invention provides at least one compound of formula I, II, III, IV or V or a pharmaceutically acceptable salt thereof, and / or the above-described pharmaceutical compositions for therapeutic purposes.

[0117] The present invention provides at least one compound of formula I, II, III, IV or V or a pharmaceutically acceptable salt thereof, and / or the above pharmaceutical composition for use in subjects to induce immune responses, induce STING-dependent type I interferon production, induce STING-dependent cytokine production, or treat cell proliferative diseases.

[0118] In some embodiments, the cell proliferative disease is cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis, or eye disease.

[0119] The present invention provides at least one compound of formula I, II, III, IV or V or a pharmaceutically acceptable salt thereof, and / or the above pharmaceutical compositions can be used as STING agonists.

[0120] The present invention provides at least one compound of formula I, II, III, IV or V or a pharmaceutically acceptable salt thereof, and / or the above pharmaceutical compositions, which can be used as pharmaceuticals.

[0121] The present invention also provides a method for inducing an immune response in a subject, comprising administering to a patient a therapeutically effective amount of at least one compound of formula I, II, III, IV or V described above, or a pharmaceutically acceptable salt thereof, and / or the pharmaceutical composition described above.

[0122] The present invention also provides a method for inducing STING-dependent type I interferon production in a subject, comprising administering to a patient a therapeutically effective amount of at least one compound of formula I, II, III, IV or V described above, or a pharmaceutically acceptable salt thereof, and / or the pharmaceutical composition described above.

[0123] The present invention also provides a method for inducing the production of STING-dependent cytokines in a subject, comprising administering to a patient a therapeutically effective amount of at least one compound of formula I, II, III, IV or V described above, or a pharmaceutically acceptable salt thereof, and / or the pharmaceutical composition described above.

[0124] The present invention also provides a method for treating a cell proliferative disease in a subject, comprising administering to the patient a therapeutically effective amount of at least one compound of formula I, II, III, IV or V described above, or a pharmaceutically acceptable salt thereof, and / or the pharmaceutical composition described above.

[0125] In some embodiments, the cell proliferative disease is cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis, or eye disease.

[0126] The compounds described in this invention may be STING agonists. These compounds may be potentially used to treat diseases or conditions, including but not limited to proliferative disorders. Proliferative disorders include, but are not limited to, cancer, benign papillomatosis, gestational trophoblastic disease, and benign neoplastic diseases such as cutaneous papillomas (warts) and genital papillomas.

[0127] In a specific implementation, the disease or condition to be treated is a proliferative disease. In some implementations, the proliferative disease is cancer. In a specific implementation, the cancer is selected from brain and spinal cord cancer, head and neck cancer, leukemia and blood cancer, skin cancer, reproductive system cancer, gastrointestinal system cancer, liver and bile duct cancer, kidney and bladder cancer, bone cancer, lung cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, cardiac tumors, germ cell tumors, malignant neuroendocrine (carcinoid) tumors, midline carcinoma, and cancers of unknown primary origin (i.e., cancers that have been found to have metastasized, but the original cancer site is unknown). In a specific implementation, the cancer is present in an adult patient; in another implementation, the cancer is present in a pediatric patient. In a specific implementation, the cancer is associated with AIDS.

[0128] In a specific implementation, the cancer is selected from brain cancer and spinal cord cancer. In a specific implementation, the cancer is selected from anaplastic astrocytoma, glioblastoma, astrocytoma, and sensory neuroblastoma (also known as olfactory blastoma). In a specific implementation, the brain cancer is selected from astrocytomas (e.g., pilocytic astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, pleomorphic luteal astrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma) and oligodendrogliomas (e.g., oligodendroglioma and anaplastic oligodendroglioma). Oligodendroastrocytomas (e.g., oligodendroastrocytomas and anaplastic follicular astrocytomas), ependymomas (e.g., myxopapillary ependymomas and anaplastic ependymomas); medulloblastomas, primitive neuroectodermal tumors, schwannomas, meningiomas, atypical meningiomas, anaplastic meningiomas, pituitary adenomas, brainstem gliomas, cerebellar astrocytomas, brain astrocytomas / malignant gliomas, optic nerve pathway and hypothalamic gliomas, and primary central nervous system lymphomas. In specific examples of these embodiments, brain cancers are selected from gliomas, glioblastomas multiforme, paragangliomas, and supratentorial primitive neuroectodermal tumors (sPNETs).

[0129] In a specific embodiment, the cancer is selected from head and neck cancers, including nasopharyngeal carcinoma, nasal cavity and sinus cancer, hypopharyngeal cancer, oral cancer (e.g., squamous cell carcinoma, lymphoma, and sarcoma), lip cancer, oropharyngeal cancer, salivary gland tumors, laryngeal cancer (e.g., laryngeal squamous cell carcinoma, rhabdomyosarcoma), or eye cancer. In a specific embodiment, the eye cancer is selected from the group consisting of intraocular melanoma and retinoblastoma.

[0130] In a specific implementation, the cancer is selected from leukemia and hematologic malignancies. In a specific implementation, the cancer is selected from myeloproliferative neoplasms, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), myeloproliferative neoplasms (MPN), post-MPN AML, post-MDS AML, del(5q)-related high-risk MDS or AML, blast crisis chronic myeloid leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerhans cell histiocytosis, hairy cell leukemia, and plasma cell tumors, including plasmacytoma and multiple myeloma. The leukemia mentioned herein can be acute or chronic.

[0131] In a specific embodiment, the cancer is selected from skin cancer. In a specific embodiment, the skin cancer is selected from the group consisting of melanoma, squamous cell carcinoma, and basal cell carcinoma.

[0132] In a specific embodiment, the cancer is selected from cancers of the reproductive system. In a specific embodiment, the cancer is selected from breast cancer, cervical cancer, vaginal cancer, ovarian cancer, prostate cancer, penile cancer, and testicular cancer. In specific examples of these embodiments, the cancer is breast cancer selected from ductal carcinoma and phyllodes tumors. In specific examples of these embodiments, the breast cancer can be male breast cancer or female breast cancer. In specific examples of these embodiments, the cancer is cervical cancer selected from squamous cell carcinoma and adenocarcinoma. In specific examples of these embodiments, the cancer is ovarian cancer selected from epithelial carcinoma.

[0133] In a specific embodiment, the cancer is selected from cancers of the gastrointestinal system. In a specific embodiment, the cancer is selected from esophageal cancer, gastric cancer (also known as stomach cancer), gastrointestinal carcinoid tumors, pancreatic cancer, gallbladder cancer, colorectal cancer, and anal cancer. In examples of these embodiments, the cancer is selected from esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gastric lymphoma, gastrointestinal lymphoma, pancreatic pseudopapillary tumors, pancreatic blastoma, islet cell tumors, pancreatic cancer (including acinar cell carcinoma and ductal adenocarcinoma), gallbladder adenocarcinoma, colorectal adenocarcinoma, and anal squamous cell carcinoma.

[0134] In a specific embodiment, the cancer is selected from liver cancer and bile duct cancer. In a specific embodiment, the cancer is liver cancer (also known as hepatocellular carcinoma). In a specific embodiment, the cancer is bile duct cancer (also known as cholangiocarcinoma); in examples of these embodiments, the bile duct cancer is selected from intrahepatic bile duct cancer and extrahepatic bile duct cancer.

[0135] In a specific embodiment, the cancer is selected from kidney cancer and bladder cancer. In a specific embodiment, the cancer is kidney cancer selected from renal cell carcinoma, nephroblastoma, and transitional cell carcinoma. In a specific embodiment, the cancer is bladder cancer selected from urethral cancer (transitional cell carcinoma), squamous cell carcinoma, and adenocarcinoma.

[0136] In a specific implementation, the cancer is selected from bone cancer. In a specific implementation, the bone cancer is selected from osteosarcoma, malignant fibrous histiocytoma of bone, Ewing sarcoma, and chordoma (bone cancer along the spine).

[0137] In a specific implementation, the cancer is selected from lung cancer. In a specific implementation, the lung cancer is selected from non-small cell lung cancer, small cell lung cancer, bronchial tumors, and pleural pulmonary blastoma.

[0138] In a specific embodiment, the cancer is selected from malignant mesothelioma. In a specific embodiment, the cancer is selected from epithelial mesothelioma and sarcoma.

[0139] In a specific embodiment, the cancer is selected from sarcomas. In a specific embodiment, the sarcoma is selected from: central chondrosarcoma, central and periosteal chondroma, fibrosarcoma, clear cell sarcoma of the tendon sheath, and Kaposi's sarcoma.

[0140] In a specific implementation, the cancer is selected from lymphomas. In a specific implementation, the cancer is selected from: Hodgkin lymphoma (e.g., Reed-Sternberg cells), non-Hodgkin lymphoma (e.g., diffuse large B-cell lymphoma, follicular lymphoma, mycosis fungoides, Sezary syndrome, primary central nervous system lymphoma), cutaneous T-cell lymphoma, and primary central nervous system lymphoma.

[0141] In a specific embodiment, the cancer is selected from adenocarcinoma. In a specific embodiment, the cancer is selected from adrenocortical carcinoma (also known as adrenocortical carcinoma or adrenocortical cancer), pheochromocytoma, paraganglioma, pituitary adenoma, thymoma, and thymic carcinoma.

[0142] In a specific embodiment, the cancer is selected from thyroid cancer. In a specific embodiment, the thyroid cancer is selected from the group consisting of medullary thyroid carcinoma, papillary thyroid carcinoma, and follicular thyroid carcinoma.

[0143] In a specific embodiment, the cancer is selected from germ cell tumors. In a specific embodiment, the cancer is selected from malignant extracranial germ cell tumors and malignant extragonadal germ cell tumors. In specific examples of these embodiments, the malignant extragonadal germ cell tumor is selected from non-seminomatous tumors and seminomas.

[0144] In a specific implementation, the cancer is selected from cardiac tumors. In a specific implementation, the cardiac tumor is selected from malignant teratoma, lymphoma, rhabdomyosarcoma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma.

[0145] In a specific implementation, the cell proliferation disorder is selected from: benign papilloma, benign neoplasm, and gestational trophoblastic disease. In a specific implementation, the benign neoplasm is selected from cutaneous papilloma (wart) and genital papilloma. In a specific implementation, the gestational trophoblastic disease is selected from hydatidiform mole and gestational trophoblastic tumor formation (e.g., invasive nevus, choriocarcinoma, placental trophoblastic tumor, and epithelioid trophoblastic tumor).

[0146] As used herein, the terms “treatment” and “curing” refer to all processes in which the progression of the disease or condition described herein may be slowed, interrupted, halted, controlled, or stopped. These terms do not necessarily mean the complete elimination of all symptoms of the disease or disorder.

[0147] The terms “administer” and / or “give” a compound should be understood to include providing a subject (patient) with the compound described herein or a pharmaceutically acceptable salt thereof, as well as a combination of the aforementioned compounds.

[0148] The amount of the compound administered to the subject is sufficient to induce an immune response and / or induce STING-dependent type I interferon production in the subject. In one embodiment, the amount of the compound may be an “effective amount” or a “therapeutic effective amount”, such that the subject compound is administered in an amount that elicits a biological or medical (i.e., intended to treat) response in the tissue, system, animal, or human being sought by the researcher, veterinarian, physician, or other clinician. An effective amount does not necessarily include toxicity and safety considerations related to the administration of the compound.

[0149] The effective amount of the compound will vary depending on the specific compound selected (e.g., taking into account the compound’s potency, efficacy and / or half-life); the route of administration selected; the condition being treated; the severity of the disease being treated; the age, body type, weight and physical condition of the subject being treated; the subject’s medical history; the duration of treatment; the nature of the same therapy; the expected therapeutic effect; and similar factors, and may be conventionally determined by those skilled in the art to which this invention pertains.

[0150] As used herein, the term “subject” (also referred to herein as “patient”) means an animal, preferably a mammal, and most preferably a human, that has become the subject of treatment, observation or experimentation.

[0151] As used herein, the term "immune response" refers to any one or more of the following: specific immune response, nonspecific immune response, specific and nonspecific reaction, innate reaction, primary immune response, adaptive immunity, secondary immune response, memory immune response, immune cell activation, immune cell proliferation, immune cell differentiation, and cytokine expression. In some embodiments, compounds of formula I, II, III, IV, or V, or pharmaceutically acceptable salts thereof, are administered together with one or more additional therapeutic agents, including antiviral compounds, vaccines designed to stimulate an immune response to one or more predetermined antigens, adjuvants, CTLA-4 and PD-1 pathway antagonists and other immunomodulators, lipids, liposomes, peptides, anticancer agents, and chemotherapeutic agents, etc.

[0152] Unless otherwise stated, the term "halogen" in this invention refers to fluorine, chlorine, bromine, or iodine. Preferably, halogens include fluorine, chlorine, and bromine. The terms "halogenated C1-6 alkyl," "halogenated C2-6 alkenyl," "halogenated C2-6 alkynyl," and "halogenated C1-6 alkoxy" mean that one or more (especially 1, 2, or 3) hydrogen atoms are substituted by halogen atoms, particularly fluorine or chlorine atoms. In some embodiments, fluorinated C1-6 alkyl, fluorinated C2-6 alkenyl, fluorinated C2-6 alkynyl, and fluorinated C1-6 alkoxy are preferred, particularly fluorinated C1-3 alkyl, such as CF3, CHF2, CH2F, CH2CH2F, CH2CHF2, CH2CF3; fluorinated C1-3 alkoxy, such as OCF3, OCHF2, OCH2F, OCH2CH2F, OCH2CHF2, or OCH2CF3; particularly CF3, OCF3, and OCHF2.

[0153] Unless otherwise stated, alkyl groups in this invention include saturated monovalent hydrocarbon groups having straight-chain, branched, or cyclic moieties. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, dibutyl, tributyl, cyclobutyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, and cyclohexyl. Similarly, C1-8 alkyl groups in this invention are defined as groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms arranged in a straight-chain or branched manner.

[0154] An alkylene group is a bifunctional group obtained by removing a hydrogen atom from an alkyl group as defined above. For example, methylene (i.e., -CH2-), ethylene (i.e., -CH2-CH2- or -CH(CH3)-) and propylene (i.e., -CH2-CH2-CH2-, -CH(-CH2-CH3)- or -CH2-CH(CH3)-).

[0155] As used herein, the term "alkenyl" refers to a monovalent, straight-chain or branched unsaturated aliphatic hydrocarbon group having a number of carbon atoms within a specific range and including one or more double bonds.

[0156] As used herein, the term “alkenyl” refers to a divalent straight-chain unsaturated aliphatic hydrocarbon group having a number of carbon atoms within a specific range and including one or more double bonds.

[0157] As used herein, the term "alkynyl" refers to a monovalent straight-chain or branched unsaturated aliphatic hydrocarbon group having a number of carbon atoms within a specific range and including one or more triple bonds.

[0158] As used herein, the term “acetylenic” refers to a divalent straight-chain unsaturated aliphatic hydrocarbon group having a number of carbon atoms within a specific range and including one or more triple bonds.

[0159] As used herein, the term "alkoxy" as used herein, alone or in combination, includes alkyl groups bonded to an oxygen atom. The term "alkoxy" also includes alkyl ether groups, wherein the term "alkyl" is as defined above, and "ether" means having an oxygen atom between two alkyl groups. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, dibutoxy, tributoxy, methoxymethane (also known as "dimethyl ether"), and methoxyethane (also known as "ethyl methyl ether").

[0160] As used herein, unless otherwise stated, the term "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon, either on its own or as part of another substituent. Preferred aryl groups are 6-10 membered aromatic ring systems, either monocyclic or bicyclic. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl group is phenyl.

[0161] Unless otherwise stated, the term "heterocycle" or "heterocyclic group" as used herein, either alone or as part of another substituent, refers to an unsubstituted or substituted monocyclic or polycyclic non-aromatic, partially unsaturated or fully saturated ring system containing one or more heteroatoms. Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides. Preferably, the ring is tri- to octetary and fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution are included in this definition, preferably one, two, or three.

[0162] Examples of such heterocyclic groups include, but are not limited to, azirrocyclobutane, pyrrolithyl, pyryl, piperyl, oxopiperyl, oxopyryl, oxazirrocycloheptyl, azirrocycloheptyl, tetrahydrofuranyl, dioxopeptyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydroazolyl, tetrahydropyranyl, mofoolinyl, thiomofoolinyl, thiomofoolinylene, oxazolyl or oxazirrocyclohexyl.

[0163] Unless otherwise stated, the term "heteroaryl" as used herein, either on its own or as part of another substituent, refers to an aromatic ring system containing carbon and at least one heteroatom. Heteroaryls can be monocyclic or polycyclic, substituted or unsubstituted. Monocyclic heteroaryls can have 1 to 4 heteroatoms in the ring, while polycyclic heteroaryls can contain 1 to 10 heteroatoms. Polycyclic heteroaryl rings can contain fused spirocyclic or bridged rings; for example, cyclic heteroaryls are polycyclic heteroaryls. Bicyclic heteroaryl rings can contain 8 to 12 member atoms. Monocyclic heteroaryl rings can contain 5 to 8 member atoms (number of carbon atoms and heteroatoms). Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrroleyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, tadalyl, indolyl, azaindolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benziisoazolyl, benzozizolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenyl, quinolinyl, or isoquinolinyl.

[0164] The term "carbocyclic ring" refers to a non-aromatic ring system containing only carbon atoms, whether substituted or unsubstituted, including monocyclic, bicyclic, bridged, fused, and spirocyclic rings. Exemplary "carbocyclic" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0165] Unless otherwise stated, the term “cycloalkyl” as used herein, either on its own or as part of another substituent, refers to a substituted or unsubstituted monocyclic, bicyclic, or polycyclic non-aromatic saturated or partially unsubstituted hydrocarbon group, which optionally includes an alkylene linker that may be linked through its cycloalkyl group. Exemplary “cycloalkyl” groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0166] The terms “carbonyl”, “-C=O”, “C=O”, “-CO”, “-C(O)” and “CO” refer to a group.

[0167] The term “oxo” refers to the group =O.

[0168] Whenever the term “alkyl” or “aryl” or any of its prefix roots appears in the name of a substituent (e.g., aralkyl or dialkylamino), unless otherwise stated, it shall be interpreted, either on its own or as part of another substituent, to include the limitations of “alkyl” and “aryl” given above. The specified number of carbon atoms (e.g., C1-6) shall independently refer to the number of carbon atoms in the alkyl portion or in the alkyl portion of the larger substituent in which the alkyl is a prefix root.

[0169] As used herein, the term “fused ring” refers to a cyclic group formed by a substituent on a single atom of a straight-chain or branched alkane, or a cyclic group formed by a substituent on a single atom of another ring.

[0170] As used herein, the term “spirocycle” or “helical ring” refers to a side ring group formed by a substituent on a single atom.

[0171] Unless otherwise stated, the term “cyclic system” as used herein includes, but is not limited to, carbocyclic, heterocyclic, heteroaromatic, etc., and may include only heterocyclic and / or heteroaromatic rings, and specifically includes which rings need to be determined as the context requires, but in any event “cyclic system” does not include cycloalkyl based on C1-6 alkyl or C1-3 alkyl groups, nor does it include cycloalkoxy based on C1-6 alkoxy or C1-3 alkoxy groups.

[0172] Unless otherwise expressly stated, all ranges referenced herein are inclusive; that is, including the upper and lower limits of the range and all values ​​in between. As an example, temperature ranges, percentages, equivalent ranges, and the like as described herein include the upper and lower limits of the range and any values ​​within a continuous range therebetween. The numerical values ​​provided herein and the use of the term “about” may include changes of ±1%, ±2%, ±3%, ±4%, ±5%, ±10%, ±15%, and ±20% and their numerical equivalents.

[0173] As used herein, the term “one or more” includes a single item selected from a list as well as a combination of two or more items selected from a list.

[0174] The term “substituted” means that one or more (preferably 1-6, more preferably 1-3) hydrogen atoms in a group are substituted by the same or different substituents. Representative substituents include, but are not limited to, X, Cl-6 alkyl, Cl-6 alkoxy, C3-20 cycloalkyl, -OR13, SR13, =O, =S, -C(O)R13, ​​-C(S)R13, ​​=NR13, -C(O)OR13, -C(S)OR13, -NR13R14, -C(O)NR13R14, cyano, nitro, -S(O)2R13, -OS(O2)OR13, -OS(O)2R13 or -OP(O)(OR13)(OR14); wherein any X is an independent halogen (F, Cl, Br or I), and R13 and R14 are independently selected from hydrogen, lower alkyl or lower haloalkyl. Preferred substituents are: –F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tributoxy, -SCH3, -SC2H5, formaldehyde, -C(OCH3), cyano, nitro, CF3, -OCF3, amino, dimethylamino, methylthio, sulfonylurea, or acetylurea. Particularly preferred substituents are -F, -Cl, or -Br.

[0175] The substituents of the two “W” in formula I, II, III, IV or V may be the same or different. Similarly, the “R1”, “X1”, “X2” or “X3” in formula I, II, III, IV or V may be the same or different.

[0176] The compounds described herein may exist in isotopically labeled or enriched form, containing one or more atoms whose atomic mass or mass number differs from the most abundant atomic mass or mass number in nature. The isotopes may be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to, 2H, 3H, 13C, 14C, 15N, 18O, 32P, 35S, 18F, 36Cl, and 125I. Compounds containing other isotopes of these and / or other atoms are within the scope of this invention. In some embodiments, one or more hydrogen atoms of any compound described herein may be substituted with deuterium to provide a corresponding labeled or enriched compound.

[0177] The compounds represented by general formulas I, II, III, IV, or V may have different isomers. For example, any asymmetric carbon atom may be present in (R)-, (S)-, or (R, S)- configurations, preferably in (R)- or (S)- configurations. Double bonds, especially substituents on the ring, may be present in cis (=Z-) or trans (=E-) forms. Thus, these compounds may exist as mixtures of isomers or preferably as pure isomers, preferably as pure diastereomers or pure enantiomers.

[0178] When the plural form (e.g., compound, salt) is used, it includes the singular (e.g., single compound, single salt). “Compound” does not exclude (e.g., in pharmaceutical preparations) the presence of more than one compound of general formula I, II, III, IV or V (or salts thereof), and “a” represents only the indefinite article. Therefore, “A” can preferably be understood as “one or more” and should not be understood as “one”.

[0179] In this invention, the term "composition" refers to a product containing a specific amount of a specific ingredient, and also includes any product composed directly or indirectly of a specific amount of a specific ingredient. Therefore, pharmaceutical compositions using compounds of this invention as active ingredients, as well as methods for preparing compounds of this invention, are also part of this invention. Furthermore, some crystalline forms of the compounds of this invention may exist in polymorphic form and are included in this invention. Additionally, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of this invention.

[0180] The compounds of the present invention may also exist in the form of pharmaceutically acceptable salts. For pharmaceutical use, the salts of the compounds of the present invention refer to non-toxic "pharmaceutically acceptable salts". Pharmaceutically acceptable salts include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Pharmaceutically acceptable acidic / anionic salts generally take the form in which the basic nitrogen is protonated by an inorganic or organic acid, representative organic or inorganic acids including but not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, hydroxyethanesulfonic acid, oxalic acid, dihydroxynaphthyl acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexaneaminosulfonic acid, salicylic acid, saccharin, or trifluoroacetic acid. Pharmaceutically acceptable basic / cationic salts include, but are not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium, and zinc.

[0181] Prodrugs containing the compounds of this invention are also included within the scope of protection of this invention. Typically, such prodrugs are functional derivatives of the compounds of this invention that are readily converted in vivo into the desired compound. Therefore, in the treatment methods of this invention, the term "administering" will include both the specifically disclosed compounds of this invention and compounds that may not be specifically disclosed, but which, upon administration to a patient, can be converted in vivo into a specific compound for the treatment of various conditions or discomforts. Conventional methods for selecting and preparing suitable prodrugs are widely described, for example, in *Prodrug Design*, edited by H. Bundgaard and Elsevier, published in 1985.

[0182] In this invention, the definition of any substituent or variable at a specific position is independent of the definition of the substituent or variable at other positions in the molecule. It should be understood that the substituents and substitution forms on the compounds of this invention can be selected by those skilled in the art to which this invention pertains, in order to provide chemically stable compounds that can be readily synthesized using techniques known in the art and the methods set forth herein.

[0183] The compounds described herein, such as certain compounds of formulas I, II, III, IV, or V, may contain asymmetrically substituted carbon atoms (or chiral centers) in the R or S configuration. This invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.

[0184] When the compounds described herein are specifically designated as R- or S-isomers in their chemical names or figures, they should be understood as enriched R- or S-isomers, respectively. For example, in any embodiment described herein, such enriched R- or S-designated isomers may be substantially free of (e.g., having less than 5%, less than 1%, or undetectable, as determined by chiral HPLC) another isomer as its respective chiral center. Enriched R- or S-isomers may be prepared by methods exemplified in this application, such as by using a chiral adjuvant such as R- or S-tert-butylsulfinamide during synthesis. Other methods for preparing enriched R- or S-isomers herein include, but are not limited to, chiral HPLC purification of stereoisomer mixtures, such as racemic mixtures. General methods for separating stereoisomers (e.g., enantiomers and / or diastereomers) using HPLC are known in the art.

[0185] The compounds included in this invention may contain one or more asymmetric centers and thus possibly diastereomers and optical isomers. This invention includes all those possible diastereomers and their racemic mixtures, their substantially pure and separable enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.

[0186] Formulas I, II, or III above do not represent stereochemistry defined at a specific position. This invention includes all stereoisomers of formulas I, II, III, IV, or V and their pharmaceutically acceptable salts. Furthermore, it includes mixtures of stereoisomers and isolated, definitive stereoisomers. In synthetic methods used to prepare these compounds, or in the use of racemic or epimerization methods known to those skilled in the art to which this invention pertains, the products of these methods may be mixtures of stereoisomers.

[0187] Unless otherwise specified, when compounds of formula I, II, III, IV or V are present in tautomers, the present invention includes any possible tautomers and their pharmaceutically acceptable salts, as well as mixtures thereof.

[0188] This invention includes any possible solvates and polymorphs when compounds of formulas I, II, III, IV, or V and their pharmaceutically acceptable salts are present in the form of solvates or polymorphs. The type of solvent forming the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone, etc., can be used.

[0189] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable, non-toxic base or acid. When the compounds of the present invention are acidic, their corresponding salts can be readily prepared from pharmaceutically acceptable, non-toxic bases (including inorganic and organic bases). When the compounds of the present invention are basic, their corresponding salts can be readily prepared from pharmaceutically acceptable, non-toxic acids (including inorganic and organic acids). Since the compounds of formulas I, II, III, IV, or VI are intended for pharmaceutical use, they are preferably provided in substantially pure form, for example, at least 60% pure, more preferably at least 75% pure, and particularly at least 98% pure (% by weight).

[0190] The pharmaceutical compositions of the present invention comprise, as an active ingredient, a compound represented by formula I, II, III, IV or V (or a pharmaceutically acceptable salt thereof), a pharmaceutically acceptable carrier, and optionally other therapeutic components or adjuvants. Although the most suitable route in any given case depends on the specific subject and the nature and severity of its condition (to which the active ingredient is administered), the compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration. The pharmaceutical compositions can be conveniently present in unit dose form and can be prepared by any method known in the pharmaceutical field.

[0191] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable, non-toxic base or acid. When the compounds of the present invention are acidic, their corresponding salts can be readily prepared from pharmaceutically acceptable, non-toxic bases (including inorganic and organic bases). When the compounds of the present invention are basic, their corresponding salts can be readily prepared from pharmaceutically acceptable, non-toxic acids (including inorganic and organic acids). Since the compounds of formula I, II, or III are intended for pharmaceutical use, they are preferably provided in substantially pure form, for example, at least 60% pure, more preferably at least 75% pure, and particularly at least 98% pure (% by weight).

[0192] The pharmaceutical compositions of the present invention comprise, as an active ingredient, a compound represented by formula I, II, III, IV or V (or a pharmaceutically acceptable salt thereof), a pharmaceutically acceptable carrier, and optionally other therapeutic components or adjuvants. Although the most suitable route in any given case depends on the specific subject and the nature and severity of its condition (to which the active ingredient is administered), the compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration. The pharmaceutical compositions can be readily available in unit dose form and can be prepared by any method known in the pharmaceutical field.

[0193] In practice, according to conventional pharmaceutical mixing techniques, compounds of formula I, II, III, IV, or V, or their prodrugs or metabolites, or their pharmaceutically acceptable salts, which are active ingredients of the present invention, can be combined with a pharmaceutical carrier in an intimate admixture. Depending on the desired formulation for administration, such as oral or parenteral (including intravenous) administration, the carrier can take various forms. Therefore, the pharmaceutical compositions of the present invention can be provided as separate units suitable for oral administration, such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the compositions can be in the form of powders, granules, solutions, suspensions in aqueous liquids, non-aqueous liquids, oil-in-water emulsions, or water-in-oil emulsions. In addition to the commonly used dosage forms described above, compounds of formula I, II, III, IV, or V, or their pharmaceutically acceptable salts, can also be administered via controlled-release devices and / or delivery devices. The compositions can be prepared by any pharmaceutical method. Typically, these methods involve the step of combining the active ingredient with a carrier containing one or more essential ingredients. Typically, the composition is prepared by uniformly and intimately admixing the active ingredient with a liquid carrier or a finely chopped solid carrier, or both. The product can then be conveniently shaped into the desired form.

[0194] Therefore, the pharmaceutical compositions of the present invention may include a pharmaceutically acceptable carrier and a compound of formula I, II, III, IV or V, or a pharmaceutically acceptable salt thereof. A compound of formula I, II or III, or a pharmaceutically acceptable salt thereof, may also be included in the pharmaceutical composition in combination with one or more other therapeutically active compounds.

[0195] The additional active agent may be one or more agents selected from the group consisting of: STING agonist compounds, antiviral compounds, antigens, adjuvants, anticancer agents, agents of CTLA-4, LAG-3 and PD-1 pathway antagonists, lipids, liposomes, peptides, cytotoxic agents, chemotherapeutic agents, immunomodulatory cell lines, checkpoint inhibitors, vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, smoothing inhibitors, alkylating agents, antitumor antibiotics, antimetabolites, retinoic acid, and immunomodulators (including but not limited to anticancer vaccines). It should be understood that such additional active agents may be provided as pharmaceutically acceptable salts. It should be understood that the descriptions of the other active agents above may overlap. It should also be understood that the treatment combination will be optimized, and it should be understood that the optimal combination of compounds of general formula I, II, III, IV or V or the aforementioned pharmaceutically acceptable salts and one or more additional active agents will be determined based on the individual needs of the patient.

[0196] The compounds disclosed herein can be used in combination with one or more other active agents, including but not limited to other anticancer agents for the prevention, treatment, control, improvement, or reduction of the risk of a specific disease or condition (e.g., proliferative disorders). In one embodiment, the compounds disclosed herein are combined with one or more other anticancer agents for the prevention, treatment, control, improvement, or reduction of the risk of a specific disease or condition to which the compounds disclosed herein are useful. Such other active agents may be administered simultaneously or sequentially with the compounds disclosed herein via their usual routes and dosages.

[0197] The drug carrier used may be solid, liquid, or gaseous. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. Any convenient drug medium may be used when preparing compositions for oral dosage forms. For example, water, ethylene glycol, oil, alcohol, flavoring agents, preservatives, coloring agents, etc., may be used to form oral liquid dosage forms (e.g., suspensions, elixirs, and solutions); while carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc., may be used to form oral solid dosage forms (e.g., powders, capsules, and tablets). Tablets and capsules are preferred oral dosage units due to ease of administration, thus using solid drug carriers. Optionally, tablets may be coated using standard aqueous or non-aqueous techniques.

[0198] Tablets containing the compositions of the present invention can be prepared by compression or molding, optionally together with one or more excipients or adjuvants. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine. Each tablet preferably contains about 0.05 mg to about 5 g of the active ingredient, and each capsule or pouch preferably contains about 0.05 mg to about 5 g of the active ingredient. For example, formulations intended for oral administration to humans may contain about 0.5 mg to about 5 g of the active agent, mixed with a suitable and convenient amount of carrier material, which may vary between about 5% and about 95% of the total composition. Unit dosage forms typically contain between about 1 mg and about 2 g of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

[0199] The pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compound in water. Suitable surfactants may include, for example, hydroxypropyl cellulose. The dispersion can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. In addition, preservatives may be included to prevent harmful microbial growth.

[0200] The pharmaceutical compositions of the present invention suitable for injection comprise sterile aqueous solutions or dispersions. Furthermore, the compositions may be in the form of sterile powders for the provisional preparation of such sterile injectable solutions or dispersions. In all cases, the final injection must be sterile and must be an effective liquid for easy injection. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; therefore, contamination by microorganisms such as bacteria and fungi is preferably prevented. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0201] The pharmaceutical compositions of the present invention may be in forms suitable for topical use, such as aerosols, creams, ointments, lotions, dusting powders, etc. Furthermore, the compositions may be in forms suitable for use in transdermal devices. These formulations can be prepared using compounds of formulas I, II, III, IV, or V of the present invention, or pharmaceutically acceptable salts thereof, by conventional processing methods. For example, creams or ointments are prepared by mixing a hydrophilic material and water, along with about 5% to about 10% by weight of the said compounds, to produce a cream or ointment with a desired consistency.

[0202] The pharmaceutical composition of the present invention may be in a form suitable for rectal administration and the carrier is solid. Preferably, the mixture forms a unit-dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppository can be conveniently formed by first mixing the composition with a softened or melted carrier, and then cooling and molding it in a mold.

[0203] In addition to the carrier components described above, the pharmaceutical formulations may, as appropriate, include one or more other carrier components, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. Furthermore, other adjuvants may be included to make the formulation isotonic with the blood of the target receptor. Compositions containing compounds described by formulas I, II, III, IV, or V, or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.

[0204] Generally, the above-mentioned conditions can be treated at a dose level of about 0.01 mg / kg body weight to about 150 mg / kg body weight per day, or optionally at a dose level of about 0.5 mg to about 7 g per patient per day. For example, inflammation, cancer, psoriasis, allergic reactions / asthma, diseases and conditions of the immune system, and diseases and conditions of the central nervous system (CNS) can be effectively treated by administering a compound at a dose of about 0.01 to 50 mg per kilogram body weight per day, or a compound at a dose of about 0.5 mg to about 3.5 g per patient per day.

[0205] However, it should be understood that the specific dose level for any particular patient will depend on a variety of factors, including age, weight, general health condition, sex, diet, time of administration, route of administration, excretion rate, drug combination, and the severity of the specific disease being treated.

[0206] These and other aspects will become clear from the following written description of the invention.

Implementation Method

[0208] The following examples are provided to better understand the present invention. Unless otherwise expressly stated, all parts and percentages are by weight, and all temperatures are in degrees Celsius.

[0209] The compounds described in this invention can be prepared in various ways based on the guidance provided herein and synthetic methods known in the art. In the following description of the synthetic methods, it should be understood that, unless otherwise stated, reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental time, and checking procedures, can all be selected as standard conditions for the reaction. Those skilled in the art of organic synthesis will understand that the function of each part of a molecule should be compatible with the reagents used and the reaction. Substituents incompatible with the reaction conditions will be obvious to those skilled in the art to which this invention pertains, and therefore alternative methods are indicated. The starting materials of the examples are commercially available or can be prepared from known materials using standard methods.

[0210] The embodiments provided herein help to provide a more complete understanding of the invention. The following embodiments are used to illustrate examples of the preparation and implementation of the subject matter of the invention. However, the scope of the invention should not be construed as limited to the specific illustrative embodiments disclosed in these embodiments. Although specific embodiments have been described herein, those skilled in the art will understand that various changes and modifications can be made without departing from the spirit and scope of this document.

[0211] The following abbreviations are used in the following reaction schemes and synthetic examples. This list is not intended to be a complete list of abbreviations used in this application, and these abbreviations are easily understood by those skilled in the art of organic synthesis and can also be used in synthetic schemes and examples. NBS N-bromobutyldiimide EA Ethyl acetate ACN Acetonitrile THF Tetrahydrofuran DCM dichloromethane DMF dimethylformamide TFA Trifluoroacetic acid TEA Triethylamine LDA Diisopropylaminolithium OXONE Potassium persulfate FA Formic acid DIEA N,N-Diisopropylethylamine Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloro CDI N,N-carbonyldiimidazole RockPhos Palladacycle Gen. 3 Methanesulfonate-(2-(di-tert-butylphosphine)-3-methoxy-6-methyl,2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) MeOH methanol EtOH ethanol INT intermediate h Hours (s) aq Aqueous solution sat saturated TLC Thin-layer chromatography Pre-TLC Preparative Thin Layer Chromatography Prep - HPLC Preparative high performance liquid chromatography

[0212] Intermediate

[0213] Intermediate A1: Ethyl 4-(5-hydroxy-6-methoxybenzothiophene-2-yl)-4-oxobutyrate Step a: At 0°C, bromomethyl methyl ether (3.15 g, 25.2073 mmol) was added to a solution of DIEA (4.10 g, 46.5111 mmol) and 2-bromoisovanillin (4.98 g, 21.5544 mmol) in dichloromethane (200 mL). The reaction mixture was stirred at 20°C for 2 hours. The resulting solution was quenched with water (10 mL) and washed with water (100 mL) and brine (100 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. 2-Bromo-4-methoxy-5-(methoxymethoxy)benzaldehyde (5.83 g, 21.1926 mmol, 98.3216% yield) was given as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 7.51 (s, 1H), 7.39 (s, 1H), 5.25 (s, 2H), 3.93 (s, 3H), 3.38 (d, J = 9.3 Hz, 3H). Step b: Methyl mercaptoacetate (2.30 g, 21.6688 mmol) was added at 20°C to a solution of 2-bromo-4-methoxy-5-(methoxymethoxy)benzaldehyde (5.83 g, 21.1926 mmol) and Cs₂CO₃ (13.99 g, 42.9380 mmol) in N,N-dimethylformamide (100 mL). The reaction mixture was heated to 50°C and stirred for 16 hours. The reaction mixture was cooled to 20°C, methyl iodine (1.81 g, 12.7520 mmol) was added, and the mixture was stirred at 20°C for 2 hours. The reaction mixture was diluted with EA (500 mL) and washed with water (2 x 100 mL) and brine (100 mL). The organic matter was evaporated under reduced pressure. The residue was purified by EA / hept (0–50%) on a silica gel column, concentrated, and dried under vacuum. Methyl 6-methoxy-5-(methoxymethoxy)benzothiophene-2-carboxylic acid was given as a yellow solid (2.98 g, 10.5557 mmol, 49.8084% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.66 (s, 1H), 7.63 (s, 1H), 5.23 (s, 2H), 3.87 (d, J = 9.2 Hz, 6H), 3.42 (s, 3H).Step c: LiOH (0.37 g, 15.4499 mmol) was added at 20 °C to a solution of methyl 6-methoxy-5-(methoxymethoxy)benzothiophene-2-carboxylic acid (2.98 g, 10.5557 mmol) in tetrahydrofuran (100 mL) and water (25 mL). The reaction mixture was heated to 50 °C and stirred for 2 hours. The mixture was evaporated under reduced pressure, diluted with water, and the pH was adjusted to 5 with HCl (1 M). The precipitate was filtered off. The filter cake was washed with water (20 mL). 6-methoxy-5-(methoxymethoxy)benzothiophene-2-carboxylic acid (2.41 g, 8.9830 mmol, 85.1008% yield) was given as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 13.22 (s, 1H), 7.93 (s, 1H), 7.62 (d, J = 10.5 Hz, 2H), 5.24 (d, J = 14.6 Hz, 2H), 3.87 (s, 3H), 3.52 – 3.35 (m, 3H). Step d: At 20 °C, 1,1'-carbonyldiimidazole (2.84 g, 17.5148 mmol) was added to a stirred solution of 6-methoxy-5-(methoxymethoxy)benzothiophene-2-carboxylic acid (2.41 g, 8.9830 mmol) in N,N-dimethylformamide (20 mL). The resulting mixture was stirred at 20 °C for 1 hour under nitrogen atmosphere. Add tert-butyl malonate and magnesium chloride (1.31 g, 13.7589 mmol) to the above mixture and stir at 20°C for 16 hours. Concentrate the reaction mixture and dilute with EA (500 mL), wash with NaHCO3aq (2 x 300 mL) and brine (200 mL). Dry the organic phase with Na2SO4, filter, and evaporate under reduced pressure. Purify the residue as EA / PE (0-80%) on a silica gel column, concentrate, and dry under vacuum. Give a yellow oil of tert-butyl 3-[6-methoxy-5-(methoxymethoxy)benzothiophene-2-yl]-3-oxo-propionic acid (2.63 g, 7.1774 mmol, 79.9000% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.67 (s, 1H), 7.62 (s, 1H), 5.24 (s, 2H), 4.03 (d, J = 9.8 Hz, 2H), 3.89 (s, 3H), 3.42 (s, 3H), 1.41 (s, 9H).Step e: At 20 °C, potassium carbonate (2.0621 g, 14.9207 mmol) and ethyl bromoacetate (1.3648 g, 8.1724 mmol) were added to a solution of tert-butyl 3-[6-methoxy-5-(methoxymethoxy)benzothiophene-2-yl]-3-oxo-propionate (2.62 g, 7.1501 mmol) in N,N-dimethylformamide (20 mL). The resulting mixture was stirred at room temperature under nitrogen for 3 h. The reaction mixture was concentrated and diluted with EA (200 mL), and washed with water (100 mL) and brine (50 mL). The organic matter was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by EA / PE (0–80%) on a silica gel column, concentrated, and dried under vacuum. O1-tert-butylO4-ethyl 2-[6-methoxy-5-(methoxymethoxy)benzothiophene-2-carbonyl]succinate (2.82 g, 6.2318 mmol, 87.1569% yield) was obtained as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.67 (s, 2H), 5.31 – 5.20 (m, 2H), 4.79 (t, J = 7.3 Hz, 1H), 4.15 – 3.96 (m, 2H), 3.89 (d, J = 6.7 Hz, 3H), 3.42 (d, J = 4.2 Hz, 3H), 3.32 (s, 3H), 2.98 – 2.81 (m, 2H), 1.31 (s, 9H). Step f: Add TFA (5 mL) to a solution of O1-tert-butylO4-ethyl 2-[6-methoxy-5-(methoxymethoxy)benzothiophene-2-carbonyl]succinate (2.82 g, 6.2318 mmol) in toluene (25 mL) at 20 °C. Heat the reaction mixture to 50 °C and stir for 30 min. Evaporate under reduced pressure, concentrate, and dilute with EA (200 mL), washing with water (100 mL) and brine (50 mL). Dry the organic phase with Na2SO4, filter, and evaporate under reduced pressure. Purify the residue on a silica gel column using EA / heptane (0-100%), concentrate, and dry under vacuum to give the crude product. Purify the residue on a silica gel column using MeCN / water (0-100%), concentrate, and dry under vacuum. Ethyl 4-(5-hydroxy-6-methoxybenzothiophene-2-yl)-4-oxo-butyrate was obtained (0.79 g, 2.5620 mmol, 41.1122% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.17 (s, 1H), 7.54 (s, 1H), 7.32 (s, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 3.31 – 3.26 (m, 2H), 2.65 (t, J = 6.3 Hz, 2H), 1.27 – 1.05 (m, 3H)。

[0214] Intermediate A2: Methyl 4-(5-chloro-6-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutyrate Step a: To a solution of 6-bromothieno[3,2-b]pyridine (30.0 g, 140.1 mmol) in DMF (300 mL), a solution of 25% MeONa (605.6 g, 2802.6 mmol) in MeOH and CuI (26.7 g, 140.1 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 2 hours. The reaction mixture was then cooled to room temperature, poured into ice water (900 mL), and filtered. It was diluted with NH3·H2O (300 mL), extracted with EtOAc (1.0 L x 2), and washed with brine (1.0 L). The organic phase was dried over Na₂SO₄, filtered, and the filtrate was concentrated to give 19.0 g (82.3%) of 6-methoxythieno[3,2-b]pyridine as a yellow solid, which could be used in the next step without further purification. ¹H NMR (300 MHz, CDCl₃): δ 8.43 (d, J = 2.7 Hz, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.53–7.51 (m, 1H), 7.47–7.45 (m, 1H), 3.91 (s, 3H). LCMS (ESI, m / z): [M+H]⁺ = 166.2. Step b: Add m-CPBA (19.8 g, 115.0 mmol) to a DCM (200 mL) solution of 6-methoxythieno[3,2-b]pyridine (19.0 g, 115.0 mmol). Stir the reaction mixture at room temperature for 16 hours. Then dilute the reaction mixture with DCM / MeOH = 10:1 (300 mL) and wash with saturated sodium bicarbonate solution (300 mL x 2) and brine (300 mL). Dry the organic phase with Na2SO4, filter, and concentrate the filtrate to give 6-methoxythieno[3,2-b]pyridine 4-oxide (13.0 g, 57.7%) as a yellow solid, which can be used in the next step without further purification. 1H NMR (300 MHz, CDCl3): δ 8.14 (d, J = 2.1 Hz, 1H), 7.74 (dd, J = 5.7 Hz, 0.6 Hz, 1H), 7.48-7.46 (m, 1H), 7.31-7.30 (m, 1H), 3.91 (s, 3H). LCMS: (ESI, m / z): [M+H]+= 182.0.Step c: 15.5 g (85.5 mmol) of 6-methoxythieno[3,2-b]pyridine 4-oxide was added in portions to POCl3 (200 mL) at room temperature. The reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was then cooled to room temperature and concentrated. The residue was diluted with water (200 mL), adjusted to pH = 8 with saturated sodium bicarbonate solution, and extracted with DCM (300 mL x 2). The organic phase was washed with brine (200 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to obtain the residue, which was purified by silica gel column chromatography (eluting with petroleum ether / EtOAc = 10:1) to give 5-chloro-6-methoxythieno[3,2-b]pyridine (9.0 g, 52.6%) as a white solid. ¹H NMR (300 MHz, CDCl₃): δ 7.65 (s, ¹H), 7.58–7.56 (m, ¹H), 7.42 (dd, J = 5.7 Hz, 0.6 Hz, ¹H), 3.99 (s, ³H). LCMS: (ESI, m / z): [M+H]⁺ = 200.0. Step d: Under nitrogen atmosphere at -78°C, LDA (2.0 M, 80 mL) was added dropwise to a THF (80 mL) solution of 5-chloro-6-methoxythieno[3,2-b]pyridine (8.0 g, 40.1 mmol). After 15 minutes, a THF (240 mL) solution of dihydrofuran-2,5-dione (22.0 g, 220.4 mmol) was added dropwise to the mixture at -40 °C under nitrogen. The reaction mixture was then heated to room temperature and stirred for 2 hours. The mixture was quenched with 2N HCl (100 mL) and extracted with EtOAc (300 mL × 2). The organic phase was washed with brine (200 mL), dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was pulped with petroleum ether / EtOAc = 1:1 and filtered to give 4-(5-chloro-6-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutyric acid (6.0 g, crude) as a white solid, which was used for the next step without further purification. LCMS: (ESI, m / z): [MH]- = 298.8. Step e: SOCl2 (12.0 g, 100.1 mmol) was added dropwise to a MeOH (120 mL) solution of 4-(5-chloro-6-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutyric acid (6.0 g crude, 20.0 mmol) at 0 °C. The reaction mixture was then heated to room temperature and stirred for 2 hours.The reaction mixture was concentrated, diluted with water (100 mL), adjusted to pH = 8 with saturated sodium bicarbonate solution, and extracted with DCM / MeOH (200 mL x 2). The organic phase was washed with brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated, a white solid precipitated, and filtered to give methyl 4-(5-chloro-6-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutyrate (1.1 g, 8.5%, steps d and e), as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.01 (s, 1H), 7.59 (s, 1H), 4.02 (s, 3H), 3.71 (s, 3H), 3.35 (t, J = 6.8 Hz, 2H), 2.80 (t, J = 6.8 Hz, 2H), LCMS: (ESI, m / z): [M+H]+= 569.20.

[0215] Intermediate A3: Methyl trans-2-(5-bromo-6-methoxybenzo[b]thiophene-2-carbonyl)cyclopropane-1-carboxylic acid Step a: At -10°C, a solution of 5-bromo-6-methoxybenzo[b]thiophene (15.0 g, 61.7 mmol) in DCE (50 mL) was added to a solution of 3-oxabicyclo[3.1.0]hexane-2,4-dione (6.3 g, 56.1 mmol) and AlCl3 (12.3 g, 92.6 mmol). The reaction mixture was heated to 45°C and stirred for 16 hours. The reaction mixture was then poured into ice water (200 mL) and extracted with DCM / MeOH = 10:1 (100 mL x 2). The organic phase was washed with brine (100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to dryness. The residue was ground and filtered with petroleum ether / EtOAc = 1:1 (50 mL) to give cis-2-(5-bromo-6-methoxybenzo[b]thiophene-2-carbonyl)cyclopropane-1-carboxylic acid (3.0 g, yield 15.1%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.32 (s, 1H), 8.26 (s, 1H), 7.80 (s, 1H), 4.05 (s, 3H), 3.01–3.09 (m, 1H), 2.25–2.31 (m, 1H), 1.65–1.68 (m, 1H), 1.58–1.52 (m, 1H). Step b: 50% aq. NaOH (45 mL) was added to a MeOH solution (3.0 g, 8.4 mmol) of cis-2-(5-bromo-6-methoxybenzo[b]thiophene-2-carbonyl)cyclopropane-1-carboxylic acid (3.0 g, 8.4 mmol) at room temperature. The reaction mixture was then heated to 40 °C and stirred for 24 h. After the reaction was complete, the solvent was removed by HPLC analysis. The residue was diluted with water (30 mL) and the pH was adjusted to 2 with 6 N HCl. A white solid was collected by filtration. This solid was dried under vacuum at 50 °C to give trans-2-(5-bromo-6-methoxybenzo[b]thiophene-2-carbonyl)cyclopropane-1-carboxylic acid (2.5 g, 83.3% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.52 (s, 1H), 8.27 (s, 1H), 7.80 (s, 1H), 3.96 (s, 3H), 3.27-3.23 (m, 1H), 2.16-2.11 (m, 1H), 1.54-1.49 (m, 2H).Step c: At room temperature, K₂CO₃ (2.4 g, 17.5 mmol) and MeI (2.0 g, 14.1 mmol) were added to a DMF (25 mL) solution of trans-2-(5-bromo-6-methoxybenzo[b]thiophene-2-carbonyl)cyclopropane-1-carboxylic acid (2.5 g, 7.0 mmol, 1.0 eq). The reaction mixture was stirred for 16 hours. The mixture was then poured into water (50 mL) and extracted with EtOAc (50 mL x 2). The organic phase was washed with water (50 mL x 2) and brine (50 mL x 2), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated to dryness. The residue was ground together with petroleum ether / EtOAc = 5:1 (50 mL) and filtered to give methyl trans-2-(5-bromo-6-methoxybenzo[b]thiophene-2-carbonyl)cyclopropane-1-carboxylic acid (2 g, yield 77.5%) as a yellow solid. LCMS: (ESI, m / z): [M+H]+=368.8, 370.8.1H NMR (400 MHz, CDCl3): δ 8.07 (s, 1H), 7.96 (s, 1H), 7.30 (s, 1H), 3.99 (s, 3H), 3.75 (s, 3H), 3.15–3.11 (m, 1H), 2.45–2.40 (m, 1H), 1.70–1.64 (m, 2H).

[0216] Intermediate A4: Ethyl 4-(4-chloro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutyrate was added in portions to a solution of ethyl 4-(5-hydroxy-6-methoxybenzothiophen-2-yl)-4-oxobutyrate (300 mg, 0.97 mmol) in DMF (6 mL) at room temperature, along with NCS (156 mg, 1.14 mmol). The reaction mixture was stirred for 5 hours. The reaction mixture was then poured into ice water (18 mL). The mixture was filtered and the filter cake was dissolved in EtOAc (20 mL). The organic phase was washed with saturated NaHCO3 solution (15 mL) and brine (10 mL). The sample was dried over Na₂SO₄ and concentrated to obtain a crude product, which was then purified by HPLC to give 4-(4-chloro-5-hydroxy-6-methoxybenzo[b]thiophene-2-ethyl-yl)-4-oxobutyrate (240 mg, 72% yield), as a white solid. ¹H NMR (300 MHz, CDCl₃): δ 8.02 (s, 1H), 7.17 (s, 1H), 6.04 (brs, 1H), 4.20–4.12 (m, 2H), 4.02 (s, 3H), 3.36 (t, J = 8.8 Hz, 2H), 2.79 (t, J = 8.8 Hz, 2H), 1.30–1.20 (m, 3H). LCMS (ESI, m / z): [M+H]⁺ = 342.9.

[0217] Intermediate A5: Ethyl 4-(5-methoxyisoindoline-2-yl)-4-oxobutyrate; Intermediate A6: Ethyl 4-(5-bromo-6-methoxy-isoindoline-2-yl)-4-oxobutyrate; Intermediate A7: Ethyl 4-(5-hydroxy-6-methoxy-isoindoline-2-yl)-4-oxobutyrate; and Intermediate A8: Ethyl 4-(5-(3-bromopropoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate. Step a: Succinic anhydride (4.40 g, 43.9681 mmol) was added in portions to 200 mL of ethanol containing 5-methoxyisoindoline hydrochloride (4.89 g, 26.3399 mmol) and triethylamine (4.73 g, 46.7440 mmol) at 20 °C. In solution, the reaction system was stirred at 20 °C for 1 h. SOCl2 (20 mL) was added to the reaction solution at 0 °C. The reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was evaporated under reduced pressure, diluted with EA (200 mL), and washed with water (100 mL) and brine (50 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure to give ethyl 4-(5-methoxyisoindoline-2-yl)-4-oxobutyrate (17.5 g, 31.5526 mmol, 119.7901% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.28 – 7.21 (m, 1H), 6.94 (s, 0.5H), 6.92 (s, 0.5H), 6.88 (s, 0.5H), 6.86 (s, 0.5H), 4.81 (s, 1H), 4.76 (s, 1H), 4.58 (s, 1H), 4.54 (s, 1H), 4.02 – 3.95 (m, 2H), 3.75 (s, 3H), 2.65 – 2.58 (m, 2H), 2.58 – 2.54 (m, 2H), 1.17 (t, J = 3.5 Hz, 3H). Step b: At 20°C, NBS (10.51 g, 59.0503 mmol) was added to a solution of ethyl 4-(5-methoxyisoindoline-2-yl)-4-oxobutyrate (17.5 g, 31.5526 mmol) in tetrahydrofuran (100 mL) and acetonitrile (100 mL). The reaction mixture was stirred overnight at 20°C. The reaction mixture was evaporated under reduced pressure. The concentrated mixture was diluted with DCM (500 mL) and washed with NaHCO3 aq. (2 x 300 mL) and brine (200 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure.The residue was purified on a silica gel column as MeOH / DCM (0-10%), concentrated, and dried under vacuum to give ethyl 4-(5-bromo-6-methoxy-isoindoline-2-yl)-4-oxobutyrate (7.26 g, 20.3812 mmol, 64.5943% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.58 (s, 0.5H), 7.57 (s, 0.5H), 7.15 (s, 0.5H), 7.12 (s, 0.5H), 4.80 (s, 1H), 4.77 (s, 1H), 4.57 (s, 1H), 4.54 (s, 1H), 4.09 – 4.01 (m, 2H), 3.84 (s, 3H), 2.65 – 2.59 (m, 2H), 2.56 – 2.53 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H). Step c: At 20°C, potassium acetate (3.74 g, 38.1080 mmol) was added to a solution of Pd(dppf)Cl2 (0.72 g, 984.0050 μmol), ethyl 4-(5-bromo-6-methoxy-isoindoline-2-yl)-4-oxobutyrate (3.64 g, 10.2187 mmol), and pinacol diboronate (3.84 g, 15.1218 mmol) in 1,4-dimethyl ether (100 mL). The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated and diluted with DCM (500 mL), washed with NaHCO3 aq. (2 x 300 mL) and brine (200 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column to obtain EA / Hept (0-100%), concentrated, and dried under vacuum to give ethyl 4-(5-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)isoindoline-2-yl)-4-oxobutyrate (2.45 g, 6.0752 mmol, 59.7809% yield), as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.49 (s, 0.5H), 7.48 (s, 0.5H), 6.98 (s, 0.5H), 6.95 (s, 0.5H), 4.83 (s, 1H), 4.74 (s, 1H), 4.60 (s, 1H), 4.53 (s, 1H), 4.09 – 4.01 (m, 2H), 3.74 (t, J = 6.2 Hz, 3H), 2.65 – 2.58 (m, 2H), 2.58 – 2.52 (m, 2H), 1.27 (s, 12H), 1.21 – 1.13 (m, 3H). Step d: Sodium perborate tetrahydrate (1 g, 6.4994 mmol) was added to a solution of ethyl 4-(5-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)isoindoline-2-yl)-4-oxobutyrate (2.45 g, 6.0752 mmol) in tetrahydrofuran (20 mL) and water (20 mL) at 20°C. The reaction mixture was stirred at 20°C for 1 h and evaporated under reduced pressure. The reaction mixture was concentrated and diluted with DCM (500 mL), washed with NaHCO3 aq. (2 x 300 mL) and brine (200 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column as MeOH / DCM (0–10%), concentrated, and dried under vacuum. Ethyl 4-(5-hydroxy-6-methoxy-isoindoline-2-yl)-4-oxo-butyrate (1.37 g, 4.6708 mmol, 76.8818% yield) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 0.5H), 8.96 (s, 0.5H), 6.91 (s, 0.5H), 6.89 (s, 0.5H), 6.73 (s, 0.5H), 6.73 (s, 0.5H), 4.71 (s, 1H), 4.69 (s, 1H), 4.50 (s, 1H), 4.47 (s, 1H), 4.08 – 4.00 (m, 2H), 3.75 (s, 3H), 2.64 – 2.58 (m, 2H), 2.56 – 2.53 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H).Step e: To a solution of ethyl 4-(5-hydroxy-6-methoxy-isoindoline-2-yl)-4-oxo-butyrate (0.72 g, 2.4547 mmol) in N,N-dimethylformamide (10 mL), 1,3-dibromopropane (0.73 g, 3.6159 mmol) and (0.86 g, 6.2226 mmol) were added. The mixture was stirred at 50 °C for 16 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed successively with water (2 × 100 mL) and saturated brine (1 × 100 mL). The organic phase was dried over Na₂SO₄, filtered, and evaporated to give the crude product. The crude product was purified by rapid silica gel chromatography with an elution gradient of 0 to 100% ethyl acetate / heptane. Ethyl 4-(5-(3-bromopropoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.43 g, 1.0379 mmol, 42.2829% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.01 – 6.93 (m, 2H), 4.75 (s, 2H), 4.53 (s, 2H), 4.10 – 4.00 (m, 4H), 3.76 (s, 3H), 3.71 – 3.62 (m, 2H), 2.65 – 2.58 (m, 2H), 2.58 – 2.53 (m, 2H), 2.28 – 2.18 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H).

[0218] Intermediate A9: 3-(5-bromo-4-fluoro-6-methoxy-benzothiophene-2-yl)-3-oxopropionic acid tert-butyl ester Step a: 3-bromo-2-fluoro-4-methoxy-benzaldehyde Titanium tetrachloride (38.06 g, 200.6548 mmol) was added dropwise to a solution of 2-bromo-3-fluoroanisole (10.17 g, 49.6039 mmol) in dichloromethane (250 mL) for 1 hour at 0 °C. The reaction mixture was stirred at 20 °C for 3 hours. The reaction mixture was quenched at 0 °C by adding ice water (200 mL). The reaction mixture was extracted with DCM (2 x 100 mL) and washed with NaHCO3 (1 x 200 mL) and brine (100 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was dried under vacuum at 60 °C. A white solid, 3-bromo-2-fluoro-4-methoxybenzaldehyde (1142 g, 49.0057 mmol, yield 98.7940%), was given. LCMS (ESI, m / z): [M+H]+= 232.954.1H NMR (400 MHz, CDCl3-d) δ 10.24 (s, 1H), 7.87 (t, J = 8.3 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.05 – 3.99 (m, 3H). Step b: (5E)-5-[(3-bromo-2-fluoro-4-methoxy-phenyl)methylene]-2-thiothiazolidin-4-one, at 20°C, potassium acetate (12.67 g, 129.0984 mmol) was added to a solution of 3-bromo-2-fluoro-4-methoxy-benzaldehyde (10.01 g, 42.9551 mmol) and rhodanine (5.72 g, 42.9456 mmol) in acetic acid (100 mL). The reaction mixture was heated to 140°C and stirred overnight. The reaction mixture was added to water (1000 mL) and stirred for 10 minutes. The precipitate was collected by filtration and washed with water (200 mL). The filter cake was dried under vacuum at 60°C. (5E)-5-[(3-bromo-2-fluoro-4-methoxy-phenyl)methylene]-2-thiothiazolidin-4-one (9.21 g, 26.4495 mmol, 61.5748% yield) was given as a yellow solid. LCMS: (ESI, m / z): [M+H]+= 347.909.1H NMR (400 MHz, DMSO-d6) δ 13.87 (s, 1H), 7.68 – 7.32 (m, 2H), 7.16 (d, J = 8.7 Hz, 1H), 3.97 (s, 3H).Step c: At 20°C, add a solution of NaOH (9.15 g, 228.7666 mmol) in water (80 mL) to a solution of (Z)-3-(3-bromo-2-fluoro-4-methoxy-phenyl)-2-sulfonylurea-2-enoic acid (8.03 g, 23.0607 mmol) in water (200 mL). Stir the reaction mixture at 60°C for 1 hour. After the reaction is complete, adjust the pH to 3 with HCl. Filter and collect the precipitate, washing with water (1 x 100 mL). Dry the filter cake under vacuum at 60°C. (Z)-3-(3-bromo-2-fluoro-4-methoxy-phenyl)-2-sulfonylurea-prop-2-enoic acid (7.37 g, 23.9959 mmol, 104.0552% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H]+= 306.936. Step d: Palladium(II) acetate (4.0934 g, 18.2330 mmol) was added to a solution of (Z)-3-(3-bromo-2-fluoro-4-methoxy-phenyl)-2-thioalkyl-prop-2-enoic acid (7 g, 22.7912 mmol) in methyl sulfoxide (50 mL) at 20°C under N2 atmosphere. The reaction mixture was heated to 100°C and stirred for 1 hour. The reaction mixture was purified by MeCN / water (0-100%) on a C-18 column, concentrated, and dried under vacuum. 5-Bromo-4-fluoro-6-methoxy-benzothiophene-2-carboxylic acid (3.9 g, 12.7819 mmol, yield 56.0824%) was given as a yellow solid. LCMS (ESI, m / z): [M+H]+ = 304.921.1H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.70 (s, 1H), 3.97 (s, 3H). Step e: 3-(5-bromo-4-fluoro-6-methoxy-benzothiophene-2-yl)-3-oxo-propionic acid tert-butyl ester was added to a stirred solution of 5-bromo-4-fluoro-6-methoxy-benzothiophene-2-carboxylic acid (3.88 g, 12.7163 mmol) in DMF (50 mL). Carbonyl diimidazole (4.12 g, 25.4088 mmol) was added at 20°C. The resulting mixture was stirred at 20°C for 1 h under nitrogen atmosphere.Magnesium chloride (1.81 g, 19.0104 mmol), tributyl malonate (3.13 g, 19.5421 mmol), and triethylamine (3.91 g, 38.6404 mmol) were added. The reaction mixture was stirred overnight at 20 °C, concentrated, diluted with EA (500 mL), and washed with NaHCO3aq (2 x 500 mL) and brine (100 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography with an elution gradient of 0 to 100% ethyl acetate / heptane, concentrated under vacuum, and dried to give tributyl 3-(5-bromo-4-fluoro-6-methoxy-benzothiophene-2-yl)-3-oxopropionic acid (3.29 g, 8.1585 mmol, 64.1574% yield) as a yellow solid. LCMS: (ESI, m / z): [M+H]+= 402.994.1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 2.2 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 4.16 (s, 2H), 3.97 (d, J = 8.2 Hz, 3H), 1.41 (d, J = 1.6 Hz, 10H).

[0219] Intermediate 10: Tertiary Butyl Ester of 4-Fluoro-5-hydroxy-6-methoxy-isoindoline-2-carboxylic Acid Step a: 4-Fluoro-5-methoxy-isoindoline At 20°C, 10% Pd / C (7.68 g, containing 55% H2O) was added to a solution of 4-fluoro-5-methoxy-2-[(4-methoxyphenyl)methyl]isoindoline (7.18 g, 24.9889 mmol) in THF (70 mL) and MeOH (70 mL). The reaction mixture was stirred overnight at 20°C, filtered, and the filter cake was washed with MeOH (70 mL). The filtrate was evaporated under reduced pressure to give 4-fluoro-5-methoxy-isoindoline (4.88 g, 29.1901 mmol, 100% yield) as a brown oil, which was used directly for the next step. LCMS: (ESI, m / z): [M+H]+ = 168.200. Step b: 4-Fluoroisoindoline-5-ol hydrobromide was prepared by dissolving 4-fluoro-5-methoxy-isoindoline (4.5 g, 26.9171 mmol) in hydrobromic acid (120 mL, 48% aq) at 20°C. The reaction mixture was heated to 100°C and stirred for 6 h, then evaporated under reduced pressure. The residue was treated with n-hexane / EA (1:2). The solid was collected by filtration and dried under reduced pressure. 4-Fluoroisoindoline-5-ol hydrobromide (4.70 g, 20.0799 mmol, 74.60% yield) was given as a brown solid. LCMS: (ESI, m / z): [M+H]+= 154.200.1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.58 (s, 2H), 7.10 – 6.93 (m, 2H), 4.57 (s, 2H), 4.44 (s, 2H). Step c: 4-Fluoro-5-hydroxy-isoindoline-2-carboxylic acid tributyl ester 0°C NaHCO3 (3.43 g, 40.8301 mmol) was added to an 80 mL solution of 4-fluoroisoindoline-5-ol hydrobromide (4.70 g, 20.0799 mmol) in water. After stirring the reaction mixture for 20 minutes, THF (60 mL) was added. A 20 mL solution of THF containing 4.45 g (20.3898 mmol) of tributyl dicarbonate was added dropwise at 0°C. After stirring for 20 min, the mixture was heated to 20°C and stirred for 2 h. The resulting reaction mixture EA (150 mL) was diluted and washed with 150 mL of brine. The organic phase was dried over Na₂SO₄, filtered, and evaporated under reduced pressure.The residue was purified by column chromatography, eluted with ethyl acetate in n-hexane (0-40%), concentrated, and dried under reduced pressure to give 4-fluoro-5-hydroxy-isoindoline-2-carboxylic acid tributyl ester (3.14 g, 12.3979 mmol, 60.78% yield), as a reddish-brown solid. LCMS: (ESI, m / z): [MH]-= 252.000.1H NMR (400 MHz, CDCl3-d) δ 7.00 – 6.93 (m, 1H), 6.93 – 6.83 (m, 1H), 4.72 (s, 2H), 4.64 (s, 2H), 1.54 (s, 9H). Step d: 6-Bromo-4-fluoro-5-hydroxy-isoindoline-2-carboxylic acid tributyl ester. NBS (2.20 g, 12.3607 mmol) was added to a solution of 4-fluoro-5-hydroxy-isoindoline-2-carboxylic acid tributyl ester (3.10 g, 12.2400 mmol) in ACN (40 mL) and THF (20 mL). The reaction mixture was stirred at 20°C for 2.5 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EA / MeOH (200 mL / 10 mL) and washed with H₂O (200 mL). The organic phase was dried over Na₂SO₄, filtered, and evaporated under vacuum. The residue was purified by column chromatography, eluted with DCM (0-5%) in MeOH, concentrated, and dried under reduced pressure to give 6-bromo-4-fluoro-5-hydroxy-isoindoline-2-carboxylic acid tributyl ester (2.70 g, 8.1285 mmol, 66.34% yield), as a white solid. LCMS: (ESI, m / z): [MH]-= 331.950.1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.33 (s, 0.5H), 7.32 (s, 0.5H), 4.58 (s, 1H), 4.55 (s, 1H), 4.52 (s, 1H), 4.50 (s, 1H), 1.45 (s, 9H). Step e: 5-Benoxy-6-bromo-4-fluoro-isoindoline-2-carboxylic acid tributyl ester. K2CO3 (2.20 g, 15.9183 mmol) was added to a DMF (50 mL) solution of 6-bromo-4-fluoro-5-hydroxy-isoindoline-2-carboxylic acid tributyl ester (2.70 g, 8.1285 mmol) at 0°C.After stirring the reaction mixture at 0°C for 0.5 h, BnBr (1.90 g, 11.1089 mmol) was added, and the reaction mixture was stirred at 20°C for 9 h. The mixture was washed with diluted EA (150 mL), water (150 mL), and brine (2 x 150 mL). The organic phase was dried over Na₂SO₄, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography, eluted with ethyl acetate in n-hexane (0-10%), concentrated, and dried under reduced pressure to give 5-benzyloxy-6-bromo-4-fluoro-isoindoline-2-carboxylic acid tributyl ester (3.43 g, 8.1224 mmol, 99.93% yield), as a white semi-solid. LCMS: (ESI, m / z): [M-tBu+ACN]+= 407.050.1H NMR (400 MHz, CDCl3-d) δ 7.54 (d, J = 7.3 Hz, 2H), 7.45 – 7.35 (m, 3H), 7.27 (s, 0.5H), 7.20 (s, 0.5H), 5.13 (s, 2H), 4.70 (s, 1H), 4.65 (s, 2H), 4.62 (s, 1H), 1.54 (s, 9H). Step f: 5-Bentoxy-4-fluoro-6-hydroxy-isoindoline-2-carboxylic acid tributyl ester. Pd(dppf)Cl2 (1.12 g, 1.5307 mmol) was added to a solution of 5-benzyloxy-6-bromo-4-fluoro-isoindoline-2-carboxylic acid tributyl ester (3.30 g, 7.8146 mmol), bis(neopentylglycolic acid) (5.46 g, 24.1716 mmol), and KOAc (2.32 g, 23.6392 mmol) in 1,4-dimethylamine (80 mL). The reaction mixture was heated to 90°C and stirred overnight under nitrogen. The reaction mixture was diluted with EA (100 mL) and filtered through diatomaceous earth; the filtrate was evaporated under reduced pressure. H₂O₂ (88.1974 mmol, 10 mL, 30% aqueous solution) was added at 0°C to a mixture of the residue and NaHCO₃ (11.9038 mmol, 20 mL, 5% aqueous solution) in THF (80 mL). The reaction mixture was stirred at 20°C for 2 h. The resulting reaction mixture was diluted with brine (150 mL) and saturated NaHSO₃ (100 mL), and extracted with EA (200 mL). The organic phase was collected, dried over Na₂SO₄, filtered, and evaporated under reduced pressure.The residue was purified by silica gel column chromatography and eluted with ethyl acetate / n-hexane (0-10%) to give 5-benzyloxy-4-fluoro-6-hydroxy-isoindoline-2-carboxylic acid tributyl ester (1.93 g, 5.3702 mmol, 68.93% yield) as a white solid. LCMS: (ESI, m / z): [MH]-= 358.100. 1H NMR (400 MHz, CDCl3-d) δ 7.46 – 7.36 (m, 5H), 6.62 (s, 0.5H), 6.58 (s, 0.5H), 5.15 (s, 2H), 4.68 (s, 1H), 4.65 (s, 1H), 4.61 (s, 1H), 4.58 (s, 1H), 1.54 (s, 9H). Step g: 5-Benyloxy-4-fluoro-6-methoxy-isoindoline-2-carboxylic acid tributyl ester. K₂CO₃ (1.18 g, 8.5380 mmol) was added to a DMF (25 mL) solution of 5-benzylidene-4-fluoro-6-hydroxy-isoindoline-2-carboxylic acid tributyl ester (1.9 g, 5.2867 mmol). The resulting mixture was stirred at 0°C for 30 min, and then CH₃I (1.12 g, 7.8908 mmol) was added. The reaction mixture was stirred at 20°C for 3 h, and the resulting reaction mixture was diluted with water (200 mL) and extracted with EA (200 mL). The organic phase was separated, washed with brine (2 x 150 mL), collected, dried over Na₂SO₄, filtered, and evaporated under reduced pressure. 5-Benoxy-4-fluoro-6-methoxy-isoindoline-2-carboxylic acid tributyl ester (1.98 g, 5.3024 mmol, 100% yield) was obtained as a colorless oil and used directly in the next step without purification. LCMS: (ESI, m / z): [M-tBu+ACN]+= 359.150.1H NMR (400 MHz, CDCl3-d) δ 7.39 (d, J = 7.4 Hz, 2H), 7.31 – 7.21 (m, 3H), 6.51 (s, 1H), 4.99 (s, 2H), 4.55 (s, 4H), 3.77 (s, 3H), 1.44 (s, 9H).Step h: 4-Fluoro-5-hydroxy-6-methoxy-isoindoline-2-carboxylic acid tributyl ester 20°C 10% Pd / C (1.98 g, containing 55% H2O) was added to a solution of 5-benzyloxy-4-fluoro-6-methoxy-isoindoline-2-carboxylic acid tributyl ester (1.96 g, 5.2488 mmol) in MeOH (40 mL) and THF (10 mL). The reaction mixture was stirred at 20°C for 5 h under H2 conditions. It was diluted with EA (20 mL) and filtered through diatomaceous earth. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography. The residue was eluted with ethyl acetate / n-hexane (0-40%), concentrated, and dried under reduced pressure to give 4-fluoro-5-hydroxy-6-methoxy-isoindoline-2-carboxylic acid tributyl ester (1.21 g, 4.2712 mmol, 80.67% yield), a brown semi-solid. LCMS: (ESI, m / z): [MH]-= 282.100.1H NMR (400 MHz, CDCl3-d) δ 6.58 (s, 1H), 4.67 (s, 2H), 4.63 (s, 2H), 3.92 (s, 3H), 1.53 (s, 9H).

[0220] Intermediate A11: Ethyl 4-(4-fluoro-5-hydroxy-6-methoxy-isoindoline-2-yl)-4-oxobutyrate Step a: 7-fluoro-6-methoxy-2-[(4-methoxyphenyl)methyl]isoindoline-1-one Under N2 conditions, at 0°C, 4-methoxybenzyl chloride (4.141 g, 26.4416 mmol) was added to a DMF (100 mL) solution of NaH (1.000 g, 25.0024 mmol) and 7-fluoro-6-methoxyisoindoline-1-one (4.336 g, 23.9342 mmol). The reaction mixture was stirred for 3 h and naturally heated to 20°C. The reaction mixture was quenched at 20°C with water (300 mL), extracted with EA (3 x 200 mL), and washed with brine (150 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column (EA / n-Hex 0-100%), concentrated and dried under vacuum to give 7-fluoro-6-methoxy-2-[(4-methoxyphenyl)methyl]isoindoline-1-one (6.51 g, 21.6055 mmol, 90.2706% yield) as a yellow solid. LCMS: (ESI, m / z): [M+H]+= 302.110.1H NMR (400 MHz, DMSO-d6) δ 7.39 (t, J = 7.9 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 6.91 (d, J = 8.3 Hz, 2H), 4.60 (s, 2H), 4.25 (s, 2H), 3.87 (s, 3H), 3.73 (s, 3H). Step b: A borane-tetrahydrofuran complex (120 mL, 120 mmol) was added to a THF (60 mL) solution of 7-fluoro-6-methoxy-2-(4-methoxybenzyl)isoindoline (6.17 g, 20.4771 mmol) at 20°C under N2 conditions. The reaction mixture was heated to 80°C and stirred for 5 h. The reaction mixture was quenched in MeOH (300 mL) at 20°C and evaporated under reduced pressure. The residue was diluted with MeOH (100 mL). The precipitate was collected by filtration, washed with MeOH (50 mL), and the filter cake was dried under vacuum to give 4-fluoro-5-methoxy-2-[(4-methoxyphenyl)methyl]isoindoline (3.854 g, 13.4132 mmol, 65.5036% yield) as a white solid.LCMS: (ESI, m / z): [M+H]+= 288.130.1H NMR (400 MHz, DMSO-d6) δ 7.41 (d, J = 8.0 Hz, 2H), 7.06 – 6.93 (m, 2H), 6.88 (d, J = 8.0 Hz, 2H), 4.53 – 4.37 (m, 2H), 4.22 – 4.08 (m, 4H), 3.79 (s, 3H), 3.74 (s, 3H). Step c: Ethyl 4-(4-fluoro-5-methoxy-isoindoline-2-yl)-4-oxobutyrate Pd / C (2.17 g, 2.0391 mmol) was added to a solution of 4-fluoro-5-methoxy-2-(4-methoxybenzyl)isoindoline (3.36 g, 11.6940 mmol) in THF (20 mL) and MeOH (20 mL) at 20°C under H2. The reaction mixture was stirred overnight at 20°C. The precipitate was collected by filtration, washed with MeOH (50 mL), and the filtrate was evaporated under reduced pressure. Ethyl succinate chloride (5.05 g, 30.6830 mmol) was added to the residue and a solution of TEA (3.91 g, 38.6404 mmol) in DCM (50 mL) at 0°C under N2. The reaction mixture was stirred at 20°C for 1 h. The reaction mixture was quenched at 20°C by adding water (50 mL), extracted with DCM (3 x 50 mL), and washed with brine (50 mL). The organic phase was dried over Na₂SO₄, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column (0–45%), concentrated under vacuum, and dried to give ethyl 4-(4-fluoro-5-methoxy-isoindoline-2-yl)-4-oxobutyrate (2.619 g, 8.8688 mmol, 75.8406% yield) as a yellow solid. LCMS: (ESI, m / z): [M+H]+= 296.120.1H NMR (400 MHz, DMSO-d6) δ 7.16 – 7.09 (m, 2H), 4.91 (s, 1H), 4.81 (s, 1H), 4.64 (s, 1H), 4.58 (s, 1H), 4.05 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 2.73 – 2.53 (m, 4H), 1.18 (t, J = 7.2 Hz, 3H).Step d: Ethyl 4-(4-fluoro-5-hydroxy-isoindoline-2-yl)-4-oxobutyrate Boron tribromide (20 mL, 20 mmol) was added to a DCM (40 mL) solution of ethyl 4-(4-fluoro-5-methoxyisoindoline-2-yl)-4-oxobutyrate (2.597 g, 8.7943 mmol). The reaction mixture was stirred at 20°C for 2 h, quenched with EtOH (100 mL), evaporated under reduced pressure, diluted with H2O (200 mL), extracted with EA (2 x 100 mL), and washed with brine (100 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure to give ethyl 4-(4-fluoro-5-hydroxy-isoindoline-2-yl)-4-oxobutyrate (2.408 g, 8.5609 mmol, 97.3461% yield), as a yellow solid. LCMS: (ESI, m / z): [M+H]+= 282.110.1H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 6.99 – 6.85 (m, 2H), 4.88 (s, 1H), 4.77 (s, 1H), 4.62 (s, 1H), 4.54 (s, 1H), 4.05 (q, J = 7.2 Hz, 2H), 2.66 – 2.53 (m, 4H), 1.18 (t, J = 7.2 Hz, 3H). Step e: Ethyl 4-(6-bromo-4-fluoro-5-hydroxy-isoindoline-2-yl)-4-oxobutyrate was added to a solution of ethyl 4-(4-bromo-5-fluoro-isoindoline-2-yl)-4-oxobutyrate (2.106 g, 7.4872 mmol) in MeCN (20 mL) and THF (20 mL) at 0°C under N2 atmosphere. The reaction mixture was stirred for 2 h and naturally heated to 20°C. The precipitate was collected by filtration. The filter cake was dried under vacuum to give ethyl 4-(6-bromo-4-fluoro-5-hydroxy-isoindoline-2-yl)-4-oxobutyrate (2.84 g, 7.8851 mmol, 105.3134% yield) as a white solid.LCMS: (ESI, m / z): [M+H]+= 359.010.1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 7.36 (s, 0.5H), 7.35 (s, 0.5H), 4.87 (s, 1H), 4.78 (s, 1H), 4.60 (s, 1H), 4.55 (s, 1H), 4.14 – 3.97 (q, J = 7.2 Hz, 2H), 2.70 – 2.52 (m, 4H), 1.18 (t, J = 7.2 Hz, 3H). Step f: Ethyl bromomethyl ether (1.20 g, 9.6028 mmol) was added to a solution of ethyl 4-(6-bromo-4-fluoro-5-(methoxymethoxy)isoindoline-2-yl)-4-oxobutyrate (2.23 g, 6.1914 mmol) and DIEA (2.55 g, 19.7304 mmol) in DCM (50 mL) at 0°C under N2 atmosphere. The reaction mixture was stirred for 2 h and allowed to warm naturally to 20°C. The 20°C was quenched by adding water (50 mL), extracted with DCM (3 x 50 mL), and washed with brine (50 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified on a C18 column using ACN / H2O (0.1% FA) (0-50%), concentrated and dried under vacuum to give ethyl 4-(6-bromo-4-fluoro-5-(methoxymethoxy)isoindoline-2-yl)-4-oxobutyrate (1.809 g, 4.4752 mmol, 72.2806% yield) as a yellow solid. LCMS: (ESI, m / z): [M+H]+= 403.140.1H NMR (400 MHz, DMSO-d6) δ 7.52 (s, 0.5H), 7.51 (s, 0.5H), 5.16 (s, 2H), 4.90 (s, 1H), 4.85 (s, 1H), 4.63 (s, 1H), 4.61 (s, 1H), 4.05 (q, J = 7.2 Hz, 2H), 3.54 (s, 3H), 2.72 – 2.53 (m, 4H), 1.24 – 1.12 (t, J = 7.2 Hz, 3H).Step g: Ethyl 4-(4-fluoro-6-hydroxy-5-(methoxymethoxy)isoindoline-2-yl)-4-oxobutyrate was added to a solution of ethyl 4-(6-bromo-4-fluoro-5-(methoxymethoxy)isoindoline-2-yl)-4-oxobutyrate (0.735 g, 1.8183 mmol) in 1,4-dimethylethane (20 mL) under N2 atmosphere at 20°C. The reaction mixture was heated to 100°C and stirred for 12 h. The reaction mixture was quenched at 20°C by adding water (150 mL), extracted with EA (3 x 150 mL), and washed with brine (50 mL). The organic phase was dried over Na₂SO₄, filtered, and evaporated under reduced pressure. Sodium perborate (0.91 g, 5.9145 mmol) was added to a solution of THF (10 mL) and H₂O (10 mL) in the residue at 20°C under N₂ atmosphere. The reaction mixture was stirred at 20°C for 1 h, evaporated under reduced pressure, and the residue was purified on a C18 column as ACN / H₂O (0.1% FA) (0-38%). The residue was concentrated and dried under vacuum to give ethyl 4-(4-fluoro-6-hydroxy-5-(methoxymethoxy)isoindoline-2-yl)-4-oxobutyrate (0.365 g, 1.0693 mmol, 30.1334% yield) as a white solid. LCMS: (ESI, m / z): [M+H]+=342.130.1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 6.68 (s, 1H), 5.04 (s, 2H), 4.80 (s, 1H), 4.76 (s, 1H), 4.55 (s, 1H), 4.53 (s, 1H), 4.05 (q, J = 7.2 Hz, 2H), 3.47 (s, 3H), 2.67 – 2.51 (m, 4H), 1.18 (t, J = 7.2 Hz, 3H). Step h: Ethyl iodomethane (0.345 g, 2.4306 mmol) was added to a mixture of potassium carbonate (0.448 g, 3.2415 mmol) and 4-(4-fluoro-6-hydroxy-5-(methoxymethoxy)isoindoline-2-yl)-4-oxobutyrate (0.328 g, 960.9441 μmol) in DMF (10 mL) under N2 conditions at 20°C.The reaction mixture was stirred at 20°C for 1 h. The reaction system was quenched at 20°C by adding water (50 mL), extracted with DCM (3 x 50 mL), and washed with brine (50 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. Trifluoroacetic acid (2 mL) was added to a solution of the residue (0.446 g, 1.2551 mmol) in DCM (5 mL) at 20°C under N2 atmosphere. The reaction mixture was stirred at 20°C for 2 h, evaporated under reduced pressure, and the residue was purified by ACN / H2O (0-80%) on a C18 column, concentrated and dried under vacuum to give ethyl 4-(4-fluoro-5-hydroxy-6-methoxy-isoindoline-2-yl)-4-oxobutyrate (0.274 g, 880.1663 μmol, 70.1286% yield) as a white solid. LCMS: (ESI, m / z): [M+H]+= 312.12.1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 6.83 (s, 0.5H), 6.80 (s, 0.5H), 4.82 (s, 1H), 4.77 (s, 1H), 4.57 (s, 1H), 4.54 (s, 1H), 4.05 (q, J = 7.2 Hz, 2H), 3.80 (d, J = 2.0 Hz, 3H), 2.68 – 2.51 (m, 4H), 1.18 (t, J = 7.2 Hz, 3H).

[0221] Intermediate A12: Ethyl 4-(6-hydroxy-5-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutyrate Step a: 6-Bromo-5-methoxythieno[3,2-b]pyridine To a MeOH (6 mL) solution of 6-bromo-5-chlorothieno[3,2-b]pyridine (1.0 g, 4.0 mmol), NaOMe (9.3 mL, 40 mmol) was added. The mixture was heated to 100°C under microwave irradiation in N2 environment and stirred for 1 h. 1 N citric acid (80 mL) was added, followed by extraction with EtOAc (70 mL x 3). The combined organic solutions were dried over Na2SO4 and concentrated to give 6-bromo-5-methoxythieno[3,2-b]pyridine (1.0 g, 4.0 mmol, 99% yield) as a brown solid. ¹H NMR (300 MHz, DMSO-d6): δ 8.75 (d, J = 0.5 Hz, 1H), 8.08 (d, J = 5.5 Hz, 1H), 7.42 (dd, J = 5.5, 0.5 Hz, 1H), 3.98 (s, 3H). LCMS: (ESI, m / z): [M+H]+ = 244.0. Step b: 6-Bromo-5-methoxythieno[3,2-b]pyridine-2-carboxylic acid was added to a THF (200 mL) solution of 6-bromo-5-methoxythieno[3,2-b]pyridine (5.0 g, 20.0 mmol) at -80 °C. The reaction mixture was stirred at -80 °C under N2 for 30 min. The solution was then poured onto a CO2 solid. The reaction mixture was stirred for about 1 hour. 1 N HCl (50 mL) and water (200 mL) were added, followed by extraction with EtOAc (70 mL x 3). The combined organic solutions were dried over Na2SO4 and concentrated to give 6-bromo-5-methoxythieno[3,2-b]pyridine-2-carboxylic acid (4.9 g, 17.0 mmol, 85% yield) as a brown solid. 1H NMR (300 MHz, DMSO-d6): δ 8.84 (s, 1H), 7.92 (s, 1H), 4.00 (s, 3H). LCMS: (ESI, m / z): [M+H]+ = 287.9.Step c: 3-(6-bromo-5-methoxythieno[3,2-b]pyridin-2-yl)-3-oxopropionic acid tributyl ester was added to a DMF (147 mL) solution of 6-bromo-5-methoxythieno[3,2-b]pyridin-2-carboxylic acid (4.9 g, 17.0 mmol) with the addition of CDI (5.5 g, 34.0 mmol). The mixture was stirred at room temperature under N2 for 2 hours, followed by the addition of 3-tert-butoxy-3-oxopropionic acid (5.5 g, 34.0 mmol), TEA (5.2 g, 51.0 mmol, 3.0 eq), and MgCl2 (3.3 g, 34.0 mmol), and then stirred overnight at room temperature. A NaHCO3 solution (200 mL) was added, followed by extraction with EtOAc (200 mL x 3). The combined organic solutions were dried over Na2SO4 and concentrated to obtain the residue, which was purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to give 3-(6-bromo-5-methoxythieno[3,2-b]pyridin-2-yl)-3-oxopropionic acid tributyl ester (5.0 g, 12.9 mmol, 62% yield) as a yellow solid. ¹H NMR (300 MHz, DMSO-d6): δ 8.87 (s, 1H), 8.33 (s, 1H), 4.17 (s, 2H), 4.01 (s, 3H), 1.40 (s, 9H). LCMS: (ESI, m / z): [M+H]+ = 386.0. Step d: K₂CO₃ (1.8 g, 12.5 mmol) was added to a solution of 3-(6-bromo-5-methoxythieno[3,2-b]pyridin-2-carbonyl)succinate in DMF (60 mL) at 0°C. Ethyl bromoacetate (1.3 g, 78 mmol). The reaction mixture was stirred at 0 °C for 5 hours under N2 atmosphere. NaHCO3 solution (100 mL) was added, followed by extraction with EtOAc (100 mL x 3). The combined organic solutions were dried over Na2SO4, concentrated to obtain the residue, which was purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to give 1-(tert-butyl)4-ethyl 2-(6-bromo-5)-methoxythieno[3,2-b]pyridine-2-carbonyl)succinate (3.3 g, 7.0 mmol, 89% yield) as a white solid.1H NMR (300 MHz, DMSO-d6): δ 8.89 (s, 1H), 8.47 (s, 1H), 5.00 (t, J = 7.3 Hz, 1H), 4.12 – 3.93 (m, 5H), 2.94 (t, J = 7.3 Hz, 2H), 1.31 (d, J = 4.5 Hz, 9H), 1.13 (t, J = 7.1 Hz, 3H). LCMS: (ESI, m / z): [M+H]+= 472.0. Step e: Ethyl 4-(6-bromo-5-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutyrate was added to a solution of 1-(tert-butyl)4-ethyl 2-(6-bromo-5-methoxythieno[3,2-b]pyridin-2-carbonyl)succinate (3.3 g, 7.0 mmol) in PhMe (66 mL) with TFA (33 mL). The solution was stirred at 50 °C for 1.5 h under N2 atmosphere. The solution was concentrated to obtain a residue. The solid obtained was treated with petroleum ether / ethyl acetate (10 / 1) to obtain crude ethyl 4-(6-bromo-5-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutyrate (2.2 g, 5.9 mmol, 84% yield), which was a brown solid. 1H NMR (300 MHz, DMSO-d6): δ 8.87 (s, 1H), 8.37 (s, 1H), 4.11 – 3.98 (m, 5H), 3.45 – 3.36 (m, 2H), 2.71 – 2.63 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H). LCMS: (ESI, m / z): [M+H]+= 372.0. Step f: Ethyl 4-(6-bromo-5-methoxythieno[3,2-b]pyridin-6-yl)boronic acid (1.6 g, 4.3 mmol), B2Pin2 (1.4 g, 5.3 mmol), AcOK (688 mg, 6.9 mmol), Pd2(dba)3 (112 mg, 0.1 mmol), and tricyclohexylphosphine (128 mg, 0.43 mmol) were placed in a reaction flask. The flask was evacuated and filled with argon three times. Then, dimethyl ether (32 mL) was added at room temperature. The mixture was stirred at 80 °C for 1 h. Add water (50 mL) to the reaction mixture, extract with EtOAc (3 × 50 mL), wash the combined organic layers with saturated brine, and dry with anhydrous sodium sulfate.The solution was concentrated to give a crude residue of (2-(4-ethoxy-4-oxobutyryl)-5-methoxythieno[3,2-b]pyridin-6-yl)boronic acid (3.2 g). This residue was used for the next step without any further purification. LCMS: (ESI, m / z): [M+H]+ = 338.1. Step g: Ethyl 4-(6-hydroxy-5-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutyrate was added to a solution of (3.2 g, 4.3 mmol) of (2-(4-ethoxy-4-oxobutyryl)-5-methoxythieno[3,2-b]pyridin-6-yl)boronic acid in acetone (48 mL), and OXONE (36 mL, 6.5 mmol) was added. The mixture was stirred at room temperature for 2 h. Add 120 mL of NaHSO3 solution, stir at room temperature for 1 h, extract with EtOAc (3 × 30 mL), wash the combined organic phases with saturated brine, and dry with anhydrous sodium sulfate. Concentrate the solution to obtain a crude residue, which is purified by column chromatography (petroleum ether / ethyl acetate = 10:1 to 5:1) to give ethyl 4-(6-hydroxy-5-methoxythieno[3,2-b]pyridine-2-yl)-4-oxobutyrate (340 mg, 1.1 mmol, 25% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d⁶): δ 10.44 (s, ¹H), 8.22 (s, ¹H), 7.65 (s, ¹H), 4.05 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H), ~3.30-3.31 (br, 2h), 2.65 (t, J = 6.1 Hz, 2H), 1.17 (t, J = 7.1 Hz, 3H). LCMS: (ESI, m / z): [M+H]⁺= 310.1. Using the above steps or modified steps, the following intermediates were synthesized from the corresponding starting materials and intermediates:

[0222] Example 1 4-(5-(3-((2-(3-carboxypropoxy)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid Step a: Potassium carbonate (0.240 g, 1.7365 mmol) was added at 20 °C to a solution of ethyl 4-(5-(3-bromopropoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.240 g, 579.3045 μmol) and ethyl 4-(5-hydroxy-6-methoxybenzothiophen-2-yl)-4-oxobutyrate (0.169 g, 576.1737 μmol) in N,N-dimethylformamide (10 mL). The reaction mixture was heated to 50 °C and stirred for 3 hours. The reaction mixture was evaporated under reduced pressure, concentrated, and diluted with EA (500 mL). It was washed with NaHCO3 aq. (2 x 300 mL) and brine (200 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column (0–100%), concentrated, and dried under vacuum. Ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.147 g, 229.0694 μmol, yield 62.8484%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.53 (s, 1H), 6.98 (dd, J = 15.7, 11.9 Hz, 2H), 4.73 (d, J = 9.4 Hz, 2H), 4.52 (s, 2H), 4.17 (dd, J = 30.4, 7.5 Hz, 4H), 4.05 (qd, J = 7.1, 3.4 Hz, 4H), 3.86 (d, J = 1.6 Hz, 3H), 3.75 (d, J = 2.0 Hz, 3H), 2.70 – 2.53 (m, 6H), 2.30 – 2.15 (m, 2H), 1.24 – 1.11 (m, 6H).Step b: LiOH (0.022 g, 918.6456 μmol) was added at 20 °C to a solution of 4-(5-(3-((2-(4-ethoxy-4-oxobutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid in tetrahydrofuran (10 mL) and water (2 mL). The reaction mixture was stirred for 2 hours, evaporated under reduced pressure, diluted with water, and adjusted to pH = 3 with HCl (1 M). The precipitate was filtered, the filter cake was washed with water (20 mL), and dried under vacuum at 60 °C. 4-(5-(3-((2-(3-carboxypropionic acid)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid (0.119 g, 203.2031 μmol, yield 90.5562%) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 2H), 8.17 (s, 1H), 7.67 – 7.55 (m, 1H), 7.53 (s, 1H), 6.98 (dd, J = 16.6, 12.5 Hz, 2H), 4.73 (d, J = 8.2 Hz, 2H), 4.53 (s, 2H), 4.18 (ddd, J = 23.1, 13.6, 6.3 Hz, 4H), 3.86 (d, J = 1.0 Hz, 3H), 3.75 (d, J = 1.9 Hz, 3H), 3.25 (d, J = 6.6 Hz, 2H), 2.67 – 2.53 (m, 4H), 2.30 – 2.11 (m, 2H).

[0223] Example 2 4-(5-(3-(((2-(3-carboxypropionic)-4-chloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid Step a: O1-tert-butylO4-ethyl 2-(5-bromo-4-fluoro-6-methoxy-benzothiophene-2-carbonyl)succinate 20°C Add K2CO3 (1.10 g, 7.9592 mmol) and ethyl bromoacetate (0.72 g, 4.3114 mmol) to a stirred solution of 3-(5-bromo-4-fluoro-6-methoxy-benzothiophene-2-yl)-3-oxo-propionic acid tert-butyl ester (1.58 g, 3.9180 mmol) in N,N-dimethylformamide (10 mL) The resulting mixture was stirred at 20°C for 2 hours under nitrogen atmosphere. The reaction mixture was concentrated, diluted with EA (200 mL), and washed with water (100 mL) and brine (50 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography with an elution gradient of 0 to 100% ethyl acetate / heptane, concentrated under vacuum, and dried to give O1-tert-butylO4-ethyl 2-(5-bromo-4-fluoro-6-methoxy-benzothiophene-2-carbonyl) succinate (1.925 g, 3.9338 mmol, 100.4016% yield) as a yellow oil. LCMS: (ESI, m / z): [M+H]+= 489.030. Step b: Ethyl 4-(5-bromo-4-fluoro-6-methoxy-benzothiophene-2-yl)-4-oxobutyrate. Trifluoroacetic acid (2 mL) was added to a toluene (10 mL) solution of O1-tert-butylO4-ethyl 2-(5-bromo-4-fluoro-6-methoxy-benzothiophene-2-carbonyl) succinate (1.85 g, 3.7805 mmol). The reaction mixture was stirred at 60°C for 2 h. The mixture was evaporated under reduced pressure, the residue was concentrated, diluted with DCM (200 mL), and washed with NaHCO3aq (2 x 100 mL) and brine (100 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography with an elution gradient of 0 to 100% ethyl acetate / heptane, concentrated and dried under vacuum to give ethyl 4-(5-bromo-4-fluoro-6-methoxy-benzothiophene-2-yl)-4-oxobutyrate (0.727 g, 1.8678 mmol, 49.4050% yield) as a yellow solid.LCMS: (ESI, m / z): [M+H]+= 388.978.1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.71 (s, 1H), 4.06 (q, J = 6.9 Hz, 2H), 3.98 (s, 3H), 3.39 (d, J = 6.2 Hz, 2H), 2.73 – 2.62 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H). Step c: Ethyl 4-(4-fluoro-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)benzo[b]thiophene-2-yl)-4-oxobutyrate Add Pd(dppf)Cl2 (0.15 g, 205.0010 μmol) to a mixture of potassium acetate (0.60 g, 6.1136 mmol), pinacol diboronate (0.97 g, 3.8198 mmol), and ethyl 4-(5-bromo-4-fluoro-6-methoxy-benzothiophene-2-yl)-4-oxobutyrate (0.72 g, 1.8498 mmol) in 1,4-dimethylethane (30 mL). Stir the reaction mixture at 100°C for 20 h under N2 atmosphere. The residue was concentrated by evaporation under reduced pressure, diluted with EA (200 mL), and washed with NaHCO3aq (2 x 100 mL) and brine (100 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography with an elution gradient of 0 to 100% ethyl acetate / heptane, concentrated under vacuum, and dried to give ethyl 4-(4-fluoro-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)benzo[b]thiophene-2-yl)-4-oxobutyrate (0.38 g, 870.9586 μmol, 47.0845% yield) as a white solid. LCMS: (ESI, m / z): [M+H]+= 437.153. Step d: Ethyl 4-(4-fluoro-5-hydroxy-6-methoxy-benzothiophen-2-yl)-4-oxobutyrate 20°C Sodium perborate tetrahydrate (0.21 g, 1.3649 mmol) was added to tetrahydrofuran (10 mL) of ethyl 4-(4-fluoro-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)benzo[b]thiophen-2-yl)-4-oxobutyrate and water (10 mL).The reaction mixture was stirred at 20°C for 1 h. The reaction mixture was concentrated, diluted with DCM (100 mL), and washed with NaHCO3aq (2 x 500 mL) and brine (50 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column as MeOH / DCM (0–5%), concentrated and dried under vacuum to give ethyl 4-(4-fluoro-5-hydroxy-6-methoxy-benzothiophene-2-yl)-4-oxobutyrate (0.263 g, 805.9094 μmol, yield 92.5313%) as a yellow solid. LCMS: (ESI, m / z): [M+H]+= 327.062.1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.25 (s, 1H), 7.47 (s, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 3.39 – 3.34 (m, 2H), 2.69 – 2.60 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H). Step e: Under nitrogen atmosphere, at 0°C, NCS (0.105 g, 786.3231 μmol) was added to a DMF (10 mL) solution of ethyl 4-(5-hydroxy-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.205 g, 698.9090 μmol). The reaction mixture was stirred for 12 h and then allowed to warm naturally to 20°C. The reaction mixture was purified by ACN / H2O (0-25%) on a C18 column, concentrated and dried under vacuum to give ethyl 4-(4-chloro-5-hydroxy-6-methoxy-isoindoline-2-yl)-4-oxobutyrate (0.148 g, 451.5507 μmol, yield 64.6079%) as a white solid. LCMS: (ESI, m / z): [M+H]+= 328.100.1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 6.97 (s, 0.5H), 6.95 (s, 0.5H), 4.81 (s, 1H), 4.76 (s, 1H), 4.59 (s, 1H), 4.51 (s, 1H), 4.05 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H), 2.69 – 2.53 (m, 4H), 1.18 (t, J = 7.2 Hz, 3H).Step f: Ethyl 4-[5-(3-bromopropoxy)-4-chloro-6-methoxy-isoindoline-2-yl]-4-oxobutyrate was added to a mixture of 1,3-dibromopropane (0.495 g, 2.4519 mmol) and K₂CO₃ (0.199 g, 1.4399 mmol) in DMF (5 mL) at 20°C under nitrogen atmosphere. The reaction mixture was stirred at 20°C for 4 h. The reaction mixture was purified on a C18 column as ACN / H2O (0.1% FA) (0-50%), concentrated and dried under vacuum to give ethyl 4-(5-(3-bromopropoxy)-4-chloro-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.163 g, 363.2433 μmol, 79.9035% yield) as a white solid. LCMS: (ESI, m / z): [M+H]+= 448.040.1H NMR (400 MHz, DMSO-d6) δ 7.10 (s, 0.5H), 7.08 (s, 0.5H), 4.87 (s, 1H), 4.79 (s, 1H), 4.64 (s, 1H), 4.53 (s, 1H), 4.06 – 4.02 (m, 4H), 3.83 (d, J = 2.4 Hz, 3H), 3.78 – 3.70 (m, 2H), 2.71 – 2.53 (m, 4H), 2.23 – 2.20 (m, 2H), 1.18 (t, J = 7.2 Hz, 3H). Step g: 4-(5-(3-((4-chloro-2-(4-ethoxy-4-oxobutyryl)-6-methoxyisoindoline-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyrate ethyl ester under nitrogen atmosphere, at 20°C, K2CO3 (0.115 g, 832.0942 μmol) was added to 4-(5-(3-bromopropoxy)-4-chloro-6-methoxyisoindoline-2-yl)-4-oxobutyrate ethyl ester (0.068 g, 151.5371 μmol), 4-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyrate ethyl ester (0.049 g, 150.1504 μmol) in DMF (3 The reaction mixture was stirred at 50°C for 4 h in a mL solution.The reaction mixture was purified on a C18 column as ACN / H2O (0.1% FA) (0-60%), concentrated, and lyophilized to give ethyl 4-(5-(3-((4-chloro-2-(4-ethoxy-4-oxobutyryl)-6-methoxyisoindoline-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyrate (0.040 g, 57.6234 μmol, yield 38.0259%) as a white solid. LCMS: (ESI, m / z): [M+H]+= 694.180.1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.57 (s, 1H), 7.07 (s, 0.5H), 7.04 (s, 0.5H), 4.84 (s, 1H), 4.73 (s, 1H), 4.62 (s, 1H), 4.49 (s, 1H), 4.29 (t, J = 6.0 Hz, 2H), 4.17 (t, J = 6.0 Hz, 2H), 4.10 – 4.01 (m, 4H), 3.89 (s, 3H), 3.80 (d, J = 2.0 Hz, 3H), 3.40 – 3.34 (m, 2H), 2.72 – 2.53 (m, 6H), 2.09 – 2.06 (m, 2H), 1.22 – 1.15 (m, 6H). Step h: 4-(5-(3-((2-(3-carboxypropionic acid)-4-chloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid 20°C. LiOH (0.048 g, 2.0043 mmol) was added to a solution of ethyl 4-(5-(3-((4-chloro-2-(4-ethoxy-4-oxobutionic acid)-6-methoxyisoindoline-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid (0.027 g, 38.8958 μmol) in THF (1 mL) and water (1 mL). The reaction mixture was stirred at 20°C for 1 h.The reaction mixture was adjusted to pH 3 with HCl (1 mol / L), and the reaction mixture was purified on a C18 column as ACN / H2O (0.1% FA) (0-52%). The mixture was concentrated and dried by lyophilization to give 4-(5-(3-((2-(3-carboxypropionic acid)-4-chloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid (0.017 g, 26.6434 μmol, yield 69.6846%) as a white solid. LCMS: (ESI, m / z): [M+H]+= 638.150.1H NMR (400 MHz, DMSO-d6) δ 12.2(s, 2H), 8.29 (s, 1H), 7.56 (s, 1H), 7.07 (s, 0.5H), 7.03 (s, 0.5H), 4.83 (s, 1H), 4.72 (s, 1H), 4.62 (s, 1H), 4.49 (s, 1H), 4.32 – 4.25 (m, 2H), 4.17 (t, J = 6.1 Hz, 2H), 3.89 (s, 3H), 3.80 (d, J = 1.7 Hz, 3H), 3.30 – 3.27 (m, 2H), 2.61 – 2.55 (m, 4H), 2.48 – 2.46 (m, 2H), 2.09 – 2.06 (m, 2H).

[0224] Example 3 4-(5-(3-(((2-(3-carboxypropoxy)-4-chloro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-4-oxobutyric acid Step a: 5-(3-bromopropoxy)-4-fluoro-6-methoxy-isoindoline-2-carboxylic acid tributyl ester was added to a DMF (10 mL) solution of 4-fluoro-5-hydroxy-6-methoxy-isoindoline-2-carboxylic acid tributyl ester (0.50 g, 1.7649 mmol), along with 1,3-dibromopropane (2.48 g, 12.2841 mmol) and K2CO3 (0.71 g, 5.1373 mmol). The reaction mixture was stirred at 20°C for 3 h, diluted with ethyl acetate (200 mL), and washed successively with water (2 x 100 mL) and saturated brine (100 mL). The organic phase was dried over Na₂SO₄, filtered, and evaporated to give the crude product. The crude product was purified on a silica gel column with an elution gradient of 0%–100% ethyl acetate / heptane to give 5-(3-bromopropoxy)-4-fluoro-6-methoxy-isoindoline-2-carboxylic acid tributyl ester (0.637 g, 1.5757 mmol, 89.2763% yield) as a white solid. LCMS: (ESI, m / z): [M+H]+= 331.100. Step b: 5-(3-((4-chloro-2-(4-ethoxy-4-oxobutyryl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-carboxylic acid tert-butyl ester. K2CO3 (0.166 g, 1.2011 mmol) was added to ethyl 4-(4-chloro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutyrate (0.147 g, 428.8290 μmol) and 5-(3-bromopropoxy)-4-fluoro-6-methoxy-isoindoline-2-carboxylic acid tert-butyl ester (0.173 g, 427.9318 μmol) at 20°C under N2 atmosphere. The reaction mixture was added to a 5 mL solution of DMF. The reaction mixture was stirred at 50°C for 3 h. The reaction mixture was purified on a C18 column using ACN / H2O (0.1% FA) (0-75%), concentrated under vacuum and dried to give 5-(3-((4-chloro-2-(4-ethoxy-4-oxobutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-carboxylic acid tertiary butyl ester (0.138 g, 207.1598 μmol, 48.3083% yield) as a yellow solid.LCMS: (ESI, m / z): [M+H]+= 666.190.1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.74 (s, 1H), 6.89 (s, 0.5H), 6.87 (s, 0.5H), 4.53 (s, 4H), 4.21 (d, J = 6.2, 4H), 4.06 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 3.77 (d, J = 3.7 Hz, 3H), 3.39 (t, J = 6.4 Hz, 2H), 2.66 (t, J = 6.3 Hz, 2H), 2.11 – 2.09 (m, 2H), 1.45 (s, 9H), 1.18 (t, J = 7.1 Hz, 3H). Step c: Ethyl 4-(4-chloro-5-(3-(((4-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyrate 20°C Add HCl (5 mL, 20 mmol, 4 M EA solution) to a EA (5 mL) solution of 5-(3-((4-chloro-2-(4-ethoxy-4-oxobutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-carboxylic acid tributyl ester (0.117 g, 175.6356 μmol). The reaction mixture was stirred at 20°C for 2 h and evaporated under reduced pressure to give ethyl 4-(4-chloro-5-(3-(((4-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyrate (0.182 g, 321.5338 μmol, 183.0687% yield), as a brown solid. LCMS: (ESI, m / z): [M+H]+= 566.130.1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 2H), 8.22 (s, 1H), 7.75 (s, 1H), 6.97 (s, 1H), 4.49 (s, 2H), 4.46 (s, 2H), 4.23 – 4.20 (m, 4H), 4.06 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 3.79 (s, 3H), 2.67 (t, J = 6.3 Hz, 2H), 2.09 – 2.11 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H).Step d: Ethyl succinate (0.097 g, 589.3557 μmol) was added to a solution of ethyl 4-(4-chloro-5-(3-((4-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyrate in DCM (5 mL) at 20°C under N2 conditions. The reaction mixture was stirred at 20°C for 1 h, evaporated under reduced pressure, and the residue was purified on a C18 column as ACN / H2O (0.1% FA) (0-60%). The residue was concentrated and dried by lyophilization to give ethyl 4-(5-(3-((4-chloro-2-(4-ethoxy-4-oxobutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.081 g, 116.6874 μmol, 39.5505% yield), as a white solid. LCMS: (ESI, m / z): [M+H]+= 694.180.1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.74 (d, J = 2.2 Hz, 1H), 6.91 (s, 0.5H), 6.89 (s, 0.5H), 4.81 (s, 1H), 4.80 (s, 1H), 4.57 (s, 2H), 4.22 (q, J = 5.9 Hz, 4H), 4.09 – 4.03 (m, 4H), 3.90 (d, J = 1.1 Hz, 3H), 3.78 (d, J = 2.5 Hz, 3H), 3.40 (s, 2H), 2.70 – 2.58 (m, 4H), 2.57 – 2.53 (m, 2H), 2.15 – 2.04 (m, 2H), 1.26 – 1.14 (m, 6H).Step e: 4-(5-(3-((2-(3-carboxypropionic acid)-4-chloro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-4-oxobutyric acid 20°C. LiOH (0.045 g, 1.8790 mmol) was added to a solution of ethyl 4-(5-(3-((4-chloro-2-(4-ethoxy-4-oxobutionic acid)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-4-oxobutyric acid (0.044 g, 63.3858 μmol) in THF (2 mL), H2O (2 mL), and ethanol (1 mL). The reaction mixture was stirred at 20°C for 1 h, the pH was adjusted to 3 with HCl (1 mol / L), and the mixture was evaporated under reduced pressure. The residue was purified on a C18 column using ACN / H2O (0.1% FA) (0-52%), concentrated, and dried by lyophilization to give 4-(5-(3-((2-(3-carboxypropionic acid)-4-chloro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-4-oxobutyric acid (0.032 g, 50.1523 μmol, 79.1223% yield), as a white solid. LCMS: (ESI, m / z): [M+H]+= 638.120.1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.73 (s, 1H), 6.91 (s, 0.5H), 6.88 (s, 0.5H), 4.79 (s, 2H), 4.57 (s, 2H), 4.25 – 4.19 (m, 4H), 3.90 (s, 3H), 3.78 (d, J = 1.7 Hz, 3H), 3.33 (t, J = 12.0 Hz, 2H), 2.63 – 2.54 (m, 4H), 2.49 – 2.45 (m, 2H), 2.15 – 2.04 (m, 2H).

[0225] Example 4 4-(5-(3-((2-(3-carboxypropoxy)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-4-oxobutyric acid Step a: Ethyl 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-4-oxobutyric acid 20°C 1,3-dibromopropane (0.708 g, 3.5069 mmol) was added to ethyl 4-(4-fluoro-5-hydroxy-6-methoxy-isoindoline-2-yl)-4-oxobutyric acid (0.217 g, 697.0656 μmol) and potassium carbonate (0.346 g, 2.5035 mmol) in DMF (5 mL) The mixture was stirred at 20°C for 3 h. The reaction mixture was purified by ACN / H2O (0.1% FA) (0-45%) on a C18 column, concentrated and dried under vacuum to give ethyl 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.211 g, 488.1091 μmol, 70.0234% yield) as a white solid. LCMS: (ESI, m / z): [M+H]+= 432.070. Step b: Ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutyryl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-4-oxobutyrate were added to ethyl 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-4-oxobutyrate at 20°C under N2 conditions. Potassium carbonate (0.079 g, 571.6126 μmol) was added to ethyl 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.070 g, 161.9319 μmol). The reaction mixture was added to a solution of N,N-dimethylformamide (3 mL) and ethyl 4-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutyrate (0.065 g, 199.1791 μmol). The reaction mixture was stirred overnight at 50 °C. The reaction mixture was purified by ACN / H2O (0.1% FA) (0-70%) on a C18 column, concentrated, and dried by lyophilization to give ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutyryl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.056 g, 82.6315 μmol, 51.0285% yield) as a yellow solid.LCMS: (ESI, m / z): [M+H]+= 678.210.1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.56 (s, 1H), 6.89 (s, 0.5H), 6.86 (s, 0.5H), 4.78 (s, 2H), 4.56 (s, 1H), 4.54 (s, 1H), 4.25 (t, J = 6.0 Hz, 2H), 4.19 (t, J = 6.0 Hz, 2H), 4.09 – 4.02 (m, 4H), 3.88 (s, 3H), 3.77 (d, J = 2.0 Hz, 3H), 3.36 (t, J = 6.4 Hz, 2H), 2.70 – 2.51 (m, 6H), 2.10 – 1.99 (m, 2H), 1.22 – 1.14 (m, 6H). Step c: 4-(5-(3-((2-(3-carboxypropionic acid)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-4-oxobutyric acid 20°C. LiOH (0.043 g, 1.7955 mmol) was added to a solution of ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutionic acid)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-4-oxobutyric acid (0.039 g, 57.5469 μmol) in THF (2 mL), H2O (2 mL), and Ethanol (1 mL). The reaction mixture was stirred overnight at 20°C. The pH of the reaction mixture was adjusted to 3 with HCl (aq., 1 M), evaporated under reduced pressure, and the residue was purified on a C18 column with ACN / H2O (0.1% FA) (0-50%), concentrated and dried under vacuum to give 4-(5-(3-((2-(3-carboxypropionic acid)-4-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-4-oxobutyric acid (0.012 g, 19.3050 μmol, 33.5465% yield), as a white solid.LCMS: (ESI, m / z): [M+H]+= 622.150.1H NMR (400 MHz, DMSO-d6) δ12.16 (s, 2H), 8.29 (s, 1H), 7.56 (s, 1H), 6.90 (s, 0.5H), 6.86 (s, 0.5H), 4.77 (s, 2H), 4.56 (s, 1H), 4.55 (s, 1H), 4.29 – 4.15 (m, 4H), 3.88 (s, 3H), 3.77 (s, 3H), 3.31 – 3.29 (m, 2H), 2.63 – 2.53 (m, 4H), 2.50 – 2.46 (m, 2H), 2.10 – 1.99 (m, 2H)。

[0226] Example 5 Disodium (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyrate Step g: At 25°C, NMI (7.96 g, 96.9507 mmol) was added to a DMF (100 mL) solution of TCFH (8.11 g, 28.9045 mmol) and (S)-4-methoxy-3-methyl-4-oxobutyric acid (2.81 g, 19.2280 mmol). The reaction mixture was stirred at 20°C for 10 min. 5-methoxyisoindoline hydrochloride (4.99 g, 26.8785 mmol) was added to the solution at 25°C. The reaction mixture was stirred at 25°C for 2 hours. The mixture was concentrated and diluted with H₂O (200 mL), extracted with EA (2 x 200 mL), and washed with brine (100 mL). The organic phase was dried over Na₂SO₄, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column using EA / n-hexane (0–55%). The residue was concentrated and dried under vacuum. This yielded a yellow solid (2S)-4-(5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyrate (3.49 g, 12.5850 mmol, 65.4512% yield). LCMS: (ESI, m / z): [M+H]+= 278.130. 1H NMR (400 MHz, DMSO-d6) δ 7.23 (t, J = 8.0 Hz, 1H), 6.95 – 6.84 (m, 2H), 4.78 (s, 1H), 4.73 (s, 1H), 4.56 (s, 1H), 4.52 (s, 1H), 3.75 (d, J = 1.8 Hz, 3H), 3.60 (s, 3H), 2.91 – 2.81 (m, 1H), 2.76 – 2.66 (m, 1H), 2.54 – 2.51 (m, 0.5H), 2.49 – 2.45 (m, 0.5H), 1.18 – 1.14 (m, 3H). Step h: At 0°C, NBS (3.717 g, 20.8839 mmol) was added to a solution of (2S)-4-(5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyrate (3.426 g, 12.3542 mmol) in THF (30 mL) and MeCN (30 mL). The reaction mixture was stirred at 25°C for 3 h.The reaction mixture was concentrated and diluted with DCM (200 mL), and washed successively with H2O (100 mL), KHCO3 (aq) (2 x 100 mL), and brine (100 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column using EA / n-hexane (0–60%). It was concentrated and dried under vacuum to give a yellow solid (2S)-4-(5-bromo-6-methoxy-isoindoline-2-yl)-2-methyl-4-oxobutyrate (3.02 g, 8.4781 mmol, 68.6255% yield). LCMS: (ESI, m / z): [M+H]+= 356.040.1H NMR (400 MHz, DMSO-d6) δ 7.57 (s, 0.5H), 7.55 (s, 0.5H), 7.14 (s, 0.5H), 7.09 (s, 0.5H), 4.78 (s, 1H), 4.75 (s, 1H), 4.56 (s, 1H), 4.53 (s, 1H), 3.86 (s, 3H), 3.59 (s, 3H), 2.93 – 2.79 (m, 1H), 2.78 – 2.64 (m, 1H), 2.49 – 2.46 (m, 1H), 1.15 (d, J = 7.1 Hz, 3H). Step i: At 25°C, potassium acetate (2.81 g, 28.6319 mmol) was added to a mixture of (2S)-4-(5-bromo-6-methoxy-isoindoline-2-yl)-2-methyl-4-oxobutyrate (3.00 g, 8.4220 mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (0.74 g, 1.0113 mmol), and pinacol diboronate (3.18 g, 12.5228 mmol) in 1,4-dioxane (100 mL). The reaction mixture was heated to 100°C and stirred overnight. The reaction mixture was diluted with EA (200 mL), filtered, and washed with EA (1 x 100 mL). The filtrate was evaporated under reduced pressure. The residue was purified on a silica gel column using EA / n-hexane (0-50%). Concentrate and vacuum dry to obtain a brown solid (2S)-4-[5-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)isoindoline-2-yl]-2-methyl-4-oxobutyrate methyl ester (2.38 g, 5.9017 mmol, 70.0746% yield).LCMS: (ESI, m / z): [M+H]+= 404.222.1H NMR (400 MHz, DMSO-d6) δ 7.49 (s, 0.5H), 7.46 (s, 0.5H), 6.97 (s, 0.5H), 6.93 (s, 0.5H), 4.81 (s, 1H), 4.73 (s, 1H), 4.59 (s, 1H), 4.52 (s, 1H), 3.73 (s, 3H), 3.59 (s, 3H), 2.90 – 2.81 (m, 1H), 2.76 – 2.65 (m, 1H), 2.54 – 2.51 (m, 1H), 1.27 (s, 12H), 1.15 (d, J = 6.6 Hz, 3H). Step j: Sodium perborate tetrahydrate (0.80 g, 5.1995 mmol) was added to a solution of (2S)-4-[5-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxobenzofuran-2-yl)isoindoline-2-yl]-2-methyl-4-oxobutyrate (1.99 g, 4.9346 mmol) in THF (25 mL) and H2O (25 mL) at 25°C. The reaction mixture was stirred at 25°C for 1 h. The mixture was concentrated and diluted with H2O (200 mL), extracted with DCM (3 x 100 mL), and washed with brine (100 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by ACN / H2O (0-40%) on a C18 column. Concentrate and dry under vacuum. A white solid (2S)-4-(5-hydroxy-6-methoxy-isoindoline-2-yl)-2-methyl-4-oxobutyrate methyl ester (1.23 g, 4.1935 mmol, 84.9809% yield) was obtained. LCMS: (ESI, m / z): [M+H]+ = 294.130. Step k: At 25°C, potassium carbonate (0.462 g, 3.3428 mmol) was added to a DMF (20 mL) solution of (2S)-4-(5-hydroxy-6-methoxy-isoindoline-2-yl)-2-methyl-4-oxobutyrate methyl ester (0.311 g, 1.0603 mmol) and 1,3-dibromopropane (1.158 g, 5.7359 mmol). The reaction mixture was stirred at 25°C for 3 h. The reaction mixture ACN / H2O (0-45%) was purified on a C18 column. It was concentrated and dried under vacuum to give a colorless oil (2R)-4-[5-(3-bromopropoxy)-6-methoxy-isoindoline-2-yl]-2-methyl-4-oxobutyrate methyl ester (0.314 g, 757.9234 μmol, 71.4822% yield).LCMS: (ESI, m / z): [M+H]+= 414.080 Step 1: Potassium carbonate (0.214 g, 1.5484 mmol) was added at 25°C to a solution of (S)-4-(5-(3-bromopropoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyrate methyl ester (0.206 g, 497.2362 μmol) and (2S)-4-(5-hydroxy-6-methoxy-benzothiophene-2-yl)-2-methyl-4-oxobutyrate ethyl ester (0.243 g, 753.7805 μmol) in DMF (5 mL). The reaction mixture was heated to 50°C and stirred overnight. The reaction mixture was concentrated, diluted with EA (200 mL), and washed with water (100 mL) and brine (100 mL). The organic phase was dried over Na₂SO₄, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column using EA / n-hexane (0-100%), concentrated under vacuum, and dried to give ethyl (S)-4-(6-methoxy-5-(3-((6-methoxy-2-((S)-4-methoxy-3-methyl-4-oxobutyryl)isoindoline-5-yl)oxy)propoxy)benzo[b]thiophene-2-yl)-2-methyl-4-oxobutyrate (0.130 g, 198.2454 μmol, yield 39.8695%) as a yellow solid. LCMS: (ESI, m / z): [M+H]+ = 656.245. Step m: LiOH (0.017 g, 709.8625 μmol) was added at 25°C to a solution of (S)-4-(6-methoxy-5-(3-((6-methoxy-2-((S)-4-methoxy-3-methyl-4-oxobutyryl)isoindoline-5-yl)oxy)propoxy)benzo[b]thiophene-2-yl)-2-methyl-4-oxobutyrate ethyl ester (0.120 g, 182.9957 μmol) in THF (4 mL) and water (1 mL). The reaction mixture was stirred overnight at 25°C, and the pH of the reaction mixture was adjusted to 7 by passing it through HCl (1 M). The mixture was then evaporated under reduced pressure to give the crude product. The crude product was purified by Prep-HPLC under the following conditions: (CXTH LC6000, HPLC-P1): column, Agela Durashell C18, 30mm*250mm, 10µm; mobile phase, water (0.1% NH3·H2O) and MeCN- (5-20-20%B (2-32-60min)); detector, UV 210 nm. Solvent was removed by lyophilization.NaHCO3 (0.019 g, 226.1727 μmol) was added to an aqueous solution of the lyophilized product and stirred at 25°C for 30 min. The solvent was removed by lyophilization to obtain disodium (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyrate (0.064 g, 97.3180 μmol, yield 53.1805%), a white solid. LCMS: (ESI, m / z): [M+H]+= 614.198.1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 0.5H), 8.05 (s, 0.5H), 7.56 (s, 1H), 7.51 (s, 0.5H), 7.50 (s, 0.5H), 7.02 – 6.89 (m, 2H), 4.90 – 4.77 (m, 1H), 4.73 – 4.62 (m, 1H), 4.50 (s, 2H), 4.24 – 4.16 (m, 2H), 4.15 – 4.05 (m, 2H), 3.85 (s, 3H), 3.74 (s, 3H), 3.45 – 3.38 (m, 2H), 2.75 – 2.57 (m, 2H), 2.47 – 2.39 (m, 1H), 2.27 – 2.14 (m, 2H), 2.11 – 1.97 (m, 1H), 1.02 (t, J = 6.5 Hz, 6H).

[0227] Example 6 Sodium (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyrate Step a: Under N2 conditions, at 0°C, diisopropylaminolithium (552.5297 mg, 5.1579 mmol) was added to a solution of 3-(5-bromo-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-3-oxopropionate tributyl ester (1.6 g, 3.9676 mmol) in ethylene glycol dimethyl ether (50 mL). Under N2 atmosphere at 0°C, the reaction mixture was stirred for 40 min, and ethyl (S)-2-(((trifluoromethyl)sulfonyl)oxy)propionate (2.9780 g, 11.9029 mmol) was added. The reaction mixture was stirred overnight under N2 atmosphere at 25°C. The reaction mixture was concentrated under N2 atmosphere at 25°C, diluted with EA (100 mL), and washed with NaHCO3(aq) (2 x 500 mL) and brine (50 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column with EA / n-hexane (0-20%), concentrated and dried under vacuum to give 1-(tert-butyl)-4-ethyl(3S)-2-(5-bromo-4-fluoro-6-methoxybenzo[b]thiophene-2-carbonyl)-3-methylsuccinate (1.15 g, 2.2846 mmol, 57.5800% yield) as a colorless oil. LCMS: (ESI, m / z): [M+H]+= 503.046.1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 0.5H), 8.46 (s, 0.5H), 7.73 (s, 1H), 4.93 – 4.77 (m, 1H), 4.13 – 4.02 (m, 2H), 4.00 – 3.94 (m, 3H), 3.24 – 3.11 (m, 1H), 1.31 (d, J = 11.5 Hz, 9H), 1.25 – 1.16 (m, 3H), 1.10 (t, J = 7.8 Hz, 3H). Step b: Add trifluoroacetic acid (4 mL) to a toluene (20 mL) solution of 1-(tert-butyl)-4-ethyl(3S)-2-(5-bromo-4-fluoro-6-methoxybenzo[b]thiophene-2-carbonyl)-3-methylsuccinate (1.02 g, 2.0263 mmol) at 25°C.The reaction mixture was stirred at 50°C for 2 h. The reaction mixture was concentrated and purified by C-18 column to obtain MeCN / water (0-100%). The mixture was then concentrated and dried under vacuum to give (S)-4-(5-bromo-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyrate ethyl ester (0.76 g, 1.8846 mmol, 93.0079% yield) as a yellow solid. LCMS: (ESI, m / z): [M+H]+= 402.994.1H NMR (400 MHz, MeOD-d4) δ 8.14 (s, 1H), 7.40 (s, 1H), 4.19 – 4.03 (m, 2H), 3.98 (s, 3H), 3.60 – 3.39 (m, 1H), 3.25 – 2.97 (m, 2H), 1.28 (d, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H). Step c: At 25°C, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloro(II) (0.13 g, 177.6676 μmol) was added to a mixture of potassium acetate (0.53 g, 5.4003 mmol) and (2S)-4-(5-bromo-4-fluoro-6-methoxy-benzothiophene-2-yl)-2-methyl-4-oxobutyrate ethyl ester (0.70 g, 1.7358 mmol) and pinacol diboronate (0.87 g, 3.4260 mmol) in 1,4-dimethylethane (30 mL). The reaction mixture was stirred overnight at 100°C under N2 atmosphere and evaporated under reduced pressure. The residue was concentrated and diluted with EA (200 mL), and washed with NaHCO3(aq) (2 x 100 mL) and brine (100 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column (0-50%), concentrated and dried under vacuum to give ethyl (S)-4-(4-fluoro-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)benzo[b]thiophene-2-yl)-2-methyl-4-oxobutyrate (452 ​​mg, 1.0037 mmol, 57.8229% yield) as a white solid.LCMS: (ESI, m / z): [M+H]+= 451.168.1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.49 (s, 1H), 4.15 – 3.99 (m, 2H), 3.86 (s, 3H), 3.57 – 3.40 (m, 2H), 3.18 (s, 1H), 1.41 – 1.23 (m, 12H), 1.19 – 1.14 (m, 6H). Step d: Sodium perborate tetrahydrate (0.23 g, 1.4949 mmol) was added at 25°C to a solution of (S)-4-(4-fluoro-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)benzo[b]thiophene-2-yl)-2-methyl-4-oxobutyrate ethyl ester (0.46 g, 1.0215 mmol) in tetrahydrofuran (20 mL) and water (20 mL). The reaction mixture was stirred at 25°C for 1 h and evaporated under reduced pressure. The residue was concentrated and diluted with DCM (200 mL), and washed with water (2 x 100 mL) and brine (200 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure to give ethyl (2S)-4-(4-fluoro-5-hydroxy-6-methoxy-benzothiophene-2-yl)-2-methyl-4-oxobutyrate (0.28 g, 822.6441 μmol, 80.5345% yield), as a yellow solid. LCMS: (ESI, m / z): [M+H]+= 341.078.1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.25 (s, 1H), 7.46 (s, 1H), 4.09 – 4.00 (m, 2H), 3.96 – 3.88 (m, 3H), 3.52 – 3.41 (m, 1H), 3.24 – 3.16 (m, 1H), 2.94 (s, 1H), 1.22 – 1.10 (m, 6H). Step e: At 25°C, ethyl (2S)-4-(4-fluoro-5-hydroxy-6-methoxy-benzothiophene-2-yl)-2-methyl-4-oxobutyrate (0.16 g, 470.0822 μmol) was added to a mixture of methyl (S)-4-(5-(3-bromopropoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyrate (0.20 g, 482.7536 μmol) and potassium carbonate (0.15 g, 1.0853 mmol) in N,N-dimethylformamide (5 mL).The reaction mixture was stirred overnight at 25°C. The reaction mixture was then purified on a C18 column using ACN / H2O (0-45%), concentrated under vacuum, and dried to give ethyl (S)-4-(4-fluoro-6-methoxy-5-(3-((6-methoxy-2-((S)-4-methoxy-3-methyl-4-oxobutyryl)isoindoline-5-yl)oxy)propoxy)benzo[b]thiophene-2-yl)-2-methyl-4-oxobutyrate (0.268 g, 397.7772 μmol, 82.3976% yield), as a colorless oil. LCMS: (ESI, m / z): [M+H]+= 674.236.1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.57 (s, 0.5H), 7.54 (s, 0.5H), 7.03 – 6.83 (m, 2H), 4.72 (s, 2H), 4.52 (s, 2H), 4.31 – 4.09 (m, 4H), 4.09 – 3.96 (m, 2H), 3.87 (s, 3H), 3.72 (s, 3H), 3.59 (s, 3H), 3.51 – 3.41 (m, 1H), 3.24 – 3.15 (m, 1H), 3.02 – 2.65 (m, 4H), 2.12 (s, 2H), 1.32 – 0.96 (m, 9H). Step f: At 25°C, LiOH (0.030 g, 1.2527 mmol) was added to a solution of (S)-4-(4-fluoro-6-methoxy-5-(3-((6-methoxy-2-((S)-4-methoxy-3-methyl-4-oxobutyryl)isoindoline-5-yl)oxy)propoxy)benzo[b]thiophene-2-yl)-2-methyl-4-oxobutyrate ethyl ester (0.258 g, 382.9348 μmol) in tetrahydrofuran (10 mL) and water (2 mL). The reaction mixture was stirred overnight at 25°C. The reaction mixture was purified by HPLC, concentrated, and dried under vacuum to obtain the free acid. NaHCO3 (0.016 g, 190.4612 μmol) was added to a solution of acetonitrile (10 mL) and water (10 mL) containing free acid at 25°C. The reaction system was stirred at 25°C for 1 h. The solvent was removed by lyophilization to obtain sodium (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyrate (0.063 g, 93.2466 μmol, 24.3505% yield), a white solid.LCMS: (ESI, m / z): [M+H]+= 632.289.1H NMR (400 MHz, DMSO-d6) δ 8.17 – 8.05 (m, 1H), 7.51 (s, 1H), 6.96 – 6.80 (m, 2H), 4.92 – 4.72 (m, 2H), 4.74 – 4.58 (m, 2H), 4.48 (s, 2H), 4.29 – 4.08 (m, 5H), 3.87 (s, 3H), 3.74 – 3.65 (m, 3H), 2.80 – 2.57 (m, 4H), 2.10 (s, 3H), 1.03 (d, J = 6.9 Hz, 6H)。

[0228] Example 7 Disodium 4-(5-(3-(((2-(3-carboxypropionic acid)-6-hydroxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate Step a: 5-Bromo-2-fluoro-4-(methoxymethoxy)benzaldehyde 0°C Bromomethyl methyl ether (0.71 g, 5.6816 mmol) was added to a DCM (20 mL) solution of DIEA (0.83 g, 6.4220 mmol) and 5-bromo-2-fluoro-4-hydroxybenzaldehyde (0.94 g, 4.2921 mmol). The reaction mixture was stirred at 25°C for 1 h. The reaction mixture was quenched by adding water (10 mL) at 20°C. The resulting mixture was washed with water (20 mL) and brine (20 mL). The organic phase was dried over Na₂SO₄, filtered, and evaporated under reduced pressure to give crude 5-bromo-2-fluoro-4-(methoxymethoxy)benzaldehyde (1.16 g, 4.4096 mmol, yield 102.7388%) as a white solid. LCMS: (ESI, m / z): [M+H]⁺= 262.950.1H NMR (400 MHz, DMSO-d₆) δ 10.03 (s, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.28 (d, J = 12.6 Hz, 1H), 5.45 (s, 2H), 3.43 (s, 3H). Step b: Methyl 5-bromo-6-(methoxymethoxy)benzothiophene-2-carboxylic acid Methyl mercaptoacetate (0.4 mL, 4.4732 mmol) was added to a DMF (10 mL) solution of 5-bromo-2-fluoro-4-(methoxymethoxy)benzaldehyde (1.06 g, 4.0295 mmol) and potassium carbonate (0.15 g, 1.0853 mmol). The reaction mixture was heated to 50°C and stirred for 2 h. The reaction mixture was quenched with water (100 mL) at 20°C. The precipitate was collected by filtration and washed with water (3 x 20 mL). The filter cake was dried under vacuum at 60°C to give methyl 5-bromo-6-(methoxymethoxy)benzothiophene-2-carboxylic acid (1.12 g, 3.3818 mmol, 83.9267% yield) as a white solid.LCMS: (ESI, m / z): [M+H]+ = 331.100. Step c: 5-Bromo-6-(methoxymethoxy)benzothiophene-2-carboxylic acid. At 25°C, LiOH (0.18 g, 7.5162 mmol) was added to a solution of methyl 5-bromo-6-(methoxymethoxy)benzothiophene-2-carboxylic acid (1.10 g, 3.3214 mmol) in THF (40 mL) and water (10 mL). The reaction mixture was stirred at 50°C for 2 h, evaporated under reduced pressure, and the residue was diluted with water and acidified to pH 3 with HCl (aq. 1 M). The precipitate was filtered, the filter cake was washed with water (20 mL), and dried under vacuum at 60°C to give 5-bromo-6-(methoxymethoxy)benzothiophene-2-carboxylic acid (1.04 g, 3.2791 mmol, 98.7268% yield) as a white solid. LCMS: (ESI, m / z): [MH]-= 314.900.1H NMR (400 MHz, DMSO-d6) δ 13.49 (s, 1H), 8.30 (s, 1H), 7.99 (s, 1H), 7.86 (s, 1H), 5.39 (s, 2H), 3.44 (s, 3H). Step d: 3-(5-bromo-6-(methoxymethoxy)benzo[b]thiophen-2-yl)-3-oxopropionic acid tributyl ester. CDI (1.13 g, 6.9689 mmol) was added to a DMF (20 mL) solution of 5-bromo-6-(methoxymethoxy)benzothiophen-2-carboxylic acid (1.01 g, 3.1846 mmol). The reaction mixture was stirred at 25°C for 2 h under N2 atmosphere. Magnesium chloride (0.64 g, 6.7219 mmol), tributyl malonate monoester (0.81 g, 5.0572 mmol), and TEA (1.06 g, 10.4754 mmol) were added, and the reaction mixture was stirred overnight at 25°C. The reaction mixture was concentrated, diluted with EA (100 mL), and washed with saturated aqueous NaHCO3 solution (2 x 50 mL) and brine (50 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column as EA / n-hexane (0-20%), concentrated and dried under vacuum to give tert-butyl 3-(5-bromo-6-(methoxymethoxy)benzo[b]thiophene-2-yl)-3-oxopropionic acid (1.12 g, 2.6969 mmol, 84.6855% yield) as a yellow solid.LCMS: (ESI, m / z): [MH]-= 412.950.1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.87 (s, 1H), 5.39 (d, J = 10.0 Hz, 2H), 4.06 (d, J = 8.4 Hz, 2H), 3.45 (s, 3H), 1.40 (s, 9H). Step e: 1-(tert-butyl)-4-ethyl 2-(5-bromo-6-(methoxymethoxy)benzo[b]thiophene-2-carbonyl)succinate. Ethyl 2-bromoacetate (0.356 g, 2.1317 mmol) was added to a solution of tert-butyl 3-(5-bromo-6-(methoxymethoxy)benzo[b]thiophene-2-yl)-3-oxopropionic acid (0.891 g, 2.1454 mmol) and potassium carbonate (0.587 g, 4.2473 mmol) in DMF (10 mL). The reaction mixture was stirred overnight at 25°C under nitrogen atmosphere. The reaction mixture was concentrated, diluted with EA (200 mL), and washed with water (100 mL) and brine (100 mL). The organic phase was dried over Na₂SO₄, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column using EA / n-hexane (0-50%), concentrated and dried under vacuum to give 1-(tert-butyl)-4-ethyl-2-(5-bromo-6-(methoxymethoxy)benzo[b]thiophene-2-carbonyl)succinate (0.771 g, 1.5377 mmol, 71.6743% yield) as a yellow oil. LCMS: (ESI, m / z): [M+H]+= 501.050. Step f: Ethyl 4-(5-bromo-6-hydroxy-benzothiophene-2-yl)-4-oxobutyrate. Trifluoroacetic acid (3 mL) was added to a toluene (9 mL) solution of 1-(tert-butyl)4-ethyl 2-(5-bromo-6-(methoxymethoxy)benzo[b]thiophene-2-carbonyl)succinate (0.750 g, 1.4959 mmol). The reaction mixture was heated to 50°C and stirred for 2 h, evaporated under reduced pressure, and the residue was purified by MeCN / water (0-50%) on a C18 column. The residue was concentrated and dried under vacuum to give ethyl 4-(5-bromo-6-hydroxy-benzothiophene-2-yl)-4-oxobutyrate (0.431 g, 1.2065 mmol, 80.6593% yield) as a white solid.LCMS: (ESI, m / z): [M+H]+= 357.000. Step g: Ethyl 4-(5-bromo-6-(methoxymethoxy)benzo[b]thiophen-2-yl)-4-oxobutyrate. At 25°C, methyl bromomethyl ether (0.198 g, 1.5845 mmol) was added to a solution of ethyl 4-(5-bromo-6-hydroxy-benzothiophen-2-yl)-4-oxobutyrate (0.427 g, 1.1953 mmol) and DIEA (0.235 g, 1.8183 mmol) in DCM (10 mL). The reaction mixture was stirred at 25°C for 1 h. The reaction mixture was concentrated, diluted with DCM (100 mL), and washed with water (50 mL) and brine (50 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure to give ethyl 4-(5-bromo-6-(methoxymethoxy)benzo[b]thiophen-2-yl)-4-oxobutyrate (0.503 g, 1.1282 mmol, 94.3798% yield), as a yellow solid. LCMS: (ESI, m / z): [M+H]+= 401.100. Step h: ethyl 4-(6-(methoxymethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)benzo[b]thiophene-2-yl)-4-oxobutyrate at 25°C. [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (0.110 g, 150.3341 μmol), ethyl 4-(5-bromo-6-(methoxymethoxy)benzo[b]thiophene-2-yl)-4-oxobutyrate (0.478 g, 1.1912 mmol), pinacol diborate (0.491 g, 1.9335 mmol), and potassium acetate (0.389 g, 3.9636 μmol) were added. The 1,4-dioxane (mmol) was dissolved in 1,4-dioxane (10 mL). The reaction mixture was heated to 100°C and stirred for 4.5 h under N2 atmosphere. The reaction mixture was concentrated, diluted with EA (200 mL), and washed with water (100 mL) and brine (100 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column using EA / n-hexane (0-50%), concentrated and dried under vacuum to give ethyl 4-(6-(methoxymethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)benzo[b]thiophene-2-yl)-4-oxobutyrate (0.420 g, 936.7968 μmol, 78.6423% yield) as a yellow oil.LCMS: (ESI, m / z): [M+H]+= 449.200. Step i: 4-(5-hydroxy-6-(methoxymethoxy)benzo[b]thiophen-2-yl)-4-oxobutyric acid 25°C Sodium perborate tetrahydrate (0.200 g, 1.2999 mmol) was added to a solution of ethyl 4-(6-(methoxymethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)benzo[b]thiophen-2-yl)-4-oxobutyrate (0.407 g, 907.8013 μmol) in THF (5 mL) and water (5 mL). The reaction mixture was stirred at 25°C for 2 h, evaporated under reduced pressure, and the residue was purified by MeCN / water (0-50%) on a C18 column. After vacuum concentration and drying, ethyl 4-(5-hydroxy-6-(methoxymethoxy)benzo[b]thiophen-2-yl)-4-oxobutyrate (0.250 g, 738.8257 μmol, yield 81.3863%) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H]+= 339.100. Step j: Ethyl 4-(5-methoxyisoindoline-2-yl)-4-oxobutyrate. Succinic anhydride (4.40 g, 43.9681 mmol) was added to a solution of 5-methoxyisoindoline hydrochloride (4.89 g, 26.3399 mmol) and TEA (4.73 g, 46.7440 mmol) in ethanol (200 mL) at 25°C. The reaction mixture was stirred at 25°C for 1 h. Thionium chloride (20 mL) was added to the above reaction mixture at 0°C. The reaction mixture was stirred at 25°C for 3 h, evaporated under reduced pressure, and the residue was diluted with EA (200 mL) and washed with water (100 mL) and brine (50 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure to give ethyl 4-(5-methoxyisoindoline-2-yl)-4-oxobutyrate (17.50 g, 31.5526 mmol, 119.7901% yield), as a yellow solid.LCMS: (ESI, m / z): [M+H]+= 278.150.1H NMR (400 MHz, DMSO-d6) δ 7.28 – 7.21 (m, 1H), 6.94 (s, 0.5H), 6.92 (s, 0.5H), 6.88 (s, 0.5H), 6.86 (s, 0.5H), 4.81 (s, 1H), 4.76 (s, 1H), 4.58 (s, 1H), 4.54 (s, 1H), 4.02 – 3.95 (m, 2H), 3.75 (s, 3H), 2.65 – 2.58 (m, 2H), 2.58 – 2.54 (m, 2H), 1.17 (t, J = 3.5 Hz, 3H). Step k: Ethyl 4-(5-bromo-6-methoxy-isoindoline-2-yl)-4-oxobutyrate. NBS (10.51 g, 59.0503 mmol) was added to a solution of ethyl 4-(5-methoxyisoindoline-2-yl)-4-oxobutyrate (17.50 g, 31.5526 mmol) in THF (100 mL) and MeCN (100 mL) at 25°C. The reaction mixture was stirred overnight at 25°C, evaporated under reduced pressure, and the residue was diluted with DCM (500 mL) and washed with saturated aqueous NaHCO3 solution (2 x 300 mL) and brine (200 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column as MeOH / DCM (0-10%), concentrated and dried under vacuum to give ethyl 4-(5-bromo-6-methoxy-isoindoline-2-yl)-4-oxobutyrate (7.26 g, 20.3812 mmol, 64.5943% yield) as a yellow solid. LCMS: (ESI, m / z): [M+H]+= 356.000.1H NMR (400 MHz, DMSO-d6) δ 7.58 (s, 0.5H), 7.57 (s, 0.5H), 7.15 (s, 0.5H), 7.12 (s, 0.5H), 4.80 (s, 1H), 4.77 (s, 1H), 4.57 (s, 1H), 4.54 (s, 1H), 4.09 – 4.01 (m, 2H), 3.84 (s, 3H), 2.65 – 2.59 (m, 2H), 2.56 – 2.53 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H).Step 1: Ethyl 4-(5-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaporane-2-yl)isoindoline-2-yl)-4-oxobutyrate was dissolved in 1,4-dimethylacetate (3.74 g, 38.1080 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.72 g, 984.0050 μmol), ethyl 4-(5-bromo-6-methoxy-isoindoline-2-yl)-4-oxobutyrate (3.64 g, 10.2187 mmol), and pinacol diboronate (3.84 g, 15.1218 mmol) in 1,4-dimethylethane (100 mL). The reaction mixture was heated to 100 °C and stirred overnight under N2 atmosphere. The reaction mixture was diluted with EA (400 mL). The precipitate was filtered through diatomaceous earth, and the filter cake was washed with EA (1 x 100 mL). The combined filtrates were evaporated under reduced pressure, and the residue was purified on a silica gel column using EA / n-hexane (0–100%), concentrated under vacuum, and dried to give ethyl 4-(5-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)isoindoline-2-yl)-4-oxobutyrate (2.70 g, 6.6952 mmol, 65.5190% yield) as a yellow solid. LCMS: (ESI, m / z): [M+H]+= 404.200.1H NMR (400 MHz, DMSO-d6) δ 7.49 (s, 0.5H), 7.48 (s, 0.5H), 6.98 (s, 0.5H), 6.95 (s, 0.5H), 4.83 (s, 1H), 4.74 (s, 1H), 4.60 (s, 1H), 4.53 (s, 1H), 4.09 – 4.01 (m, 2H), 3.74 (t, J = 6.2 Hz, 3H), 2.65 – 2.58 (m, 2H), 2.58 – 2.52 (m, 2H), 1.27 (s, 12H), 1.21 – 1.13 (m, 3H). Step m: Ethyl 4-(5-hydroxy-6-methoxy-isoindoline-2-yl)-4-oxobutyrate. Sodium perborate tetrahydrate (1.00 g, 6.4994 mmol) was added to a solution of ethyl 4-(5-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)isoindoline-2-yl)-4-oxobutyrate (2.45 g, 6.0752 mmol) in THF (20 mL) and water (20 mL). The reaction mixture was stirred at 20°C for 1 h and evaporated under reduced pressure.The reaction mixture was concentrated, diluted with DCM (500 mL), and washed with saturated aqueous NaHCO3 solution (2 x 300 mL) and brine (200 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column as MeOH / DCM (0–10%), concentrated under vacuum, and dried to give ethyl 4-(5-hydroxy-6-methoxy-isoindoline-2-yl)-4-oxobutyrate (1.37 g, 4.6708 mmol, 76.8818% yield) as a yellow solid. LCMS: (ESI, m / z): [M+H]+= 294.100.1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 0.5H), 8.96 (s, 0.5H), 6.91 (s, 0.5H), 6.89 (s, 0.5H), 6.73 (s, 0.5H), 6.73 (s, 0.5H), 4.71 (s, 1H), 4.69 (s, 1H), 4.50 (s, 1H), 4.47 (s, 1H), 4.08 – 4.00 (m, 2H), 3.75 (s, 3H), 2.64 – 2.58 (m, 2H), 2.56 – 2.53 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H). Step n: Ethyl 4-(5-(3-bromopropoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate 1,3-dibromopropane (0.73 g, 3.6159 mmol) was added to a solution of ethyl 4-(5-hydroxy-6-methoxy-isoindoline-2-yl)-4-oxobutyrate (0.72 g, 2.4547 mmol) and potassium carbonate (0.86 g, 6.2226 mmol) in DMF (10 mL). The reaction mixture was stirred overnight at 50 °C. The reaction mixture was diluted with EA (100 mL) and washed successively with water (2 x 100 mL) and saturated brine (100 mL). The organic phase was dried over Na₂SO₄, filtered, and evaporated to give the crude product. The crude product was purified by silica gel column chromatography with an elution gradient of 0 to 100% ethyl acetate / heptane to give ethyl 4-(5-(3-bromopropoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.43 g, 1.0379 mmol, 42.2829% yield) as a white solid.LCMS: (ESI, m / z): [M+H]+= 414.050.1H NMR (400 MHz, DMSO-d6) δ 7.01 – 6.93 (m, 2H), 4.75 (s, 2H), 4.53 (s, 2H), 4.10 – 4.00 (m, 4H), 3.76 (s, 3H), 3.71 – 3.62 (m, 2H), 2.65 – 2.58 (m, 2H), 2.58 – 2.53 (m, 2H), 2.28 – 2.18 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H). Step o: Ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutyryl)-6-(methoxymethoxy)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate 25°C. Ethyl 4-[5-hydroxy-6-(methoxymethoxy)benzothiophen-2-yl]-4-oxobutyrate (0.101 g, 298.4856 μmol) was added to a solution of ethyl 4-(5-(3-bromopropoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.127 g, 306.5486 μmol) and potassium carbonate (0.142 g, 1.0275 mmol) in DMF (5 mL). The reaction mixture was heated to 50°C and stirred overnight. The reaction mixture was concentrated, diluted with EA (200 mL), and washed with water (100 mL) and brine (100 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column as EA / n-hexane (0-100%), concentrated and dried under vacuum to give ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutyryl)-6-(methoxymethoxy)benzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.055 g, 81.8754 μmol, 27.4303% yield) as a yellow solid.LCMS: (ESI, m / z): [M+H]+= 672.250. Step p: Ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutyryl)-6-hydroxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate. At 25°C, trifluoroacetic acid (1.0 mL, 13.4622 mmol) was added to a solution of ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutyryl)-6-(methoxymethoxy)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.054 g, 80.3867 μmol) in toluene (2 mL). The reaction mixture was heated to 50°C and stirred for 30 min, evaporated under reduced pressure, and the residue was diluted with water and neutralized to pH 8 with a saturated NaHCO3 aqueous solution. The resulting mixture was extracted with EA (100 mL), washed with water (50 mL) and brine (50 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure to give ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutyryl)-6-hydroxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.057 g, 77.1865 μmol, 96.0190% yield) as a yellow solid. LCMS: (ESI, m / z): [M+H]+= 628.200. Step q: Disodium 4-(5-(3-((2-(3-carboxypropionic acid)-6-hydroxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate was added to a solution of ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutionic acid)-6-hydroxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.055 g, 87.6215 μmol) in THF (4 mL) and water (1 mL) at 25°C. The reaction mixture was stirred overnight at 25°C, evaporated under reduced pressure, and the residue was acidified with HCl (1 M) to pH 4 and evaporated under reduced pressure to obtain the crude product. The crude product was purified by Prep-HPLC under the following conditions: (CXTH LC6000, HPLC-P1): column, Daisogel-C18, 50 mm * 250 mm, 10 μm; mobile phase, water (0.1% TFA) and MeCN-(15-40-60% B (2-30-60 min); detector, UV 216 nm).Solvent removal was achieved by lyophilization. NaHCO3 (0.004 g, 47.6153 μmol) was added to an aqueous solution of the lyophilized product, and the mixture was stirred at 25°C for 30 min. Solvent removal was then achieved by lyophilization to obtain disodium 4-(5-(3-((2-(3-carboxypropionic acid)-6-hydroxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.012 g, 19.4945 μmol, 22.2485% yield), a pale yellow solid. LCMS: (ESI, m / z): [M+H]+= 572.150.1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 0.5H), 7.97 (s, 0.5H), 7.39 (s, 0.5H), 7.37 (s, 0.5H), 7.30 (s, 0.5H), 7.28 (s, 0.5H), 6.99 – 6.87 (m, 2H), 4.74 (s, 1H), 4.70 (s, 1H), 4.49 (s, 1H), 4.47 (s, 1H), 4.20 – 4.08 (m, 4H), 3.73 (s, 3H), 3.07 (t, J = 6.8 Hz, 2H), 2.47 – 2.40 (m, 2H), 2.36 – 2.16 (m, 6H).

[0229] Example 8 Disodium 4-(5-(3-(((2-(3-carboxypropoxy)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutyrate Step a: At 25°C, (3-bromopropoxy)-tert-butyldimethylsilane (518 mg, 2.0456 mmol) and K2CO3 (320 mg, 2.3154 mmol) were added to a solution of ethyl 4-(5-hydroxy-6-methoxyisoindoline-2-yl)-4-oxobutyrate (200 mg, 681.8624 μmol) in N,N-dimethylformamide (8 mL). The reaction mixture was stirred at 25°C for 2 h. Tetrabutylammonium fluoride (178 mg, 681.8624 μmol) was added to the above mixture, and the mixture was stirred at 25°C for 2 h. The reaction mixture was concentrated, diluted with EA (100 mL), and washed with NaHCO3(aq) (100 mL) and brine (50 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column as MeOH / DCM (0–10%), concentrated and dried under vacuum to give ethyl 4-(5-(3-hydroxypropoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate (106 mg, 301.6564 μmol, yield 44.2401%) as a white solid. LCMS: (ESI, m / z): [M+H]+= 352.168.1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 6.95 (d, J = 9.4 Hz, 2H), 4.74 (s, 2H), 4.53 (s, 2H), 4.00 (t, J = 6.1 Hz, 2H), 3.75 (s, 3H), 3.20 – 3.13 (m, 2H), 2.63 – 2.51 (m, 4H), 1.57 (s, 2H), 1.38 – 1.21 (m, 2H), 0.94 (t, J = 7.1 Hz, 3H).Step b: At 25°C, K3PO4 (151 mg, 711.3706 μmol) and RockPhos Palladacycle Gen.3 (11 mg, 13.1041 μmol) were added to a solution of ethyl 4-(5-(3-hydroxypropoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate (50 mg, 142.2907 μmol) and methyl 4-(5-chloro-6-methoxy-thieno[3,2-b]pyridin-2-yl)-4-oxobutyrate (66 mg, 210.3544 μmol) in toluene (10 mL). The reaction mixture was stirred at 130°C for 16 h under N2 atmosphere. The reaction mixture was purified by MeCN / water (0-100%) on a C-18 column, concentrated and dried under vacuum to give ethyl 4-(5-methoxy-6-(3-((6-methoxy-2-(4-methoxy-4-oxobutyryl)thieno[3,2-b]pyridin-5-yl)oxy)propoxy)isoindoline-2-yl)-4-oxobutyrate (4.1 mg, 6.5215 μmol, 4.5832% yield) as a yellow oil. LCMS: (ESI, m / z): [M+H]+= 629.209. Step c: At 25°C, LiOH (0.006 g, 250.5397 μmol) was added to a solution of ethyl 4-(5-methoxy-6-(3-((6-methoxy-2-(4-methoxy-4-oxobutyryl)thiopheno[3,2-b]pyridin-5-yl)oxy)propoxy)isoindoline-2-yl)-4-oxobutyrate (0.013 g, 20.6780 μmol) in tetrahydrofuran (4 mL) and water (1 mL). The reaction mixture was stirred at 25°C for 2 h, evaporated under reduced pressure, the residue was concentrated, and diluted with water (2 mL). The resulting mixture was adjusted to pH 7 by permeation with HCl (1 M) at 25°C and evaporated under reduced pressure. The residue was purified by HPLC, concentrated, and dried by lyophilization to obtain the free acid. NaHCO3 (0.001 g, 11.9038 μmol) was added to a mixture of acetonitrile (2 mL) and water (1 mL) containing free acid at 25°C. The mixture was stirred at 25°C for 1 h and then lyophilized to give disodium 4-(5-(3-((2-(3-carboxypropionic acid)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutyrate (0.0043 g, 6.8192 μmol, yield 32.9781%) as a white solid.LCMS: (ESI, m / z): [M+H]+= 587.162.1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 0.5H), 8.03 (s, 0.5H), 7.96 (s, 1H), 7.02 – 6.93 (m, 2H), 4.80 – 4.73 (m, 2H), 4.50 (s, 4H), 4.13 (s, 2H), 3.88 (s, 3H), 3.75 – 3.73 (m, 3H), 3.08 (s, 2H), 2.43 (s, 2H), 2.24 (s, 4H), 2.15 (s, 2H)。

[0230] Example 9 4-(5-(3-((6-bromo-2-(3-carboxypropionic)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid Step a: 4-(5-(3-((6-bromo-2-(4-ethoxy-4-oxobutionic)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid ethyl ester. Under N2 conditions, at 25°C, potassium carbonate (0.080 g, 578.8482 μmol) was added to 4-(5-(3-bromopropoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid ethyl ester (0.075 g, 181.0327 μmol). The reaction mixture was added to a solution of ethyl 4-(6-bromo-5-hydroxybenzo[b]thiophen-2-yl)-4-oxobutyrate (0.071 g, 198.7576 μmol) in DMF (2 mL). The reaction mixture was heated to 50 °C and stirred overnight. The reaction mixture was purified by ACN / H2O (0.1% FA) (0-60%) on a C18 column, concentrated, and dried by lyophilization to give ethyl 4-(5-(3-((6-bromo-2-(4-ethoxy-4-oxobutyryl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.080 g, 115.8418 μmol, 63.9894% yield) as a white solid. LCMS: (ESI, m / z): [M+H]+= 690.13.1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.26 (s, 1H), 7.69 (s, 1H), 7.05 – 6.92 (m, 2H), 4.73 (s, 1H), 4.72 (s, 1H), 4.51 (d, J = 3.6 Hz, 2H), 4.29 (s, 2H), 4.19 (t, J = 6.4 Hz, 2H), 4.11 – 4.00 (m, 4H), 3.73 (d, J = 2.0 Hz, 3H), 3.40 – 3.34 (m, 2H), 2.68 (t, J = 6.3 Hz, 2H), 2.63 – 2.53 (m, 4H), 2.26 (t, J = 6.3 Hz, 2H), 1.18 (t, J = 7.1 Hz, 6H).Step b: 4-(5-(3-((6-bromo-2-(3-carboxypropionic)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid. At 25°C, LiOH (0.050 g, 2.0878 mmol) was added to a solution of ethyl 4-(5-(3-((6-bromo-2-(4-ethoxy-4-oxobutionic)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid (0.044 g, 63.7130 μmol) in THF (2 mL), EtOH (1 mL), and water (2 mL). The reaction mixture was stirred at 25°C for 2 h, and the pH of the reaction mixture was adjusted to 3 with HCl (1 mol / L). The reaction mixture was purified on a C18 column as ACN / H2O (0.1% FA) (0-55%), concentrated, and dried by lyophilization to give 4-(5-(3-((6-bromo-2-(3-carboxypropionic acid)benzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid (0.012 g, 18.9128 μmol, 29.6844% yield) as a white solid. LCMS: (ESI, m / z): [M+H]+= 634.07.1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 8.24 (d, J = 3.1 Hz, 1H), 7.68 (d, J = 3.8 Hz, 1H), 7.04 – 6.92 (m, 2H), 4.73 (s, 1H), 4.71 (s, 1H), 4.51 (d, J = 4.7 Hz, 2H), 4.29 (s, 2H), 4.23 – 4.15 (m, 2H), 3.73 (s, 3H), 3.33 – 3.25 (m, 2H), 2.63 – 2.54 (m, 4H), 2.53 – 2.50 (m, 2H), 2.31 – 2.20 (m, 2H).

[0231] Example 10 4-(5-(3-((2-(3-carboxypropionic acid)-4-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid Step a: 4-(5-(3-((2-(4-ethoxy-4-oxobutionic acid)-4-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid ethyl ester Under N2 conditions, at 25°C, potassium carbonate (0.099 g, 716.3246 μmol) was added to 4-(5-hydroxy-6-methoxybenzothiophene-2-yl)-4-oxobutyric acid ethyl ester (0.062 g, 201.0709 μmol). The mixture was added to a DMF (3 mL) solution of ethyl 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.069 g, 159.6186 μmol). The reaction mixture was stirred overnight at 50 °C. The mixture was purified by ACN / H2O (0.1% FA) (0-50%) on a C18 column, concentrated, and lyophilized to give ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutyryl)-4-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyrate (0.071 g, 107.6218 μmol, 67.4244% yield) as a white solid. LCMS: (ESI, m / z): [M+H]+= 660.220.1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.59 (s, 1H), 7.50 (d, J = 3.4 Hz, 1H), 6.92 (s, 0.5H), 6.88 (s, 0.5H), 4.80 (s, 1H), 4.78 (s, 1H), 4.57 (s, 2H), 4.27 – 4.20 (m, 2H), 4.17 (t, J = 6.0 Hz, 2H), 4.10 – 4.02 (m, 4H), 3.85 (s, 3H), 3.76 (s, 3H), 3.31 – 3.28 (m, 2H), 2.69 – 2.53 (m, 6H), 2.20 – 2.09 (m, 2H), 1.18 (t, J = 7.1 Hz, 6H).Step b: 4-(5-(3-((2-(3-carboxypropionic acid)-4-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid 25°C. LiOH (0.044 g, 1.8373 mmol) was added to a solution of ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutionic acid)-4-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid (0.100 g, 155.1150 μmol) in THF (2 mL), EtOH (2 mL), and water (2 mL). The reaction mixture was stirred at 25°C for 2 h. The reaction mixture was adjusted to pH 3 with HCl (1 mol / L), concentrated under reduced pressure, and the residue was purified on a C18 column as ACN / H2O (0.1% FA) (0-40%). After vacuum concentration and drying, 4-(5-(3-((2-(3-carboxypropionic acid)-4-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid (0.026 g, 43.0741 μmol, 66.0854% yield) was given as a white solid. LCMS: (ESI, m / z): [M+H]+= 604.160.1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.59 (s, 1H), 7.50 (d, J = 3.0 Hz, 1H), 6.91 (s, 0.5H), 6.88 (s, 0.5H), 4.79 (s, 1H), 4.77 (s, 1H), 4.56 (s, 2H), 4.27 – 4.20 (m, 2H), 4.17 (t, J = 6.0 Hz, 2H), 3.85 (s, 3H), 3.76 (s, 3H), 3.26 – 3.24 (m, 2H), 2.63 – 2.54 (m, 4H), 2.48 – 2.44 (m, 2H), 2.19 – 2.10 (m, 2H).

[0232] Example 11 4-(5-(3-((6-(3-carboxypropyl)-3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propoxy)-6-methoxythiopheno[3,2-b]pyridin-2-yl)-4-oxobutyric acid Step a: 3-methoxy-2-(3-tetrahydropyran-2-yloxypropoxy)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine 25°C Pd / C (2.553 g, 2.3990 2.464 g (5.7500 mmol) of 3-methoxy-6-(4-methoxybenzyl)-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (60 mL) was added to a solution of ethyl acetate. The reaction mixture was stirred overnight at 25 °C under H2 conditions. The resulting mixture was filtered, and the filter cake was washed with EA (3 x 100 mL). The filtrate was concentrated under reduced pressure to give 3-methoxy-2-(3-tetrahydropyran-2-yloxypropoxy)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (1.936 g, 4.3947 mmol, 76.4291% yield) as a yellow oil. LCMS: (ESI, m / z): [M+H]+= 309.174. Step b: 3-((3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propane-1-ol. 4-Methylbenzenesulfonic acid (0.69 g, 2.5430 mmol) was added to a MeOH (40 mL) solution of 3-methoxy-2-(3-tetrahydropyran-2-yloxypropoxy)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (1.91 g, 4.3357 mmol) at 25°C. The reaction mixture was stirred at 25°C for 2 h, evaporated under reduced pressure, and the residue was purified by MeCN / water (0-50%) on a C18 column. After vacuum concentration and drying, 3-((3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propane-1-ol (0.814 g, 3.6298 mmol, 83.7191% yield) was given as a yellow oil.LCMS: (ESI, m / z): [M+H]+= 225.116. Step c: Ethyl 4-(2-(3-hydroxypropoxy)-3-methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxobutyrate ethyl ester was added at 0°C to a solution of 3-((3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propane-1-ol (0.366 g, 1.6321 mmol) and triethylamine (0.363 g, 3.5873 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred at 25°C for 1 h. The reaction mixture was purified by passing MeCN / water (0-100%) on a C-18 column, concentrated under vacuum and dried to give ethyl 4-(2-(3-hydroxypropoxy)-3-methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxobutyrate (224 mg, 635.6750 μmol, 38.9491% yield) as a white solid. LCMS: (ESI, m / z): [M+H]+= 353.163.1H NMR (400 MHz, DMSO-d6) δ 7.38 – 7.26 (m, 1H), 4.81 – 4.73 (m, 1H), 4.68 (s, 1H), 4.54 (s, 2H), 4.42 (s, 1H), 4.30 (t, J = 6.3 Hz, 2H), 4.11 – 3.99 (m, 2H), 3.78 (s, 3H), 3.57 – 3.50 (m, 2H), 2.66 – 2.59 (m, 2H), 2.58 – 2.52 (m, 2H), 1.91 – 1.80 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H).Step d: Ethyl 4-(3-methoxy-2-(3-((6-methoxy-2-(4-methoxy-4-oxobutyryl)thieno[3,2-b]pyridin-5-yl)oxy)propoxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxobutyrate 25°C. Potassium phosphate (0.212 g, 998.7454 μmol) and RockPhos Palladacycle Gen.3 (0.022 g, 26.2082 μmol) were added to ethyl 4-(2-(3-hydroxypropoxy)-3-methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxobutyrate (0.087 g, 246.8916 μmol). Methyl 4-(5-chloro-6-methoxy-thieno[3,2-b]pyridin-2-yl)-4-oxobutyrate (0.120 g, 382.4626 μmol) was added to a 20 mL solution of toluene. The reaction mixture was stirred overnight at 25°C under N2 environment, evaporated under reduced pressure, and the residue was purified by MeCN / water (0-100%) on a C-18 column. The residue was concentrated and dried under vacuum, purified by HPLC, concentrated and lyophilized to give ethyl 4-(3-methoxy-2-(3-((6-methoxy-2-(4-methoxy-4-oxobutyryl)thieno[3,2-b]pyridin-5-yl)oxy)propoxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxobutyrate (20 mg, 31.7623 μmol, 12.8649% yield), as a white solid. LCMS: (ESI, m / z): [M+H]+= 630.204.1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 3.6 Hz, 1H), 7.97 (d, J = 4.8 Hz, 1H), 7.37 – 7.28 (m, 1H), 4.73 (s, 1H), 4.61 (s, 1H), 4.55 – 4.48 (m, 3H), 4.47 – 4.36 (m, 3H), 4.09 – 4.01 (m, 2H), 3.89 (s, 3H), 3.78 (s, 3H), 3.61 (d, J = 5.6 Hz, 3H), 2.68 (d, J = 6.5 Hz, 2H), 2.62 – 2.54 (m, 3H), 2.25 (d, J = 4.2 Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H).Step e: 4-(5-(3-((6-(3-carboxypropyl)-3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propoxy)-6-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutyric acid 25°C LiOH (0.004 g, 167.0265 μmol) was added to ethyl 4-(3-methoxy-2-(3-((6-methoxy-2-(4-methoxy-4-oxobutyryl)thieno[3,2-b]pyridin-5-yl)oxy)propoxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxobutyric acid (0.010 g, 15.8812 μmol). The mixture was added to a solution of tetrahydrofuran (4 mL) and water (1 mL) at 25°C for 2 h. The reaction mixture was stirred under reduced pressure, evaporated, and the residue was concentrated and diluted with water (2 mL). The resulting mixture was adjusted to pH 7 by passing through HCl (1 M) at 25°C, evaporated under reduced pressure, and the residue was purified by HPLC, concentrated, and lyophilized to give 4-(5-(3-((6-(3-carboxypropyl)-3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propoxy)-6-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutyric acid (2.6 mg, 4.4248 μmol, yield 27.8619%) as a white solid. LCMS: (ESI, m / z): [M+H]+= 588.157.1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.97 (d, J = 3.4 Hz, 1H), 7.35 – 7.28 (m, 1H), 4.73 (s, 2H), 4.61 (s, 2H), 4.51 (s, 4H), 4.47 – 4.33 (m, 4H), 3.88 (s, 3H), 3.78 (s, 3H), 2.71 – 2.61 (m, 4H), 2.26 (s, 2H).

[0233] Example 12 4-(5-(3-((2-(4-ethoxy-4-oxobutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid Step a: Tertiary butyl 5-methoxyisoindoline-2-carboxylic acid ester TEA (33.12 g, 327.3070 mmol) was added to a DCM (500 mL) solution of 5-methoxyisoindoline hydrochloride (20.01 g, 107.7833 mmol) and ditertiary dicarbonate (35.28 g, 161.6523 mmol) at 20°C. The reaction mixture was stirred overnight at 20°C, evaporated under reduced pressure, and the residue was purified on a silica gel column with EA / n-hexane (0-50%). The residue was concentrated and dried under vacuum to give 5-methoxyisoindoline-2-carboxylic acid tributyl ester (30.66 g, 104.5347 mmol, 96.9859% yield) as a white solid. LCMS: (ESI, m / z): [M+H-tBu+ACN]+= 235.136.1H NMR (400 MHz, DMSO-d6) δ 7.24 – 7.18 (m, 1H), 6.90 (d, J = 4.5 Hz, 1H), 6.85 (s, 0.5H), 6.83 (s, 0.5H), 4.58 – 4.44 (m, 4H), 3.74 (s, 3H), 1.45 (s, 9H). Step b: 5-Bromo-6-methoxy-isoindoline-2-carboxylic acid tributyl ester. At 20°C, NBS (43.64 g, 245.1906 mmol) was added to a solution of 5-methoxy-isoindoline-2-carboxylic acid tributyl ester (30.40 g, 121.9390 mmol) in tetrahydrofuran (300 mL) and acetonitrile (300 mL). The reaction mixture was stirred overnight at 20°C, evaporated under reduced pressure, concentrated, diluted with EA (1000 mL), and washed with NaHCO3(aq) (3 x 200 mL) and brine (300 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column with EA / n-hexane (0-50%), concentrated and dried under vacuum to give 5-bromo-6-methoxy-isoindoline-2-carboxylic acid tributyl ester (17.61 g, 53.6562 mmol, 44.0025% yield) as a yellow solid.LCMS: (ESI, m / z): [M+H-tBu+ACN]+= 313.047.1H NMR (400 MHz, DMSO-d6) δ 7.54 (d, J = 5.3 Hz, 1H), 7.11 (d, J = 4.2 Hz, 1H), 4.51 (t, J = 9.8 Hz, 4H), 3.82 (d, J = 3.7 Hz, 3H), 1.45 (s, 9H). Step c: 5-Methoxy-6-(4,4,5,5-Tetramethyl-1,3,2-dioxapentylborane-2-yl)isoindoline-2-carboxylic acid tert-butyl ester. At 20°C, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.10 g, 2.8700 mmol), pinacol diborate (11.71 g, 46.1137 mmol), and potassium acetate (9.76 g, 99.4475 mmol) were added to a solution of 5-bromo-6-methoxy-isoindoline-2-carboxylic acid tert-butyl ester (10.04 g, 30.5910 mmol) in 1,4-dimethylethane (200 mL). The reaction mixture was heated to 100°C and stirred overnight under N2 atmosphere. The reaction mixture was concentrated, diluted with EA (500 mL), and washed with water (200 mL) and brine (200 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column as EA / n-hexane (0-50%), concentrated under vacuum, and dried to give an oily product, 5-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)isoindoline-2-carboxylic acid tertiary butyl ester (11.00 g, 29.3126 mmol, 95.8208% yield). LCMS: (ESI, m / z): [M+H-tBu+ACN]+= 361.222. Step d: 5-Hydroxy-6-methoxy-isoindoline-2-carboxylic acid tributyl ester. Sodium perborate tetrahydrate (6.28 g, 40.8164 mmol) was added to a solution of 5-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)isoindoline-2-carboxylic acid tributyl ester (9.75 g, 25.9816 mmol) in tetrahydrofuran (150 mL) and water (150 mL). The reaction mixture was stirred at 20°C for 2 h. The reaction mixture was concentrated, diluted with EA (600 mL), and washed with water (300 mL) and brine (300 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure.The residue was purified by EA / DCM (0-100%) on a silica gel column, concentrated and dried under vacuum to give 5-hydroxy-6-methoxy-isoindoline-2-carboxylic acid tributyl ester (6.58 g, 24.8017 mmol, 95.4589% yield) as a yellow oil. LCMS: (ESI, m / z): [M+H-tBu+ACN]+= 251.131.1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 6.88 (d, J = 5.8 Hz, 1H), 6.70 (d, J = 2.3 Hz, 1H), 4.44 (t, J = 9.6 Hz, 4H), 3.74 (d, J = 3.4 Hz, 3H), 1.44 (s, 9H). Step e: 5-(3-bromopropoxy)-6-methoxy-isoindoline-2-carboxylic acid tributyl ester was added to a DMF mixture of potassium carbonate (0.286 g, 2.0694 mmol) and 5-hydroxy-6-methoxyisoindoline-2-carboxylic acid tributyl ester (0.179 g, 674.6977 μmol) at 20°C under N2 conditions. The reaction mixture was stirred at 20°C for 5 h. The mixture was purified on a C18 column as ACN / H2O (0.1% FA) (0-50%), concentrated and dried under vacuum to give 5-(3-bromopropoxy)-6-methoxy-isoindoline-2-carboxylic acid tributyl ester (0.154 g, 398.6747 μmol, 59.0894% yield), as a white oil. LCMS: (ESI, m / z): [M+H]+= 386.090.1H NMR (400 MHz, DMSO-d6) δ 6.96 (t, J = 5.8 Hz, 2H), 4.50 (s, 2H), 4.48 (s, 2H), 4.03 (q, J = 5.5 Hz, 2H), 3.74 (d, J = 3.4 Hz, 3H), 3.66 (t, J = 6.5 Hz, 2H), 2.27 – 2.19 (m, 2H), 1.45 (s, 9H).Step f: 5-(3-((2-(4-ethoxy-4-oxobutyryl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-carboxylic acid tertiary butyl ester. Under N2 conditions, at 20°C, potassium carbonate (0.079 g, 571.6126 μmol) was added to a DMF (3 mL) solution of 5-(3-bromopropoxy)-6-methoxyisoindoline-2-carboxylic acid tertiary butyl ester (0.079 g, 204.5150 μmol) and 4-(5-hydroxy-6-methoxybenzothiophen-2-yl)-4-oxobutyrate ethyl ester (0.064 g, 207.5571 μmol). The reaction mixture was stirred overnight at 50°C. The reaction mixture was quenched by adding water (50 mL) at 20°C. Extracted with EA (3 x 50 mL) and washed with brine (50 mL). The organic phase was dried over Na₂SO₄, filtered, and evaporated under reduced pressure. Crude 5-(3-((2-(4-ethoxy-4-oxobutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-carboxylic acid tert-butyl ester (0.088 g, 143.3886 μmol, 70.1115% yield) was obtained as a yellow oil. It was used directly for the next step. LCMS: (ESI, m / z): [M+H]+= 614.230. Step g: 4-(5-(3-((2-(4-ethoxy-4-oxobutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid. At 20°C, trifluoroacetic acid (1 mL) was added to a solution of 5-(3-((2-(4-ethoxy-4-oxobutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-carboxylic acid tributyl ester (0.084 g, 136.8709 μmol) in DCM (3 mL). The reaction mixture was stirred at 20°C for 1 h and evaporated under reduced pressure. Succinic anhydride (0.050 g, 499.6373 μmol) and TEA (0.195 g, 1.9271 mmol) were added to a DCM (5 mL) solution of the residue at 0°C under N2 atmosphere. The reaction mixture was stirred and naturally heated to 20°C. At 20°C, water (50 mL) was added to quench the reaction mixture, the pH was adjusted to 3 with HCl (1 mol / L), extracted with EA (3 x 50 mL), and washed with brine (50 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure.The residue was purified on a C18 column using ACN / H2O (0.1% FA) (0-40%), concentrated and dried under vacuum to give 4-(5-(3-((2-(4-ethoxy-4-oxobutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid (0.038 g, 61.9221 μmol, 45.2413% yield), as a white solid. LCMS: (ESI, m / z): [M+H]+= 614.200.1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.60 (s, 1H), 7.53 (s, 1H), 7.02 (s, 0.5H), 6.98 (s, 0.5H), 6.97 (s, 0.5H), 6.95 (s, 0.5H), 4.74 (s, 1H), 4.72 (s, 1H), 4.52 (s, 2H), 4.20 (t, J = 6.3 Hz, 2H), 4.14 (t, J = 6.3 Hz, 2H), 4.06 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 3.75 (s, 3H), 3.30 – 3.28 (m, 2H), 2.70 – 2.64 (m, 2H), 2.58 – 2.52 (m, 4H), 2.27 – 2.18 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H).

[0234] Example 13 Disodium 4-(5-(3-((2-(3-carboxypropionic)-5-methoxythiopheno[2,3-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate Step a: 2,3-Dimethoxy-5-vinyl-pyridine At 20°C, vinyl borate pinacol ester (9.25 g, 60.0595 mmol), potassium carbonate (18.91 g, 136.8252 mmol) and Pd(dppf)Cl2 (1.97 g, 2.6923 mmol) were added to a solution of 5-bromo-2,3-dimethoxypyridine (9.88 g, 45.3112 mmol) in 1,4-dimethyl alkylene (100 mL) and water (20 mL). The reaction mixture was stirred at 80°C for 2 h under nitrogen atmosphere. The reaction mixture was concentrated, diluted with EA (100 mL), and washed with NaHCO3(aq) (100 mL) and brine (50 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by ethyl acetate / Heptane (0-20%) on a silica gel column, concentrated and dried under vacuum to give 2,3-dimethoxy-5-vinylpyridine (5.22 g, 31.6002 mmol, 69.7404% yield) as a colorless oil. LCMS: (ESI, m / z): [M+H]+= 166.079.1H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 1.9 Hz, 1H), 7.46 (t, J = 5.8 Hz, 1H), 6.73 – 6.63 (m, 1H), 5.83 (dd, J = 17.6, 0.8 Hz, 1H), 5.24 (dd, J = 11.0, 0.8 Hz, 1H), 3.86 (s, 3H), 3.82 (s, 3H). Step b: 5,6-Dimethoxypyridine-3-carboxaldehyde. A solution of potassium osmium tetroxide (VI) anhydrous (0.55 g, 1.4927 mmol) in water (25 mL) was added to a solution of 2,3-dimethoxy-5-vinylpyridine (5.17 g, 31.2975 mmol) and 4-methylmorpholine N-oxide (7.44 g, 63.5105 mmol) in tetrahydrofuran (100 mL). The reaction mixture was stirred at 20°C for 30 min. Sodium periodate (6.82 g, 31.8854 mmol) was added to the reaction mixture at 20°C.The reaction mixture was stirred overnight at 20°C, concentrated, diluted with EA (500 mL), washed with water (200 mL) and brine (50 mL), and the organic phase was dried over Na₂SO₄, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column as EA / Hept (0–20%), concentrated and dried under vacuum to give 5,6-dimethoxypyridine-3-carboxaldehyde (3.51 g, 20.9976 mmol, 67.0904% yield) as a white solid. LCMS: (ESI, m / z): [M+H]+= 168.058.1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.34 (d, J = 1.9 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 3.99 (s, 3H), 3.87 (s, 3H). Step c: (5,6-Dimethoxy-3-pyridyl)methanol. NaBH4 (0.4 g, 10.5729 mmol) was added to a methanol (100 mL) solution of 5,6-dimethoxypyridin-3-carboxaldehyde (3.51 g, 20.9976 mmol). The reaction mixture was stirred at 20°C for 1 h. The reaction mixture was concentrated, diluted with EA (500 mL), and washed with water (200 mL) and brine (200 mL). The organic phase was dried over Na2SO4, filtered, evaporated under reduced pressure, concentrated and dried under vacuum to give (5,6-dimethoxy-3-pyridyl)methanol (3.33 g, 19.6835 mmol, 93.7418% yield) as a yellow oil. LCMS: (ESI, m / z): [M+H]+= 170.074.1H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 1.6 Hz, 1H), 7.23 (t, J = 6.4 Hz, 1H), 5.13 (t, J = 5.7 Hz, 1H), 4.43 (d, J = 5.7 Hz, 2H), 3.84 (s, 3H), 3.77 (s, 3H). Step d: (2-bromo-5,6-dimethoxy-3-pyridyl)methanol. NBS (4.26 g, 23.9347 mmol) and acetic acid (0.5 mL) were added to a solution of (5,6-dimethoxy-3-pyridyl)methanol (3.30 g, 19.5062 mmol) in acetonitrile (100 mL) at 20°C.The reaction mixture was stirred at 20°C for 2 h, evaporated under reduced pressure, and the residue was diluted with EA (200 mL) and washed with NaHCO3 (aq) (2 x 100 mL) and brine (100 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column (0-100%), concentrated under vacuum, and dried to give (2-bromo-5,6-dimethoxy-3-pyridyl)methanol (2.91 g, 11.7304 mmol, 60.1369% yield) as a white solid. LCMS: (ESI, m / z): [M+H]+= 247.984.1H NMR (400 MHz, DMSO-d6) δ 7.40 (s, 1H), 5.45 (t, J = 5.4 Hz, 1H), 4.42 (d, J = 5.5 Hz, 2H), 3.85 (s, 3H), 3.80 (s, 3H). Step e: 2-Bromo-5,6-dimethoxy-pyridin-3-carboxaldehyde. At 20°C, Dysmart oxidant (7.3 g, 17.2113 mmol) was added to a solution of (2-bromo-5,6-dimethoxy-3-pyridyl)methanol (2.91 g, 11.7304 mmol) in DCM (100 mL). The reaction mixture was stirred at 20°C for 1 h, evaporated under reduced pressure, concentrated, diluted with EA (200 mL), and washed with NaHCO3 (aq) (2 x 100 mL) and brine (100 mL). The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column (EA / Hept 0-100%), concentrated and dried under vacuum to give 2-bromo-5,6-dimethoxy-pyridine-3-carboxaldehyde (2.7 g, 10.9730 mmol, 93.5437% yield) as a white solid. LCMS: (ESI, m / z): [M+H]+= 245.969.1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 7.52 (s, 1H), 3.99 (s, 3H), 3.87 (s, 3H). Step f: 5,6-Dimethoxythieno[2,3-b]pyridine-2-carboxylic acid methyl mercaptoacetate (1.1870 g, 11.1830 mmol) was added at 20°C to a mixture of 2-bromo-5,6-dimethoxy-pyridine-3-carboxaldehyde (2.68 g, 10.8918 mmol) and potassium carbonate (4.65 g, 33.6455 mmol) in N,N-dimethylformamide (50 mL). The reaction mixture was stirred overnight at 60°C under N2 environment.The reaction mixture was concentrated and diluted with water (500 mL). The precipitate was collected by filtration and washed with water (100 mL). LiOH (0.40 g, 16.7026 mmol) was added to a solution of tetrahydrofuran (50 mL) and (10 mL) in the filter cake at 20°C. The reaction mixture was stirred at 20°C for 2 h. The reaction mixture was concentrated and diluted with water (200 mL). The mixture was adjusted to pH 3 with HCl (1 M). The precipitate was collected by filtration, washed with water (100 mL), and dried under vacuum to give 5,6-dimethoxythieno[2,3-b]pyridine-2-carboxylic acid (2.32 g, 9.6971 mmol, 89.0313% yield) as a white solid. LCMS: (ESI, m / z): [M+H]+= 240.065.1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.80 (s, 1H), 3.98 (s, 3H), 3.85 (s, 3H). Step g: 3-(5,6-dimethoxythieno[2,3-b]pyridin-2-yl)-3-oxo-propionic acid tributyl ester 20°C. Carbonyl diimidazole (3.11 g, 19.1799 mmol) was added to a solution of 5,6-dimethoxythieno[2,3-b]pyridin-2-carboxylic acid (2.29 g, 9.5717 mmol) in N,N-dimethylformamide (50 mL). The reaction mixture was stirred at 20°C for 30 min under nitrogen atmosphere, and then tert-butyl malonate (3.16 g, 19.7294 mmol), magnesium chloride (1.87 g, 19.6406 mmol), and triethylamine (2.96 g, 29.2521 mmol) were added. The reaction mixture was stirred overnight at 20°C. The reaction mixture was concentrated, diluted with EA (500 mL), washed with NaHCO3(aq) (2 x 300 mL) and brine (200 mL), and the organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column with EA / n-hexane (0-50%), concentrated and dried under vacuum to give tert-butyl 3-(5,6-dimethoxythieno[2,3-b]pyridin-2-yl)-3-oxo-propionic acid (2.37 g, 7.0245 mmol, 73.3885% yield) as a white solid.LCMS: (ESI, m / z): [M+H]+= 338.098.1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 9.8 Hz, 1H), 7.83 (d, J = 7.7 Hz, 1H), 4.06 (d, J = 8.5 Hz, 2H), 3.98 (s, 3H), 3.88 (s, 3H), 1.41 (s, 9H). Step h: O1-tert-butylO4-ethyl 2-(5,6-dimethoxythieno[2,3-b]pyridin-2-carbonyl)succinate. Ethyl bromoacetate (0.63 g, 3.7724 mmol) was added to a mixture of 3-(5,6-dimethoxythieno[2,3-b]pyridin-2-yl)-3-oxo-propionic acid tert-butyl ester (1.2 g, 3.5567 mmol) and potassium carbonate (0.80 g, 5.7885 mmol) in N,N-dimethylformamide (20 mL). The reaction mixture was stirred at 20°C for 6 h. The reaction mixture was concentrated, diluted with EA (200 mL), washed with NaHCO3(aq) (200 mL) and brine (200 mL), the organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column with EA / n-hexane (0-50%), concentrated and dried under vacuum to give O1-tert-butylO4-ethyl 2-(5,6-dimethoxythieno[2,3-b]pyridine-2-carbonyl) succinate (1.72 g, 4.0616 mmol, 114.1951% yield), as a yellow oil. LCMS: (ESI, m / z): [M+H]+= 424.135.1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.86 (s, 1H), 4.82 (t, J = 7.3 Hz, 1H), 4.05 (m, 2H), 4.00 (s, 3H), 3.87 (s, 3H), 2.92 (d, J = 7.2 Hz, 2H), 1.32 (s, 9H), 1.18 – 1.06 (m, 3H). Step i: Ethyl 4-(5,6-dimethoxythieno[2,3-b]pyridin-2-yl)-4-oxobutyrate 20°C. Trifluoroacetic acid (2 mL) was added to a toluene (10 mL) solution of O1-tert-butylO4-ethyl 2-(5,6-dimethoxythieno[2,3-b]pyridin-2-carbonyl) succinate (1.51 g, 3.5657 mmol).The reaction mixture was stirred at 50°C for 1 h, evaporated under reduced pressure, and the residue was purified by MeCN / water (0-100%) on a C-18 column. After vacuum concentration and drying, ethyl 4-(5,6-dimethoxythieno[2,3-b]pyridin-2-yl)-4-oxobutyrate (0.94 g, 2.9069 mmol, 81.5252% yield) was given as a white solid. LCMS: (ESI, m / z): [M+H]+= 324.083.1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.79 (s, 1H), 4.00-4.08 (m, 2H), 3.99 (s, 3H), 3.87 (s, 3H), 3.30-3.33 (m, 2H), 2.67 (t, J = 6.1 Hz, 2H), 1.18 (t, J = 7.0 Hz, 3H). Step j: Ethyl 4-(6-chloro-5-methoxy-thieno[2,3-b]pyridin-2-yl)-4-oxobutyrate 20°C Ethyl 4-(5,6-dimethoxythieno[2,3-b]pyridin-2-yl)-4-oxobutyrate (0.308 g, 952.4899 μmol) was added to HCl (10 mL). The reaction mixture was stirred at 100°C for 1 h, cooled to 20°C, and POCl3 (1 mL) was added to the reaction mixture. The reaction mixture was stirred at 100°C for 2 h under N2 environment, evaporated under reduced pressure, and the residue was purified by MeCN / water (0-100%) on a C-18 column. After vacuum concentration and drying, ethyl 4-(6-chloro-5-methoxy-thieno[2,3-b]pyridin-2-yl)-4-oxobutyrate (0.25 g, 762.7004 μmol, 80.0744% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H]+= 328.033.1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.14 (s, 1H), 4.00-4.08 (m 2H), 3.99 (s, 3H), 3.44 – 3.36 (m, 2H), 2.70 (t, J = 6.2 Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H).Step k: 4-(5-(3-((2-(4-ethoxy-4-oxobutyryl)-5-methoxythiopheno[2,3-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate ethyl ester at 20°C. RockPhos Palladacycle Gen.3 (0.03 g, 35.7385 μmol) was added to 4-(6-chloro-5-methoxy-thiopheno[2,3-b]pyridin-2-yl)-4-oxobutyrate ethyl ester (0.10 g, 305.0799 μmol), 4-(5-(3-hydroxypropoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate ethyl ester (0.18 g, 512.2470 μmol), and potassium carbonate (0.20 g, ...). The mixture was added to a solution of 942.2127 μmol) of toluene (10 mL). The reaction mixture was stirred overnight at 130 °C under N2 atmosphere, evaporated under reduced pressure, and the residue was purified by MeCN / water (0-100%) on a C-18 column. The residue was concentrated and dried under vacuum to give ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutyryl)-5-methoxythieno[2,3-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.013 g, 20.2267 μmol, 6.6300% yield) as a yellow oil. LCMS: (ESI, m / z): [M+H]+= 643.225. Step 1: Disodium 4-(5-(3-((2-(3-carboxypropionic acid)-5-methoxythiopheno[2,3-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate 20°C. LiOH (3 mg, 125.2699 μmol) was added to tetrahydrofuran (4 mL) and water (1 mL) of ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutionic acid)-5-methoxythiopheno[2,3-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.018 g, 28.0062 μmol). The reaction mixture was stirred at 20°C for 1 h. The reaction system was purified by Prep-HPLC, concentrated, and dried by lyophilization.NaHCO3 (3.4 mg, 40.4730 μmol) was added to an aqueous (5 mL) solution of the lyophilized product, and the mixture was stirred at 20°C for 1 h. The solvent was removed by lyophilization to obtain disodium 4-(5-(3-((2-(3-carboxypropionic acid)-5-methoxythieno[2,3-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate (13 mg, 20.6162 μmol, 73.6129% yield), as a white solid. LCMS: (ESI, m / z): [M+H]+ = 587.162.

[0235] Example 14 4-(5-(3-((2-(3-carboxypropoxy)-4-chloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutyric acid Step a: Ethyl 4-[5-(3-bromopropoxy)-6-methoxy-benzothiophen-2-yl]-4-oxobutyrate In N2 environment, at 20°C, potassium carbonate (0.113 g, 817.6230 μmol) was added to a DMF (5 mL) solution of ethyl 4-(5-hydroxy-6-methoxybenzothiophen-2-yl)-4-oxobutyrate (0.081 g, 262.6894 μmol) and 1,3-dibromopropane (0.263 g, 1.3027 mmol). The reaction mixture was stirred overnight at 20°C. The mixture was purified by ACN / H2O (0-60%) on a C18 column, concentrated and dried under vacuum to give ethyl 4-[5-(3-bromopropoxy)-6-methoxy-benzothiophene-2-yl]-4-oxobutyrate (0.074 g, 172.3638 μmol, 65.6150% yield) as a white solid. LCMS: (ESI, m / z): [M+H]+= 309.070.1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.62 (s, 1H), 7.53 (s, 1H), 4.14 (t, J = 6.0 Hz, 2H), 4.06 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 3.70 (t, J = 6.5 Hz, 2H), 3.30 (t, J = 6.5 Hz, 2H), 2.66 (t, J = 6.4 Hz, 2H), 2.35 – 2.26 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H). Step b: 4-(5-(3-((4-chloro-2-(4-ethoxy-4-oxobutyryl)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutyrate ethyl ester. Under N2 conditions, at 20°C, potassium carbonate (0.094 g, 680.1466 μmol) was added to a DMF (3 mL) solution of 4-[5-(3-bromopropoxy)-6-methoxy-benzothiophen-2-yl]-4-oxobutyrate ethyl ester (0.092 g, 214.2904 μmol) and 4-(4-chloro-5-hydroxy-6-methoxyisoindoline-2-yl)-4-oxobutyrate ethyl ester (0.072 g, 219.6763 μmol). Heat the reaction mixture to 50°C and stir overnight.The mixture was purified on a C18 column using ACN / H2O (0.1% FA) (0-60%), concentrated and dried under vacuum to give ethyl 4-(5-(3-((4-chloro-2-(4-ethoxy-4-oxobutyryl)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyrate (0.089 g, 131.6233 μmol, 61.4229% yield), as a white solid. LCMS: (ESI, m / z): [M+H]+= 676.190.1H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1H), 7.60 (s, 1H), 7.51 (d, J = 4.3 Hz, 1H), 7.07 (s, 0.5H), 7.04 (s, 0.5H), 4.83 (s, 1H), 4.75 (s, 1H), 4.61 (s, 1H), 4.50 (s, 1H), 4.26 (s, 2H), 4.15 (t, J = 6.0 Hz, 2H), 4.10 – 4.01 (m, 4H), 3.86 (s, 3H), 3.77 (s, 3H), 3.31 – 3.27 (m, 2H), 2.70 – 2.52 (m, 6H), 2.24 – 2.14 (m, 2H), 1.18 (t, J = 7.1 Hz, 6H). Step c: 4-(5-(3-((2-(3-carboxypropionic acid)-4-chloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid. LiOH (0.051 g, 2.1296 mmol) was added to a solution of ethyl 4-(5-(3-((4-chloro-2-(4-ethoxy-4-oxobutionic acid)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid (0.040 g, 59.1565 μmol) in THF (2 mL) and H2O (2 mL). The reaction mixture was stirred at 20°C for 2 h. Adjust the pH of the reaction mixture to 3 using HCl (1 mol / L).The mixture was purified on a C18 column as ACN / H2O (0.1% FA) (0-45%), concentrated, and dried by lyophilization to give 4-(5-(3-((2-(3-carboxypropionic acid)-4-chloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid (0.025 g, 40.3183 μmol, 68.1552% yield) as a white solid. LCMS: (ESI, m / z): [M+H]+= 620.130.1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.59 (s, 1H), 7.50 (d, J = 3.3 Hz, 1H), 7.06 (s, 0.5H), 7.03 (s, 0.5H), 4.82 (s, 1H), 4.74 (s, 1H), 4.61 (s, 1H), 4.50 (s, 1H), 4.31 – 4.22 (m, 2H), 4.15 (t, J = 6.1 Hz, 2H), 3.86 (s, 3H), 3.77 (s, 3H), 3.26 – 3.24 (m, 2H), 2.61 – 2.55 (m, 4H), 2.54 – 2.44 (m, 2H), 2.19 (t, J = 6.2 Hz, 2H).

[0236] Example 15 4-(5-(3-((2-(3-carboxypropionic acid)-5-methoxythiopheno[3,2-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid Step a: Ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutionic acid)-5-methoxythiopheno[3,2-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid In N2 environment, at 20°C, potassium carbonate (0.089 g, 643.9686 μmol) was added to ethyl 4-(6-hydroxy-5-methoxythiopheno[3,2-b]pyridin-2-yl)-4-oxobutyric acid (0.069 g, The reaction mixture was added to a DMF (2 mL) solution of ethyl 4-(5-(3-bromopropoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.079 g, 190.6877 μmol). The reaction mixture was heated to 50 °C and stirred overnight. The reaction mixture was purified by ACN / H2O (0.1% FA) (0-55%) on a C18 column, concentrated, and dried by lyophilization to give ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutyryl)-5-methoxythieno[3,2-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.075 g, 116.6925 μmol, 61.1956% yield) as a white solid. LCMS: (ESI, m / z): [M+H]+= 690.130.1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.03 (s, 1H), 7.06 – 6.89 (m, 2H), 4.74 (s, 1H), 4.72 (s, 1H), 4.51 (s, 2H), 4.27 (t, J = 6.2 Hz, 2H), 4.12 (t, J = 6.7 Hz, 2H), 4.09 – 4.01 (m, 4H), 3.96 (s, 3H), 3.74 (d, J = 2.1 Hz, 3H), 3.40 – 3.34 (m, 2H), 2.68 – 2.54 (m, 6H), 2.29 – 2.19 (m, 2H), 1.18 (t, J = 7.1 Hz, 6H).Step b: 4-(5-(3-((2-(3-carboxypropionic acid)-5-methoxythiopheno[3,2-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid 20°C. LiOH (0.050 g, 2.0878 mmol) was added to a solution of ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutionic acid)-5-methoxythiopheno[3,2-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid (0.051 g, 79.3509 μmol) in THF (2 mL), H2O (2 mL), and ethanol (1 mL). The reaction mixture was stirred at 20°C for 2 h. The pH of the reaction mixture was adjusted to 3 with HCl (1 mol / L). The reaction mixture was purified on a C18 column as ACN / H2O (0.1% FA) (0-45%). The solution was concentrated and dried by lyophilization to give 4-(5-(3-(((2-(3-carboxypropionic acid)-5-methoxythieno[3,2-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid (0.015 g, 25.5707 μmol, 32.2248% yield), as a white solid. LCMS: (ESI, m / z): [M+H]+= 586.160.1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.02 (s, 1H), 7.02 – 6.92 (m, 2H), 4.73 (s, 1H), 4.71 (s, 1H), 4.51 (s, 2H), 4.27 (t, J = 6.2 Hz, 2H), 4.12 (s, J = 4.0 Hz, 2H), 3.96 (s, 3H), 3.74 (s, 3H), 3.40 – 3.34 (m, 2H), 2.63 – 2.46 (m, 6H), 2.24 (t, J = 6.2 Hz, 2H).

[0237] Example 16 4-(5-((2-(((2-(3-carboxypropyl)-4-chloro-6-methoxyisoindoline-5-yl)oxy)methyl)allyl)oxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid Step a: Ethyl 4-[4-chloro-5-[2-(chloromethyl)allyloxy]-6-methoxy-isoindoline-2-yl]-4-oxobutyrate Under N2 conditions, at 20°C, 3-chloro-2-(chloromethyl)prop-1-ene (0.507 g, 2.2635 mmol) was added to potassium carbonate (0.202 g, 1.4616 mmol) and ethyl 4-(4-chloro-5-hydroxy-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.154 g, The reaction mixture was added to a 5 mL DMF mixture containing 469.8574 μmol. The reaction mixture was stirred at 20°C for 3 h. The reaction mixture was purified by ACN / H2O (0.1% FA) (0-50%) on a C18 column, concentrated and dried under vacuum to give ethyl 4-[4-chloro-5-[2-(chloromethyl)allyloxy]-6-methoxy-isoindoline-2-yl]-4-oxobutyrate (0.151 g, 362.7238 μmol, 77.1987% yield) as a white solid. LCMS: (ESI, m / z): [M+H]+= 416.100. Step b: 4-(5-((2-(((4-chloro-2-(4-ethoxy-4-oxobutyryl)-6-methoxyisoindoline-5-yl)oxy)methyl)allyl)oxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyrate ethyl ester. Under N2 conditions, at 20°C, K2CO3 (0.092 g, 665.6754 μmol) was added to 4-(4-chloro-5-((2-(chloromethyl)allyl)oxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate ethyl ester (0.068 g, 163.3458 μmol). The reaction mixture was added to a DMF (3 mL) mixture of ethyl 4-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutyrate (0.049 g, 150.1504 μmol). The reaction mixture was stirred overnight at 50 °C. The reaction mixture was purified by ACN / H2O (0.1% FA) (0-60%) on a C18 column, concentrated, and dried by lyophilization to give ethyl 4-(5-((2-(((4-chloro-2-(4-ethoxy-4-oxobutyryl)-6-methoxyisoindoline-5-yl)oxy)methyl)allyl)oxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutyrate (0.022 g, 31.1538 μmol, 19.0723% yield) as a white solid.LCMS: (ESI, m / z): [M+H]+= 706.180.1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.56 (s, 1H), 7.07 (s, 0.5H), 7.04 (s, 0.5H), 5.34 (d, J = 10.9 Hz, 2H), 4.83 (s, 1H), 4.77 (s, 2H), 4.70 (s, 1H), 4.66 (s, 2H), 4.61 (s, 1H), 4.47 (s, 1H), 4.06 (q, J = 7.1 Hz, 4H), 3.89 (s, 3H), 3.81 (s, 3H), 3.40 – 3.34 (m, 2H), 2.69 – 2.54 (m, 6H), 1.21 – 1.14 (m, 6H). Step c: 4-(5-((2-(((2-(3-carboxypropyl)-4-chloro-6-methoxyisoindoline-5-yl)oxy)methyl)allyl)oxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid 20°C. LiOH (0.037 g, 1.5450 mmol) was added to a solution of ethyl 4-(5-((2-(((4-chloro-2-(4-ethoxy-4-oxobutyryl)-6-methoxyisoindoline-5-yl)oxy)methyl)allyl)oxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid (0.012 g, 16.9930 μmol) in THF (1 mL) and H2O (1 mL). The reaction mixture was stirred at 20°C for 1 h, and the pH of the reaction mixture was adjusted to 3 with HCl (1 mol / L). The mixture was evaporated under reduced pressure, and the residue was purified on a C18 column as ACN / H2O (0.1% FA) (0-50%). The residue was concentrated and dried by lyophilization to give 4-(5-((2-(((2-(3-carboxypropyl)-4-chloro-6-methoxyisoindoline-5-yl)oxy)methyl)allyl)oxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid (0.011 g, 16.9213 μmol, 99.5782% yield), as a white solid.LCMS: (ESI, m / z): [M-H]-= 648.120.1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 3.0 Hz, 1H), 7.56 (s, 1H), 7.06 (s, 0.5H), 7.03 (s, 0.5H), 5.34 (d, J = 10.8 Hz, 2H), 4.82 (s, 1H), 4.77 (d, J = 3.3 Hz, 2H), 4.68 (s, 1H), 4.66 (s, 2H), 4.61 (s, 1H), 4.46 (s, 1H), 3.89 (s, 3H), 3.81 (s, 3H), 3.32 – 3.26 (m, 2H), 2.61 – 2.53 (m, 4H), 2.48 – 2.44 (m, 2H)。

[0238] Example 17 (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid Step a: 4-fluoro-6-methoxyisoindoline-5-ol hydrochloride 20°C Add EA solution (3 mL, 12 mmol) of HCl to EA solution (1 mL) of 4-fluoro-5-hydroxy-6-methoxyisoindoline-2-carboxylic acid tributyl ester (0.103 g, 363.5790 μmol). The reaction mixture was stirred at 20°C for 2 h and evaporated under reduced pressure to give 4-fluoro-6-methoxyisoindoline-5-ol hydrochloride (0.12 g, 655.0962 μmol, 180.1799% yield), as a white solid. It was used directly in the next step. LCMS: (ESI, m / z): [M+H]+= 184.070. Step b: Methyl (2S)-4-(4-fluoro-5-hydroxy-6-methoxy-isoindoline-2-yl)-2-methyl-4-oxobutyrate was added to a solution of (S)-4-methoxy-3-methyl-4-oxobutyric acid (0.108 g, 739.0133 μmol), HATU (0.197 g, 518.1084 μmol), and DIEA (0.450 g, 3.4818 mmol) in DMF (10 mL) at 20°C under N2 conditions. The reaction mixture was stirred at 20°C for 2 h. The reaction mixture was purified on a C18 column as ACN / H2O (0.1% FA) (0-55%), concentrated and dried under vacuum to give methyl (2S)-4-(4-fluoro-5-hydroxy-6-methoxy-isoindoline-2-yl)-2-methyl-4-oxobutyrate (0.061 g, 195.9494 μmol, 32.0481% yield) as a white solid.LCMS: (ESI, m / z): [M+H]+= 312.120. Step c: (2S)-4-[5-(3-bromopropoxy)-4-fluoro-6-methoxy-benzo[b]thiophen-2-yl]-2-methyl-4-oxobutyrate ethyl ester. Under N2 conditions, at 20°C, 1,3-dibromopropane (0.255 g, 1.2631 mmol) was added to a mixture of (S)-4-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-2-methyl-4-oxobutyrate ethyl ester (0.061 g, 179.2189 μmol) and potassium carbonate (0.129 g, 933.3927 μmol) in DMF (3 mL). The reaction mixture was stirred at 20°C for 3 h. The mixture was purified on a C18 column as ACN / H2O (0.1% FA) (0-70%), concentrated and dried under vacuum to give ethyl (2S)-4-[5-(3-bromopropoxy)-4-fluoro-6-methoxy-benzothiophene-2-yl]-2-methyl-4-oxobutyrate (0.66 g, 1.4306 mmol, 798.2476% yield) as a white solid. LCMS: (ESI, m / z): [M+H]+= 461.040. Step d: (S)-4-(4-fluoro-5-(3-((4-fluoro-6-methoxy-2-((S)-4-methoxy-3-methyl-4-oxobutyryl)isoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyrate ethyl ester. Potassium carbonate (0.074 g, 535.4346 μmol) was added to (2S)-4-[5-(3-bromopropoxy)-4-fluoro-6-methoxy-benzothiophene-2-yl]-2-methyl-4-oxobutyrate ethyl ester (0.071 g, 153.8990 μmol) at 20°C. The reaction mixture was added to a DMF (3 mL) solution of methyl (2S)-4-(4-fluoro-5-hydroxy-6-methoxy-isoindoline-2-yl)-2-methyl-4-oxobutyrate (0.056 g, 179.8880 μmol). The reaction mixture was stirred overnight at 50 °C under N2 atmosphere. The reaction mixture was purified on a C18 column using ACN / H2O (0.1% FA) (0-50%), concentrated and dried under vacuum to give ethyl (S)-4-(4-fluoro-5-(3-((4-fluoro-6-methoxy-2-((S)-4-methoxy-3-methyl-4-oxobutyryl)isoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyrate (61 mg, 88.1841 μmol, 57.3000% yield), as a white solid.LCMS: (ESI, m / z): [M+H]+= 692.230.1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.56 (s, 1H), 6.90 (s, 0.5H), 6.85 (s, 0.5H), 4.77 (s, 2H), 4.56 (s, 1H), 4.54 (s, 1H), 4.25 (t, J = 6.1 Hz, 2H), 4.19 (t, J = 6.1 Hz, 2H), 4.05 (q, J = 7.0 Hz, 2H), 3.88 (s, 3H), 3.77 (d, J = 2.1 Hz, 3H), 3.59 (s, 3H), 3.55 – 3.43 (m, 1H), 3.26 – 3.15 (m, 1H), 3.00 – 2.90 (m, 1H), 2.90 – 2.79 (m, 1H), 2.76 – 2.66 (m, 1H), 2.50 – 2.44 (m, 1H), 2.09 – 1.99 (m, 2H), 1.21 – 1.10 (m, 9H). Step e: (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 20°C. LiOH (0.038 g, 1.5868 mmol) was added to (S)-4-(4-fluoro-5-(3-((4-fluoro-6-methoxy-2-((S)-4-methoxy-3-methyl-4-oxobutyryl)isoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid ethyl ester (0.038 g, 54.9344 μmol) in THF (2 mL) and H2O (2 mL). The mixture was stirred at 20°C for 2 h. The reaction mixture was adjusted to pH 3 with HCl (1 mol / L), evaporated under reduced pressure, and the residue was purified on a C18 column using ACN / H2O (0.1% FA) (0-45%). The residue was concentrated and dried by lyophilization to give (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid (18 mg, 27.7070 μmol, 50.4365% yield) as a white solid.LCMS: (ESI, m / z): [M+H]+= 650.18.1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 2H), 8.30 (s, 1H), 7.56 (s, 1H), 6.90 (s, 0.5H), 6.85 (s, 0.5H), 4.76 (s, 2H), 4.56 (s, 1H), 4.54 (s, 1H), 4.26 (t, J = 6.5 Hz, 2H), 4.19 (t, J = 6.1 Hz, 2H), 3.88 (s, 3H), 3.77 (s, 3H), 3.53 – 3.44 (m, 1H), 3.17 – 3.05 (m, 1H), 2.93 – 2.83 (m, 1H), 2.79 – 2.61 (m, 2H), 2.45 – 2.35 (m, 1H), 2.11 – 1.98 (m, 2H), 1.22 – 1.10 (m, 6H)。

[0239] Example 18 4-(5-(3-((2-((2-carboxyethyl)aminomethoxy)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid Step a: Ethyl 3-[[6-methoxy-5-(methoxymethoxy)benzo[b]thiophene-2-carbonyl]amino]propionate 20°C Add ethyl aminopropionate hydrochloride (0.34 g, 2.2134 mmol) to a DMF (15 mL) solution of HATU (0.85 g, 2.2355 mmol), DIEA (0.77 g, 5.9578 mmol) and 6-methoxy-5-(methoxymethoxy)benzo[b]thiophene-2-carboxylic acid (0.29 g, 1.0809 mmol). The reaction mixture was stirred at 20°C for 2 h. The mixture was purified by ACN / H2O (0.1% FA) (0-50%) on a C18 column, concentrated and dried under vacuum to give ethyl 3-[[6-methoxy-5-(methoxymethoxy)benzothiophene-2-carbonyl]amino]propionate (0.35 g, 952.5987 μmol, yield 88.1269%) as a yellow oil. LCMS: (ESI, m / z): [M+H]+= 368.110. Step b: Ethyl 3-[(5-hydroxy-6-methoxy-benzothiophene-2-carbonyl)amino]propionate ethyl 3-[[6-methoxy-5-(methoxymethoxy)benzothiophene-2-carbonyl]amino]propionate (0.29 g, 789.2963 μmol) was added to acetic acid (10 mL) at 20°C. The reaction mixture was heated to 120 °C and stirred for 4 h. The mixture was purified by ACN / H2O (0.1% FA) (0-40%) on a C18 column, concentrated and dried under vacuum to give ethyl 3-[(5-hydroxy-6-methoxy-benzothiophene-2-carbonyl)amino]propionate (0.23 g, 711.2738 μmol, yield 90.1149%) as a white solid. LCMS: (ESI, m / z): [M+H]+= 324.080. Step c: Ethyl 4-(5-(3-(((2-((3-ethoxy-3-oxopropyl)aminomethoxy)-6-methoxybenzo[b]thiophene-5-yl)oxy)propyl)-6-methoxyisoindoline-2-yl)-4-oxobutyrate was added to a DMF (5 mL) solution of ethyl 3-[(5-hydroxy-6-methoxybenzothiophene-2-carbonyl)amino]propionate (0.21 g, 649.4249 μmol) and ethyl 4-(5-(3-bromopropoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.21 g, 506.8913 μmol).The reaction mixture was heated to 50°C and stirred for 8 hours under N2 atmosphere. The reaction mixture was purified by ACN / H2O (0.1% FA) (0-65%) on a C18 column. It was concentrated and dried under vacuum to give ethyl 4-(5-(3-((2-((3-ethoxy-3-oxopropyl)aminomethyl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propyl)-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.147 g, 223.8324 μmol, 34.4662% yield). LCMS: (ESI, m / z): [M+H]+= 657.240. Step d: 4-(5-(3-((2-((2-carboxyethyl)aminomethyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid 20°C. LiOH (0.101 g, 4.2174 mmol) was added to a solution of ethyl 4-(5-(3-((2-((3-ethoxy-3-oxopropyl)aminomethyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid (0.082 g, 124.8589 μmol) in THF (8 mL) and H2O (8 mL). The reaction mixture was stirred at 20°C for 2 h. The pH of the reaction mixture was adjusted to 3 with HCl (1 mol / L), evaporated under reduced pressure, and the residue was purified on a C18 column using ACN / H2O (0.1% FA) (0-45%). The residue was concentrated and dried by lyophilization to give 4-(5-(3-((2-((2-carboxyethyl)aminomethyl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid (49 mg, 81.5803 μmol, 65.3380% yield) as a white solid.LCMS: (ESI, m / z): [M+H]+= 601.180.1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 2H), 8.69 (t, J = 5.5 Hz, 1H) ,7.88 (s, 1H), 7.56 (s, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.08 – 6.90 (m, 2H), 4.74 (s, 1H), 4.71 (s, 1H), 4.53 (s, 2H), 4.25 – 4.16 (m, 2H), 4.16 – 4.09 (m, 2H), 3.84 (d, J = 1.5 Hz, 3H), 3.74 (d, J = 2.1 Hz, 3H), 3.50 – 3.42 (m, 2H), 2.60 – 2.52 (m, 4H), 2.50 – 2.47 (m, 2H), 2.27 – 2.17 (m, 2H)。

[0240] Example 19 4-(5-((2-(((2-(3-carboxypropyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)methyl)allyl)oxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid Step a: Ethyl 4-[5-[2-(chloromethyl)allyloxy]-6-methoxy-isoindoline-2-yl]-4-oxobutyrate 20°C 3-chloro-2-(chloromethyl)prop-1-ene (1.108 g, 8.8643 mmol) was added to ethyl 4-(5-hydroxy-6-methoxyisoindoline-2-yl)-4-oxobutyrate (0.507 g, 1.7285 mmol) and potassium carbonate (0.816 g, 5.9043 mmol) in DMF (20 The reaction mixture was stirred at 20°C for 8 h. The reaction mixture was quenched with water (100 mL) at 20°C, extracted with EA (3 x 50 mL), and washed with brine (50 mL). The organic phase was dried over Na₂SO₄, filtered, and evaporated under reduced pressure. The residue was purified by EA / n-Hex (0-70%) on a silica gel column, concentrated under vacuum, and dried to give ethyl 4-[5-[2-(chloromethyl)allyloxy]-6-methoxy-isoindoline-2-yl]-4-oxobutyrate (0.27 g, 707.0847 μmol, 40.9069% yield) as a yellow oil. LCMS: (ESI, m / z): [M+H]+= 382.130. Step b: 4-[5-[2-[[2-(4-ethoxy-4-oxy-butyryl)-6-methoxy-isoindoline-5-yl]oxymethyl]allyloxy]-6-methoxy-benzothiophene-2-yl]-4-oxobutyrate ethyl ester. Sodium iodide (0.179 g, 1.1942 mmol) was added to 4-[5-[2-(chloromethyl)allyloxy]-6-methoxy-isoindoline-2-yl]-4-oxobutyrate ethyl ester (0.216 g, 55.6671 μmol) and 4-(5-hydroxy-6-methoxybenzothiophene-2-yl)-4-oxobutyrate ethyl ester (0.186 g, 603.2128 μmol) at 20°C. The mixture was added to a 5 mL solution of DMF containing 1.7221 μmol of potassium carbonate (0.238 g, 1.7221 mmol). The reaction mixture was stirred at 20°C for 5 h under N2 atmosphere.The mixture was purified on a C18 column using ACN / H2O (0.1% FA) (0-70%), concentrated and dried under vacuum to give ethyl 4-[5-[2-[[2-(4-ethoxy-4-oxy-butyryl)-6-methoxy-isoindoline-5-yl]oxymethyl]allyloxy]-6-methoxy-benzothiophene-2-yl]-4-oxobutyrate (0.169 g, 258.5135 μmol, 45.7006% yield), as a white solid. LCMS: (ESI, m / z): [M+H]+= 654.230.1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.63 (d, J = 4.9 Hz, 1H), 7.53 (s, 1H), 7.05 – 6.87 (m, 2H), 5.45 – 5.32 (m, 2H), 4.81 – 4.72 (m, 3H), 4.66 (s, 3H), 4.52 (s, 1H), 4.50 (s, 1H), 4.10 – 4.00 (m, 4H), 3.87 (d, J = 1.9 Hz, 3H), 3.76 (d, J = 2.8 Hz, 3H), 3.32 – 3.26 (m, 2H), 2.72 – 2.52 (m, 6H), 1.21 – 1.13 (m, 6H). Step c: 4-(5-((2-(((2-(3-carboxypropyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)methyl)allyl)oxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid. LiOH (0.073 g, 3.0482 mmol) was added to a mixture of ethyl 4-[5-[2-[[2-(4-ethoxy-4-oxy-butyryl)-6-methoxy-isoindoline-5-yl]oxymethyl]allyloxy]-6-methoxy-benzothiophen-2-yl]-4-oxobutyric acid (0.075 g, 114.7249 μmol) in THF (4 mL) and H2O (2 mL). The reaction mixture was stirred at 20°C for 2 h. The reaction mixture was adjusted to pH 3 with HCl (1 mol / L) and evaporated under reduced pressure. The residue was purified on a C18 column as ACN / H2O (0.1% FA) (0-45%), concentrated, and dried by lyophilization to give 4-(5-((2-(((2-(3-carboxypropyl)-6-methoxybenzo[b]thiophene-5-yl)oxy)methyl)allyl)oxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid (0.0423 g, 70.7794 μmol, 61.6949% yield) as a white solid.LCMS: (ESI, m / z): [M+H]+= 598.170.1H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 2H), 8.15 (s, 1H), 7.63 (d, J = 4.0 Hz, 1H), 7.53 (s, 1H), 7.06 – 6.90 (m, 2H), 5.45 – 5.32 (m, 2H), 4.78 – 4.70 (m, 3H), 4.66 (t, J = 3.3 Hz, 3H), 4.53 (s, 1H), 4.50 (s, 1H), 3.87 (d, J = 1.6 Hz, 3H), 3.76 (d, J = 2.6 Hz, 3H), 3.29 – 3.24 (m, 2H), 2.65 – 2.50 (m, 6H)。

[0241] Example 20 4-(5-(3-((2-(3-carboxypropionic acid)-4-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid Step a: Ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutionic acid)-4-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid 20°C Ethyl 4-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophene-2-yl)-4-oxobutyric acid (0.081 g, 248.2078 μmol) and potassium carbonate (0.136 g, 984.0419 μmol) 4-(5-(3-bromopropoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate ethyl ester (0.103 g, 248.6182 μmol) was added to a solution of N,N-dimethylformamide (10 mL). The reaction mixture was stirred overnight at 50 °C. The mixture was diluted with ethyl acetate (100 mL) and washed successively with water (100 mL) and brine (100 mL). The organic phase was dried over Na₂SO₄, filtered, and evaporated under reduced pressure. The residue was purified by MeCN / water (0-100%) on a C-18 column, concentrated and dried under vacuum to give ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutyryl)-4-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyrate (66 mg, 100.0428 μmol, 40.2396% yield), as a white solid. LCMS: (ESI, m / z): [M+H]+= 432.070.1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.57 (d, J = 3.2 Hz, 1H), 6.98 (s, 0.5H), 6.95 (s, 1H), 6.92 (s, 0.5H), 4.74 (s, 2H), 4.53 (s, 2H), 4.31 – 4.09 (m, 4H), 4.09 – 3.98 (m, 4H), 3.87 (s, 3H), 3.73 (s, 3H), 3.41 – 3.34 (m, 2H), 2.70 – 2.53 (m, 6H), 2.17 – 2.04 (m, 2H), 1.21 – 1.12 (m, 6H).Step b: 4-(5-(3-((2-(3-carboxypropionic acid)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid was added to a solution of ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutionic acid)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid (0.052 g, 78.8217 μmol) in tetrahydrofuran (10 mL) and water (2 mL). The reaction mixture was stirred at 50°C for 2 h. The reaction system was acidified to pH 4 by permeation with HCl (1 M) and evaporated under reduced pressure. The residue was purified by MeCN / water (0-100%) on a C-18 column, concentrated and dried under vacuum to give 4-(5-(3-((2-(3-carboxypropionic acid)-4-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyric acid (22 mg, 36.4473 μmol, 46.2402% yield), as a white solid. LCMS: (ESI, m / z): [M+H]+= 604.157.1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 2H), 8.30 (s, 1H), 7.57 (s, 1H), 6.98 (s, 0.5H), 6.95 (s, 1H), 6.92 (s, 0.5H), 4.74 (s, 2H), 4.53 (s, 2H), 4.33 – 4.06 (m, 4H), 3.91 (s, 3H), 3.68 (s, 3H), 3.30-3.38 (m, 2H), 2.71 – 2.53 (m, 6H), 2.18 – 2.10 (m, 2H).

[0242] Example 21 Trans-2-(5-(3-((2-(3-carboxypropionic acid)-4-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-carbonyl)cyclopropane-1-carboxylic acid Step a: Trans-2-[5-(5,5-dimethyl-1,3,2-dioxananaphthyl)-6-methoxy-benzothiophene-2-carbonyl]cyclopropane carboxylic acid methyl ester Add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.203 g, 277.4347 μmol) to trans-2-(5-bromo-6-methoxybenzo[b]thiophene-2-carbonyl)cyclopropane-1-carboxylic acid methyl ester (0.510 g, 1.3813 μmol) The reaction mixture was heated to 90°C and stirred overnight under N2 atmosphere. The reaction mixture was filtered through a diatomaceous earth mat, and the filtrate was evaporated under reduced pressure to give crude trans-2-[5-(5,5-dimethyl-1,3,2-dioxananaphthyl-2-yl)-6-methoxy-benzothiophene-2-carbonyl]cyclopropane methyl ester (1.61 g, 2.0012 mmol, 144.8795% yield) as a black oil, which was used directly in the next step. LCMS: (ESI, m / z): [M+H]+= 403.13. Step b: Methyl trans-2-(5-hydroxy-6-methoxy-benzothiophene-2-carbonyl)cyclopropane carboxylate H₂O₂ (3.0 mL, 24.7468 mmol, 30% aqueous solution) was added to a mixture of trans-2-[5-(5,5-dimethyl-1,3,2-dioxananaphthyl)-6-methoxy-benzothiophene-2-carbonyl]cyclopropane carboxylate (1.56 g, 1.9390 mmol) and NaHCO₃ (3.0 mL, 1.6722 mmol, 5% aqueous solution) in THF (30 mL). The reaction mixture was stirred at 20°C for 1 h. The resulting reaction mixture was diluted with brine (150 mL), extracted with EA (150 mL), and washed with brine (150 mL). The organic matter was collected, dried over Na₂SO₄, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / n-hexane (0-100%), concentrated and dried under reduced pressure to give trans-2-(5-hydroxy-6-methoxy-benzothiophene-2-carbonyl)cyclopropanecarboxylic acid methyl ester (0.30 g, 979.3261 μmol, yield 71.43%), as a reddish-brown solid.LCMS: (ESI, m / z): [M+H]+= 307.05.1H NMR (400 MHz, CDCl3-d) δ 7.98 (s, 1H), 7.38 (s, 1H), 7.26 (s, 1H), 4.02 (s, 3H), 3.76 (s, 3H), 3.23 – 3.11 (m, 1H), 2.49 – 2.38 (m, 1H), 1.73 – 1.66 (m, 1H), 1.65 – 1.58 (m, 1H). Step c: 4-Fluoro-6-methoxy-5-[3-[6-methoxy-2-[trans-2-methoxycarbonylcyclopropanecarbonyl]benzothiophene-5-yl]oxypropoxy]isoindoline-2-carboxylic acid tert-butyl ester. At 20°C, K₂CO₃ (0.501 g, 3.6250 mmol) was added to a DMF (10 mL) solution of trans-2-(5-hydroxy-6-methoxy-benzothiophene-2-carbonyl)cyclopropanecarboxylic acid methyl ester (0.300 g, 979.3264 μmol) and 5-(3-bromopropoxy)-4-fluoro-6-methoxyisoindoline-2-carboxylic acid tert-butyl ester (0.406 g, 1.0043 mmol). The reaction mixture was heated to 60°C and stirred overnight. The resulting reaction mixture was diluted with H₂O (150 mL), extracted with EA (150 mL), and washed with brine (2 x 150 mL). The organic phase was collected, dried over Na₂SO₄, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / n-hexane (0-50%), concentrated, and dried under reduced pressure to give 4-fluoro-6-methoxy-5-[3-[6-methoxy-2-[trans-2-methoxycarbonylcyclopropanecarbonyl]benzothiophene-5-yl]oxypropoxy]isoindoline-2-carboxylic acid tributyl ester (0.45 g, 714.6357 μmol, yield 72.9722%) as a pale yellow solid.LCMS: (ESI, m / z): [M+H-Boc]+= 530.20.1H NMR (400 MHz, CDCl3-d) δ 7.92 (s, 1H), 7.29 (s, 1H), 7.18 (s, 1H), 6.50 (s, 1H), 4.55 (s, 4H), 4.28 (t, J = 6.4 Hz, 2H), 4.20 (t, J = 5.8 Hz, 2H), 3.87 (s, 3H), 3.71 (s, 3H), 3.67 (s, 3H), 3.11 – 3.04 (m, 1H), 2.38 – 2.31 (m, 1H), 2.30 – 2.20 (m, 2H), 1.65 – 1.58 (m, 1H), 1.57 – 1.50 (m, 1H), 1.44 (s, 9H). Step d: Methyl trans-2-[5-[3-(4-fluoro-6-methoxy-isoindoline-5-yl)oxypropoxy]-6-methoxy-benzothiophene-2-carbonyl]cyclopropanecarboxylate. At 20°C, a solution of EA (15 mL, 60 mmol) in HCl (4 N) was added to a solution of EA (5 mL) in 0.45 g (714.6351 μmol) of tert-butyl 4-fluoro-6-methoxy-5-[3-[6-methoxy-2-[trans-2-methoxycarbonylcyclopropanecarbonyl]benzothiophene-5-yl]oxypropoxy]isoindoline-2-carboxylate. The reaction mixture was stirred at 20°C for 2 h. The resulting reaction mixture was concentrated under reduced pressure to give trans-2-[5-[3-(4-fluoro-6-methoxy-isoindoline-5-yl)oxypropoxy]-6-methoxy-benzothiophene-2-carbonyl]cyclopropane carboxylate methyl ester (0.42 g, 667.8009 μmol, 93.4464% yield, HCl salt), as a gray solid.LCMS: (ESI, m / z): [M+H]+= 530.20.1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 2H), 8.49 (s, 1H), 7.63 (s, 1H), 7.52 (s, 1H), 6.98 (s, 1H), 4.50 (s, 2H), 4.46 (s, 2H), 4.23 (t, J = 6.0 Hz, 2H), 4.17 (t, J = 5.8 Hz, 2H), 3.86 (s, 3H), 3.77 (s, 3H), 3.68 (s, 3H), 3.30 – 3.26 (m, 1H), 2.27 – 2.20 (m, 1H), 2.19 – 2.11 (m, 2H), 1.54 (t, J = 7.1 Hz, 2H). Step e: A solution of trans-2-[5-[3-[2-(4-ethoxy-4-oxy-butyryl)-4-fluoro-6-methoxy-isoindoline-5-yl]oxypropoxy]-6-methoxy-benzothiophene-2-carbonyl]cyclopropanecarboxylate was added dropwise at 0°C to a solution of trans-2-[5-[3-(4-fluoro-6-methoxy-isoindoline-5-yl)oxypropoxy]-6-methoxy-benzothiophene-2-carbonyl]cyclopropanecarboxylate (0.202 g, 356.8671 μmol, hydrochloride) and N,N-diisopropylethylamine (0.185 mL, 1.0621 mmol) in THF (4... The reaction mixture was stirred at 20°C for 2 h with a solution of 4 mL of ACN and 4 mL of acetone. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC with DCM / MeOH (25:1) as the developing solvent to give trans-2-[5-[3-[2-(4-ethoxy-4-oxy-butyryl)-4-fluoro-6-methoxy-isoindoline-5-yl]oxypropoxy]-6-methoxy-benzothiophene-2-carbonyl]cyclopropane carboxylate (0.221 g, 336.0184 μmol, 94.1579% yield) as a grayish-white semi-solid.LCMS: (ESI, m / z): [M+H]+= 658.25.1H NMR (400 MHz, CDCl3-d) δ 7.93 (s, 1H), 7.19 (s, 2H), 6.54 (s, 0.5H), 6.49 (s, 0.5H), 4.74 (d, J = 7.7 Hz, 2H), 4.68 (d, J = 5.6 Hz, 2H), 4.29 (s, 2H), 4.21 (s, 2H), 4.09 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 3.73 (s, 3H), 3.68 (s, 3H), 3.15 – 3.02 (m, 1H), 2.72 – 2.54 (m, 4H), 2.40 – 2.31 (m, 1H), 2.30 – 2.18 (m, 2H), 1.65 – 1.51 (m, 2H), 1.20 (t, J = 7.0 Hz, 3H). Step f: trans-2-(5-(3-((2-(3-carboxypropionic acid)-4-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-carbonyl)cyclopropane-1-carboxylic acid. At 20°C, LiOH (0.027 g, 1.1274 mmol) was added to a solution of trans-2-[5-[3-[2-(4-ethoxy-4-oxy-butyryl)-4-fluoro-6-methoxy-isoindoline-5-yl]oxypropoxy]-6-methoxy-benzothiophene-2-carbonyl]cyclopropanecarboxylic acid methyl ester (0.165 g, 250.8735 μmol) in THF (6 mL) and H₂O (2 mL). The reaction mixture was stirred at 20°C for 2 h. The resulting reaction mixture was adjusted to pH 2–3 with HCl (6 N) and evaporated under reduced pressure. The residue was purified by reverse-phase C18 column chromatography, eluted with mobile phase ACN / H2O (0.1% FA) (0–100%), concentrated, and lyophilized overnight to give trans-2-(5-(3-((2-(3-carboxypropionic acid)-4-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-carbonyl)cyclopropane-1-carboxylic acid (0.052 g, 84.4674 μmol, 33.6693% yield), as a white solid.LCMS: (ESI, m / z): [M+H]+= 616.20.1H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 2H), 8.48 (s, 1H), 7.61 (s, 1H), 7.51 (d, J = 2.2 Hz, 1H), 6.91 (s, 0.5H), 6.88 (s, 0.5H), 4.78 (d, J = 5.5 Hz, 2H), 4.56 (s, 2H), 4.23 (t, J = 5.0 Hz, 2H), 4.17 (t, J = 5.9 Hz, 2H), 3.86 (s, 3H), 3.76 (s, 3H), 3.27 – 3.19 (m, 1H), 2.60 – 2.53 (m, 2H), 2.49 – 2.44 (m, 2H), 2.21 – 2.07 (m, 3H), 1.49 (t, J = 7.1 Hz, 2H). The following examples in Table 2 were synthesized using the above steps or modified steps, with the corresponding starting materials and intermediates. Table 2. Example Chemical name structural MS: (M+H) + & 1 HNMR twenty two. 4-(5-(3-((2-(3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 614 twenty three. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 614 twenty four. (S)-4-(5-(3-((2-(3-carboxypropyl)-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 600 25. (S)-4-(5-(3-((2-(3-carboxypropyl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 600 26. (S)-4-(5-(2-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)ethoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 600 27. (S)-4-(5-(4-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)butoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 628 28. (S)-4-(5-((5-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)pentyl)oxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 642 29. (S)-4-(5-(4-(2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)butoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 612 30. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)amino)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 613 31. (S)-4-(5-(4-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)amino)butyl)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 611 32. (S)-4-(5-(4-(2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)butyl)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 596 33. (S)-4-(5-(5-(2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)pentyl)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 610 34. (2S)-4-(5-((4-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)pentane-2-yl)oxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 642 35. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)-2,2-dimethylpropoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 642 36. (S)-4-(5-((1-(((2-(((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)methyl)cyclopropyl)methoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 640 37. 4-(5-(3-((2-(3-carboxypropionic acid)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2,2-dimethyl-4-oxobutyric acid 614 38. 4-(5-(3-((2-(3-carboxypropionic acid)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2,2-dimethyl-4-oxobutyric acid 614 39. 4-(5-(3-((2-(3-carboxy-3-methylbutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2,2-dimethyl-4-oxobutyric acid 642 40. (S)-4-(5-((4-(2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)butyl)amino)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 611 41. (S)-4-(5-((3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propyl)amino)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 613 42. (S)-4-(5-(4-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)butyl)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 612 43. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 632 44. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 648 45. (S)-4-(5-(3-((4-bromo-2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 692 46. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[d]thiazolyl-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 615 47. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-hydroxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 600 48. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 650 49. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-dichloro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 682 50. (2S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxy-3-methylisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 628 51. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 632 52. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 648 53. (S)-4-(5-(3-((4-bromo-2-((S)-3-carboxybutyryl)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 692 54. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-hydroxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 600 55. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 632 56. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-chloro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 648 57. (S)-4-(5-(3-((7-bromo-2-((S)-3-carboxybutyryl)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 692 58. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 650 59. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-7-chloro-4-fluoro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 666 60. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-dichloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 682 61. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 666 62. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-6-methoxyisoindolin-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 666 63. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-chloro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 682 64. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-7-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 650 65. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-7-chloro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 666 66. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-7-chloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-7-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 666 67. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-7-chloro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 684 68. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-7-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 668 69. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-7-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-7-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 684 70. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 668 71. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-7-chloro-4-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 684 72. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-4,7-dichloro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 700 73. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-7-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-7-chloro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 700 74. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-dichloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-7-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 700 75. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-7-chloro-4-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-7-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 684 76. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-chloro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 684 77. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-4-chloro-7-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-chloro-5-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 700 78. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-fluoro-6-hydroxyisoindoline-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 636 79. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-6-hydroxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 652 80. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-6-hydroxyisoindoline-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 652 81. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-6-hydroxyisoindololin-5-yl)oxy)propoxy)-4-chloro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 668 82. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-5-hydroxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 618 83. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-7-fluoro-6-hydroxyisoindoline-5-yl)oxy)propoxy)-7-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 636 84. (S)-4-(6-(3-((2-((S)-3-carboxybutyryl)-7-chloro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-5-hydroxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 652 85. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-7-chloro-6-hydroxyisoindoline-5-yl)oxy)propoxy)-7-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 652 86. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-4-chloro-7-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 702 87. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-7-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-chloro-7-fluoro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 718 88. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4,7-difluoro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 686 89. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-difluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-7-chloro-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 702 90. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-dichloro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4,7-difluoro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 718 91. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-dichloro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-chloro-7-fluoro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 734 92. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-7-fluoro-6-methoxyisoindoline-5-yl)oxy)propoxy)-7-chloro-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 718 93. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4,7-dichloro-6-methoxyisoindoline-5-yl)oxy)propoxy)-4-chloro-7-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 734 94. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-4-chloro-7-fluoro-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-7-chloro-4-fluoro-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 718 95. (2S,2'S)-4,4'-(7,8,11,13,17,18-hexahydro-6H,12H,16H-thieno[2'',3'':4',5']benzo[1',2':9,10][1,4,8,11]tetraoxylatetetraaza[2,3-f]isoindole-2,12-diyl)bis(2-methyl-4-oxobutyric acid) 626 96. (S)-4-(6-methoxy-5-(3-((6-methoxy-2-((S)-3-methyl-4-(methylsulfonamide)-4-oxobutyryl)isoindoline-5-yl)oxy)propoxy)benzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 691 97. (S)-4-(5-(3-((2-((S)-4-((N,N-dimethylaminosulfonyl)amino)-3-methyl-4-oxobutyryl)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 720 98. (S)-4-(5-(3-((2-(3-cyanopropionic acid)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 581 99. 4-(5-(3-((2-(3-cyanopropionic acid)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-4-oxobutyronitrile 548 100. (S)-4-(5-(3-((2-(3-cyanopropionic acid)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 581 101. (1R,2R)-2-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-carbonyl)cyclobutane-1-carboxylic acid 626 102. (1R,2R)-2-(5-(3-((2-((1R,2R)-2-carboxycyclobutane-1-carbonyl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-carbonyl)cyclobutane-1-carboxylic acid 638 103. (1R,2R)-2-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-carbonyl)cyclobutane-1-carboxylic acid 626 104. (1R,2R)-2-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-carbonyl)cyclopropane-1-carboxylic acid 612 105. (1R,2R)-2-(5-(3-((2-((1R,2R)-2-carboxycyclopropane-1-carbonyl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-carbonyl)cyclopropane-1-carboxylic acid 610 106. (1R,2R)-2-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-carbonyl)cyclopropane-1-carboxylic acid 612 107. (S)-N-(N,N-dimethylaminosulfonylurea)-4-(5-(3-((2-((S)-4-((N,N-dimethylaminosulfonylurea)amino)-3-methyl-4-oxobutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyramine 826 108. (S)-4-(5-(3-((2-((S)-4-((N,N-dimethylaminosulfonyl)amino)-3-methyl-4-oxobutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 720 109. (S)-4-(6-methoxy-5-(3-((6-methoxy-2-((S)-3-methyl-4-(methylsulfonyl)-4-oxobutyryl)isoindolin-5-yl)oxy)propoxy)benzo[b]thiophene-2-yl)-2-methyl-N-(methylsulfonyl)-4-oxobutyrylamine 768 110. (S)-4-(5-methoxy-6-(3-((6-methoxy-2-((S)-3-methyl-4-(methylsulfonamide)-4-oxobutyryl)benzo[b]thiophene-5-yl)oxy)propoxy)isoindolin-2-yl)-2-methyl-4-oxobutyric acid 691 111. (S)-4-(4-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 614 112. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-4-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 614 113. (S)-4-(4-(4-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)butyl)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 612 114. (S)-4-(4-(4-(2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)butoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 612 115. (S)-4-(5-(4-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-4-yl)oxy)butyl)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 612 116. (S)-4-(5-(4-(2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-4-yl)butoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 612 117. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-methylbenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 598 118. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-ethylbenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 612 119. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxyisoindoline-5-yl)oxy)propoxy)-6-vinylbenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 610 120. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-ethynylbenzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 608 121. (S)-4-(5-(3-((6-amino-2-((S)-3-carboxybutyryl)benzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 599 122. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-(methylamino)benzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 613 123. (S)-4-(5-(3-((6-bromo-2-((S)-3-carboxybutyryl)benzo[b]thiophene-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-yl)-2-methyl-4-oxobutyric acid 662 124. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-methylisoindoline-2-yl)-2-methyl-4-oxobutyric acid 598 125. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-ethylisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 612 126. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-6-vinylisoindoline-2-yl)-2-methyl-4-oxobutyric acid 610 127. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-ethynylisoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 608 128. (S)-4-(5-(3-((6-amino-2-((S)-3-carboxybutyryl)isoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 599 129. (S)-4-(5-(3-((2-((S)-3-carboxybutyryl)-6-(methylamino)isoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 613 130. (S)-4-(5-(3-((6-bromo-2-((S)-3-carboxybutyryl)isoindoline-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 662 131. (S)-4-(5-(3-((6-((S)-3-carboxybutyryl)-3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 615 132. (S)-4-(5-(3-((6-((S)-3-carboxybutyryl)-3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 633 133. (S)-4-(5-(3-((6-((S)-3-carboxybutyryl)-3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propoxy)-4-chloro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutyric acid 649 134. (S)-4-(5-(3-((6-((S)-3-carboxybutyryl)-3-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propoxy)-6-methoxythienolo[3,2-b]pyridin-2-yl)-2-methyl-4-oxobutyric acid 602 135. (S)-4-(5-(3-((6-((S)-3-carboxybutyryl)-3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propoxy)-6-hydroxythienolo[3,2-b]pyridi...

Claims

1. A compound of formula I-1, or a pharmaceutically acceptable salt thereof: , I-1 wherein, Each R1 is independently selected from H, deuterium, and halogen; R2 and R3 are independently selected from the group consisting of: O-(C1-C4 alkylene), -Ta-C1-C6 alkyl-Tb-, and -Ta-O-Tb; wherein the C1-C6 alkyl group is optionally substituted with one or more deuterium or halogens; each Ta and Tb is independently absent, -O-, C1-C6 alkyl, -O-(C1-C6 alkyl)-, or -(C1-C6 alkyl)-O-; each R4 is independently selected from the group consisting of: H; deuterium; halogens; and OR6; each R6 is independently selected from -H, deuterium, and C1-6 alkyl; and each group may be independently and optionally substituted with deuterium or -OH; each X1 is C=O; Each X2 is independently selected from (C(R8)2)(1-3), NR8(C(R8)2)(1-3) and -NH(C(R8)2)(1-3); wherein each R8 is independently selected from the group consisting of H, deuterium and C1-C6 alkyl; and each X3 is independently selected from the group consisting of COOR6, SO2R6 and CN.

2. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein, Each R1 is independently selected from the following groups: H, deuterium, F, Cl, and Br.

3. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein, R2-R3 are selected from and ; wherein each R10 is independently hydrogen or C1-2 alkyl.

4. The compound as claimed in claim 3 or a pharmaceutically acceptable salt thereof, wherein, R10 is either hydrogen or methyl.

5. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein, R2-R3 are selected from -O(CH2)2O-, -O(CH2)3O-, -O(CH2)4O- and -OCH(CH3)CH2CH(CH3)O-.

6. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein, Each R4 is independently selected from the following groups: H, deuterium, Br, and OR6.

7. The compound as claimed in claim 6 or a pharmaceutically acceptable salt thereof, wherein, Each R4 is independently selected from the group consisting of: H, deuterium, Br, OH, and OC1-C3 alkyl groups.

8. The compound as claimed in claim 7 or a pharmaceutically acceptable salt thereof, wherein, Each R4 is independently selected from the following groups: H, deuterium, Br, OH, and OCH3.

9. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein, Each X2 is CH2CHR8, where R8 is selected from the group consisting of H, deuterium, and C1-C3 alkyl groups.

10. The compound as claimed in claim 9 or a pharmaceutically acceptable salt thereof, wherein, Each X2 is independently -CH2CH2-.

11. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein, Each X3 is independently selected from the following groups: COOH and...

12. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from [the group consisting of the following].

13. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from [the group consisting of the following].

14. A pharmaceutical composition comprising at least a therapeutically effective amount of any one of claims 1-13 of the compound or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

15. Use of a compound as described in any one of claims 1-13 or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition as described in claim 14, for the preparation of a medicament.

16. The use as described in claim 15, wherein, The drug is used to induce an immune response in a subject; the drug is used to induce STING-dependent type I interferon production in a subject; the drug is used to induce STING-dependent cytokine production in a subject; or the drug is used to treat a proliferative disease in a subject.

17. The use as described in claim 16, wherein, The aforementioned proliferative disease is cancer.