Novel compounds useful as STING agonists and uses thereof

Abstract

Provided are compounds of general formulas I, II, III, IV, and V, and pharma- ceutically acceptable salts thereof, which may be useful as inducers of type I interferon production, in particular as STING activators. Also provided are syntheses, compositions, and uses of such compounds. [Formula 1] JPEG2024511832000311.jpg153170

Description

[Technical field]

[0001] The present invention relates to compounds and derivatives thereof that may be useful as STING agonists that activate the STING (Stimulator of Interferon Genes) pathway. The present invention also relates to compositions containing such compounds, processes for the synthesis of such compounds, and the use of such compounds to induce immune responses, to induce STING-dependent type I interferon production, and / or to treat cell proliferation disorders such as cancer.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to PCT application No. PCT / CN2021 / 128942, filed November 5, 2021; PCT application No. PCT / CN2021 / 130097, filed November 11, 2021; PCT application No. PCT / CN2021 / 138806, filed December 16, 2021; PCT application No. PCT / CN2021 / 143043, filed December 30, 2021; and PCT application No. PCT / CN2022 / 071548, filed January 12, 2022. The contents of all of these applications are incorporated herein by reference in their entireties. [Background technology]

[0003] The immune system has evolved to recognize and neutralize various types of threats to maintain host homeostasis and is generally divided into the adaptive and innate immune systems. The adaptive immune system is specialized to recognize antigens not naturally expressed in the host as foreign and mount an anti-antigen response through the coordinated action of many leukocyte subsets. A hallmark of the adaptive immune response is its ability to provide "memory" or long-lasting immunity against encountered antigens. Such specific and long-lasting effects are essential for the health and survival of the host, but the adaptive immune response takes time to mount a full-scale response.

[0004] The innate immune system is specialized to compensate for this time lag and respond rapidly to a variety of injury and danger signals. 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 and tissue damage. The innate immune system is not antigen specific, but responds to a variety of effector mechanisms. Opsonization, phagocytosis, activation of the complement system, and production of soluble bioactive molecules such as cytokines and chemokines are all mechanisms by which the innate immune system mediates responses. By responding to the above damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), the innate immune system can protect the host from a wide variety of threats.

[0005] Free cytoplasmic DNA and RNA are among these PAMPs and DAMPs. In recent years, it has become clear that the main sensor for cytoplasmic DNA is cGAS (cyclic GMP-AMP synthase). Upon recognition of cytoplasmic DNA, cGAS catalyzes the production of the cyclic dinucleotide 2'3'-cGAMP, which is an atypical second messenger that tightly binds to the ER transmembrane adaptor protein STING. Upon binding to cGAMP, STING undergoes a conformational change and translocates to the perinuclear compartment, inducing the activation of key transcription factors IRF-3 and NF-κΒ. This leads to a strong induction of type I interferons and the production of inflammatory cytokines such as IL-6, TNF-α, and IFN-γ.

[0006] The importance of type I interferons and inflammatory cytokines in various cells of the immune system is very well known. In particular, these molecules potently promote T cell activation by enhancing the ability of dendritic cells and macrophages to uptake, 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 costimulatory molecules such as CD80 and CD86. Finally, type I interferons can rapidly bind to their cognate receptors and trigger the activation of interferon-responsive genes, which contributes significantly to the activation of adaptive immune cells.

[0007] From a therapeutic standpoint, type I interferons have been shown to have antiviral activity by directly inhibiting the replication of human hepatitis B and C viruses, and by stimulating the immune response against virus-infected cells. Compounds capable of inducing the production of type I interferons are also used in vaccines, acting as adjuvants to enhance the specific immune response to antigens and thus minimizing side effects by reducing the dose and broadening the immune response.

[0008] Furthermore, interferons and compounds capable of inducing interferon production may be used to treat human cancers. Such molecules may be useful as anticancer drugs with multiple pathways of activity. Interferons can directly inhibit human tumor cell proliferation and may synergize with various approved chemotherapeutic agents. Type I interferons may significantly enhance antitumor immune responses by inducing the activation of adaptive and innate immune cells. Finally, tumor invasiveness may be inhibited by interferons by regulating the expression of enzymes involved in tissue remodeling.

[0009] Considering the potential of type I interferons and type I interferon-inducing compounds as antiviral and anticancer agents, there remains a need for new agents that can induce potent type I interferon production. With increasing data demonstrating that the cGAS-STING cytoplasmic DNA-sensitive pathway has the important ability to induce type I interferons, the development of STING activators is rapidly becoming an important part of modern antitumor therapy.

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

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

[0012] The present invention relates to novel compounds of the general structure of Formula I, II, III, IV, V, or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony Each W is a CR 1 or N independently selected; Each R 1 H, deuterium, halogen, OR 6 , N(R 6 ) 2 , COOR 6 , or C(O)N(R 6 ) 2 , CN or C 1 -C 6 alkyl; 1 -C 6 Alkyl is a group that contains one or more deuterium, halogen, OR 6 , N(R 6 ) 2 , COOR 6 , or C(O)N(R 6 ) 2 is optionally substituted with; R 2 and R 3 is O-(C 1 -C 4 alkylene or haloalkylene), C 1 -C 5 Alkylene or haloalkylene, N(R 6 )-(C 1 -C 4alkylene or haloalkylene), -T a -C 1 -C 6 Alkyl-T b -, -T a -N(Rs)-T b , -T a -OT b , -T a -PEG n -OT b , -T a -SST b , -T a -SSST b , -T a -N(R s )-N(Rs)-T b -, -T a -C 2 -C 6 Alkenyl-T b -, -T a -C 2 -C 6 Alkynyl-T b -, -T a -C(=O)-T b -, -T a -C(=CH 2 )-T b -, -T a -C(=O)-C(=O)-T b -, -T a -C(=O)-(C 1 -C 6 Alkyl)-C(=O)-T b -, -T a -C(=O)-(C 3 -C 12 Cycloalkyl)-C(=O)-T b -, -T a -C(=O)-(C 1 -C 6 Alkyl)-(C 3 -C 12 Cycloalkyl)-(C 1 -C 6 Alkyl)-C(=O)-T b -, -T a -C(=O)-(3- to 12-membered heterocycloalkyl)-C(=O)-T b -, -T a-C(=O)-(C 1 -C 6 alkyl)-(3- to 12-membered heterocycloalkyl)-(C 1 -C 6 Alkyl)-C(=O)-T b -, -T a -C(=S)-T b -, -T a -S(=O) 2 -T b -, -T a -S(=O)-T b -, -T a -P(=O)(-ORs)-T b -, -T a -(C 3 -C 12 Cycloalkyl)-T b -, -T a -(C 6 -C 12 Aryl)-T b -, -T a -(3- to 12-membered heterocycloalkyl)-T b -, or -T a -(5- to 12-membered heteroaryl)-T b - independently selected from, where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 6 -C 12 Aryl, 3- to 12-membered heterocycloalkyl, or 5- to 12-membered heteroaryl may be substituted with one or more deuterium, halogen, -ORs, -N(Rs) 2 or optionally substituted with -C(=O)ORs; PEG n is (-OCH 2 CH 2 -) n where n=1 to 8; T a and T b are each independently absent, -N(Rs)-, -O-, C 1 -C6 Alkyl, -N(Rs)-(C 1 -C 6 Alkyl)-, -(C 1 -C 6 alkyl)-N(Rs)-, -N(Rs)-(C 1 -C 6 alkyl)-N(Rs)-, -O-(C 1 -C 6 Alkyl)-, -(C 1 -C 6 alkyl)-O-, or -O-(C 1 -C 6 alkyl)-O-; 1 -C 6 The alkyl is optionally substituted with one or more halogens; and Each Rs is independently H, deuterium, or C optionally substituted with one or more halogens. 1 -C 6 is alkyl; Each R 4 H, deuterium, halogen, CN, OR 6 , N(R 6 ) 2 , COOR 6 , C(O)N(R 6 ) 2 , S.O. 2 R 6 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, OR 6 C replaced with 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Haloalkenyl, OR 6 C replaced with 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 2 -C 6 Haloalkynyl, OR 6 C replaced with 2 -C 6 Alkynyl, C 3-C 6 Cycloalkyl, as well as O, S, and N(R 6 ) independently selected from the group consisting of 3- to 6-membered heterocycles containing 1 to 2 ring members selected from the group consisting of; Each R 6 is -H, deuterium, halogen, -NH 2 , -CN, -OH, -N 3 , -NO 2 , carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 6-10 Aryl, -C 5-10 Heteroaryl, C 3-10 Heterocycle or C 3-10 carbocycles; and each of which is independently selected from the group consisting of deuterium, halogen, -NH 2 , -CN, -OH, -NO 2 , carbonyl, =O, oxo, carboxyl, C 1-6 Alkoxy, or C 1-6 optionally substituted with alkyl; and each of the heteroaryl and heterocycle contains at least one heteroatom selected from N, O, or S; each X 1 is C=O, -CH 2 -, -CHF-, and -CF 2 - independently selected from the group consisting of; each X 2 is (C(R 8 ) 2 ) (1-3) , -NR 8 (C(R 8 ) 2 ) (1-3) , -NH(C(R 8 ) 2 ) (1-3) , -N(C 1-6 Alkyl)(C(R 8 ) 2 ) (1-3) or -N(HaloC 1-6 Alkyl)(C(R 8 ) 2 ) (1-3)where each R 8 H, deuterium, halogen, C 1 -C 6 Alkyl, CN, OR 6 , N(R 6 ) 2 , C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, OR 6 C replaced with 1 -C 6 Alkyl, and N(R 6 ) 2 C replaced with 1 -C 6 alkyl; optionally, two R on different carbon atoms are independently selected from the group consisting of 8 may form a 3- to 6-membered fused ring together with the atom to which they are attached; and optionally, two R 8 may together with the atoms to which they are attached form a 3- to 6-membered spiro ring; each X 3 COOR 6 , C(O)SR 6 , C(S)OR 6 , S.O. 2 R 6 , C(O)N(R 9 ) 2 , [ka] and CN; and each R 9 H, deuterium, COOR 6 , S.O. 2 R 6 , (CH 2 ) 1-3 -C(=O)OR 6 , OR 6 , S.R. 6 , N.H. 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 , O(C 1-C 6 alkyl), O(C 6 -C 10 aryl), O(C 1 -C 6 Alkyl)-OR 6 , S(C 1 -C 6 alkyl), S(C 6 -C 10 Aryl), S(=O) 2 R 6 , S(=O) 2 OR 6 , P(=O)(R 6 ) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl, C 6 -C 10 is independently selected from aryl, 3- to 8-membered heterocycloalkyl, or 3- to 10-membered heteroaryl.

[0013] In some embodiments of Formula I, [ka] teeth, [ka] are independently selected from the group consisting of: [ka] teeth, [ka] are independently selected from the group consisting of:

[0014] In some embodiments of Formula I, [ka] teeth, [ka] and [ka] teeth, [ka] are independently selected from the group consisting of:

[0015] In some embodiments of Formula I, the compound is of formula I-1. [ka]

[0016] In some embodiments of Formula II, [ka] teeth, [ka] are independently selected from the group consisting of: [ka] teeth, [ka] are independently selected from the group consisting of:

[0017] In some embodiments of Formula II, [ka] teeth, [ka] are independently selected from the group consisting of: [ka] teeth, [ka] are independently selected from the group consisting of:

[0018] In some embodiments of Formula III, [ka] teeth, [ka] are independently selected from the group consisting of: [ka] teeth, [ka] are independently selected from the group consisting of:

[0019] In some embodiments of Formula III, [ka] teeth, [ka] are independently selected from the group consisting of: [ka] teeth, [ka] are independently selected from the group consisting of:

[0020] In some embodiments of Formula IV, [ka] teeth, [ka] are independently selected from the group consisting of: [ka] teeth, [ka] are independently selected from the group consisting of:

[0021] In some embodiments of Formula IV, [ka] teeth, [ka] are independently selected from the group consisting of: [ka] teeth, [ka] are independently selected from the group consisting of:

[0022] In some embodiments of Formula V, [ka] teeth, [ka] are independently selected from the group consisting of: [ka] teeth, [ka] are independently selected from the group consisting of:

[0023] In some embodiments of Formula V, [ka] teeth, [ka] are independently selected from the group consisting of: [ka] teeth, [ka] are independently selected from the group consisting of:

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

[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 formula 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 R 1 are independently H, deuterium, halogen, OR 6 , N(R 6 ) 2 , COOR 6 , or C(O)N(R 6 ) 2 , CN or C 1 -C 6 alkyl; 1 -C 6 Alkyl is a group that contains one or more deuterium, halogen, OR 6 , N(R 6 ) 2 , COOR 6 , or C(O)N(R 6 ) 2is optionally replaced by

[0028] In some embodiments of formula I, I-1, II, III, IV or V, each R 1 H, deuterium, halogen, C 1 -C 3 Alkyl, CN and C 1 -C 3 haloalkyl.

[0029] In some embodiments of formula I, I-1, II, III, IV or V, each R 1 H, deuterium, halogens, CN and C 1 -C 3 alkyl.

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

[0031] In some embodiments, each R 1 is independently hydrogen or halogen.

[0032] In some embodiments, each R 1 is independently hydrogen or F.

[0033] In some embodiments, each R 1 is independently hydrogen or CN.

[0034] In some embodiments, each R 1 are independently deuterium.

[0035] In some embodiments of Formula I, I-1, II, III, IV or V, R 2 and R 3 -T a -C 1 -C 6 Alkyl-Tb -, -T a -N(Rs)-T b , -T a -OT b , -T a -PEG n -OT b , -T a -SST b , -T a -SSST b , -T a -N(R s )-N(Rs)-T b -, -T a -C 2 -C 6 Alkenyl-T b -, -T a -C 2 -C 6 Alkynyl-T b -, -T a -C(=O)-T b -, -T a -C(=CH 2 )-T b -, -T a -C(=O)-C(=O)-T b -, -T a -C(=O)-(C 1 -C 6 Alkyl)-C(=O)-T b -, -T a -C(=O)-(C 3 -C 12 Cycloalkyl)-C(=O)-T b -, -T a -C(=O)-(C 1 -C 6 Alkyl)-(C 3 -C 12 Cycloalkyl)-(C 1 -C 6 Alkyl)-C(=O)-T b -, -T a -C(=O)-(3- to 12-membered heterocycloalkyl)-C(=O)-T b -, -T a -C(=O)-(C 1 -C 6 alkyl)-(3- to 12-membered heterocycloalkyl)-(C 1-C 6 Alkyl)-C(=O)-T b -, -T a -C(=S)-T b -, -T a -S(=O) 2 -T b -, -T a -S(=O)-T b -, -T a -P(=O)(-ORs)-T b -, -T a -(C 3 -C 12 Cycloalkyl)-T b -, -T a -(C 6 -C 12 Aryl)-T b -, -T a -(3- to 12-membered heterocycloalkyl)-T b -, or -T a -(5- to 12-membered heteroaryl)-T b - independently selected from, where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 6 -C 12 Aryl, 3- to 12-membered heterocycloalkyl, or 5- to 12-membered heteroaryl may be substituted with 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, R 2 and R 3 -T a -C 1 -C 6 Alkyl-T b -, -T a -N(Rs)-T b , -T a -OT b , -T a-PEG n -OT b , -T a -SST b , -T a -SSST b , -T a -N(R s )-N(Rs)-T b -, -T a -C 2 -C 6 Alkenyl-T b -, -T a -C 2 -C 6 Alkynyl-T b -, -T a -C(=O)-T b -, -T a -C(=CH 2 )-T b -, -T a -C(=O)-C(=O)-T b -, -T a -C(=O)-(C 1 -C 6 Alkyl)-C(=O)-T b -, -T a -C(=O)-(C 3 -C 12 Cycloalkyl)-C(=O)-T b -, -T a -C(=O)-(C 1 -C 6 Alkyl)-(C 3 -C 12 Cycloalkyl)-(C 1 -C 6 Alkyl)-C(=O)-T b -, -T a -C(=O)-(3- to 12-membered heterocycloalkyl)-C(=O)-T b -, -T a -C(=O)-(C 1 -C 6 alkyl)-(3- to 12-membered heterocycloalkyl)-(C 1 -C 6 Alkyl)-C(=O)-T b -, -T a -C(=S)-T b -, -T a-S(=O) 2 -T b -, -T a -S(=O)-T b -, -T a -P(=O)(-ORs)-T b -, -T a -(C 3 -C 12 Cycloalkyl)-T b -, -T a -(C 6 -C 12 Aryl)-T b -, -T a -(3- to 12-membered heterocycloalkyl)-T b -, or -T a -(5- to 12-membered heteroaryl)-T b - independently selected from, where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 6 -C 12 Aryl, 3- to 12-membered heterocycloalkyl, or 5- to 12-membered heteroaryl may be substituted with one or more deuterium, halogen, -ORs, -N(Rs) 2 or -C(=O)ORs, where -T a -(C 3 -C 12 Cycloalkyl)-T b -or-T a -(3- to 12-membered heterocycloalkyl)-T b - In C 3 -C 12 Cycloalkyl or 3- to 12-membered heterocycloalkyl is C 3 -C 12 T via two different atoms of cycloalkyl or 3- to 12-membered heterocycloalkyl a and T b are respectively bound to; PEG n is (-OCH 2 CH2 -) n where n=1 to 8; T a and T b are each independently absent, -N(Rs)-, -O-, C 1 -C 6 Alkyl, -N(Rs)-(C 1 -C 6 Alkyl)-, -(C 1 -C 6 alkyl)-N(Rs)-, -N(Rs)-(C 1 -C 6 alkyl)-N(Rs)-, -O-(C 1 -C 6 Alkyl)-, -(C 1 -C 6 alkyl)-O-, or -O-(C 1 -C 6 alkyl)-O-; 1 -C 6 The alkyl is optionally substituted with one or more halogens; and Each Rs is independently H, deuterium, or C optionally substituted with one or more halogens. 1 -C 6 It is an alkyl.

[0037] In some embodiments of Formula I, I-1, II, III, IV or V, R 2 and R 3 -T a -C 1 -C 6 Alkyl-T b -, -T a -N(Rs)-T b , -T a -OT b , -T a -PEG n -OT b , -T a -SST b , -T a -SSST b , -T a -N(R s )-N(Rs)-T b -, -T a -C2 -C 6 Alkenyl-T b -, -T a -C 2 -C 6 Alkynyl-T b -, -T a -C(=O)-T b -, -T a -C(=CH 2 )-T b -, -T a -C(=O)-C(=O)-T b -, -T a -C(=S)-T b -, -T a -S(=O) 2 -T b -, -T a -S(=O)-T b -, -T a -P(=O)(-ORs)-T b -, -T a -(C 3 -C 12 Cycloalkyl)-T b -, -T a -(C 6 -C 12 Aryl)-T b -, -T a -(3- to 12-membered heterocycloalkyl)-T b -, or -T a -(5- to 12-membered heteroaryl)-T b - independently selected from, where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 6 -C 12 Aryl, 3- to 12-membered heterocycloalkyl, or 5- to 12-membered heteroaryl may be substituted with 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, R 2 and R 3 -T a -C 1 -C 6 Alkyl-T b -, -T a -N(Rs)-T b , -T a -OT b , -T a -PEG n -OT b , -T a -SST b , -T a -SSST b , -T a -N(R s )-N(Rs)-T b -, -T a -C 2 -C 6 Alkenyl-T b -, -T a -C 2 -C 6 Alkynyl-T b -, -T a -C(=O)-T b -, -T a -C(=CH 2 )-T b -, -T a -C(=O)-C(=O)-T b -, -T a -C(=S)-T b -, -T a -S(=O) 2 -T b -, -T a -S(=O)-T b -, -T a -P(=O)(-ORs)-T b -, -T a -(C 3 -C 12 Cycloalkyl)-T b -, -T a -(C 6 -C 12 Aryl)-T b -, -T a -(3- to 12-membered heterocycloalkyl)-Tb -, or -T a -(5- to 12-membered heteroaryl)-T b - independently selected from, where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 6 -C 12 Aryl, 3- to 12-membered heterocycloalkyl, or 5- to 12-membered heteroaryl may be substituted with one or more deuterium, halogen, -ORs, -N(Rs) 2 or -C(=O)ORs; and 3 -C 12 Cycloalkyl or 3- to 12-membered heterocycloalkyl is C 3 -C 12 T via two different atoms of cycloalkyl or 3- to 12-membered heterocycloalkyl a and T b are respectively bound to; PEG n is (-OCH 2 CH 2 -) n where n=1 to 8; T a and T b are each independently absent, -N(Rs)-, -O-, C 1 -C 6 Alkyl, -N(Rs)-(C 1 -C 6 Alkyl)-, -(C 1 -C 6 alkyl)-N(Rs)-, -N(Rs)-(C 1 -C 6 alkyl)-N(Rs)-, -O-(C 1 -C 6 Alkyl)-, -(C 1 -C 6 alkyl)-O-, or -O-(C 1 -C 6 alkyl)-O-;1 -C 6 alkyl is optionally substituted with one or more halogens; and each Rs is independently H, deuterium, or C optionally substituted with one or more halogens. 1 -C 6 It is an alkyl.

[0039] In some embodiments of Formula I, I-1, II, III, IV or V, R 2 and R 3 is O-(C 1 -C 4 Alkylene or C 1 -C 4 Haloalkylene)-C 2 -C 6 Alkenyl, C 1 -C 5 Alkylene or C 1 -C 5 Haloalkylene, (C 1 -C 4 Alkylene or C 1 -C 4 haloalkylene)-N(R 6 ), and N(R 6 )-(C 1 -C 4 Alkylene or C 1 -C 4 Haloalkylene)-C 2 -C 6 Alkenyl, -C 0-6 Alkyl-NH-C 0-6 Alkyl-, -C 0-6 Alkyl-N(C 1-6 Alkyl)-C 0-6 Alkyl-, -C 0-6 Alkyl-OC 0-6 Alkyl-, -C 0-6 Alkyl-PEG n -OC 0-6 Alkyl, -C 0-6 Alkyl-SSC 0-6 Alkyl, -C 0-6 Alkyl-SSSC 0-6 Alkyl, -C 0-6 Alkyl-C 2 -C 6Alkenyl-C 0-6 Alkyl-, -C 0-6 Alkyl-C 2 -C 6 Alkynyl-C 0-6 Alkyl-, -C 0-6 Alkyl-C(=O)-C 0-6 Alkyl-, -C 0-6 Alkyl-C(=CH 2 )-C 0-6 Alkyl-, -C 0-6 Alkyl-C(=O)-C(=O)-C 0-6 Alkyl-, -C 0-6 Alkyl-C(=S)-C 0-6 Alkyl-, -C 0-6 Alkyl-S(=O) 2 -C 0-6 Alkyl-, -C 0-6 Alkyl-S(=O)-C 0-6 Alkyl-, -C 0-6 Alkyl-P(=O)(-OH)-C 0-6 Alkyl-, -C 0-6 Alkyl-C 3 -C 12 Cycloalkyl-C 0-6 Alkyl-, -C 0-6 Alkyl-C 6 -C 12 Aryl-C 0-6 Alkyl-, -C 0-6 Alkyl-(3- to 12-membered heterocyclyl)-C 0-6 Alkyl-, -C 0-6 Alkyl-(5-12 membered heteroaryl)-C 0-6 Alkyl-, -C 0-6 Alkyl-O-(5- to 12-membered heteroaryl)-OC 0-6 Alkyl-, -C 0-6 Alkyl-OC(=O)-NH-C 0-6 Alkyl-, -C 0-6 Alkyl-OC(=O)-C 0-6 Alkyl-, -C 0-6 Alkyl-NH-C(=O)-C 0-6 independently selected from alkyl-, -OC(=O)-O-, -NH-C(=O)-NH-, or -NH-C(=S)-NH-; 2-C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 6 -C 12 Aryl, 3- to 12-membered heterocycloalkyl, or 5- to 12-membered heteroaryl may be substituted with one or more deuterium, halogen, -ORs, -N(Rs) 2 or -C(=O)ORs.

[0040] In some embodiments of Formula I, I-1, II, III, IV or V, R 2 and R 3 -T a -C 2 -C 6 Alkenyl-T b -, -T a -C(=O)-T b -, -T a -PEG n -OT b , -T a -SST b , -T a -SSST b , -TC(=CH 2 )-T-, or -T a -(C 6 -C 12 Aryl)-T b - independently selected from, where C 2 -C 6 Alkenyl or C 6 -C 12 Aryl is one or more deuterium, halogen, -ORs, -N(Rs) 2 or optionally substituted with -C(=O)ORs; PEG n is (-OCH 2 CH 2 -) n where n=1 to 8; T a and T b are each independently -N(Rs)-, -O-, -(C 1 -C 6alkyl)-O-, or -O-(C 1 -C 6 alkyl)-O-; 1 -C 6 Alkyl is optionally substituted with one or more halogens; each Rs is independently H, deuterium, or C optionally substituted with one or more halogens. 1 -C 6 It is an alkyl.

[0041] In some embodiments of Formula I, I-1, II, III, IV or V, R 2 -R 3 teeth, [Table 1] Selected from JPEG2024511832000046.jpg217170JPEG2024511832000047.jpg227170JPEG2024511832000048.jpg243170JPEG2024511832000049.jpg168170, During the ceremony, Each R 5 are independently -OR 7 , N.R. 7 OR -C(O)OR 7 and; Each R 7 are independently hydrogen, deuterium or C 1-2 is alkyl; and Each R 10 are independently hydrogen, deuterium, and C 1-2 It is alkyl or halogen.

[0042] In some embodiments of formula I, I-1, II, III, IV or V, each R 7 is independently hydrogen, deuterium, or methyl.

[0043] In some embodiments, each R 10 is independently hydrogen, deuterium, methyl or fluorine.

[0044] In some embodiments, one R 10 is hydrogen, and the other R 10 is methyl or fluorine.

[0045] In some embodiments, one R 10 is deuterium, and the other R 10 is methyl or fluorine.

[0046] In some embodiments of Formula I, I-1, II, III, IV or V, R 2 -R 3 is -(CH 2 ) 2-8 -, -O(CH 2 ) 1-7 -, -O(CH 2 ) 1-6 O-, -OCH 2 CH(CH 3 )CH 2 O-, -OCH(CH 3 )CH 2 CH(CH 3 )O-, [ka] -NH(CH 2 ) 1-7 -, -(CH 2 ) 1-6 NH(CH 2 ) 1-6 -, -(CH 2 ) 1-6 N(CH 3 )(CH 2 ) 1-6 -, -NH(CH 2 ) 1-6 O-, -NH-CO-NH-, -N(CH 3 )CO-NH-, [ka] JPEG2024511832000052.jpg206170JPEG2024511832000053.jpg229170JPEG2024511832000054.jpg55170.

[0047] In some embodiments of Formula I, I-1, II, III, IV or V, R 2 -R 3 is -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -O(CH 2 ) 2 -, -O(CH 2 ) 3 -, -O(CH 2 ) 4 -, -O(CH 2 ) 2 O-, -O(CH 2 ) 3 O-, -O(CH 2 ) 4 O-, -OCH 2 CH(CH 3 )CH 2 O-, -OCH(CH 3 )CH 2 CH(CH 3 )O-, [ka] -O(CH 2 ) 4 O-, -O(CH 2 ) 5 O-, -NH(CH 2 ) 2 -, -NH(CH 2 ) 3 -, -NH(CH 2 ) 4 -, -(CH 2 ) 2 NH-, -(CH 2 ) 3 NH-, -(CH 2 ) 4 NH-, -CH 2 NHCH 2 -, -CH 2 N(CH 3 )CH 2 -, -NH(CH2 ) 3 O-, -NH-CO-NH-, [ka] or -N(CH 3 ) CONH-.

[0048] In some embodiments of formula I, I-1, II, III, or IV, each R 4 is H, deuterium, F, Cl, Br, I, CN, OR 6 , N(R 6 ) 2 , COOR 6 , C(O)N(R 6 ) 2 , S.O. 2 R 6 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, OR 6 C replaced with 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Haloalkenyl, OR 6 C replaced with 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 2 -C 6 Haloalkynyl, OR 6 C replaced with 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, as well as O, S, and N(R 6 ) is independently selected from the group consisting of 3- to 6-membered heterocycles containing 1 to 2 ring members selected from the group consisting of

[0049] In some embodiments of formula I, I-1, II, III, or IV, each R 4 are H, deuterium, F, Cl, Br, I, OH, and C. 1-C 3 Alkyl, C 1 -C 3 Haloalkyl, OC 1 -C 3 Alkyl, OC 1 -C 3 Haloalkyl, C 2 -C 3 Alkenyl, C 2 -C 3 Alkynyl, and N(R 6 ) 2 are independently selected from the group consisting of:

[0050] In some embodiments of formula I, I-1, II, III, or IV, each R 4 is H, deuterium, Br, Cl, OH, CH 3 , C.H. 2 CH 3 , CH=CH 2 , C≡CH, OCH 3 , O.C.F.H. 2 , OCF 2 H, OCF 3 , and N(R 6 ) 2 are independently selected from the group consisting of:

[0051] In some embodiments of formula I, I-1, II, III, or IV, each R 4 is H, deuterium, Br, OH, CH 3 , C.H. 2 CH 3 , CH=CH 2 , C≡CH, OCH 3 , N.H. 2 and N.H.H. 3 are independently selected from the group consisting of:

[0052] In some embodiments of formula I, I-1, II, III, IV or V, each R 6 are -H, deuterium, -F, -Cl, -Br, -I, -NH 2 , -CN, -OH, -N 3 , -NO 2 , carboxyl, C 1 -C 3 Alkyl, C1 -C 3 Alkoxy, C 2 -C 4 Alkenyl, C 2 -C 4 is independently selected from the group consisting of alkynyl, 6-membered aryl, 7-membered aryl, 8-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 5-membered heterocycle, 6-membered heterocycle, 7-membered heterocycle, 8-membered heterocycle, 5-membered carbocycle, 6-membered carbocycle, 7-membered carbocycle, or 8-membered carbocycle; and each of these is independently selected from the group consisting of deuterium, -F, -Cl, -Br, -I, -NH 2 , -CN, -OH, -NO 2 , carbonyl, =O, oxo, carboxyl, C 1 -C 3 Alkoxy, or C 1 -C 3 alkyl, optionally substituted; and heteroaryl and heterocycle each contain 1 or 2 heteroatoms selected from N, O or S.

[0053] In some embodiments of formula I, I-1, II, III, IV or V, each R 6 are -H, deuterium, -F, -Cl, -Br, -I, -NH 2 , -CN, -OH, -N 3 , -NO 2 , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, ethylene, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic, or 6-membered carbocyclic; and each of these is independently selected from the group consisting of deuterium, -F, -Cl, -Br, -I, -NH 2 , -CN, -OH, -NO 2 , carbonyl, =O, oxo, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy; and each of the heteroaryl and heterocycle contains 1 or 2 heteroatoms selected from N, O, or S.

[0054] In some embodiments of formula I, I-1, II, III, IV or V, each R 6 is H, deuterium, -F, -Cl, -Br, -I, -NH 2 , -CN, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH2F, -CHF2, [ka] and -CF3.

[0055] In some embodiments of formula I, I-1, II, III, IV or V, each X 1 is C=O, -CH 2 -, -CHF-, and -CF 2 - Independently selected from the group consisting of:

[0056] In some embodiments of formula I, I-1, II, III, IV or V, each X 1 is C=O and -CH 2 - is selected from the group consisting of:

[0057] In some embodiments of formula I, I-1, II, III, IV or V, each X 1 is C=O.

[0058] In some embodiments of formula I, I-1, II, III, IV or V, each X 2 is (C(R 8 ) 2 ) (1-3) where each R 8 H, deuterium, halogen, C 1 -C 6 Alkyl, CN, OR 6 , N(R 6 ) 2 , C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, OR 6 C replaced with1 -C 6 Alkyl, and N(R 6 ) 2 C replaced with 1 -C 6 alkyl; optionally, two R on different carbon atoms are independently selected from the group consisting of 8 may form a 3- to 6-membered fused ring together with the atom to which they are attached; and, optionally, two R 8 may form a 3- to 6-membered spiro ring together with the atom to which they are attached.

[0059] In some embodiments, each X 2 are independently -(C(R 8 ) 2 ) 1-3 -, where each R 8 are hydrogen, deuterium, halogens, C 1 -C 6 Alkyl, CN, OR 6 , N(R 6 ) 2 , or C 3 -C 6 cycloalkyl; 1 -C 6 Alkyl is one or more halogens, OR 6 , or N(R 6 ) 2 , optionally substituted.

[0060] In some embodiments, each X 2 are independently -(C(R 8 ) 2 ) 1-3 where at least two R 8 are C together with the atom or atoms to which they are attached. 3 -C 6 It forms a cycloalkyl or a 3- to 6-membered heterocycloalkyl.

[0061] In some embodiments, each X 2 are independently -C(R 8 ) 1-3 -It is.

[0062] In some embodiments, each X 2 are independently -(CH 2 ) 1-3 -It is.

[0063] In some embodiments, each X 2 are independently -C(R 8 ) 2 -It is.

[0064] In some embodiments, each X 2 are independently -CH 2 -It is.

[0065] In some embodiments, each X 2 are independently -C(R 8 ) 2 C(R 8 ) 2 -It is.

[0066] In some embodiments, each X 2 are independently -CH 2 CH 2 -It is.

[0067] In some embodiments, each X 2 are independently -C(R 8 )2C(R 8 ) 2 C(R 8 ) 2 -It is.

[0068] In some embodiments, each X 2 are independently -CH 2 CH 2 CH 2 -It is.

[0069] In some embodiments of formula I, I-1, II, III, IV or V, each X 2 CH 2 CHR 8 where R 8is H, deuterium, C 1 -C 3 Alkyl, C substituted with OH 1 -C 3 Alkyl, OC 1 -C 3 Alkyl-substituted C 1 -C 3 Alkyl, and C 3 -C 6 cycloalkyl.

[0070] In some embodiments of formula I, I-1, II, III, IV or V, each X 2 CH 2 CHR 8 where R 8 is H, deuterium, CH 3 , C.H. 2 OH, CH 2 CH 3 , C.H. 2 CH 2 CH 3 , CH(CH 3 ) 2 , C.H. 2 OCH 3 and cyclopropyl.

[0071] In some embodiments of formula I, I-1, II, III, IV or V, each X 2 is CHR 8 CHR 8 where each R 8 is H, deuterium, C 1 -C 3 Alkyl, C substituted with OH 1 -C 3 Alkyl, OC 1 -C 3 Alkyl-substituted C 1 -C 3 Alkyl, and C 3 -C 6 cycloalkyl, and optionally, two R on different carbon atoms 8 form a 3- to 6-membered fused ring together with the atoms to which they are attached.

[0072] In some embodiments of formula I, I-1, II, III, IV or V, each X 2 is CHR 8 CHR 8 where each R 8 H, deuterium and C 1 -C 3 alkyl, and optionally, two R on different carbon atoms 8 form a 3- to 6-membered fused ring together with the atoms to which they are attached.

[0073] In some embodiments of formula I, I-1, II, III, IV or V, each X 2 CH 2 C(R 8 ) 2 where each R 8 is H, deuterium, C 1 -C 3 Alkyl, C substituted with OH 1 -C 3 Alkyl, OC 1 -C 3 Alkyl-substituted C 1 -C 3 Alkyl, and C 1 -C 3 cycloalkyl, and optionally two R on a single carbon atom; 8 form a 3- to 6-membered spiro ring together with the atoms to which they are attached.

[0074] In some embodiments of formula I, I-1, II, III, IV or V, each X 2 CH 2 C(R 8 ) 2 where each R 8 H, deuterium and C 1 -C 3 alkyl, and optionally, two R on a single carbon atom; 8 form a 3- to 6-membered spiro ring together with the atoms to which they are attached.

[0075] In some embodiments of formula I, I-1, II, III, IV or V, each X 3 COOR 6 , C(O)SR 6 , C(S)OR 6 , S.O. 2 R 6 , C(O)N(R 9 ) 2 , [ka] and CN.

[0076] In some embodiments of formula I, I-1, II, III, IV or V, each X 3 COOR 6 , S.O. 2 R 6 , C(O)N(R 9 ) 2 , [ka] and CN.

[0077] In some embodiments of formula I, I-1, II, III, IV or V, each X 3 COOR 6 , C(O)N(R 9 ) 2 , [ka] and CN.

[0078] In some embodiments of formula I, I-1, II, III, IV or V, each X 3 COOH, COOCH 3 ,CONH 2 , CONH-SO 2 -N(CH 3 ) 2 , CONH-SO 2 -CH 3 , [ka] and CN.

[0079] In some embodiments of formula I, I-1, II, III, IV or V, each R 9 H, deuterium, COOR 6 , and S.O. 2 R 6 are independently selected from the group consisting of:

[0080] In some embodiments of formula I, I-1, II, III, IV or V, each R 9 is H or deuterium, preferably H.

[0081] In some embodiments, the compound is a compound of formula Ia, IIa, IIIa, IVa, or Va: [ka] or a pharma- ceutically acceptable salt thereof.

[0082] In some embodiments, the compound is a compound of formula Ib, IIb, IIIb, or IVb: [ka] or a pharma- ceutically acceptable salt thereof.

[0083] In some embodiments, a compound of formula Ic, IIc, IIIc, IVc, or Vc: [ka] or a pharma- ceutically acceptable salt thereof.

[0084] In some embodiments of the preceding formulae defined herein, each heterocyclic group and each carbocyclic group includes single rings, spiral rings, bridge rings, fused rings, and various combinations of spiral rings, bridge rings, and / or fused rings.

[0085] In some embodiments of the preceding formulae defined herein, the compound is selected from the compounds set forth in Table 1 and their pharma- ceutically acceptable salts.

[0086] In some embodiments of the preceding formulae defined herein, the compound is a compound set forth in Table 1.

[0087] [Table 2] JPEG2024511832000066.jpg215170JPEG2024511832000067.jpg209170JPEG2024511832000068.jpg217170JPEG2024511832000069.jpg206170 JPEG2024511832000070.jpg194170JPEG2024511832000071.jpg198170JPEG2024511832000072.jpg200170JPEG2024511832000073.jpg197170 JPEG2024511832000074.jpg207170JPEG2024511832000075.jpg213170JPEG2024511832000076.jpg213170JPEG2024511832000077.jpg202170 JPEG2024511832000078.jpg213170JPEG2024511832000079.jpg199170JPEG2024511832000080.jpg211170JPEG2024511832000081.jpg201170

[0088] In some embodiments, the compound is an isotopic derivative (eg, an isotopically labeled compound) of any one of the compounds of the formulas disclosed herein.

[0089] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1, as well as prodrugs and pharma- ceutically acceptable salts thereof.

[0090] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1, and pharma- ceutically acceptable salts thereof.

[0091] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds set forth in Table 1, and pharma- ceutically acceptable salts thereof.

[0092] In some embodiments, the isotopic derivatives are deuterium-labeled compounds.

[0093] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 1, and prodrugs and pharma- ceutically acceptable salts thereof.

[0094] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 1, and pharma- ceutically acceptable salts thereof.

[0095] In some embodiments, the compound is a deuterium-labeled compound of any one of the prodrugs of the compounds set forth in Table 1, and pharma- ceutically acceptable salts thereof.

[0096] Preparation method The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis using the methods described below, or variations thereof as will be appreciated by those of skill in the art. References cited herein are incorporated herein by reference in their entireties.

[0097] The synthetic methods described herein below are intended as illustrative of the present invention and are not intended to limit the scope of the subject matter and the claimed compounds to these examples. Where the preparation of starting compounds is not described, they may be commercially available or may be prepared analogously to known compounds or methods described herein. Compounds of any of the formulas described herein may be synthesized with reference to the methods shown in the following schemes. As shown herein, the final compounds are products having the same structural formula as any of the formulas. It will be understood that any compound of the formulas may be prepared by appropriate selection of reagents having appropriate substituents. Solvents, temperatures, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. Protecting groups are handled according to standard methods of organic synthesis (TW Green and PGM Wuts (1999) Protective Groups in Organic Synthesis, 3 th These groups are removed at some stage in the compound synthesis using methods apparent to those skilled in the art.

[0098] By way of example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, e.g., alkanoyl groups such as acetyl, alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl groups, arylmethoxycarbonyl groups such as benzyloxycarbonyl, or aroyl groups such as benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, acyl groups, e.g., alkanoyl groups, or alkoxycarbonyl groups or aroyl groups, can be removed by hydrolysis with a suitable base, e.g., an alkali metal hydroxide, e.g., lithium hydroxide or sodium hydroxide. Alternatively, acyl groups, e.g., tert-butoxycarbonyl groups, can be removed by treatment with a suitable acid, e.g., hydrochloric acid, sulfuric acid, phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups, e.g., benzyloxycarbonyl groups, can be removed by hydrogenation in a catalyst such as palladium on carbon, or by treatment with a Lewis acid, e.g., tri(trifluoroacetoxy)borane. A suitable protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0099] Suitable protecting groups for hydroxyl groups are, for example, acyl groups, e.g., alkanoyl groups such as acetyl groups, aroyl groups such as benzoyl groups, or arylmethyl groups such as benzyl groups. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, acyl groups such as alkanoyl or aroyl groups can be removed by hydrolysis with a suitable base, e.g., an alkali metal hydroxide, e.g., lithium hydroxide, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups such as benzyl groups can be removed by hydrogenation in a catalyst, e.g., palladium on carbon.

[0100] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or ethyl group which may be removed by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed by hydrogenation in a catalyst such as palladium on carbon.

[0101] When a compound of the present disclosure is synthesized by any of the processes defined herein, then it may further comprise the following additional steps: (i) removing any protecting groups present; (ii) converting the compound of the present disclosure into another compound of the present disclosure; (iii) forming a pharma- ceutically acceptable salt, a hydrate thereof; and / or (iv) forming a prodrug thereof.

[0102] For illustrative purposes, schemes 1 and 2 show general synthetic methods for preparing the compounds described herein.For more detailed descriptions of the individual reaction steps, please refer to the Examples section below.Those skilled in the art will understand that other synthetic routes can be used to synthesize compounds.In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0103] General routes to exemplary compounds of the present invention are depicted in Schemes 1 and 2, where W, R 1 , X 1 , X 2 , X 3 , R 2 , R 3 , and R 4 The substituents, such as , are as previously defined herein or are functional groups that can be converted to the desired final substituent.

[0104] In the following methods and schemes, LG represents a leaving group, which may be a halide or triflate group. The variables contained in the methods and schemes have the meanings provided; exemplary catalysts are defined by abbreviations (see below).

[0105] [ka]

[0106] CDI, MgCl 2 Reaction of B6 with 3-(tert-butoxy)-3-oxopropanoic acid under basic conditions in the presence of LDA or K gives B7. 2 CO 3 B7 is reacted with H6 in the presence of to give B8. B8 is reacted with TFA to give B1.

[0107] A'1 is subjected to a substitution reaction with H1 under basic conditions to give A2.

[0108] Substitution reaction of A2 with B1 under basic conditions gives D.

[0109] [ka]

[0110] CDI, MgCl 2 Reaction of B3 with 3-(tert-butoxy)-3-oxopropanoic acid in the presence of and under basic conditions gives B4. Reaction of B4 with H6 under basic conditions gives B5. Reaction of B5 with TFA to remove the tert butyl gives B2.

[0111] Reaction of A4 with H2 in the presence of NaH gives A3.

[0112] Reaction of A3 with B2 in the presence of a palladium catalyst affords D.

[0113] The present invention also provides a pharmaceutical composition comprising at least one compound of formula I, I-1, II, III, IV or V or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable carrier, wherein the compound of formula I, I-1, II, III, IV or V or a pharma- ceutically acceptable salt thereof is contained in a weight ratio of about 0.0001 to about 10 relative to the carrier in the composition.

[0114] The pharmaceutical compositions of the present invention may further comprise at least one additional active agent selected from STING agonist compounds, antiviral compounds, antigens, adjuvants, CTLA-4 and PD-1 pathway antagonists and other immunomodulatory agents, lipids, liposomes, peptides, anti-cancer agents, and chemotherapeutic agents, etc.

[0115] The present invention further provides the use of at least one compound of formula I, I-1, II, III, IV or V or a pharma- ceutically acceptable salt thereof, or said pharmaceutical composition, for the manufacture of a medicament.

[0116] In some embodiments, the medicament is used to induce an immune response, induce STING-dependent type I interferon production, induce STING-dependent cytokine production, or treat a cell proliferation disorder in a subject.

[0117] In some embodiments, the cell proliferation disorder is cancer, cancer metastasis, cardiovascular disease, immunological disorder, fibrosis, or eye disease.

[0118] At least one compound of formula I, I-1, II, III, IV or V or a pharma- ceutically acceptable salt thereof, and / or a pharmaceutical composition as described herein, for use in therapy.

[0119] At least one compound of Formula I, I-1, II, III, IV or V or a pharma- ceutically acceptable salt thereof, and / or a pharmaceutical composition as described herein, for use in inducing an immune response, inducing STING-dependent type I interferon production, inducing STING-dependent cytokine production, or treating a cell proliferation disorder in a subject.

[0120] In some embodiments, the cell proliferation disorder is cancer, cancer metastasis, cardiovascular disease, immunological disorder, fibrosis, or eye disease.

[0121] At least one compound of formula I, I-1, II, III, IV or V or a pharma- ceutically acceptable salt thereof, and / or a pharmaceutical composition as described herein, for use as a STING agonist.

[0122] At least one compound of formula I, I-1, II, III, IV or V or a pharma- ceutically acceptable salt thereof, and / or a pharmaceutical composition as described herein, for use as a medicament.

[0123] The present invention further provides a method of inducing an immune response in a subject, the method comprising administering to a patient a therapeutically effective amount of at least one compound of formula I, I-1, II, III, IV or V or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described above.

[0124] The present invention further provides a method for inducing STING-dependent type I interferon production in a subject, the method comprising administering to the patient a therapeutically effective amount of at least one compound of Formula I, I-1, II, III, IV or V or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described above.

[0125] The present invention further provides a method of inducing STING-dependent cytokine production in a subject, the method comprising administering to the patient a therapeutically effective amount of at least one compound of Formula I, I-1, II, III, IV or V or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described above.

[0126] The present invention further provides a method of treating a cell proliferation disorder in a subject, the method comprising administering to the patient a therapeutically effective amount of at least one compound of formula I, I-1, II, III, IV or V or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described above.

[0127] In some embodiments, the cell proliferation disorder is cancer, cancer metastasis, cardiovascular disease, immunological disorder, fibrosis, or eye disease.

[0128] The compounds disclosed herein can be STING agonists.These compounds are potentially useful for treating diseases or disorders, including but not limited to cell proliferation disorders.Cell proliferation disorders include but are not limited to cancer, benign papillomatosis, gestational trophoblastic diseases, and benign neoplastic diseases such as skin papilloma (wart) and genital papilloma.

[0129] In certain embodiments, the disease or disorder to be treated is a cell proliferation disorder. In certain embodiments, the cell proliferation disorder is cancer. In certain embodiments, the cancer is brain and spinal cord cancer, head and neck cancer, leukemia and blood cancer, skin cancer, reproductive system cancer, digestive system cancer, liver and bile duct cancer, kidney and bladder cancer, bone cancer, lung cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, heart tumor, germ cell tumor, malignant neuroendocrine (carcinoid) tumor, midline duct carcinoma, and cancer of unknown primary site (i.e., cancer in which metastatic cancer is found but the primary cancer site is unknown). In certain embodiments, the cancer is present in an adult patient; in further embodiments, the cancer is present in a pediatric patient. In certain embodiments, the cancer is AIDS-related.

[0130] In certain embodiments, the cancer is selected from brain cancer and spinal cancer. In certain embodiments, the cancer is selected from the group consisting of anaplastic astrocytoma, glioblastoma, astrocytoma, and olfactory neuroblastoma (also known as olfactory blastoma). In certain embodiments, the brain tumor is an astrocytic tumor (e.g., pilocytic astrocytoma, subependymal giant-cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma), an oligodendroglial tumor (e.g., oligodendroglioma, and anaplastic oligodendroglioma), an oligoastrocytic tumors (e.g., oligoastrocytoma, and anaplastic oligoastrocytoma), ependymoma (e.g., myxopapillary ependymoma, and anaplastic ependymoma); medulloblastoma, primitive neuroectodermal tumor, schwannoma, meningioma, atypical meningioma, anaplastic meningioma, pituitary adenoma, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, optic nerve hypothalamic glioma, and primary central nervous system malignant lymphoma.In certain aspects of these embodiments, the brain tumor is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, and suprantentorial primordial neuroectodermal tumor (sPET).

[0131] In certain embodiments, the cancer is selected from nasopharyngeal cancer, nasal and paranasal 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), and head and neck cancer, including eye or ocular cancer. In certain embodiments, the ocular cancer is selected from the group consisting of intraocular melanoma and retinoblastoma.

[0132] In certain embodiments, the cancer is selected from leukemia and hematological cancers. In certain embodiments, the cancer is selected from the group consisting of myeloproliferative neoplasm, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), myeloproliferative neoplasm (MPN), post-MPN AML, post-MDS AML, del(5q)-associated high-risk MDS or AML, blast-phase chronic myeloid leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia (acute lymphocytic leukemia), Langerans cell histiocytosis, hairy cell leukemia, and plasma cell neoplasms, including plasmacytoma and multiple myeloma. Leukemia, as referred to herein, may be acute or chronic.

[0133] In certain embodiments, the cancer is selected from skin cancer, hi certain embodiments, the skin cancer is selected from the group consisting of melanoma, squamous cell carcinoma, and basal cell carcinoma.

[0134] In certain embodiments, the cancer is selected from cancers of the reproductive system. In certain embodiments, the cancer is selected from the group consisting of breast cancer, cervical cancer, vaginal cancer, ovarian cancer, prostate cancer, penile cancer, and testicular cancer. In certain aspects of these embodiments, the cancer is breast cancer selected from the group consisting of ductal carcinoma and phyllodes tumor. In certain aspects of these embodiments, the breast cancer may be male breast cancer or female breast cancer. In certain aspects of these embodiments, the cancer is cervical cancer selected from the group consisting of squamous cell carcinoma and adenocarcinoma. In certain aspects of these embodiments, the cancer is ovarian cancer selected from the group consisting of epithelial cancer.

[0135] In certain embodiments, the cancer is selected from cancer of the digestive system. In certain embodiments, the cancer is selected from the group consisting of esophageal cancer, gastric cancer (also known as stomach cancer), gastrointestinal carcinoid tumor, pancreatic cancer, gallbladder cancer, colorectal cancer, and anal cancer. In aspects of these embodiments, the cancer is selected from the group consisting of esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gastric lymphoma, gastrointestinal lymphoma, solid pseudopapillary tumor, pancreatoblastoma, islet cell tumor, pancreatic cancer including acinar cell carcinoma and ductal adenocarcinoma, gallbladder adenocarcinoma, colorectal adenocarcinoma, and anal squamous cell carcinoma.

[0136] In certain embodiments, the cancer is selected from liver cancer and bile duct cancer. In certain embodiments, the cancer is liver cancer (also known as hepatocellular carcinoma). In certain embodiments, the cancer is bile duct cancer (also known as cholangiocarcinoma); in aspects of these embodiments, the bile duct cancer is selected from the group consisting of intrahepatic bile duct cancer and extrahepatic bile duct cancer.

[0137] In certain embodiments, the cancer is selected from kidney cancer and bladder cancer. In certain embodiments, the cancer is kidney cancer selected from the group consisting of renal cell carcinoma, Wilms tumor, and transitional cell cancer. In certain embodiments, the cancer is bladder cancer selected from the group consisting of urothelial carcinoma (transitional cell carcinoma), squamous cell carcinoma, and adenocarcinoma.

[0138] In certain embodiments, the cancer is selected from bone cancer, hi certain embodiments, the bone cancer is selected from the group consisting of osteosarcoma, malignant fibrous histiocytoma of bone, Ewing sarcoma, and chordoma (cancer of the bones along the spine).

[0139] In certain embodiments, the cancer is selected from lung cancer. In certain embodiments, the lung cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, bronchial tumor, and pleuropulmonary blastoma.

[0140] In certain embodiments, the cancer is selected from malignant mesothelioma. In certain embodiments, the cancer is selected from the group consisting of epithelial mesothelioma and sarcomatoid carcinoma.

[0141] In certain embodiments, the cancer is selected from a sarcoma. In certain embodiments, the sarcoma is selected from the group consisting of central chondrosarcoma, central and periosteal chondroma, fibrosarcoma, clear cell sarcoma of tendon sheaths, and Kaposi's sarcoma.

[0142] In certain embodiments, the cancer is selected from lymphoma. In certain embodiments, the cancer is selected from the group consisting of Hodgkin's lymphoma (e.g., Reed-Sternberg cell), non-Hodgkin's lymphoma (e.g., diffuse large B-cell lymphoma, follicular lymphoma, mycosis fungoide, Sezary syndrome, primary central nervous system lymphoma), cutaneous T-cell lymphoma, and primary central nervous system lymphoma.

[0143] In certain embodiments, the cancer is selected from a glandular cancer. In certain embodiments, the cancer is selected from the group consisting of adrenocortical cancer (also known as adrenocortical carcinoma or adrenal cortical carcinoma), pheochromocytoma, paraganglioma, pituitary tumor, thymoma, and thymic carcinoma.

[0144] In certain embodiments, the cancer is selected from thyroid cancer. In certain embodiments, the thyroid cancer is selected from the group consisting of medullary thyroid carcinoma, papillary thyroid carcinoma, and follicular thyroid carcinoma.

[0145] In certain embodiments, the cancer is selected from a germ cell tumor. In certain embodiments, the cancer is selected from the group consisting of malignant extracranial germ cell tumor and malignant extragonadal germ cell tumor. In certain aspects of these embodiments, the malignant extragonadal germ cell tumor is selected from the group consisting of nonseminoma and seminoma.

[0146] In certain embodiments, the cancer is selected from a cardiac tumor. In certain embodiments, the cardiac tumor is selected from the group consisting of malignant teratoma, lymphoma, rhabdomyosacroma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma.

[0147] In certain embodiments, the cell proliferative disorder is selected from benign papilloma, benign neoplastic disease, and gestational trophoblastic disease. In certain embodiments, the benign papilloma is selected from skin papilloma (wart) and genital papilloma. In certain embodiments, the gestational trophoblastic disease is selected from the group consisting of hydatidiform mole, and gestational trophoblastic neoplasia (e.g., invasive mole, choriocarcinoma, placental-site trophoblastic tumor, and epithelioid trophoblastic tumor).

[0148] As used herein, the terms "treatment" and "treating" refer to any process that slows, interrupts, prevents, controls, or halts the progression of a disease or disorder described herein. The term does not necessarily indicate the complete elimination of all symptoms of the disease or disorder.

[0149] The terms "administration" and "administering" a compound should be understood to include providing a compound described herein, or a pharma- ceutically acceptable salt thereof, and any of the above compositions to a subject.

[0150] 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 can be an "effective amount" or a "therapeutically effective amount", where the compound of interest is administered in an amount that elicits the biological or medical (i.e., intended to treat) response of a tissue, system, animal, or human, respectively, as desired by a researcher, veterinarian, physician, or other clinician. An effective amount does not necessarily include toxicity or safety considerations regarding administration of the compound.

[0151] The effective amount of a compound will vary depending on factors such as the particular compound selected (e.g., taking into account the potency, efficacy, and / or half-life of the compound); the selected route of administration; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the subject being treated; the medical history of the subject being treated; the duration of treatment; the characteristics of concurrent treatments; the desired therapeutic effect; and the like, and can be routinely determined by one of ordinary skill in the art.

[0152] The term "subject" (also referred to herein as "patient"), as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0153] As used herein, the term "immune response" refers to any one or more of specific immune response, non-specific immune response, both specific and non-specific response, innate immune response, primary immune response, adaptive immunity, secondary immune response, memory immune response, immune cell activation, immune cell proliferation, immune cell differentiation, and cytokine expression. In certain embodiments, the compound of general formula I, I-1, II, III, IV or V, or a pharma- ceutically acceptable salt thereof, is administered in combination with one or more additional therapeutic agents, including antiviral compounds, vaccines intended to stimulate an immune response against one or more predetermined antigens, adjuvants, CTLA-4 and PD-1 pathway antagonists and other immunomodulatory agents, lipids, liposomes, peptides, anti-cancer agents, and chemotherapeutic agents.

[0154] The term "halogen" as used herein means fluoro, chloro, bromo or iodo, unless otherwise specified. 1-6 Alkyl, HaloC 2-6 alkenyl", "haloC 2-6 Alkynyl and HaloC 1-6 "Alkoxy" refers to a C alkyl group in which one or more (particularly one, two or three) hydrogen atoms have been replaced by halogen atoms, particularly fluorine or chlorine atoms. 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6In some embodiments, fluoro C is preferably 1-6 Alkyl group, Fluoro C 2-6 Alkenyl group, Fluoro C 2-6 Alkynyl groups and fluoro C 1-6 Alkoxy groups, especially fluoro C 1-3 Alkyl groups, such as CF 3 , CHF 2 , C.H. 2 F, C.H. 2 CH 2 F, C.H. 2 CHF 2 , C.H. 2 CF 3 and Fluoro C 1-3 Alkoxy groups, such as OCF 3 , O.C.H.F. 2 , O.C.H. 2 F, O.C.H. 2 CH 2 F, O.C.H. 2 CHF 2 or OCH 2 CF 3 , especially CF 3 , OCF 3 and O.C.H.F. 2 It is.

[0155] As used herein, unless otherwise specified, alkyl includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. Similarly, C 1-8 C in alkyl 1-8 is defined to identify groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear or branched arrangement.

[0156] Alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group, as defined above. For example, methylene (i.e., -CH 2 -), ethylene (i.e., -CH 2 -CH 2 -or-CH(CH 3 )-) and propylene (i.e., -CH 2 -CH 2 -CH 2 -, -CH(-CH 2 -CH 3 )- or -CH 2 -CH(CH 3 )-) are mentioned.

[0157] As used herein, the term "alkenyl" refers to a monovalent straight or branched chain unsaturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range and containing one or more double bonds.

[0158] As used herein, the term "alkenylene" refers to a divalent linear unsaturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range and containing one or more double bonds.

[0159] As used herein, the term "alkynyl" refers to a monovalent straight or branched chain unsaturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range and containing one or more triple bonds.

[0160] As used herein, the term "alkynylene" refers to a divalent linear unsaturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range and containing one or more triple bonds.

[0161] As used herein, the term "alkoxy", alone or in combination, includes an alkyl group connected to an oxy connecting atom. The term "alkoxy" also includes alkyl ether groups, where the term "alkyl" is defined above, and "ether" means two alkyl groups with an oxygen atom between them. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, methoxymethane (also known as "dimethyl ether"), and methoxyethane (also known as "ethyl methyl ether").

[0162] The term "aryl," as used herein, by itself or as part of another substituent, refers to a monocyclic or polycyclic aromatic hydrocarbon, unless otherwise specified. Preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls. The most preferred aryl is phenyl.

[0163] The terms "heterocycle", "heterocyclyl" or "heterocycle" as used herein, unless otherwise specified, refer to unsubstituted and substituted monocyclic or polycyclic non-aromatic, partially unsaturated or fully saturated ring systems containing one or more heteroatoms, by themselves or as part of another substituent. Preferred heteroatoms include N, O, and S, including nitrogen oxides, sulfur oxides, and dioxides. Preferably, the rings are 3-8 membered and are fully saturated or have one or more degrees of unsaturation. Multiple degrees of substitution, preferably 1, 2 or 3, are included in this definition.

[0164] Examples of such heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl.

[0165] The term "heteroaryl" as used herein, by itself or as part of another substituent, unless otherwise specified, refers to an aromatic ring system containing carbon and at least one heteroatom. Heteroaryls may be monocyclic or polycyclic, substituted or unsubstituted. Monocyclic heteroaryl groups may have 1-4 heteroatoms in the ring, and polycyclic heteroaryls may have 1-10 heteroatoms. Polycyclic heteroaryl rings may contain fused, spiro or bridged ring junctions, e.g., a bicyclic heteroaryl is a polycyclic heteroaryl. Bicyclic heteroaryl rings may contain 8-12 member atoms. Monocyclic heteroaryl rings may contain 5-8 member atoms (carbon and heteroatoms). Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzoisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl, or isoquinolinyl.

[0166] The term "carbocycle" refers to a substituted or unsubstituted monocyclic, bicyclic, bridged, fused, or spirocyclic non-aromatic ring system containing carbon atoms. Exemplary "carbocycle" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0167] The term "cycloalkyl," as used herein, unless otherwise specified, by itself or as part of another substituent, refers to a substituted or unsubstituted monocyclic, bicyclic or polycyclic non-aromatic saturated or partially unsaturated hydrocarbon group, optionally including an alkylene linker to which the cycloalkyl may be attached. Exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0168] The terms "carbonyl", "-C=O", "C=O", "-CO", "-C(O)", and "CO" refer to the radical [ka] Refers to...

[0169] The term "oxo" refers to the radical =O.

[0170] Whenever the terms "alkyl" or "aryl" or either of their prefix roots appear in a substituent name (e.g., aralkyl or dialkylamino), by themselves or as part of another substituent, they shall be construed to include the limitations given above for "alkyl" and "aryl", unless otherwise specified. l-6 ) shall refer independently to the number of carbon atoms in the alkyl portion or in the alkyl portion of a larger substituent in which alkyl appears as the prefix root.

[0171] As used herein, the term "fused ring" refers to a cyclic group formed by substituents on separate atoms in a straight or branched chain alkane or by substituents on separate atoms in another ring.

[0172] As used herein, the term "spiro ring" or "spirocyclic ring" refers to a pendant cyclic group formed by substituents on a single atom.

[0173] As used herein, unless otherwise specified, the term "ring system" includes, but is not limited to, carbocyclic rings, heterocyclic rings, heteroaromatic rings, and the like, and may also include only heterocyclic rings and / or only heteroaromatic rings, and the specific rings included must be determined by the context, but in any case, "ring system" includes any of the C 1-6 Alkyl group or C 1-3 Not including cycloalkyl based on alkyl groups, C 1-6 Alkoxy group or C 1-3 It does not include cycloalkoxy based alkoxy groups.

[0174] Unless expressly stated to the contrary, all ranges cited herein are inclusive; that is, the ranges include the upper and lower limits of the range and all values ​​therebetween. By way of example, temperature ranges, percentages, equivalent ranges, etc. described herein include the upper and lower limits of the range and any consecutive values ​​therebetween. Numerical values ​​provided herein, and the use of the word "about" may include variations of ±1%, ±2%, ±3%, ±4%, ±5%, ±10%, ±15%, ±20%, and their numerical equivalents.

[0175] As used herein, the term "one (one) or more" items includes not only a single item selected from a list, but also a mixture of two (2) or more items selected from a list.

[0176] Here, the term "substituted" refers to the above group in which one or more (preferably 1 to 6, more preferably 1 to 3) hydrogen atoms are each independently replaced with the same or different substituents. Typical substituents include X, C, l-6 Alkyl, C l-6 Alkoxy, C 3-20 Cycloalkyl, -OR 13 , S.R. 13 , =O, =S, -C(O)R 13 , -C(S)R 13 , =NR 13 , -C(O)OR 13 , -C(S)OR 13 , -NR13 R 14 , -C(O)NR 13 R 14 , cyano, nitro, -S(O) 2 R 13 , -OS(O 2 ) OR 13 , -OS(O) 2 R 13 , or -OP(O)(OR 13 )(OR 14 wherein each X is a halogen (F, Cl, Br, or I) and R 13 and R 14 are independently -H, C 1-6 Alkyl and C 1-6 In some embodiments, the substituents are independently selected from haloalkyl, -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, t-butyloxy, -SCH 3 , -SC 2 H 5 , formaldehyde group, -C(OCH 3 ), cyano, nitro, CF 3 , -OCF 3 , amino, dimethylamino, methylthio, sulfonyl and acetyl. Particularly preferred substituents are -F, -Cl or -Br.

[0177] The substituents "W" of formula I, I-1, II, III, IV or V may be the same or different. Similarly to "W", "R" of formula I, I-1, II, III, IV or V may be the same or different. 1 ", "X 1 ", "X 2 " or "X 3 " may be the same or different.

[0178] The compounds described herein may be present in isotopically labeled or isotopically enriched forms, including one or more atoms with atomic masses or mass numbers different from the atomic masses or mass numbers most abundant in nature.Isotopes may be radioactive or non-radioactive isotopes.Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 32 P, 35 S, 18 F, 36 Cl, and 125 I and the like. Compounds containing other isotopes of these and / or other atoms are within the scope of the present invention. In some embodiments, one or more hydrogen atoms of any of the compounds described herein can be replaced with deuterium to provide the corresponding deuterium-labeled or deuterium-enriched compound.

[0179] When a plural form (e.g., compound, salt) is used, this includes a single entity (e.g., a single compound, a single salt). "Compound" does not exclude the presence of multiple compounds (or salts) of formula I, I-1, II, III, IV or V, and "a" simply represents an indefinite article. Thus, "A" can be read preferably as "one (one) or more," more preferably as "one (one)."

[0180] The term "composition" as used herein is intended to include those that contain a particular amount of a particular component, as well as those that result directly or indirectly from the combination of a particular amount of a particular component. Thus, pharmaceutical compositions containing the compounds of the present invention as active ingredients, as well as methods for preparing the compounds, are also part of the present invention. In addition, some of the crystalline forms of the compounds may exist as polymorphs, and as such, are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be included in the scope of the present invention.

[0181] The compounds of the present invention may be in the form of pharmaceutically acceptable salts. For use in medicine, the salts of the compounds of the present invention refer to non-toxic "pharmaceutically acceptable salts". The pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic salts or basic / cationic salts. The pharmaceutically acceptable acidic / anionic salts are generally in the form in which the basic nitrogen is protonated with an inorganic or organic acid. Representative organic or inorganic acids include 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, benzenesulfonic acid, oxalic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, salicylic acid, saccharic acid, or trifluoroacetic acid. Pharmaceutically acceptable basic / cationic salts include, but are not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium, zinc, and the like.

[0182] The present invention includes within its scope prodrugs of the compounds of the present invention. In general, such prodrugs will be functional derivatives of the compounds that are easily converted in vivo into the required compound. Thus, in the therapeutic methods of the present invention, the term "administering" is intended to include the treatment of various disorders described with a specifically disclosed compound or a compound that may not be specifically disclosed but that converts to a particular compound in vivo after administration to a subject. Conventional techniques for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985.

[0183] It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of the invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and readily synthesized by techniques well known in the art as well as the methods described herein.

[0184] The compounds described herein, for example certain compounds of formula I, I-1, II, III, IV or V, may contain carbon atoms (or chiral centers) asymmetrically substituted in the R or S configuration. The invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.

[0185] Compounds described herein, when specifically designated as R- or S-isomers in chemical names or drawings, should be understood as enriched R- or S-isomers, respectively. For example, in any of the embodiments described herein, such enriched R- or S-designated isomers may be substantially free of the other isomer for each chiral center (e.g., less than 5%, less than 1%, or non-detectable as determined by chiral HPLC). Enriched R- or S-isomers can be prepared by methods exemplified herein, such as using chiral auxiliaries such as R- or S-tert-butylsulfinamide in the synthetic steps. Other methods for preparing enriched R- or S-isomers include, but are not limited to, chiral HPLC purification of a stereoisomeric mixture, such as a racemic mixture. General methods for separating stereoisomers (such as enantiomers and / or diastereomers) using HPLC are known in the art.

[0186] The compounds of formula I, I-1, II, III, IV or V may have different isomers. For example, any asymmetric carbon atom may be present in (R)-, (S)- or (R,S)-configuration, preferably in (R)- or (S)-configuration. Substituents on double bonds or especially on rings may be present in cis (=Z-) or trans (=E-) configuration. Thus, the compounds may be present as mixtures of isomers or preferably as pure isomers, preferably as pure diastereomers or pure enantiomers.

[0187] The present invention includes the compounds described, which may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers, as well as their racemic mixtures, substantially pure resolved enantiomers, all possible geometric isomers, and pharma- ceutically acceptable salts thereof.

[0188] The above formula I, I-1, II, III, IV or V is shown without a definitive stereochemistry at a particular position. The present invention includes all stereoisomers of formula I, I-1, II, III, IV or V and their pharma-ceutically acceptable salts. In addition, mixtures of stereoisomers as well as isolated specific stereoisomers are included. During the synthetic procedures used to prepare such compounds, or when using racemization or epimerization procedures known to those skilled in the art, the products of such procedures may be mixtures of stereoisomers.

[0189] In cases where tautomers of the compounds of Formula I, I-1, II, III, IV or V exist, the present invention includes any possible tautomers and pharma- ceutically acceptable salts thereof, and mixtures thereof, unless specifically stated otherwise.

[0190] When the compound of formula I, I-1, II, III, IV or V and its pharmaceutically acceptable salts exist in the form of solvate or polymorph, the present invention includes any possible solvate and polymorph.The type of solvent that forms the solvate is not particularly limited as long as it is a pharmaceutically acceptable solvent.For example, water, ethanol, propanol, acetone, etc. can be used.

[0191] The term "pharmaceutical acceptable salt" refers to a salt prepared from a pharmaceutical non-toxic base or acid. If the compound of the present invention is acidic, its corresponding salt can be easily prepared from a pharmaceutical non-toxic base, including inorganic bases and organic bases. If the compound of the present invention is basic, its corresponding salt can be easily prepared from a pharmaceutical non-toxic acid, including inorganic acids and organic acids. Since the compound of formula I, I-1, II, III, IV or V is intended for pharmaceutical use, it is preferably provided in a substantially pure form, for example at least 60% pure, more preferably at least 75% pure, particularly at least 98% pure (% is by weight).

[0192] The pharmaceutical compositions of the present invention comprise a compound represented by formula I, I-1, II, III, IV or V (or a pharma- ceutically acceptable salt thereof) as an active ingredient, a pharma- ceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. The compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host and the nature and severity of the condition for which the active ingredient is to be administered. The pharmaceutical compositions are conveniently presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy.

[0193] In practice, the compound of formula I, I-1, II, III, IV or V of the present invention, or a prodrug or metabolite, or a pharma- ceutically acceptable salt thereof, can be formulated as an active ingredient by intimately mixing with a pharmaceutical carrier by conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms, depending on the formulation desired for administration, e.g., oral or parenteral (including intravenous) administration. Thus, the pharmaceutical composition of the present invention can be expressed as discrete units suitable for oral administration, such as capsules, oblates or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the composition can be expressed as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion. In addition to the common dosage forms described above, the compound of formula I, I-1, II, III, IV or V, or a pharma- ceutically acceptable salt thereof, can also be administered by controlled release means and / or delivery devices. The composition can be prepared by any of the methods of pharmacy. In general, such method comprises the step of mixing the active ingredient with the carrier that constitutes one or more necessary ingredients.In general, the composition is prepared by uniformly and intimately mixing the active ingredient with liquid carrier or finely divided solid carrier or both.Then, the product can be shaped into desired form.

[0194] Thus, the pharmaceutical compositions of the present invention may include a pharma- ceutically acceptable carrier and a compound or a pharma- ceutically acceptable salt of Formula I, I-1, II, III, IV or V. The compound or a pharma- ceutically acceptable salt of Formula I, I-1, II, III, IV or V may also be included in the pharmaceutical composition in combination with one or more additional therapeutically active agents.

[0195] The additional active agent may be one or more agents selected from the group consisting of immunomodulatory agents, including but not limited to STING agonist compounds, antiviral compounds, antigens, adjuvants, anti-cancer agents, 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, alkylating agents, topoisomerase II inhibitors, smorten inhibitors, immunomodulatory cell lines, checkpoint inhibitors, vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, smoothened inhibitors, alkylating agents, antitumor antibiotics, antimetabolites, retinoids, and anticancer vaccines. It will be understood that such additional active agents may be provided as pharma-ceutically acceptable salts. It should be understood that the descriptions of the additional active agents may overlap. It will also be understood that therapeutic combinations are subject to optimization, and that the optimal combination of a compound of general formula I, I-1, II, III, IV or V or a pharma- ceutically acceptable salt thereof with one or more additional active agents will be determined based on the needs of the individual patient.

[0196] The compounds disclosed herein may be used in combination with one or more other active agents, including but not limited to other anti-cancer agents used to prevent, treat, control, improve, or reduce the risk of a particular disease or condition (e.g., cell proliferation disorder). In one embodiment, the compounds disclosed herein are combined with one or more other anti-cancer agents for use in preventing, treating, improving control, or reducing the risk of a particular disease or condition for which the compounds disclosed herein are useful. Such other active agents can be administered simultaneously or sequentially with the compounds disclosed herein, by routes and in amounts commonly used.

[0197] The pharmaceutical carriers employed can be, for example, solid, liquid, or gaseous. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers include simple syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. When preparing compositions for oral dosage forms, any convenient pharmaceutical medium can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like can be used to form oral liquid preparations such as suspensions, elixirs, solutions, and the like; carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules, tablets, and the like. Because of their ease of administration, tablets and capsules are the preferred oral dosage units in which solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.

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

[0199] The pharmaceutical composition of the present invention suitable for parenteral administration can be prepared as a solution or suspension of the active compound in water.It can contain a suitable surfactant, such as hydroxypropylcellulose.Dispersion can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil.In addition, it can contain a preservative to prevent harmful growth of microorganisms.

[0200] The pharmaceutical composition of the present invention suitable for injection use includes sterile aqueous solution or dispersion.Furthermore, the composition can be in the form of sterile powder for extemporaneous preparation of such sterile injectable solution or dispersion.In all cases, the final injectable form must be sterile and effectively fluid for easy injection.The pharmaceutical composition must be stable under the conditions of manufacture and storage, and thus should preferably be preserved against the contaminating action of microorganisms such as bacteria and fungi.The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.

[0201] The pharmaceutical compositions of the present invention can be in a form suitable for topical use, such as, for example, an aerosol, cream, ointment, lotion, dusting powder, etc. Additionally, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared by conventional processing methods utilizing the compounds of formula I, I-1, II, III, IV or V, II, III or IV of the present invention, or pharma- ceutically acceptable salts thereof. As an example, a cream or ointment is prepared by mixing about 5 wt% to about 10 wt% of the compound with a hydrophilic material and water to produce a cream or ointment having the desired consistency.

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

[0203] In addition to the above-mentioned carrier components, the pharmaceutical formulations may optionally contain one or more additional carrier components such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. In addition, other adjuvants may be included to make the formulation isotonic with the blood of the intended recipient. The compositions comprising the compounds described by formula I, I-1, II, III, IV or V or pharma-ceutically acceptable salts thereof may also be prepared in the form of powder or liquid concentrate.

[0204] In general, dosage levels on the order of about 0.01 mg / kg to about 150 mg / kg of body weight per day, or alternatively about 0.5 mg to about 7 g per patient per day, are useful in treating the above conditions. For example, inflammation, cancer, psoriasis, allergy / asthma, immune system diseases and conditions, central nervous system (CNS) diseases and conditions can be effectively treated by administration of about 0.01 mg to about 50 mg of compound per kg of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day.

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

[0206] These and other aspects will become apparent from the description of the invention provided below. EXAMPLES

[0207] The following examples are provided to better illustrate the present invention. All parts and percentages are by weight and all temperatures are in degrees Celsius unless otherwise stated.

[0208] The compounds described herein can be prepared in many ways based on the teachings contained herein and synthetic procedures known in the art.In the description of synthetic methods described below, it should be understood that all proposed reaction conditions, including solvent selection, reaction atmosphere, reaction temperature, experimental time, and work-up procedures, can be selected to be standard conditions for the reaction, unless otherwise specified.It is understood by those skilled in the art of organic synthesis that the functionality present on various parts of the molecule should be compatible with the reaction with the proposed reagent.Substituents that are not compatible with the reaction conditions will be clear to those skilled in the art, and therefore alternative methods are shown.The starting materials of the examples are commercially available or can be easily prepared from known materials by standard methods.

[0209] Examples are provided herein to facilitate a more complete understanding of the present disclosure. The following examples are useful for illustrating exemplary aspects of making and carrying out the subject matter of the present disclosure. However, the scope of the present disclosure should not be interpreted as being limited to the specific embodiments disclosed in these examples, which are merely illustrative. Although specific embodiments of the present disclosure have been described, those skilled in the art will understand that various changes and modifications can be made without departing from the spirit and scope of the present disclosure.

[0210] The following abbreviations are used in the reaction schemes and synthetic examples which follow: This list is not intended to be an exhaustive list of abbreviations used in this application, as additional standard abbreviations readily understood by one skilled in the art of organic synthesis may also be used in the synthetic schemes and examples.

[0211] [Table 3]

[0212] Intermediates Intermediate A1: Ethyl 4-(5-hydroxy-6-methoxy-benzothiophen-2-yl)-4-oxo-butanoate [ka]

[0213] Step a: To a solution of DIEA (4.10 g, 46.5111 mmol) and 2-bromoisovanillin (4.98 g, 21.5544 mmol) in dichloromethane (200 mL) was added bromomethyl methyl ether (3.15 g, 25.2073 mmol) at 0° C. The resulting solution was quenched with water (10 mL) and washed with water (100 mL) and brine (100 mL). The organics were washed with Na 2 SO 4 It was dried over 100 ml, filtered and evaporated under reduced pressure to give 2-bromo-4-methoxy-5-(methoxymethoxy)benzaldehyde (5.83 g, 21.1926 mmol, 98.3216% yield) as a white solid. 1 H 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).

[0214] Step b: 2-Bromo-4-methoxy-5-(methoxymethoxy)benzaldehyde (5.83 g, 21.1926 mmol) and Cs in N,N-dimethylformamide (100 mL) 2 CO 3(13.99 g, 42.9380 mmol) was added methyl thioglycolate (2.30 g, 21.6688 mmol) at 20° C. The reaction mixture was heated to 50° C. and stirred for 16 h. The reaction mixture was cooled to 20° C. and methyl iodide (1.81 g, 12.7520 mmol) was added to the reaction solution and stirred at 20° C. for 2 h. The reaction mixture was diluted with EA (500 mL) and washed with water (2 x 100 mL) and brine (100 mL). The organics were evaporated under reduced pressure. The residue was purified on a silica gel column EA / hept (0-50%). The pure fractions were concentrated and dried under vacuum. Methyl 6-methoxy-5-(methoxymethoxy)benzothiophene-2-carboxylate (2.98 g, 10.5557 mmol, 49.8084% yield) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0215] Step c: To a solution of methyl 6-methoxy-5-(methoxymethoxy)benzothiophene-2-carboxylate (2.98 g, 10.5557 mmol) in tetrahydrofuran (100 mL) and water (25 mL) at 20° C., LiOH (0.37 g, 15.4499 mol) was added. The reaction mixture was heated to 50° C. and stirred for 2 h. The reaction mixture was 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). 6-Methoxy-5-(methoxymethoxy)benzothiophene-2-carboxylic acid (2.41 g, 8.9830 mmol, 85.1008% yield) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6) 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).

[0216] Step d: 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) was added 1,1'-carbonyldiimidazole (2.84 g, 17.5148 mmol) at 20 °C. The resulting mixture was stirred at 20 °C under nitrogen atmosphere for 1 h. To the above mixture was added 3-tert-butoxy-3-oxopropanoic acid and magnesium chloride (1.31 g, 13.7589 mmol). The reaction mixture was concentrated, diluted with EA (500 mL) and diluted with NaHCO 3 The organics were washed with aq. (2 x 300 mL) and brine (200 mL). 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / PE (0-80%). The pure fractions were concentrated and dried under vacuum. tert-Butyl 3-[6-methoxy-5-(methoxymethoxy)benzothiophen-2-yl]-3-oxo-propanoate (2.63 g, 7.1774 mmol, 79.9000% yield) was obtained as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0217] Step e: To a stirred solution of tert-butyl 3-[6-methoxy-5-(methoxymethoxy)benzothiophen-2-yl]-3-oxo-propanoate (2.62 g, 7.1501 mmol) in N,N-dimethylformamide (20 mL) at 20° C. was added potassium carbonate (2.0621 g, 14.9207 mmol) and ethyl bromoacetate (1.3648 g, 8.1724 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 h. The reaction mixture was concentrated, diluted with EA (200 mL) and washed with water (100 mL) and brine (50 mL). The organics were washed with Na 2 Dry over SO4, filter and evaporate under reduced pressure. The residue was purified on a silica gel column EA / PE (0-80%). Pure fractions were concentrated and dried under vacuum. O1-tert-butyl O4-ethyl 2-[6-methoxy-5-(methoxymethoxy)benzothiophene-2-carbonyl]butanedioate (2.82 g, 6.2318 mmol, 87.1569% yield) was obtained as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0218] Step f: To O1-tert-butyl O4-ethyl 2-[6-methoxy-5-(methoxymethoxy)benzothiophene-2-carbonyl]butanedioate (2.82 g, 6.2318 mmol) in toluene (25 mL) was added TFA (5 mL) at 20° C. The reaction mixture was heated to 50° C. and stirred for 30 min. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated, diluted with EA (200 mL) and washed with water (100 mL) and brine (50 mL). The organics were washed with Na 2 SO4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / heptane (0-100%). The pure fractions were concentrated and dried under vacuum to give the crude product. The residue was purified on a silica gel column MeCN / water (0-100%). The pure fractions were concentrated and dried under vacuum to give ethyl 4-(5-hydroxy-6-methoxy-benzothiophen-2-yl)-4-oxo-butanoate (0.79 g, 2.5620 mmol, 41.1122% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0219] Intermediate A2: Methyl 4-(5-chloro-6-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutanoate [ka]

[0220] Step a: To a solution of 6-bromothieno[3,2-b]pyridine (30.0 g, 140.1 mmol) in DMF (300 mL) was added a solution of 25% MeONa (605.6 g, 2802.6 mmol) and CuI (26.7 g, 140.1 mmol) in MeOH. The reaction mixture was heated to 100 °C and stirred for 2 h, then cooled to room temperature, poured into ice water (900 mL), and filtered. The filtrate was diluted with NH 3 .H 2 The mixture was diluted with O (300 mL), extracted with EtOAc (1.0 L x 2), and washed with brine (1.0 L). 2 SO 4The mixture was dried over water, filtered, and the filtrate was concentrated to give 6-methoxythieno[3,2-b]pyridine (19.0 g, 82.3%) as a yellow solid. 1 H NMR (300 MHz, CDCl 3 ): 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.

[0221] Step b: To a solution of 6-methoxythieno[3,2-b]pyridine (19.0 g, 115.0 mmol) in DCM (200 mL) was added m-CPBA (19.8 g, 115.0 mmol). The reaction mixture was stirred at room temperature for 16 h, then diluted with DCM / MeOH = 10:1 (300 mL) and washed with saturated aqueous sodium bicarbonate (300 mL x 2) and brine (300 mL). The organic layer was extracted with Na 2 SO 4 It was dried over, filtered, and the filtrate was concentrated to give 6-methoxythieno[3,2-b]pyridine 4-oxide (13.0 g, 57.7%) as a yellow solid, which was used in the next step without further purification. 1 H NMR (300 MHz, CDCl 3 ): 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.

[0222] Step c: At room temperature, POCl 3To the resulting mixture (200 mL) was added 6-methoxythieno[3,2-b]pyridine 4-oxide (15.5 g, 85.5 mmol) in portions. The reaction mixture was heated to 100° C. and stirred for 16 h, 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 layer was washed with brine (200 mL) and diluted with Na 2 SO 4 The mixture was dried over 100 ml, filtered, and the filtrate was concentrated to give a residue which was purified by column chromatography on silica gel (eluted 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. 1 H NMR (300 MHz, CDCl 3 ): 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.

[0223] Step d: To a solution of 5-chloro-6-methoxythieno[3,2-b]pyridine (8.0 g, 40.1 mmol) in THF (80 mL) was added LDA (2.0 M, 80 mL) dropwise at −78° C. under nitrogen. After 15 min, a solution of dihydrofuran-2,5-dione (22.0 g, 220.4 mmol) in THF (240 mL) was added dropwise to the mixture at −40° C. under nitrogen. The reaction mixture was then allowed to warm to room temperature and stirred for 2 h. The reaction was then quenched with 2N hydrochloric acid (100 mL) and extracted with EtOAc (300 mL x 2). The organic layer was washed with brine (200 mL) and concentrated with Na 2 SO 4The mixture was dried over 100 ml of ethyl acetate, filtered, and the filtrate was concentrated. The residue was triturated with petroleum ether / EtOAc = 1: 1 and filtered to give 4-(5-chloro-6-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutanoate (6.0 g, crude) as a white solid, which was used in the next step without further purification. LCMS: (ESI, m / z): [MH] - = 298.8.

[0224] Step e: To a solution of 4-(5-chloro-6-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutanoate (6.0 g crude, 20.0 mmol) in MeOH (120 mL), add SOCl 2 (12.0 g, 100.1 mmol) was added dropwise at 0 °C. The reaction mixture was then warmed to room temperature and stirred for 2 h. The reaction was concentrated, diluted with water (100 mL), adjusted to pH = 8 with saturated aqueous sodium bicarbonate, and extracted with DCM / MeOH (200 mL x 2). The organic layer was washed with brine (100 mL) and diluted with Na 2 SO 4 The filtrate was concentrated to precipitate a white solid, which was filtered to give methyl 4-(5-chloro-6-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutanoate (1.1 g, 8.5% total for the two steps d and e) as a white solid. 1 H NMR (400 MHz, CDCl 3 ): 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.

[0225] Intermediate A3: Methyl trans-2-(5-bromo-6-methoxybenzo[b]thiophene-2-carbonyl)cyclopropane-1-carboxylate [ka]

[0226] Step a: 3-oxabicyclo[3.1.0]hexane-2,4-dione (6.3 g, 56.1 mmol) and AlCl in DCE (150 mL) 3 To a solution of (12.3 g, 92.6 mmol) was added a solution of 5-bromo-6-methoxybenzo[b]thiophene (15.0 g, 61.7 mmol) in DCE (50 mL) at -10 °C. The reaction mixture was then heated to 45 °C and stirred for 16 h. The reaction mixture was then poured into ice water (200 mL) and extracted with DCM / MeOH=10:1 (100 mL x 2). The organic layer was washed with brine (100 mL) and diluted with Na 2 SO 4 The mixture was dried over 100 ml, filtered, and the filtrate was concentrated to dryness. The residue was triturated with petroleum ether / EtOAc=1:1 (50 mL) and filtered to give cis-2-(5-bromo-6-methoxybenzo[b]thiophene-2-carbonyl)cyclopropane-1-carboxylic acid (3.0 g, 15.1% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): 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).

[0227] Step b: To a solution of cis-2-(5-bromo-6-methoxybenzo[b]thiophene-2-carbonyl)cyclopropane-1-carboxylic acid (3.0 g, 8.4 mmol) in MeOH (30 mL) was added 50% aq.NaOH (45 mL) at room temperature. After completion of the reaction, the reaction was analyzed by HPLC and the solvent was concentrated and removed. The residue was diluted with water (30 mL) and adjusted to pH ~2 with 6N hydrochloric acid. The white solid was collected by filtration. The solid was dried in 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. 1 H NMR (400 MHz, DMSO-d 6 ): 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).

[0228] Step c: To a solution of trans -2-(5-bromo-6-methoxybenzo[b]thiophene-2-carbonyl)cyclopropane-1-carboxylic acid (2.5 g, 7.0 mmol) in DMF (25 mL), 2 CO 3 (2.4 g, 17.5 mmol) and MeI (2.0 g, 14.1 mmol) were added at room temperature. After the reaction mixture was stirred for 16 h, the mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 2). The organic layer was washed with water (50 mL x 2) and brine (50 mL x 2). The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and the filtrate was concentrated to dryness. The residue was triturated 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-carboxylate (2 g, 77.5% yield) as a yellow solid. LCMS: (ESI, m / z): [M+H] + =368.8, 370.8.1 H NMR (400 MHz, CDCl 3 ): 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).

[0229] Intermediate A4: Ethyl 4-(4-chloro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate [ka]

[0230] To a solution of ethyl 4-(5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (300 mg, 0.97 mmol) in DMF (6 mL) was added NCS (156 mg, 1.14 mmol) in portions at room temperature. The reaction mixture was then stirred for 5 h and the reaction mixture was poured into ice water (18 mL). The mixture was filtered and the filter cake was dissolved in EtOAc (20 mL). The organic layer was washed with saturated aq. NaHCO 3 (15 mL) and brine (10 mL), and then washed with Na 2 SO 4 Drying over and concentration gave the crude product, which was purified by HPLC to give ethyl 4-(4-chloro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (240 mg, 72% yield) as a white solid. 1 H NMR (300 MHz, CDCl 3 ): 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.

[0231] Intermediate A5: Ethyl 4-(5-methoxyisoindolin-2-yl)-4-oxo-butanoate Intermediate A6: Ethyl 4-(5-bromo-6-methoxy-isoindolin-2-yl)-4-oxo-butanoate Intermediate A7: Ethyl 4-(5-hydroxy-6-methoxyisoindolin-2-yl)-4-oxobutanoate and intermediate A8: ethyl 4-(5-(3-bromopropoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate [ka]

[0232] Step a: To a solution of 5-methoxyisoindoline hydrochloride (4.89 g, 26.3399 mmol) and triethylamine (4.73 g, 46.7440 mmol) in ethanol (200 mL) was added succinic anhydride (4.40 g, 43.9681 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 1 h. SOCl 2 (20 mL) was added to the above solution at 0° C. The reaction mixture was stirred at 20° C. for 3 h. The reaction mixture was evaporated under reduced pressure. The reaction mixture was diluted with EA (200 mL) and washed with water (100 mL) and brine (50 mL). The organics were washed with Na 2 SO 4 It was dried over 100 ml, filtered and evaporated under reduced pressure to give ethyl 4-(5-methoxyisoindolin-2-yl)-4-oxo-butanoate (17.5 g, 31.5526 mmol, 119.7901% yield) as a yellow solid.

[0233] 1 H NMR (400 MHz, DMSO-d 6) 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).

[0234] Step b: NBS (10.51 g, 59.0503 mmol) was added to ethyl 4-(5-methoxyisoindolin-2-yl)-4-oxo-butanoate in tetrahydrofuran (100 mL) and acetonitrile (100 mL) at 20° C. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated, diluted with DCM (500 mL) and diluted with NaHCO 3 The organics were washed with aq. (2 x 300 mL) and brine (200 mL). 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column MeOH / DCM (0-10%). The pure fractions were concentrated and dried under vacuum to give ethyl 4-(5-bromo-6-methoxy-isoindolin-2-yl)-4-oxo-butanoate (7.26 g, 20.3812 mmol, 64.5943% yield) as a yellow solid.

[0235] 1 H NMR (400 MHz, DMSO-d 6) 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).

[0236] Step c: Pd(dppf)Cl in 1,4-dioxane (100 mL) 2 (0.72 g, 984.0050 μmol), ethyl 4-(5-bromo-6-methoxy-isoindolin-2-yl)-4-oxo-butanoate (3.64 g, 10.2187 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.84 g, 15.1218 mmol) were added potassium acetate (3.74 g, 38.1080 mmol) at 20 °C. The reaction mixture was stirred at 100 °C for 16 h and evaporated under reduced pressure. The reaction mixture was concentrated, diluted with DCM (500 mL) and diluted with NaHCO 3 The organics were washed with aq. (2 x 300 mL) and brine (200 mL). 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / Hept (0-100%). The pure fractions were concentrated and dried under vacuum. Ethyl 4-(5-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)-4-oxobutanoate (2.45 g, 6.0752 mmol, 59.7809% yield) was obtained as a yellow solid.

[0237] 1 H NMR (400 MHz, DMSO-d 6) 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).

[0238] Step d: Sodium perborate tetrahydrate (1 g, 6.4994 mmol) was added to ethyl 4-(5-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)-4-oxobutanoate (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. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated, diluted with DCM (500 mL), washed with NaHCO3 aq. (2×300 mL) and brine (200 mL). The organics were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column MeOH / DCM (0-10%). The pure fractions were concentrated and dried under vacuum. Ethyl 4-(5-hydroxy-6-methoxyisoindolin-2-yl)-4-oxobutanoate (1.37 g, 4.6708 mmol, 76.8818% yield) was obtained as a yellow solid.

[0239] Step e: To a solution of ethyl 4-(5-hydroxy-6-methoxy-isoindolin-2-yl)-4-oxo-butanoate (0.72 g, 2.4547 mmol) in N,N-dimethylformamide (10 mL) was added 1,3-dibromopropane (0.73 g, 3.6159 mmol) and potassium carbonate (0.86 g, 6.2226 mmol). The mixture was stirred at 50 °C for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed successively with water (2 x 100 mL) and saturated brine (1 x 100 mL). The organic layer was extracted with Na 2 SO 4 The mixture was dried over hexanes, filtered and evaporated to give the crude product. The crude product was purified by flash silica chromatography eluting with a 0-100% gradient of ethyl acetate in heptane to give ethyl 4-(5-(3-bromopropoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.43 g, 1.0379 mmol, 42.2829% yield) as a white solid.

[0240] 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0241] Intermediate A9: tert-Butyl 3-(5-bromo-4-fluoro-6-methoxy-benzothiophen-2-yl)-3-oxo-propanoate Step a: 3-Bromo-2-fluoro-4-methoxy-benzaldehyde [ka]

[0242] Titanium tetrachloride (38.06 g, 200.6548 mmol) was added dropwise over 1 h to a solution of 2-bromo-3-fluoroanisole (10.17 g, 49.6039 mmol) in dichloromethane (250 mL) at 0 °C. The reaction mixture was quenched by the addition of ice water (200 mL) at 0 °C. The reaction mixture was extracted with DCM (2 x 100 mL) and diluted with NaHCO 3 (1 x 200 mL) and brine (100 mL). The organics were washed with Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate, filtered and evaporated under reduced pressure. The residue was dried under vacuum at 60° C. to give 3-bromo-2-fluoro-4-methoxy-benzaldehyde (11.42 g, 49.0057 mmol, 98.7940% yield) as a white solid. LCMS: (ESI, m / z): [M+H] + = 232.954. 1 H NMR (400 MHz, CDCl 3 -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).

[0243] Step b: (5E)-5-[(3-bromo-2-fluoro-4-methoxy-phenyl)methylene]-2-thioxo-thiazolidin-4-one [ka]

[0244] To a mixture 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) at 20° C., potassium acetate (12.67 g, 129.0984 mmol) was added. The reaction mixture was heated to 140° C. and stirred overnight. The reaction mixture was added to water (1000 mL) and stirred for 10 min. The precipitate was collected by filtration and washed with water (200 mL). The filtrate cake was dried under vacuum at 60° C. (5E)-5-[(3-bromo-2-fluoro-4-methoxy-phenyl)methylene]-2-thioxo-thiazolidin-4-one (9.21 g, 26.4495 mmol, 61.5748% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 347.909. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.87 (s, 1H), 7.68 - 7.32 (m, 2H), 7.16 (d, J = 8.7 Hz, 1H), 3.97 (s, 3H).

[0245] Step c: (Z)-3-(3-bromo-2-fluoro-4-methoxy-phenyl)-2-sulfanyl-prop-2-enoic acid [ka]

[0246] To a stirred mixture of (5E)-5-[(3-bromo-2-fluoro-4-methoxy-phenyl)methylene]-2-thioxo-thiazolidin-4-one (8.03 g, 23.0607 mmol) in water (200 mL) was added NaOH (9.15 g, 228.7666 mmol) in water (80 mL) at 20 °C. After completion of the reaction, the pH was adjusted to 3 with hydrochloric acid. The precipitate was collected by filtration and washed with water (1 x 100 mL). The filtrate was dried under vacuum at 60 °C. (Z)-3-(3-bromo-2-fluoro-4-methoxy-phenyl)-2-sulfanyl-prop-2-enoic acid (7.37 g, 23.9959 mmol, 104.0552% yield) was obtained as a yellow solid.

[0247] Step d: 5-Bromo-4-fluoro-6-methoxy-benzothiophene-2-carboxylic acid [ka]

[0248] To a solution of (Z)-3-(3-bromo-2-fluoro-4-methoxy-phenyl)-2-sulfanyl-prop-2-enoic acid (7 g, 22.7912 mmol) in methyl sulfoxide (50 mL) was added palladium(II) acetate (4.0934 g, 18.2330 mmol) at 20° C. under N2 atmosphere. The reaction mixture was heated to 100° C. and stirred for 1 h. The reaction mixture was purified on a C-18 column MeCN / water (0-100%). The pure fractions were concentrated and dried under vacuum. 5-Bromo-4-fluoro-6-methoxy-benzothiophene-2-carboxylic acid (3.9 g, 12.7819 mmol, 56.0824% yield) was obtained as a yellow solid.

[0249] Step e: tert-Butyl 3-(5-bromo-4-fluoro-6-methoxy-benzothiophen-2-yl)-3-oxo-propanoate [ka]

[0250] 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) at 20° C., carbonyldiimidazole (4.12 g, 25.4088 mmol) was added. The resulting mixture was stirred at 20° C. for 1 h under nitrogen atmosphere. To the above mixture was added magnesium chloride (1.81 g, 19.0104 mmol), 3-tert-butoxy-3-oxopropanoic acid (3.13 g, 19.5421 mmol) and triethylamine (3.91 g, 38.6404 mmol). The reaction mixture was stirred at 20° C. overnight. The reaction mixture was concentrated, diluted with EA (500 mL) and diluted with NaHCO 3 The organics were washed with aq (2 x 500 mL) and brine (100 mL). 2 SO 4 The mixture was dried over hexanes, filtered and evaporated under reduced pressure. The residue was purified by flash silica chromatography eluting with a gradient of 0-100% ethyl acetate in heptane. Pure fractions were concentrated and dried under vacuum to give tert-butyl 3-(5-bromo-4-fluoro-6-methoxy-benzothiophen-2-yl)-3-oxo-propanoate (3.29 g, 8.1585 mmol, 64.1574% yield) as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 402.994. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0251] Intermediate A10: tert-Butyl 4-fluoro-5-hydroxy-6-methoxy-isoindoline-2-carboxylate Step a: 4-Fluoro-5-methoxy-isoindoline [ka]

[0252] 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) was added to 10% Pd / C (7.68 g, 55% H 2 O was added. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was filtered and the filter cake was washed with MeOH (70 mL). The filtrate was evaporated under reduced pressure. 4-Fluoro-5-methoxy-isoindoline (4.88 g, 29.1901 mmol, 100% yield) was obtained as a brown oil which was used directly in the next step.

[0253] Step b: 4-Fluoroisoindolin-5-ol hydrobromide [ka]

[0254] 4-Fluoro-5-methoxy-isoindoline (4.5 g, 26.9171 mmol) was dissolved in hydrobromic acid (120 mL, 48% aq) at 20° C. The reaction mixture was 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-Fluoroisoindolin-5-ol hydrobromide (4.70 g, 20.0799 mmol, 74.60% yield) was obtained as a brown solid. LCMS: (ESI, m / z): [M+H] + = 154.200. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.09 (s, 1H), 9.58 (s, 2H), 7.10 - 6.93 (m, 2H), 4.57 (s, 2H), 4.44 (s, 2H).

[0255] Step c: tert-Butyl 4-fluoro-5-hydroxy-isoindoline-2-carboxylate [ka]

[0256] NaHCO 3 (3.43 g, 40.8301 mmol) was added to a solution of 4-fluoroisoindolin-5-ol hydrobromide (4.70 g, 20.0799 mmol) in water (80 mL) at 0 °C. After the reaction mixture was stirred for 20 min, THF (60 mL) was added to the reaction mixture and di-tert-butyl dicarbonate (4.45 g, 20.3898 mmol) in THF (20 mL) was added dropwise to the mixture at 0 °C. After stirring for 20 min, the reaction mixture was warmed to 20 °C and stirred for 2 h. The resulting reaction mixture was diluted with EA (150 mL) and washed with brine (150 mL). The organic layer was extracted with Na 2 Dry over SO4, filter and evaporate under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate in n-hexane (0-40%). Pure fractions were concentrated and dried under reduced pressure to give tert-butyl 4-fluoro-5-hydroxy-isoindoline-2-carboxylate (3.14 g, 12.3979 mmol, 60.78% yield) as a red-brown solid. LCMS: (ESI, m / z): [MH] - = 252.000. 1 H NMR (400 MHz, CDCl 3 -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).

[0257] Step d: tert-Butyl 6-bromo-4-fluoro-5-hydroxy-isoindoline-2-carboxylate [ka]

[0258] NBS (2.20 g, 12.3607 mmol) was added to a solution of tert-butyl 4-fluoro-5-hydroxy-isoindoline-2-carboxylate (3.10 g, 12.2400 mmol) in ACN (40 mL) and THF (20 mL) at 0° C. 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 diluted with H 2 The organic layer was washed with NaO (200 mL). 2 Dry over SO4, filter and evaporate in vacuo. The residue was purified by flash chromatography eluting with MeOH in DCM (0-5%). Pure fractions were concentrated and dried under reduced pressure to give tert-butyl 6-bromo-4-fluoro-5-hydroxy-isoindoline-2-carboxylate (2.70 g, 8.1285 mmol, 66.34% yield) as a white solid. LCMS: (ESI, m / z): [MH] - = 331.950. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0259] Step e: tert-Butyl 5-benzyloxy-6-bromo-4-fluoro-isoindoline-2-carboxylate [ka]

[0260] K 2 CO 3(2.20 g, 15.9183 mmol) was added to a solution of tert-butyl 6-bromo-4-fluoro-5-hydroxy-isoindoline-2-carboxylate (2.70 g, 8.1285 mmol) in DMF (50 mL) at 0 °C. After the reaction mixture was stirred at 0 °C for 0.5 h, BnBr (1.90 g, 11.1089 mmol) was added to the reaction mixture. The reaction mixture was stirred at 20 °C for 9 h. The reaction mixture was diluted with EA (150 mL) and washed with water (150 mL) and brine (2 x 150 mL). The organics were washed with Na 2 SO 4 The mixture was dried over ice, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate in n-hexane (0-10%). Pure fractions were concentrated and dried under reduced pressure to give tert-butyl 5-benzyloxy-6-bromo-4-fluoro-isoindoline-2-carboxylate (3.43 g, 8.1224 mmol, 99.93% yield) as a white semi-solid. LCMS: (ESI, m / z): [M-tBu+ACN] + = 407.050. 1 H NMR (400 MHz, CDCl 3 -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).

[0261] Step f: tert-Butyl 5-benzyloxy-4-fluoro-6-hydroxy-isoindoline-2-carboxylate [ka]

[0262] Pd(dppf)Cl 2(1.12 g, 1.5307 mmol) was added at 20° C. to a solution of tert-butyl 5-benzyloxy-6-bromo-4-fluoro-isoindoline-2-carboxylate (3. 30 g, 7.8146 mmol), bis(neopentylglycolato)diboron (5.46 g, 24.1716 mmol) and KOAc (2.32 g, 23.6392 mmol) in 1,4-dioxane (80 mL). The reaction mixture was heated to 90° C. and stirred overnight under nitrogen atmosphere. The reaction mixture was diluted with EA (100 mL) and filtered through Celite. The filtrate was evaporated under reduced pressure. H 2 O 2 (88.1974 mmol, 10 mL, 30% aqueous solution) was dissolved in THF (80 mL) and NaHCO 3 (11.9038 mmol, 20 mL, 5% aqueous solution). The reaction mixture was stirred at 20° C. for 2 h. The resulting reaction mixture was diluted with brine (150 mL) and saturated NaHSO 3 (100 mL) and extracted with EA (200 mL). The organic layer was collected and 2 SO 4 The mixture was dried over 100 ml, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate / n-hexane (0-10%) to give tert-butyl 5-benzyloxy-4-fluoro-6-hydroxy-isoindoline-2-carboxylate (1.93 g, 5.3702 mmol, 68.93% yield) as an off-white solid. LCMS: (ESI, m / z): [MH] - = 358.100. 1 H NMR (400 MHz, CDCl 3 -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).

[0263] Step g: tert-Butyl 5-benzyloxy-4-fluoro-6-methoxy-isoindoline-2-carboxylate [ka]

[0264] K 2 CO 3 (1.18 g, 8.5380 mmol) was added to a solution of tert-butyl 5-benzyloxy-4-fluoro-6-hydroxy-isoindoline-2-carboxylate (1.9 g, 5.2867 mmol) in DMF (25 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min and then diluted with CH 3 I (1.12 g, 7.8908 mmol) was added. The reaction mixture was stirred at 20° C. for 3 h. The resulting reaction mixture was diluted with water (200 mL) and extracted with EA (200 mL). The organic layer was separated and washed with brine (2 x 150 mL). The organic layer was collected and washed with Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate, filtered and evaporated under reduced pressure to give tert-butyl 5-benzyloxy-4-fluoro-6-methoxy-isoindoline-2-carboxylate (1.98 g, 5.3024 mmol, 100% yield) as a colorless oil, which was used directly in the next step without purification. LCMS: (ESI, m / z): [M-tBu+ACN] + = 359.150. 1 H NMR (400 MHz, CDCl 3 -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).

[0265] Step h: tert-Butyl 4-fluoro-5-hydroxy-6-methoxy-isoindoline-2-carboxylate [ka]

[0266] 10%Pd / C (1.98 g, 55%H 2 The reaction mixture was stirred for 2 h at 20 °C for 1 h (containing 1.2 mL of tert-butyl 5-benzyloxy-4-fluoro-6-methoxy-isoindoline-2-carboxylate (1.96 g, 5.2488 mmol) in MeOH (40 mL) and THF (10 mL). 2 The mixture was stirred at 20°C under ambient atmosphere for 5 h. The reaction mixture was diluted with EA (20 mL) and filtered through Celite. The filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluted with ethyl acetate / n-hexane (0-40%). The pure fractions were concentrated and dried under reduced pressure. tert-Butyl 4-fluoro-5-hydroxy-6-methoxy-isoindoline-2-carboxylate (1.21 g, 4.2712 mmol, 80.67% yield) was obtained as a brown semi-solid. LCMS: (ESI, m / z): [MH] - = 282.100. 1 H NMR (400 MHz, CDCl 3 -d) δ 6.58 (s, 1H), 4.67 (s, 2H), 4.63 (s, 2H), 3.92 (s, 3H), 1.53 (s, 9H).

[0267] Intermediate A11: Ethyl 4-(4-fluoro-5-hydroxy-6-methoxy-isoindolin-2-yl)-4-oxo-butanoate Step a: 7-Fluoro-6-methoxy-2-[(4-methoxyphenyl)methyl]isoindolin-1-one [ka]

[0268] 4-Methoxybenzyl chloride (4.141g, 26.4416 mmol) was dissolved in N 2To a solution of NaH (1.000 g, 25.0024 mmol) and 7-fluoro-6-methoxyisoindolin-1-one (4.336 g, 23.9342 mmol) in DMF (100 mL) was added under ambient conditions at 0° C. The reaction mixture was stirred for 3 h and allowed to warm to 20° C. The reaction mixture was quenched into water (300 mL) at 20° C., extracted with EA (3 x 200 mL) and washed with brine (150 mL). The organics were washed with Na 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / n-Hex (0-100%). The pure fractions were concentrated and dried under vacuum. 7-Fluoro-6-methoxy-2-[(4-methoxyphenyl)methyl]isoindolin-1-one (6.51 g, 21.6055 mmol, 90.2706% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 302.110. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0269] Step b: 4-Fluoro-5-methoxy-2[(4-methoxyphenyl)methyl]isoindoline [ka]

[0270] A solution of 7-fluoro-6-methoxy-2-(4-methoxybenzyl)isoindolin-1-one (6.17 g, 20.4771 mmol) in THF (60 mL) was added to 2Borane-tetrahydrofuran complex (120 mL, 120 mmol) was added at 20° C. under ambient conditions. The reaction mixture was heated to 80° C. and stirred for 5 h. The reaction mixture was quenched by pouring into 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 and washed with MeOH (50 mL). The filter cake was dried under vacuum. 4-Fluoro-5-methoxy-2[(4-methoxyphenyl)methyl]isoindoline (3.854 g, 13.4132 mmol, 65.5036% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 288.130. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0271] Step c: Ethyl 4-(4-fluoro-5-methoxy-isoindolin-2-yl)-4-oxo-butanoate [ka]

[0272] 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. The reaction mixture was stirred for 1 h. 2 The mixture was stirred overnight at 20° C. under atmospheric pressure. The precipitate was collected by filtration and washed with MeOH (50 mL). The filtrate was evaporated under reduced pressure. A solution of the residue and TEA (3.91 g, 38.6404 mmol) in DCM (50 mL) was diluted with N 2Ethyl succinate chloride (5.05 g, 30.6830 mmol) was added at 0° C. under atmospheric pressure. The reaction mixture was stirred at 20° C. for 1 h. The reaction mixture was quenched by the addition of water (50 mL) at 20° C., extracted with DCM (3 x 50 mL) and washed with brine (50 mL). The organics were washed with Na 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / n-Hex (0-45%). The pure fractions were concentrated and dried under vacuum. Ethyl 4-(4-fluoro-5-methoxy-isoindolin-2-yl)-4-oxo-butanoate (2.619 g, 8.8688 mmol, 75.8406% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 296.120. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0273] Step d: Ethyl 4-(4-fluoro-5-hydroxy-isoindolin-2-yl)-4-oxo-butanoate [ka]

[0274] Tribromoboron (20 mL, 20 mmol) was dissolved in N 2 The mixture was added to a solution of ethyl 4-(4-fluoro-5-methoxyisoindolin-2-yl)-4-oxobutanoate (2.597 g, 8.7943 mmol) in DCM (40 mL) at 0° C. under atmospheric pressure. The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was quenched by addition to EtOH (100 mL) at 20° C., and the reaction mixture was evaporated under reduced pressure and H 2The organics were diluted with O (200 mL), extracted with EA (2 x 100 mL) and washed with brine (100 mL). 2 SO 4 It was dried over 100 ml of ethyl acetate, filtered and evaporated under reduced pressure to give ethyl 4-(4-fluoro-5-hydroxy-isoindolin-2-yl)-4-oxo-butanoate (2.408 g, 8.5609 mmol, 97.3461% yield) as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 282.110. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0275] Step e: Ethyl 4-(6-bromo-4-fluoro-5-hydroxy-isoindolin-2-yl)-4-oxo-butanoate [ka]

[0276] NBS (1.194 g, 6.7085 mmol) was added to N 2 A solution of ethyl 4-(4-fluoro-5-hydroxy-isoindolin-2-yl)-4-oxo-butanoate (2.106 g, 7.4872 mmol) in MeCN (20 mL) and THF (20 mL) was added at 0° C. under ambient conditions. The reaction mixture was stirred for 2 h and allowed to warm to 20° C. naturally. The precipitate was collected by filtration. The filter cake was dried under vacuum. Ethyl 4-(6-bromo-4-fluoro-5-hydroxy-isoindolin-2-yl)-4-oxo-butanoate (2.84 g, 7.8851 mmol, 105.3134% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H]+ = 359.010. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0277] Step f: Ethyl 4-(6-bromo-4-fluoro-5-(methoxymethoxy)isoindolin-2-yl)-4-oxobutanoate [ka]

[0278] Bromomethyl methyl ether (1.20 g, 9.6028 mmol) was dissolved in N 2 A solution of ethyl 4-(6-bromo-4-fluoro-5-hydroxy-isoindolin-2-yl)-4-oxo-butanoate (2.23 g, 6.1914 mmol) and DIEA (2.55 g, 19.7304 mmol) in DCM (50 mL) was added under ambient conditions at 0° C. The reaction mixture was stirred for 2 h and allowed to warm to 20° C. The reaction mixture was quenched at 20° C. by the addition of water (50 mL), extracted with DCM (3 x 50 mL) and washed with brine (50 mL). The organics were washed with Na 2 SO 4 The mixture was dried over 1000 ml of water, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on a C18 column with ACN / H 2 0 (0.1% FA) (0-50%). Pure fractions were concentrated and dried under vacuum to give ethyl 4-(6-bromo-4-fluoro-5-(methoxymethoxy)isoindolin-2-yl)-4-oxobutanoate (1.809 g, 4.4752 mmol, 72.2806% yield) as a yellow solid. LCMS: (ESI, m / z): [M+H] += 403.140. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0279] Step g: Ethyl 4-(4-fluoro-6-hydroxy-5-(methoxymethoxy)isoindolin-2-yl)-4-oxobutanoate [ka]

[0280] Pd(dppf)Cl 2 (0.228 g, 311.6016 μmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.170 g, 4.6074 mmol) and potassium acetate (0.743 g, 7.5706 mmol) were added to N 2 To a solution of ethyl 4-(6-bromo-4-fluoro-5-(methoxymethoxy)isoindolin-2-yl)-4-oxobutanoate (0.735 g, 1.8183 mmol) in 1,4-dioxane (20 mL) was added under atmospheric pressure at 20° C. The reaction mixture was heated to 100° C. and stirred for 12 h. The reaction mixture was quenched by the addition of water (150 mL) at 20° C., extracted with EA (3 x 150 mL) and washed with brine (50 mL). The organics were washed with Na 2 SO 4 The mixture was dried over 1000 ml of THF, filtered and evaporated under reduced pressure. 2 A solution of the residue in O (10 mL) was added 2Sodium perborate (0.91 g, 5.9145 mmol) was added under atmospheric pressure at 20° C. The reaction mixture was stirred at 20° C. for 1 h. The reaction mixture was evaporated under reduced pressure. The residue was purified by column chromatography on a C18 column with ACN / H 2 0 (0.1% FA) (0-38%). Pure fractions were concentrated and dried under vacuum to give ethyl 4-(4-fluoro-6-hydroxy-5-(methoxymethoxy)isoindolin-2-yl)-4-oxobutanoate (0.365 g, 1.0693 mmol, 58.8% yield) as a white solid. LCMS: (ESI, m / z): [M+H] + =342.130. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0281] Step h: Ethyl 4-(4-fluoro-5-hydroxy-6-methoxy-isoindolin-2-yl)-4-oxo-butanoate [ka]

[0282] A mixture of potassium carbonate (0.448 g, 3.2415 mmol) and ethyl 4-(4-fluoro-6-hydroxy-5-(methoxymethoxy)isoindolin-2-yl)-4-oxobutanoate (0.328 g, 960.9441 μmol) in DMF (10 mL) was added to the 2Methyl iodide (0.345 g, 2.4306 mmol) was added at 20° C. under atmospheric pressure. The reaction mixture was stirred at 20° C. for 1 h. The reaction mixture was quenched by the addition of water (50 mL) at 20° C., extracted with DCM (3 x 50 mL) and washed with brine (50 mL). The organics were washed with Na 2 SO 4 The mixture was dried over 1000 ml of water, filtered and evaporated under reduced pressure. Trifluoroacetic acid (2 mL) was dissolved in N 2 The residue (0.446 g, 1.2551 mmol) was added to a solution of DCM (5 mL) under atmosphere at 20° C. The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was evaporated under reduced pressure. The residue was purified by column chromatography on a C18 CAN / H column. 2 0 (0-80%). The pure fractions were concentrated and dried under vacuum to give ethyl 4-(4-fluoro-5-hydroxy-6-methoxy-isoindolin-2-yl)-4-oxo-butanoate (0.274 g, 880.1663 μmol, 91.6% yield) as a white solid.

[0283] Intermediate A12: Ethyl 4-(6-hydroxy-5-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutanoate Step a: 6-Bromo-5-methoxythieno[3,2-b]pyridine [ka]

[0284] In a microwave reactor, N 2 A solution of 6-bromo-5-chlorothieno[3,2-b]pyridine (1.0 g, 4.0 mmol) and NaOMe (9.3 mL, 40 mmol) in MeOH (6 mL) was stirred at 100 °C under atmospheric pressure for 1 h. 1N citric acid (80 mL) was added and extracted with EtOAc (70 mL x 3). The combined organic solution was diluted with Na 2 SO 4 Drying and concentration afforded 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-d 6 ): 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.

[0285] Step b: 6-Bromo-5-methoxythieno[3,2-b]pyridine-2-carboxylic acid [ka]

[0286] To a solution of 6-bromo-5-methoxythieno[3,2-b]pyridine (5.0 g, 20.0 mmol) in THF (200 mL) was added LDA (20 ml, 40 mmol) at −80° C. The reaction mixture was stirred under nitrogen atmosphere at −80° C. for 30 min. The solution was then irradiated with CO 2 The reaction mixture was stirred for about 1 h. 1 N HCl (50 mL) and water (200 mL) were added and extracted with EtOAc (70 mL x 3). The combined organic solution was washed with Na 2 SO 4 Drying and concentration afforded 6-bromo-5-methoxythieno[3,2-b]pyridine-2-carboxylic acid (4.9 g, 17.0 mmol, 85% yield) as a brown solid. 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.84 (s, 1H), 7.92 (s, 1H), 4.00 (s, 3H). LCMS: (ESI, m / z): [M+H] + = 287.9.

[0287] Step c: tert-Butyl 3-(6-bromo-5-methoxythieno[3,2-b]pyridin-2-yl)-3-oxopropanoate [ka]

[0288] To a solution of 6-bromo-5-methoxythieno[3,2-b]pyridine-2-carboxylic acid (4.9 g, 17.0 mmol) in DMF (147 mL) was added CDI (5.5 g, 34.0 mmol). After stirring at room temperature for 2 h under N2 atmosphere, 3-tert-butoxy-3-oxopropanoic acid (5.5 g, 34.0 mmol), TEA (5.2 g, 51.0 mmol, 3.0 eq) and MgCl 2 (3.3 g, 34.0 mmol) was added and stirred at RT overnight. Upon completion, sat. NaHCO 3 The combined organic solution was diluted with Na 2 SO 4 The mixture was dried over water and concentrated to give a residue which was purified by column chromatography (petroleum ether / ethyl acetate=20:1) to give tert-butyl 3-(6-bromo-5-methoxythieno[3,2-b]pyridin-2-yl)-3-oxopropanoate (5.0 g, 12.9 mmol, 62% yield) as a yellow solid.

[0289] 1 H NMR (300 MHz, DMSO-d 6 ): 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.

[0290] Step d: 1-(tert-butyl) 4-ethyl 2-(6-bromo-5-methoxythieno[3,2-b]pyridine-2-carbonyl)succinate [ka]

[0291] A solution of tert-butyl 3-(6-bromo-5-methoxythieno[3,2-b]pyridin-2-yl)-3-oxopropanoate (3.0 g, 7.8 mmol) in DMF (60 mL) was heated at 0 °C for 1 h at 37 °C. 2 CO 3 (1.8 g, 12.5 mmol) and ethyl bromoacetate (1.3 g, 78 mmol) were added. The reaction mixture was then cooled to 4° C. for 2 h. 2 The mixture was stirred at 0°C for 5 hours under atmospheric conditions. 3 Solution (100 mL) was added and extracted with EtOAc (100 mL x 3). The combined organic solution was diluted with Na 2 SO 4 The mixture was dried over water and concentrated to give a 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.

[0292] 1 H NMR (300 MHz, DMSO-d 6 ): 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.

[0293] Step e: Ethyl 4-(6-bromo-5-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutanoate [ka]

[0294] To a solution of 1-(tert-butyl) 4-ethyl 2-(6-bromo-5-methoxythieno[3,2-b]pyridine-2-carbonyl)succinate (3.3 g, 7.0 mmol) in PhMe (66 mL) was added TFA (33 ml). 2 After stirring at 50° C. under atmospheric pressure for 1.5 hours, the solution was concentrated to give a residue, and the resulting solid was triturated with petroleum ether / ethyl acetate (10 / 1) to give the crude compound ethyl 4-(6-bromo-5-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutanoate (2.2 g, 5.9 mmol, 84% yield) as a brown solid. 1 H NMR (300 MHz, DMSO-d 6 ): 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.

[0295] Step f: (2-(4-ethoxy-4-oxobutanoyl)-5-methoxythieno[3,2-b]pyridin-6-yl)boronic acid [ka]

[0296] Ethyl 4-(6-bromo-5-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutanoate (1.6 g, 4.3 mmol), B 2 Pin 2 (1.4 g, 5.3 mmol), AcOK (688 mg, 6.9 mmol), Pd 2(dba)3 (112 mg, 0.1 mmol) and tricyclohexylphosphine (128 mg, 0.43 mmol) were placed in a reaction bottle. The bottle was evacuated and filled with argon three times. Dioxane (32 mL) was then added at room temperature. Water (50 mL) was added to the reaction mixture, which was extracted with EtOAc (3 x 50 mL), and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solution was concentrated to give (2-(4-ethoxy-4-oxobutanoyl)-5-methoxythieno[3,2-b]pyridin-6-yl)boronic acid (3.2 g) as a crude residue, which was used in the next step without further purification. LCMS: (ESI, m / z): [M+H] + = 338.1.

[0297] Step G: [ka]

[0298] To a solution of (2-(4-ethoxy-4-oxobutanoyl)-5-methoxythieno[3,2-b]pyridin-6-yl)boronic acid (3.2 g, 4.3 mmol, crude) in acetone (48 mL) was added oxone (36 mL, 6.5 mmol). After stirring at room temperature for 2 h, Sat.NaHSO 3 After adding solution (120 mL) and stirring at room temperature for 1 h, the mixture was extracted with EtOAc (3 x 30 mL), and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solution was concentrated to give a crude residue, which was purified by column chromatography (petroleum ether / ethyl acetate = 10:1 to 5:1) to give ethyl 4-(6-hydroxy-5-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutanoate (340 mg, 1.1 mmol, 25% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6): 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.

[0299] The following intermediates were synthesized using the corresponding starting materials and intermediates by the procedures described above or modified procedures. [Table 4]

[0300] Example 1 4-(5-(3-((2-(3-carboxypropanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid [ka]

[0301] Step a: To a solution of ethyl 4-(5-(3-bromopropoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.240 g, 579. 3045 μmol) and ethyl 4-(5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (0.169 g, 576.1737 μmol) in N,N-dimethylformamide (10 mL) at 20 °C, potassium carbonate (0.240 g, 1.7365 mmol) was added. The reaction mixture was heated to 50 °C and stirred for 3 h. The reaction mixture was concentrated, diluted with EA (500 mL) and diluted with NaHCO 3 The organics were washed with aq. (2 x 300 mL) and brine (200 mL). 2 SO 4The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / Hept (0-100%). The pure fractions were concentrated and dried under vacuum. Ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.147 g, 229.0694 μmol, yield 62.8484%) was obtained as a yellow solid.

[0302] 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0303] Step b: To a solution of ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate in tetrahydrofuran (10 mL) and water (2 mL) at 20° C., LiOH (0.022 g, 918.6456 μmol) was added. The reaction mixture was stirred for 2 h. The reaction mixture was 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). The filtrate cake was dried in vacuum at 60° C. 4-(5-(3-((2-(3-carboxypropanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid (0.119 g, 203.2031 μmol, 90.5562% yield) was obtained as a yellow solid.

[0304] 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0305] Example 2 4-(5-(3-((2-(3-carboxypropanoyl)-4-chloro-6-methoxyisoindolin-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid Step a: O1-tert-butyl O4-ethyl 2-(5-bromo-4-fluoro-6-methoxy-benzothiophene-2-carbonyl)butanedioate [ka]

[0306] A stirred solution of tert-butyl 3-(5-bromo-4-fluoro-6-methoxy-benzothiophen-2-yl)-3-oxo-propanoate (1.58 g, 3.9180 mmol) in N,N-dimethylformamide (10 mL) was added to the flask at 20 °C. 2 CO 3 (1.10 g, 7.9592 mmol) and ethyl bromoacetate (0.72 g, 4.3114 mmol) were added. The resulting mixture was stirred under nitrogen at 20° C. for 2 h. The reaction mixture was concentrated, diluted with EA (200 mL) and washed with water (100 mL) and brine (50 mL). The organics were washed with Na 2 SO 4 The mixture was dried over hexanes, filtered and evaporated under reduced pressure. The residue was purified by flash silica chromatography eluting with a gradient of 0-100% ethyl acetate in heptane. Pure fractions were concentrated and dried under vacuum to give O1-tert-butyl O4-ethyl 2-(5-bromo-4-fluoro-6-methoxy-benzothiophene-2-carbonyl)butanedioate (1.925 g, 3.9338 mmol, 100.4016% yield) as a yellow oil. LCMS: (ESI, m / z): [M+H] + = 489.030.

[0307] Step b: Ethyl 4-(5-bromo-4-fluoro-6-methoxy-benzothiophen-2-yl)-4-oxobutanoate [ka]

[0308] To a solution of O1-tert-butyl O4-ethyl 2-(5-bromo-4-fluoro-6-methoxy-benzothiophene-2-carbonyl)butanedioate (1.85 g, 3.7805 mmol) in toluene (10 mL) was added trifluoroacetic acid (2 mL) at 20° C. The reaction mixture was stirred at 60° C. for 2 h. The reaction mixture was evaporated under reduced pressure. The residue was concentrated, diluted with DCM (200 mL) and diluted with NaHCO 3 The organics were washed with aq (2 x 100 mL) and brine (100 mL). 2 SO 4 The mixture was dried over hexanes, filtered and evaporated under reduced pressure. The residue was purified by flash silica chromatography eluting with a gradient of 0-100% ethyl acetate in heptane. Pure fractions were concentrated and dried under vacuum to give ethyl 4-(5-bromo-4-fluoro-6-methoxy-benzothiophen-2-yl)-4-oxo-butanoate (0.727 g, 1.8678 mmol, 49.4050% yield) as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 388.978. 1 H NMR (400 MHz, DMSO-d 6 ) 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 = 7.1Hz, 3H).

[0309] Step c: Ethyl 4-(4-fluoro-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)-4-oxobutanoate [ka]

[0310] A mixture of potassium acetate (0.60 g, 6.1136 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0. 97 g, 3.8198 mmol) and ethyl 4-(5-bromo-4-fluoro-6-methoxy-benzothiophen-2-yl)-4-oxo-butanoate (0.72 g, 1.8498 mmol) in 1,4-dioxane (30 mL) was added to Pd(dppf)Cl at 20 °C. 2 Added N 2 The reaction mixture was stirred under atmosphere at 100° C. for 20 h. The reaction mixture was evaporated under reduced pressure. The residue was concentrated, diluted with EA (200 mL) and diluted with NaHCO 3 The organics were washed with aq (2 x 100 mL) and brine (100 mL). 2 SO 4 The mixture was dried over silica gel, filtered and evaporated under reduced pressure. The residue was purified by flash silica chromatography eluting with a gradient of 0-100% ethyl acetate in heptane. Pure fractions were concentrated and dried under vacuum to give ethyl 4-(4-fluoro-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)-4-oxobutanoate (0.38 g, 870.9586 μmol, 47.0845% yield) as a white solid. LCMS: (ESI, m / z): [M+H] + = 437.153.

[0311] Step d: Ethyl 4-(4-fluoro-5-hydroxy-6-methoxy-benzothiophen-2-yl)-4-oxobutanoate [ka]

[0312] To a solution of ethyl 4-(4-fluoro-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)-4-oxobutanoate in tetrahydrofuran (10 mL) and water (10 mL) was added sodium perborate tetrahydrate (0.21 g, 1.3649 mmol) at 20 °C. The reaction mixture was concentrated, diluted with DCM (100 mL) and diluted with NaHCO 3 The organics were washed with aq (2 x 500 mL) and brine (50 mL). 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column MeOH / DCM (0-5%). The pure fractions were concentrated and dried under vacuum. Ethyl 4-(4-fluoro-5-hydroxy-6-methoxy-benzothiophen-2-yl)-4-oxo-butanoate (0.263 g, 805.9094 μmol, 92.5313% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 327.062. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0313] Step e: Ethyl 4-(4-chloro-5-hydroxy-6-methoxy-isoindolin-2-yl)-4-oxobutanoate [ka]

[0314] A solution of ethyl 4-(5-hydroxy-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.205 g, 698.9090 μmol) in DMF (10 mL) was 2NCS (0.105 g, 786.3231 μmol) was added at 0° C. under atmospheric conditions. The reaction mixture was stirred for 12 h and allowed to warm to 20° C. naturally. The reaction mixture was then loaded onto a C18 column ACN / H 2 0 (0-25%). The pure fractions were concentrated and dried under vacuum. Ethyl 4-(4-chloro-5-hydroxy-6-methoxy-isoindolin-2-yl)-4-oxobutanoate (0.148 g, 451.5507 μmol, 64.6079% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 328.100. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0315] Step f: Ethyl 4-[5-(3-bromopropoxy)-4-chloro-6-methoxy-isoindolin-2-yl]-4-oxobutanoate [ka]

[0316] K in DMF (5 mL) 2 CO 3 (0.199 g, 1.4399 mmol), ethyl 4-(4-chloro-5-hydroxy-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.149 g, 454.6023 μmol), 2 1,3-Dibromopropane (0.495 g, 2.4519 mmol) was added at 20° C. under atmospheric pressure. The reaction mixture was stirred at 20° C. for 4 hours. The reaction mixture was then purified by column chromatography on C18 ACN / H 20 (0.1% FA) (0-50%). The pure fractions were concentrated and dried under vacuum. Ethyl 4-(5-(3-bromopropoxy)-4-chloro-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.163 g, 363.2433 μmol, 79.9035% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 448.040. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0317] Step g: Ethyl 4-(5-(3-((4-chloro-2-(4-ethoxy-4-oxobutanoyl)-6-methoxyisoindolin-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate [ka]

[0318] A solution of ethyl 4-(5-(3-bromopropoxy)-4-chloro-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.068 g, 151.5371 μmol), ethyl 4-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (0.049 g, 150.1504 μmol) in DMF (3 mL) was incubated at 20 °C under N2 atmosphere. 2 CO 3(0.115 g, 832.0942 μmol) was added dropwise. The reaction mixture was stirred at 50° C. for 4 h. The reaction mixture was then column-eluted with ACN / H 2 0 (0.1% FA) (0-60%). Pure fractions were concentrated and lyophilized. Ethyl 4-(5-(3-((4-chloro-2-(4-ethoxy-4-oxobutanoyl)-6-methoxyisoindolin-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (0.040 g, 57.6234 μmol, 38.0259% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 694.180. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0319] Step h: 4-(5-(3-((2-(3-carboxypropanoyl)-4-chloro-6-methoxyisoindolin-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid [ka]

[0320] To a solution of ethyl 4-(5-(3-((4-chloro-2-(4-ethoxy-4-oxobutanoyl)-6-methoxyisoindolin-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (0. 027 g, 38.8958 μmol) in THF (1 mL) and water (1 mL) was added LiOH (0.048 g, 2.0043 mmol) at 20° C. 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 by column chromatography on a C18 column in ACN / H. 2 0 (0.1% FA) (0-52%). Pure fractions were concentrated and lyophilized to dryness. 4-(5-(3-((2-(3-carboxypropanoyl)-4-chloro-6-methoxyisoindolin-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid (0.017 g, 26.6434 μmol, 69.6846% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 638.150. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0321] Example 3 4-(5-(3-((2-(3-carboxypropanoyl)-4-chloro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid Step a: tert-Butyl 5-(3-bromopropoxy)-4-fluoro-6-methoxy-isoindoline-2-carboxylate [ka]

[0322] A solution of tert-butyl 4-fluoro-5-hydroxy-6-methoxy-isoindoline-2-carboxylate (0.50 g, 1.7649 mmol) in DMF (10 mL) was treated with 1,3-dibromopropane (2.48 g, 12.2841 mmol) and K 2 CO 3 (0.71 g, 5.1373 mmol) was added. The reaction mixture was stirred at 20° C. for 3 h. The reaction mixture was diluted with ethyl acetate (200 mL) and washed successively with water (2 x 100 mL) and saturated brine (100 mL). The organic layer was extracted with Na 2 SO 4 The mixture was dried over hexane, filtered and evaporated to give the crude product. The crude product was purified by flash silica chromatography eluting with 0% to 100% ethyl acetate in heptane to give tert-butyl 5-(3-bromopropoxy)-4-fluoro-6-methoxy-isoindoline-2-carboxylate (0.637 g, 1.5757 mmol, 89.2763% yield) as a white solid. LCMS: (ESI, m / z): [M+H] + = 331.100.

[0323] Step b: tert-butyl 5-(3-((4-chloro-2-(4-ethoxy-4-oxobutanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-carboxylate [ka]

[0324] A solution of ethyl 4-(4-chloro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (0.147 g, 428.8290 μmol) and tert-butyl 5-(3-bromopropoxy)-4-fluoro-6-methoxy-isoindoline-2-carboxylate (0.173 g, 427.9318 μmol) in DMF (5 mL) was diluted with N 2 At 20°C under atmospheric conditions 2 CO 3 (0.166 g, 1.2011 mmol) was added. The reaction mixture was stirred at 50° C. for 3 h. The reaction mixture was then purified by column chromatography on a C18 column with ACN / H 2 0 (0.1% FA) (0-75%). Pure fractions were concentrated and dried under vacuum. tert-Butyl 5-(3-((4-chloro-2-(4-ethoxy-4-oxobutanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-carboxylate (0.138 g, 207.1598 μmol, 48.3083% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 666.190. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0325] Step c: Ethyl 4-(4-chloro-5-(3-((4-fluoro-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate [ka]

[0326] To a solution of tert-butyl 5-(3-((4-chloro-2-(4-ethoxy-4-oxobutanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindoline-2-carboxylate (0.117 g, 175.6356 μmol) in EA (5 mL) was added HCl (5 mL, 20 mmol, 4 M in EA) at 20° C. The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was evaporated under reduced pressure. Ethyl 4-(4-chloro-5-(3-((4-fluoro-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (0.182 g, 321.5338 μmol, 183.0687% yield) was obtained as a brown solid. LCMS: (ESI, m / z): [M+H] + = 566.130. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0327] Step d: Ethyl 4-(5-(3-((4-chloro-2-(4-ethoxy-4-oxobutanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindolin-2-yl)-4-oxobutanoate [ka]

[0328] A solution of ethyl 4-(4-chloro-5-(3-((4-fluoro-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (0.167 g, 295.0337 μmol) and TEA (0.164 g, 1.6207 mmol) in DCM (5 mL) was diluted with N 2 Ethyl succinyl chloride was added under atmospheric pressure at 20° C. The reaction mixture was stirred at 20° C. for 1 h. The reaction mixture was evaporated under reduced pressure. The residue was purified by column chromatography on a C18 column with ACN / H 2 0 (0.1% FA) (0-60%). Pure fractions were concentrated and lyophilized. Ethyl 4-(5-(3-((4-chloro-2-(4-ethoxy-4-oxobutanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.081 g, 116.6874 μmol, 39.5505% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 694.180. 1 H NMR (400 MHz, DMSO-d 6) 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).

[0329] Step e: 4-(5-(3-((2-(3-carboxypropanoyl)-4-chloro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid [ka]

[0330] To a solution of ethyl 4-(5-(3-((4-chloro-2-(4-ethoxy-4-oxobutanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.044 g, 63.3858 μmol) in THF (2 mL), HO (2 mL) and ethanol (1 mL) was added LiOH (0.045 g, 1.8790 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was adjusted to pH = 3 with HCl (1 mol / L). The reaction mixture was evaporated under reduced pressure. The residue was purified by column chromatography on a C18 ACN / H 20 (0.1% FA) (0-52%). Pure fractions were concentrated and lyophilized. 4-(5-(3-((2-(3-carboxypropanoyl)-4-chloro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid (0.032 g, 50.1523 μmol, 79.1223% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 638.120. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0331] Example 4 4-(5-(3-((2-(3-carboxypropanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid Step a: Ethyl 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxyisoindolin-2-yl)-4-oxobutanoate [ka]

[0332] To a mixture of ethyl 4-(4-fluoro-5-hydroxy-6-methoxy-isoindolin-2-yl)-4-oxo-butanoate (0.217 g, 697.0656 μmol) and potassium carbonate (0.346 g, 2.5035 mmol) in DMF (5 mL) was added 1,3-dibromopropane (0.708 g, 3.5069 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 3 h. The reaction mixture was chromatographed on a C18 column ACN / H 2 0 (0.1% FA) (0-45%). Pure fractions were concentrated and dried under vacuum. Ethyl 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.211 g, 488.1091 μmol, 70.0234% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 432.070.

[0333] Step b: Ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindolin-2-yl)-4-oxobutanoate [ka]

[0334] A solution of ethyl 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.070 g, 161.9319 μmol) and ethyl 4-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (0.065 g, 199.1791 μmol) in N,N-dimethylformamide (3 mL) was added to the 2 Potassium carbonate (0.079 g, 571.6126 μmol) was added under atmosphere at 20° C. The reaction mixture was stirred at 50° C. overnight. The reaction mixture was then loaded onto a C18 column ACN / H 20 (0.1% FA) (0-70%). Pure fractions were concentrated and lyophilized. Ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.056 g, 82.6315 μmol, 51.0285% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 678.210. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0335] Step c: 4-(5-(3-((2-(3-carboxypropanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid [ka]

[0336] THF (2 mL), 2To a solution of ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.039 g, 57.5469 μmol) in 2 mL of HO and ethanol (1 mL) was added LiOH (0.043 g, 1.7955 mmol) at 20° C. The reaction mixture was stirred overnight at 20° C. The reaction mixture was adjusted to pH = 3 with HCl (aq. 1 M) and the reaction mixture was evaporated under reduced pressure. The residue was purified by column chromatography on a C18 column in ACN / H 2 0 (0.1% FA) (0-50%). Pure fractions were concentrated and dried under vacuum. 4-(5-(3-((2-(3-carboxypropanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid (0.012 g, 19.3050 μmol, 33.5465% yield) was obtained as a white solid.

[0337] Example 5 Sodium (S)-4-(5-(3-((2-((S)-3-carboxylate butanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-2-methyl-4-oxobutanoate [ka]

[0338] Step a: To a solution of N,N-diisopropylethylamine (97.64 g, 755.4796 mmol) and 2-bromo-5-hydroxy-4-methoxybenzaldehyde (102.80 g, 444.9386 mmol) in DCM (1500 mL), add N 2Bromomethyl methyl ether (60.56 g, 484.6196 mmol) was added at 0° C. under atmospheric pressure. The resulting solution was quenched by the addition of water (1000 mL) at 25° C. The resulting mixture was extracted with DCM (2×1000 mL) and washed with water (500 mL) and brine (500 mL). The organics were washed with Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate, filtered and evaporated under reduced pressure to give 2-bromo-4-methoxy-5-(methoxymethoxy)benzaldehyde (115.25 g, 418.9454 mmol, 94.1580% yield) as a pale yellow solid. LCMS: (ESI, m / z): [M+H] + = 274.984. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.06 (s, 1H), 7.51 (s, 1H), 7.39 (s, 1H), 5.25 (s, 2H), 3.93 (s, 3H), 3.39 (s, 3H).

[0339] Step b: A solution of 2-bromo-4-methoxy-5-(methoxymethoxy)benzaldehyde (115.11 g, 418.4365 mmol) and cesium fluoride (130.32 g, 857.9136 mmol) in N,N-dimethylformamide (1200 mL) was added to the reaction mixture with N 2Methyl thioglycolate (53.415 g, 503.2348 mmol) was added under atmosphere at 25° C. The reaction mixture was heated to 50° C. and stirred overnight. The reaction mixture was poured into water (10 L) and stirred for 1 h. The precipitate was collected by filtration and washed with water (3 x 200 mL). The filter cake was dried under vacuum at 60° C. to give the crude product. The crude product was diluted with DCM (200 mL). The mixture was poured into n-hexane (2000 mL) and stirred for 1 h. The precipitate was collected by filtration and washed with n-hexane (3 x 100 mL). The filter cake was dried under vacuum at 60° C. Methyl 6-methoxy-5-(methoxymethoxy)benzothiophene-2-carboxylate (65.50 g, 232.0131 mmol, 55.4476% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 284.056. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.07 (s, 1H), 7.69 (s, 1H), 7.65 (s, 1H), 5.25 (s, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.44 (s, 3H).

[0340] Step c: To a solution of methyl 6-methoxy-5-(methoxymethoxy)benzothiophene-2-carboxylate (51.16 g, 181.2181 mmol) in THF (600 mL) and water (200 mL) was added LiOH (17.58 g, 734.0813 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was evaporated under reduced pressure. The residue was diluted with water and adjusted to pH = 4 with HCl (1 M). The precipitate was collected by filtration and washed with water (2 x 50 mL). The filtrate cake was dried under vacuum. 6-Methoxy-5-(methoxymethoxy)benzothiophene-2-carboxylic acid (44.17 g, 164.6382 mmol, 90.8509% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [MH] - = 267.041. 1 H NMR (400 MHz, DMSO-d6 ) δ 13.17 (s, 1H), 7.95 (s, 1H), 7.64 (s, 1H), 7.62 (s, 1H), 5.23 (s, 2H), 3.88 (s, 3H), 3.43 (s, 3H).

[0341] Step d: To a stirred solution of 6-methoxy-5-(methoxymethoxy)benzothiophene-2-carboxylic acid (53.21 g, 198.3337 mmol) in DMF (1000 mL) at 25 °C was added CDI (64.55 g, 398.0919 mmol). The reaction mixture was stirred at 25 °C for 2 h. To the above mixture was added 3-(tert-butoxy)-3-oxopropanoic acid (49.03 g, 306.1174 mmol), TEA (62.33 g, 615.9736 mmol) and magnesium chloride (29.11 g, 305.7420 mmol). The reaction mixture was stirred at 25 °C overnight. The reaction mixture was concentrated, diluted with EA (3000 mL) and washed with water (2 x 3000 mL) and brine (3000 mL). The organics were washed with Na 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / n-hexane (0-50%). The pure fractions were concentrated and dried under vacuum. tert-Butyl 3-(6-methoxy-5-(methoxymethoxy)benzo[b]thiophen-2-yl)-3-oxopropanoate (36.19 g, 98.7643 mmol, 49.7971% yield) was obtained as a yellow oil. LCMS: (ESI, m / z): [M+H] + = 367.114. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.20 (s, 1H), 7.67 (s, 1H), 7.62 (s, 1H), 5.24 (s, 2H), 4.05 (s, 2H), 3.89 (s, 3H), 3.42 (s, 3H), 1.41 (s, 9H).

[0342] Step e: To a solution of tert-butyl 3-(6-methoxy-5-(methoxymethoxy)benzo[b]thiophen-2-yl)-3-oxopropanoate (18.02 g, 49.1775 mmol) in 2,5-dioxahexane (200 mL), add N 2 LDA (7.9020 g, 73.7662 mmol) was added at 0° C. under atmospheric pressure. The reaction mixture was then purified with N 2 The mixture was stirred at 0° C. for 40 minutes under atmospheric pressure. Ethyl (S)-2-(((trifluoromethyl)sulfonyl)oxy)propanoate (18.06 g, 72.1843 mmol) was added to N 2 The mixture was added under atmospheric pressure at 0°C. 2 The mixture was stirred at 0° C. for 3 hours under atmospheric conditions. The reaction mixture was diluted with KHCO 3 (100 mL) was added to quench the reaction mixture. The reaction mixture was concentrated, diluted with EA (500 mL) and washed with water (200 mL) and brine (100 mL). The organics were washed with Na 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / n-hexane (0-100%). The pure fractions were concentrated and dried under vacuum. 1-(tert-butyl) 4-ethyl (3S)-2-(6-methoxy-5-(methoxymethoxy)benzo[b]thiophene-2-carbonyl)-3-methylsuccinate (21.55 g, 46.1908 mmol, 93.9267% yield) was obtained as a yellow oil. LCMS: (ESI, m / z): [M+H] + = 467.166.

[0343] Step f: To a solution of 1-(tert-butyl)4-ethyl(3S)-2-(6-methoxy-5-(methoxymethoxy)benzo[b]thiophene-2-carbonyl)-3-methylsuccinate (21.52 g, 46.1265 mmol) in toluene (198 mL) at 25 °C, TFA (101.31 g, 888.5026 mmol) was added. The reaction mixture was heated to 50 °C and stirred for 2 h. The residue was purified on a silica gel column EA / n-hexane (0-50%). The pure fractions were concentrated and dried under vacuum. Ethyl (2S)-4-(5-hydroxy-6-methoxy-benzothiophen-2-yl)-2-methyl-4-oxo-butanoate (6.78 g, 21.0314 mmol, 45.5950% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 323.087. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.39 (s, 1H), 8.17 (s, 1H), 7.54 (s, 1H), 7.31 (s, 1H), 4.10 - 3.98 (m, 2H), 3.87 (s, 3H), 3.44 - 3.35 (m, 1H), 3.19 - 3.08 (m, 1H), 2.98 - 2.88 (m, 1H), 1.21 - 1.10 (m, 6H).

[0344] Step g: To a solution of TCFH (8.11 g, 28.9045 mmol) and (S)-4-methoxy-3-methyl-4-oxobutanoic acid (2.81 g, 19.2280 mmol) in DMF (100 mL) at 25° C., NMI (7.96 g, 96.9507 mmol) was added. 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 h. The reaction mixture was concentrated and purified by H 2 The organics were diluted with O (200 mL), extracted with EA (2 x 200 mL) and washed with brine (100 mL). 2 SO 4The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / n-hexane (0-55%). The pure fractions were concentrated and dried under vacuum. Methyl (2S)-4-(5-methoxyisoindolin-2-yl)-2-methyl-4-oxo-butanoate (3.49 g, 12.5850 mmol, 65.4512% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 278.130. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0345] Step h: To a solution of methyl (2S)-4-(5-methoxyisoindolin-2-yl)-2-methyl-4-oxo-butanoate (3.426 g, 12.3542 mmol) in THF (30 mL) and MeCN (30 mL) was added NBS (3.717 g, 20.8839 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was concentrated, diluted with DCM (200 mL) and diluted with H 2 O (100 mL), KHCO 3 The organics were washed with aqueous (aq) (2 x 100 mL) and brine (100 mL). 2 SO 4The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / n-hexane (0-60%). The pure fractions were concentrated and dried under vacuum. Methyl (2S)-4-(5-bromo-6-methoxy-isoindolin-2-yl)-2-methyl-4-oxo-butanoate (3.02 g, 8.4781 mmol, 68.6255% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 356.040. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0346] Step i: To a mixture of methyl (2S)-4-(5-bromo-6-methoxy-isoindolin-2-yl)-2-methyl-4-oxobutanoate (3.00 g, 8. 4220 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.74 g, 1.0113 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.18 g, 12.5228 mmol) in 1,4-dioxane (100 mL) was added potassium acetate (2.81 g, 28.6319 mmol) at 25° C. The reaction mixture was heated to 100° C. and stirred overnight. The reaction mixture was diluted with EA (200 mL) and the precipitate was collected by filtration and washed with EA (1 x 100 mL). The filtrate was evaporated under reduced pressure. The residue was purified on a silica gel column EA / n-hexane (0-50%). Pure fractions were concentrated and dried under vacuum. Methyl (2S)-4-[5-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]-2-methyl-4-oxo-butanoate (2.38 g, 5.9017 mmol, 70.0746% yield) was obtained as a brown solid. LCMS: (ESI, m / z): [M+H] + = 404.222. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0347] Step j: THF (25 mL) and H 2To a solution of methyl (2S)-4-[5-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]-2-methyl-4-oxo-butanoate (1.99 g, 4.9346 mmol) in HO (25 mL) was added sodium perborate tetrahydrate (0.80 g, 5.1995 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated and diluted with H 2 The organics were diluted with O (200 mL), extracted with DCM (3 x 100 mL) and washed with brine (100 mL). 2 SO 4 The mixture was dried over 1000 ml of water, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on a C18 column with ACN / H 2 2H 2 O (0-40%). The pure fractions were concentrated and dried under vacuum to give methyl (2S)-4-(5-hydroxy-6-methoxy-isoindolin-2-yl)-2-methyl-4-oxo-butanoate (1.23 g, 4.1935 mmol, 84.9809% yield) as a white solid. LCMS: (ESI, m / z): [M+H] + = 294.130.

[0348] Step k: To a solution of methyl (2S)-4-(5-hydroxy-6-methoxy-isoindolin-2-yl)-2-methyl-4-oxo-butanoate (0.311 g, 1.0603 mmol) and 1,3-dibromopropane (1.158 g, 5.7359 mmol) in DMF (20 mL) was added potassium carbonate (0.462 g, 3.3428 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was purified by column chromatography on a C18 column ACN / H 2 0 (0-45%). The pure fractions were concentrated and dried under vacuum. Methyl (2R)-4-[5-(3-bromopropoxy)-6-methoxy-isoindolin-2-yl]-2-methyl-4-oxo-butanoate (0.314 g, 757.9234 μmol, 71.4822% yield) was obtained as a colorless oil. LCMS: (ESI, m / z): [M+H] + = 414.080.

[0349] Step l: To a solution of methyl (S)-4-(5-(3-bromopropoxy)-6-methoxyisoindolin-2-yl)-2-methyl-4-oxobutanoate (0. 206 g, 497.2362 μmol) and ethyl (2S)-4-(5-hydroxy-6-methoxy-benzothiophen-2-yl)-2-methyl-4-oxobutanoate (0.243 g, 753.7805 μmol) in DMF (5 mL) at 25 °C, potassium carbonate (0.214 g, 1.5484 mmol) was added. 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 organics were washed with Na 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / n-hexane (0-100%). The pure fractions were concentrated and dried under vacuum. Ethyl (S)-4-(6-methoxy-5-(3-((6-methoxy-2-((S)-4-methoxy-3-methyl-4-oxobutanoyl)isoindolin-5-yl)oxy)propoxy)benzo[b]thiophen-2-yl)-2-methyl-4-oxobutanoate (0.130 g, 198.2454 μmol, 39.8695% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 656.245.

[0350] Step m: To a solution of ethyl (S)-4-(6-methoxy-5-(3-((6-methoxy-2-(((S)-4-methoxy-3-methyl-4-oxobutanoyl)isoindolin-5-yl)oxy)propoxy)benzo[b]thiophen-2-yl)-2-methyl-4-oxobutanoate (0.120 g, 182.9957 μmol) in THF (4 mL) and water (1 mL) at 25 °C, LiOH (0.017 g, 709.8625 μmol) was added. The reaction mixture was stirred at 25 °C overnight. The reaction mixture was adjusted to pH = 7 with HCl (1 M). The reaction mixture was evaporated under reduced pressure to give the crude product. The crude product was purified by Prep-HPLC with the following conditions: (CXTH LC6000, HPLC-P1): Column, Agela Durashell C18, 30 mm * 250 mm, 10 μm; mobile phase, water (0.1% NH 3 .H 2 20O) and MeCN-(5-20-20%B (2-32-60 min); detector, uv 210 nm). The solvent was removed by lyophilization. The lyophilizates in water were diluted with NaHCO 3 (0.019 g, 226.1727 μmol) was added and stirred at 25° C. for 30 minutes. The solvent was removed by lyophilization. Sodium (S)-4-(5-(3-((2-((S)-3-carboxylate butanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-2-methyl-4-oxobutanoate (0.064 g, 97.3180 μmol, 53.1805% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 614.198. 1 H NMR (400 MHz, DMSO-d 6) 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).

[0351] Example 6 Sodium (S)-4-(5-(3-((2-((S)-3-carboxylate butanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-2-methyl-4-oxobutanoate [ka]

[0352] Step a: To a solution of tert-butyl 3-(5-bromo-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-3-oxopropanoate (1.6 g, 3.9676 mmol) in 2,5-dioxahexane (50 mL), add N 2 Lithium diisopropylamide (552.5297 mg, 5.1579 mmol) was added under 0° C. atmosphere. The reaction mixture was then cooled to 10° C. with 50° C. 2 The mixture was stirred at 0° C. for 40 minutes under atmospheric pressure. Ethyl (S)-2-(((trifluoromethyl)sulfonyl)oxy)propanoate (2.9780 g, 11.9029 mmol) was added to N 2 The mixture was added under atmospheric pressure at 0°C. 2The mixture was stirred overnight at 25° C. under atmospheric pressure. The reaction mixture was concentrated, diluted with EA (100 mL) and diluted with NaHCO 3 The organics were washed with aqueous (aq) (2 x 500 mL) and brine (50 mL). 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / n-hexane (0-20%). The pure fractions were concentrated and dried under vacuum. 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) was obtained as a colorless oil. LCMS: (ESI, m / z): [M+H] + = 503.046. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0353] Step b: To a 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) in toluene (20 mL) at 25° C., trifluoroacetic acid (4 mL) was added. The reaction mixture was stirred at 50° C. for 2 h. The reaction mixture was concentrated and purified on a C-18 column MeCN / water (0-100%). The pure fractions were concentrated and dried under vacuum. Ethyl (S)-4-(5-bromo-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2-methyl-4-oxobutanoate (0.76 g, 1.8846 mmol, 93.0079% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 402.994. 1 H NMR (400 MHz, MeOD-d 4 ) 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).

[0354] Step c: To a mixture of potassium acetate (0.53 g, 5.4003 mmol), ethyl (2S)-4-(5-bromo-4-fluoro-6-methoxy-benzothiophen-2-yl)-2-methyl-4-oxo-butanoate (0.70 g, 1. 7358 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.87 g, 3.4260 mmol) in 1,4-dioxane (30 mL) at 25 °C, add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.13 g, 177.6676 μmol). The reaction mixture was cooled to 100° C. for 2 h and cooled to 37° C. for 1 h. 2 The mixture was stirred under atmospheric pressure at 100° C. overnight. The reaction mixture was evaporated under reduced pressure. The residue was concentrated, diluted with EA (200 mL) and diluted with NaHCO3 The organics were washed with aqueous (aq) (2 x 100 mL) and brine (100 mL). 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / Hept (0-50%). The pure fractions were concentrated and dried under vacuum. Ethyl (S)-4-(4-fluoro-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)-2-methyl-4-oxobutanoate (452 ​​mg, 1.0037 mmol, yield 57.8229%) was obtained as a white solid.

[0355] Step d: To a solution of ethyl (S)-4-(4-fluoro-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)-2-methyl-4-oxobutanoate (0. 46 g, 1.0215 mmol) in tetrahydrofuran (20 mL) and water (20 mL) was added sodium perborate tetrahydrate (0.23 g, 1.4949 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 1 h and evaporated under reduced pressure. The residue was concentrated, diluted with DCM (200 mL) and washed with water (2 x 100 mL) and brine (200 mL). The organics were washed with Na 2 SO 4 It was dried over 100 ml of ethyl (2S)-4-(4-fluoro-5-hydroxy-6-methoxy-benzothiophen-2-yl)-2-methyl-4-oxo-butanoate (0.28 g, 822.6441 μmol, 80.5345% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 341.078. 1 H NMR (400 MHz, DMSO-d 6) 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).

[0356] Step e: To methyl (S)-4-(5-(3-bromopropoxy)-6-methoxyisoindolin-2-yl)-2-methyl-4-oxobutanoate (0. 20 g, 482.7536 μmol) and potassium carbonate (0.15 g, 1.0853 mmol) in N,N-dimethylformamide (5 mL) was added ethyl (2S)-4-(4-fluoro-5-hydroxy-6-methoxy-benzothiophen-2-yl)-2-methyl-4-oxobutanoate (0.16 g, 470.0822 μmol) at 25° C. The reaction mixture was stirred at 25° C. overnight. The reaction mixture was purified by column chromatography on a C18 ACN / H column. 2 0 (0-45%). Pure fractions were concentrated and dried under vacuum. There was obtained ethyl (S)-4-(4-fluoro-6-methoxy-5-(3-((6-methoxy-2-((S)-4-methoxy-3-methyl-4-oxobutanoyl)isoindolin-5-yl)oxy)propoxy)benzo[b]thiophen-2-yl)-2-methyl-4-oxobutanoate (0.268 g, 397.7772 μmol, 82.3976% yield) as a colorless oil. LCMS: (ESI, m / z): [M+H] + = 674.236. 1 H NMR (400 MHz, DMSO-d 6) 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).

[0357] Step f: To a solution of ethyl (2S)-4-[4-fluoro-6-methoxy-5-[3-[6-methoxy-2-[(3S)-4-methoxy-3-methyl-4-oxo-butanoyl]isoindolin-5-yl]oxypropoxy]benzothiophen-2-yl]-2-methyl-4-oxo-butanoate (0.258g, 382.9348 μmol) in tetrahydrofuran (10 mL) and water (2 mL) at 25° C., LiOH (0.030 g, 1.2527 mmol) was added. The reaction mixture was stirred at 25° C. overnight. The reaction mixture was purified by HPLC. The pure fractions were concentrated and dried under vacuum to give the free acid. The free acid in acetonitrile (10 mL) and water (10 mL) was dissolved in NaHCO 3 at 25° C. 3 (0.016 g, 190.4612 μmol) was added. The mixture was stirred at 25° C. for 1 h and the solvent was removed by lyophilization. Sodium (S)-4-(5-(3-((2-((S)-3-carboxylate butanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-2-methyl-4-oxobutanoate (0.063 g, 93.2466 μmol, 24.3505% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 632.289. 1 H NMR (400 MHz, DMSO-d 6) 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).

[0358] Example 7 Sodium 4-(5-(3-((2-(3-carboxylatepropanoyl)-6-hydroxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate Step a: 5-bromo-2-fluoro-4-(methoxymethoxy)benzaldehyde [ka]

[0359] To a solution of DIEA (0.83 g, 6.4220 mmol) and 5-bromo-2-fluoro-4-hydroxybenzaldehyde (0.94 g, 4.2921 mmol) in DCM (20 mL) was added bromomethyl methyl ether (0.71 g, 5.6816 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was quenched by the addition of water (10 mL) at 20° C. The resulting mixture was washed with water (20 mL) and brine (20 mL). The organics were washed with Na 2 SO 4 The mixture was dried over 100 ml, filtered and evaporated under reduced pressure to give crude 5-bromo-2-fluoro-4-(methoxymethoxy)benzaldehyde (1.16 g, 4.4096 mmol, 102.7388% yield) as a white solid. LCMS: (ESI, m / z): [M+H] + = 262.950. 1 H NMR (400 MHz, DMSO-d 6) 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).

[0360] Step b: Methyl 5-bromo-6-(methoxymethoxy)benzothiophene-2-carboxylate [ka]

[0361] To a solution of 5-bromo-2-fluoro-4-(methoxymethoxy)benzaldehyde (1.06 g, 4.0295 mmol) and potassium carbonate (0.15 g, 1.0853 mmol) in DMF (10 mL) at 25° C., methyl thioglycolate (0.4 mL, 4.4732 mmol) was added. The reaction mixture was heated to 50° C. and stirred for 2 h. Water (100 mL) was added and the reaction mixture was quenched at 20° C. The precipitate was collected by filtration and washed with water (3 x 20 mL). The filtrate cake was dried under vacuum at 60° C. Methyl 5-bromo-6-(methoxymethoxy)benzothiophene-2-carboxylate (1.12 g, 3.3818 mmol, 83.9267% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 331.100.

[0362] Step c: 5-Bromo-6-(methoxymethoxy)benzothiophene-2-carboxylic acid [ka]

[0363] To a solution of methyl 5-bromo-6-(methoxymethoxy)benzothiophene-2-carboxylate (1.10 g, 3.3214 mmol) in THF (40 mL) and water (10 mL) at 25° C., LiOH (0.18 g, 7.5162 mmol) was added. The reaction mixture was stirred at 50° C. for 2 h. The reaction mixture was evaporated under reduced pressure. The residue was diluted with water and acidified to pH = 3 with HCl (aq., 1 M). The precipitate was filtered and the filtrate cake was washed with water (20 mL). The filtrate cake was dried under vacuum at 60° C. 5-Bromo-6-(methoxymethoxy)benzothiophene-2-carboxylic acid (1.04 g, 3.2791 mmol, 98.7268% yield) was obtained as a white solid. LCMS: (ESI, m / z): [MH] - = 314.900. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0364] Step d: tert-Butyl 3-(5-bromo-6-(methoxymethoxy)benzo[b]thiophen-2-yl)-3-oxopropanoate [ka]

[0365] To a solution of 5-bromo-6-(methoxymethoxy)benzothiophene-2-carboxylic acid (1.01 g, 3.1846 mmol) in DMF (20 mL) was added CDI (1.13 g, 6.9689 mmol) at 25 °C. The reaction mixture was stirred at 25 °C under nitrogen atmosphere for 2 h. Magnesium chloride (0.64 g, 6.7219 mmol), 3-tert-butoxy-3-oxopropanoic acid (0.81 g, 5.0572 mmol) and TEA (1.06 g, 10.4754 mmol) were added to the reaction mixture. The reaction mixture was stirred at 25 °C overnight. The reaction mixture was concentrated, diluted with EA (100 mL) and washed with saturated NaHCO 3 The organics were washed with aqueous solution (2 x 50 mL) and brine (50 mL). 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / n-hexane (0-20%). The pure fractions were concentrated and dried under vacuum. tert-Butyl 3-(5-bromo-6-(methoxymethoxy)benzo[b]thiophen-2-yl)-3-oxopropanoate (1.12 g, 2.6969 mmol, 84.6855% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [MH] - = 412.950. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0366] Step e: 1-(tert-butyl) 4-ethyl 2-(5-bromo-6-(methoxymethoxy)benzo[b]thiophene-2-carbonyl)succinate [ka]

[0367] To a solution of tert-butyl 3-(5-bromo-6-(methoxymethoxy)benzo[b]thiophen-2-yl)-3-oxopropanoate (0.891 g, 2.1454 mmol) and potassium carbonate (0.587 g, 4.2473 mmol) in DMF (10 mL) was added ethyl 2-bromoacetate (0.356 g, 2.1317 mmol) at 25° C. 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 organics were washed with Na 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / n-hexane (0-50%). The pure fractions were concentrated and dried under vacuum. 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) was obtained as a yellow oil. LCMS: (ESI, m / z): [M+H] + = 501.050.

[0368] Step f: Ethyl 4-(5-bromo-6-hydroxy-benzothiophen-2-yl)-4-oxo-butanoate [ka]

[0369] To a solution of 1-(tert-butyl)4-ethyl 2-(5-bromo-6-(methoxymethoxy)benzo[b]thiophene-2-carbonyl)succinate (0.750 g, 1.4959 mmol) in toluene (9 mL) was added trifluoroacetic acid (3 mL) at 25° C. The reaction mixture was heated to 50° C. and stirred for 2 h. The residue was purified on a C18 column MeCN / water (0-50%). The pure fractions were concentrated and dried under vacuum. Ethyl 4-(5-bromo-6-hydroxy-benzothiophen-2-yl)-4-oxo-butanoate (0.431 g, 1.2065 mmol, 80.6593% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 357.000.

[0370] Step g: Ethyl 4-(5-bromo-6-(methoxymethoxy)benzo[b]thiophen-2-yl)-4-oxobutanoate [ka]

[0371] To a solution of ethyl 4-(5-bromo-6-hydroxy-benzothiophen-2-yl)-4-oxo-butanoate (0.427 g, 1.1953 mmol) and DIEA (0.235 g, 1.8183 mmol) in DCM (10 mL) at 25° C., bromomethyl methyl ether (0.198 g, 1.5845 mmol) was added. 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 organics were washed with Na 2 SO 4 The mixture was dried over 100 ml of ethyl 4-(5-bromo-6-(methoxymethoxy)benzo[b]thiophen-2-yl)-4-oxobutanoate (0.503 g, 1.1282 mmol, 94.3798% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 401.100.

[0372] Step h: Ethyl 4-(6-(methoxymethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)-4-oxobutanoate [ka]

[0373] A mixture of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.110 g, 150.3341 μmol), ethyl 4-(5-bromo-6-(methoxymethoxy)benzo[b]thiophen-2-yl)-4-oxobutanoate (0.478 g, 1. 1912 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.491 g, 1.9335 mmol) and potassium acetate (0.389 g, 3.9636 mmol) was dissolved in 1,4-dioxane (10 mL) at 25 °C. The reaction mixture was heated to 100 °C and cooled to 10 °C with N 2 The mixture was stirred under atmospheric pressure for 4.5 h. The reaction mixture was concentrated, diluted with EA (200 mL) and washed with water (100 mL) and brine (100 mL). The organics were washed with Na 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / n-hexane (0-50%). The pure fractions were concentrated and dried under vacuum. Ethyl 4-(6-(methoxymethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)-4-oxobutanoate (0.420 g, 936.7968 μmol, 78.6423% yield) was obtained as a yellow oil. LCMS: (ESI, m / z): [M+H] + = 449.200.

[0374] Step i: Ethyl 4-(5-hydroxy-6-(methoxymethoxy)benzo[b]thiophen-2-yl)-4-oxobutanoate [ka]

[0375] To a solution of ethyl 4-(6-(methoxymethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)-4-oxobutanoate (0.407 g, 907.8013 μmol) in THF (5 mL) and water (5 mL) at 25 °C was added sodium perborate tetrahydrate (0.200 g, 1.2999 mmol). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was evaporated under reduced pressure. The residue was purified on a C18 column MeCN / water (0-50%). Pure fractions were concentrated and dried under vacuum. Ethyl 4-(5-hydroxy-6-(methoxymethoxy)benzo[b]thiophen-2-yl)-4-oxobutanoate (0.250 g, 738.8257 μmol, 81.3863% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 339.100.

[0376] Step j: Ethyl 4-(5-methoxyisoindolin-2-yl)-4-oxo-butanoate [ka]

[0377] 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) was added succinic anhydride (4.40 g, 43.9681 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h. Thionyl chloride (20 mL) was added to the above solution at 0° C. The reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was evaporated under reduced pressure. The residue was diluted with EA (200 mL) and washed with water (100 mL) and brine (50 mL). The organics were washed with Na 2 SO 4It was dried over 100 ml of ethyl 4-(5-methoxyisoindolin-2-yl)-4-oxo-butanoate (17.50 g, 31.5526 mmol, 119.7901% yield) as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 278.150. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0378] Step k: Ethyl 4-(5-bromo-6-methoxy-isoindolin-2-yl)-4-oxo-butanoate [ka]

[0379] To a solution of ethyl 4-(5-methoxyisoindolin-2-yl)-4-oxo-butanoate (17.50 g, 31.5526 mmol) in THF (100 mL) and MeCN (100 mL) was added NBS (10.51 g, 59.0503 mmol) at 25° C. The reaction mixture was stirred at 25° C. overnight. The reaction mixture was evaporated under reduced pressure. The residue was diluted with DCM (500 mL) and saturated NaHCO 3 The organics were washed with aqueous solution (2 x 300 mL) and brine (200 mL). 2 SO 4The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column MeOH / DCM (0-10%). The pure fractions were concentrated and dried under vacuum. Ethyl 4-(5-bromo-6-methoxy-isoindolin-2-yl)-4-oxo-butanoate (7.26 g, 20.3812 mmol, 64.5943% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 356.000. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0380] Step l: Ethyl 4-(5-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)-4-oxobutanoate [ka]

[0381] A mixture of potassium acetate (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-isoindolin-2-yl)-4-oxo-butanoate (3. 64 g, 10.2187 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.84 g, 15.1218 mmol) was dissolved in 1,4-dioxane (100 mL) at 25° C. The reaction mixture was heated to 100° C. and N2 The mixture was stirred under atmosphere overnight. The reaction mixture was diluted with EA (400 mL). The precipitate was filtered through Celite and the filtrate was washed with EA (1 x 100 mL). The combined filtrate was evaporated under reduced pressure. The residue was purified on a silica gel column EA / n-hexane (0-100%). The pure fractions were concentrated and dried under vacuum. Ethyl 4-(5-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)-4-oxobutanoate (2.70 g, 6.6952 mmol, 65.5190% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 404.200. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0382] Step m: Ethyl 4-(5-hydroxy-6-methoxy-isoindolin-2-yl)-4-oxo-butanoate [ka]

[0383] To a solution of ethyl 4-(5-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)-4-oxobutanoate (2.45 g, 6.0752 mmol) in THF (20 mL) and water (20 mL) at 25° C. was added sodium perborate tetrahydrate (1.00 g, 6.4994 mmol). The reaction mixture was stirred at 20° C. for 1 h. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated, diluted with DCM (500 mL) and washed with saturated NaHCO 3 The organics were washed with aqueous solution (2 x 300 mL) and brine (200 mL). 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column MeOH / DCM (0-10%). The pure fractions were concentrated and dried under vacuum. Ethyl 4-(5-hydroxy-6-methoxy-isoindolin-2-yl)-4-oxo-butanoate (1.37 g, 4.6708 mmol, 76.8818% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 294.100. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0384] Step n: Ethyl 4-(5-(3-bromopropoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate [ka]

[0385] To a solution of ethyl 4-(5-hydroxy-6-methoxy-isoindolin-2-yl)-4-oxo-butanoate (0.72 g, 2.4547 mmol) and potassium carbonate (0.86 g, 6.2226 mmol) in DMF (10 mL) was added 1,3-dibromopropane (0.73 g, 3.6159 mmol). The reaction mixture was stirred at 50° C. overnight. 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 layer was extracted with Na 2 SO 4 The crude product was purified by flash silica chromatography eluting with a gradient of 0-100% ethyl acetate in heptane to give ethyl 4-(5-(3-bromopropoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.43 g, 1.0379 mmol, 42.2829% yield) as a white solid. LCMS: (ESI, m / z): [M+H] + = 414.050. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0386] Step o: Ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-6-(methoxymethoxy)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate [ka]

[0387] To a solution of ethyl 4-(5-(3-bromopropoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.127 g, 306.5486 μmol) and potassium carbonate (0.142 g, 1.0275 mmol) in DMF (5 mL) at 25° C., ethyl 4-[5-hydroxy-6-(methoxymethoxy)benzothiophen-2-yl]-4-oxobutanoate (0.101 g, 298.4856 μmol) was added. 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 organics were washed with Na 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / n-hexane (0-100%). The pure fractions were concentrated and dried under vacuum. Ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-6-(methoxymethoxy)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.055 g, 81.8754 μmol, 27.4303% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 672.250.

[0388] Step p: Ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-6-hydroxybenzo[b]thiophen-5-yl)oxo)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate [ka]

[0389] To a solution of ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-6-(methoxymethoxy)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.054 g, 80.3867 μmol) in toluene (2 mL) at 25° C. was added trifluoroacetic acid (1.0 mL, 13.4622 mmol). The reaction mixture was heated to 50° C. and stirred for 30 min. The reaction mixture was evaporated under reduced pressure. The residue was diluted with water and washed with saturated NaHCO 3 The mixture was neutralized with aqueous EA to pH = 8. The resulting mixture was extracted with EA (100 mL) and washed with water (50 mL) and brine (50 mL). The organics were washed with Na 2 SO 4 The mixture was dried over 100 ml of ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-6-hydroxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.057 g, 77.1865 μmol, 96.0190% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 628.200.

[0390] Step Q: 4-(5-(3-((2-(3-carboxylatepropanoyl)-6-hydroxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate sodium [ka]

[0391] To a solution of ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-6-hydroxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.055 g, 87.6215 μmol) in THF (4 mL) and water (1 mL) was added LiOH (0.023 g, 960.4022 μmol) at 25° C. The reaction mixture was stirred at 25° C. overnight. The reaction mixture was evaporated under reduced pressure. The residue was acidified to pH = 4 with HCl (1 M). The reaction mixture was evaporated under reduced pressure to give the crude product. The crude product was purified by Prep-HPLC with 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 was removed by lyophilization. The product lyophilized in water was washed with NaHCO 3 (0.004 g, 47.6153 μmol) was added and stirred at 25° C. for 30 minutes. The solvent was removed by lyophilization. Sodium 4-(5-(3-((2-(3-carboxylatepropanoyl)-6-hydroxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.012 g, 19.4945 μmol, yield 22.2485%) was obtained as a pale yellow solid.

[0392] Example 8 Sodium 4-(5-(3-((2-(3-carboxylatepropanoyl)-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutanoate [ka]

[0393] Step a: To a solution of ethyl 4-(5-hydroxy-6-methoxyisoindolin-2-yl)-4-oxobutanoate (200 mg, 681.8624 μmol) in N,N-dimethylformamide (8 mL) at 25 °C, (3-bromopropoxy)-tert-butyldimethylsilane (518 mg, 2.0456 mmol) and K 2 CO 3 (320 mg, 2.3154 mmol) was added. The reaction mixture was stirred at 25° C. for 2 h. Tetrabutylammonium fluoride (178 mg, 681.8624 μmol) was added to the mixture. The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated, diluted with EA (100 mL) and diluted with NaHCO 3 The organics were washed with aqueous (aq) (100 mL) and brine (50 mL). 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column MeOH / DCM (0-10%). The pure fractions were concentrated and dried under vacuum. Ethyl 4-(5-(3-hydroxypropoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (106 mg, 301.6564 μmol, 44.2401% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 352.168. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0394] Step b: A solution of ethyl 4-(5-(3-hydroxypropoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (50 mg, 142.2907 μmol) and methyl 4-(5-chloro-6-methoxy-thieno[3,2-b]pyridin-2-yl)-4-oxobutanoate (66 mg, 210.3544 μmol) in toluene (10 mL) was heated at 25 °C for 1 h at 37 °C. 3 PO 4 (151 mg, 711.3706 μmol) and RockPhos Palladacycle Gen.3 (11 mg, 13.1041 μmol). The reaction mixture was heated to 100° C. for 24 hours. 2 The mixture was stirred at 130° C. under atmospheric pressure for 16 hours. The reaction mixture was purified on a C-18 column MeCN / water (0-100%). Pure fractions were concentrated and dried under vacuum. Ethyl 4-(5-methoxy-6-(3-((6-methoxy-2-(4-methoxy-4-oxobutanoyl)thieno[3,2-b]pyridin-5-yl)oxy)propoxy)isoindolin-2-yl)-4-oxobutanoate (4.1 mg, 6.5215 μmol, 4.5832% yield) was obtained as a yellow oil. LCMS: (ESI, m / z): [M+H] + = 629.209.

[0395] Step c: To a solution of ethyl 4-(5-methoxy-6-(3-((6-methoxy-2-(4-methoxy-4-oxobutanoyl)thieno[3,2-b]pyridin-5-yl)oxy)propoxy)isoindolin-2-yl)-4-oxobutanoate (0.013 g, 20.6780 μmol) in tetrahydrofuran (4 mL) and water (1 mL) at 25° C., LiOH (0.006 g, 250.5397 μmol) was added. The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was evaporated under reduced pressure. The residue was concentrated and diluted with water (2 mL). The resulting mixture was adjusted to pH = 7 with HCl (1 M) at 25° C. and evaporated under reduced pressure. The residue was purified by HPLC. The pure fractions were concentrated and lyophilized to dryness to give the free acid. To a mixture of the free acid in acetonitrile (2 mL) and water (1 mL) at 25 °C, add NaHCO 3 (0.001 g, 11.9038 μmol) was added. The mixture was stirred at 25° C. for 1 h and lyophilized. Sodium 4-(5-(3-((2-(3-carboxylatopropanoyl)-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutanoate (0.0043 g, 6.8192 μmol, 32.9781% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 587.162. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0396] Example 9 4-(5-(3-((6-bromo-2-(3-carboxypropanoyl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid Step a: Ethyl 4-(5-(3-((6-bromo-2-(4-ethoxy-4-oxobutanoyl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate [ka]

[0397] A solution of ethyl 4-(5-(3-bromopropoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.075 g, 181.0327 μmol) and ethyl 4-(6-bromo-5-hydroxybenzo[b]thiophen-2-yl)-4-oxobutanoate (0.071 g, 198.7576 μmol) in DMF (2 mL) was diluted with N 2 Potassium carbonate (0.080 g, 578.8482 μmol) was added under atmosphere at 25° C. The reaction mixture was heated to 50° C. and stirred overnight. The reaction mixture was then loaded onto a C18 column ACN / H 2 0 (0.1% FA) (0-60%). Pure fractions were concentrated and lyophilized. Ethyl 4-(5-(3-((6-bromo-2-(4-ethoxy-4-oxobutanoyl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.080 g, 115.8418 μmol, 63.9894% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 690.13. 1 H NMR (400 MHz, DMSO-d 6) 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).

[0398] Step b: 4-(5-(3-((6-bromo-2-(3-carboxypropanoyl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid [ka]

[0399] To a solution of ethyl 4-(5-(3-((6-bromo-2-(4-ethoxy-4-oxobutanoyl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.044 g, 63.7130 μmol) in THF (2 mL), EtOH (1 mL) and water (2 mL) was added LiOH (0.050 g, 2.0878 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was adjusted to pH = 3 with HCl (1 mol / L). The reaction mixture was purified by column chromatography on a C18 ACN / H 20 (0.1% FA) (0-55%). Pure fractions were concentrated and lyophilized to give 4-(5-(3-((6-bromo-2-(3-carboxypropanoyl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid (0.012 g, 18.9128 μmol, 29.6844% yield) as a white solid. LCMS: (ESI, m / z): [M+H] + = 634.07. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0400] Example 10 4-(5-(3-((2-(3-carboxypropanoyl)-4-fluoro-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid Step a: Ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-4-fluoro-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate [ka]

[0401] A solution of ethyl 4-(5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (0.062 g, 201.0709 μmol) and ethyl 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.069 g, 159.6186 μmol) in DMF (3 mL) was diluted with N 2 Potassium carbonate (0.099 g, 716.3246 μmol) was added dropwise under atmospheric conditions at 25° C. The reaction mixture was stirred at 50° C. overnight. The mixture was then loaded onto a C18 column with ACN / H 2 0 (0.1% FA) (0-50%). Pure fractions were concentrated and further dried by lyophilization. Ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-4-fluoro-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (0.071 g, 107.6218 μmol, 67.4244% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 660.220. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0402] Step b: 4-(5-(3-((2-(3-carboxypropanoyl)-4-fluoro-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid [ka]

[0403] To a mixture of ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-4-fluoro-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (0.100 g, 155.1150 μmol) in THF (2 mL), EtOH (2 mL) and water (2 mL) was added LiOH (0.044 g, 1.8373 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was adjusted to pH = 3 with HCl (1 mol / L) and the mixture was evaporated under reduced pressure. The residue was purified by column chromatography on a C18 column ACN / H 2 0 (0.1% FA) (0-40%). Pure fractions were concentrated and dried under vacuum. 4-(5-(3-((2-(3-carboxypropanoyl)-4-fluoro-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid (0.026 g, 43.0741 μmol, 66.0854% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 604.160. 1 H NMR (400 MHz, DMSO-d 6) 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).

[0404] Example 11 4-(5-(3-((6-(3-carboxypropanoyl)-3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propoxy)-6-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutanoic acid Step a: 3-Methoxy-2-(3-tetrahydropyran-2-yloxypropoxy)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine [ka]

[0405] To a solution of 3-methoxy-6-(4-methoxybenzyl)-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (2.464 g, 5.7500 mmol) in ethyl acetate (60 mL) at 25 °C was added Pd / C (2.553 g, 2.3990 mmol). The reaction mixture was stirred overnight at 25 °C under H2 atmosphere. The resulting mixture was filtered. The filter cake was washed with EA (3 x 100 mL). The filtrate was concentrated under reduced pressure. 3-Methoxy-2-(3-tetrahydropyran-2-yloxypropoxy)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (.936 g, 4.3947 mmol, 76.4291% yield) was obtained as a yellow oil. LCMS: (ESI, m / z): [M+H] + = 309.174.

[0406] Step b: 3-((3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propan-1-ol [ka]

[0407] To a solution of 3-methoxy-2-(3-tetrahydropyran-2-yloxypropoxy)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (1.91 g, 4.3357 mmol) in MeOH (40 mL) was added 4-methylbenzenesulfonic acid (0.69 g, 2.5430 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was evaporated under reduced pressure. The residue was purified on a C18 column MeCN / water (0-50%). Pure fractions were concentrated and dried under vacuum. 3-((3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propan-1-ol (0.814 g, 3.6298 mmol, 83.7191% yield) was obtained as a yellow oil. LCMS: (ESI, m / z): [M+H] + = 225.116.

[0408] Step c: Ethyl 4-(2-(3-hydroxypropoxy)-3-methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxobutanoate [ka]

[0409] To a solution of 3-((3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propan-1-ol (0.366 g, 1.6321 mmol) and triethylamine (0.363 g, 3.5873 mmol) in tetrahydrofuran (20 mL) was added ethylsuccinate chloride (0.232 g, 1.4096 mmol) at 0° C. under N2 atmosphere. The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was purified on a C-18 column MeCN / water (0-100%). The pure fractions were concentrated and dried under vacuum. Ethyl 4-(2-(3-hydroxypropoxy)-3-methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxobutanoate (224 mg, 635.6750 μmol, 38.9491% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 353.163. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0410] Step d: Ethyl 4-(3-methoxy-2-(3-((6-methoxy-2-(4-methoxy-4-oxobutanoyl)thieno[3,2-b]pyridin-5-yl)oxy)propoxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxobutanoate [ka]

[0411] To a solution of ethyl 4-(2-(3-hydroxypropoxy)-3-methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxobutanoate (0.087 g, 246.8916 μmol) and methyl 4-(5-chloro-6-methoxy-thieno[3,2-b]pyridin-2-yl)-4-oxobutanoate (0.120 g, 382.4626 μmol) in toluene (20 mL) at 25° C., potassium phosphate tribasic (0.212 g, 998.7454 μmol) and RockPhos Palladacycle Gen.3 (0.022 g, 26.2082 μmol) were added. The reaction mixture was cooled to 37° C. for 1 hour and then cooled to 37° C. for 1 hour. 2 The mixture was stirred overnight at 25° C. under ambient conditions. The reaction mixture was evaporated under reduced pressure. The residue was purified on a C-18 column MeCN / water (0-100%). The residue was purified by HPLC. Pure fractions were concentrated and lyophilized. Ethyl 4-(3-methoxy-2-(3-((6-methoxy-2-(4-methoxy-4-oxobutanoyl)thieno[3,2-b]pyridin-5-yl)oxy)propoxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxobutanoate (20 mg, 31.7623 μmol, 12.8649% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 630.204. 1 H NMR (400 MHz, DMSO-d 6) 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).

[0412] Step e: 4-(5-(3-((6-(3-carboxypropanoyl)-3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propoxy)-6-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutanoic acid [ka]

[0413] To a solution of ethyl 4-(3-methoxy-2-(3-((6-methoxy-2-(4-methoxy-4-oxobutanoyl)thieno[3,2-b]pyridin-5-yl)oxy)propoxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxobutanoate (0.010 g, 15.8812 μmol) in tetrahydrofuran (4 mL) and water (1 mL) was added dropwise LiOH (0.004 g, 167.0265 μmol) at 25° C. The reaction mixture was stirred at 25° C. for 2 h and evaporated under reduced pressure. The residue was concentrated and diluted with water (2 mL). The resulting mixture was adjusted to pH = 7 with HCl (1 M) at 25° C. and evaporated under reduced pressure. The residue was purified by HPLC. Pure fractions were concentrated and lyophilized. 4-(5-(3-((6-(3-carboxypropanoyl)-3-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)oxy)propoxy)-6-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutanoic acid (2.6 mg, 4.4248 μmol, 27.8619% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 588.157. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0414] Example 12 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid Step a: tert-Butyl 5-methoxyisoindoline-2-carboxylic acid [ka]

[0415] To a solution of 5-methoxyisoindoline hydrochloride (20.01 g, 107.7833 mmol) and di-tert-butyl dicarbonate (35.28 g, 161.6523 mmol) in DCM (500 mL) at 20° C., TEA (33.12 g, 327.3070 mmol) was added. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was evaporated under reduced pressure. The residue was purified on a silica gel column EA / n-hexane (0-50%). The pure fractions were concentrated and dried under vacuum. tert-Butyl 5-methoxyisoindoline-2-carboxylate (30.66 g, 104.5347 mmol, 96.9859% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H-tBu+ACN] + = 235.136. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0416] Step b: tert-Butyl 5-bromo-6-methoxy-isoindoline-2-carboxylate [ka]

[0417] To a solution of tert-butyl 5-methoxyisoindoline-2-carboxylate (30.40 g, 121.9390 mmol) in tetrahydrofuran (300 mL) and acetonitrile (300 mL) was added NBS (43.64 g, 245.1906 mmol) at 20° C. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated, diluted with EA (1000 mL) and diluted with NaHCO 3 The organics were washed with aqueous (aq) (3 x 200 mL) and brine (300 mL). 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / n-hexane (0-50%). The pure fractions were concentrated and dried under vacuum. tert-Butyl 5-bromo-6-methoxy-isoindoline-2-carboxylate (17.61 g, 53.6562 mmol, 44.0025% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H-tBu+ACN] + = 313.047. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0418] Step c: tert-Butyl 5-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate [ka]

[0419] To a solution of tert-butyl 5-bromo-6-methoxy-isoindoline-2-carboxylate (10.04 g, 30.5910 mmol) in 1,4-dioxane (200 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.10 g, 2.8700 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (11.71 g, 46.1137 mmol) and potassium acetate (9. 76 g, 99.4475 mmol) at 20 °C. The reaction mixture was heated to 100 °C and stirred overnight under nitrogen atmosphere. The reaction mixture was concentrated, diluted with EA (500 mL) and washed with water (200 mL) and brine (200 mL). The organics were washed with Na 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / n-hexane (0-50%). The pure fractions were concentrated and dried under vacuum. tert-Butyl 5-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate (11.00 g, 29.3126 mmol, 95.8208% yield) was obtained as an oil. LCMS: (ESI, m / z): [M+H-tBu+ACN] + = 361.222.

[0420] Step d: tert-Butyl 5-hydroxy-6-methoxy-isoindoline-2-carboxylic acid [ka]

[0421] To a solution of tert-butyl 5-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate (9.75 g, 25.9816 mmol) in tetrahydrofuran (150 mL) and water (150 mL) was added sodium perborate tetrahydrate (6.28 g, 40.8164 mmol) at 20° C. 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 organics were washed with Na 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / DCM (0-100%). The pure fractions were concentrated and dried under vacuum to give tert-butyl 5-hydroxy-6-methoxy-isoindoline-2-carboxylate (6.58 g, 24.8017 mmol, 95.4589% yield) as a yellow oil.

[0422] Step e: tert-Butyl 5-(3-bromopropoxy)-6-methoxy-isoindoline-2-carboxylate [ka]

[0423] A mixture of potassium carbonate (0.286 g, 2.0694 mmol) and tert-butyl 5-hydroxy-6-methoxyisoindoline-2-carboxylate (0.179 g, 674.6977 μmol) in DMF (3 mL) was added to the 2 1,3-Dibromopropane (0.564 g, 2.7936 mmol) was added under atmospheric pressure at 20° C. The reaction mixture was stirred at 20° C. for 5 hours. The mixture was then purified by column chromatography on a C18 column with ACN / H 20 (0.1% FA) (0-50%). Pure fractions were concentrated and dried under vacuum to give tert-butyl 5-(3-bromopropoxy)-6-methoxy-isoindoline-2-carboxylate (0.154 g, 398.6747 μmol, 59.0894% yield) as a white oil. LCMS: (ESI, m / z): [M+H] + = 386.090. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0424] Step f: tert-Butyl 5-(3-((2-(4-ethoxy-4-oxobutanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-carboxylate [ka]

[0425] A solution of tert-butyl 5-(3-bromopropoxy)-6-methoxyisoindoline-2-carboxylate (0.079 g, 204.5150 μmol) and ethyl 4-(5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (0.064 g, 207.5571 μmol) in DMF (3 mL) was diluted with N 2Potassium carbonate (0.079 g, 571.6126 μmol) was added dropwise under atmosphere at 20° C. The reaction mixture was stirred at 50° C. overnight. 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 organics were dried over Na2SO4, filtered and evaporated under reduced pressure. Crude tert-butyl 5-(3-((2-(4-ethoxy-4-oxobutanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-carboxylate (0.088 g, 143.3886 μmol, 70.1115% yield) was obtained as a yellow oil and used directly in the next step. LCMS: (ESI, m / z): [M+H] + = 614.230.

[0426] Step g: 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid [ka]

[0427] To a solution of tert-butyl 5-(3-((2-(4-ethoxy-4-oxobutanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindoline-2-carboxylate (0.084 g, 136.8709 μmol) in DCM (3 mL) was added trifluoroacetic acid (1 mL) at 20° C. The reaction mixture was stirred at 20° C. for 1 h. The reaction mixture was evaporated under reduced pressure. To a solution of the residue in DCM (5 mL) was added N 2Dihydrofuran-2,5-dione (0.050 g, 499.6373 μmol) and TEA (0.195 g, 1.9271 mmol) were added under atmosphere at 0°C. The reaction mixture was stirred and allowed to warm to 20°C naturally. The reaction mixture was quenched at 20°C by the addition of water (50 mL), adjusted to pH = 3 with HCl (1 mol / L), extracted with EA (3 x 50 mL) and washed with brine (50 mL). The organics were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on a C18 ACN / H 2 0 (0.1% FA) (0-40%). Pure fractions were concentrated and dried under vacuum. 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid (0.038 g, 61.9221 μmol, 45.2413% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 614.200. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0428] Example 13 4-(5-(3-((2-(3-carboxylate propanoyl)-5-methoxythieno[2,3-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate sodium Step a: 2,3-Dimethoxy-5-vinyl-pyridine [ka]

[0429] To a solution of 5-bromo-2,3-dimethoxypyridine (9.88 g, 45.3112 mmol) in 1,4-dioxane (100 mL) and water (20 mL) at 20 °C was added 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.25 g, 60.0595 mmol), potassium carbonate (18.91 g, 136.8252 mmol) and Pd(dppf)Cl 2 (1.97 g, 2.6923 mmol) was added. The reaction mixture was stirred at 80° C. under nitrogen atmosphere for 2 h. The reaction mixture was concentrated, diluted with EA (100 mL) and added NaHCO 3 The organics were washed with aqueous (aq) (100 mL) and brine (50 mL). 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column with ethyl acetate / heptane (0-20%). The pure fractions were concentrated and dried under vacuum. 2,3-Dimethoxy-5-vinyl-pyridine (5.22 g, 31.6002 mmol, 69.7404% yield) was obtained as a colorless oil. LCMS: (ESI, m / z): [M+H] + = 166.079. 1 H NMR (400 MHz, DMSO-d 6) 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).

[0430] Step b: 5,6-Dimethoxypyridine-3-carbaldehyde [ka]

[0431] To a solution of 2,3-dimethoxy-5-vinyl-pyridine (5.17 g, 31.2975 mmol) and 4-methylmorpholine N-oxide (7.44 g, 63.5105 mmol) in tetrahydrofuran (100 mL) was added potassium osmate(VI) dihydrate (0.55 g, 1.4927 mmol) in water (25 mL) at 20° C. The reaction mixture was stirred at 20° C. for 30 min. Sodium periodate (6.82 g, 31.8854 mmol) was added to the mixture at 20° C. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was concentrated, diluted with EA (500 mL) and washed with water (200 mL) and brine (50 mL). The organics were washed with Na 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / Hept (0-20%). The pure fractions were concentrated and dried under vacuum. 5,6-Dimethoxypyridine-3-carbaldehyde (3.51 g, 20.9976 mmol, 67.0904% yield) was obtained as a white solid.

[0432] Step c: (5,6-dimethoxy-3-pyridyl)methanol [ka]

[0433] To a solution of 5,6-dimethoxypyridine-3-carbaldehyde (3.51 g, 20.9976 mmol) in methanol (100 mL) was added NaBH4 (0.4 g, 10.5729 mmol) at 20 °C. The reaction mixture was concentrated, diluted with EA (500 mL) and washed with water (200 mL) and brine (200 mL). The organics were washed with Na 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The pure fractions were 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. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0434] Step d: (2-Bromo-5,6-dimethoxy-3-pyridyl)methanol [ka]

[0435] To a solution of (5,6-dimethoxy-3-pyridyl)methanol (3.30 g, 19.5062 mmol) in acetonitrile (100 mL) was added NBS (4.26 g, 23.9347 mmol) and acetic acid (0.5 mL) at 20° C. The reaction mixture was stirred at 20° C. for 2 h and evaporated under reduced pressure. The residue was diluted with EA (200 mL) and diluted with NaHCO 3 The organics were washed with aqueous (aq) (2 x 100 mL) and brine (100 mL). 2 SO 4The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / Hept (0-100%). The pure fractions were concentrated and dried under vacuum. (2-Bromo-5,6-dimethoxy-3-pyridyl)methanol (2.91 g, 11.7304 mmol, 60.1369% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 247.984. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0436] Step e: 2-Bromo-5,6-dimethoxy-pyridine-3-carbaldehyde [ka]

[0437] To a solution of (2-bromo-5,6-dimethoxy-3-pyridyl)methanol (2.91 g, 11.7304 mmol) in DCM (100 mL) was added Dess-Martin periodinane (7.3 g, 17.2113 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 1 h and evaporated under reduced pressure. The reaction mixture was concentrated, diluted with EA (200 mL) and diluted with NaHCO 3 The organics were washed with aqueous (aq) (2 x 100 mL) and brine (100 mL). 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / Hept (0-100%). The pure fractions were concentrated and dried under vacuum. 2-Bromo-5,6-dimethoxy-pyridine-3-carbaldehyde (2.7 g, 10.9730 mmol, 93.5437% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 245.969. 1H NMR (400 MHz, DMSO-d 6 ) δ 10.04 (s, 1H), 7.52 (s, 1H), 3.99 (s, 3H), 3.87 (s, 3H).

[0438] Step f: 5,6-dimethoxythieno[2,3-b]pyridine-2-carboxylic acid [ka]

[0439] To a mixture of 2-bromo-5,6-dimethoxy-pyridine-3-carbaldehyde (2.68 g, 10.8918 mmol) and potassium carbonate (4.65 g, 33.6455 mmol) in N,N-dimethylformamide (50 mL) at 20 °C was added methyl thioglycolate (1.1870 g, 11.1830 mmol). The reaction mixture was cooled to 100 °C and cooled to 37 °C. 2 The mixture was stirred at 60° C. under ambient conditions overnight. The reaction mixture was concentrated and diluted with water (500 mL). The precipitate was collected by filtration and washed with water (100 mL). To a solution of the filtrate cake in tetrahydrofuran (50 mL) and water (10 mL) was added LiOH (0.40 g, 16.7026 mmol) 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 and washed with water (100 mL). The pure fractions were dried under vacuum. 5,6-Dimethoxythieno[2,3-b]pyridine-2-carboxylic acid (2.32 g, 9.6971 mmol, 89.0313% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 240.065. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.91 (s, 1H), 7.80 (s, 1H), 3.98 (s, 3H), 3.85 (s, 3H).

[0440] Step g: tert-Butyl 3-(5,6-dimethoxythieno[2,3-b]pyridin-2-yl)-3-oxo-propanoate [ka]

[0441] To a solution of 5,6-dimethoxythieno[2,3-b]pyridine-2-carboxylic acid (2.29 g, 9.5717 mmol) in N,N-dimethylformamide (50 mL) was added carbonyldiimidazole (3.11 g, 19.1799 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 30 min under nitrogen atmosphere. 3-tert-Butoxy-3-oxopropanoic acid (3.16 g, 19.7294 mmol), magnesium chloride (1.87 g, 19.6406 mmol) and triethylamine (2.96 g, 29.2521 mmol) were added to the mixture at 20 °C. The reaction mixture was stirred at 20 °C overnight. The reaction mixture was concentrated, diluted with EA (500 mL) and diluted with NaHCO 3 The organics were washed with aqueous (aq) (2 x 300 mL) and brine (200 mL). 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / n-hexane (0-50%). The pure fractions were concentrated and dried under vacuum. tert-Butyl 3-(5,6-dimethoxythieno[2,3-b]pyridin-2-yl)-3-oxopropanoate (2.37 g, 7.0245 mmol, 73.3885% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 338.098. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0442] Step h: O1-tert-butyl O4-ethyl 2-(5,6-dimethoxythieno[2,3-b]pyridine-2-carbonyl)butanedioate [ka]

[0443] To a mixture of tert-butyl 3-(5,6-dimethoxythieno[2,3-b]pyridin-2-yl)-3-oxo-propanoate (1.2 g, 3.5567 mmol) and potassium carbonate (0.80 g, 5.7885 mmol) in N,N-dimethylformamide (20 mL) was added ethyl bromoacetate (0.63 g, 3.7724 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 6 h. The reaction mixture was concentrated, diluted with EA (200 mL) and diluted with NaHCO 3 The organics were washed with aqueous (aq) (200 mL) and brine (200 mL). 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / n-hexane (0-50%). The pure fractions were concentrated and dried under vacuum. O1-tert-butyl O4-ethyl 2-(5,6-dimethoxythieno[2,3-b]pyridine-2-carbonyl)butanedioate (1.72 g, 4.0616 mmol, 114.1951% yield) was obtained as a yellow oil. LCMS: (ESI, m / z): [M+H] + = 424.135. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0444] Step i: Ethyl 4-(5,6-dimethoxythieno[2,3-b]pyridin-2-yl)-4-oxo-butanoate [ka]

[0445] To a solution of O1-tert-butyl O4-ethyl 2-(5,6-dimethoxythieno[2,3-b]pyridine-2-carbonyl)butanedioate (1.51 g, 3.5657 mmol) in toluene (10 mL) at 20° C., trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at 50° C. for 1 h. The reaction mixture was evaporated under reduced pressure. The residue was purified on a C-18 column MeCN / water (0-100%). The pure fractions were concentrated and dried under vacuum. Ethyl 4-(5,6-dimethoxythieno[2,3-b]pyridin-2-yl)-4-oxo-butanoate (0.94 g, 2.9069 mmol, 81.5252% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 324.083. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0446] Step j: Ethyl 4-(6-chloro-5-methoxy-thieno[2,3-b]pyridin-2-yl)-4-oxo-butanoate [ka]

[0447] To HCl (10 mL) was added ethyl 4-(5,6-dimethoxythieno[2,3-b]pyridin-2-yl)-4-oxo-butanoate (0.308 g, 952.4899 μmol) at 20° C. The reaction mixture was stirred at 100° C. for 1 h. The reaction mixture was cooled to 20° C. and POCl 3 (1 mL) was added to the reaction mixture. The reaction mixture was then rinsed with N 2 The mixture was stirred at 100° C. under atmospheric pressure for 2 hours. The reaction mixture was evaporated under reduced pressure. The residue was purified on a C-18 column MeCN / water (0-100%). The pure fractions were concentrated and dried under vacuum. Ethyl 4-(6-chloro-5-methoxy-thieno[2,3-b]pyridin-2-yl)-4-oxo-butanoate (0.25 g, 762.7004 μmol, 80.0744% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 328.033. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0448] Step k: Ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-5-methoxythieno[2,3-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate [ka]

[0449] To a mixture of ethyl 4-(6-chloro-5-methoxy-thieno[2,3-b]pyridin-2-yl)-4-oxo-butanoate (0.10 g, 305.0799 μmol), ethyl 4-(5-(3-hydroxypropoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.18 g, 512.2470 μmol) and potassium phosphate (0.20 g, 942.2127 μmol) in toluene (10 mL) at 20° C., RockPhos Palladacycle Gen.3 (0.03 g, 35.7385 μmol) was added. The reaction mixture was cooled to 37° C. and cooled to 37° C. for 1 hour. 2 The mixture was stirred at 130° C. under ambient atmosphere overnight. The reaction mixture was evaporated under reduced pressure. The residue was purified on a C-18 column MeCN / water (0-100%). Pure fractions were concentrated and dried under vacuum. Ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-5-methoxythieno[2,3-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.013 g, 20.2267 μmol, yield 6.6300%) was obtained as a yellow oil.

[0450] Step l: Sodium 4-(5-(3-((2-(3-carboxylatepropanoyl)-5-methoxythieno[2,3-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate [ka]

[0451] To a solution of ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-5-methoxythieno[2,3-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.018 g, 28.0062 μmol) in tetrahydrofuran (4 mL) and water (1 mL) at 20° C., LiOH (3 mg, 125.2699 μmol) was added. The reaction mixture was stirred at 20° C. for 1 h. Pure fractions were concentrated and lyophilized. The lyophilized product in water (5 mL) was diluted with NaHCO 3 (3.4 mg, 40.4730 μmol) was added and stirred at 20° C. for 1 hour. Sodium 4-(5-(3-((2-(3-carboxylatepropanoyl)-5-methoxythieno[2,3-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (13 mg, 20.6162 μmol, 73.6129% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 587.162.

[0452] Example 14 4-(5-(3-((2-(3-carboxypropanoyl)-4-chloro-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid Step a: Ethyl 4-[5-(3-bromopropoxy)-6-methoxy-benzothiophen-2-yl]-4-oxo-butanoate [ka]

[0453] A solution of ethyl 4-(5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (0.081 g, 262.6894 μmol) and 1,3-dibromopropane (0.263 g, 1.3027 mmol) in DMF (5 mL) was diluted with N 2Potassium carbonate (0.113 g, 817.6230 μmol) was added under atmosphere at 20° C. The reaction mixture was stirred overnight at 20° C. The mixture was then loaded onto a C18 column ACN / H 2 0 (0-60%). The pure fractions were concentrated and dried under vacuum. Ethyl 4-[5-(3-bromopropoxy)-6-methoxy-benzothiophen-2-yl]-4-oxo-butanoate (0.074 g, 172.3638 μmol, 65.6150% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 309.070. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0454] Step b: Ethyl 4-(5-(3-((4-chloro-2-(4-ethoxy-4-oxobutanoyl)-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate [ka]

[0455] A solution of ethyl 4-[5-(3-bromopropoxy)-6-methoxy-benzothiophen-2-yl]-4-oxobutanoate (0.092 g, 214.2904 μmol) and ethyl 4-(4-chloro-5-hydroxy-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.072 g, 219.6763 μmol) in DMF (3 mL) was diluted with N 2Potassium carbonate (0.094 g, 680.1466 μmol) was added under atmosphere at 20° C. The reaction mixture was heated to 50° C. and stirred overnight. The mixture was then loaded onto a C18 column ACN / H 2 0 (0.1% FA) (0-60%). Pure fractions were concentrated and dried under vacuum. Ethyl 4-(5-(3-((4-chloro-2-(4-ethoxy-4-oxobutanoyl)-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (0.089 g, 131.6233 μmol, 61.4229% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 676.190. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0456] Step c: 4-(5-(3-((2-(3-carboxypropanoyl)-4-chloro-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid [ka]

[0457] THF (2 mL) and H 2To a solution of ethyl 4-(5-(3-((4-chloro-2-(4-ethoxy-4-oxobutanoyl)-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (0.040 g, 59.1565 μmol) in 2 mL of HO (2 mL) was added LiOH (0.051 g, 2.1296 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was adjusted to pH = 3 with HCl (1 mol / L). The mixture was purified by column chromatography on C18 ACN / H2O. 2 0 (0.1% FA) (0-45%). Pure fractions were concentrated and lyophilized to give 4-(5-(3-((2-(3-carboxypropanoyl)-4-chloro-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid (0.025 g, 40.3183 μmol, 68.1552% yield) as a white solid. LCMS: (ESI, m / z): [M+H] + = 620.130. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0458] Example 15 4-(5-(3-((2-(3-carboxypropanoyl)-5-methoxythieno[3,2-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid Step a: Ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-5-methoxythieno[3,2-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate [ka]

[0459] A mixture of ethyl 4-(6-hydroxy-5-methoxythieno[3,2-b]pyridin-2-yl)-4-oxobutanoate (0.069 g, 223.0577 μmol) and ethyl 4-(5-(3-bromopropoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.079 g, 190.6877 μmol) in DMF (2 mL) was diluted with N 2 Potassium carbonate (0.089 g, 643.9686 μmol) was mixed at 20° C. under atmospheric conditions. The reaction mixture was heated to 50° C. and stirred overnight. The reaction mixture was then loaded onto a C18 column ACN / H 2 0 (0.1% FA) (0-55%). Pure fractions were concentrated and lyophilized to give ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-5-methoxythieno[3,2-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.075 g, 116.6925 μmol, 61.1956% yield) as a white solid. LCMS: (ESI, m / z): [M+H] + = 690.130. 1 H NMR (400 MHz, DMSO-d 6) 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).

[0460] Step b: 4-(5-(3-((2-(3-carboxypropanoyl)-5-methoxythieno[3,2-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid [ka]

[0461] HF (2 mL), H 2 To a solution of ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-5-methoxythieno[3,2-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.051 g, 79.3509 μmol) in 2 mL of HO and ethanol (1 mL) was added LiOH (0.050 g, 2.0878 mmol) at 20° C. 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 the reaction mixture was purified by column chromatography on a C18 column in ACN / H2O. 20 (0.1% FA) (0-45%). Pure fractions were concentrated and lyophilized to dryness. 4-(5-(3-((2-(3-carboxypropanoyl)-5-methoxythieno[3,2-b]pyridin-6-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid (0.015 g, 25.5707 μmol, 32.2248% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 586.160. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0462] Example 16 4-(5-((2-(((2-(3-carboxypropanoyl)-4-chloro-6-methoxyisoindolin-5-yl)oxy)methyl)allyl)oxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid Step a: Ethyl 4-[4-chloro-5-[2-(chloromethyl)allyloxy]-6-methoxy-isoindolin-2-yl]-4-oxo-butanoate [ka]

[0463] A mixture of potassium carbonate (0.202 g, 1.4616 mmol) and ethyl 4-(4-chloro-5-hydroxy-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.154 g, 469.8574 μmol) in DMF (5 mL) was added to the2 3-Chloro-2-(chloromethyl)prop-1-ene (0.507 g, 2.2635 mmol) was added under atmospheric pressure at 20° C. The reaction mixture was stirred at 20° C. for 3 hours. The reaction mixture was then purified by column chromatography on a C18 column with ACN / H 2 0 (0.1% FA) (0-50%). Pure fractions were concentrated and dried under vacuum. Ethyl 4-[4-chloro-5-[2-(chloromethyl)allyloxy]-6-methoxy-isoindolin-2-yl]-4-oxo-butanoate (0.151 g, 362.7238 μmol, 77.1987% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 416.100.

[0464] Step b: Ethyl 4-(5-((2-(((4-chloro-2-(4-ethoxy-4-oxobutanoyl)-6-methoxyisoindolin-5-yl)oxy)methyl)allyl)oxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate [ka]

[0465] A mixture of ethyl 4-(4-chloro-5-((2-(chloromethyl)allyl)oxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.068 g, 163.3458 μmol) and ethyl 4-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (0.049 g, 150.1504 μmol) in DMF (3 mL) was 2 At 20°C under atmospheric conditions, 2 CO 3 (0.092 g, 665.6754 μmol) was added. The reaction mixture was stirred at 50° C. overnight. The reaction mixture was then column-coated with ACN / H 20 (0.1% FA) (0-60%). Pure fractions were concentrated and lyophilized to give ethyl 4-(5-((2-((4-chloro-2-(4-ethoxy-4-oxobutanoyl)-6-methoxyisoindolin-5-yl)oxy)methyl)allyl)oxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (0.022 g, 31.1538 μmol, 19.0723% yield) as a white solid. LCMS: (ESI, m / z): [M+H] + = 706.180. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0466] Step c: 4-(5-((2-(((2-(3-carboxypropanoyl)-4-chloro-6-methoxyisoindolin-5-yl)oxy)methyl)allyl)oxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid [ka]

[0467] THF (1 mL) and H 2To a solution of ethyl 4-(5-(2-((4-chloro-2-(4-ethoxy-4-oxobutanoyl)-6-methoxyisoindolin-5-yl)oxy)methyl)allyl)oxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (0.012 g, 16.9930 μmol) in 20° C. (1 mL) was added LiOH (0.037 g, 1.5450 mmol). The reaction mixture was stirred at 20° C. for 1 h. The reaction mixture was adjusted to pH = 3 with HCl (1 mol / L). The reaction mixture was evaporated under reduced pressure. The residue was purified by column chromatography on a C18 column in ACN / H 2 0 (0.1% FA) (0-50%). Pure fractions were concentrated and lyophilized to give 4-(5-((2-((2-(3-carboxypropanoyl)-4-chloro-6-methoxyisoindolin-5-yl)oxy)methyl)allyl)oxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid (0.011 g, 16.9213 μmol, 99.5782% yield) as a white solid. LCMS: (ESI, m / z): [MH] - = 648.120. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0468] Example 17 (S)-4-(5-(3-((2-((S)-3-carboxypropanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindolin-2-yl)-2-methyl-4-oxobutanoic acid Step a: 4-Fluoro-6-methoxyisoindolin-5-ol hydrochloride [ka]

[0469] To a solution of tert-butyl 4-fluoro-5-hydroxy-6-methoxyisoindoline-2-carboxylate (0.103 g, 363.5790 μmol) in EA (1 mL) was added HCl in EA (3 mL, 12 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was evaporated under reduced pressure. 4-Fluoro-6-methoxyisoindolin-5-ol hydrochloride (0.12 g, 655.0962 μmol, 180.1799% yield) was obtained as a white solid, which was used as such in the next step. LCMS: (ESI, m / z): [M+H] + = 184.070.

[0470] Step b: Methyl (2S)-4-(4-fluoro-5-hydroxy-6-methoxy-isoindolin-2-yl)-2-methyl-4-oxo-butanoate [ka]

[0471] A solution of (S)-4-methoxy-3-methyl-4-oxobutanoic 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) was diluted with N 24-Fluoro-6-methoxyisoindolin-5-ol hydrochloride (0.112 g, 611.4238 μmol) was added under atmosphere at 20° C. The reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was then eluted with a C18 column ACN / H 2 0 (0.1% FA) (0-55%). Pure fractions were concentrated and dried under vacuum. Methyl (2S)-4-(4-fluoro-5-hydroxy-6-methoxy-isoindolin-2-yl)-2-methyl-4-oxo-butanoate (0.061 g, 195.9494 μmol, 32.0481% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 312.120.

[0472] Step c: Ethyl (2S)-4-[5-(3-bromopropoxy)-4-fluoro-6-methoxy-benzothiophen-2-yl]-2-methyl-4-oxo-butanoate [ka]

[0473] To a mixture of ethyl (S)-4-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-2-methyl-4-oxobutanoate (0.061 g, 179.2189 μmol) and potassium carbonate (0.129 g, 933.3927 μmol) in DMF (3 mL) was added 1,3-dibromopropane (0.255 g, 1.2631 mmol) at 20° C. under N2 atmosphere. The reaction mixture was stirred at 20° C. for 3 h. The mixture was purified by column chromatography on a C18 ACN / H column. 2 0 (0.1% FA) (0-70%). Pure fractions were concentrated and dried under vacuum. Ethyl (2S)-4-[5-(3-bromopropoxy)-4-fluoro-6-methoxy-benzothiophen-2-yl]-2-methyl-4-oxo-butanoate (0.66 g, 1.4306 mmol, 798.2476% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 461.040.

[0474] Step d: Ethyl (S)-4-(4-fluoro-5-(3-((4-fluoro-6-methoxy-2-((S)-4-methoxy-3-methyl-4-oxobutanoyl)isoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-2-methyl-4-oxobutanoate [ka]

[0475] To a solution of ethyl (2S)-4-[5-(3-bromopropoxy)-4-fluoro-6-methoxy-benzothiophen-2-yl]-2-methyl-4-oxo-butanoate (0. 071 g, 153.8990 μmol) and methyl (2S)-4-(4-fluoro-5-hydroxy-6-methoxy-isoindolin-2-yl)-2-methyl-4-oxo-butanoate (0.056 g, 179.8880 μmol) in DMF (3 mL) at 20° C., potassium carbonate (0.074 g, 535.4346 μmol) was added. The reaction mixture was cooled to 37° C. with 50° C. for 1 hour. 2 The reaction mixture was stirred overnight at 50° C. under atmospheric conditions. 2 0 (0.1% FA) (0-50%). Pure fractions were concentrated and dried under vacuum. Ethyl (S)-4-(4-fluoro-5-(3-((4-fluoro-6-methoxy-2-((S)-4-methoxy-3-methyl-4-oxobutanoyl)isoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-2-methyl-4-oxobutanoate (61 mg, 88.1841 μmol, 57.3000% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 692.230. 1 H NMR (400 MHz, DMSO-d 6) 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).

[0476] Step e: (S)-4-(5-(3-((2-((S)-3-carboxybutanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindolin-2-yl)-2-methyl-4-oxobutanoic acid [ka]

[0477] THF (2 mL) and H 2 To a mixture of ethyl (S)-4-(4-fluoro-5-(3-((4-fluoro-6-methoxy-2-((S)-4-methoxy-3-methyl-4-oxobutanoyl)isoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-2-methyl-4-oxobutanoate (0.038 g, 54.9344 μmol) in 2 mL of HO was added LiOH (0.038 g, 1.5868 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was adjusted to pH = 3 with HCl (1 mol / L). The reaction mixture was evaporated under reduced pressure. The residue was purified by column chromatography on a C18 column in ACN / H 20 (0.1% FA) (0-45%). Pure fractions were concentrated and lyophilized to dryness. (S)-4-(5-(3-((2-((S)-3-carboxybutanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxyisoindolin-2-yl)-2-methyl-4-oxobutanoic acid (18 mg, 27.7070 μmol, 50.4365% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 650.18. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0478] Example 18 4-(5-(3-((2-((2-carboxyethyl)carbamoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid Step a: Ethyl 3-[[6-methoxy-5-(methoxymethoxy)benzothiophene-2-carbonyl]amino]propanoate [ka]

[0479] To a 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) in DMF (15 mL) was added ethyl 3-aminopropanoate hydrochloride (0.34 g, 2.2134 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 2 h. The mixture was purified by column chromatography on a C18 column ACN / H 2 0 (0.1% FA) (0-50%). Pure fractions were concentrated and dried under vacuum. Ethyl 3-[[6-methoxy-5-(methoxymethoxy)benzothiophene-2-carbonyl]amino]propanoate (0.35 g, 952.5987 μmol, 88.1269% yield) was obtained as a yellow oil. LCMS: (ESI, m / z): [M+H] + = 368.110.

[0480] Step b: Ethyl 3-[(5-hydroxy-6-methoxy-benzothiophene-2-carbonyl)amino]propanoate [ka]

[0481] Ethyl 3-[[6-methoxy-5-(methoxymethoxy)benzothiophene-2-carbonyl]amino]propanoate (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 column chromatography on C18 ACN / H 2 0 (0.1% FA) (0-40%). Pure fractions were concentrated and dried under vacuum. Ethyl 3-[(5-hydroxy-6-methoxy-benzothiophene-2-carbonyl)amino]propanoate (0.23 g, 711.2738 μmol, 90.1149% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 324.080.

[0482] Step c: Ethyl 4-[5-[3-[2-[(3-ethoxy-3-oxo-propyl)carbamoyl]-6-methoxy-benzothiophen-5-yl]oxypropoxy]-6-methoxy-isoindolin-2-yl]-4-oxo-butanoate ethyl [ka]

[0483] A solution of ethyl 3-[(5-hydroxy-6-methoxy-benzothiophene-2-carbonyl)amino]propanoate (0.21 g, 649.4249 μmol) and ethyl 4-(5-(3-bromopropoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.21 g, 506.8913 μmol) in DMF (5 mL) was diluted with N 2 Potassium carbonate (0.25 g, 1.8089 mmol) was added at 20° C. under atmospheric pressure. The reaction mixture was heated to 50° C. and stirred for 8 hours. The reaction mixture was then purified by column chromatography on a C18 column with ACN / H 2 0 (0.1% FA) (0-65%). Pure fractions were concentrated and dried under vacuum. Ethyl 4-[5-[3-[2-[(3-ethoxy-3-oxo-propyl)carbamoyl]-6-methoxy-benzothiophen-5-yl]oxypropoxy]-6-methoxy-isoindolin-2-yl]-4-oxo-butanoate (0.147 g, 223.8324 μmol, 34.4662% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 657.240.

[0484] Step d: 4-(5-(3-((2-((2-carboxyethyl)carbamoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid [ka]

[0485] THF (8 mL) and H2 To a solution of ethyl 4-[5-[2-[(3-ethoxy-3-oxo-propyl)carbamoyl]-6-methoxy-benzothiophen-5-yl]oxypropoxy]-6-methoxy-isoindolin-2-yl]-4-oxo-butanoate (0.082 g, 124.8589 μmol) in 200 (8 mL) was added LiOH (0.101 g, 4.2174 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was adjusted to pH = 3 with HCl (1 mol / L). The mixture was evaporated under reduced pressure. The residue was purified by column chromatography on a C18 column in ACN / H 2 0 (0.1% FA) (0-45%). Pure fractions were concentrated and lyophilized to give 4-(5-(3-((2-((2-carboxyethyl)carbamoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid (49 mg, 81.5803 μmol, 65.3380% yield) as a white solid. LCMS: (ESI, m / z): [M+H] + = 601.180. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0486] Example 19 4-(5-((2-(((2-(3-carboxypropanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)methyl)allyl)oxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid Step a: Ethyl 4-[5-[2-(chloromethyl)allyloxy]-6-methoxy-isoindolin-2-yl]-4-oxo-butanoate [ka]

[0487] To a mixture of ethyl 4-(5-hydroxy-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.507 g, 1.7285 mmol) and potassium carbonate (0.816 g, 5.9043 mmol) in DMF (20 mL) was added 3-chloro-2-(chloromethyl)prop-1-ene (1.108 g, 8.8643 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 8 h. The reaction mixture was quenched by the addition of water (100 mL) at 20 °C, extracted with EA (3 x 50 mL) and washed with brine (50 mL). The organics were washed with Na 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column EA / n-Hex (0-70%). The pure fractions were concentrated and dried under vacuum. Ethyl 4-[5-[2-(chloromethyl)allyloxy]-6-methoxy-isoindolin-2-yl]-4-oxo-butanoate (0.27 g, 707.0847 μmol, 40.9069% yield) was obtained as a yellow oil. LCMS: (ESI, m / z): [M+H] + = 382.130.

[0488] Step b: Ethyl 4-[5-[2-[[2-(4-ethoxy-4-oxo-butanoyl)-6-methoxy-isoindolin-5-yl]oxymethyl]allyloxy]-6-methoxy-benzothiophen-2-yl]-4-oxo-butanoate [ka]

[0489] To a mixture of ethyl 4-[5-[2-(chloromethyl)allyloxy]-6-methoxy-isoindolin-2-yl]-4-oxobutanoate (0.216 g, 55.6671 μmol), ethyl 4-(5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (0.186 g, 603.2128 μmol) and potassium carbonate (0.238 g, 1.7221 mmol) in DMF (5 mL) at 20 °C, sodium iodide (0.179 g, 1.1942 mmol) was added. The reaction mixture was cooled to 37 °C for 1 h and cooled to 37 °C. 2 The mixture was stirred at 20°C for 5 hours under atmospheric conditions. 2 0 (0.1% FA) (0-70%). Pure fractions were concentrated and dried under vacuum. Ethyl 4-[5-[[2-(4-ethoxy-4-oxo-butanoyl)-6-methoxy-isoindolin-5-yl]oxymethyl]allyloxy]-6-methoxy-benzothiophen-2-yl]-4-oxo-butanoate (0.169 g, 258.5135 μmol, 45.7006% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 654.230. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0490] Step c: 4-(5-((2-(((2-(3-carboxypropanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)methyl)allyl)oxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid [ka]

[0491] THF (4 mL) and H 2 To a mixture of ethyl 4-[5-[[2-(4-ethoxy-4-oxo-butanoyl)-6-methoxy-isoindolin-5-yl]oxymethyl]allyloxy]-6-methoxy-benzothiophen-2-yl]-4-oxo-butanoate (0.075 g, 114.7249 μmol) in 2 mL of HO (2 mL) was added LiOH (0.073 g, 3.0482 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was adjusted to pH = 3 with HCl (1 mol / L). The mixture was evaporated under reduced pressure. The residue was purified by column chromatography on a C18 column in ACN / H 2 0 (0.1% FA) (0-45%). Pure fractions were concentrated and lyophilized. 4-(5-((2-((2-(3-carboxypropanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)methyl)allyl)oxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid (0.0423 g, 70.7794 μmol, 61.6949% yield) was obtained as a white solid.

[0492] Example 20 4-(5-(3-((2-(3-carboxypropanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid Step a: Ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate [ka]

[0493] To a solution of ethyl 4-(5-(3-bromopropoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.103 g, 248.6182 μmol) in N,N-dimethylformamide (10 mL) was added ethyl 4-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (0.081 g, 248.2078 μmol) and potassium carbonate (0.136 g, 984.0419 μmol) at 20° C. The reaction mixture was stirred at 50° C. overnight. The reaction mixture was diluted with ethyl acetate (100 mL) and washed successively with water (100 mL) and brine (100 mL). The organic layer was extracted with Na 2 SO 4 The mixture was dried over ice, filtered and evaporated under reduced pressure. The residue was purified on a C-18 column MeCN / water (0-100%). The pure fractions were concentrated and dried under vacuum. Ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (66 mg, 100.0428 μmol, 40.2396% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 432.070. 1 H NMR (400 MHz, DMSO-d 6) 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).

[0494] Step b: 4-(5-(3-((2-(3-carboxypropanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid [ka]

[0495] To a solution of ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoate (0.052 g, 78.8217 μmol) in tetrahydrofuran (10 mL) and water (2 mL) was added LiOH (0.010 g, 417.5662 μmol). The reaction mixture was stirred at 50° C. for 2 h. The reaction mixture was acidified to pH = 4 with HCl (1 M). The mixture was evaporated under reduced pressure. The residue was purified on a C-18 column MeCN / water (0-100%). The pure fractions were concentrated and dried under vacuum. 4-(5-(3-((2-(3-carboxypropanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxyisoindolin-2-yl)-4-oxobutanoic acid (22 mg, 36.4473 μmol, 46.2402% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H]+ = 604.157. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0496] Example 21 trans-2-(5-(3-((2-(3-carboxypropanoyl)-4-fluoro-6-methoxyisoindolin-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-dioxaborinane-2-yl)-6-methoxy-benzothiophene-2-carbonyl]cyclopropanecarboxylate [ka]

[0497] To a mixture of methyl trans-2-(5-bromo-6-methoxybenzo[b]thiophene-2-carbonyl)cyclopropane-1-carboxylate (0. 510 g, 1.3813 mmol), bis(neopentylglycolato)diboron (0.953 g, 4.2190 mmol) and KOAc (0.437 g, 4.4527 mmol) in 1,4-dioxane (20 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.203 g, 277.4347 μmol) at 20°C. The reaction mixture was heated to 90°C and stirred overnight under N2 atmosphere. The reaction mixture was filtered through a pad of Celite. The filtrate was evaporated under reduced pressure. The crude methyl trans-2-[5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-6-methoxy-benzothiophene-2-carbonyl]cyclopropanecarboxylate (1.61 g, 2.0012 mmol, 144.8795% yield) was obtained as a black oil, which was used directly in the next step. LCMS: (ESI, m / z): [M+H] + = 403.13.

[0498] Step b: Methyl trans-2-(5-hydroxy-6-methoxy-benzothiophene-2-carbonyl)cyclopropanecarboxylate [ka]

[0499] Methyl trans-2-[5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-6-methoxy-benzothiophene-2-carbonyl]cyclopropanecarboxylate (1.56 g, 1.9390 mmol) and NaHCO in THF (30 mL). 3 (3.0 mL, 1.6722 mmol, 5% aqueous solution) at 20°C. 2 O 2(3.0 mL, 24.7468 mmol, 30% in water) was added. 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 layer was collected and washed with Na 2 SO 4 The mixture was dried over hexane, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with ethyl acetate / n-hexane (0-100%). The pure fractions were concentrated and dried under reduced pressure. Methyl trans-2-(5-hydroxy-6-methoxy-benzothiophene-2-carbonyl)cyclopropanecarboxylate (0.30 g, 979.3261 μmol, 71.43% yield) was obtained as a red-brown solid. LCMS: (ESI, m / z): [M+H] + = 307.05. 1 H NMR (400 MHz, CDCl 3 -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).

[0500] Step c: tert-Butyl 4-fluoro-6-methoxy-5-[3-[6-methoxy-2-[trans-2-methoxycarbonylcyclopropanecarbonyl]benzothiophen-5-yl]oxypropoxy]isoindoline-2-carboxylate [ka]

[0501] A solution of methyl trans -2-(5-hydroxy-6-methoxy-benzothiophene-2-carbonyl)cyclopropanecarboxylate (0.300 g, 979.3264 μmol) and tert-butyl 5-(3-bromopropoxy)-4-fluoro-6-methoxyisoindoline-2-carboxylate (0.406 g, 1.0043 mmol) in DMF (10 mL) was heated at 20 °C for 30 min at 37 °C. 2 CO 3 (0.501 g, 3.6250 mmol) was added. The reaction mixture was heated to 60° C. and stirred overnight. The resulting reaction mixture was 2 The mixture was diluted with 2×O (150 mL), extracted with EA (150 mL) and washed with brine (2×150 mL). The organic layer was collected and washed with Na 2 SO 4 The mixture was dried over 100 ml, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate / n-hexane (0-50%). The pure fractions were concentrated and dried under reduced pressure. tert-Butyl 4-fluoro-6-methoxy-5-[3-[6-methoxy-2-[trans-2-methoxycarbonylcyclopropanecarbonyl]benzothiophen-5-yl]oxypropoxy]isoindoline-2-carboxylate (0.45 g, 714.6357 μmol, 72.9722% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M+H-Boc] + = 530.20. 1 H NMR (400 MHz, CDCl 3-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).

[0502] Step d: Methyl trans-2-[5-[3-(4-fluoro-6-methoxy-isoindolin-5-yl)oxypropoxy]-6-methoxy-benzothiophene-2-carbonyl]cyclopropanecarboxylate [ka]

[0503] To a solution of tert-butyl 4-fluoro-6-methoxy-5-[3-[6-methoxy-2-[trans-2-methoxycarbonylcyclopropanecarbonyl]benzothiophen-5-yl]oxypropoxy]isoindoline-2-carboxylate (0.45 g, 714.6351 μmol) in EA (5 mL) at 20° C., HCl (4 N) in EA (15 mL, 60 mmol) was added. The reaction mixture was stirred at 20° C. for 2 h. The resulting reaction mixture was concentrated under reduced pressure. Methyl trans-2-[5-[3-(4-fluoro-6-methoxy-isoindolin-5-yl)oxypropoxy]-6-methoxy-benzothiophene-2-carbonyl]cyclopropanecarboxylate (0.42 g, 667.8009 μmol, 93.4464% yield, hydrochloride salt) was obtained as a grey solid. LCMS: (ESI, m / z): [M+H] + = 530.20. 1 H NMR (400 MHz, DMSO-d 6) 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).

[0504] Step e: Methyl trans-2-[5-[3-[2-(4-ethoxy-4-oxo-butanoyl)-4-fluoro-6-methoxy-isoindolin-5-yl]oxypropoxy]-6-methoxy-benzothiophene-2-carbonyl]cyclopropanecarboxylate [ka]

[0505] To a solution of methyl trans-2-[5-[3-(4-fluoro-6-methoxy-isoindolin-5-yl)oxypropoxy]-6-methoxy-benzothiophene-2-carbonyl]cyclopropanecarboxylate (0.202 g, 356.8671 μmol, hydrochloride salt) and N,N-diisopropylethylamine (0.185 mL, 1.0621 mmol) in THF (4 mL) and ACN (4 mL) was added dropwise 4-chloro-4-oxobutanoic acid ethyl (0.055 mL, 385.9673 μmol) in DCM (2 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC using DCM / MeOH (25:1) as the developing solvent. Methyl trans-2-[5-[3-[2-(4-ethoxy-4-oxo-butanoyl)-4-fluoro-6-methoxy-isoindolin-5-yl]oxypropoxy]-6-methoxy-benzothiophene-2-carbonyl]cyclopropanecarboxylate (0.221 g, 336.0184 μmol, 94.1579% yield) was obtained as an off-white semi-solid. LCMS: (ESI, m / z): [M+H] + = 658.25. 1 H NMR (400 MHz, CDCl 3 -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).

[0506] Step f: trans-2-(5-(3-((2-(3-carboxypropanoyl)-4-fluoro-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-carbonyl)cyclopropane-1-carboxylic acid [ka]

[0507] THF (6 mL) and H 2 To a solution of methyl trans-2-[5-[3-[2-(4-ethoxy-4-oxo-butanoyl)-4-fluoro-6-methoxy-isoindolin-5-yl]oxypropoxy]-6-methoxy-benzothiophene-2-carbonyl]cyclopropanecarboxylate (0.165 g, 250.8735 μmol) in 2 mL of HO (2 mL) was added LiOH (0.027 g, 1.1274 mmol) at 20 °C. 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 C18 column chromatography using the mobile phase ACN / H 2 Elution with 0 (0.1% FA) (0-100%). Pure fractions were concentrated and lyophilized overnight. trans-2-(5-(3-((2-(3-carboxypropanoyl)-4-fluoro-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-carbonyl)cyclopropane-1-carboxylic acid (0.052 g, 84.4674 μmol, 33.6693% yield) was obtained as a white solid. LCMS: (ESI, m / z): [M+H] + = 616.20. 1 H NMR (400 MHz, DMSO-d 6) 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).

[0508] The following examples shown in Table 2 were synthesized using the above procedure using the corresponding starting materials.

[0509] [Table 5] JPEG2024511832000214.jpg201170JPEG2024511832000215.jpg205170JPEG2024511832000216.jpg200170JPEG2024511832000217.jpg210170JPEG2024511832000218.jpg175170JPEG2024511832000219.jpg177170JPEG2024511832000220.jpg172170JPEG2024511832000221.jpg176170JPEG2024511832000222.jpg178170JPEG2024511832000223.jpg193170JPEG2024511832000224.jpg196170JPEG2024511832000225.jpg193170JPEG2024511832000226.jpg186170JPEG2024511832000227.jpg193170JPEG2024511832000228.jpg192170JPEG2024511832000229.jpg205170JPEG2024511832000230.jpg193170JPEG2024511832000231.jpg215170JPEG2024511832000232.jpg208170JPEG2024511832000233.jpg206170JPEG2024511832000234.jpg205170JPEG2024511832000235.jpg200170JPEG2024511832000236.jpg203170JPEG2024511832000237.jpg216170JPEG2024511832000238.jpg204170JPEG2024511832000239.jpg200170JPEG2024511832000240.jpg189170JPEG2024511832000241.jpg197170JPEG2024511832000242.jpg195170JPEG2024511832000243.jpg205170JPEG2024511832000244.jpg210170JPEG2024511832000245.jpg208170JPEG2024511832000246.jpg217170JPEG2024511832000247.jpg211170.

[0510] Example A: Human STING WT binding assay Cisbio Bioassays Human STING WT Binding Assay (#64BDSTGPEG & 64BDSTGPEH, Cisbio) is for the quantitative measurement of human STING WT ligand using HTRF® technology.

[0511] 1. Compound Addition Negative control: Dispense 5 μL of diluent into each negative control well. Standard: Dispense 5 μL of human STING WT standard 2'3'-cGAMP (Std 0~Std 7) into each standard well. Compound: Dispense 5 μL of compound into each compound well.

[0512] 2. Adding Protein Negative control: Add 5 μL of detection buffer to all wells. Other wells: Add 5 μL of human STING WT protein 6His tag protein to all wells.

[0513] 3. Antibody Addition Add 10 μL of premixed STING WT ligand d2 reagent and 6His Tb antibody working solution to all wells.

[0514] 4.RT Incubation Seal the plate and incubate at RT for 3 h or overnight as needed.

[0515] 5. Reading the Plate The plate sealer was removed and read in a HTRF® compatible reader (PerkinElmer, USA). The results were analyzed by the dual wavelength signal ratio: intensity (665 nm) / intensity (620 nm).

[0516] 6. Curve fitting Calculate the HTRF ratio as follows:

number

[0517] Fit the data in GraphPad and calculate the IC using equation (2). 50 Find the value. Equation (2): Y = Bottom + (Top-Bottom) / (1+10^ ((LogIC 50 -X) * Hill Slope Y is the HTRF ratio and X is the compound concentration. IC of binding assay against human STING WT 50 The values ​​were:

[0518] [Table 6]

[0519] The compound of the present invention is preferably formulated as a pharmaceutical composition that can be administered by various routes.Most preferably, such compositions are for oral administration.Such pharmaceutical compositions and the process for preparing them are well known in the art.See, for example, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al, eds., 19th ed., Mack Publishing Co., 1995).The compound of formula I is generally effective over a wide dose range.

[0520] For example, the daily dose is usually within the range of about 0.2 mg to about 100 mg, preferably within the range of 0.2 mg to 50 mg, more preferably within the range of 0.2 mg to 20 mg. In some cases, a dose level below the lower limit of the above range may be more than sufficient, while in other cases, a larger dose may be employed. The above dose ranges are not intended to limit the scope of the invention. It will be understood that the amount of compound actually administered will be determined by the physician in light of the relevant circumstances, such as the condition to be treated, the route of administration selected, the compound or compounds actually administered, the age, weight, response of the individual patient, and the severity of the patient's symptoms.

Claims

1. A compound of formula I or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 During the ceremony Each W is a CR 1 or N; Each R 1 H, deuterium, halogen, OR 6 , N(R 6 ) 2 , COOR 6 , or C(O)N(R 6 ) 2 , CN, or C 1 -C 6 alkyl; 1 -C 6 Alkyl is a group that contains one or more deuterium, halogen, OR 6 , N(R 6 ) 2 , COOR 6 , or C(O)N(R 6 ) 2 optionally substituted with; R 2 and R 3 is O-(C 1 -C 4 Alkylene or C 1 -C 4 haloalkylene), C 1 -C 5 Alkylene or C 1 -C 5 Haloalkylene, N(R 6 )-(C 1 -C 4 Alkylene or C 1 -C 4 haloalkylene), -T a -C 1 -C 6 Alkyl-T b -, -T a -N(Rs)-T b , -T a -OT b , -T a -PEG n -OT b , -T a -SST b , -T a -SSST b , -T a -N(R s )-N(Rs)-T b -, -T a -C 2 -C 6 Alkenyl-T b -, -T a -C 2 -C 6 Alkynyl-T b -, -T a -C(=O)-T b -, -T a -C(=CH 2 )-T b -, -T a -C(=O)-C(=O)-T b -, -T a -C(=O)-(C 1 -C 6 Alkyl)-C(=O)-T b -, -T a -C(=O)-(C 3 -C 12 Cycloalkyl)-C(=O)-T b -, -T a -C(=O)-(C 1 -C 6 Alkyl)-(C 3 -C 12 Cycloalkyl)-(C 1 -C 6 Alkyl)-C(=O)-T b -, -T a -C(=O)-(3- to 12-membered heterocycloalkyl)-C(=O)-T b -, -T a -C(=O)-(C 1 -C 6 alkyl)-(3- to 12-membered heterocycloalkyl)-(C 1 -C 6 Alkyl)-C(=O)-T b -, -T a -C(=S)-T b -, -T a -S(=O) 2 -T b -, -T a -S(=O)-T b -, -T a -P(=O)(-ORs)-T b -, -T a -(C 3 -C 12 Cycloalkyl)-T b -, -T a -(C 6 -C 12 Aryl)-T b -, -T a -(3- to 12-membered heterocycloalkyl)-T b -, or -T a -(5- to 12-membered heteroaryl)-T b - independently selected from, where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 6 -C 12 Aryl, 3- to 12-membered heterocycloalkyl, or 5- to 12-membered heteroaryl may be substituted with one or more deuterium, halogen, -ORs, -N(Rs) 2 or -C(=O)ORs; PEG n is (-OCH 2 CH 2 -) n where n=1 to 8; T a and T b are each independently absent, -N(Rs)-, -O-, C 1 -C 6 Alkyl, -N(Rs)-(C 1 -C 6 Alkyl)-, -(C 1 -C 6 alkyl)-N(Rs)-, -N(Rs)-(C 1 -C 6 alkyl)-N(Rs)-, -O-(C 1 -C 6 Alkyl)-, -(C 1 -C 6 alkyl)-O-, or -O-(C 1 -C 6 alkyl)-O-; 1 -C 6 The alkyl is optionally substituted with one or more halogens; and Each Rs is independently H, deuterium, or C optionally substituted with one or more halogens. 1 -C 6 is alkyl; Each R 4 H, deuterium, halogen, CN, OR 6 , N(R 6 ) 2 , COOR 6 , C(O)N(R 6 ) 2 , S.O. 2 R 6 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, OR 6 C replaced with 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Haloalkenyl, OR 6 C replaced with 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 2 -C 6 Haloalkynyl, OR 6 C replaced with 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, as well as O, S, and N(R 6 ) independently selected from the group consisting of 3- to 6-membered heterocycles containing 1 to 2 ring members selected from the group consisting of Each R 6 is -H, deuterium, halogen, -NH 2 , -CN, -OH, -N 3 , -NO 2 , carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 6-10 Aryl, -C 5-10 Heteroaryl, C 3-10 Heterocycle or C 3-10 carbocycles, each of which is independently selected from the group consisting of deuterium, halogen, -NH 2 , -CN, -OH, -NO 2 , carbonyl, =O, oxo, carboxyl, C 1-6 Alkoxy, or C 1-6 optionally substituted with alkyl; and each of the heteroaryl and heterocycle contains at least one heteroatom selected from N, O, or S; each X 1 is C=O, -CH 2 -, -CHF-, and -CF 2 - independently selected from the group consisting of; each X 2 is (C(R 8 ) 2 ) (1-3) , -NR 8 (C(R 8 ) 2 ) (1-3) , -NH(C(R 8 ) 2 ) (1-3) , -N(C 1-6 Alkyl)(C(R 8 ) 2 ) (1-3) or -N(HaloC 1-6 Alkyl)(C(R 8 ) 2 ) (1-3) where each R 8 H, deuterium, halogen, C 1 -C 6 Alkyl, CN, OR 6 , N(R 6 ) 2 , C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, OR 6 C replaced with 1 -C 6 Alkyl, and N(R 6 ) 2 C replaced with 1 -C 6 alkyl; and optionally, two R on different carbon atoms. 8 may form a 3- to 6-membered fused ring together with the atom to which they are attached; and optionally, two R 8 may together with the atoms to which they are attached form a 3- to 6-membered spiro ring; Each X 3 is COOR 6 , C(O)SR 6 , C(S)OR 6 , SO 2 R 6 , C(O)N(R 9 ) 2 , 【Chemistry 2】 and CN; and each R 9 H, deuterium, COOR 6 , S.O. 2 R 6 , (CH 2 ) 1-3 -C(=O)OR 6 , OR 6 , S.R. 6 , N.H. 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 , O(C 1 -C 6 alkyl), O(C 6 -C 10 aryl), O(C 1 -C 6 Alkyl)-OR 6 , S(C 1 -C 6 alkyl), S(C 6 -C 10 Aryl), S(=O) 2 R 6 , S(=O) 2 OR 6 , P(=O)(R 6 ) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl, C 6 -C 10 is independently selected from aryl, 3- to 8-membered heterocycloalkyl, or 3- to 10-membered heteroaryl. 【Request 2】 【Chemistry 3】 but, 【Chemistry 4】 are independently selected from the group consisting of: 【Chemistry 5】 but, 【Chemistry 6】 2. The compound of claim 1, independently selected from the group consisting of:

3. Each R 1 H, deuterium, halogen, OR 6 , N(R 6 ) 2 , C 1 -C 6 alkyl; 1 -C 6 Alkyl is one or more deuterium, halogen, OR 6 , N(R 6 ) 2 , COOR 6 , or C(O)N(R 6 ) 2 and preferably each R 1 H, deuterium, halogens, C 1 -C 3 Alkyl, and C 1 -C 3 haloalkyl; preferably, each R 1 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein is independently selected from the group consisting of H, deuterium, F, Cl, Br, CN and methyl.

4. R 2 and R 3 But -T a -C 1 -C 6 Alkyl-T b -, -T a -N(Rs)-T b , -T a -OT b , -T a -PEG n -OT b , -T a -SST b , -T a -SSST b , -T a -N(R s )-N(Rs)-T b -, -T a -C 2 -C 6 Alkenyl-T b -, -T a -C 2 -C 6 Alkynyl-T b -, -T a -C(=O)-T b -, -T a -C(=CH 2 )-T b -, -T a -C(=O)-C(=O)-T b -, -T a -C(=O)-(C 1 -C 6 Alkyl)-C(=O)-T b -, -T a -C(=O)-(C 3 -C 12 Cycloalkyl)-C(=O)-T b -, -T a -C(=O)-(C 1 -C 6 Alkyl)-(C 3 -C 12 Cycloalkyl)-(C 1 -C 6 Alkyl)-C(=O)-T b -, -T a -C(=O)-(3- to 12-membered heterocycloalkyl)-C(=O)-T b -, -T a -C(=O)-(C 1 -C 6 alkyl)-(3- to 12-membered heterocycloalkyl)-(C 1 -C 6 Alkyl)-C(=O)-T b -, -T a -C(=S)-T b -, -T a -S(=O) 2 -T b -, -T a -S(=O)-T b -, -T a -P(=O)(-ORs)-T b -, -T a -(C 3 -C 12 Cycloalkyl)-T b -, -T a -(C 6 -C 12 Aryl)-T b -, -T a -(3- to 12-membered heterocycloalkyl)-T b -, or -T a -(5- to 12-membered heteroaryl)-T b - independently selected from, where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 6 -C 12 Aryl, 3- to 12-membered heterocycloalkyl, or 5- to 12-membered heteroaryl may be substituted with one or more deuterium, halogen, -ORs, -N(Rs) 2 or -C(=O)ORs; preferably, R 2 and R 3 But -T a -C 1 -C 6 Alkyl-T b -, -T a -N(Rs)-T b , -T a -OT b , -T a -PEG n -OT b , -T a -SST b , -T a -SSST b , -T a -N(R s )-N(Rs)-T b -, -T a -C 2 -C 6 Alkenyl-T b -, -T a -C 2 -C 6 Alkynyl-T b -, -T a -C(=O)-T b -, -T a -C(=CH 2 )-T b -, -T a -C(=O)-C(=O)-T b -, -T a -C(=O)-(C 1 -C 6 Alkyl)-C(=O)-T b -, -T a -C(=O)-(C 3 -C 12 Cycloalkyl)-C(=O)-T b -, -T a -C(=O)-(C 1 -C 6 Alkyl)-(C 3 -C 12 Cycloalkyl)-(C 1 -C 6 Alkyl)-C(=O)-T b -, -T a -C(=O)-(3- to 12-membered heterocycloalkyl)-C(=O)-T b -, -T a -C(=O)-(C 1 -C 6 alkyl)-(3- to 12-membered heterocycloalkyl)-(C 1 -C 6 Alkyl)-C(=O)-T b -, -T a -C(=S)-T b -, -T a -S(=O) 2 -T b -, -T a -S(=O)-T b -, -T a -P(=O)(-ORs)-T b -, -T a -(C 3 -C 12 Cycloalkyl)-T b -, -T a -(C 6 -C 12 Aryl)-T b -, -T a -(3- to 12-membered heterocycloalkyl)-T b -, or -T a -(5- to 12-membered heteroaryl)-T b - independently selected from, where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 6 -C 12 Aryl, 3- to 12-membered heterocycloalkyl, or 5- to 12-membered heteroaryl may be substituted with one or more deuterium, halogen, -ORs, -N(Rs) 2 or -C(=O)ORs; a -(C 3 -C 12 Cycloalkyl)-T b -or-T a -(3- to 12-membered heterocycloalkyl)-T b - In C 3 -C 12 Cycloalkyl or 3- to 12-membered heterocycloalkyl is C 3 -C 12 T via two different atoms of cycloalkyl or 3- to 12-membered heterocycloalkyl a and T b are each bound to PEG n is (-OCH 2 CH 2 -) n where n=1 to 8; T a and T b are each independently absent, -N(Rs)-, -O-, C 1 -C 6 Alkyl, -N(Rs)-(C 1 -C 6 Alkyl)-, -(C 1 -C 6 alkyl)-N(Rs)-, -N(Rs)-(C 1 -C 6 alkyl)-N(Rs)-, -O-(C 1 -C 6 Alkyl)-, -(C 1 -C 6 alkyl)-O-, or -O-(C 1 -C 6 alkyl)-O-; 1 -C 6 The alkyl is optionally substituted with one or more halogens; and Each Rs is independently H, deuterium, or C optionally substituted with one or more halogens. 1 -C 6 alkyl; preferably, R 2 and R 3 But -T a -C 1 -C 6 Alkyl-T b -, -T a -N(Rs)-T b , -T a -OT b , -T a -PEG n -OT b , -T a -SST b , -T a -SSST b , -T a -N(R s )-N(Rs)-T b -, -T a -C 2 -C 6 Alkenyl-T b -, -T a -C 2 -C 6 Alkynyl-T b -, -T a -C(=O)-T b -, -T a -C(=CH 2 )-T b -, -T a -C(=O)-C(=O)-T b -, -T a -C(=S)-T b -, -T a -S(=O) 2 -T b -, -T a -S(=O)-T b -, -T a -P(=O)(-ORs)-T b -, -T a -(C 3 -C 12 Cycloalkyl)-T b -, -T a -(C 6 -C 12 Aryl)-T b -, -T a -(3- to 12-membered heterocycloalkyl)-T b -, or -T a -(5- to 12-membered heteroaryl)-T b - independently selected from, where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 6 -C 12 Aryl, 3- to 12-membered heterocycloalkyl, or 5- to 12-membered heteroaryl may be substituted with one or more deuterium, halogen, -ORs, -N(Rs) 2 or -C(=O)ORs; preferably, R 2 and R 3 But -T a -C 1 -C 6 Alkyl-T b -, -T a -N(Rs)-T b , -T a -OT b , -T a -PEG n -OT b , -T a -SST b , -T a -SSST b , -T a -N(R s )-N(Rs)-T b -, -T a -C 2 -C 6 Alkenyl-T b -, -T a -C 2 -C 6 Alkynyl-T b -, -T a -C(=O)-T b -, -T a -C(=CH 2 )-T b -, -T a -C(=O)-C(=O)-T b -, -T a -C(=S)-T b -, -T a -S(=O) 2 -T b -, -T a -S(=O)-T b -, -T a -P(=O)(-ORs)-T b -, -T a -(C 3 -C 12 Cycloalkyl)-T b -, -T a -(C 6 -C 12 Aryl)-T b -, -T a -(3- to 12-membered heterocycloalkyl)-T b -, or -T a -(5- to 12-membered heteroaryl)-T b - independently selected from, where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 6 -C 12 Aryl, 3- to 12-membered heterocycloalkyl, or 5- to 12-membered heteroaryl may be substituted with one or more deuterium, halogen, -ORs, -N(Rs) 2 or -C(=O)ORs; and 3 -C 12 Cycloalkyl or 3- to 12-membered heterocycloalkyl is C 3 -C 12 T through two different atoms of a cycloalkyl or a 3- to 12-membered heterocycloalkyl a and T b are each bound to PEG n is (-OCH 2 CH 2 -) n where n=1 to 8; T a and T b are each independently absent, -N(Rs)-, -O-, C 1 -C 6 Alkyl, -N(Rs)-(C 1 -C 6 Alkyl)-, -(C 1 -C 6 alkyl)-N(Rs)-, -N(Rs)-(C 1 -C 6 alkyl)-N(Rs)-, -O-(C 1 -C 6 Alkyl)-, -(C 1 -C 6 alkyl)-O-, or -O-(C 1 -C 6 alkyl)-O-; 1 -C 6 alkyl is optionally substituted with one or more halogens; and each Rs is independently H, deuterium, or C optionally substituted with one or more halogens. 1 -C 6 alkyl; preferably, R 2 and R 3 But O-(C 1 -C 4 alkylene or haloalkylene)-C 2 -C 6 Alkenyl, C 1 -C 5 Alkylene or haloalkylene, (C 1 -C 4 alkylene or haloalkylene)-N(R 6 ), and N(R 6 )-(C 1 -C 4 alkylene or haloalkylene)-C 2 -C 6 Alkenyl, -C 0-6 Alkyl-NH-C 0-6 Alkyl-, -C 0-6 Alkyl-N(C 1-6 Alkyl)-C 0-6 Alkyl-, -C 0-6 Alkyl-OC 0-6 Alkyl-, -C 0-6 Alkyl-PEG n -OC 0-6 Alkyl, -C 0-6 Alkyl-SSC 0-6 Alkyl, -C 0-6 Alkyl-SSSC 0-6 Alkyl, -C 0-6 Alkyl-C 2 -C 6 Alkenyl-C 0-6 Alkyl-, -C 0-6 Alkyl-C 2 -C 6 Alkynyl-C 0-6 Alkyl-, -C 0-6 Alkyl-C(=O)-C 0-6 Alkyl-, -C 0-6 Alkyl-C(=CH 2 )-C 0-6 Alkyl-, -C 0-6 Alkyl-C(=O)-C(=O)-C 0-6 Alkyl-, -C 0-6 Alkyl-C(=S)-C 0-6 Alkyl-, -C 0-6 Alkyl-S(=O) 2 -C 0-6 Alkyl-, -C 0-6 Alkyl-S(=O)-C 0-6 Alkyl-, -C 0-6 Alkyl-P(=O)(-OH)-C 0-6 Alkyl-, -C 0-6 Alkyl-C 3 -C 12 Cycloalkyl-C 0-6 Alkyl-, -C 0-6 Alkyl-C 6 -C 12 Aryl-C 0-6 Alkyl-, -C 0-6 Alkyl-(3- to 12-membered heterocyclyl)-C 0-6 Alkyl-, -C 0-6 Alkyl-(5- to 12-membered heteroaryl)-C 0-6 Alkyl-, -C 0-6 Alkyl-O-(5- to 12-membered heteroaryl)-OC 0-6 Alkyl-, -C 0-6 Alkyl-OC(=O)-NH-C 0-6 Alkyl-, -C 0-6 Alkyl-OC(=O)-C 0-6 Alkyl-, -C 0-6 Alkyl-NH-C(=O)-C 0-6 independently selected from alkyl-, -OC(=O)-O-, -NH-C(=O)-NH-, or -NH-C(=S)-NH-; 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 6 -C 12 Aryl, 3- to 12-membered heterocycloalkyl, or 5- to 12-membered heteroaryl may be substituted with one or more deuterium, halogen, -ORs, -N(Rs) 2 or -C(=O)ORs; preferably, R 2 and R 3 But -T a -C 2 -C 6 Alkenyl-T b -, -T a -C(=O)-T b -, -T a -PEG n -OT b , -T a -SST b , -T a -SSST b , -T a -C(=CH 2 )-T b -, or -T a -(C 6 -C 12 Aryl)-T b - independently selected from, where C 2 -C 6 Alkenyl or C 6 -C 12 Aryl is one or more deuterium, halogen, -ORs, -N(Rs) 2 or -C(=O)ORs; PEG n is (-OCH 2 CH 2 -) n where n=1 to 8; T a and T b are each independently -N(Rs)-, -O-, -(C 1 -C 6 alkyl)-O-, or -O-(C 1 -C 6 alkyl)-O-; 1 -C 6 Alkyl is optionally substituted with one or more halogens; each Rs is independently H, deuterium, or C optionally substituted with one or more halogens. 1 -C 6 alkyl; preferably, R 2 -R 3 but, 【Table 1】 【change】 【change】 【change】 【change】 is selected from During the ceremony: Each R 5 are independently -OR 7 , N.R. 7 OR -C(O)OR 7 and Each R 7 are independently hydrogen or C 1-2 is alkyl; and Each R 10 are independently hydrogen, C 1-2 alkyl or halogen; preferably, each R 7 is independently hydrogen, deuterium or methyl; Each R 10 is independently hydrogen, deuterium, methyl or fluorine; or One R 10 is hydrogen, and the other R 10 is methyl or fluorine; preferably, R 2 -R 3 But -(CH 2 ) 2-8 -, -O(CH 2 ) 1-7 -, -O(CH 2 ) 1-6 O-, -OCH 2 CH(CH 3 )CH 2 O-, -OCH(CH 3 )CH 2 CH(CH 3 )O-, 【Chemistry 7】 -NH(CH 2 ) 1-7 -、-(CH 2 ) 1-6 NH(CH 2 ) 1-6 -、-(CH 2 ) 1-6 N(CH 3 )(CH 2 ) 1-6 -、-NH(CH 2 ) 1-6 O-、-NH-CO-NH-、-N(CH 3 )CO-NH- 【Chemistry 8】 【change】 【change】 Preferably, R 2 -R 3 But -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -O(CH 2 ) 2 -, -O(CH 2 ) 3 -, -O(CH 2 ) 4 -, -O(CH 2 ) 2 O-, -O(CH 2 ) 3 O-, -O(CH 2 ) 4 O-, -OCH 2 CH(CH 3 )CH 2 O-, -OCH(CH 3 )CH 2 CH(CH 3 )O-, 【Chemistry 9】 -O(CH 2 ) 4 O-、-O(CH 2 ) 5 O-、-NH(CH 2 ) 2 -、-NH(CH 2 ) 3 -、-NH(CH 2 ) 4 -、-(CH 2 ) 2 NH-、-(CH 2 ) 3 NH-、-(CH 2 ) 4 NH-、-CH 2 NHCH 2 -、-CH 2 N(CH 3 )CH 2 -、-NH(CH 2 ) 3 O-、-NH-CO-NH-、 【Chemistry 10】 or -N(CH 3 4. The compound according to claim 1, wherein the compound is selected from the group consisting of:

5. Each R 4 H, Deuterium, F, Cl, Br, I, CN, OR 6 , N(R 6 ) 2 , COOR 6 , C(O)N(R 6 ) 2 , S.O. 2 R 6 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, OR 6 C replaced with 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Haloalkenyl, OR 6 C replaced with 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 2 -C 6 Haloalkynyl, OR 6 C replaced with 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, as well as O, S, and N(R 6 ) 3- to 6-membered heterocycles containing 1 to 2 ring members selected from the group consisting of; preferably, each R 4 H, deuterium, F, Cl, Br, I, OH, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, OC 1 -C 3 Alkyl, OC 1 -C 3 Haloalkyl, C 2 -C 3 Alkenyl, C 2 -C 3 Alkynyl, and N(R 6 ) 2 Preferably, each R 4 H, deuterium, Br, Cl, OH, CH 3 , C.H. 2 CH 3 , CH=CH 2 , C≡CH, OCH 3 , O.C.F.H. 2 , OCF 2 H, OCF 3 , and N(R 6 ) 2 Preferably, each R 4 H, deuterium, Br, OH, CH 3 , C.H. 2 CH 3 , CH=CH 2 , C≡CH, OCH 3 , N.H. 2 and N.H.H. 3 The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, independently selected from the group consisting of:

6. Each R 6 -H, deuterium, -F, -Cl, -Br, -I, -NH 2 , -CN, -OH, -N 3 , -NO 2 , carboxyl, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C 2 -C 4 Alkenyl, C 2 -C 4 are independently selected from the group consisting of alkynyl, 6-membered aryl, 7-membered aryl, 8-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 5-membered heterocycle, 6-membered heterocycle, 7-membered heterocycle, 8-membered heterocycle, 5-membered carbocycle, 6-membered carbocycle, 7-membered carbocycle, or 8-membered carbocycle, each of which is independently selected from deuterium, -F, -Cl, -Br, -I, -NH 2 , -CN, -OH, -NO 2 , carbonyl, =O, oxo, carboxyl, C 1 -C 3 Alkoxy, or C 1 -C 3 and each of the heteroaryl and heterocycle contains 1 or 2 heteroatoms selected from N, O, or S; preferably, each R 6 -H, deuterium, -F, -Cl, -Br, -I, -NH 2 , -CN, -OH, -N 3 , -NO 2 , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, ethylene, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocycle, 6-membered heterocycle, 5-membered carbocycle, or 6-membered carbocycle, each of which is independently selected from the group consisting of deuterium, -F, -Cl, -Br, -I, -NH 2 , -CN, -OH, -NO 2 , carbonyl, =O, oxo, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy; and each of the heteroaryl and heterocycle contains 1 or 2 heteroatoms selected from N or O or S; preferably, each R 6 -H, deuterium, -F, -Cl, -Br, -I, -NH 2 , -CN, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH 2 F, -CHF 2 , 【Chemistry 11】 and -CF 3 6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, independently selected from the group consisting of:

7. each X 1 C=O, -CH 2 -, -CHF- and -CF 2 -, preferably, each X 1 C=O and -CH 2 -; preferably, each X 1 The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein is C=O.

8. each X 2 But, (C(R 8 ) 2 ) (1-3) where each R 8 H, deuterium, halogens, C 1 -C 6 Alkyl, CN, OR 6 , N(R 6 ) 2 , C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, OR 6 C replaced with 1 -C 6 Alkyl, and N(R 6 ) 2 C replaced with 1 -C 6 alkyl; and optionally, two R on different carbon atoms. 8 may form a fused 3- to 6-membered ring together with the atom to which they are attached; and, optionally, two R 8 may form a 3- to 6-membered spiro ring together with the atom to which they are attached; preferably, each X 2 But, CH 2 CHR 8 where R 8 But H, deuterium, C 1 -C 3 Alkyl, C substituted with OH 1 -C 3 Alkyl, OC 1 -C 3 Alkyl-substituted C 1 -C 3 Alkyl, and C 3 -C 6 cycloalkyl; preferably, each X 2 But, CH 2 CHR 8 where R 8 H, deuterium, CH 3 , C.H. 2 OH, CH 2 CH 3 , C.H. 2 CH 2 CH 3 , CH(CH 3 ) 2 , C.H. 2 OCH 3 and cyclopropyl; preferably, each X 2 But CHR 8 CHR 8 where each R 8 But H, deuterium, C 1 -C 3 Alkyl, C substituted with OH 1 -C 3 Alkyl, OC 1 -C 3 Alkyl-substituted C 1 -C 3 Alkyl, and C 3 -C 6 cycloalkyl, and optionally two R on different carbon atoms. 8 form a 3- to 6-membered fused ring together with the atoms to which they are attached; preferably, each X 2 But CHR 8 CHR 8 where each R 8 But H, deuterium and C 1 -C 3 alkyl, and optionally, two R on different carbon atoms 8 form a 3- to 6-membered fused ring together with the atoms to which they are attached; preferably, each X 2 But, CH 2 C(R 8 ) 2 where each R 8 But H, deuterium, C 1 -C 3 Alkyl, C substituted with OH 1 -C 3 Alkyl, OC 1 -C 3 Alkyl-substituted C 1 -C 3 Alkyl, and C 1 -C 3 cycloalkyl, and optionally two R on a single carbon atom; 8 form a 3- to 6-membered spiro ring together with the atoms to which they are attached; preferably, each X 2 CH 2 C(R 8 ) 2 where each R 8 But H, deuterium and C 1 -C 3 alkyl, and optionally two R on a single carbon atom; 8 8. The compound according to claim 1, wherein, together with the atom to which they are attached, form a 3- to 6-membered spiro ring, or a pharma- ceutically acceptable salt thereof.

9. each X 3 is COOR 6 C(O)SR 6 C(S)OR 6 SO 2 R 6 C(O)N(R 9 ) 2 and 【Chemistry 12】 and CN; preferably, each X 3 But COOR 6 , S.O. 2 R 6 , C(O)N(R 9 ) 2 , 【Chemistry 13】 and CN; preferably, each X 3 But COOR 6 , C(O)N(R 9 ) 2 , 【Chemistry 14】 and CN; preferably, each X 3 But COOH, COOCH 3 ,CONH 2 , 【Chemistry 15】 9. The compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, independently selected from the group consisting of:

10. Each R 9 H, deuterium, COOR 6 , and S.O. 2 R 6 Preferably, each R 9 The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein are independently H or deuterium.

11. A compound or a pharma- ceutically acceptable salt thereof, wherein the compound is a compound of general formula I-1, 【Chemistry 16】 In the formula, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 and X 3 is as defined in any one of claims 1 to 10; or The compound is of general formula II, 【Chemistry 17】 In the formula, W, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 and X 3 is as defined in any one of claims 1 to 10; preferably 【Chemistry 18】 but, 【Chemistry 19】 are independently selected from the group consisting of: 【Chemistry 20】 but, 【Chemistry 21】 are independently selected from the group consisting of: or The compound is of general formula III, 【Chemical 22】 In the formula, W, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 and X 3 is as defined in any one of claims 1 to 10; preferably 【Chemistry 23】 but, 【Chemistry 24】 are independently selected from the group consisting of: 【Chemistry 25】 but, 【Chemistry 26】 are independently selected from the group consisting of: or The compound is of general formula IV 【Chemistry 27】 In the formula, W, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 and X 3 is as defined in any one of claims 1 to 10; preferably 【Chemistry 28】 but, 【Chemical Formula 29】 are independently selected from the group consisting of: 【Chemistry 30】 but, 【Chemistry 31】 are independently selected from the group consisting of: or The compound is of general formula V, 【Chemistry 32】 In the formula, W, R 1 , R 2 , R 3 , X 1 , X 2 and X 3 is as defined in any one of claims 1 to 10; preferably 【Chemical 33】 but, 【Chemical 34】 are independently selected from the group consisting of: 【Chemistry 35】 but, 【Chemical 36】 or a pharma- ceutically acceptable salt thereof, independently selected from the group consisting of:

12. The compound is 【Table 2】 12. The compound according to any one of claims 1 to 11, wherein:

13. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 12 and at least one pharma- ceutically acceptable excipient; preferably, the compound or the pharma- ceutically acceptable salt thereof is contained in a weight ratio in the range of about 0.0001 to about 10 relative to the excipient.

14. 14. The pharmaceutical composition of claim 13, further comprising at least one additional active agent selected from STING agonist compounds, antiviral compounds, antigens, adjuvants, CTLA-4 and PD-1 pathway antagonists and other immunomodulatory agents, lipids, liposomes, peptides, anti-cancer agents, and chemotherapeutic agents.

15. or for use in treatment of a cell proliferation disorder in a subject, wherein the cell proliferation disorder is cancer; or for use as a STING agonist; or for use as a medicament; or at least one compound or a pharma- ceutically acceptable salt thereof as defined in any one of claims 1 to 12, and / or a pharmaceutical composition according to any one of claims 13 to 14, for use in therapy; or for use in inducing an immune response in a subject; or for use in inducing STING-dependent type I interferon production in a subject; or for use in inducing STING-dependent cytokine production in a subject; or for use in the treatment of a cell proliferation disorder in a subject, wherein the cell proliferation disorder is cancer; or for use as a STING agonist; or for use as a medicament;

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