STING agonist compounds

Abstract

The present invention relates to STING agonists, pharmaceutical compositions thereof, and uses of the agonists and pharmaceutical compositions to induce STING-mediated immune responses and / or to treat STING-mediated diseases and conditions (e.g., cell proliferative diseases, including but not limited to cancer).

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims and enjoys the benefit of U.S. Provisional Application No. 63 / 365,919, filed on June 6, 2022, the contents of which are hereby incorporated by reference in their entirety. Field of the Invention

[0002] The present invention relates to STING agonists, pharmaceutical compositions thereof, and uses of the agonists and pharmaceutical compositions to induce STING-mediated immune responses and / or treat diseases and disorders mediated by STING (e.g., cell proliferative diseases, including but not limited to cancer). Background of the Invention

[0003] The innate and adaptive immune systems work closely together to fight foreign substances and invading pathogens. While the adaptive immune system is highly specific and persistent due to the production of memory T cells, the innate immune system quickly takes effect as the body's first line of defense. The innate immune system responds nonspecifically to both pathogen-derived cytoplasmic DNA and host cytoplasmic DNA. In the process, the innate immune system not only provides broad protection against threats such as bacteria and viruses, but also responds to signals of cell damage and tissue damage.

[0004] One protein that is important for innate immunity is stimulator of interferon genes (STING), and the cGAS-STING pathway in particular helps sense and defend against harmful cytoplasmic DNA. cGAS recognizes cytoplasmic DNA and catalyzes the synthesis of cyclic dinucleotides (CDNs), including cGAMP, which in turn binds to and activates STING. Once STING binds to CDNs, STING undergoes a conformational change, translocates from the endoplasmic reticulum to the Golgi apparatus, and triggers the transcription factor TBK1 to phosphorylate the transcription factor interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-κB). This induces the production of type I interferons (IFNs) and proinflammatory cytokines such as IL-6, TNF-α, and IFN-γ.

[0005] Through this mechanism, various DNA viruses have been shown to activate the STING pathway, including herpes simplex virus type I (HSV-1), Kaposi's sarcoma herpes virus (KSHV), cytomegalovirus (CMV), hepatitis B virus (HBV), human papillomavirus (HPV), adenovirus, and baculovirus. Studies have also shown that STING protects against RNA infection. For example, STING knockout mice are more susceptible to RNA virus infection (Ishikawa, H., et al. Nature, 2009, 461, pages 788–792). In addition, intracellular bacteria have been shown to produce CDNs that can activate the STING pathway and induce immune responses. For example, strains of Listeria monocytogenes can trigger STING-induced immune responses.

[0006] Although exogenous factors can activate the STING pathway, many viruses have developed methods to block or inhibit the immune response promoted by STING. For example, many HSV-1 viral genes can inhibit the STING signaling pathway, including HSV-1γ34.5, which disrupts the transport of STING from the endoplasmic reticulum to the Golgi apparatus (Christensen, MH, et al., EMBO, 2016, 35, 568). Similarly, studies have also shown that Kaposi's sarcoma herpes virus (KSHV), human papillomavirus (HPV), cytomegalovirus (CMV), and hepatitis B (HBV) viral genes have developed mechanisms to escape the STING pathway (Ahn, J. et al. Experimental and Molecular Medicine, 2019, 51, 155).

[0007] In addition, some RNA viruses can affect the production of IFN. For example, it has been reported that dengue protease (DENV) (a single-stranded positive-strand RNA virus) can inhibit the production of type I INF by targeting and cleaving STING. In primary cells lacking STING, DENV replication is highly increased (Yu, C. et al. PLoS Pathog. 2012, 8, e1002780; Aguirre, S., et al. PLoS Pathog. 2012, 8, e1002934). Similarly, the protease of Zika virus (ZIKV) (another single-stranded positive-strand RNA virus belonging to the Flaviviridae family) can also cleave STING and reduce the production of type I IFN through downstream effects (Ding, et al. Proc. Natl. Acad. Sci. USA 2018, 115, E6310; Zheng et al. EMBO, 2018, 37: e99347).

[0008] In addition to playing a role in generating immune responses to invasion by foreign pathogens, the STING pathway also recognizes host cytoplasmic DNA. Since the cytoplasm does not usually contain DNA, cytoplasmic DNA leakage is usually an indication of DNA damage events and can indicate tumorigenesis. Detection of host cytoplasmic DNA by STING leads to the production of IFN, immunostimulatory genes, and proinflammatory cytokines. It has been determined that IFN can inhibit tumor cell proliferation through a variety of mechanisms. As described in Jiang, M. et al. Journal of Hematology & Oncology, 2020, 81, 13, STING defects are associated with cancer incidence in at least melanoma cell lines, colorectal adenocarcinoma human cell lines, and lung cancer.

[0009] Many STING agonists have been developed and studied for oncology indications (Le Naour et al. Oncoimmunology, 2020; 9(1): 1777624), including DMXAA (or Vadimezan), a tumor vascular disruptor that has been studied in clinical trials for advanced solid tumors, prostate cancer, urothelial carcinoma, and small cell lung cancer. Despite promising preclinical results, DMXAA has so far achieved only poor results in human clinical trials. MIW815 (ADU-S100) in combination with pembrolizumab was recently studied in a Phase 2 trial in patients with head and neck cancer but was terminated due to lack of significant antitumor activity (NCT03937141). A Phase I trial investigating the efficacy of MIW815 alone and in combination with ipilimumab in patients with advanced / metastatic solid tumors or lymphomas (NCT02675439) was also terminated due to lack of significant antitumor activity.

[0010] Other STING agonists used for various cancer treatments include BMS-986301, E7766, GSK3745417, MK-1454, MK-2118, BI 1387446, and SB11285. Dimeric STING agonists have been described in PCT application WO 2021 / 113679 assigned to Mersana Therapeutics and in U.S. Patent No. US10,793,557 assigned to Merck Sharp and Dohme. Other STING agonists are also described in U.S. Application No. US2021 / 0009608 assigned to Merck.

[0011] Given the importance of the STING pathway in inducing immune responses to foreign pathogens and immune responses to damaged DNA associated with cell proliferative diseases, there is a medical need to develop STING agonists. Therefore, the present invention aims to provide novel compounds and compositions that can induce STING-mediated immune responses and / or provide treatments for diseases and conditions mediated by STING (e.g., cell proliferative diseases). Summary of the Invention

[0012] In one aspect, the STING agonist is a compound represented by Formula I, Formula II, or Formula III: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; in: L 1 Selected from C1-C6 alkylene, Where L 1 Any substitutable carbon atom in the 1-6 Alkyl, C 1-6 Alkylamino, C 3-10 Cycloalkyl, hydroxyl, cyano, -NR 9a R 9b , and -COOR 10 Substituents are substituted; A is selected from R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from H, halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, halo-C 1-6 Alkyl, Hydroxyl-C 1-6 Alkyl, hydroxyl, -NR 9a R 9b , amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, and -COOR 10 ; X 1 and X4 Each independently selected from -C(O)-, -C(R 12a R 12b )-, -CH=CH-, and -C(R 12a R 12b )C(R 13a R 13b )-; X 2 and X 5 Each independently selected from -(C(R 12a R 12b )) 1-6 -, and -(C(R 12a R 12b )C(R 13a R 13b )) 1-3 -; X 3 Selected from -COOR 10 , -CONR 9a R 9b , -C(O)NR 9a S(O)2R 14 , -S(O)2OR 10 , -S(O)OR 10 , -P(O)(OR 15 )2, -OP(O)(OR 15 )2, and -P(O)(NR 16a R 16b )(OR 15 ); X 6 Selected from -C(O)NR 9a S(O)2R 17 , -C(O)NR 9a R 18 , -S(O)2OH, -S(O)OH, -P(O)(OR 15 )2, -OP(O)(OR 15 )2, and -P(O)(NR 16a R 16b )(OR 15 ); X 7 is -CH=CH-, a C2 alkynyl group, or -C(R 12a R 12c )C(R 13a R 13c )-; X 8 Selected from -COOR 10 , -CONR 9a R 9b , -C(O)NR9a S(O)2R 14 、-S(O)2OR 10 、-S(O)OR 10 、-P(O)(OR 15 )2.-OP(O)(OR 15 )2、and-P(O)(NR 16a R 16b )(OR 15 ); X 9 , X 10 and X 11 Each independently selected from CR 19 and N; Y 1 independently selected from CH2, O, NH, and S; Y 2 independently selected from O, NH, and S; R 9a and R 9b are independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, aryl, aryl-C 1-6 Alkyl, amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 alkyl, and heteroaryl; R 10 Independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, aryl, aryl-C 1-6 alkyl, and heteroaryl; R 11 Independently selected from H and C 1-6 alkyl; R 12a , R 12b , R 13a and R 13b are independently selected from H and C 1-6 alkyl; or R 12b With R 13b Connected together to form C3-C 10 Cycloalkyl, the C3-C 10 Cycloalkyl is optionally selected from halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, hydroxyl, cyano, -NR 9a R 9b and-COOR 10 Substituents are substituted; R 12c With R 13c Connected together to form C3-C 10 Cycloalkyl, the C3-C 10 Cycloalkyl is optionally selected from halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, hydroxyl, cyano, -NR 9a R 9b and-COOR 10 Substituents are substituted; R 14 Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, halo-C 1-6 Alkyl, amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, Aryl, Aryl-C 1-6 alkyl, and heteroaryl; R 15 , R 16a and R 16b are independently selected from H, C 1-6 Alkyl, and C 3-10 Cycloalkyl; R 17 It is amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, C 3-10 Cycloalkylamino-C 1-6 Alkyl, Aryl, Aryl-C 1-6 Alkyl or heteroaryl; R 18 It is amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, C 3-10 Cycloalkylamino-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, aryl, aryl-C 1-6 alkyl, or heteroaryl; and R 19 are independently selected from H, halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, halo-C1-6 Alkyl, Hydroxyl-C 1-6 Alkyl, hydroxyl, -NR 9a R 9b , and -COOR 10 ;and a and b are each an integer independently selected from 0, 1, 2, 3, 4 and 5.

[0013] In one embodiment, the STING agonist is a compound represented by Formula Ia: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; Where L 1 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9a , R 9b , R 10 , R 11 , R 12a , R 12b , R 13a , R 13b , R 14 , R 15 , R 16a , R 16b , a and b are as defined in the present invention.

[0014] In one embodiment, the STING agonist is a compound represented by Formula Ib: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; Where L 1 , X 1 , X 2 , X 3 , X 5 , X 7 , X 8 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6, R 7 , R 8 , R 9a , R 9b , R 10 , R 11 , R 12a , R 12b , R 12c , R 13a , R 13b , R 13c , R 14 , R 15 , R 16a , R 16b , a and b are as defined in the present invention.

[0015] In one embodiment, the STING agonist is a compound represented by Formula Ic: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; Where L 1 , X 1 , X 2 , X 3 , X 4 , X 5 , X 8 , X 9 , X 10 , X 11 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9a , R 9b , R 10 , R 11 , R 12a , R 12b , R 13a , R 13b , R 14 , R 15 , R 16 , R 16b , R 19 , a and b are as defined in the present invention.

[0016] In one embodiment, the STING agonist is a compound represented by Formula Id: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; Where L1 , X 1 , X 2 , X 3 , X 4 , X 5 , X 8 , Y 1 , Y 2 , R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9a , R 9b , R 10 , R 11 , R 12a , R 12b , R 13a , R 13b , R 14 , R 15 , R 16 , R 16b , R 19 , a and b are as defined in the present invention.

[0017] In one embodiment, the STING agonist is a compound represented by Formula IIa: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; Where L 1 , X 1 , X 2 , X 3 , X 4 , X 5 , X 8 , X 9 , X 10 , X 11 , R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9a , R 9b , R 10 , R 11 , R 12a , R 12b , R 13a , R 13b , R 14 , R 15 , R 16 , R16b , R 19 , a and b are as defined in the present invention.

[0018] In one embodiment, the STING agonist is a compound represented by Formula IIb: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; Where L 1 , X 1 , X 2 , X 3 , X 4 , X 5 , X 8 , Y 1 , Y 2 , R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9a , R 9b , R 10 , R 11 , R 12a , R 12b , R 13a , R 13b , R 14 , R 15 , R 16 , R 16b , a and b are as defined in the present invention.

[0019] In one embodiment, the STING agonist is a compound represented by formula IIIa: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; Where L 1 , X 1 , X 2 , X 3 , X 4 , X 5 , X 8 , Y 1 , Y 2 , R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9a , R9b , R 10 , R 11 , R 12a , R 12b , R 13a , R 13b , R 14 , R 15 , R 16 , R 16b , a and b are as defined in the present invention.

[0020] The present invention provides at least the following embodiments: a) a compound of Formula I, Formula II, Formula III, Formula Ia, Formula Ib, Formula Ic, Formula Id, Formula IIa, Formula IIb, or Formula IIIa, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; b) a compound selected from Compound 1 to Compound 31 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; c) a compound selected from Compound 32 to Compound 62, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; d) a pharmaceutical composition comprising a compound represented by Formula I, Formula II, Formula III, Formula Ia, Formula Ib, Formula Ic, Formula Id, Formula IIa, Formula IIb, or Formula IIIa, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient, diluent, or carrier; e) a pharmaceutical composition comprising the compound described in (b) or (c) and a pharmaceutically acceptable excipient, diluent or carrier; f) a method for treating a disease or condition mediated by STING in a subject in need thereof, comprising administering a therapeutically effective amount of the compound of (a)-(c) or the pharmaceutical composition of (d)-(e); g) The method as described in (f), wherein the disease or condition is a cell proliferative disorder, including but not limited to cancer; h) The method of (g), wherein the cancer is selected from acute myeloid leukemia; breast cancer; colorectal cancer; glioma; head and neck squamous cell carcinoma; lung cancer, including non-small cell lung cancer; head and neck cancer; lymphoma, including malignant lymphoma; melanoma; nasopharyngeal carcinoma; ovarian cancer; pancreatic cancer; prostate cancer; urothelial carcinoma; and tongue squamous cell carcinoma; i) a method of inducing an immune response in a subject in need thereof, comprising administering a therapeutically effective amount of the compound described in (a)-(c) or the pharmaceutical composition described in (d)-(e); j) a method for inducing STING-dependent type I interferon production in a subject in need thereof, comprising administering a therapeutically effective amount of the compound described in (a)-(c) or the pharmaceutical composition described in (d)-(e); k) a method for inducing STING-dependent cytokine production in a subject in need thereof, comprising administering a therapeutically effective amount of the compound described in (a)-(c) or the pharmaceutical composition described in (d)-(e); l) The method of any one of embodiments (f)-(k), wherein the compound described in (a)-(c) or the pharmaceutical composition described in (d)-(e) is administered in combination with an immunomodulator (including but not limited to a checkpoint inhibitor, such as a PD-1 inhibitor or a CTLA-4 inhibitor); m) using a therapeutically effective amount of the compound described in (a)-(c) or the pharmaceutical composition described in (d)-(e) to treat a disease or condition mediated by STING in a subject in need thereof; n) Use of a therapeutically effective amount of the compound described in (a)-(c) or the pharmaceutical composition described in (d)-(e) to induce an immune response in a subject in need thereof; o) Use of a therapeutically effective amount of the compound described in (a)-(c) or the pharmaceutical composition described in (d)-(e) to induce STING-dependent type I interferon production in a subject in need thereof; p) Use of a therapeutically effective amount of the compound described in (a)-(c) or the pharmaceutical composition described in (d)-(e) to induce STING-dependent cytokine production in a subject in need thereof; q) use of a therapeutically effective amount of the compound described in (a)-(c) or the pharmaceutical composition described in (d)-(e) in the preparation of a medicament for treating a disease or condition mediated by STING in a subject in need thereof; r) use of a therapeutically effective amount of the compound described in (a)-(c) or the pharmaceutical composition described in (d)-(e) in the preparation of a medicament for inducing an immune response in a subject in need thereof; s) Use of a therapeutically effective amount of the compound described in (a)-(c) or the pharmaceutical composition described in (d)-(e) for preparing a medicament for inducing STING-dependent type I interferon production in a subject in need thereof; t) use of a therapeutically effective amount of the compound described in (a)-(c) or the pharmaceutical composition described in (d)-(e) in the preparation of a medicament for inducing STING-dependent cytokine production in a subject in need thereof; and u) A kit comprising a therapeutically effective amount of the compound described in (a)-(c) or the pharmaceutical composition described in (d)-(e) and instructions for use of the compound. DETAILED DESCRIPTION OF THE INVENTION definition

[0021] When referring to the compounds provided by the present invention, unless otherwise stated, the following terms have the following meanings. Unless otherwise defined, all technical terms and scientific terms used in the present invention have the same meanings as those of ordinary skill in the art are generally understood. If a term of the present invention has multiple definitions, unless otherwise stated, the definitions in this section shall prevail.

[0022] The term "alkyl" used in the present invention, unless otherwise indicated, refers to a saturated straight or branched hydrocarbon. In certain embodiments, the alkyl group is a primary, secondary or tertiary hydrocarbon. In certain embodiments, the alkyl group includes a saturated straight or branched hydrocarbon with 1-6 carbon atoms, i.e., a C1-C6 alkyl or a lower alkyl. The term includes substituted and unsubstituted group parts. In some or any embodiments, the alkyl group is unsubstituted. In some or any embodiments, the alkyl group is substituted. In certain embodiments, the alkyl group is a fluorinated alkyl group. Non-limiting examples of moieties that can be used to replace the alkyl group are selected from the group consisting of halogen (fluorine, chlorine, bromine or iodine), hydroxy, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate, wherein each moiety is independently unprotected or protected as known to those skilled in the art, such as Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, which is incorporated herein by reference. In certain embodiments, the alkyl group is selected from the group consisting of methyl, CF3, CCl3, CFCl2, CF2Cl, ethyl, CH2CF3, CF2CF3, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl.

[0023] As used herein, the term "alkylene", unless otherwise indicated, refers to a divalent alkyl group, wherein alkyl is as defined herein. In some or any embodiments, the alkylene is unsubstituted.

[0024] The term "aryl" refers to an aromatic group containing only carbon atoms in the aromatic ring. In one embodiment, the aryl group contains 1 to 3 independent or fused rings and has 6 to about 14 or 18 ring atoms, without heteroatoms as ring members. When indicated, such aryl groups may be further substituted by carbon or non-carbon atoms or groups. Such substitutions may include fused to saturated or partially unsaturated cyclic groups consisting of 4 to 7 or 5 to 7 atoms, the cyclic groups optionally containing 1, 2 or 3 heteroatoms independently selected from N, O, B, P, Si and / or S to form, for example, 3,4-methylenedioxyphenyl groups. Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one embodiment, the aryl group is pendant. An example of a pendant ring is a phenyl group substituted by a phenyl group. In one embodiment, the aryl group may be optionally substituted as described above.

[0025] The terms "alkoxy" and "alkoxy group" refer to the group -OR", where R" is an alkyl or cycloalkyl group. For example, alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

[0026] The term "amino" refers to the group -NH2.

[0027] The term "aminoalkyl" refers to an alkyl group as defined herein, substituted with one or more amino groups. In some or any embodiments, an aminoalkyl group is an alkyl group substituted with one -NH2 group (e.g., R'(NH2), wherein R' is an alkyl group, as defined herein). In some or any embodiments, an aminoalkyl group is an alkyl group substituted with two -NH2 groups. In certain embodiments, an "aminoalkyl" group is an amino-C 1-6 alkyl.

[0028] The term "alkylamino" refers to the group -NHR', wherein R' is an alkyl group as defined herein. In some or any embodiments, the alkylamino group is C 1-6 Alkylamino.

[0029] The term "dialkylamino" refers to the group -NR'R', wherein R' is an alkyl group as defined herein. In some or any embodiments, the dialkylamino group is a di-C 1-6 Alkylamino.

[0030] The term "alkylaminoalkyl" refers to an alkyl group as defined herein substituted with one or more alkylamino groups as defined herein. In some embodiments, "alkylaminoalkyl" is C 1-6 Alkylamino-C 1-6 In some embodiments, each alkyl group in the alkylaminoalkyl group is independently selected.

[0031] The term "dialkylaminoalkyl" refers to an alkyl group as defined herein substituted with one or more dialkylamino groups as defined herein. In some embodiments, "dialkylaminoalkyl" is a di-C 1-6 Alkylamino-C 1-6 In some embodiments, each alkyl group in the dialkylaminoalkyl group is independently selected.

[0032] The term "aralkyl" refers to an alkyl group as defined herein substituted with an aryl group as defined herein. In one embodiment, "aralkyl" is benzyl.

[0033] The term "haloalkyl" refers to an alkyl group as defined herein that is substituted with one or more halogen groups. Halogenated alkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, and -CH2F3.

[0034] The term "hydroxyalkyl" refers to an alkyl group, as defined herein, substituted with one or more hydroxy groups.

[0035] As used herein, the terms "halogen" and "halo", unless otherwise indicated, are synonymous and refer to chlorine, bromine, fluorine or iodine.

[0036] The term "hydroxy" refers to an -OH group.

[0037] The term "cyano" refers to a -CN group.

[0038] The term "cycloalkyl" as used herein, unless otherwise specified, refers to a saturated cyclic hydrocarbon. In certain embodiments, the cycloalkyl group may be a saturated, and / or bridged, and / or non-bridged, and / or fused bicyclic group. In certain embodiments, the cycloalkyl group contains 3-10 carbon atoms, i.e., C3-C 10 In some embodiments, the cycloalkyl group has 3-10 (C 3-10 ) or 3-6(C 3-6 ) carbon atoms. In certain embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl or adamantyl. In some or any embodiments, the cycloalkyl is substituted with 1, 2 or 3 groups independently selected from halogen (fluorine, chlorine, bromine or iodine), alkyl, haloalkyl, hydroxyl, amino, alkylamino and alkoxy.

[0039] The term "heteroaryl" refers to a monovalent monocyclic aromatic group and / or a polycyclic aromatic group, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S and N in the ring. Each ring of the heteroaryl may contain 1 or 2 O atoms, 1 or 2 S atoms and / or 1-4 N atoms, provided that the total number of heteroatoms in each ring is 4 or less, and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has 5-20, 5-15 or 5-10 ring atoms. The heteroaryl may be connected to the rest of the molecule by a nitrogen or carbon atom. In some embodiments, the monocyclic heteroaryl group includes but is not limited to furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl and triazolyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridinyl, quinolyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, and thienopyridinyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthroline, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl and xanthenyl. In certain embodiments, heteroaryl may also be optionally substituted as described herein. "Substituted heteroaryl" is a heteroaryl substituted as defined for aryl.

[0040] The term "protecting group" used in the present invention, unless otherwise specified, refers to a group added to an oxygen, nitrogen or phosphorus atom to prevent further reaction or for other purposes. Various oxygen protecting groups and nitrogen protecting groups are known to those skilled in the art of organic synthesis.

[0041] "Pharmaceutically acceptable salt" refers to any salt of a compound provided herein that retains the biological properties of the compound and is non-toxic or otherwise undesirable for pharmaceutical use. Such salts may be derived from various organic and inorganic counterions known in the art. Such salts include, but are not limited to: (1) with organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, caproic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid , cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, benzoic acid, glutamic acid or (2) when an acidic proton is present in the parent compound, (a) it is replaced by a metal ion such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, or an alkali metal or alkaline earth metal hydroxide such as sodium, potassium, calcium, magnesium, aluminum, lithium, zinc and barium, or ammonia, or (b) it is coordinated with an organic base such as an aliphatic, alicyclic or aromatic organic amine such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, etc. to form a base addition salt.

[0042] By way of example only and not limitation, pharmaceutically acceptable salts further include sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, tetraalkylammonium salts, and the like; when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, such as hydrohalides such as hydrochlorides and hydrobromides, sulfates, phosphates, sulfamates, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoic acid Salt, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethanedisulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (benzenesulfonate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylaminosulfonate, quinate, muconate, etc.

[0043] With respect to compositions, the term "substantially free of" or "substantially absent of" means that the composition comprises at least 85% by weight or 90% by weight, in certain embodiments, 95%, 98%, 99% by weight or 100% by weight of the compound. In certain embodiments, in the methods and compounds provided by the invention, the compound is substantially free of enantiomers.

[0044] Likewise, with respect to a composition, the term "isolated" means that the composition comprises at least 85%, 90%, 95%, 98%, 99% to 100% by weight of the compound, with the remainder comprising other chemical species or enantiomers.

[0045] "Solvate" means that the compound or salt thereof provided by the present invention further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0046] "Isotopic composition" refers to the amount of each isotope present for a given atom, and "natural isotopic composition" refers to the naturally occurring isotopic composition or abundance of a given atom. Atoms having their natural isotopic composition may also be referred to as "non-enriched" atoms in the present invention. Unless otherwise indicated, atoms of the compounds described herein are intended to represent any stable isotopes of the atom. For example, unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen", the position is understood to be hydrogen having its natural isotopic composition.

[0047] "Isotopic enrichment" refers to the percentage of incorporation of an amount of a specific isotope at a given atom in a molecule in place of the natural isotopic abundance of the atom. For example, a 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Since the natural distribution of deuterium is about 0.0156%, the deuterium enrichment at any position in a compound synthesized using a non-enriched starting material is about 0.0156%. The isotopic enrichment of the compounds provided by the present invention can be determined using conventional analytical methods known to those of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0048] "Isotopically enriched" refers to atoms having an isotopic composition other than the natural isotopic composition of said atoms. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of said atoms.

[0049] As used herein, “alkyl,” “alkylene,” “aryl,” “alkoxy,” “aminoalkyl,” “alkylamino,” “dialkylamino,” “alkylaminoalkyl,” “dialkylaminoalkyl,” “aralkyl,” “haloalkyl,” “cycloalkyl,” and “heteroaryl” groups optionally contain deuterium at one or more positions where hydrogen atoms are present, and wherein the deuterium composition of said one or more atoms is other than the natural isotopic composition.

[0050] Likewise, the "alkyl", "alkylene", "aryl", "alkoxy", "aminoalkyl", "alkylamino", "dialkylamino", "alkylaminoalkyl", "dialkylaminoalkyl", "aralkyl", "haloalkyl", "cycloalkyl" and "heteroaryl" groups used herein optionally contain C-13 in amounts other than the natural isotopic composition recited.

[0051] The term "optionally substituted", unless otherwise indicated, refers to a group that is unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) substituents listed for the group, wherein the substituents may be identical or different. In certain embodiments, the optionally substituted group is unsubstituted. In certain embodiments, the optionally substituted group has one substituent. In certain embodiments, the optionally substituted group has two substituents. In certain embodiments, the optionally substituted group has three substituents. In certain embodiments, the optionally substituted group has four substituents. In certain embodiments, the optionally substituted group has 1 to 2, 1 to 3, 1 to 4 or 1 to 5 substituents. When there are multiple substituents, unless otherwise indicated, each substituent is independently selected. For example, each (C1-C4 alkyl) substituent on the group-N (C1-C4 alkyl) (C1-C4 alkyl) can be selected independently of another substituent, thereby generating groups such as-N (CH3) (CH2CH3).

[0052] The term "substituted", whether or not prefixed with the term "optionally", as used herein, generally refers to the replacement of hydrogen atoms in a given structure with a group of a specific substituent. Specific substituents are described in the above definitions and in the description of compounds and embodiments thereof below. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specific group, the substituent may be the same or different at each position.

[0053] One of ordinary skill in the art will recognize that combinations of substituents envisioned in this specification are those combinations that result in the formation of stable or chemically feasible compounds.

[0054] The phrase "stable or chemically feasible" as used herein refers to a compound that does not undergo substantial changes when subjected to conditions that allow its production, detection, and recovery, purification, and use for one or more purposes disclosed herein. In some embodiments, a stable compound or a chemically feasible compound refers to a compound that does not undergo substantial changes when stored at a temperature of 40° C. or less, in the absence of moisture or other chemically reactive conditions, for at least one week.

[0055] Unless specific isotopes of elements are indicated in the general formula, the present invention includes all isotopologues of the compounds disclosed herein, for example, deuterated derivatives (wherein H may be 2H, i.e., D) of the compounds. Isotopologues may have isotopic substitutions at any or all positions in the structure, or may have atoms present in natural abundance at any or all positions in the structure.

[0056] The present invention also includes any or all stereochemical forms, including any enantiomeric or diastereomeric forms of the compounds described in the present invention, as well as cis / trans or E / Z isomers. Unless stereochemistry is clearly indicated in a chemical structure or name, the structure or name is intended to cover all possible stereoisomers of the compound. In addition, when describing a specific stereochemical form, it should be understood that all other stereochemical forms are also described and included in the present invention, as well as the general non-stereospecific forms of the disclosed compounds and mixtures in any proportion, including mixtures of two or more stereochemical forms disclosed in any proportion, thereby including racemates, non-racemates, enantiomeric enrichments and ratio isomeric mixtures of compounds. Compounds with alkenyl functional groups can exist as E isomers, Z isomers, or mixtures of E isomers and Z isomers.

[0057] The present invention also relates to compositions comprising the disclosed compounds, such as compositions of substantially pure compounds (including specific stereochemical forms thereof). The present invention also encompasses compositions comprising mixtures of the disclosed compounds in any proportion, including compositions comprising mixtures of two or more stereochemical forms of the disclosed compounds in any proportion, such that the present invention encompasses racemates, non-racemates, enantiomerically enriched and ratio isomeric mixtures of the compounds. If the stereochemistry of one or more parts of a molecule is explicitly indicated, but the stereochemistry of another part or parts of the molecule is not explicitly indicated, the structure is intended to encompass all possible stereoisomers of the part or parts for which the stereochemistry is not explicitly indicated.

[0058] The present invention also encompasses any and all tautomeric forms of the compounds described herein.

[0059] The "EC 50 ” refers to the dose, concentration or amount of a specific test compound that elicits a dose-dependent response at 50% of the maximal expression of a specific response induced, elicited or potentiated by the specific test compound.

[0060] The term "IC 50 ” refers to the amount, concentration or dose of a particular test compound that achieves a 50% inhibition of the maximal response in an assay measuring such response.

[0061] The terms "subject" and "patient" used in the present invention are used interchangeably in the present invention. The term "subject" refers to an animal, such as a mammal including non-primates (e.g., cattle, pigs, horses, cats, dogs, rats and mice) and primates (e.g., monkeys such as cynomolgus monkeys, chimpanzees and humans), and in certain embodiments is a human. In another embodiment, the subject is a farm animal (e.g., horse, cattle, pig, etc.) or a pet (e.g., dog or cat). In certain embodiments, the subject is a human.

[0062] The terms "therapeutic agent" and "therapeutic drug / agent" as used herein refer to any drug / agent that can be used to treat or prevent a disease / disorder or one or more symptoms thereof. In certain embodiments, the term "therapeutic agent" includes compounds provided herein. In certain embodiments, a therapeutic agent is a drug / agent that is known to be useful or has been used or is currently being used to treat or prevent a disease / disorder or one or more symptoms thereof.

[0063] The term "therapeutically effective amount" or "effective amount" as used herein refers to an amount of a compound or composition that is effective in treating a disease or condition when administered to a subject. In some embodiments, a therapeutically effective amount or effective amount refers to an amount of a compound or composition that is effective in preventing or ameliorating a disease or disease progression or causing amelioration of symptoms when administered to a subject. The "therapeutically effective amount" may vary depending on, inter alia, the compound, the condition and its severity, and the age, weight, etc., of the subject to be treated.

[0064] In certain embodiments, "treating" or "managing" any disease or condition refers to improving the disease or condition present in a subject. In another embodiment, "treating" or "managing" includes improving at least one physical parameter, which may not be perceived by the subject. In yet another embodiment, "treating" or "managing" includes regulating the disease or condition, whether physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physiological parameters) or both. In another embodiment, "treating" or "managing" includes postponing or preventing the onset of the disease or condition, or postponing or preventing the recurrence of the disease or condition. In yet another embodiment, "treating" or "managing" includes reducing or eliminating the disease or condition, or delaying the progression of the disease or condition or one or more symptoms of the disease or condition, or reducing the severity of the disease or condition or one or more symptoms of the disease or condition.

[0065] Throughout the specification, the term "cancer" refers to the pathological process that allows cancerous or malignant tumors to form and grow, that is, abnormal tissues (solid) or cells (non-solid) that grow by cell proliferation, usually faster than normal, and continue to grow after the stimulus that triggered the new growth has ceased. Malignant tumors exhibit partial or complete lack of structural organization and functional coordination with normal tissues, most of which invade surrounding tissues, can metastasize to multiple sites, may recur after attempted resection, and may cause death of the patient unless adequately treated. The term neoplasia used in the present invention is used to describe all cancerous disease states and includes or encompasses pathological processes associated with malignant hematogenous, ascites and solid tumors.

[0066] The terms "immune response" or "immune reaction" as used in the present invention relate to any one or more of the following: specific immune response, nonspecific immune response, specific and nonspecific response, innate response, primary immune response, adaptive immunity, secondary immune response, memory immune response, immune cell activation, immune cell proliferation, immune cell differentiation, and cytokine expression.

[0067] As used herein, the term "inhibit growth" (e.g., in reference to cells, such as tumor cells) is intended to include any measurable reduction in cell growth (e.g., tumor cell growth) when contacted with a compound of the invention as compared to the growth of the same cell not contacted with a compound of the invention. In some embodiments, growth may be inhibited by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%, or 100%. Reduction in cell growth may occur by a variety of mechanisms, including, but not limited to, apoptosis, necrosis, and / or effector function-mediated activity. STING agonists

[0068] In one aspect, the STING agonist is a compound represented by Formula I, Formula II, or Formula III: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; in: L 1 Selected from C1-C6 alkylene, Where L 1 Any substitutable carbon atom in the 1-6 Alkyl, C 1-6 Alkylamino, C 3-10 Cycloalkyl, hydroxyl, cyano, -NR 9a R 9b , and -COOR 10 Substituents are substituted; A is selected from R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from H, halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, halo-C 1-6 Alkyl, Hydroxyl-C1-6 alkyl, hydroxy, -NR 9a R 9b , amino-C 1-6 alkyl, C 1-6 alkylamino-C 1-6 alkyl, diC 1-6 alkylamino-C 1-6 alkyl, and -COOR 10 ; X 1 and X 4 are each independently selected from -C(O)-, -C(R 12a R 12b ))-, -CH=CH-, and -C(R 12a R 12b ))C(R 13a R 13b )); X 2 and X 5 are each independently selected from -(C(R 12a R 12b )) 1-6 -, and -(C(R 12a R 12b ))C(R 13a R 13b )) 1-3 -; X 3 is selected from -COOR 10 , -CONR 9a R 9b , -C(O)NR 9a S(O)2R 14 , -S(O)2OR 10 , -S(O)OR 10 , -P(O)(OR 15 )2, -OP(O)(OR 15 )2, and -P(O)(NR 16a R 16b )(OR 15 ); X 6 is selected from -C(O)NR 9a S(O)2R 17 , -C(O)NR 9a R 18 , -S(O)2OH, -S(O)OH, -P(O)(OR 15 )2, -OP(O)(OR 15 )2, and -P(O)(NR 16a R 16b )(OR 15 ); X 7 is -CH=CH-, C2 alkynyl, or -C(R 12a R 12c )C(R 13a R 13c )-; X 8 Selected from -COOR 10 、-CONR 9a R 9b 、-C(O)NR 9a S(O)2R 14 、-S(O)2OR 10 、-S(O)OR 10 、-P(O)(OR 15 )2.-OP(O)(OR 15 )2、and-P(O)(NR 16a R 16b )(OR 15 ); X 9 , X 10 and X 11 Each independently selected from CR 19 and N; Y 1 independently selected from CH2, O, NH, and S; Y 2 independently selected from O, NH, and S; R 9a and R 9b are independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, aryl, aryl-C 1-6 Alkyl, amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 alkyl, and heteroaryl; R 10 Independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, aryl, aryl-C 1-6 alkyl, and heteroaryl; R 11 Independently selected from H and C 1-6 alkyl; R 12a , R 12b , R 13a and R 13b are independently selected from H and C 1-6 alkyl; or R 12b With R 13b Connected together to form C3-C 10 Cycloalkyl, the C3-C 10 Cycloalkyl is optionally selected from halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, hydroxyl, cyano, -NR 9a R 9b and-COOR 10 Substituents are substituted; R 12c With R 13c Connected together to form C3-C 10 Cycloalkyl, the C3-C 10 Cycloalkyl is optionally selected from halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, hydroxyl, cyano, -NR 9a R 9b and-COOR 10 Substituents are substituted; R 14 Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, halo-C 1-6 Alkyl, amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, Aryl, Aryl-C 1-6 alkyl, and heteroaryl; R 15 , R 16a and R 16b are independently selected from H, C 1-6 Alkyl, and C 3-10 Cycloalkyl; R 17 It is amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, C 3-10 Cycloalkylamino-C 1-6 Alkyl, Aryl, Aryl-C 1-6 Alkyl or heteroaryl; R 18 It is amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6Alkylamino-C 1-6 Alkyl, C 3-10 Cycloalkylamino-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, aryl, aryl-C 1-6 alkyl, or heteroaryl; and R 19 are independently selected from H, halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, halo-C 1-6 Alkyl, Hydroxyl-C 1-6 Alkyl, hydroxyl, -NR 9a R 9b , and -COOR 10 ;and a and b are each an integer independently selected from 0, 1, 2, 3, 4 and 5.

[0069] In certain embodiments, the compound of formula I is selected from the following structural formulas:

[0070] In certain embodiments, the compound of formula I is selected from the following structural formulas:

[0071] In certain embodiments, the compound of formula I is selected from the following structural formulas:

[0072] In certain embodiments, the compound represented by formula II is selected from the following structural formulas:

[0073] In certain embodiments, the compound represented by formula III is selected from the following structural formulas:

[0074] In one embodiment, A is In certain embodiments, A is selected from:

[0075] In one embodiment, A is In certain embodiments, A is selected from:

[0076] In one embodiment, A is In certain embodiments, A is selected from:

[0077] In one embodiment, A is In certain embodiments, A is selected from:

[0078] Non-limiting examples of A include:

[0079] Additional non-limiting examples of A include:

[0080] Additional non-limiting examples of A include:

[0081] Additional non-limiting examples of A include:

[0082] Additional non-limiting examples of A include:

[0083] In one embodiment, the STING agonist is a compound represented by Formula Ia: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; Where L 1 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9a , R 9b , R 10 , R 11 , R 12a , R 12b , R 13a , R 13b , R 14 , R 15 , R 16a , R16b , a and b are as defined in the present invention.

[0084] In one embodiment, the compound represented by formula Ia is selected from the following:

[0085] Non-limiting examples of Formula Ia include, but are not limited to, the following:

[0086] In one embodiment, the STING agonist is a compound represented by Formula Ib: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; Where L 1 , X 1 , X 2 , X 3 , X 5 , X 7 , X 8 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9a , R 9b , R 10 , R 11 , R 12a , R 12b , R 12c , R 13a , R 13b , R 13c , R 14 , R 15 , R 16a , R 16b , a and b are as defined in the present invention.

[0087] In one embodiment, the compound represented by formula Ib is selected from the following:

[0088] Non-limiting examples of Formula Ib include, but are not limited to, the following:

[0089] In one embodiment, the STING agonist is a compound represented by Formula Ic: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; Where L 1 , X 1 , X 2 , X 3 , X 4 , X 5 , X 8 , X 9 , X 10 , X 11 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9a , R 9b , R 10 , R 11 , R 12a , R 12b , R 13a , R 13b , R 14 , R 15 , R 16 , R 16b , R 19 , a and b are as defined in the present invention.

[0090] In one embodiment, the compound represented by formula Ic is selected from the following:

[0091] Non-limiting examples of Formula Ic include, but are not limited to, the following:

[0092] In one embodiment, the STING agonist is a compound represented by Formula Id: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; Where L 1 , X 1 , X 2, X 3 , X 4 , X 5 , X 8 , Y 1 , Y 2 , R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9a , R 9b , R 10 , R 11 , R 12a , R 12b , R 13a , R 13b , R 14 , R 15 , R 16 , R 16b , R 19 , a and b are as defined in the present invention.

[0093] In one embodiment, the compound represented by formula Id is selected from the following:

[0094] Non-limiting examples of Formula Id include, but are not limited to, the following:

[0095] In one embodiment, the STING agonist is a compound represented by Formula IIa: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; Where L 1 , X 1 , X 2 , X 3 , X 4 , X 5 , X 8 , X 9 , X 10 , X 11 , R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9a , R 9b , R10 , R 11 , R 12a , R 12b , R 13a , R 13b , R 14 , R 15 , R 16 , R 16b , R 19 , a and b are as defined in the present invention.

[0096] In one embodiment, the compound represented by formula IIa is selected from the following:

[0097] Non-limiting examples of Formula IIa include, but are not limited to, the following:

[0098] In one embodiment, the STING agonist is a compound represented by Formula IIb: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; Where L 1 , X 1 , X 2 , X 3 , X 4 , X 5 , X 8 , Y 1 , Y 2 , R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9a , R 9b , R 10 , R 11 , R 12a , R 12b , R 13a , R 13b , R 14 , R 15 , R 16 , R 16b , a and b are as defined in the present invention.

[0099] In one embodiment, the compound represented by formula IIb is selected from the following:

[0100] Non-limiting examples of Formula IIb include, but are not limited to, the following:

[0101] In one embodiment, the STING agonist is a compound represented by formula IIIa: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; Where L 1 , X 1 , X 2 , X 3 , X 4 , X 5 , X 8 , Y 1 , Y 2 , R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9a , R 9b , R 10 , R 11 , R 12a , R 12b , R 13a , R 13b , R 14 , R 15 , R 16 , R 16b , a and b are as defined in the present invention.

[0102] In one embodiment, the compound represented by formula IIIa is:

[0103] Non-limiting examples of Formula IIIa include, but are not limited to, the following:

[0104] In one embodiment, including any of the preceding embodiments, L 1 It is C 1-6 In one embodiment, including any of the foregoing embodiments, L 1 In one embodiment, including any of the foregoing embodiments, L 1 In one embodiment, including any of the foregoing embodiments, L 1In one embodiment, including any of the foregoing embodiments, L 1 It is a C6 alkylene group.

[0105] In one embodiment, including any of the preceding embodiments, L 1 yes In certain embodiments, including any of the foregoing embodiments, L 1 yes

[0106] In certain embodiments, including any of the foregoing embodiments, L 1 yes In certain embodiments, including any of the foregoing embodiments, L 1 yes In certain embodiments, including any of the foregoing embodiments, L 1 yes

[0107] In one embodiment, including any of the foregoing embodiments, a is 0. In one embodiment, including any of the foregoing embodiments, a is 1. In one embodiment, including any of the foregoing embodiments, a is 2. In one embodiment, including any of the foregoing embodiments, a is 3. In one embodiment, including any of the foregoing embodiments, a is 4. In one embodiment, including any of the foregoing embodiments, a is 5.

[0108] In one embodiment, including any of the foregoing embodiments, b is 0. In one embodiment, including any of the foregoing embodiments, b is 1. In one embodiment, including any of the foregoing embodiments, b is 2. In one embodiment, including any of the foregoing embodiments, b is 3. In one embodiment, including any of the foregoing embodiments, b is 4. In one embodiment, including any of the foregoing embodiments, b is 5.

[0109] In one embodiment, including any of the foregoing embodiments, a and b are both 0. In one embodiment, including any of the foregoing embodiments, a and b are both 1. In one embodiment, including any of the foregoing embodiments, a and b are both 2. In one embodiment, including any of the foregoing embodiments, a and b are both 3. In one embodiment, including any of the foregoing embodiments, a and b are both 4. In one embodiment, including any of the foregoing embodiments, a and b are both 5.

[0110] In one embodiment, including any of the foregoing embodiments, one of a or b is 0. In one embodiment, including any of the foregoing embodiments, one of a or b is 1. In one embodiment, including any of the foregoing embodiments, one of a or b is 2. In one embodiment, including any of the foregoing embodiments, one of a or b is 3. In one embodiment, including any of the foregoing embodiments, one of a or b is 4. In one embodiment, including any of the foregoing embodiments, one of a or b is 5.

[0111] In certain embodiments, including any of the foregoing embodiments, R 11 In one embodiment, including any of the foregoing embodiments, R 11 is H. In one embodiment, including any of the preceding embodiments, R 11 It's methyl.

[0112] In certain embodiments, L 1 Selected from In one embodiment, L 1 yes In certain embodiments, including any of the foregoing embodiments, L 1 yes

[0113] In certain embodiments, including any of the foregoing embodiments, R 1 is selected from H and halogen. In certain embodiments, including any of the foregoing embodiments, R 7 Selected from H, halogen, and C 1-6 In one embodiment, including any of the foregoing embodiments, R 1 and R 7 In one embodiment, including any of the foregoing embodiments, R 1 and R 7 Both C 1-6 In one embodiment, including any of the foregoing embodiments, R 1 and R 7 are H. In one embodiment, including any of the foregoing embodiments, R 1 is a halogen, and R 7 is H. In one embodiment, including any of the preceding embodiments, R 1 is H, and R 7 In one embodiment, including any of the foregoing embodiments, R 1 and R 7 In one embodiment, R 1 is H, and R 7 is F. In one embodiment, R 1 It is F, and R7 is H. In one embodiment, including any of the preceding embodiments, R 1 and R 7 All are methyl.

[0114] In certain embodiments, including any of the foregoing embodiments, R 2 is selected from alkoxy and H. In certain embodiments, including any of the foregoing embodiments, R 5 Selected from alkoxy, hydroxy, amino-C 1-6 alkyl, and H. In certain embodiments, including any of the preceding embodiments, R 5 is selected from alkoxy and H. In certain embodiments, including any of the foregoing embodiments, R 5 Selected from hydroxy and amino-C 1-6 In one embodiment, including any of the foregoing embodiments, R 2 and R 5 In one embodiment, including any of the foregoing embodiments, R 2 is H, and R 5 In one embodiment, including any of the foregoing embodiments, R 2 is an alkoxy group, and R 5 is H. In one embodiment, including any of the preceding embodiments, R 2 and R 5 In one embodiment, including any of the foregoing embodiments, R 2 is H, and R 5 In one embodiment, including any of the foregoing embodiments, R 2 is a methoxy group, and R 5 is H. In certain embodiments, including any of the foregoing embodiments, R 5 is a hydroxyl group, and R 2 In certain embodiments, including any of the foregoing embodiments, R 5 It is amino-C 1-6 Alkyl, and R 2 In certain embodiments, including any of the foregoing embodiments, R 5 Is hydroxy or amino-C 1-6 Alkyl, and R 2 In certain embodiments, including any of the foregoing embodiments, R 5 is –CH2NH2, and R 2 It is an alkoxy group.

[0115] In certain embodiments, including any of the foregoing embodiments, R 1 and R 7 are selected from H, halogen, and C 1-6Alkyl, and R 2 and R 5 In one embodiment, including any of the foregoing embodiments, R 1 and R 7 are halogens, and R 2 and R 5 In one embodiment, including any of the foregoing embodiments, R 1 and R 7 Both C 1-6 Alkyl, and R 2 and R 5 In one embodiment, including any of the foregoing embodiments, R 1 and R 7 Both are F, and R 2 and R 5 In one embodiment, including any of the foregoing embodiments, R 1 and R 7 are methyl, and R 2 and R 5 All are alkoxy groups.

[0116] In certain embodiments, including any of the foregoing embodiments, R 1 and R 7 Both F, R 2 is an alkoxy group, and R 5 Is hydroxy or amino-C 1-6 In certain embodiments, including any of the foregoing embodiments, R 1 and R 7 All are halogen, R 2 is an alkoxy group, and R 5 In certain embodiments, including any of the foregoing embodiments, R 1 and R 7 All are halogen, R 2 is an alkoxy group, and R 5 It is amino-C 1-6 alkyl.

[0117] In one embodiment, including any of the preceding embodiments, R 3 , R 4 , R 6 and R 8 They are H respectively.

[0118] In certain embodiments, including any of the foregoing embodiments, R 1 and R 7 are selected from H, halogen, and C 1-6 Alkyl; R 2 and R 5 are selected from H, alkoxy, hydroxy, and amino-C1-6 Alkyl; and R 3 , R 4 , R 6 and R 8 In certain embodiments, including any of the foregoing embodiments, R 1 and R 7 are selected from H, halogen, and C 1-6 Alkyl; R 2 and R 5 are independently selected from H and alkoxy; and R 3 , R 4 , R 6 and R 8 In certain embodiments, including any of the foregoing embodiments, R 1 and R 7 are selected from H, halogen, and C 1-6 Alkyl; R 2 and R 5 are selected from H and alkoxy; R 3 , R 4 , R 6 and R 8 H; and L 1 yes In certain embodiments, including any of the foregoing embodiments, R 1 and R 7 are halogen; R 2 and R 5 are alkoxy; R 3 , R 4 , R 6 and R 8 H; and L 1 yes In certain embodiments, including any of the foregoing embodiments, R 1 and R 7 are halogen; R 2 and R 5 are alkoxy; R 3 , R 4 , R 6 and R 8 H; and L 1 yes

[0119] In one embodiment, including any of the preceding embodiments, X 1 In one embodiment, including any of the foregoing embodiments, X 1 In one embodiment, including any of the foregoing embodiments, X 2 Yes-(C(R 12a R12b )) 1-6 -. In one embodiment, including any of the foregoing embodiments, X 2 Yes - (CH2) 1-6 -. In one embodiment, including any of the foregoing embodiments, X 2 is -(CH2)- or -(CH2)2-. In one embodiment, including any of the foregoing embodiments, X 2 Yes-(C(R 12a R 12b )C(R 13a R 13b )) 1-3 -. In one embodiment, including any of the foregoing embodiments, X 2 Yes -(CH2C(CH3)2) 1-3 -. In one embodiment, including any of the foregoing embodiments, X 2 is -(CH2C(CH3)2)-. In one embodiment, including any of the foregoing embodiments, X 3 Yes-COOR 10 In one embodiment, including any of the foregoing embodiments, X 3 In one embodiment, including any of the foregoing embodiments, X 3 Yes-C(O)OC 1-6 In one embodiment, including any of the foregoing embodiments, X 3 In one embodiment, including any of the foregoing embodiments, X 3 Yes-P(O)(OR 15 ) 2. In one embodiment, including any of the foregoing embodiments, X 3 It is -P(O)(OH)2.

[0120] In one embodiment, including any of the preceding embodiments, yes In one embodiment, including any of the preceding embodiments, yes In one embodiment, including any of the preceding embodiments, yes In one embodiment, including any of the preceding embodiments, yes In one embodiment, including any of the preceding embodiments, yes In one embodiment, including any of the preceding embodiments, Selected from In one embodiment, including any of the preceding embodiments, yes

[0121] In one embodiment, including any of the preceding embodiments, yes In one embodiment, including any of the preceding embodiments, yes In one embodiment, including any of the preceding embodiments, yes In one embodiment, including any of the preceding embodiments, yes In one embodiment, including any of the preceding embodiments, yes In one embodiment, including any of the preceding embodiments, yes In one embodiment, including any of the preceding embodiments, yes

[0122] In certain embodiments, including any of the foregoing embodiments, Selected from In certain embodiments, including any of the foregoing embodiments, Selected from In certain embodiments, including any of the foregoing embodiments, Selected from

[0123] In one embodiment, including any of the preceding embodiments, yes In one embodiment, including any of the preceding embodiments, yes In one embodiment, including any of the preceding embodiments, yes In one embodiment, including any of the preceding embodiments, yes Non-limiting examples include

[0124] In certain embodiments, including any of the foregoing embodiments, Selected from and L 1 Selected from In the aforementioned embodiments, represents the point of attachment to the rest of the compound.

[0125] In one embodiment, including any of the preceding embodiments, X 4 In one embodiment, including any of the foregoing embodiments, X 4 In one embodiment, including any of the foregoing embodiments, X 4 It is -CH=CH-.

[0126] In one embodiment, including any of the preceding embodiments, X 5 Yes-(C(R 12a R 12b )) 1-6 -. In one embodiment, including any of the foregoing embodiments, X 5 Yes - (CH2) 1-6 -. In one embodiment, including any of the foregoing embodiments, X 5 In one embodiment, including any of the foregoing embodiments, X 5 In one embodiment, including any of the foregoing embodiments, X 5 Yes-(C(R 12a R 12b )C(R 13a R 13b )) 1-3 -. In one embodiment, including any of the foregoing embodiments, X 5 Yes -(CH2C(CH3)2) 1-3 -. In one embodiment, including any of the foregoing embodiments, X 5 It is -(CH2C(CH3)2)-.

[0127] In one embodiment, including any of the preceding embodiments, X 6 Yes-C(O)NR 9a S(O)2R 17 In one embodiment, including any of the foregoing embodiments, X 6 Yes-C(O)NR 9a S(O)2R 17 In one embodiment, including any of the foregoing embodiments, X 6 Yes -C(O)NHS(O)2R 17 In one embodiment, including any of the foregoing embodiments, X 6 It is -C(O)NHS(O)2-amino-C 1-6 In one embodiment, including any of the foregoing embodiments, X 6 is -C(O)NHS(O)2(CH2)2NH2. In one embodiment, including any of the foregoing embodiments, X 6In one embodiment, including any of the foregoing embodiments, X 6 Yes-P(O)(OR 15 ) 2. In one embodiment, including any of the foregoing embodiments, X 6 is -P(O)(OH)2. In one embodiment, including any of the foregoing embodiments, X 6 Yes-P(O)(OC 1-6 In one embodiment, including any of the foregoing embodiments, X 6 is -P(O)(OCH3)2. In one embodiment, including any of the foregoing embodiments, X 6 Yes-C(O)NR 9a R 18 In one embodiment, including any of the foregoing embodiments, X 6 Yes-C(O)NHR 18 In one embodiment, including any of the foregoing embodiments, X 6 It is -C(O)NH-amino-C 1-6 In one embodiment, including any of the foregoing embodiments, X 6 It is -C(O)NH(CH2)2NH2.

[0128] In one embodiment, including any of the preceding embodiments, X 7 Yes-C(R 12a R 12c )C(R 13a R 13c )-. In one embodiment, including any of the foregoing embodiments, X 7 yes In one embodiment, including any of the preceding embodiments, X 7 yes wherein the cycloalkyl group is optionally selected from halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, hydroxyl, cyano, -NR 9a R 9b , and -COOR 10 In one embodiment, including any of the foregoing embodiments, X 7 It is -CH=CH-.

[0129] In one embodiment, including any of the preceding embodiments, X 8 Yes-COOR 10 In one embodiment, including any of the foregoing embodiments, X 8 In one embodiment, including any of the foregoing embodiments, X 8 Yes-C(O)OC1-6 In one embodiment, including any of the foregoing embodiments, X 8 In one embodiment, including any of the foregoing embodiments, X 8 Yes-P(O)(OR 15 ) 2. In one embodiment, including any of the foregoing embodiments, X 8 It is -P(O)(OH)2.

[0130] In one embodiment, including any of the preceding embodiments, R 9a is H. In one embodiment, including any of the preceding embodiments, R 9a It is C 1-6 Alkyl groups include, but are not limited to, methyl groups.

[0131] In one embodiment, including any of the preceding embodiments, R 10 is H. In one embodiment, including any of the preceding embodiments, R 10 It is C 1-6 In one embodiment, including any of the foregoing embodiments, R 10 It is C 3-10 In one embodiment, including any of the foregoing embodiments, R 10 Selected from aryl, aryl-C 1-6 alkyl, and heteroaryl.

[0132] In certain embodiments, including any of the foregoing embodiments, R 14 It is amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, or C 3-10 Cycloalkylamino-C 1-6 In one embodiment, including any of the foregoing embodiments, R 14 It is amino-C 1-6 In one embodiment, including any of the foregoing embodiments, R 14 It is halogenated-C 1-6 In one embodiment, including any of the foregoing embodiments, R 14 It is C 1-6 alkyl.

[0133] In certain embodiments, including any of the foregoing embodiments, R 17 It is amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C1-6 Alkyl, or C 3-10 Cycloalkylamino-C 1-6 In one embodiment, including any of the foregoing embodiments, R 17 It is amino-C 1-6 In certain embodiments, including any of the foregoing embodiments, R 18 It is amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, or C 3-10 Cycloalkylamino-C 1-6 In one embodiment, including any of the foregoing embodiments, R 18 It is amino-C 1-6 alkyl.

[0134] In certain embodiments, including any of the foregoing embodiments, R 15 Independently selected from H and C 1-6 In one embodiment, including any of the foregoing embodiments, R 15 is H. In one embodiment, including any of the preceding embodiments, R 15 It is C 1-6 In one embodiment, including any of the foregoing embodiments, R 15 It's methyl.

[0135] In certain embodiments, including any of the foregoing embodiments, Selected from In one embodiment, including any of the preceding embodiments, yes In one embodiment, including any of the preceding embodiments, yes

[0136] In certain embodiments, including any of the foregoing embodiments, Selected from

[0137] In certain embodiments, including any of the foregoing embodiments, Selected from In certain embodiments, including any of the foregoing embodiments, yes In one embodiment, including any of the preceding embodiments, yes In certain embodiments, including any of the foregoing embodiments, yes In certain embodiments, including any of the foregoing embodiments, yes In one embodiment, including any of the preceding embodiments, yes

[0138] In certain embodiments, including any of the foregoing embodiments, Selected from In certain embodiments, including any of the foregoing embodiments, Selected from In certain embodiments, including any of the foregoing embodiments, Selected from

[0139] In certain embodiments, including any of the foregoing embodiments, yes Where R 17 It is amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, or C 3-10 Cycloalkylamino-C 1-6 In one embodiment, including any of the foregoing embodiments, yes

[0140] In certain embodiments, including any of the foregoing embodiments, yes Where R 18 It is amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, or C 3-10 Cycloalkylamino-C 1-6 In one embodiment, including any of the foregoing embodiments, yes In certain embodiments, including any of the foregoing embodiments, yes or and R 15 Independently selected from H and C 1-6 In one embodiment, including any of the foregoing embodiments, R 15 It's methyl.

[0141] In certain embodiments, including any of the foregoing embodiments, Selected from In one embodiment, including any of the preceding embodiments, yes

[0142] In certain embodiments, including any of the foregoing embodiments, Selected from In certain embodiments, including any of the foregoing embodiments, yes In one embodiment, including any of the preceding embodiments, yes In certain embodiments, including any of the foregoing embodiments, Selected from

[0143] In certain embodiments, including any of the foregoing embodiments, Selected from

[0144] In certain embodiments, including any of the foregoing embodiments, Selected from

[0145] Non-limiting examples include:

[0146] In certain embodiments, including any of the foregoing embodiments, Selected from

[0147] In certain embodiments, including any of the foregoing embodiments, Selected from

[0148] In certain embodiments, including any of the foregoing embodiments, Selected from

[0149] In certain embodiments, including any of the foregoing embodiments, Selected from

[0150] In certain embodiments, including any of the foregoing embodiments, Selected from

[0151] In certain embodiments, including any of the foregoing embodiments, Selected from

[0152] Non-limiting examples include

[0153] Non-limiting examples include

[0154] In certain embodiments, including any of the foregoing embodiments, Selected from

[0155] In certain embodiments, including any of the foregoing embodiments, Selected from

[0156] In certain embodiments, including any of the foregoing embodiments, Selected from

[0157] In certain embodiments, including any of the foregoing embodiments, Selected from In certain embodiments, including any of the foregoing embodiments, yes In certain embodiments, including any of the foregoing embodiments, yes

[0158] Non-limiting examples include

[0159] In certain embodiments, including any of the foregoing embodiments, Selected from Selected from

[0160] In certain embodiments, including any of the foregoing embodiments, Selected from Selected from

[0161] In certain embodiments, including any of the foregoing embodiments, Selected from Selected from

[0162] In certain embodiments, including any of the foregoing embodiments, Selected from Selected from

[0163] In certain embodiments, including any of the foregoing embodiments, yes yes

[0164] In certain embodiments, including any of the foregoing embodiments, yes yes

[0165] In certain embodiments, including any of the foregoing embodiments, yes yes

[0166] In certain embodiments, including any of the foregoing embodiments, yes yes

[0167] In certain embodiments, including any of the foregoing embodiments, yes yes

[0168] In certain embodiments, including any of the foregoing embodiments, yes yes

[0169] In certain embodiments, including any of the foregoing embodiments, yes yes

[0170] In certain embodiments, including any of the foregoing embodiments, yes and yes

[0171] In certain embodiments, including any of the foregoing embodiments, yes and yes

[0172] In certain embodiments, including any of the foregoing embodiments, yes yes

[0173] In certain embodiments, including any of the foregoing embodiments, yes yes

[0174] In one embodiment, including any of the preceding embodiments, R 12a and R 12b Each is H. In one embodiment, including any of the preceding embodiments, R 12a , R 12b , R 13a and R 13b Each is H. In one embodiment, including any of the preceding embodiments, R 12a and R 12b H, and R 13a and R 13b Each is C 1-6 In one embodiment, including any of the foregoing embodiments, R 12a and R 12b H, and R 13a and R 13b Each is a methyl group.

[0175] In certain embodiments, including any of the foregoing embodiments, R 12a and R 12b H, and R 12c With R 12d Connected together to form C3-C 10 Cycloalkyl, the C3-C 10 Cycloalkyl is optionally selected from halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, hydroxyl, cyano, -NR 9a R 9b and-COOR 10In certain embodiments, including any of the foregoing embodiments, R 12a and R 13b H, and R 12c With R 12d are connected together to form a cyclopropyl group, the cyclopropyl group is optionally selected from halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, hydroxyl, cyano, -NR 9a R 9b and-COOR 10 In certain embodiments, including any of the foregoing embodiments, R 12a and R 13b H, and R 12c With R 12d Linked together to form an unsubstituted cyclopropyl group.

[0176] In certain embodiments, including any of the foregoing embodiments, X 9 , X 10 and X 11 Each independently selected from CR 19 and N, and R 19 is H. In certain embodiments, including any of the foregoing embodiments, X 9 , X 10 and X 11 Each independently selected from CR 19 and N, and R 19 are independently selected from H, halogen, C 1-6 In certain embodiments, including any of the foregoing embodiments, X 9 , X 10 and X 11 Each is CR 19 , and R 19 is H. In certain embodiments, including any of the foregoing embodiments, X 9 , X 10 and X 11 Each is CR 19 , and R 19 Selected from H, halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, halo-C 1-6 Alkyl, Hydroxyl-C 1-6 Alkyl, hydroxyl, -NR 9a R 9b , and -COOR 10 In one embodiment, including any of the foregoing embodiments, X 9 is N, and X 10 and X 11 CR 19In one embodiment, including any of the foregoing embodiments, X 10 is N, and X 9 and X 11 CR 19 In one embodiment, including any of the foregoing embodiments, X 11 is N, and X 10 and X 9 CR 19 In one embodiment, including any of the foregoing embodiments, X 9 It is N, X 10 is N, and X 11 Yes CR 19 In one embodiment, including any of the foregoing embodiments, X 9 It is N, X 11 is N, and X 10 Yes CR 19 In one embodiment, including any of the foregoing embodiments, X 10 It is N, X 11 is N, and X 9 Yes CR 19 .

[0177] In certain embodiments, the STING agonist disclosed in the present invention is a compound selected from the following or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0178] In certain embodiments, the STING agonist disclosed in the present invention is a compound selected from the following or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: Uses of compounds and compositions

[0179] In one aspect, an effective amount of a compound or composition of the invention is used to treat a medical condition or disease mediated by STING in a subject in need thereof. In one embodiment, the medical condition or disease is a cell proliferative disease, including but not limited to cancer. In another aspect, an effective amount of a compound or composition of the invention is used to induce an immune response in a subject in need thereof. In another aspect, an effective amount of a compound or composition of the invention is used to induce STING-dependent type I interferon production in a subject in need thereof. In another aspect, an effective amount of a compound or composition of the invention is used to induce STING-dependent cytokine production in a subject in need thereof.

[0180] In one embodiment, an effective amount of the compounds or compositions of the present invention is used to treat abnormal cell proliferation, including but not limited to cancer. In certain embodiments, the term "cancer" includes but is not limited to the following cancers: epidermoid oral cavity: buccal cavity, lip, tongue, mouth, pharynx, head and neck squamous cell carcinoma (HNSCC); heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; lung: bronchogenic carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, cartilaginous hamartoma, mesothelioma, non-small cell lung Cancer (NSCLC); Gastrointestinal: Gastric cancer, Esophageal (squamous cell carcinoma, laryngeal carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), Stomach (carcinoma, lymphoma, leiomyosarcoma), Pancreatic (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, vipoma), Small intestine (adenocarcinoma, lymphoma, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), Large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), Colon, Colorectal, Colorectal, Microsatellite stable colorectal cancer (MSS Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma), metastatic castration-resistant prostate cancer (mCRPC), muscle-invasive urothelial carcinoma; liver: liver cancer (hepatocellular carcinoma), bile duct carcinoma, hepatoblastoma, hepatocellular adenoma, hemangioma, biliary tumor; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, Ewing's sarcoma sarcoma), malignant lymphoma (reticulum cell sarcoma), malignant giant cell tumor of osteochondrosis (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor of bone; nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningosarcomas, gliomas), brain (astrocytomas, medulloblastomas, gliomas, germ cell tumors (pinealomas), glioblastomas multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas);Gynecology: Uterus (endometrial cancer), cervix (cervical cancer, cervical carcinoma, precancerous cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor of the ovary tumors), dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), fallopian tube (carcinoma), breast cancer, triple-negative breast cancer (TNBC), platinum-resistant epithelial ovarian cancer (EOC); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma (MM), myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma) hairy cell; lymphoid disorders (e.g., mantle cell lymphoma, Waller's; macroglobulinemia, marginal zone lymphoma, and follicular lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, keratoacanthoma, molesdysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; Thyroid: papillary thyroid carcinoma, follicular thyroid carcinoma; medullary thyroid carcinoma, anaplastic thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid carcinoma, pheochromocytoma, paraganglioma; Adrenal gland: neuroblastoma; and metastatic melanoma.

[0181] In certain embodiments, the cancer is selected from acute myeloid leukemia, breast cancer, colorectal cancer, glioma, head and neck squamous cell carcinoma, lung cancer (including non-small cell lung cancer), head and neck cancer, lymphoma (including malignant lymphoma), melanoma, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, prostate cancer, urothelial carcinoma, and tongue squamous cell carcinoma.

[0182] In certain embodiments, the cancer is a solid tumor. The solid tumor used in the present invention refers to an abnormal tissue mass that does not usually contain a cyst or liquid area. Different types of solid tumors are named after the cell type that forms them. Examples of solid tumor categories include, but are not limited to, sarcomas, carcinomas, and lymphomas. Other examples of solid tumors include, but are not limited to, squamous cell carcinoma, colon cancer, breast cancer, prostate cancer, lung cancer, liver cancer, pancreatic cancer, and melanoma. In one embodiment, the solid tumor is an advanced solid tumor.

[0183] Non-limiting examples of cancers that can be treated using the compounds of the invention include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma), appendix cancer, benign monoclonal gammopathy, bile duct cancer (e.g., hepatobiliary carcinoma), bladder cancer, breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, breast cancer, medullary breast carcinoma), brain cancer (e.g., meningioma, neuroendocrine tumors), ovarian cancer, ovarian cancer, bladder cancer, ovarian cancer, ovarian cancer, cerebral cancer (e.g., ovarian cancer, cerebral cancer), cerebral cancer (e.g., pelvic ... glioma, astrocytoma, oligodendroglioma; medulloblastoma), bronchogenic carcinoma, carcinoid tumor, cervical cancer, choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endothelial sarcoma (e.g., multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma), eye cancer (e.g., intraocular melanoma, retinoblastoma), familial hypereosinophilia, gallbladder cancer, stomach cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumors (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma (OSCC)), pharyngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal carcinoma, oropharyngeal cancer), hematopoietic cancer, heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immune cell amyloidosis, kidney cancer (e.g., Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma (HCC), malignant liver cancer), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma), leiomyosarcoma (LMS), mastocytosis (e.g., e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), myelodysplastic syndrome of unknown cause (AMM) also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibromas (e.g., neurofibromatosis type 1 or type 2 (NF), schwannomatosis), neuroendocrine cancers (e.g., gastroenteropancreatic neuroendocrine tumors (GEP-NET), carcinoid tumors), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor), penile cancer (e.g.,Paget's disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small intestine cancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland cancer, sweat gland cancer, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma), Wilms' tumor, urethral cancer, vaginal cancer, and vulvar cancer (e.g., Paget's disease of the vulva vulva)).

[0184] In one embodiment, the cancer is a sarcoma, including but not limited to, Ewing's sarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma (including anaplastic astrocytoma, diffuse astrocytoma and low-grade astrocytoma), oligodendroglioma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pinealocyte tumor, meningioma, meningiosarcoma, neurofibroma, and schwannoma.

[0185] In one embodiment, the cancer is a hematopoietic cancer, including but not limited to leukemias, such as acute lymphocytic leukemia (ALL), also known as acute lymphoblastic leukemia or acute lymphocytic leukemia (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), acute granulocytic leukemia, chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), and hairy cell leukemia (HCL). In one embodiment, the hematopoietic cancer is a lymphoma, such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL), non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL, such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma (Burkitt lymphoma), The present invention relates to NHLs of the present invention, such as progenitor T lymphoblastic lymphoma, peripheral T cell lymphoma (PTCL), cutaneous T cell lymphoma (CTCL), (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T cell lymphoma, extranodal natural killer T cell lymphoma, enteropathy-type T cell lymphoma, subcutaneous panniculitis-like T cell lymphoma, anaplastic large cell lymphoma, and mixtures of one or more leukemias / lymphomas as described above.Other leukemias and lymphomas include T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B ALL, pre-B lymphoma, large B-cell lymphoma, Philadelphia chromosome-positive ALL, Philadelphia chromosome-positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (a subtype of AML), large granular lymphocytic leukemia, adult T-cell chronic leukemia, diffuse large B-cell lymphoma, follicular lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B-cell lymphoma, nodal marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; splenic lymphoma / leukemia, splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma.

[0186] In certain embodiments, the cancer treated using the compounds disclosed herein is selected from adenosarcoma, adrenal cancer, adrenocortical carcinoma, bile duct cancer, bone cancer, bone marrow cancer, brain stem glioma, breast cancer (including but not limited to, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are negative), single negative breast cancer (one of estrogen, progesterone and HER-2 is negative), estrogen receptor positive, HER2 negative breast cancer, estrogen receptor negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, Her2 negative breast cancer, HER2 positive or negative breast cancer, progesterone receptor negative breast cancer, progesterone receptor positive breast cancer, recurrent breast cancer, or inflammatory breast cancer (IBC),mesothelioma (metastatic breast cancer), colorectal cancer, skin lymphoma, skin melanoma, ductal carcinoma in situ (DCIS), endometrial cancer, epithelioid sarcoma, esophageal cancer, extrahepatic eye cancer, fallopian tube cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid, gastrointestinal stromal tumor (GIST), germ cell tumor, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, hemangioendothelioma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC), infiltrating lobular carcinoma (ILC), intestinal cancer, intrahepatic bile duct cancer, invasive / invasive breast cancer, islet cell carcinoma, jaw cancer, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastasis, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma carcinoma), mesenchymal chondrosarcoma, mesenchymal cell tumor, metastatic melanoma, metastatic squamous neck carcinoma, mixed glioma, monodermal teratoma, oral cancer, mucinous carcinoma, mucosal melanoma, multiple myeloma, mycosis fungoides Fungoides), myelodysplastic syndrome, nasal cancer, nasopharyngeal cancer, cervical cancer, neuroblastoma, neuroendocrine tumor (NET), oat cell cancer, eye cancer, ocular melanoma, oligodendroglioma, mouth cancer, oral cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian primary peritoneal cancer, ovarian sex cord stromal tumor, Paget's disease, pancreatic cancer, papillary cancer, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineoblastoma, pituitary cancer , primary central nervous system (CNS) lymphoma, rectal cancer, renal cell carcinoma, renal pelvic cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, osteosarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, vertebral cancer, spinal cancer, spinal cord cancer, squamous cell carcinoma, stomach cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma / thymic cancer, thyroid cancer, tongue cancer, tonsil cancer, transitional cell carcinoma, fallopian tube cancer, tubular cancer, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, plasma cell myeloma, solitary plasmacytoma of bone, and extraosseous plasmacytoma. ,

[0187] In other embodiments, the cell proliferative disease is selected from benign papillomatosis, benign neoplastic disease, and gestational trophoblastic disease. In certain embodiments, the benign neoplastic disease is selected from skin papilloma (warts) and genital papilloma. In certain embodiments, the gestational trophoblastic disease is selected from the group consisting of hydatidiform mole, and gestational trophoblastic tumor (e.g., invasive hydatidiform mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor).

[0188] In alternative aspects, an effective amount of the compound or composition of the present invention is used to treat a medical condition or disease mediated by STING in a subject in need, wherein the condition or disease is a viral infection, such as a double-stranded DNA virus. In certain embodiments, the virus is from the Herpesviridae family, including but not limited to herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (epstein-Barr virus, EBV), cytomegalovirus (CMV) and Kaposi's sarcoma-associated herpesvirus (KSHV). In one embodiment, the virus is an adenovirus. In certain embodiments, the virus is from the Papillomaviridae family, including but not limited to human papillomavirus (HPV). In alternative aspects, the viral infection is an RNA viral infection, such as a virus from the Flaviviridae family, including Flaviviruses (e.g., yellow fever virus, West Nile virus, dengue virus and Zika virus) and Hepacivirus (e.g., hepatitis B and hepatitis C).

[0189] The compounds of the present invention can be administered at any dosage deemed suitable by practitioners in the art. In certain embodiments, the dosage is 0.1-1000 mg / kg. In certain embodiments, the dosage is 0.1-900 mg / kg. In certain embodiments, the dosage is 0.1-800 mg / kg. In certain embodiments, the dosage is 0.1-700 mg / kg. In certain embodiments, the dosage is 0.1-600 mg / kg. In certain embodiments, the dosage is 0.1-500 mg / kg. In certain embodiments, the dosage is 0.1-400 mg / kg. In certain embodiments, the dosage is 0.1-300 mg / kg. In certain embodiments, the dosage is 0.1-200 mg / kg. In certain embodiments, the dosage is 0.1-100 mg / kg. In certain embodiments, the dosage is selected from the group consisting of 100 mg / kg, 200 mg / kg, 300 mg / kg, 450 mg / kg, 600 mg / kg, 800 mg / kg, and 1000 mg / kg. In certain embodiments, the dosage is about 25 mg / kg. In certain embodiments, the dosage is about 50 mg / kg. In certain embodiments, the dosage is about 75 mg / kg. In certain embodiments, the dosage is about 100 mg / kg. In certain embodiments, the dosage is about 150 mg / kg. In certain embodiments, the dosage is about 200 mg / kg. In certain embodiments, the dosage is about 250 mg / kg. In certain embodiments, the dosage is about 300 mg / kg. In certain embodiments, the dosage is about 400 mg / kg. In certain embodiments, the dosage is about 450 mg / kg. In certain embodiments, the dosage is about 500 mg / kg. In certain embodiments, the dosage is about 600 mg / kg. In certain embodiments, the dosage is about 700 mg / kg. In certain embodiments, the dosage is about 750 mg / kg. In certain embodiments, the dosage is about 800 mg / kg. In certain embodiments, the dosage is about 900 mg / kg. In certain embodiments, the dosage is about 1000 mg / kg.

[0190] The dosage may be administered according to a dosage regimen deemed appropriate by one skilled in the art. In certain embodiments, the dosage is administered once a day. In certain embodiments, the dosage is administered twice a day. In certain embodiments, the dosage is administered three times a day. In certain embodiments, the dosage is administered four times a day. In certain embodiments, the dosage is administered in divided doses. In certain embodiments, the dosage is administered in divided doses twice a day. In certain embodiments, the dosage is administered in divided doses three times a day. In certain embodiments, the dosage is administered in divided doses four times a day.

[0191] Administration can continue for any length of time deemed appropriate by a person skilled in the art. In certain embodiments, the dose is administered daily for 14 days. In certain embodiments, the dose is administered daily for 13 days. In certain embodiments, the dose is administered daily for 12 days. In certain embodiments, the dose is administered daily for 11 days. In certain embodiments, the dose is administered daily for 10 days. In certain embodiments, the dose is administered daily for 9 days. In certain embodiments, the dose is administered daily for 8 days. In certain embodiments, the dose is administered daily for 7 days. In certain embodiments, the dose is administered daily for 6 days. In certain embodiments, the dose is administered daily for 5 days. In certain embodiments, the dose is administered daily for 4 days. In certain embodiments, the dose is administered daily for 3 days. In certain embodiments, the dose is administered daily for 2 days. In certain embodiments, the dose is administered for 1 day.

[0192] In the dosing regimen, the doses may be administered over consecutive days or in cycles, at the discretion of the skilled person. In certain embodiments, the doses are administered over consecutive days. In certain embodiments, the doses are administered with intervals between doses. In certain embodiments, the interval is 1 day. In certain embodiments, the interval is 2 days. In certain embodiments, the interval is 3 days. In certain embodiments, the interval is 4 days. In certain embodiments, the interval is 5 days. In certain embodiments, the interval is 6 days.

[0193] In certain embodiments, the dose is administered once a week. In certain embodiments, the dose is administered twice a week. In certain embodiments, the dose is administered three times a week.

[0194] In certain embodiments, the dose is administered for a period of time at a first interval between doses, and then the dose is administered again for a period of time after the first interval between doses, wherein the dosing regimen may be repeated (i.e., cyclically or periodically, for example, after the second, third, etc. intervals between subsequent dose administrations) at the discretion of one skilled in the art. For example, in one embodiment, the first dose is administered for one week, followed by a first interval of 1 week without administering the first dose; then, the second dose is administered for another week, followed by a second interval of 1 week without administering the first dose or the second dose, and so on. As understood by practitioners in the art and patient needs, the present invention contemplates other perturbations for the first, second, third, etc. doses and subsequent perturbations for the first, second, third, etc. intervals and combinations thereof. For example, in one embodiment, the first dose is administered daily for one week, followed by a first interval of 3 weeks without administering the first daily dose; then, the second dose is administered again every two weeks for another week, followed by a second interval of 4 weeks without administering the first daily dose or the second biweekly dose, and so on.

[0195] The compound can be administered by any route of administration deemed suitable by a person skilled in the art. In certain embodiments, the dose is administered orally. The formulations and techniques for administration are described in detail below. Pharmaceutical composition

[0196] The compounds of the present invention can be formulated into pharmaceutical compositions further comprising a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment, the present invention provides a pharmaceutical composition comprising the above-mentioned compound of the present invention and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle.

[0197] According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle. The pharmaceutical composition of the present invention comprises a therapeutically effective amount of a compound shown in Formula I, Formula II, Formula III, Formula Ia, Formula Ib, Formula Ic, Formula Id, Formula IIa, Formula IIb or Formula IIIa, or a pharmaceutically acceptable salt, stereoisomer or salt thereof.

[0198] It should also be understood that certain compounds of the present invention may exist in free form for treatment, or in the form of pharmaceutically acceptable derivatives thereof (e.g., salts) where appropriate. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adducts / isolates or derivatives that can be provided directly or indirectly when administered to a patient in need thereof, such as compounds described elsewhere herein, or metabolites or residues thereof.

[0199] The term "pharmaceutically acceptable salt" or "salt" as used herein refers to those salts which are, within the scope of sound medical judgment, suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like.

[0200] Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which are incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include salts formed by amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or with organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), or salts formed by other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4The present invention also contemplates the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Water-soluble or oil-soluble or dispersible products can be obtained by such quaternization. Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, etc. Pharmaceutically acceptable salts also include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, where appropriate.

[0201] A pharmaceutically acceptable carrier may contain inert ingredients that do not unduly inhibit the biological activity of the compound. A pharmaceutically acceptable carrier should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic, or have no other adverse reactions or side effects when administered to a subject. Standard pharmaceutical formulation techniques may be used.

[0202] The pharmaceutically acceptable carriers, adjuvants or vehicles used in the present invention include any and all solvents, diluents, or other liquid vehicles, dispersing or suspending aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc. suitable for the desired specific dosage form. Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers for preparing pharmaceutically acceptable compositions and known techniques for their preparation. Unless any conventional carrier medium is incompatible with the compounds described in the present invention, for example, by producing any undesirable biological effects or interacting with any other components of the pharmaceutically acceptable composition in a harmful manner, the use of such conventional carrier media is also included in the scope of the present invention. The phrase "side effects" used in the present invention covers undesirable and adverse effects of a therapy (e.g., a preventive or therapeutic agent). Side effects are always undesirable, but undesirable side effects are not necessarily adverse. Side effects of a therapy (e.g., a preventive or therapeutic agent) may be harmful, uncomfortable or risky. Side effects include, but are not limited to, fever, chills, lethargy, gastrointestinal toxicity (including gastric and intestinal ulcers and erosions), nausea, vomiting, neurotoxicity, nephrotoxicity, renal toxicity (including conditions such as papillary necrosis and chronic interstitial nephritis), hepatotoxicity (including elevated serum liver enzyme levels), myelotoxicity (including leukopenia, bone marrow suppression, thrombocytopenia, and anemia), dry mouth, metallic taste, prolonged gestation, weakness, somnolence, pain (including muscle pain, bone pain, and headache), alopecia, fatigue, dizziness, extrapyramidal symptoms, akathisia, cardiovascular disease, and sexual dysfunction.

[0203] Some examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., Tween 80, phosphates, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, methylcellulose, hydroxypropyl methylcellulose, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and maize starch; potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol, and phosphate buffer solutions, and other nontoxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), as well as colorants, release agents, coating agents, sweeteners, flavoring agents and perfuming agents. Preservatives and antioxidants may also be present in the composition at the discretion of the formulator.

[0204] The composition of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or by implanted reservoirs. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally or intravenously. The sterile injection form of the composition of the present invention can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injection preparation can also be a sterile injection solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are generally used as solvents or suspension media.

[0205] For this purpose, any bland fixed oil may be used, including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives, may be used to prepare injections, as may natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the preparation of pharmaceutically acceptable dosage forms (including emulsions and suspensions). Other commonly used surfactants, such as Tweens, Spans and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms may also be used for formulation purposes.

[0206] The pharmaceutically acceptable compositions of the present invention can be orally administered in any oral acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. For oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also usually added. For oral administration in the form of capsules, useful diluents include lactose and dry corn starch. When an oral aqueous suspension is required, the active ingredient is combined with an emulsifier and a suspending agent. If necessary, certain sweeteners, flavoring agents or coloring agents may also be added.

[0207] Alternatively, the pharmaceutically acceptable compositions of the present invention can be used in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature, so it will melt in the rectum or vaginal cavity to release the drug. Such materials include cocoa butter, polyethylene glycol or suppository wax, which is solid at ambient temperature but liquid at body temperature, so it melts in the rectum or vaginal cavity and releases the active compound.

[0208] The pharmaceutically acceptable compositions of this invention can also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical or external formulations can be readily prepared for each of these areas or organs.

[0209] Topical application to the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical transdermal patches may also be used.

[0210] For topical application, the pharmaceutically acceptable composition can be formulated into a suitable ointment containing an active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water. Alternatively, the pharmaceutically acceptable composition can be formulated into a suitable lotion or cream containing an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, hexadecyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0211] For ophthalmic use, the pharmaceutically acceptable composition can be formulated into a micronized suspension in, for example, isotonic, pH-adjusted sterile saline or other aqueous solution, or preferably formulated into a solution in isotonic, pH-adjusted sterile saline or other aqueous solution, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition can be formulated into an ointment, such as vaseline. The pharmaceutically acceptable composition of the present invention can also be applied by nasal aerosol or nasal inhalation. Such compositions can be prepared according to techniques well known in the field of pharmaceutical preparations, and can be prepared into saline solutions using benzyl alcohol or other suitable preservatives, absorption promoters that enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0212] In certain embodiments, the compositions of the present invention can be administered orally. The pharmaceutically acceptable compositions of the present invention can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. For oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also usually added. For oral administration in the form of capsules, useful diluents include lactose and dry corn starch. When an oral aqueous suspension is required, the active ingredient is combined with an emulsifier and a suspending agent. If necessary, certain sweeteners, flavoring agents or coloring agents may also be added.

[0213] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound of the present invention, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and flavoring agents.

[0214] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound of the invention is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarder, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0215] Solid compositions of similar type can also be used as fillers in soft and hard filled gelatin capsules, and the excipients used are lactose and high molecular weight polyethylene glycol, etc. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shell coatings such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. The solid dosage form may optionally contain opacifiers. The solid dosage forms may also have components that allow them to release one or more active ingredients only, for example, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding components that can be used include polymeric substances and waxes. Solid compositions of similar type can also be used as fillers in soft and hard filled gelatin capsules, and the excipients used are lactose and high molecular weight polyethylene glycol, etc.

[0216] The compounds of the present invention may also be present in microcapsule form with one or more excipients as described above. Solid dosage forms of tablets, dragees, capsules, pills and granules may be prepared with coatings and shell coatings such as enteric coatings, controlled release coatings and other coatings well known in the field of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Conventionally, such dosage forms may also contain other substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. For capsules, tablets and pills, the dosage forms may also contain buffers. The dosage forms may optionally contain opacifiers and may also have components that allow them to release one or more active ingredients only, for example, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding components that can be used include polymeric substances and waxes.

[0217] The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The phrase "dosage unit form" used herein refers to physically discrete units of a drug suitable for a patient to be treated. However, it should be understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of reasonable medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the disease being treated and the severity of the disease; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex and diet; the time of administration, route of administration and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or concurrently with the specific compound used, and similar factors well known in the medical field.

[0218] The amount of a compound of the invention that can be combined with a carrier material to produce a single dosage composition will vary depending on the host being treated, the particular mode of administration, and other factors. The compositions should be formulated so that a dose of 0.01-100 mg / kg body weight / day of the compound or inhibitor can be administered to a patient receiving these compositions. Combination / Joint

[0219] The compounds or compositions of the present invention may be administered simultaneously with, before or after one or more additional therapeutic agents. In general, each agent will be administered at a dose and / or schedule determined for the agent. It should be further understood that the additional therapeutic agents used in the combination can be administered together with a single composition or separately with different compositions. The specific combination used in the scheme will take into account the compatibility of the compounds of the present invention with the additional therapeutic agents and / or the desired therapeutic effect to be achieved. In general, it is expected that the amount of the additional therapeutic agent used in combination will not exceed the amount used alone. In some embodiments, the amount used in combination will be lower than the amount used alone. Additional therapeutic agents include, but are not limited to, small organic molecules, such as pharmaceutical compounds (e.g., compounds approved by the Food and Drug Administration as specified in the U.S. Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional therapeutic agent is a cancer drug (e.g., a biotherapeutic cancer drug or a chemotherapeutic cancer drug).

[0220] In one embodiment, the additional active agent can be one or more agents selected from the group consisting of: STING agonist compounds, antiviral compounds, antigens, adjuvants, anticancer drugs, CTLA-4, LAG-3 and PD-1 pathway antagonists, lipids, liposomes, peptides, cytotoxic drugs, chemotherapeutic drugs, immunomodulatory cell lines, checkpoint inhibitors, vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, smoothened inhibitors, alkylating agents, anti-tumor antibiotics, antimetabolites, retinoids, and immunomodulators including but not limited to anti-cancer vaccines.

[0221] In one embodiment, the additional therapeutic agent is an anti-inflammatory agent. In one aspect of this embodiment, the additional therapeutic agent is an immunomodulator, including but not limited to checkpoint inhibitors, such as PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, V domain Ig T cell activation inhibitor (VISTA) inhibitors, small molecules, peptides, nucleotides or other inhibitors. In some aspects, the immunomodulator is an antibody, such as a monoclonal antibody.

[0222] PD-1 inhibitors that block the interaction between PD-1 and PD-L1 by binding to the PD-1 receptor, thereby inhibiting immunosuppression, include, for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-224 (AstraZeneca and Medlmmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Co., Ltd. and Incyte Corporation), TSR-042 (Tesaro), and the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.). Blocking the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor, thereby inhibiting immunosuppression PD-L1 inhibitors include, for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and Medlmmune), KN035 (Alphamab) and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibit immunosuppression include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and Medlmmune), AGEN1884 and AGEN2041 (Agenus). LAG-3 checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro).

[0223] In alternative embodiments, the PD-1 antagonist as a second therapeutic agent is a monoclonal antibody (mAb) or an antigen-binding fragment thereof that specifically binds to PD-1 or PD-L1, and preferably specifically binds to human PD-1 or human PD-L1. mAbs can be human antibodies, humanized antibodies, or chimeric antibodies, and can include human constant regions. In some embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in preferred embodiments, the human constant region is an IgG1 or IgG4 constant region. In some embodiments, the antigen-binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv, and Fv fragments.

[0224] In one embodiment, the additional therapeutic agent is a cytotoxic drug or a chemotherapeutic drug. Examples of cytotoxic drugs that can be used in combination with the compounds or pharmaceutically acceptable salts of the present invention include, but are not limited to, arsenic trioxide (trade name Asparaginase (also known as L-asparaginase and Erwinia L-asparaginase, sold under the trade names and sell).

[0225] Chemotherapeutic drugs that can be used in combination with the compounds or pharmaceutically acceptable salts of the present invention include abiraterone acetate, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, BMS184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide, bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-methyl yl-L-valyl-L-prolyl-1-L-prolyl-tert-butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3′,4′-didehydro-4′-deoxy-8′-norvinblastine, docetaxel, cyclophosphamide, carboplatin n), carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, dolastatin, doxorubicin, etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyurea with taxanes, ifosfamide, liarozole, lonidamine, lomustine (CCNU), MDV3100, nitrogen mustard, melphalan, mivobulin isethionate (mivobulinisethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxanes, nilutamide, nivolumab, onapristone, paclitaxel, pembrolizumab, prednimustine, procarbazine, RPR109881, stramustine phosphate, tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunine. Where appropriate, such chemotherapeutic agents may be provided in the form of pharmaceutically acceptable salts. In one embodiment, the additional therapeutically active agent is a vascular endothelial growth factor (VEGF) receptor inhibitor, including but not limited to bevacizumab (AVASTIN), axitinib, brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl) 2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide), pasireotide, sunitinib (SUTENT), and sorafenib (NEXAVAR).

[0226] In one embodiment, the additional therapeutically active agent is a topoisomerase II inhibitor, including but not limited to etoposide (also known as VP-16 and etoposide phosphate, sold under the trade names TOPOSAR, VEPESID, and ETOPOPHOS) and teniposide (also known as VM-26, sold under the trade name VUMON).

[0227] In one embodiment, the additional therapeutically active agent is an alkylating agent, including but not limited to 5-azacytidine (VIDAZA), decitabine (DECOGEN), temozolomide (TEMCAD, TEMODAR, and TEMODAL), dactinomycin (also known as actinomycin D, sold under the trade name COSMEGEN), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the trade name ALKERAN), hexamethylmelamine (also known as hexamethylmelamine (HMM), sold under the trade name HEXALEN), carmustine (BCNU), bendamustine (TREANDA), busulfan ( and ), Carboplatin , lomustine (also known as CCNU, sold under the trade name Cisplatin (also known as CDDP, sold under the trade name and -AQ for sale), Chlorambucil Cyclophosphamide ( and ), dacarbazine (also known as DTIC, DIC and imidazole carboxamide, sold under the trade name DTIC- Sold), hexamethylmelamine (also known as hexamethylmelamine (HMM), sold under the trade name Ifosfamide Methyl procarbazine Nitrogen mustard (also known as nitrogen mustard, nitrogen mustard and nitrogen mustard hydrochloride, known by the trade name For sale), streptozotocin Thiotepa (also known as thiophosphoramide, TESPA, and TSPA, and sold under the trade name Where appropriate, such alkylating agents may be provided in the form of pharmaceutically acceptable salts.

[0228] Examples of antitumor antibiotics include, but are not limited to, doxorubicin (trade name and Bleomycin (sold under the trade name Sold), daunorubicin (also known as daunorubicin hydrochloride, daunomycin and daunorubicin hydrochloride, sold under the trade name Sold), daunorubicin liposomes (daunorubicin citrate liposomes, sold under the trade name Mitoxantrone (also known as DHAD, sold under the trade name Sold under the trade name ELLENCE TM Sold), Idabixin (trade name and mitomycin C (sold under the trade name If appropriate, such antitumor antibiotics may be provided in the form of pharmaceutically acceptable salts.

[0229] In one embodiment, the additional therapeutically active agent is an antimetabolite, including but not limited to cladribine (2-chlorodeoxyadenosine, ), 5-fluorouracil 6-Thioguanine Pemetrexed Cytosine arabinoside (also known as cytosine arabinoside (Ara-C), sold under the trade name CYTOSAR- cytarabine liposomes (also known as liposome Ara-C, sold under the trade name DEPOCYT TM Sold), decitabine Hydroxyurea ( DROXIA TM and MYLOCEL TM )、Fludarabine( Fluridine Cladribine (also known as 2-chlorodeoxyadenosine (2-CdA), sold under the trade name LEUSTATIN TM Sold), methotrexate (also known as methotrexate, methotrexate sodium (MTX), and sold under the trade name and TREXALL TM Sold) and Pentostatin Where appropriate, such antimetabolites may be provided in the form of pharmaceutically acceptable salts.

[0230] In one embodiment, the additional therapeutically active agent is a retinoid, including but not limited to alitretinoin. Retinoic acid (all-trans retinoic acid, also known as ATRA, sold under the trade name isotretinoin (13-c / s-retinoic acid, sold under the trade name and Sold) and bexarotene

[0231] The amount of additional therapeutic agent present in the compositions of the present invention is no more than the amount normally administered in a composition comprising the therapeutic agent as the only active agent. The amount of additional therapeutic agent in the compositions disclosed herein is about 50% to 100% of the amount normally present in a composition comprising the drug as the only therapeutically active agent.

[0232] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts are co-administered with one or more additional therapeutic agents (including vaccines intended to stimulate immune responses). Antigens and adjuvants that can be used in combination with the compounds of the present invention or pharmaceutically acceptable salts include B7 co-stimulatory molecules, interleukin-2, interferon-γ, GM-CSF, CTLA-4 antagonists, OX-40 / OX-40 ligands, CD40 / CD40 ligands, sargramostim, levamisole, vaccinia virus, BCG (BCG), liposomes, alum, Freund's complete or incomplete adjuvant, detoxified endotoxins, mineral oils, surfactants (such as lipophosphatidylcholine), pluronic polyols, polyanions, peptides, and oil or hydrocarbon emulsions. Adjuvants, such as aluminum hydroxide or aluminum phosphate, can be added to increase the ability of vaccines to trigger, enhance or prolong immune responses. Other materials, such as cytokines, chemokines and bacterial nucleic acid sequences, such as CpG, Toll-like receptor (TLR) 9 agonists and other agonists for TLR 2, TLR 4, TLR 5, TLR 7, TLR 8, TLR 9, including lipoprotein, LPS, monophosphoryllipid A, lipoteichoic acid, imiquimod, resiquimod, and retinoic acid-induced gene I (RIG-I) agonists, such as poly I: C, are also potential adjuvants when used alone or in combination with the composition. Where appropriate, such antigens and adjuvants as the second therapeutic agent may be provided in the form of a pharmaceutically acceptable salt.

[0233] Antiviral compounds that can be used in combination with the compounds or pharmaceutically acceptable salts of the present invention include hepatitis B virus (HBV) inhibitors, hepatitis C virus (HCV) protease inhibitors, HCV polymerase inhibitors, HCV NS4A inhibitors, HCV NS5A inhibitors, HCV NS5b inhibitors, and human immunodeficiency virus (HIV) inhibitors. Where appropriate, such antiviral compounds can be provided in the form of pharmaceutically acceptable salts. Products and kits

[0234] The present invention also provides articles comprising any compound or pharmaceutical composition described herein. The articles include suitable containers or packaging materials for the compound or pharmaceutical composition. Examples of suitable containers include, but are not limited to, bottles, vials, syringes, intravenous bags, or tubes.

[0235] The present invention also provides a kit comprising any compound or pharmaceutical composition described in the present invention. The kit may include the compound or pharmaceutical composition in a suitable container or packaging material, including but not limited to bottles, vials, syringes, intravenous bags, or tubes. The kit may include the compound or pharmaceutical composition for application to an individual in a single dose form or in a multi-dose form. The kit may further include instructions or labels for applying the compound or pharmaceutical composition to an individual according to any method disclosed in the present invention. The kit may further include equipment for applying the compound or pharmaceutical composition to an individual, including but not limited to a needle, a syringe, a catheter, or an intravenous bag. The kit may further include instructions for generating any compound or pharmaceutical composition disclosed in the present invention.

[0236] The present invention also provides a product comprising any compound, vaccine or pharmaceutical composition described in the present invention. The product includes a suitable container or packaging material for the compound or pharmaceutical composition. The product includes a suitable container or packaging material for the compound, oncolytic virus or pharmaceutical composition. Examples of suitable containers include, but are not limited to, bottles, vials, syringes, intravenous infusion bags, or tubes.

[0237] The present invention will be more fully understood by reference to the following examples. However, it should not be construed as limiting the scope of the present invention. It should be understood that the embodiments and embodiments described in the present invention are only for illustrative purposes, and the various modifications / modifications or changes / variations that those skilled in the art will carry out according to the present invention will be included in the spirit and scope of the present application and in the scope of the appended claims. Example

[0238] The compounds provided by the present invention can be prepared or synthesized according to any technique deemed suitable by a person skilled in the art. An exemplary synthesis scheme is described below. Preparation of compounds

[0239] Proton nuclear magnetic resonance (NMR) spectroscopy at Bruker Ascend TMAcquired on a 500 MHz spectrometer. NMR spectra are reported as follows: chemical shift δ (ppm), multiplicity, coupling constant J (Hz) and integration. Abbreviations used throughout the text: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet and br = broad. Mass spectral data were measured using the following system: Agilent Technologies 1290 series, binary pump, diode array detector. Data were acquired using Agilent software, and purity was characterized by UV wavelength 220 nm, evaporative light scattering detection (ELSD) and electrospray positive ionization (ESI) (chromatographic column: Agilent Poroshell 120EC-C18, 2.7 μm, 4.6×50 mm). Solvents used: acetonitrile / water containing 0.1% formic acid; flow rate was 1 mL / min.

[0240] The abbreviations used in the examples include:

[0241] For all of the following examples, standard post-treatment and purification methods known to those skilled in the art may be used. Unless otherwise stated, all temperatures are expressed in ° C (Celsius). Unless otherwise stated, all reactions are carried out at room temperature. The synthetic methodology shown in the present invention is intended to illustrate applicable chemistry by using specific examples, rather than to indicate the scope of the present invention disclosed.

[0242] As used herein, the symbols and conventions used in these processes / methods, schemes and examples, whether or not particular abbreviations are specifically defined, are consistent with those used in the contemporary scientific literature (e.g., Journal of Biological Chemistry and / or Journal of the American Chemical Society).

[0243] For all the following examples, standard work-up and purification methods known to those skilled in the art can be used. Unless otherwise stated, all temperatures are expressed in ° C (degrees Celsius). Unless otherwise stated, all methods are carried out at room temperature ("rt" or "rt" or "RT").

[0244] The following synthetic schemes are provided for illustration and not limitation. The following examples illustrate various methods for preparing the compounds of the present invention. It should be understood that those skilled in the art can prepare the compounds by similar methods or in combination with other methods known to those skilled in the art. It should also be understood that those skilled in the art can prepare in a manner similar to that described below by using appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial suppliers, or synthesized from sources known to those skilled in the art or prepared as described in the present invention. Example 1: Synthesis of selected STING agonists

[0245] Common intermediates for the STING agonist examples described below were prepared according to the following schemes. These intermediates were then used to prepare the STING agonist compounds of the present invention.

[0246] Scheme 1: Synthesis of intermediate compound A:

[0247] 1-Fluoro-2,3-dimethoxybenzene (A2): CH3I (83.1 g, 585.4 mmol) was added to a stirred solution of compound A1 (30 g, 234 mmol) and K2CO3 (80.9 g, 585.4 mmol) in DMF (300 mL) at 0°C. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was diluted with water (3 L) and then extracted with EtOAc (3x1 L). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound A2 (35 g, 95% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ6.95 (td, J = 8.4, 6.0 Hz, 1H), 6.75–6.66 (m, 2H), 3.92 (d, J = 1.1 Hz, 3H), 3.87 (s, 3H).

[0248] 2-Fluoro-3,4-dimethoxybenzaldehyde (A3): To a stirred solution of compound A2 (35 g, 224.1 mmol) in DCM (200 mL) was added a solution of TiCl4 (63.7 g, 336.1 mmol) in DCM (100 mL) at -20 °C under N2 atmosphere. A solution of dichloromethyl methyl ether (28.3 g, 246.5 mmol) in DCM (100 mL) was then added to the reaction. Thereafter, the reaction was stirred at room temperature for 16 hours. The reaction mixture was added dropwise to water (400 mL) and extracted with (DCM / EtOAc=5 / 1, v / v). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography to give compound A3 (20 g, 48% yield) as a light yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.04(s,1H),7.59(dd,J=8.8,7.7Hz,1H),7.09(dd,J=8.9,1.5Hz,1H),3.93(s,3H),3.83(s,3H).

[0249] (E)-5-(2-fluoro-3,4-dimethoxybenzylidene)-2-thiothiazolidine-4-one (A4): A solution of compound A3 (18.2 g, 98.8 mmol), 2-thiothiazolidine-4-one (13.1 g, 98.8 mmol) and NaOAc (24.3 g, 296.4 mmol) in acetic acid (200 mL) was stirred overnight at 100 ° C. The reaction mixture was cooled to room temperature and slowly added to water (600 mL). A precipitate was formed, filtered, and washed with water (15 mL x 3) to give compound A4 (28 g, 94% yield) as a bright yellow solid, which was used directly without further purification. LCMS (ESI) = m / z 300 (M+H); 1 H NMR (400MHz, DMSO-d6) δ7.53 (s, 1H), 7.20 (t, J = 8.4Hz, 1H), 7.09 (dd, J = 9.0, 1.5Hz, 1H), 3.91 (s, 3H), 3.82 (s, 3H).

[0250] (Z)-3-(2-fluoro-3,4-dimethoxyphenyl)-2-mercaptoacrylic acid (A5): Compound A4 (54.5 g, 0.18 mmol) was added to a NaOH solution (29.1 g, 0.73 mol of 200 mL H2O and 200 mL EtOH solution), and the reaction mixture was stirred overnight at room temperature, and then the reaction was diluted with water (500 mL) and EtOAc (250 mL). The aqueous phase was collected, acidified to pH~3 by adding 1N HCl, extracted with EtOAC (200 mLx3), and the combined organic layers were concentrated to obtain compound A5 (18.2, yield: 38.7%) as a yellow solid, which can be directly used in the next step. 1 H NMR (400MHz, DMSO-d6) δ 13.08 (s, 1H), 7.71 (s, 1H), 7.67–7.56 (m, 1H), 7.04 (dd, J = 9.0, 1.7Hz, 1H), 3.88 (s, 3H), 3.80 (s, 3H).

[0251] 4-Fluoro-5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid (A6): A solution of compound A5 (18.2 g, 0.07 mmol) and I2 (53.5 g, 0.21 mmol) in DME (540 mL) was stirred at 80 °C overnight. The reaction mixture was cooled to room temperature, quenched with aqueous Na2S2O3 (300 mL), and then 2.0 equivalents of NaOH were added. The mixture was extracted with EtOAc (600 mL). The aqueous phase was collected, the pH was adjusted to ~3, and extracted with EtOAc. The combined organic phases were concentrated under reduced pressure to give compound A6 (17.0 g, 94% yield) as a bright yellow solid.1 H NMR (400MHz, CHCl3-d) δ8.12(s,1H),7.09(s,1H),3.99(s,3H),3.97(s,3H).

[0252] 4-Fluoro-5,6-dimethoxybenzo[b]thiophene (A7): A solution of compound A6 (10.0 g, 39 mmol), 1,10-phenanthroline (2.79 g, 19 mmol) and Cu2O (1.76 g, 9.76 mmol) in DMSO (200 mL) was stirred at 160°C for 8 hours. The reaction mixture was cooled to room temperature, then 1N HCl (40 mL) was added and filtered through celite. The filtrate was extracted with EtOAc. The combined organic phases were concentrated under reduced pressure and the crude residue was purified by silica gel chromatography to give the desired product (4.3 g, 51% yield). 1 H NMR (400MHz, CDCl3) δ7.34–7.30(m,1H),7.27(s,1H),7.14–7.11(m,1H),3.98(d,J=0.9Hz,3H),3.94(s,3H).

[0253] 4-(4-Fluoro-5,6-dimethoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid (A8): A solution of 3,3-dimethyldihydrofuran-2,5-dione (2.8 g, 22.6 mmol) and AlCl3 (1.9 g, 14.7 mmol) in DCM (15 mL) was stirred at 0°C for 10 minutes, and then a solution of compound A7 (2.4 g, 11.3 mmol) in DCM (5 mL) was slowly added to the suspension. The reaction mixture was stirred at room temperature overnight. Afterwards, the reaction was carefully quenched with water (10 mL) and then extracted with CHCl3 / IPA (3 / 1, v / v, 15x3 mL). The combined organic phases were concentrated and the residue was purified by silica gel chromatography to give the desired product (1.5 g, 39% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.29(s,1H),7.56(s,1H),3.92(s,3H),3.85(s,3H),3.57(s,2H),1.23(s,6H).

[0254] Methyl 4-(4-fluoro-5,6-dimethoxybenzo[b]thiophene-2-yl)-2,2-dimethyl-4-oxobutanoate (A9): A solution of compound A8 (1.5 g, 4.4 mmol), K2CO3 (1.83 g, 13.2 mmol) and CH3I (936.8 mg, 8.25 mmol) in DMF (10 mL) was stirred at room temperature for 12 hours. The reaction mixture was quenched with water and then extracted with EtOAc (15 mL x 3). The combined organic phases were concentrated under reduced pressure and the residue was purified by silica gel chromatography to give the desired product A9 (840 mg, 54% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.30(s,1H),7.57(s,1H),3.92(s,3H),3.86(s,3H),3.57(s,3H),3.43(s,2H),1.24(s,6H).

[0255] 4-(4-Fluoro-5-hydroxy-6-methoxybenzo[b]thiophene-2-yl)-2,2-dimethyl-4-oxobutanoic acid methyl ester (A10): A solution of compound A9 (860 mg, 2.42 mmol) and AlCl3 (1.9 g, 14.52 mmol) in DMF (20 mL) was stirred at room temperature for 12 hours. The reaction mixture was quenched with ice water (20 mL) and then extracted with CHCl3 / IPA (3 / 1, v / v, 15 mLx3). The combined organic phase was concentrated and the residue was purified by silica gel chromatography to give the desired product A10 (560 mg, 67.9% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ9.52(d,J=0.9Hz,1H),8.23(s,1H),7.46(s,1H),3.91(s,3H),3.56(s,3H),3.42(s,2H),1.23(s,6H).

[0256] 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2,2-dimethyl-4-oxobutanoic acid methyl ester (A): A mixture of compound A10 (220 mg, 0.64 mmol), 1,3-dibromopropane (6.5 g, 32.3 mmol) and Cs2CO3 (1.0 g, 3.23 mmol) in CH3CN (6 mL) was stirred at 65 ° C for 4 h, then the reaction was cooled to room temperature, quenched with water, and then extracted with EtOAc (15 mLx3). The combined organic phase was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give the desired product A (260 mg, 88% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ8.31 (s, 1H), 7.59 (s, 1H), 4.15 (t, J = 5.9Hz, 2H), 3.92 (s, 3H) ,3.73(t,J=6.5Hz,2H),3.57(s,3H),3.43(s,2H),2.21(p,J=6.2Hz,2H),1.24(s,6H).

[0257] Scheme 2: Synthesis of compound 1:

[0258] 4-Fluoro-5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid chloride (2): Oxalyl chloride (1.39 g, 10.9 mmol) and DMF (0.05 mL) were added to a stirred solution of 4-fluoro-5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid A6 (700 mg, 2.73 mmol) in DCM (7 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hours, then the reaction was concentrated under reduced pressure and compound 2 was used directly in the next step.

[0259] Methyl 2-(4-fluoro-5,6-dimethoxybenzo[b]thiophene-2-yl)ethane-1-sulfonate (4): To a solution of methyl methanesulfonate (613 mg, 5.57 mmol) in THF (7 mL) was added n-BuLi (2.2 mL, 5.57 mmol) at -78°C. After the reaction was stirred at -78°C for 30 minutes, a solution of 4-fluoro-5,6-dimethoxybenzo[b]thiophene-2-carbonyl chloride (2) in THF (8 mL) was added. The reaction was stirred at room temperature overnight. TLC showed the disappearance of SM, and the reaction was quenched with aqueous NH4Cl solution, then extracted with EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography to give compound 4 (347 mg) as a solid. 1 H NMR (400MHz, DMSO-d6) δ 8.60 (s, 1H), 7.63 (s, 1H), 5.40 (s, 2H), 3.98 (d, J = 1.5Hz, 3H), 3.94 (s, 3H), 3.87 (s, 3H).

[0260] 2-(4-Fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-2-oxoethane-1-sulfonic acid (5): To a solution of methyl 2-(4-fluoro-5,6-dimethoxybenzo[b]thiophen-2-yl)ethane-1-sulfonate (4) (344 mg, 0.99 mmol) in DCM (5 mL) was added AlCl3 (921.7 mg, 6.9 mmol) at 0°C. The reaction mixture was stirred at room temperature overnight. TLC showed that SM disappeared. The reactant was slowly added to ice-cold water and extracted with DCM. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by reverse phase column to give compound 5 (285 mg) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.24(s,1H),7.44(s,1H),4.17(s,2H),3.91(s,3H).

[0261] 4-(4-Fluoro-5-(3-((4-fluoro-6-methoxy-2-(2-sulfacetyl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid (Compound 1): To a solution of 2-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-2-oxoethane-1-sulfonic acid 5 (140 mg, 0.44 mmol) in DMF (2 mL) was added methyl 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate (A) (241.9 mg, 0.52 mmol) and Cs2CO3 (996.8 mg, 3.06 mmol) at room temperature. The mixture was stirred overnight at 65° C. The reaction was cooled to room temperature and purified by preparative HPLC to give the desired compound 1 (11 mg) as a white solid. 1 HNMR(400MHz,DMSO-d6)δ8.27(d,J=9.7Hz,2H),7.54(d,J=6.2Hz,2H),4.28(t,J=6.1Hz, 4H), 4.19 (s, 2H), 3.88 (d, J = 3.1Hz, 6H), 3.37 (s, 2H), 2.10 (p, J = 6.1Hz, 2H), 1.24 (s, 6H).

[0262] Scheme 3: Synthesis of compound 2:

[0263] 4-Fluoro-5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid methyl ester (2): To a solution of 4-fluoro-5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid A6 (21 g, 0.08 mol) and K2CO3 (14.5 g, 0.24 mol) in DMF (180 mL) was added CH3I (41.8 g, 0.14 mol) at 0°C. The reaction mixture was stirred at room temperature overnight. The mixture was then diluted with water, extracted with EtOAc, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give compound 2 (10 g) as a solid. 1 H NMR (400MHz, CHCl3-d) δ 8.04 (s, 1H), 7.07 (s, 1H), 3.98 (d, J = 1.1Hz, 3H), 3.96 (s, 3H), 3.93 (s, 3H).

[0264] Methyl 2-(4-fluoro-5,6-dimethoxybenzo[b]thiophene-2-yl)-2-oxoethane-1-sulfonate (3): To a solution of methyl methanesulfonate (12.22 g, 0.037 mol) in THF (200 mL) was added n-BuLi (44.4 ml, 0.11 mol) at -78 °C and the reaction mixture was stirred for 30 minutes. After that, a solution of methyl 4-fluoro-5,6-dimethoxybenzo[b]thiophene-2-carboxylate (2) in THF (150 ml) was added and the reaction was stirred at room temperature overnight. The reaction was quenched with aqueous NH4Cl solution and then extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give compound 3 (8 g) as a solid. 1 H NMR (400MHz, DMSO-d6) δ 8.60 (s, 1H), 7.63 (s, 1H), 5.40 (s, 2H), 3.98 (d, J = 1.5Hz, 3H), 3.94 (s, 3H), 3.87 (s, 3H).

[0265] 2-(4-Fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-2-oxoethane-1-sulfonic acid (4): To a solution of methyl 2-(4-fluoro-5,6-dimethoxybenzo[b]thiophen-2-yl)-2-oxoethane-1-sulfonate 3 (8 g, 0.02 mol) in DCM (80 mL) was added AlCl3 (21.4 g, 0.16 mol) at 0°C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then added to ice-cold water and extracted with THF. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to afford compound 4 (4.9 g) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ8.24(s,1H),7.44(s,1H),4.17(s,2H),3.91(s,3H).

[0266] 2-(4-Fluoro-5-(3-((4-fluoro-6-methoxy-2-(4-methoxy-3,3-dimethyl-4-oxobutanoyl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-2-oxoethane-1-sulfonic acid (Compound 2): At room temperature, add 2-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-2-oxoethane-1-sulfonic acid (4) (4.38 g, 0.013 mol) to D 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethylpent-4-enoic acid methyl ester (A) (7.57 g, 0.016 mol), Cs2CO3 (13.37 g, 0.04 mol) and NaI (4.1 g, 0.027 mol) were added to the MF (50 mL) solution in sequence. The mixture was stirred at room temperature overnight, then diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative reverse phase HPLC to obtain the desired product compound 2 (880 mg) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.29(s,2H),7.55(d,J=9.0Hz,2H),4.29(t,J=6.1Hz,4H),4.21(s ,2H),3.89(d,J=3.0Hz,6H),3.59(s,3H),3.45(s,2H),2.11(p,J=6.1Hz,2H),1.26(s,6H).

[0267] Scheme 4: Synthesis of Compound 3 and Compound 4:

[0268] 4-Fluoro-5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylic acid methyl ester (3): To a suspension of AlCl3 (10.8 g, 81.4 mmol) in DCM (180 mL) at 0°C was added 4-fluoro-5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid methyl ester 2 (4.4 g, 16.3 mmol). The reaction mixture was warmed to ambient temperature and stirred under nitrogen for 16 hours. TLC showed that SM had been consumed, and then the mixture was diluted with water (100 mL), acidified to pH~2 by adding 1M HCl, and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product 3 (2 g, 47.9%) as a light yellow solid. LCMS (ESI) = 255.1 [M-1]; 1 H NMR (400MHz, DMSO-d6) δ9.58–9.52(m,1H),7.94(s,1H),7.48(s,1H),3.91(s,3H),3.86(s,3H).

[0269] 4-Fluoro-6-methoxy-5-((triisopropylsilyl)oxy)benzo[b]thiophene-2-carboxylic acid methyl ester (4): To a solution of 4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylic acid methyl ester 3 (2 g, 7.8 mmol) in DMF (40 mL) were added 1H-imidazole (1.3 g, 18.7 mmol) and triisopropylsilyl chloride (3 g, 15.61 mmol). The mixture was stirred at room temperature overnight under nitrogen atmosphere, and then the reaction mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product 4 (2.6 g, 81%) as a light yellow solid. 1 H NMR (400MHz, CDCl3) δ8.26 (s, 1H), 7.52 (s, 1H), 4.18 (s, 3H), 4.15 (s, 3H), 1.59–1.48 (m, 4H), 1.35 (d, J = 7.4Hz, 18H).

[0270] Dimethyl (2-(4-fluoro-6-methoxy-5-((triisopropylsilyl)oxy)benzo[b]thiophen-2-yl)-2-oxoethyl)phosphonate (5): To a solution of dimethyl methylphosphonate (1.54 g, 12.46 mmol) in THF (30 mL) was added n-BuLi (5 mL, 2.5 M in THF, 12.46 mmol) at -78°C, and the reaction was stirred for 45 minutes. Thereafter, a solution of compound 4 (2.57 g, 6.23 mmol) in THF (20 mL) was added to the above solution, and the reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. Thereafter, the reaction was quenched with saturated aqueous NH4Cl solution (40 mL) at -40°C and extracted with EtOAc (60 mL×3). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography to give the desired product 5 (2.87 g, 91.4%) as a light yellow solid. LCMS (ESI): m / z 505.2 (M+H).

[0271] Dimethyl (2-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-2-oxoethyl)phosphonate (6): To a solution of dimethyl (2-(4-fluoro-6-methoxy-5-((triisopropylsilyl)oxy)benzo[b]thiophen-2-yl)-2-oxoethyl)phosphonate 5 (2.87 g, 5.69 mmol) in THF (12 mL) was added tetrabutylammonium fluoride (6.8 mL, 1 M in THF, 6.82 mmol) dropwise. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 h, then the mixture was quenched with water (30 mL), acidified to pH~3 by adding 1 M HCl, and extracted with EtOAc (80 mL×3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product 6 (1.87 g, 94.4%) as a yellow solid. LCMS (ESI) = m / z 349.1 (M+H).

[0272] 4-(5-(3-((2-(2-(dimethoxyphosphoryl)acetyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid methyl ester (Compound 3): to (2-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-2-oxoethyl)phosphonic acid dimethyl ester 6 (1.8 g, 5.17 mmol) and 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid methyl ester (A) (2.4 g, 5.17 mmol) in CH3CN (40 mL) were added Cs2CO3 (5.1 g, 15.50 mmol), and the mixture was stirred at 65°C under nitrogen atmosphere for 2 hours. After that, the reaction was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product, compound 3 (2.6 g, 69.1%), as a light yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.43(s,1H),8.26(s,1H),7.55(d,J=3.4Hz,2H),4.28(td,J=6.3,3.3Hz,4H),4.00(s,1H),3.94 (s,1H),3.87(d,J=1.8Hz,6H),3.70(s,3H),3.67(s,3H),3.57(s,3H),3.42(s,2H),2.09(p,J=6.2Hz,2H),1.24(s,6H).

[0273] 4-(5-(3-((2-(2-(dimethoxyphosphoryl)acetyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid (Compound 4): To a solution of methyl 4-(5-(3-((2-(2-(dimethoxyphosphoryl)acetyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate Compound 3 (20 mg, 0.03 mmol) in DCE (1 mL) was added Sn(CH3)3OH (20 mg, 0.11 mmol) at room temperature. The mixture was then heated to 80°C and stirred overnight under nitrogen atmosphere. The reaction was cooled to room temperature, concentrated under reduced pressure and the residue was purified by preparative HPLC to give the desired product, compound 4 (8 mg, 41%), as a white solid. 1H NMR(400MHz,DMSO-d6)δ8.26(s,2H),7.54(s,1H),7.50(s,1H),4.31–4.22(m,4H),3.87(d, J=5.6Hz,6H),3.57(s,3H),3.46(s,2H),3.42(s,3H),3.33(m,2H)2.08(m,2H),1.23(s,6H).

[0274] Scheme 5. Synthesis of Compound 5:

[0275] (2-(4-fluoro-5-(3-((4-fluoro-6-methoxy-2-(4-methoxy-3,3-dimethyl-4-oxobutanoyl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-2-oxoethyl)phosphonic acid (Compound 5): 4-(5-(3-((2-(2-(dimethoxyphosphoryl)acetyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-2-oxoethyl)phosphonic acid was added to 4-(5-(3-((2-(2-(dimethoxyphosphoryl)acetyl)-4-fluoro-6-methoxybenzo[b]thiophene-5-yl) at 0°C. N,O-bis(trimethylsilyl)trifluoroacetamide (6.4 g, 24.70 mmol) and iodotrimethylsilane (4.1 g, 20.58 mmol) were added to a solution of compound 3 (3.0 g, 4.12 mmol) in DCM (120 mL), and the mixture was stirred under nitrogen atmosphere for 1 h. The reactant was concentrated under reduced pressure, and the residue was purified by reverse phase column to obtain the desired product compound 5 (1.69 g, 58.6%) as a light orange solid. LCMS (ESI) = m / z 699.2 (MH). 1 H NMR (400MHz, DMSO-d6) δ 8.26 (s, 2H), 7.54 (d, J = 4.2Hz, 2H), 4.27 (t, J = 6.1Hz, 4H), 3.87 (s, 6H), 3.62–3.52 (m, 5H), 2.10 (q, J = 6.2Hz, 2H), 1.24 (s, 6H).

[0276] Scheme 6. Synthesis of compound 6:

[0277] 4-(4-Fluoro-5-(3-((4-fluoro-6-methoxy-2-(2-phosphonoacetyl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid: To a solution of (2-(4-fluoro-5-(3-((4-fluoro-6-methoxy-2-(4-methoxy-3,3-dimethyl-4-oxobutanoyl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-2-oxoethyl)phosphonic acid compound 5 (21 mg, 0.03 mmol) in MeOH (0.7 mL), THF (0.7 mL) and H2O (0.7 mL) was added KOH (14 mg, 0.24 mmol) at room temperature and the reaction was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product, Compound 6 (10 mg, 47%), as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.22(s,1H),8.01(s,1H),7.45(s,1H),7.36(s,1H),4.28(m,4H), 3.86(s,3H),3.80(s,3H),3.29(m,2H),3.17(d,J=20.7Hz,2H),2.05(m,2H),1.24(s,6H).

[0278] Scheme 7. Synthesis of compound 7:

[0279] 4-Fluoro-5-hydroxy-N,6-dimethoxy-N-methylbenzo[b]thiophene-2-carboxamide (2): To a solution of 4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylic acid (3.46 g, 14.3 mmol) in DMF (35 mL) were added N,O-dimethylhydroxylamine (1.95 g, 20 mmol), TBTU (5.05 g, 15.7 mmol) and DIEA (4.6 g, 35.7 mmol). The mixture was stirred at room temperature overnight. Afterwards, the reaction was diluted with water and then extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to afford compound 2 (1.33 g) as a solid. 1 H NMR (400MHz, DMSO-d6) δ7.96(s,1H),7.43(s,1H),3.90(s,3H),3.80(s,3H),3.32(s,3H).

[0280] 1-(4-Fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)prop-2-en-1-one (3): To a solution of 4-fluoro-5-hydroxy-N,6-dimethoxy-N-methylbenzo[b]thiophene-2-carboxamide 2 (1.26 g, 4.42 mmol) in THF (25 mL) was added vinylmagnesium bromide (22.1 ml, 22 mmol) at 0°C and the reaction mixture was stirred at room temperature for 30 minutes. The reactants were added to ice-cold 1 M HCl solution at 0°C and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give compound 3 (564 mg) as a solid. 1 H NMR (400MHz, DMSO-d6) δ9.55 (s, 1H), 8.40 (s, 1H), 7.57 (dd, J = 16.9, 10.4Hz, 1H), 7. 49(s,1H),6.38(dd,J=16.9,1.9Hz,1H),5.95(dd,J=10.3,1.9Hz,1H),3.92(s,3H).

[0281] Dimethyl (3-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-3-oxopropyl)phosphonate (4): To a solution of 1-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)prop-2-en-1-one 3 (539 mg, 2.1 mmol) in DCM (5 mL) was added dimethyl phosphonate (940 mg, 8.54 mmol) and DBU (162.4 mg, 1.07 mmol) at room temperature and the mixture was stirred at 65 °C for 2 hours. TLC showed that SM disappeared. The mixture was diluted with water and then extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give compound 4 (343 mg) as a solid. 1 H NMR (400MHz, DMSO-d6) δ8.24(s,1H),7.44(s,1H),3.88(s,3H),3.63(s,3H),3.61(s,3H),3.23(m,2H),2.14–2.04(m,2H).

[0282] Methyl 4-(5-(3-((2-(3-(dimethoxyphosphoryl)propionyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (5): To a solution of dimethyl (3-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-3-oxopropyl)phosphonate 4 (148 mg, 0.41 mmol) in CH3CN (2 mL) was added methyl 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate A (177 mg, 0.41 mmol) and Cs2CO3 (399.3 mg, 1.23 mmol) at room temperature and the reaction mixture was stirred at 65°C for 2 hours. The reaction was diluted with water and then extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain compound 5. 1 H NMR(400MHz,CHCl3-d)δ7.93(s,2H),7.05(s,2H),4.39(d,J=6.1Hz,4H),3.91(s,6H),3.78(dd,J=10.8,2.5 Hz, 6H), 3.72 (d, J = 2.5Hz, 3H), 3.32 (d, J = 6.8Hz, 2H), 2.80 (t, J = 6.7Hz, 2H), 2.31–2.17 (m, 4H), 0.87 (s, 2H).

[0283] 4-(4-Fluoro-5-(3-((4-fluoro-2-(3-(hydroxy(methoxy)phosphoryl)propionyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid (6): To a solution of methyl 4-(5-(3-((2-(3-(dimethoxyphosphoryl)propionyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate 5 (109 mg, 0.15 mmol) in THF / MeOH / H2O (0.5 mL / 0.5 mL / 0.5 mL) was added LiOH (14.6 mg, 0.61 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with 1M HCl solution, extracted with EtOAc, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give compound 6 (82 mg) as a white solid. LCMS (ESI) = m / z 685 (MH).

[0284] 4-(4-Fluoro-5-(3-((4-fluoro-6-methoxy-2-(3-phosphonopropionyl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid (Compound 7): To a CH3CN solution of 4-(4-fluoro-5-(3-((4-fluoro-2-(3-(hydroxy(methoxy)phosphoryl)propionyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid 6 (50 mg, 0.07 mmol) was added BSTFA (75 mg, 0.29 mmol) and TMSI (87.4 mg, 0.44 mmol) at 0°C. After 1 hour, the reaction mixture was concentrated and the crude product was purified by preparative HPLC to give the desired compound 7 (18 mg) as a white solid. LCMS (ESI) = m / z 670.95 (MH); 1 H NMR (400MHz, DMSO-d6) δ8.23(s,1H),8.14(s,1H),7.53(s,2H),4.27(t,J=6.1Hz,4H),3.87(s,6H),3.3 0(s,2H),3.24–3.20(m,2H),2.59(t,J=6.4Hz,2H),2.08(p,J=6.2Hz,2H),1.89(dt,J=16.3,7.7Hz,2H).

[0285] Scheme 8. Synthesis of Compound 8: Compound 8 was synthesized from Compound 5 in a similar manner using the same method as described above.

[0286] Scheme 9. Synthesis of compound 9:

[0287] 1-(4-Fluoro-5,6-dimethoxybenzo[b]thiophene-2-yl)-3-methylbut-2-ene-1-one (2): To a solution of AlCl3 (1.4 g, 10.41 mmol) in DCM (20 mL) was added 4-fluoro-5,6-dimethoxybenzo[b]thiophene (1.7 g, 8.01 mmol) and 3-methylbut-2-enoyl chloride (1.43 g, 12.01 mmol) at -78°C. The reaction was stirred at room temperature overnight. Afterwards, the reaction mixture was added to ice water, extracted with EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give compound 2 (2.18 g) as a solid. 1H NMR (400MHz, DMSO-d6) δ8.29(s,1H),7.55(s,1H),7.11(s,1H),3.91(s,3H),3.84(s,3H),2.19(d,J=1.2Hz,3H),2.02(d,J=1.3Hz,3H).

[0288] 1-(4-Fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-3-methylbut-2-en-1-one (3): To a solution of 1-(4-fluoro-5,6-dimethoxybenzo[b]thiophen-2-yl)-3-methylbut-2-en-1-one 2 (1.58 g, 5.37 mmol) in DCM (20 mL) was added AlCl3 (6.4 g, 48.3 mmol) at 0°C. The reaction was stirred at room temperature overnight, and then the mixture was slowly added to ice water and extracted with THF. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give compound 3 (1.45 g) as a yellow solid. 1 H NMR (400MHz, CHCl3-d) δ7.90 (d, J = 1.3 Hz, 1H), 7.07 (s, 1H), 6.78 (d, J = 2.0 Hz, 1H), 4.01 (d, J = 1.4 Hz, 3H), 2.28 (d, J = 1.5 Hz, 3H), 2.05 (d, J = 1.5 Hz, 3H).

[0289] Methyl 4-(4-fluoro-5-(3-((4-fluoro-6-methoxy-2-(3-methylbut-2-enoyl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate (4): To a solution of 1-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-3-methylbut-2-en-1-one 3 (941 mg, 3.36 mmol) in DMF (15 mL) were added methyl 4-(5-(3-bromopropoxy)-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethylbutanoate A (1.55 g, 3.36 mmol), Cs2CO3 (5.5 g, 16.8 mmol), and the reaction mixture was stirred at 65°C for 2 hours. The reaction was cooled to room temperature, diluted with water, then extracted with EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give compound 4 (375 mg) as a white solid. 1H NMR (400MHz, DMSO-d6) δ8.23(s,2H),7.52(d,J=9.2Hz,2H),7.09(s,1H),4.27(t,J=6.1Hz,4 H), 3.86 (s, 6H), 3.56 (s, 3H), 2.20 (s, 3H), 2.09 (q, J = 6.3Hz, 2H), 2.03 (s, 3H), 1.23 (s, 6H).

[0290] Methyl 4-(5-(3-((2-(3-(dimethoxyphosphoryl)-3-methylbutanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate (5): To a mixture of P(OMe)3 (347.4 mg, 2.8 mmol) and N,O-bis(trimethylsilyl)acetamide (569 mg, 2.8 mmol) in DCM (4 mL) at 0°C was added TMSOTf (622.3 mg, 2.8 mmol). After 30 minutes, methyl 4-(4-fluoro-5-(3-((4-fluoro-6-methoxy-2-(3-methylbut-2-enoyl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate 4 (370 mg, 0.55 mmol) was added and the reaction was stirred at 0°C for 1 hour. The reaction mixture was stirred with 3 mL of 1M HCl for 3 hours to hydrolyze the enolsilane intermediate. The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give compound 5 (178 mg) as a white solid. 1 HNMR (400MHz, DMSO-d6) δ8.24(s,1H),8.12(s,1H),7.53(d,J=3.1Hz,2H),4.27(t,J=6.1Hz,4 H), 3.86 (s, 6H), 3.65 (s, 3H), 3.62 (s, 3H), 3.57 (s, 3H), 2.08 (q, J = 6.1Hz, 2H), 1.23 (s, 12H).

[0291] 4-(5-(3-((2-(3-(dimethoxyphosphoryl)-3-methylbutyryl)-4-fluoro-6-methoxybenzo[b]thien-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thien-2-yl)-2,2-dimethyl-4-oxobutanoic acid (6): 4-(5-(3-((2-(3-(dimethoxyphosphoryl)-3-methylbutyryl)-4-fluoro-6-methoxybenzo[b]thien-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thien-2-yl)-2,2-dimethyl-4-oxobutanoic acid To a solution of methyl 4-oxobutyrate 5 (68 mg, 0.08 mmol) in THF / MeOH / H2O (0.5 mL / 0.5 mL / 0.5 mL) was added LiOH (8.5 mg, 0.35 mmol), and the mixture was stirred overnight at room temperature, and then the reaction was acidified by adding 1 M HCl solution, extracted with EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give compound 6 (65 mg) as a white solid.

[0292] 4-(4-fluoro-5-(3-((4-fluoro-6-methoxy-2-(3-methyl-3-phosphonobutyryl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid (Compound 9): At 0°C, 4-(5-(3-((2-(3-(dimethoxyphosphoryl)-3-methylbutyryl)-4-fluoro-6- To a solution of 6-(methoxybenzo[b]thiophene-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2,2-dimethyl-4-oxobutanoic acid (63 mg, 0.08 mmol) in DCM, BSTFA (85.7 mg, 0.33 mmol) and TMSI (99.9 mg, 0.50 mmol) were added sequentially, and the reaction was stirred for 1 h and then concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the desired compound 9 (25 mg) as a white solid. LCMS (ESI) = m / z 727.05 (MH); 1 H NMR(400MHz,DMSO-d6)δ8.21(s,1H),8.00(s,1H),7.50(s,2H),4.26(t,J=6.2Hz,4H), 3.86 (s, 6H), 3.34 (s, 2H), 3.09 (d, J = 9.3Hz, 2H), 2.07 (t, J = 6.7Hz, 2H), 1.22 (s, 12H).

[0293] Scheme 10. Synthesis of compound 10: Compound 10 was prepared in a similar manner using the same method described for the synthesis of compound 5 in Scheme 5.

[0294] Scheme 11. Synthesis of compound 11:

[0295] 4-(4-Fluoro-5,6-dimethoxybenzo[b]thiophene-2-yl)-4-oxobutanoic acid (2): To a solution of 4-fluoro-5,6-dimethoxybenzo[b]thiophene (2 g, 9.43 mmol) and succinic anhydride (1.4 g, 14.13 mmol) in DCM (90 mL) was added AlCl3 (2.5 g, 18.86 mmol) in portions and the reaction was stirred at room temperature overnight. The reaction was slowly quenched with ice water (500 mL) and extracted with EtOAc (400 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product 2 (1.8 g, 62%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ12.17(s,1H),8.31(s,1H),7.57(s,1H),3.92(s,3H),3.86(s,3H),3.30(s,2H),2.59(t,J=6.4Hz,2H).

[0296] Methyl 4-(4-fluoro-5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (3): A solution of 4-(4-fluoro-5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid 2 (5.44 g, 17.4 mmol), K2CO3 (7.2 g, 52.3 mmol) and CH3I (4.9 g, 34.87 mmol) in DMF (155 mL) was stirred at room temperature for 12 hours. The reaction mixture was diluted into 800 mL of water and extracted with EtOAc (400 mL x 3), the combined organic layers were concentrated, and the residue was purified by silica gel column chromatography to give the desired product 3 (4.57 g, 81% yield) as a yellow solid. LCMS (ESI) = m / z 326.9 (M+H).

[0297] Methyl 4-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (4): To a suspension of AlCl3 (9.4 g, 70.5 mmol) in DCM (225 mL) was added 4-(4-fluoro-5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid 3 (4.5 g, 14 mmol) at 0°C. The mixture was warmed to ambient temperature and stirred under nitrogen for 16 hours. The mixture was quenched with water (500 mL), acidified to pH ~2 by slow addition of 1 M HCl, and extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product 4 (3.9 g, 90%) as a light yellow solid. 1 H NMR (400MHz, DMSO-d6) δ9.51(s,1H),8.24(s,1H),7.46(s,1H),3.91(s,3H),3.60(s,3H),3.37(t,J=6.4Hz,2H),2.67(t,J=6.3Hz,2H).

[0298] Methyl 4-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophene-2-yl)-4-hydroxybutanoate (5): To a solution of methyl 4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylate 4 (400 mg, 1.33 mmol) in THF (5 mL) at 0°C was added NaBH4 (38 mg, 1.33 mmol) in portions and the reaction was stirred at room temperature for 1 hour. The reaction was then diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product 5 (220 mg, 54%) as a light yellow solid. LCMS (ESI) = m / z 314.9 (M+H).

[0299] 4-(4-fluoro-5-(3-((4-fluoro-6-methoxy-2-(5-oxotetrahydrofuran-2-yl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid methyl ester (6): 4-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-hydroxybutanoic acid methyl ester 5( To a solution of methyl 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate A (200 mg, 0.64 mmol) and methyl 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate A (310 mg, 0.67 mmol) in CH3CN (10 mL) was added Cs2CO3 (1.01 g, 3.18 mmol), and the mixture was stirred at 65°C for 2 hours. The reaction was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product 6 (180 mg, 43%) as a light yellow solid.

[0300] 4-(5-(3-((2-(3-carboxy-1-hydroxypropyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid (7): To a solution of methyl 4-(4-fluoro-5-(3-((4-fluoro-6-methoxy-2-(5-oxotetrahydrofuran-2-yl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate 6 (170 mg, 0.26 mmol) in THF / MeOH / H2O (1 mL / 5 ml / 1 ml) was added LiOH (216 mg, 3.18 mmol) and the reaction was stirred at room temperature overnight. After that, the mixture was acidified to pH = 1 by adding 1M HCl solution, extracted with EtOAc (15 mL x 3), and the combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography to give the desired product 7 (155 mg, 92%) as a light yellow solid. LCMS (ESI) = m / z 665.2 (MH).

[0301] (E)-4-(5-(3-((2-(3-carboxy-3-methylbutanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)but-3-enoic acid (Compound 11): To a solution of 4-(5-(3-((2-(3-carboxy-1-hydroxypropyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid 7 (90 mg, 0.14 mmol) in CH3CN (0.3 mL) and DCM (1 mL) were added CBr4 (93 mg, 0.28 mmol) and PPh3 (74 mg, 0.28 mmol) at -25°C under nitrogen atmosphere. The mixture was stirred at room temperature overnight. After that, the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (DCM / MeOH=10 / 1, v / v) to give the desired product, Compound 11 (18 mg, 20%), as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.24(s,1H),7.53(s,1H),7.41(s,1H),7.21(s,1H),6.76(d,J=16.0Hz,1H),6.06(m ,1H),4.24(m,4H),3.86(s,3H),3.82(s,3H),3.36(s,2H),3.23(d,J=7.2Hz,2H),2.07(m,2H),1.23(s,6H).

[0302] Scheme 12. Synthesis of compound 12:

[0303] (4-Fluoro-5,6-dimethoxybenzo[b]thiophene-2-yl)methanol (2): To a solution of 4-fluoro-5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid 1 (3.84 g, 14.98 mmol) in THF (45 mL) was added lithium aluminum hydride (1 M, 44.9 mL, 45.0 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 3 hours. LCMS showed the reaction was complete. The reaction mixture was carefully quenched with ice water, acidified to pH ~3 by adding 1N HCl, and extracted with EtOAc (30x3 mL). The combined organic phases were concentrated and the residue was purified on a silica gel column to give the desired product 2 (1.64 g, 45% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ7.45 (s, 1H), 7.17 (s, 1H), 5.63 (t, J = 5.8Hz, 1H), 4.69 (dd, J = 5.9, 1.1Hz, 2H), 3.87 (s, 3H), 3.81 (s, 3H).

[0304] 4-Fluoro-5,6-dimethoxybenzo[b]thiophene-2-carbaldehyde (3): PDC (5.09 g, 13.53 mmol) was added to a solution of (4-fluoro-5,6-dimethoxybenzo[b]thiophene-2-yl)methanol 2 (1.64 g, 6.76 mmol) in DCM (40 mL), and the mixture was stirred at room temperature for 16 hours. After that, the mixture was concentrated and the crude material was purified by silica gel column chromatography to give compound 3 (1.43 g, 88% yield) as a yellow semi-solid. 1 H NMR (400MHz, DMSO-d6) δ10.04(s,1H),8.37(s,1H),7.63(s,1H),3.93(s,3H),3.86(s,3H).

[0305] 4-Fluoro-5-hydroxy-6-methoxybenzo[b]thiophene-2-carbaldehyde (4): To a solution of 4-fluoro-5,6-dimethoxybenzo[b]thiophene-2-carbaldehyde 3 (1.43 g, 5.95 mmol) in DCM (60 mL) was added AlCl3 (6.35 g, 47.62 mmol) at 0°C. The mixture was stirred at room temperature overnight and LCMS showed the reaction was complete. The mixture was slowly added to ice water and extracted with DCM (40 x 3 mL). The organic layer was dried over Na2SO4 and concentrated to give the crude product, which was purified by silica gel column chromatography to give compound 4 (1.12 g, 83%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.02(s,1H),9.61(s,1H),8.30(s,1H),7.52(s,1H),3.93(s,3H).

[0306] 4-Fluoro-6-methoxy-5-((4-methoxybenzyl)oxy)benzo[b]thiophene-2-carboxaldehyde (5): PMBCl (84 mg, 0.53 mmol) and K2CO3 (91.2 mg, 0.66 mmol) were added to a solution of 4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxaldehyde 4 (100 mg, 0.44 mmol) in DMF (3 mL), and the reaction was stirred at room temperature overnight. LCMS showed that the reaction was complete, and the mixture was diluted with water and then extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give a crude product, which was purified by silica gel column chromatography to give compound 5 (140 mg, 90%). 1 H NMR (400MHz, DMSO-d6) δ10.02(s,1H),8.33(s,1H),7.62(s,1H),7.38–7.29(m,2H),6.94–6.87(m,2H),5.03(s,2H),3.95(s,3H),3.74(s,3H).

[0307] Tert-butyl((4-(4-fluoro-6-methoxy-5-((4-methoxybenzyl)oxy)benzo[b]thiophen-2-yl)but-3-en-1-yl)oxy)dimethylsilane (6): To a solution of 4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophene-2-carbaldehyde 5 (580 mg, 1.67 mmol) and 2-((3-((tert-butyldimethylsilyl)oxy)propyl)sulfonyl)benzo[d]thiazole (531.2 mg, 2.51 mmol) in THF (15 mL) was added KHMDS (1 M) (3.36 mL, 3.36 mmol) at room temperature and the reaction mixture was stirred under N atmosphere for 1 h. LCMS showed the reaction was complete, then the mixture was diluted with water, extracted with EtOAc (15 mL x 3), the organic layer was dried over NaSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 6 (760 mg, 90%) as a white solid.

[0308] 4-(4-Fluoro-6-methoxy-5-((4-methoxybenzyl)oxy)benzo[b]thiophen-2-yl)but-3-en-1-ol (7): To a solution of tert-butyl((4-(4-fluoro-6-methoxy-5-((4-methoxybenzyl)oxy)benzo[b]thiophen-2-yl)but-3-en-1-yl)oxy)dimethylsilane 6 (670 mg, 1.33 mmol) in THF (13 mL) was added TBAF (1.4 g, 5.33 mmol) at room temperature and the reaction was stirred overnight. LCMS showed the reaction was complete and the mixture was diluted with water and then extracted with EtOAc (15 x 3 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 7 (300 mg, 58%) as a yellow oil.

[0309] 2-(2-(4-Fluoro-6-methoxy-5-((4-methoxybenzyl)oxy)benzo[b]thiophen-2-yl)cyclopropyl)ethan-1-ol (8): To a solution of diazomethane (0.1 M in ether, 30 mL, 30.8 mmol) at 0°C was added a solution of 4-(4-fluoro-6-methoxy-5-((4-methoxybenzyl)oxy)benzo[b]thiophen-2-yl)but-3-en-1-ol 7 (600 mg, 1.54 mmol) and Pd(OAc)2 (69.4 mg, 0.31 mmol) in THF (3 mL) and the mixture was stirred overnight. LCMS showed the desired product and the reaction mixture was concentrated and the residue was purified on a reverse phase column to give compound 8 (250 mg, 40%).

[0310] 2-(2-(4-fluoro-6-methoxy-5-((4-methoxybenzyl)oxy)benzo[b]thiophen-2-yl)cyclopropyl)acetaldehyde (9): To a solution of 2-(2-(4-fluoro-6-methoxy-5-((4-methoxybenzyl)oxy)benzo[b]thiophen-2-yl)cyclopropyl)ethan-1-ol 8 (300 mg, 0.74 mmol) in DCM (12 mL) was added Dessmartin periodinane (632 mg, 1.49 mmol) at 0°C and the reaction was stirred at room temperature for 2 hours. The mixture was diluted with water and then extracted with EtOAc (15 x 3 mL), the organic layer was dried over Na2SO4 and concentrated under reduced pressure to give compound 9 as a yellow solid which was used directly without further purification; LCMS (ESI) = m / z 401.2 (M+H).

[0311] 2-(2-(4-fluoro-6-methoxy-5-((4-methoxybenzyl)oxy)benzo[b]thiophen-2-yl)cyclopropyl)acetic acid (10): To a solution of 2-(2-(4-fluoro-6-methoxy-5-((4-methoxybenzyl)oxy)benzo[b]thiophen-2-yl)cyclopropyl)acetaldehyde 9 (628 mg, 1.57 mmol) in tBuOH / H2O (3 / 1, v / v, 10 mL) at 0°C was added KH2PO4 (258 mg, 1.90 mmol), 2-methyl-2-butene (166 mg, 2.37 mmol) and NaClO2 (171 mg, 1.90 mmol). The mixture was stirred at room temperature overnight. LCMS showed the reaction was complete, the reaction was diluted with water and then extracted with EtOAc, the organic layer was dried over Na2SO4, concentrated under reduced pressure, and the crude compound was purified by silica gel column chromatography to give compound 10 (400 mg, purity 80%).

[0312] Methyl 2-(2-(4-fluoro-6-methoxy-5-((4-methoxybenzyl)oxy)benzo[b]thiophen-2-yl)cyclopropyl)acetate (11): To a solution of 2-(2-(4-fluoro-6-methoxy-5-((4-methoxybenzyl)oxy)benzo[b]thiophen-2-yl)cyclopropyl)acetate 10 (670 mg, 1.61 mmol) in DMF (3 mL) were added CH3I (342.9 mg, 2.42 mmol) and K2CO3 (667.8 mg, 4.83 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and then extracted with EtOAc, the organic layer was dried over Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 11 (156 mg, 22% yield). 1 H NMR(400MHz,DMSO-d6)δ7.38(s,1H),7.35–7.29(m,2H),6.97(s,1H),6.93–6.86(m,2H),3.86(s,3H),3.74(s,4H),3 .62(s,3H),2.04(dt,J=9.1,4.9Hz,1H),1.40–1.31(m,1H),1.06(dt,J=8.9,5.1Hz,1H),0.97(dt,J=8.4,5.3Hz,1H).

[0313] Methyl 2-(2-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)cyclopropyl)acetate (12): To a solution of methyl 2-(2-(4-fluoro-6-methoxy-5-((4-methoxybenzyl)oxy)benzo[b]thiophen-2-yl)cyclopropyl)acetate 11 (156 mg, 0.36 mmol) in THF (5 mL) was added HCl (1 drop) and Pd / C (20 mg, 10%). The mixture was stirred at 60 °C under H2 atmosphere overnight. The reaction mixture was cooled and carefully filtered through a pad of celite, the filtrate was concentrated under reduced pressure, and the crude material was purified by preparative TLC to afford compound 12 (62 mg, 55% yield) as a yellow solid.

[0314] 4-(4-fluoro-5-(3-((4-fluoro-6-methoxy-2-(2-(2-methoxy-2-oxoethyl)cyclopropyl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid methyl ester (13): 2-(2-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)cyclopropyl)acetate 12 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid methyl ester A (93.83 mg, 0.203 mmol) and Cs2CO3 (276.12 mg, 0.847 mmol) were added to a solution of CH3CN (52.6 mg, 0.169 mmol) and the mixture was reacted at 65°C for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the desired product 13 (100 mg, 85% yield) as a yellow solid.

[0315] 4-(5-(3-((2-(2-(carboxymethyl)cyclopropyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid (Compound 12): 4-(4-fluoro-5-(3-((4-fluoro-6-methoxy-2-(2-(2-methoxy-2-oxoethyl) A solution of methyl 6-methoxybenzo[b]thiophene-2-yl)-2,2-dimethyl-4-oxobutanoate 13 (130 mg, 0.188 mmol) and LiOH (41.96 mg, 1.5 mmol) in THF / MeOH / H2O (2 / 2 / 1, v / v / v, 5 mL) was stirred at 40°C for 14 h. The reactant was concentrated and the residue was purified by silica gel column chromatography to give the desired product compound 12 (80 mg, 64% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ8.23(s,1H),7.52(s,1H),7.35(s,1H),6.96(s,1H),4.25(t,J=6.2Hz,2H),4.20(t,J=6.1Hz,2H),3.86(s, 3H),3.79(s,3H),3.45-3.40(m,2H),2.37-2.0(m,2H),2.05(dp,J=12.0,5.7Hz,3H),1.35(s,1H),1.23(s,6H),1.08–0.92(m,2H). 19 F NMR (376MHz, DMSO-d6) δ-134.15,-137.06.

[0316] Scheme 13. Synthesis of compound 13:

[0317] 4-(6-Methoxynaphthalene-2-yl)-4-oxobutanoic acid (2): To a solution of 2-methoxynaphthalene (10.0 g, 63.21 mmol) and dihydrofuran-2,5-dione (12.65 g, 126.42 mmol) in DCM (200 mL) was added AlCl3 (16.84 g, 126.40 mmol) in portions at 0°C. The mixture was stirred at room temperature overnight. Afterwards, the reaction mixture was carefully quenched with ice-cold water (500 mL) and then extracted with EtOAc (400 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product 2 (1.6 g, 10%) as a yellow solid. 1 H NMR(400MHz, DMSO-d6)δ8.65(s,1H),8.07(d,J=9.0Hz,1H),8.01–7.90(m,2H),7.44(d,J=2.2H z, 1H), 7.29 (dd, J = 8.9, 2.4Hz, 1H), 3.94 (s, 3H), 3.44 (t, J = 6.3Hz, 2H), 2.73 (d, J = 12.6Hz, 2H).

[0318] Methyl 4-(6-methoxynaphthalen-2-yl)-4-oxobutanoate (3): To a solution of 4-fluoro-5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid 2 (1.6 g, 6.12 mmol) in DMF (30 mL) was added K2CO3 (2.11 g, 15.3 mmol) and CH3I (8.3 g, 58.5 mmol) at ℃. The mixture was stirred at room temperature for 3 hours. After that, the reaction mixture was diluted with water (300 mL) and then extracted with EtOAc (150 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product 3 (1.54 g, 95%) as a yellow solid. LCMS (ESI) = m / z 273.2 (M+H).

[0319] Methyl 4-(6-hydroxynaphthalen-2-yl)-4-oxobutanoate (4): To a solution of methyl 4-(6-methoxynaphthalen-2-yl)-4-oxobutanoate 3 (125 mg, 0.46 mmol) in DCM (4 mL) was added AlCl3 (368 mg, 2.74 mmol) at 0°C. The mixture was stirred at 45°C overnight and TLC showed the disappearance of the starting material. The reaction mixture was diluted with water (10 mL) and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product 4 (25 mg, 21%) as a light yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.20(s,1H),8.57(s,1H),7.99(d,J=9.6Hz,1H),7.87(d,J=8.7Hz,1H),7.76( d, J=8.7Hz, 1H), 7.17 (dd, J=6.9, 2.3Hz, 2H), 3.61 (s, 3H), 3.40 (t, J=6.3Hz, 2H), 2.69 (t, J=6.3Hz, 2H).

[0320] 4-(5-(3-((6-(3-carboxypropanoyl)naphthalen-2-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid (5): To a solution of methyl 4-(6-hydroxynaphthalen-2-yl)-4-oxobutanoate 4 (20 mg, 0.07 mmol) and methyl 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate A (38 mg, 0.08 mmol) in CH3CN (40 mL) was added Cs2CO3 (126 mg, 0.38 mmol). The mixture was stirred at 65°C for 2 h. The reaction was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product 5 (36 mg, 73%) as a light yellow solid. LCMS (ESI) = m / z 639.1 (M+H).

[0321] 4-(5-(3-((6-(3-carboxypropanoyl)naphthalen-2-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid (Compound 13): To a solution of methyl 4-(4-fluoro-6-methoxy-5-(3-((6-(4-methoxy-4-oxobutanoyl)naphthalen-2-yl)oxy)propoxy)benzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate 5 (30 mg, 0.046 mmol) in THF / MeOH / H2O (0.5 mL / 0.5 ml / 0.5 ml) was added LiOH (18 mg, 0.46 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and LCMS showed the reaction was complete. The pH value of the reaction mixture was adjusted to 1 by adding 1M HCl, and then extracted with EtOAc (5 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC to give the desired product, compound 13 (23 mg, 80%), as a white solid. 1HNMR(400MHz,DMSO-d6)δ12.10(s,2H),8.63(d,J=1.6Hz,1H),8.27(s,1H),8.05(d,J =9.2Hz,1H),7.96(d,J=10.0Hz,1H),7.91(d,J=8.8Hz,1H),7.55(s,1H),7.45(s,1H), 7.27(dd,J=8.8,2.4Hz,1H),4.37(t,J=6.0Hz,2H),4.26(t,J=6.0Hz,2H),3.83(s,3H ),3.39–3.34(m,4H),2.63(t,J=6.2Hz,2H),2.22(m,2H),1.22(s,6H).LCMS(ESI)=m / z 609.2(M+H).

[0322] Scheme 14. Synthesis of compound 14:

[0323] 3-(Benzylthio)propanoyl chloride (2): To a solution of 3-(benzylthio)propanoic acid 1 (820 mg, 4.18 mmol) in DCM (35 mL) was added oxalyl chloride (1.6 g, 12.53 mmol) at 0°C, followed by a drop of DMF to the reaction mixture. The reaction was stirred at room temperature under nitrogen for 3 hours. Afterwards, the mixture was concentrated under reduced pressure to give the desired product 2 as a yellow oil, which was used in the next step.

[0324] 3-(Benzylthio)-1-(4-fluoro-5,6-dimethoxybenzo[b]thiophen-2-yl)propan-1-one (3): To a solution of 4-fluoro-5,6-dimethoxybenzo[b]thiophene (446 mg, 2.1 mmol) in DCM (12 mL) was added 3-(benzylthio)propanoyl chloride 2 (900 mg, 4.2 mmol) and AlCl3 (336 mg, 2.52 mmol) at 0°C under nitrogen atmosphere. The reaction was stirred overnight at room temperature. The reaction mixture was diluted with water (20 mL) and then extracted with DCM (10 mL x 3), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product 3 (510 mg, 62%) as a yellow solid. 1 H NMR(400MHz, CDCl3)δ7.84(s,1H),7.35-7.03(m,5H),7.06(s,1H),3.99(s, 3H), 3.97 (s, 2H), 3.96 (s, 3H), 3.14 (t, J = 7.2Hz, 2H), 2.85 (t, J = 7.2Hz, 2H).

[0325] 3-(4-Fluoro-5,6-dimethoxybenzo[b]thiophen-2-yl)-3-oxopropane-1-sulfonic acid (4): 1M HCl (2 mL, 2 mmol) was added to a solution of NCS (684 mg, 5.12 mmol) in CH3CN (5 mL), and the reaction mixture was stirred at 0°C for 10 minutes. Then, a solution of 3-(benzylthio)-1-(4-fluoro-5,6-dimethoxybenzo[b]thiophen-2-yl)propan-1-one 3 (800 mg, 2.04 mmol) in 3 mL CH3CN was added to the reaction, and the mixture was stirred at room temperature for 1 hour. After that, the mixture was directly concentrated under reduced pressure, and the crude product was purified by reverse phase column to obtain the desired product 4 (445 mg, 62%) as a solid. 1 H NMR (400MHz, CDCl3) δ7.96 (s, 1H), 7.08 (s, 1H), 3.99 (s, 3H), 3.96 (s, 3H), 3.93 (t, J = 7.2Hz, 2H), 3.45 (t, J = 7.2Hz, 2H).

[0326] 3-(4-Fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-3-oxopropane-1-sulfonic acid (5): To a solution of 3-(4-fluoro-5,6-dimethoxybenzo[b]thiophen-2-yl)-3-oxopropane-1-sulfonic acid 4 (90 mg, 0.26 mmol) in DCM (4 mL) was added AlCl3 (242 mg, 1.8 mmol) at 0°C. The mixture was then stirred at room temperature overnight. Afterwards, the reaction mixture was carefully diluted with water (10 mL) and then extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse phase column to give the desired product 5 (47 mg, 89%) as a white solid. LCMS (ESI) = m / z 333.1 (M+H).

[0327] 3-(4-Fluoro-5-(3-((4-fluoro-6-methoxy-2-(4-methoxy-3,3-dimethyl-4-oxobutanoyl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-3-oxopropane-1-sulfonic acid (6): To a solution of 3-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-3-oxopropane-1-sulfonic acid 5 (47 mg, 0.14 mmol) in DMF (1 mL) was added Cs2CO3 (184 mg, 0.56 mmol) and methyl 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate A (68 mg, 0.14 mmol) at room temperature. The mixture was heated to 65°C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=10 / 1, v / v) to give the desired product 6 (52 mg, 52%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.25(s,1H),8.14(s,1H),7.54(d,J=7.7Hz,2H),4.27(t,J=6.1Hz,4H) ,3.87(d,J=5.5Hz,6H),3.29(s,2H),2.77(t,J=7.5Hz,2H),2.08(q,J=6.2Hz,2H),1.23(s,6H).

[0328] 4-(4-Fluoro-5-(3-((4-fluoro-6-methoxy-2-(3-sulfopropanoyl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid (Compound 14): To a solution of 3-(4-fluoro-5-(3-((4-fluoro-6-methoxy-2-(4-methoxy-3,3-dimethyl-4-oxobutanoyl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-3-oxopropane-1-sulfonic acid 6 (45 mg, 0.062 mmol) in THF / MeOH / H2O (1.5 mL) was added LiOH (4.5 mg, 0.189 mmol) at room temperature and the reaction was stirred overnight. TLC showed the disappearance of SM. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product, Compound 14 (7 mg, 92%), as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ8.23(s,1H),8.14(s,1H),7.53(d,J=2.7Hz,2H),4.27(t,J=6.1Hz,4H),3.87(d,J=4.4Hz, 6H),3.35(s,2H),3.29(t,J=7.5Hz,2H),2.77(t,J=7.5Hz,2H),2.09(t,J=6.1Hz,2H),1.23(s,6H).LCMS(ESI)=m / z 699(MH).

[0329] Scheme 15. Synthesis of compound 15:

[0330] 1-Fluoronaphthalene-2-ol (2): Selectfluor (2.7 g, 8 mmol) and BMIMPF6 (13.79 g, 48 mmol) were added to a solution of naphthalene-2-ol (2.0 g, 14 mmol) in MeOH (40 mL) at room temperature. The mixture was then stirred overnight at room temperature. Afterwards, the reaction mixture was quenched with ice water (100 mL), extracted with EtOAc (40 mL×3), and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography to give the desired product 2 (480 mg, 21%) as an oil. 1 H NMR (400MHz, CHCl3-d) δ7.96 (d, J = 8.4Hz, 1H), 7.78 (d, J = 8.4Hz, 1H), 7.59–7.48 (m, 2H), 7.38 (t, J = 7.6Hz, 1H), 7.23 (t, J = 8.6Hz, 1H).

[0331] 1-Fluoro-2-methoxynaphthalene (3): To a solution of 1-fluoronaphthalene-2-ol 2 (480 mg, 2.96 mmol) in DMF (8 mL) was added K2CO3 (1.02 g, 7.40 mmol) and CH3I (1.05 g, 7.40 mmol) at 0°C. The reaction mixture was then stirred at room temperature under nitrogen for 3 hours. The mixture was diluted with water (60 mL) and then extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product 3 (390 mg, 74%) as an oil. LCMS (ESI) = m / z 177 (M+H).

[0332] 4-(5-Fluoro-6-methoxynaphthalene-2-yl)-4-oxobutanoic acid (4): To a solution of 1-fluoro-2-methoxynaphthalene 3 (380 mg, 2.16 mmol) and dihydrofuran-2,5-dione (431 mg, 4.31 mmol) in DCM (8 mL) was slowly added AlCl3 (431 mg, 3.24 mmol) at 0°C, and the mixture was stirred at room temperature overnight. The mixture was quenched with ice water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product 4 (330 mg, 55%) as a yellow solid. 1 H NMR(400MHz,MeOH-d4)δ8.56(d,J=1.6Hz,1H),8.06–7.98(m,2H),7.85(d,J=9.2Hz,1 H), 7.51 (t, J = 8.8Hz, 1H), 4.03 (s, 3H), 3.42 (t, J = 6.4Hz, 2H), 2.75 (t, J = 6.4Hz, 2H).

[0333] Methyl 4-(5-fluoro-6-methoxynaphthalen-2-yl)-4-oxobutanoate (5): To a solution of 4-(5-fluoro-6-methoxynaphthalen-2-yl)-4-oxobutanoic acid 4 (300 mg, 1.09 mmol) in DMF (3 mL) was added K2CO3 (450 mg, 3.26 mmol) and CH3I (231 mg, 1.63 mmol) at 0°C. The mixture was then stirred at room temperature for 3 hours under a nitrogen atmosphere. The mixture was diluted with water (30 mL) and then extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (300 mg, 95%) as an oil. LCMS (ESI) = m / z 291 (M+H).

[0334] Methyl 4-(5-fluoro-6-hydroxynaphthalen-2-yl)-4-oxobutanoate (6): To a suspension of AlCl3 (326 mg, 2.5 mmol) in DCM (1 mL) was added methyl 4-(5-fluoro-6-methoxynaphthalen-2-yl)-4-oxobutanoate 5 (71 mg, 0.25 mmol) at 0°C. The reaction mixture was warmed to ambient temperature and stirred under nitrogen for 16 hours. Afterwards, the mixture was quenched with water (10 mL), the pH value was adjusted to 2 by adding 1 M HCl, and then extracted with EtOAc (6 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product 6 (51 mg, 72%) as a light yellow solid. LCMS (ESI) = m / z 275.1 (M+H).

[0335] 4-(4-fluoro-5-(3-((1-fluoro-6-(4-methoxy-4-oxobutanoyl)naphthalen-2-yl)oxy)propoxy)-6-methoxybenzo[b]thiophene-2-yl To a solution of methyl 4-(5-fluoro-6-hydroxynaphthalen-2-yl)-4-oxobutanoate 6 (35 mg, 0.11 mmol) and methyl 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate A (51 mg, 0.12 mmol) in CH3CN (40 mL) was added Cs2CO3 (92 mg, 0.38 mmol) and the mixture was stirred at 65°C under nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product 7 (52 mg, 62%) as a light yellow solid. LCMS(ESI)=m / z 657.2(M+H).

[0336] 4-(5-(3-((6-(3-carboxypropanoyl)-1-fluoronaphthalen-2-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid (Compound 15): To a solution of methyl 4-(4-fluoro-5-(3-((1-fluoro-6-(4-methoxy-4-oxobutanoyl)naphthalen-2-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate 7 (25 mg, 0.038 mmol) in THF / MeOH / H2O (0.5 mL / 0.5 ml / 0.5 ml) was added LiOH (10 mg, 0.38 mmol). The mixture was stirred at room temperature overnight. The mixture was adjusted to pH 1 by adding 1M HCl and extracted with EtOAc (5 mL×3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative TLC to give the desired product, compound 15 (18 mg, 75%), as a white solid. LCMS (ESI) = m / z 627.2 (M+H); 1 H NMR (400MHz, DMSO-d6) δ12.11(s,2H),8.73(s,1H),8.25(s,1H),8.07–7.97(m,3H),7.68(d,J=9.2Hz,1H),7.53(s,1H),4 .49(t,J=6.0Hz,2H),4.26(t,J=6.0Hz,2H),3.83(s,3H),3.38(m,4H),2.67–2.60(m,2H),2.25–2.17(m,2H),1.23(s,6H).

[0337] Scheme 16. Synthesis of compound 16:

[0338] 4-(6,7-Dimethoxynaphthalene-2-yl)-4-oxobutanoic acid (2): To a solution of dihydrofuran-2,5-dione (3.2 g, 31.8 mmol, 2.0 equiv) in DCM (40 mL) was added AlCl3 (6.4 g, 47.8 mmol), the mixture was stirred at 0°C for 10 minutes, and then a solution of 2,3-dimethoxynaphthalene (3.0 g, 15.9 mmol) in DCM (15 mL) was slowly added to the resulting suspension. The reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was quenched with water (60 mL) and then extracted with CHCl3 / IPA (3 / 1, v / v, 40x3 mL). The combined organic phases were concentrated and the residue was purified by silica gel column chromatography to give the desired product 2 (2.8 g, 60% yield) as a dark yellow solid. 1 H NMR(400MHz,CHCl3-d)δ8.34(d,J=1.8Hz,1H),7.87(dd,J=8.6,1.8Hz,1H),7.69(d,J=8.5Hz,1H), 7.20(s,1H),7.11(s,1H),3.99(s,3H),3.99(s,3H),3.39(t,J=6.7Hz,2H),2.78(t,J=6.7Hz,2H).

[0339] Methyl 4-(6,7-dimethoxynaphthalen-2-yl)-4-oxobutanoate (3): To a solution of 4-(6,7-dimethoxynaphthalen-2-yl)-4-oxobutanoic acid 2 (2.8 g, 10.40 mmol) in DMF (40 mL) was added K2CO3 (3.5 g, 26 mmol) and CH3I (2.2 g, 15.6 mmol) at 0°C. The mixture was stirred at room temperature for 12 hours. LCMS showed that the reaction was complete. The mixture was extracted with EtOAc (40 x 3 mL), the organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 3 (2.7 g, 93%) as a yellow solid.

[0340] Methyl 4-(5-fluoro-6,7-dimethoxynaphthalen-2-yl)-4-oxobutanoate (4): Selectfluor (1.7 g, 4.96 mmol) was added to a solution of methyl 4-(6,7-dimethoxynaphthalen-2-yl)-4-oxobutanoate 3 (1 g, 3.3 mmol) in DMF (8 mL) at room temperature. The mixture was stirred at 65 °C for 2 h. The reaction mixture was cooled to room temperature, quenched with water (80 mL), and then extracted with EtOAc (20 x 3 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography to give compound 4 (116 mg, 11%) as a yellow solid. 1 H NMR (400MHz, CHCl3-d) δ8.37(t,J=1.8Hz,1H),8.01(d,J=8.7Hz,1H),7.94(dd,J=8.8,1.6Hz,1H),7.08(d,J =1.6Hz,1H),4.12(d,J=2.0Hz,3H),4.01(s,3H),3.73(s,4H),3.43(t,J=6.7Hz,2H),2.82(t,J=6.7Hz,3H); 19 F NMR (376MHz, CHCl3-d) δ-141.86.

[0341] Methyl 4-(5-fluoro-6-hydroxy-7-methoxynaphthalene-2-yl)-4-oxobutanoate (5): A mixture of methyl 4-(5-fluoro-6,7-dimethoxynaphthalene-2-yl)-4-oxobutanoate 4 (110 mg, 0.34 mmol) and AlCl (155.9 g, 1.03 mmol) in DCM (5 mL) was stirred at 25 °C for 12 h. LCMS showed that the reaction was complete, and the reaction mixture was quenched with ice water (20 mL) and then extracted with CHCl / IPA (3 / 1, v / v, 15 mLx3). The combined organic phases were concentrated and the residue was purified by silica gel column chromatography to give the desired product 5 (88 mg, 83% yield) as a white solid. 1 H NMR(400MHz,CHCl3-d)δ8.38(s,1H),8.02–7.93(m,2H),7.08(s,1H),5.89(s ,1H),4.07(s,3H),3.73(s,3H),3.43(t,J=6.7Hz,2H),2.82(t,J=6.7Hz,2H).

[0342] Methyl 4-(4-fluoro-5-(3-((1-fluoro-3-methoxy-6-(4-methoxy-4-oxobutanoyl)naphthalen-2-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate (6): A mixture of methyl 4-(5-fluoro-6-hydroxy-7-methoxynaphthalen-2-yl)-4-oxobutanoate 5 (35 mg, 0.081 mmol, 1.0 equiv), methyl 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate A (41.4 mg, 0.089 mmol) and Cs2CO3 (85.7 mg, 0.24 mmol) in CH3CN (6 mL) was stirred at 65°C for 4 h. LCMS showed the reaction was complete, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give the desired product 6 (25 mg, 44% yield) as a white solid. 1 H NMR (400MHz, CHCl3-d) δ8.36(s,1H),8.00–7.92(m,2H),7.88(s,1H),7.05(s,1H),7.01(s,1H),4.52(t,J=6.1Hz,2H),4.40(t,J=6.1Hz,2H),3. 94(s,3H),3.86(s,3H),3.73(s,3H),3.70(s,3H),3.43(t,J=6.7Hz,2H) ,3.28(s,2H),2.83(t,J=6.6Hz,2H),2.28(t,J=6.1Hz,2H),1.35(s,6H).

[0343] 4-(5-(3-((6-(3-carboxypropanoyl)-1-fluoro-3-methoxynaphthalen-2-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl 4-(4-Fluoro-5-(3-((1-fluoro-3-methoxy-6-(4-methoxy-4-oxobutanoyl)naphthalen-2-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid methyl ester 6 (35 mg, 0.051 mmol) and LiOH (12.2 mg, 0.305 mmol) in THF / MeOH / H2O (2 / 2 / 1, v / v / v, 5 mL) were stirred at 40 °C for 14 hours. LCMS showed that the reaction was complete. The reaction mixture was acidified to pH~3 by adding 1N HCl and extracted with EtOAc (15x3 mL). The combined organic phases were concentrated under reduced pressure to give the desired product, compound 16 (28 mg, 82% yield), as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ12.13(s,2H),8.61(s,1H),8.23(s,1H),8.02–7.85(m,2H),7.51(s,2H),4.41(t,J=6.1Hz,2H), 4.29(t,J=6.1Hz,2H),3.91(s,3H),3.84(s,3H),3.37(s,2H),2.64(t,J=6.3Hz,2H),2.13(d,J=6.1Hz,2H),1.22(s,6H).

[0344] Scheme 17. Synthesis of compound 17:

[0345] 4-(5-(3-((2-(4-((2-((tert-butoxycarbonyl)amino)ethyl)sulfonamido)-3,3-dimethyl-4-oxobutanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid tert-butyl ester: 4-(5-(3-((2-(4-(tert-butoxy)-3,3-dimethyl-4-oxobutanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid tert-butyl ester To a mixture of dichloromethane (5mL) was added HATU (58.6mg, 0.15mmol) and DMAP (12.6mg, 0.10mmol) in 1% 4-nitropropoxy)-4-fluoro-6-methoxybenzo[b]thiophene-2-yl)-2,2-dimethyl-4-oxobutanoic acid 1 (77mg, 0.1mmol), tert-butyl N-(2-sulfamoylethyl)carbamate (46mg, 0.2mmol), and DIEA (66mg, 0.51mmol, 0.09mL). After 2h, DBU (23.5mg, 0.15mmol, 0.02mL) was added. The reaction mixture was stirred at room temperature for 21h. LCMS showed that the reaction was complete, the reaction mixture was diluted with water, the organic layer was extracted with DCM, and the organic matter was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound 2 (50mg, 51%). LCMS (ESI) = m / z 955.2 (M+H), 977.2 (M+Na).

[0346] 4-(5-(3-((2-(4-((2-aminoethyl)sulfonamido)-3,3-dimethyl-4-oxobutanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid (Compound 17): A mixture of Compound 2 (37 mg, 0.04 mmol) in 5% TFA / 1,1,1,3,3,3-hexafluoro-2-propanol (3 mL) was stirred at room temperature for 0.5 h, and the mixture was concentrated. LCMS showed the reaction was complete, MTBE was added to the residue, and the resulting suspension was re-concentrated. This process was repeated twice. The residue was purified by reverse phase HPLC (C-18 column, 10% to 80% acetonitrile in water with 0.1% formic acid over 30 min). The fractions were combined and freeze-dried to give 4-(5-(3-((2-(4-((2-aminoethyl)sulfonamido)-3,3-dimethyl-4-oxobutanoyl)-4-fluoro-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid compound 17 as a white powder (20.2 mg, 33%); 1 H NMR (400MHz, DMSO-d6) δ8.23(s,1H),8.14(s,1H),7.52(d,J=15.7Hz,2H),6.70(s,1H),4.31–4.23(m,4H),3.85(d,J=6.9Hz,6H),3.41(d ,J=72.6Hz,2H),3.21–3.06(m,4H),3.00(t,J=6.6Hz,2H),2.08(p,J=6.0Hz,2H),1.21(s,6H),1.15(s,6H).LCMS(ESI)=m / z=799.2(M+H).

[0347] Scheme 18. Synthesis of compound 18:

[0348] Compound 18 was synthesized in a similar manner using the same method as above.

[0349] Scheme 19. Synthesis of compound 19:

[0350] Compound 19 was synthesized by the same method as above.

[0351] Compound 20, compound 21, compound 22, compound 24, compound 25, compound 26, compound 27, compound 28, compound 29, compound 30 and compound 31 were synthesized by methods similar to the above.

[0352] Scheme 20. Synthesis of compound 23:

[0353] 1-Fluoro-2,3-dimethoxy-5-nitrobenzene (2): 1-Fluoro-2,3-dimethoxybenzene (12 g, 76.84 mmol, 1.0 equiv) was dissolved in 120 mL HNO3 at 0°C and the mixture was stirred at room temperature for 30 minutes. TLC showed that the starting material had been consumed. The reaction mixture was poured into water (300 mL) and extracted with EtOAc (150 mL x 3). The combined organic phases were then washed with aqueous NaHCO3, dried over Na2SO4, concentrated, and the crude product was purified by silica gel chromatography to give the desired product 2 (11 g, 55%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.87-7.84(m,1H),7.73-7.12(m,1H),3.95(s,6H).

[0354] 3-Fluoro-4,5-dimethoxyaniline (3): To a solution of 1-fluoro-2,3-dimethoxy-5-nitrobenzene 2 (11 g, 54.68 mmol, 1.0 equiv) in IPA (400 mL) was added Pd / C (20%, 1 g). The mixture was then stirred at room temperature overnight under a hydrogen atmosphere. TLC showed that the starting material had been consumed. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the desired product 3 (9.3 g, 98%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ6.05 (s, 1H), 5.95 (dd, J = 12.8, 2.4Hz, 1H), 5.11 (s, 2H), 3.70 (s, 3H), 3.60 (s, 3H).

[0355] 5-Fluoro-6,7-dimethoxyquinoline (4): 3-Fluoro-4,5-dimethoxyaniline 3 (7.3 g, 42.59 mmol, 1.0 equiv) was dissolved in H2O (20 mL) and concentrated H2SO4 (18 mL), to which was added a mixture of 4-nitrophenol (6.5 g, 46.80 mmol) and glycerol (23.5 g, 255.6 mmol). The reaction mixture was then stirred at 140°C for 4 hours. The mixture was cooled to room temperature and poured into ice-cold water. The mixture was adjusted to pH 8 with aqueous NaHCO3 solution and extracted with EtOAc (100 mL×3). The combined organic phases were dried over Na2SO4 and concentrated, and the crude product was purified by silica gel chromatography to give the desired product 4 (6.76 g, 76%) as a white solid. 1 H NMR (400MHz, CHCl3-d) δ8.80 (dd, J=4.4, 1.6Hz, 1H), 8.28 (dd, J=8.4, 1.6Hz, 1H ), 7.32 (dd, J = 8.4, 4.4Hz, 1H), 7.28 (d, J = 1.7Hz, 1H), 4.09 (s, 3H), 4.02 (s, 3H).

[0356] 5-Fluoro-1-hydroxy-6,7-dimethoxyquinolin-1-ium (5): 5-Fluoro-6,7-dimethoxyquinoline 4 (8.4 g, 40 mmol, 1.0 equiv) was dissolved in DCM (130 mL) and MCPBA (14 g, 80 mmol) solution was added at 0°C. The mixture was then stirred at room temperature overnight. The reaction mixture was poured into water and extracted with EtOAc (300 mL×3). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure to give the crude product 5 (9 g, 96%) as a white solid; LCMS [M+1] + =224.1.

[0357] 5-Fluoro-6,7-dimethoxyquinoline-2-carbonitrile (6): 5-Fluoro-1-hydroxy-6,7-dimethoxyquinolin-1-ium 5 (11.4 g, 51.07 mmol, 1.0 equiv) was dissolved in DCE (300 mL) and a mixture of TMSCN (66 g, 204 mmol) and (diacetoxyiodo)benzene (20 g, 204 mmol) was added at room temperature. The mixture was then stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the crude product was purified by silica gel chromatography to give the desired product 6 (5.2 g, 44%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 8.56 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.48 (s, 1H), 4.02 (s, 6H).

[0358] 5-Fluoro-6-hydroxy-7-methoxyquinoline-2-carboxylic acid (7): 5-Fluoro-6,7-dimethoxyquinoline-2-carbonitrile 6 (1 g, 4.31 mmol, 1.0 equiv) was dissolved in concentrated HCl (10 mL) and the mixture was stirred overnight at 110° C. The reaction mixture was concentrated under reduced pressure and the crude product was purified by silica gel chromatography to give the desired product 7 (820 mg, 80%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.41 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.45 (s, 1H), 4.02 (s, 3H).

[0359] 5-Fluoro-6-hydroxy-7-methoxyquinoline-2-carbonyl chloride (8): 5-Fluoro-6-hydroxy-7-methoxyquinoline-2-carboxylic acid 7 (800 mg, 3.37 mmol, 1.0 equiv) was dissolved in anhydrous DCM and a solution of oxalyl chloride (1.29 g, 10 mmol) was added at 0°C. Then a drop of DMF was added and the reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo to give the crude product 8, which was used directly. LCMS [M+1] + =252.0.

[0360] Diethyl 2-(5-fluoro-6-hydroxy-7-methoxyquinoline-2-carbonyl)succinate (9): To a solution of diethyl succinate (554 mg, 6.36 mmol, 1.0 equiv) in anhydrous THF (15 mL) was added dropwise a solution of KHMDS (5.8 ml, 5.72 mmol) at -78°C, and the mixture was stirred at this temperature for 30 minutes. Then a solution of 5-fluoro-6-hydroxy-7-methoxyquinoline-2-carbonyl chloride 8 (814 mg, 3.37 mmol, 1.0 equiv) in THF (5 mL) was added. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with aqueous NH4Cl (20 mL) at 0°C, and then extracted with EA (300 mL×3). The combined organic phases were dried over Na2SO4, concentrated, and the crude product was purified by silica gel chromatography to give the desired product 9 (720 mg, 54%) as a white solid. 1 H NMR(400MHz,CHCl3-d)δ8.39(d,J=8.8Hz,1H),8.05(d,J=8.8Hz,1H),7.33(s,1H) ,5.53(t,J=7.2Hz,1H),4.06(s,3H),3.70(s,3H),3.66(s,3H),3.11-3.03(m,2H).

[0361] Diethyl 2-(5-fluoro-6-(3-((4-fluoro-6-methoxy-2-(4-methoxy-3,3-dimethyl-4-oxobutanoyl)benzo[b]thiophen-5-yl)oxy)propoxy)-7-methoxyquinoline-2-carbonyl)succinate (10): To a solution of diethyl 2-(5-fluoro-6-hydroxy-7-methoxyquinoline-2-carbonyl)succinate 9 (300 mg, 0.76 mmol, 1.0 equiv) and methyl 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate Compound A (352 mg, 0.76 mmol) in CH3CN (10 mL) was added Cs2CO3 (994 mg, 3.05 mmol). The mixture was stirred at 65°C under nitrogen atmosphere for 2 h. LCMS showed that the reaction was complete. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH=80 / 1, v / v) to give the desired product 10 (420 mg, 71%) as a light yellow solid; LCMS [M+1] + =774.1.

[0362] 4-(5-(3-((2-(3-carboxypropanoyl)-5-fluoro-7-methoxyquinolin-6-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoic acid (Compound 23): To a solution of diethyl 2-(5-fluoro-6-(3-((4-fluoro-6-methoxy-2-(4-methoxy-3,3-dimethyl-4-oxobutanoyl)benzo[b]thiophen-5-yl)oxy)propoxy)-7-methoxyquinoline-2-carbonyl)succinate 10 (80 mg, 0.1 mmol, 1.0 equiv) in THF (1 mL) was added 6M HCl (1 mL) at room temperature. The mixture was then stirred at 80°C overnight. LCMS showed the reaction was complete. The mixture was concentrated and the crude product was purified by silica gel chromatography (DCM / MeOH=10 / 1) to give the desired product, compound 23 (20 mg, 30%), as a light yellow solid; 1 H NMR(400MHz,CHCl3-d)δ8.27(d,J=8.8Hz,1H),7.92(d,J=8.8Hz,1H),7.82(s,1H),7.26(s,1H),6.97(s,1H)4.47(t,J=6.0Hz,2H), 4.31(t,J=6.0Hz,2H),3.92(s,3H),3.79(s,3H),3.59(s,2H),3.21(s,2H),2.72(t,J=6.7Hz,2H),2.19-2.16(m,2H),1.27(s,6H).

[0363] The following compounds were synthesized according to the above method. Example 2: Selected STING agonists based on in vitro cell activity

[0364] Certain STING compounds of the invention were evaluated in in vitro cell-based assays.

[0365] 293-Dual hSTING-R232 and mSTING cells (Invivogen) were seeded at 25,000 cells / well (50 μL) and co-cultured with STING agonists (2x concentration, 50 μL) in transparent, half-area, 96-well polystyrene plates. Cells and test samples were prepared in DMEM supplemented with 10% FBS, Glutamax, and PenStrep. After incubation overnight at 37°C in a CO2 incubator, 20 μL of supernatant was added to QUANTI-Blue detection reagent (Invivogen). After incubation for 1 hour at 37°C, the plates were read at 640 / 650 nm on an EnVision plate reader (PerkinElmer). OD values ​​were plotted using GraphPad Prism software by log (agonist) versus response, variable slope, four-parameter curve fit (logarithmic transformation) to determine EC 50 value.

[0366] Table 1 provides the results of ISG reporter gene induction in 293 human / mouse reporter gene cells. (“A” indicates EC 50 ≤50 nM; "B" means >50 nM and <150 nM; "C" means >150 nM). Table 1: Activity of selected compounds in SG reporter gene-induced 293 human and mouse reporter gene cells Example 3: Thermal shift and surface plasmon resonance of selected STING agonists

[0367] The thermal shift assay was performed based on the published method described in Ramanjulu et al. Nature, 2018, 564, 439. The results are provided in Table 2. Table 2: Thermal shifts of selected STING agonists

[0368] The surface plasmon resonance assay was performed based on the published method described in Pan et al., Science, 2020 369, eaba6098. (“A” indicates EC 50 The results are provided in Table 3. Table 3: Surface plasmon resonance of selected STING agonists

[0369] The above embodiments and examples are intended to be illustrative only and not limiting. Those skilled in the art will recognize or be able to determine numerous equivalents of specific compounds, materials and procedures using no more than routine experimentation. All such equivalents are deemed to be included within the scope of the present invention and are included in the appended claims.

Claims

1. Compounds of formula I: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; in: L 1 Selected from C1-C6 alkylene, Where L 1 Any substitutable carbon atom in the 1-6 Alkyl, C 1-6 Alkylamino, C 3-10 Cycloalkyl, hydroxyl, cyano, -NR 9a R 9b , and -COOR 10 Substituents are substituted; A is selected from R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from H, halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, halo-C 1-6 Alkyl, Hydroxyl-C 1-6 Alkyl, hydroxyl, -NR 9a R 9b , amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, and -COOR 10 ; X 1 and X 4 are independently selected from -C(O)-, -C(R 12a R 12b )-, -CH=CH-, and -C(R 12a R 12b )C(R 13a R 13b )-; X 2 and X 5 are each independently selected from -(C(R 12a R 12b )) 1-6 -, and -(C(R 12a R 12b )C(R 13a R 13b )) 1-3 -; X 3 Selected from -COOR 10 、 -CONR 9a R 9b 、 -C(O)NR 9a S(O)2R 14 、 -S(O)2OR 10 、 -S(O)OR 10 、 -P(O)(OR 15 )2、 -OP(O)(OR 15 )2、 and -P(O)(NR 16a R 16b )(OR 15 ); X 6 selected from -C(O)NR 9a S(O)2R 17 、-C(O)NR 9a R 18 、-S(O)2OH, -S(O)OH, -P(O)(OR 15 )2, -OP(O)(OR 15 )2, and -P(O)(NR 16a R 16b )(OR 15 ); X 7 is -CH=CH-, C2 alkynyl, or -C(R 12a R 12c )C(R 13a R 13c )-; X 8 selected from -COOR 10 、 -CONR 9a R 9b 、 -C(O)NR 9a S(O)2R 14 、 -S(O)2OR 10 、 -S(O)OR 10 、 -P(O)(OR 15 )2、 -OP(O)(OR 15 )2、 and -P(O)(NR 16a R 16b )(OR 15 ); X 9 , X 10 and X 11 Each independently selected from CR 19 and N; Y 1 independently selected from CH2, O, NH, and S; Y 2 independently selected from O, NH, and S; R 9a and R 9b are independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, aryl, aryl-C 1-6 Alkyl, amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 alkyl, and heteroaryl; R 10 Independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, aryl, aryl-C 1-6 alkyl, and heteroaryl; R 11 Independently selected from H and C 1-6 alkyl; R 12a , R 12b , R 13a and R 13b are independently selected from H and C 1-6 alkyl; or R 12b With R 13b Connected together to form C3-C 10 Cycloalkyl, the C3-C 10 Cycloalkyl is optionally selected from halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, hydroxyl, cyano, -NR 9a R 9b and-COOR 10 Substituents are substituted; R 12c With R 13c Connected together to form C3-C 10 Cycloalkyl, the C3-C 10 Cycloalkyl is optionally selected from halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, hydroxyl, cyano, -NR 9a R 9b and-COOR 10 Substituents are substituted; R 14 Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, halo-C 1-6 Alkyl, amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, Aryl, Aryl-C 1-6 alkyl, and heteroaryl; R 15 , R 16a and R 16b are independently selected from H, C 1-6 Alkyl, and C 3-10 Cycloalkyl; R 17 It is amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, C 3-10 Cycloalkylamino-C 1-6 Alkyl, Aryl, Aryl-C 1-6 Alkyl or heteroaryl; R 18 It is amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, C 3-10 Cycloalkylamino-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, aryl, aryl-C 1-6 alkyl, or heteroaryl; and R 19 are independently selected from H, halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, halo-C 1-6 Alkyl, Hydroxyl-C 1-6 Alkyl, hydroxyl, -NR 9a R 9b , and -COOR 10 ;and a and b are each an integer independently selected from 0, 1, 2, 3, 4 and 5.

2. Compound represented by formula II: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; in: L 1 Selected from C1-C6 alkylene, Where L 1 Any substitutable carbon atom in the 1-6 Alkyl, C 1-6 Alkylamino, C 3-10 Cycloalkyl, hydroxyl, cyano, -NR 9a R 9b , and -COOR 10 Substituents are substituted; A is selected from R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from H, halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, halo-C 1-6 Alkyl, Hydroxyl-C 1-6 Alkyl, hydroxyl, -NR 9a R 9b , amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, and -COOR 10 ; X 1 and X 4 are independently selected from -C(O)-, -C(R 12a R 12b )-, -CH=CH-, and -C(R 12a R 12b )C(R 13a R 13b )-; X 2 and X 5 are each independently selected from -(C(R 12a R 12b )) 1-6 -, and -(C(R 12a R 12b )C(R 13a R 13b )) 1-3 -; X 3 selected from -COOR 10 、 -CONR 9a R 9b 、 -C(O)NR 9a S(O)2R 14 、 -S(O)2OR 10 、 -S(O)OR 10 、 -P(O)(OR 15 )2、 -OP(O)(OR 15 )2、 and -P(O)(NR 16a R 16b )(OR 15 ); X 6 selected from -C(O)NR 9a S(O)2R 17 、-C(O)NR 9a R 18 、-S(O)2OH, -S(O)OH, -P(O)(OR 15 )2, -OP(O)(OR 15 )2, and -P(O)(NR 16a R 16b )(OR 15 ) X 7 is -CH=CH-, C2 alkynyl, or -C(R 12a R 12c )C(R 13a R 13c )-; X 8 selected from -COOR 10 、 -CONR 9a R 9b 、 -C(O)NR 9a S(O)2R 14 、 -S(O)2OR 10 、 -S(O)OR 10 、 -P(O)(OR 15 )2、 -OP(O)(OR 15 )2、 and -P(O)(NR 16a R 16b )(OR 15 ); X 9 , X 10 and X 11 Each independently selected from CR 19 and N; Y 1 independently selected from CH2, O, NH, and S; Y 2 independently selected from O, NH, and S; R 9a and R 9b are independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, aryl, aryl-C 1-6 Alkyl, amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 alkyl, and heteroaryl; R 10 Independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, aryl, aryl-C 1-6 alkyl, and heteroaryl; R 11 Independently selected from H and C 1-6 alkyl; R 12a , R 12b , R 13a and R 13b are independently selected from H and C 1-6 alkyl; or R 12b With R 13b Connected together to form C3-C 10 Cycloalkyl, the C3-C 10 Cycloalkyl is optionally selected from halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, hydroxyl, cyano, -NR 9a R 9b and-COOR 10 Substituents are substituted; R 12c With R 13c Connected together to form C3-C 10 Cycloalkyl, the C3-C 10 Cycloalkyl is optionally selected from halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, hydroxyl, cyano, -NR 9a R 9b and-COOR 10 Substituents are substituted; R 14 Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, halo-C 1-6 Alkyl, amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, Aryl, Aryl-C 1-6 alkyl, and heteroaryl; R 15 , R 16a and R 16b are independently selected from H, C 1-6 Alkyl, and C 3-10 Cycloalkyl; R 17 It is amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, C 3-10 Cycloalkylamino-C 1-6 Alkyl, Aryl, Aryl-C 1-6 Alkyl or heteroaryl; R 18 It is amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, C 3-10 Cycloalkylamino-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, aryl, aryl-C 1-6 alkyl, or heteroaryl; and R 19 are independently selected from H, halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, halo-C 1-6 Alkyl, Hydroxyl-C 1-6 Alkyl, hydroxyl, -NR 9a R 9b , and -COOR 10 ;and a and b are each an integer independently selected from 0, 1, 2, 3, 4 and 5.

3. Compound represented by formula III: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; in: L 1 Selected from C1-C6 alkylene, Where L 1 Any substitutable carbon atom in the 1-6 Alkyl, C 1-6 Alkylamino, C 3-10 Cycloalkyl, hydroxyl, cyano, -NR 9a R 9b , and -COOR 10 Substituents are substituted; A is selected from R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from H, halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, halo-C 1-6 Alkyl, Hydroxyl-C 1-6 Alkyl, hydroxyl, -NR 9a R 9b , amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, and -COOR 10 ; X 1 and X 4 are independently selected from -C(O)-, -C(R 12a R 12b )-, -CH=CH-, and -C(R 12a R 12b )C(R 13a R 13b )-; X 2 and X 5 are each independently selected from -(C(R 12a R 12b )) 1-6 -, and -(C(R 12a R 12b )C(R 13a R 13b )) 1-3 -; X 3 selected from -COOR 10 、-CONR 9a R 9b 、-C(O)NR 9a S(O)2R 14 、-S(O)2OR 10 、-S(O)OR 10 、-P(O)(OR 15 )2、-OP(O)(OR 15 )2、and -P(O)(NR 16a R 16b )(OR 15 ); X 6 selected from -C(O)NR 9a S(O)2R 17 、-C(O)NR 9a R 18 、-S(O)2OH, -S(O)OH, -P(O)(OR 15 )2, -OP(O)(OR 15 )2, and -P(O)(NR 16a R 16b )(OR 15 ) X 7 is -CH=CH-, C2 alkynyl, or -C(R 12a R 12c )C(R 13a R 13c )-; X 8 Selected from -COOR 10 、 -CONR 9a R 9b 、 -C(O)NR 9a S(O)2R 14 、 -S(O)2OR 10 、 -S(O)OR 10 、 -P(O)(OR 15 )2、 -OP(O)(OR 15 )2、 and -P(O)(NR 16a R 16b )(OR 15 ); X 9 , X 10 and X 11 Each independently selected from CR 19 and N; Y 1 independently selected from CH2, O, NH, and S; Y 2 independently selected from O, NH, and S; R 9a and R 9b are independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, aryl, aryl-C 1-6 Alkyl, amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 alkyl, and heteroaryl; R 10 Independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, aryl, aryl-C 1-6 alkyl, and heteroaryl; R 11 Independently selected from H and C 1-6 alkyl; R 12a , R 12b , R 13a and R 13b are independently selected from H and C 1-6 alkyl; or R 12b With R 13b Connected together to form C3-C 10 Cycloalkyl, the C3-C 10 Cycloalkyl is optionally selected from halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, hydroxyl, cyano, -NR 9a R 9b and-COOR 10 Substituents are substituted; R 12c With R 13c Connected together to form C3-C 10 Cycloalkyl, the C3-C 10 Cycloalkyl is optionally selected from halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, hydroxyl, cyano, -NR 9a R 9b and-COOR 10 Substituents are substituted; R 14 Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, halo-C 1-6 Alkyl, amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, Aryl, Aryl-C 1-6 alkyl, and heteroaryl; R 15 , R 16a and R 16b are independently selected from H, C 1-6 Alkyl, and C 3-10 Cycloalkyl; R 17 It is amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, C 3-10 Cycloalkylamino-C 1-6 Alkyl, Aryl, Aryl-C 1-6 Alkyl or heteroaryl; R 18 It is amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, C 3-10 Cycloalkylamino-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, aryl, aryl-C 1-6 alkyl, or heteroaryl; and R 19 are independently selected from H, halogen, alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, halo-C 1-6 Alkyl, Hydroxyl-C 1-6 Alkyl, hydroxyl, -NR 9a R 9b , and -COOR 10 ;and a and b are each an integer independently selected from 0, 1, 2, 3, 4 and 5.

4. The compound according to claim 1, which has a structure shown in Formula Ia: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

5. The compound according to claim 1, which has the structure shown in Formula Ib: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

6. The compound according to claim 1, which has the structure shown in Formula Ic: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

7. The compound according to claim 1, which has the structure shown in Formula Id: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

8. The compound according to claim 2, which has a structure shown in Formula IIa: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

9. The compound according to claim 2, which has a structure shown in Formula IIb: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

10. The compound according to claim 3, which has a structure shown in Formula IIIa: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

11. The compound according to any one of claims 1 to 10, wherein L 1 Selected from C1-C6 alkylene, 12. The compound according to any one of claims 1 to 10, wherein L 1 yes 13. The compound according to any one of claims 1 to 10, wherein L 1 Selected from 14. The compound according to claim 4, wherein The compound represented by formula Ia is a compound of formula (Iai), (Iaii), (Iaiii), or (Iaiv): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

15. The compound according to claim 5, wherein The compound represented by formula Ib is a compound of formula (Ibi) or (Ibii): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

16. The compound according to claim 6, wherein The compound represented by formula Ic is a compound of formula (Ici), (Icii), (Iciii), or (Iciv): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

17. The compound according to claim 7, wherein The compound represented by formula Id is a compound of formula (Idi): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

18. The compound according to claim 8, wherein The compound represented by formula IIa is a compound of formula (IIai): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

19. The compound according to any one of claims 1 to 18, wherein R 1 and R 7 are independently selected from H and halogen; R 2 is selected from H and alkoxy; and R 5 Selected from alkoxy, hydroxy, and amino-C 1-6 alkyl.

20. The compound according to any one of claims 1 to 18, wherein R 1 and R 7 are each halogen, and R 2 and R 5 Each is an alkoxy group.

21. The compound according to claim 19, wherein R 1 It's a halogen.

22. The compound according to claim 19, wherein R 7 It's a halogen.

23. The compound according to claim 21 or 22, wherein Halogen is F.

24. The compound according to any one of claims 1 to 23, wherein R 2 It is an alkoxy group.

25. The compound according to any one of claims 1 to 24, wherein R 5 is selected from alkoxy and H.

26. The compound according to any one of claims 1 to 25, wherein Alkoxy is methoxy.

27. The compound according to any one of claims 1 to 26, wherein a is 2 or 3.

28. The compound according to claim 27, wherein a is 2.

29. The compound according to any one of claims 1 to 28, wherein Selected from in represents the point of attachment to the rest of the compound.

30. The compound according to claim 29, wherein Selected from in represents the point of attachment to the rest of the compound.

31. The compound according to claim 29, wherein Selected from in represents the point of attachment to the rest of the compound.

32. The compound according to claim 29, wherein Selected from in represents the point of attachment to the rest of the compound.

33. A compound according to any one of claims 1-4, 6-14 and 16-32, wherein X 4 is -C(O)-, and X 5 Selected from -CH2-, -CH2CH2-, and -CH2C(CH3)2-.

34. A compound according to any one of claims 1-4, 6-14 and 16-32, wherein Selected from in represents the point of attachment to the rest of the compound.

35. The compound according to any one of claims 1-4, 6-14 and 16-32, wherein yes in represents the point of attachment to the rest of the compound.

36. A compound according to any one of claims 1-4, 6-14 and 16-32, wherein yes in represents the point of attachment to the rest of the compound.

37. The compound according to claim 34, wherein R 17 It is amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, or di-C 1-6 Alkylamino-C 1-6 alkyl.

38. The compound according to claim 37, wherein R 17 It is amino-C 1-6 alkyl.

39. The compound according to claim 36, wherein R 18 It is amino-C 1-6 Alkyl, C 1-6 Alkylamino-C 1-6 Alkyl, di-C 1-6 Alkylamino-C 1-6 Alkyl, or C 1-6 alkyl.

40. The compound according to claim 39, wherein R 18 It is amino-C 1-6 alkyl.

41. The compound according to claim 35, wherein R 15 Independently selected from H, C 1-6 Alkyl, and C 3-10 Cycloalkyl.

42. The compound according to claim 41, wherein R 15 It's H.

43. The compound according to claim 41, wherein R 15 It is C 1-6 alkyl.

44. A compound according to any one of claims 1-3, 5, 11-13, 15 and 19-32, wherein Selected from in represents the point of attachment to the rest of the compound.

45. A compound according to any one of claims 1-3, 5, 11-13, 15 and 19-32, wherein Selected from in represents the point of attachment to the rest of the compound.

46. ​​A compound according to any one of claims 1-3, 5, 11-13, 15 and 19-32, wherein Selected from in represents the point of attachment to the rest of the compound.

47. A compound according to any one of claims 1 to 46, wherein R 10 It is H, C 1-6 Alkyl, or C 3-10 Cycloalkyl.

48. The compound according to claim 47, wherein R 10 It's H.

49. A compound according to any one of claims 1 to 48, wherein X 5 Selected from -CH2-, -CH2CH2-, and -CH2C(CH3)2-.

50. A compound according to any one of claims 1-3, 6, 8, 11-13 and 18-43, wherein X 9 , X 10 and X 11 Each independently selected from CR 19 and N.

51. The compound according to claim 50, wherein X 9 is N, and X 10 and X 11 Each independently selected from CR 19 and N.

52. The compound according to claim 50, wherein X 10 is N, and X 9 and X 11 Each independently selected from CR 19 and N.

53. The compound according to claim 50, wherein X 11 is N, and X 9 and X 10 Each independently selected from CR 19 and N.

54. A compound according to any one of claims 50 to 53, wherein R 19 are independently selected from H, halogen, C 1-6 Alkyl, and alkoxy.

55. A compound according to any one of claims 50 to 53, wherein R 19 It's H.

56. A compound according to any one of claims 1-3, 7, 9-13, 17 and 19-43, wherein Y 1 is O or N, and Y 2 It's O.

57. The compound according to claim 4, having the structure shown in the following formula: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

58. The compound according to claim 57, having the structure shown in the following formula: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

59. The compound according to claim 5, having the structure shown in the following formula: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

60. The compound according to claim 59, having the structure shown in the following formula: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

61. The compound according to claim 1, wherein The compound is selected from: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

62. The compound according to claim 1, wherein The compound is selected from: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

63. The compound according to claim 1, wherein The compound is selected from: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

64. The compound according to claim 1, wherein The compound is selected from: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

65. A pharmaceutical composition comprising the compound according to any one of claims 1 to 64 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient.

66. A method of treating a disease or condition mediated by STING in a subject in need thereof, comprising administering a compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition of claim 65.

67. A method of inducing an immune response in a subject in need thereof, comprising administering a compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition of claim 65.

68. The method of claim 67, wherein: The immune response induces STING-dependent type I interferon production in a subject in need thereof.

69. The method of claim 67 or 68, wherein: The immune response induces STING-dependent cytokine production in a subject in need thereof.

70. A method of treating abnormal cell proliferation in a subject in need thereof, comprising administering a compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition of claim 65.

71. The method of claim 70, wherein: Such abnormal cell proliferation is cancer.

72. The method of claim 71, wherein: The cancer is a solid tumor.

73. The method of claim 71, wherein: The cancer is selected from the group consisting of lymphoma, head and neck squamous cell carcinoma, urothelial carcinoma, lung cancer, prostate cancer, SCLC, bladder cancer, and melanoma.

74. Use of the compound of any one of claims 1-64 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or the pharmaceutical composition of claim 65 for treating a disease or condition mediated by STING in a subject in need thereof.

75. Use of the compound of any one of claims 1-64 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or the pharmaceutical composition of claim 65 to induce an immune response in a subject in need thereof.

76. The use according to claim 75, wherein The immune response induces STING-dependent type I interferon production in a subject in need thereof.

77. The use according to claim 75 or 76, wherein The immune response induces STING-dependent cytokine production in a subject in need thereof.

78. Use of a compound according to any one of claims 1 to 64 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition according to claim 65 for treating abnormal cell proliferation in a subject in need thereof.

79. The use according to claim 78, wherein Such abnormal cell proliferation is cancer.

80. The use according to claim 79, wherein The cancer is a solid tumor.

81. The use according to claim 79, wherein The cancer is selected from the group consisting of lymphoma, head and neck squamous cell carcinoma, urothelial carcinoma, lung cancer, prostate cancer, SCLC, bladder cancer, and melanoma.

82. Use of a compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition according to claim 65, in the preparation of a medicament for treating a disease or condition mediated by STING in a subject in need thereof.

83. Use of a compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition according to claim 65, in the preparation of a medicament for inducing an immune response in a subject in need thereof.

84. Use of a compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition according to claim 65, in the preparation of a medicament for treating abnormal cell proliferation in a subject in need thereof.

85. A kit comprising a compound according to any one of claims 1 to 64 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and instructions for use of the compound.

86. A kit comprising the pharmaceutical composition of claim 65 and instructions for use of the compound.

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