STING agonist compound

Abstract

The present disclosure relates to STING agonists, pharmaceutical compositions thereof, and the use of agonists and pharmaceutical compositions for inducing STING-mediated immune responses and / or treating STING-mediated diseases and disorders, such as, but not limited to, proliferative diseases including cancer.

Description

Technical Field

[0001] Cross - Reference to Related Applications

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 365,919, filed Jun. 6, 2022, the entire content of which is incorporated herein by reference.

[0002] Field

[0002] The present disclosure relates to STING agonists, pharmaceutical compositions thereof, and the use of agonists and pharmaceutical compositions for inducing STING - mediated immune responses and / or treating cell proliferative diseases and disorders mediated by STING, such as, but not limited to, cancer.

Background Art

[0003] Background

[0003] The innate and adaptive immune systems function closely together to address foreign substances and invading pathogens. The adaptive system is highly specific and long - lasting due to the production of memory T cells, and the innate system functions rapidly as the front - line of host defense. The innate system responds non - specifically to both pathogen - derived cytosolic DNA and host cytosolic DNA. In doing so, the innate immune system provides broad protection against threats such as bacteria and viruses, as well as responds to signals of cell and tissue damage.

[0004]

[0004] One protein important for innate immunity is stimulator of interferon genes (STING), and the cGAS-STING pathway promotes the sensing and protection against particularly harmful cytosolic DNA. cGAS recognizes cytosolic DNA, catalyzes the synthesis of cyclic dinucleotides (CDNs) such as cGAMP, and then binds to and activates STING. When STING binds to CDN, STING undergoes a conformational change, translocates from the endoplasmic reticulum to the Golgi apparatus, and serves as an inducer for the transcription factor TBK1 to phosphorylate transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB). Thereby, type I interferon (IFN) is induced, and pro-inflammatory cytokines such as IL-6, TNF-α, and IFN-γ are produced.

[0005]

[0005] Through this mechanism, various DNA viruses such as herpes simplex virus type I (HSV-1), Kaposi's sarcoma herpesvirus (KSHV), cytomegalovirus (CMV), hepatitis B virus (HBV), human papillomavirus (HPV), adenovirus, and baculovirus have been shown to activate the STING pathway. Studies have also shown that STING can protect against RNA infection. For example, STING knockout mice are highly susceptible to RNA viruses (Ishikawa, H., et al. Nature, 2009, 461, pages 788-792). Furthermore, intracellular bacteria have been shown to be able to activate the STING pathway and produce CDNs that can induce an immune response. For example, the Listeria monocytogenes bacterial strain induces an immune response mediated by STING.

[0006]

[0006] While exogenous factors can activate the STING pathway, many viruses have developed ways to suppress or inhibit the STING-promoted immune response. For example, many HSV-1 viral genes such as HSV-1 γ34.5 can suppress the STING signaling pathway, thereby disrupting the transport of STING from the endoplasmic reticulum to the Golgi apparatus (Christensen, M. H., et al., EMBO, 2016, 35, 568). Similarly, it has also been demonstrated that genes of Kaposi's sarcoma herpesvirus (KSHV), human papillomavirus (HPV), cytomegalovirus (CMV), and hepatitis B virus (HBV) have developed mechanisms to evade the STING pathway (Ahn, J. et al. Experimental and Molecular Medicine, 2019, 51, 155).

[0007]

[0007] Furthermore, certain RNA viruses affect IFN production. For example, it has been reported that the protease of dengue virus (DENV), a positive single-stranded RNA virus, can target and cleave STING, thereby inhibiting the production of type I INF. In STING-deficient primary cells, the replication of DENV increases significantly (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 positive single-stranded RNA virus of the same 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 initiating the immune response against the invasion of foreign pathogens, the STING pathway also recognizes host cytosolic DNA. Since the cytosol usually does not contain DNA, leaked cytosolic DNA is often an indicator of DNA damage events and can represent tumorigenesis. Detection of host cytosolic DNA by STING causes the production of IFN, immunostimulatory genes, and pro-inflammatory cytokines. It has been established that IFN can inhibit tumor cell proliferation through multiple mechanisms. As described in Jiang, M. et al. Journal of Hematology & Oncology, 2020, 81, 13, STING deficiency correlates with cancer incidence at least in melanoma cell lines, colorectal adenocarcinoma human cell lines, and lung cancer.

[0009] For oncological indications (Le Naour et al. Oncoimmunology, 2020; 9(1): 1777624), many STING agonists have been developed and studied, such as the tumor vascular disrupting agent DMXAA (or vadimezan), which has been investigated in clinical trials for its effects on advanced solid tumors, prostate cancer, urothelial carcinomas, and small cell lung cancer. Despite promising preclinical results, DMXAA has so far only obtained unsatisfactory results in human clinical trials. Recently, MIW815 (ADU-S100) in combination with pembrolizumab was studied in a phase 2 clinical trial regarding patients with head and neck cancer but was terminated due to lack of substantial antitumor activity (NCT03937141). A phase 1 trial to study the effect of MIW815 as a single agent and in combination with ipilimumab in patients with advanced / metastatic solid tumors or lymphoma also ended due to lack of substantial antitumor activity (NCT02675439).

[0010]

[0010] Other STING agonists for various cancer treatments include BMS-986301, E7766, GSK3745417, MK-1454, MK-2118, BI 1387446, and SB11285. Dimeric STIN agonists are described in International Publication No. 2021 / 113679, assigned to Mersana Therapeutics, Inc., and U.S. Patent No. 10,793,557, assigned to Merck Sharp and Dohme. Other STING agonists are also described in U.S. Patent Application Publication No. 2021 / 0009608, assigned to Merck.

Summary of the Invention

Problems to be Solved by the Invention

[0011]

[0011] Considering the importance of the STING pathway in the induction of immune responses in response to both foreign pathogens and damaged DNA associated with cell proliferative diseases, there is a medical need to develop STING agonists. Accordingly, an object of the present disclosure is to provide novel compounds and compositions that can induce STING-mediated immune responses and / or provide treatment for STING-mediated diseases and disorders, such as cell proliferative diseases.

Means for Solving the Problems

[0012] Summary

[0012] In one aspect, the STING agonist is a compound of Formula I, Formula II, or Formula III:

Chemical

Chemical

Chemical formula

[0013]

[0013] In one embodiment, the STING agonist is of formula Ia:

Chemical formula

[0014]

[0014] In one embodiment, the STING agonist is of formula Ib:

Chemical formula

[0015]

[0015] In one embodiment, the STING agonist is of formula Ic:

Chemical formula

[0016]

[0016] In one embodiment, the STING agonist is of formula Id:

Chem.

[0017]

[0017] In one embodiment, the STING agonist is of formula IIa:

Chem.

[0018]

[0018] In one embodiment, the STING agonist is of formula IIb:

Chemical Formula

[0019]

[0019] In one embodiment, the STING agonist is of formula IIIa:

Chemical formula

[0020]

[0020] The present disclosure 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 Compounds 1 to 31 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, c) a compound selected from Compounds 32 to 62 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, d) A pharmaceutical composition comprising 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, in a pharmaceutically acceptable excipient, diluent or carrier, e) A pharmaceutical composition comprising a compound of (b) or (c) in a pharmaceutically acceptable excipient, diluent or carrier, f) A method of treating a STING-mediated disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of (a)-(c) or a pharmaceutical composition of (d)-(e), g) The method of (f), wherein the disease or disorder is a cell proliferative disease such as, 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 such as non-small cell lung cancer, head and neck cancer, lymphoma such as malignant lymphoma, melanoma, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, prostate cancer, urothelial cancer 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 a compound of (a)-(c) or a pharmaceutical composition of (d)-(e), j) A method of inducing STING-dependent type I interferon production in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of (a)-(c) or a pharmaceutical composition of (d)-(e), l) The method according to any one of embodiments (f)-(k), wherein the compound of (a)-(c) or the pharmaceutical composition of (d)-(e) is administered in combination with an immune-modifying substance such as, but not limited to, a checkpoint inhibitor, for example a PD-1 inhibitor or a CTLA-4 inhibitor, m) Use of a therapeutically effective amount of a compound of (a)-(c) or a pharmaceutical composition of (d)-(e) for treating a STING-mediated disease or disorder in a subject in need thereof, n) Use of a therapeutically effective amount of a compound of (a)-(c) or a pharmaceutical composition of (d)-(e) for inducing an immune response in a subject in need thereof, o) Use of a therapeutically effective amount of a compound of (a)-(c) or a pharmaceutical composition of (d)-(e) for inducing STING-dependent type I interferon production in a subject in need thereof. p) Use of a therapeutically effective amount of a compound of (a)-(c) or a pharmaceutical composition of (d)-(e) for inducing STING-dependent cytokine production in a subject in need thereof. q) Use of a therapeutically effective amount of a compound of (a)-(c) or a pharmaceutical composition of (d)-(e) in the manufacture of a medicament for treating a STING-mediated disease or disorder in a subject in need thereof. r) Use of a therapeutically effective amount of a compound of (a)-(c) or a pharmaceutical composition of (d)-(e) in the manufacture of a medicament for inducing an immune response in a subject in need thereof. s) Use of a therapeutically effective amount of a compound of (a)-(c) or a pharmaceutical composition of (d)-(e) in the manufacture of a medicament for inducing STING-dependent type I interferon production in a subject in need thereof. t) Use of a therapeutically effective amount of a compound of (a)-(c) or a pharmaceutical composition of (d)-(e) in the manufacture 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 a compound of (a)-(c) or a pharmaceutical composition of (d)-(e) and instructions for using the compound.

Mode for Carrying Out the Invention

[0021] Detailed Description Definitions

[0021] When referring to the compounds provided herein, the following terms have the following meanings unless otherwise specified. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. When there are multiple definitions for a term in this specification, the terms in this section shall prevail unless otherwise specified.

[0022]

[0022] As used herein, the term "alkyl" means a saturated straight-chain or branched-chain hydrocarbon, unless otherwise specified. In certain embodiments, the alkyl group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, the alkyl group includes a saturated straight-chain or branched-chain hydrocarbon having 1 to 6 carbon atoms, i.e., C1-C6 alkyl or lower alkyl. The term includes both substituted and unsubstituted sites. In some or any embodiments, the alkyl is unsubstituted. In some or any embodiments, the alkyl is substituted. In certain embodiments, the alkyl group is a fluorinated alkyl group. Non-limiting examples of sites where the alkyl group can be substituted include, for example, halogen (fluoro, chloro, bromo, or iodo), hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, which are unprotected or protected as needed, as known to those skilled in the art, as taught in 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, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.

[0023]

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

[0024]

[0024] The term "aryl" refers to an aromatic group containing only carbon in one or more aromatic rings. In one embodiment, the aryl group contains 1 to 3 individual or fused rings and is a 6- to about 14- or 18-membered ring atom containing no heteroatoms as ring members. When shown, such an aryl group may be further substituted with a carbon or non-carbon atom or group. Such substitution may optionally contain 1, 2 or 3 heteroatoms independently selected from N, O, B, P, Si and / or S and include fusion to a 4- to 7-membered or 5- to 7-membered saturated or partially unsaturated cyclic group which may form, for example, a 3,4-methylenedioxyphenyl group. Examples of aryl groups include phenyl and naphthyl such as 1-naphthyl and 2-naphthyl. In one embodiment, the aryl group is a pendant group. An example of a pendant ring is a phenyl group substituted with a phenyl group. In one embodiment, the aryl group is optionally substituted as described above.

[0025]

[0025] The terms "alkoxy" and "alkoxyl" mean an -OR'' group, where R'' is alkyl or cycloalkyl. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, s-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy and the like.

[0026]

[0026] The term "amino" means an -NH2 group.

[0027]

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

[0028]

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

[0029]

[0029] The term "dialkylamino" means an -NR'R' group where R' is an alkyl as defined herein. In some or any embodiments, the dialkylamino is di-C 1~6 alkylamino.

[0030]

[0030] The term "alkylaminoalkyl" means an alkyl group as defined herein substituted with one or more alkyl groups as defined herein. In some embodiments, "alkylaminoalkyl" is C 1~6 alkyl-amino-C 1~6 alkyl. In some embodiments, the alkyls in alkylaminoalkyl are each independently selected.

[0031]

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

[0032]

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

[0033]

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

[0034]

[0034] The term "hydroxyalkyl" means an alkyl group as defined herein that is substituted with one or more hydroxy groups.

[0035]

[0035] As used herein and unless otherwise specified, the terms "halogen" and "halo" are synonymous and mean chloro, bromo, fluoro, or iodo.

[0036]

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

[0037]

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

[0038]

[0038] As used herein and unless otherwise specified, the term "cycloalkyl" means a saturated cyclic hydrocarbon. In certain embodiments, the cycloalkyl group can be saturated, and / or bridged, and / or unbridged, and / or a fused bicyclic group. In certain embodiments, the cycloalkyl group contains 3 to 10 carbon atoms, i.e., C3-C 10 cycloalkyl. In some embodiments, cycloalkyl is 3 to 10 (C 3~10 ) or has 3 to 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, cycloalkyl is substituted with 1, 2, or 3 groups independently selected from halogen (fluoro, chloro, bromo, or iodo), alkyl, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy.

[0039] As used herein, the term "heteroaryl" means a monovalent monocyclic aromatic group and / or polycyclic aromatic group in which at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N in the ring. Each ring may contain one or two O atoms, one or two S atoms, and / or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, heteroaryl has 5 to 20, 5 to 15, or 5 to 10 ring atoms. Heteroaryl can be attached to the remainder of the molecule via a nitrogen or carbon atom. In some embodiments, monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, 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, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazolothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, heteroaryl may also be optionally substituted as described herein."Replacement heteroaryl" is heteroaryl that is substituted as defined for aryl.

[0040]

[0040] As used herein and unless otherwise defined, the term "protecting group" means a group that is added to oxygen, nitrogen, or phosphorus atoms to prevent further reaction thereof or for other purposes. A variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.

[0041] As used herein, the term "pharmaceutically acceptable salt" means any salt of a compound provided herein that retains its biological properties and is not toxic or otherwise undesirable for pharmaceutical use. Such salts can be derived from a variety of organic and inorganic counterions well known in the art.Examples of such salts include, but are not limited to: (1) 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, hexanoic acid, cyclopentylpropionic 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, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid, etc., and acid addition salts formed therefrom; or (2) salts formed when the acidic proton present in the parent compound 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 hydroxide, potassium, calcium, magnesium, aluminum, lithium, zinc, and barium hydroxide, ammonia, or when 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.

[0042]

[0042] Pharmaceutically acceptable salts include, by way of example and without limitation, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrohalic acids, for example hydrochloride and hydrobromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbic acid, malate, maleate, fumarate, tartrate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelic acid, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, t-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, etc. are further included.

[0043]

[0043] The terms “substantially free of” or “substantially absent from” with respect to a composition mean a composition containing at least 85% or 90% by weight, and in certain embodiments 95, 98, 99 or 100% by weight of the compound. In certain embodiments, in the methods and compounds provided herein, the compound is substantially free of enantiomers.

[0044]

[0044] Similarly, the term “isolated” with respect to a composition means a composition containing at least 85, 90, 95, 98, 99 to 100% by weight of the compound, with the remainder containing other chemical species or enantiomers.

[0045]

[0045] As used herein, "solvate" means a compound provided herein or a salt thereof that further contains 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]

[0046] "Isotope composition" means the amount of each isotope present for a given atom, and "natural isotope composition" means the natural isotope composition or abundance ratio for a given atom. Atoms containing their natural isotope composition may also be referred to herein as "non-enriched" atoms. Unless otherwise specified, atoms of the compounds described herein are meant to represent any stable isotope of that atom. For example, unless otherwise specified, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen in its natural isotope composition.

[0047]

[0047] "Isotope enrichment" means the percentage of incorporation of a specific isotope at a given atom in a molecule, instead of the natural isotope abundance ratio of that atom. For example, 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at the designated position. Since the natural abundance of deuterium is about 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is 0.0156%. The isotope enrichment of the compounds provided herein can be determined using conventional analytical methods known to those skilled in the art, such as mass spectrometry and nuclear magnetic resonance spectroscopy.

[0048]

[0048] "Isotopically enriched" means an atom having an isotope composition other than the natural isotope composition of that atom. "Isotopically enriched" may also mean a compound containing at least one atom having an isotope composition other than the natural isotope composition of that atom.

[0049]

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

[0050]

[0050] As used herein, the “alkyl”, “alkylene”, “aryl”, “alkoxy”, “aminoalkyl”, “alkylamino”, “dialkylamino”, “alkylaminoalkyl”, “dialkylaminoalkyl”, “arylalkyl”, “haloalkyl”, “cycloalkyl” and “heteroaryl” groups optionally contain carbon 13 in an amount other than the natural isotope composition.

[0051]

[0051] Unless otherwise specified, the term “optionally substituted” means that a group is unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents shown for that group, and the substituents can be the same or different. In certain embodiments, the optionally substituted group is an unsubstituted group. In certain embodiments, the optionally substituted group has at least 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 multiple substituents are present, unless otherwise specified, the substituents are each independently selected. For example, the (C1-C4 alkyl) substituents on the -N(C1-C4 alkyl)(C1-C4 alkyl) group can each independently be selected from other groups such that groups such as -N(CH3)(CH2CH3) are formed.

[0052]

[0052] As used herein, the term "substituted", whether or not preceded by the term "optionally", generally means the replacement of a hydrogen atom in a given structure with a radical of a specified substituent. Specific substituents are listed above in the definitions and below in the descriptions of the compounds and their examples. Unless otherwise specified, an optionally substituted group may have substituents at each substitutable position of the group, and when a plurality of positions in a given structure may be substituted with a plurality of substituents selected from the specified groups, the substituents may be the same or different at all positions.

[0053]

[0053] As will be recognized by those skilled in the art, the combinations of substituents contemplated herein are those that form stable or chemically feasible compounds.

[0054]

[0054] As used herein, the phrase "stable or chemically feasible" refers to a compound that does not substantially change when subjected to the conditions that enable its manufacture, detection, and its recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or a chemically feasible compound is a compound that does not substantially change when maintained at a temperature of 40 °C or less for at least one week in the absence of moisture or other chemically reactive conditions.

[0055]

[0055] Unless a specific isotope of an element is shown in the formula, the present disclosure includes all isotopologs of the compounds disclosed herein, for example deuterated derivatives of the compounds (where H may be 2H, i.e., D). Isotopologs may have isotope substitutions at any or all positions in the structure, or may have atoms present in their natural abundance ratios at any or all positions in the structure.

[0056]

[0056] The present disclosure encompasses any or all of the enantiomeric or diastereomeric forms and stereochemical forms such as cis / trans or E / Z isomers of the compounds described herein. Unless otherwise specified by chemical structure or name, the structure or name is intended to encompass all possible stereoisomers of the indicated compound. Further, when a specific stereochemical form is indicated, general non-stereochemical forms and mixtures of two or more stereochemical forms of the disclosed compounds in any ratio, such as mixtures of two or more stereochemical forms of the disclosed compounds in any ratio including all other stereochemical forms as well as racemic, non-racemic, enantiomerically enriched and scalemic mixtures, are described and understood to be encompassed by the present disclosure. Compounds having an alkenyl functional group can exist as the E isomer, the Z isomer, or a mixture of the E and Z isomers.

[0057]

[0057] Compositions containing the disclosed compounds, such as compositions of substantially pure compounds including their specific stereochemical forms, are also intended. Mixtures of the disclosed compounds in any ratio, such as compositions containing mixtures of two or more stereochemical forms of the disclosed compounds in any ratio, are encompassed by the present disclosure such that racemic, non-racemic, enantiomerically enriched and scalemic mixtures are encompassed by the present disclosure. When stereochemistry is specified for one or more parts of a molecule but not for one or more other parts of the molecule, the structure is intended to encompass all possible stereoisomers with respect to the one or more parts for which stereochemistry is not specified.

[0058]

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

[0059]

[0059] As used herein, EC 50 means the dose, concentration or amount of a particular test compound that induces a dose-dependent response at 50% of the maximum manifestation of a particular response induced, elicited or enhanced by the particular test compound.

[0060]

[0060] As used herein, IC50 It refers to the amount, concentration or dosage of a specific test compound that achieves 50% inhibition of the maximum response in an assay for measuring such a response.

[0061]

[0061] As used herein, the terms "subject" and "patient" are used interchangeably herein. The term "subject" or "subjects" refers to animals, such as mammals including non - primates (e.g., cows, pigs, horses, cats, dogs, rats and mice) and primates (e.g., monkeys such as cynomolgus monkeys, chimpanzees, etc. and humans), for example, humans. In another embodiment, the subject is a domestic animal (e.g., horse, cow, pig, etc.) or a pet (e.g., dog or cat). In a particular embodiment, the subject is a human.

[0062]

[0062] As used herein, the term "therapeutic agent" or "therapeutic agents" refers to any agent that can be used in the treatment or prevention of a disease or one or more symptoms thereof. In certain embodiments, the term "therapeutic agent" includes the compounds provided herein. In certain embodiments, a therapeutic agent is an agent that is known to be useful, or has been used, or is currently being used for the treatment or prevention of a disease or one or more symptoms thereof.

[0063]

[0063] As used herein, the term "therapeutically effective amount" or "effective amount" means the amount of a compound or composition that is effective in the treatment of a disease or disorder when administered to a subject. In some embodiments, a therapeutically effective amount or effective amount means the amount of a compound or composition that is effective to prevent or ameliorate a disease or the progression of a disease, or as a result, to improve symptoms, when administered to a subject. A "therapeutically effective amount" can vary, inter alia, depending on the compound, the disease and its severity, and the age, weight, etc. of the subject being treated.

[0064] As used herein, "treatment" or "therapy" of a disease or disorder, in certain embodiments, means amelioration of a disease or disorder present in a subject. In another embodiment, "treatment" or "therapy" encompasses improvement of at least one physical parameter not distinguishable by the subject. In yet another embodiment, "treatment" or "therapy" includes modulating a disease or disorder physically (e.g., stabilization of discernible symptoms) or physiologically (stabilization of physical parameters) or both. In yet another embodiment, "treatment" or "therapy" includes delaying or preventing the onset of a disease or disorder or delaying or preventing recurrence of a disease or disorder. In yet another embodiment, "treatment" or "therapy" includes reducing or eliminating a disease or disorder, or delaying the progression of a disease or disorder or the progression of one or more symptoms of a disease or disorder, or reducing the severity of a disease or disorder or the severity of one or more symptoms of a disease or disorder.

[0065] As used herein, the term "cancer" is used throughout the specification to mean the pathological process by which a cancerous or malignant neoplasm, i.e., abnormal tissue (solid) or cells (non-solid) that grow by rapid cell proliferation more often than normal, form and proliferate, and continue to proliferate after a stimulus that initiates a new growth arrest. Malignant neoplasms show a partial or complete lack of structural organization and functional cooperation with normal tissue, most infiltrate surrounding tissue, can metastasize to some sites, may recur after attempted resection, and can result in death to the patient if not properly treated. The term neoplasia as used herein is used to describe all cancerous disease states and includes or encompasses the pathological processes associated with malignant hematogenous, ascites, and solid tumors.

[0066] As used herein, the term "immune response" refers to any one or more of a specific immune response, a non-specific immune response, both specific and non-specific responses, an innate response, a primary immune response, an adaptive immunity, a secondary immune response, a memory immune response, immune cell activation, immune cell proliferation, immune cell differentiation, and cytokine expression.

[0067]

[0067] As used herein, the term "inhibiting proliferation" (e.g., when referring to cells such as tumor cells) is intended to encompass a measurable decrease in cell proliferation (e.g., tumor cell proliferation) when contacted with a compound described herein, compared to the proliferation of the same cells not contacted with the compound described herein. In some embodiments, proliferation can be inhibited by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99% or 100%. The decrease in cell proliferation can occur by various mechanisms including, but not limited to, apoptosis, necrosis and / or effector function-mediated activity.

[0068] STING agonist

[0068] In one aspect, the STING agonist is a compound of formula I, formula II or formula III:

Chemical formula

Chemical formula

Chemical formula

[0069]

[0069] In certain embodiments, the compound of formula I is

Chemical formula

[0070]

[0070] In a specific embodiment, the compound of formula I is

Chemical formula

[0071]

[0071] In a specific embodiment, the compound of formula I is

Chemical formula

[0072]

[0072] In a specific embodiment, the compound of formula II is

Chemical formula

[0073]

[0073] In a specific embodiment, the compound of formula III is

Chemical formula

[0074]

[0074] In one embodiment, A is

Chemical formula

Chemical formula

[0075]

[0075] In one embodiment, A is [Chemistry] It is. In a particular embodiment, A is [Chemistry] selected from

[0076]

[0076] In one embodiment, A is [Chemistry] It is. In a particular embodiment, A is [Chemistry] selected from

[0077]

[0077] In one embodiment, A is [Chemistry] It is. In a particular embodiment, A is [Chemistry] selected from

[0078]

[0078] Non-limiting examples of A include [Chemistry] are included.

[0079]

[0079] Further non-limiting examples of A include [Chemistry] are included.

[0080]

[0080] Further non-limiting examples of A include

Chem.

[0081]

[0081] Further non-limiting examples of A include

Chem.

[0082]

[0082] Further non-limiting examples of A include

Chem.

[0083]

[0083] In one embodiment, the STING agonist is a compound of formula Ia:

Chem.

[0084]

[0084] In one embodiment, the compound of formula Ia is

Chemical formula

[0085]

[0085] Non-limiting examples of formula Ia include, but are not limited to,

Chemical formula

Chemical formula

Chemical formula

[0086]

[0086] In one embodiment, the STING agonist is a compound of formula Ib:

Chemical formula

[0087]

[0087] In one embodiment, the compound of formula Ib is

Chemical formula

[0088]

[0088] Non-limiting examples of formula Ib include, but are not limited to,

Chemical formula

Chemical formula

Chemical formula

[0089]

[0089] In one embodiment, the STING agonist is of formula Ic:

Chemical formula

[0090]

[0090] In one embodiment, the compound of formula Ic is

Chem.

Chem.

[0091]

[0091] Non-limiting examples of formula Ic include, but are not limited to,

Chem.

Chem.

Chem.

[0092]

[0092] In one embodiment, the STING agonist is of formula Id:

Chem.

[0093]

[0093] In one embodiment, the compound of formula Id is

Chemical formula

[0094]

[0094] Non-limiting examples of formula Id include, but are not limited to,

Chemical formula

[0095]

[0095] In one embodiment, the STING agonist is of formula IIa:

Chemical formula

[0096]

[0096] In one embodiment, the compound of formula IIa is

Chem.

[0097]

[0097] Non-limiting examples of formula IIa include

Chem.

[0098]

[0098] In one embodiment, the STING agonist is of formula IIb:

Chem.

[0099]

[0099] In one embodiment, the compound of formula IIb is

Chemical formula

[0100]

[0100] Non-limiting examples of formula IIb include

Chemical formula

[0101]

[0101] In one embodiment, the STING agonist is of formula IIIa:

Chemical formula

[0102]

[0102] In one embodiment, the compound of formula IIIa is

Chemical formula

[0103]

[0103] Non-limiting examples of formula IIIa include

Chemical formula

[0104]

[0104] In one embodiment including any of the above, L 1 is C 1~6 alkylene. In one embodiment including any of the above, L 1 is C3 alkylene. In one embodiment including any of the above, L 1 is C4 alkylene. In one embodiment including any of the above, L 1 is C5 alkylene. In one embodiment including any of the above, L 1 is C6 alkylene.

[0105]

[0105] In one embodiment including any of the above, L 1 is

Chemical formula

Chemical formula

[0106]

[0106] In a specific embodiment including any of the above, L 1 is

Chemical formula

Chemical formula

Chemical formula

[0107]

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

[0108]

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

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

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

[0111]

[0111] In a specific embodiment including any of the above, R 11 is independently selected from hydrogen and methyl. In one embodiment including any of the above, R 11 is hydrogen. In one embodiment including any of the above, R 11 is methyl.

[0112]

[0112] In a specific embodiment, L 1 is

Chemical formula

Chemical formula

Chemical formula

[0113]

[0113] In a specific embodiment including any of the above, R 1 is selected from hydrogen and halogen. In a specific embodiment including any of the above, R 7 is selected from hydrogen, halogen and C 1~6 alkyl. In an embodiment including any of the above, R 1 and R 7 are both halogen. In an embodiment including any of the above, R 1 and R 7 are both C 1~6 alkyl. In an embodiment including any of the above, R 1 and R 7 are both hydrogen. In an embodiment including any of the above, R 1 is halogen and R 7 is hydrogen. In an embodiment including any of the above, R 1 is hydrogen and R 7 is halogen. In an embodiment including any of the above, R 1 and R 7 are both fluorine. In an embodiment, R 1 is hydrogen and R 7 is fluorine. In an embodiment, R 1 is fluorine and R 7 is hydrogen. In an embodiment including any of the above, R 1 and R 7 are both methyl.

[0114]

[0114] In a specific embodiment including any of the above, R 2 is selected from alkoxy and hydrogen. In a specific embodiment including any of the above, R 5 is selected from alkoxy, hydroxy, amino-C 1~6 alkyl and hydrogen. In a specific embodiment including any of the above, R 5 is selected from alkoxy and hydrogen. In a specific embodiment including any of the above, R 5is hydroxyl and amino-C 1~6 is selected from alkyl. In one embodiment including any of the above, R 2 and R 5 are both alkoxy. In one embodiment including any of the above, R 2 is hydrogen and R 5 is alkoxy. In one embodiment including any of the above, R 2 is alkoxy and R 5 is hydrogen. In one embodiment including any of the above, R 2 and R 5 are both methoxy. In one embodiment including any of the above, R 2 is hydrogen and R 5 is methoxy. In one embodiment including any of the above, R 2 is methoxy and R 5 is hydrogen. In a specific embodiment including any of the above, R 5 is hydroxy and R 2 is alkoxy. In a specific embodiment including any of the above, R 5 is amino-C 1~6 alkyl and R 2 is alkoxy. In a specific embodiment including any of the above, R 5 is hydroxy or amino-C 1~6 alkyl and R 2 is methoxy. In a specific embodiment including any of the above, R 5 is -CH2NH2 and R 2 is alkoxy.

[0115]

[0115] In a specific embodiment including any of the above, R 1 and R 7 are selected from hydrogen, halogen and C 1~6 alkyl, and R 2 and R 5 are both alkoxy. In one embodiment including any of the above, R 1 and R 7 are both halogen, and R 2 and R5 are both alkoxy. In one embodiment including any of the above, R 1 and R 7 are both C 1~6 alkyl, and R 2 and R 5 are both alkoxy. In one embodiment including any of the above, R 1 and R 7 are both fluorine, and R 2 and R 5 are both methoxy. In one embodiment including any of the above, R 1 and R 7 are both methyl, and R 2 and R 5 are both alkoxy.

[0116]

[0116] In a specific embodiment including any of the above, R 1 and R 7 are both fluorine, R 2 is alkoxy, and R 5 is hydroxyl or amino-C 1~6 alkyl. In a specific embodiment including any of the above, R 1 and R 7 are both halogen, R 2 is alkoxy, and R 5 is hydroxyl. In a specific embodiment including any of the above, R 1 and R 7 are both halogen, R 2 is alkoxy, and R 5 is amino-C 1~6 alkyl.

[0117]

[0117] In one embodiment including any of the above, R 3 , R 4 , R 6 and R 8 are hydrogen.

[0118]

[0118] In a specific embodiment including any of the above, R 1and R 7 is selected from hydrogen, halo and C 1~6 alkyl, and R 2 and R 5 is selected from hydrogen, alkoxy, hydroxyl and amino-C 1~6 alkyl, and R 3 , R 4 , R 6 and R 8 are hydrogen. In certain embodiments including any of the above, R 1 and R 7 is selected from hydrogen, halogen and C 1~6 alkyl, and R 2 and R 5 is selected from hydrogen and alkoxy, and R 3 , R 4 , R 6 and R 8 are hydrogen. In certain embodiments including any of the above, R 1 and R 7 is selected from hydrogen, halogen and C 1~6 alkyl, and R 2 and R 5 is selected from hydrogen and alkoxy, and R 3 , R 4 , R 6 and R 8 are hydrogen, and L 1 is

Chemical formula

Chemical formula

Chemical formula

[0119]

[0119] In one embodiment including any of the above, X 1 is -C(O)-. In one embodiment including any of the above, X 1 is -CH=CH-. In one embodiment including any of the above, X 2 is -(C(R 12a R 12b )) 1~6 -. In one embodiment including any of the above, X 2 is -(CH2) 1~6 -. In one embodiment including any of the above, X 2 is -(CH2)- or -(CH2)2-. In one embodiment including any of the above, X 2 is -(C(R 12a R 12b )C(R 13a R 13b )) 1~3 -. In one embodiment including any of the above, X 2 is -(CH2C(CH3)2) 1~3 -. In one embodiment including any of the above, X 2 is -(CH2C(CH3)2)-. In one embodiment including any of the above, X 3 is -COOR 10 . In one embodiment including any of the above, X 3 is -COOH. In one embodiment including any of the above, X 3 is -C(O)OC 1~6 is alkyl. In one embodiment including any of the above, X3 is -C(O)OCH3. In one embodiment including any of the above, X 3 is -P(O)(OR 15 )2. In one embodiment including any of the above, X 3 is -P(O)(OH)2.

[0120]

[0120] In one embodiment including any of the above,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

[0121]

[0121] In one embodiment including any of the above,

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0122]

[0122] In a specific embodiment including any of the above,

Chem.

Chemical

Chemical

Chemical

Chemical

Chemical

[0123]

[0123] In one embodiment including any of the above,

Chemical

Chemical

Chemical

Chemical

Chemical

[0124]

[0124] In a specific embodiment including any of the above, [Chemistry] is [Chemistry] selected from and L 1 is [Chemistry] selected from. In the above embodiment, [Chemistry] indicates the bonding point to the remaining part of the compound.

[0125]

[0125] In one embodiment including any of the above, X 4is -C(O)-. In one embodiment including any of the above, X 4 is -CH2-. In one embodiment including any of the above, X 4 is -CH=CH-.

[0126]

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

[0127]

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

[0128]

[0128] In one embodiment including any of the above, X 7 is -C(R 12a R 12c )C(R 13a R 13c )-. In one embodiment including any of the above, X 7 is

Chemical formula

Chemical formula

[0129]

[0129] In one embodiment including any of the above, X 8 is -COOR 10 In one embodiment including any of the above, X 8 is -COOH. In one embodiment including any of the above, X 8 is -C(O)OC 1~6 alkyl. In one embodiment including any of the above, X 8 is -C(O)OCH3. In one embodiment including any of the above, X 8 is -P(O)(OR 15 )2. In one embodiment including any of the above, X 8 is -P(O)(OH)2.

[0130]

[0130] In one embodiment including any of the above, R 9a is hydrogen. In one embodiment including any of the above, R 9a is, but not limited to, C 1~6 alkyl such as methyl.

[0131]

[0131] In one embodiment including any of the above, R 10 is hydrogen. In one embodiment including any of the above, R 10 is C 1~6 alkyl. In one embodiment including any of the above, R 10 is C 3~10 cycloalkyl. In one embodiment including any of the above, R 10 is selected from aryl, aryl-C 1~6 alkyl and heteroaryl.

[0132] In certain embodiments including any of the above, R 14 is amino-C 1~6 alkyl, C 1~6 alkyl-amino-C 1~6 alkyl, di-C 1~6 alkylamino-C 1~6 alkyl or C 3~10 cycloalkyl-amino-C 1~6 alkyl. In one embodiment including any of the above, R 14 is amino-C 1~6 alkyl. In one embodiment including any of the above, R 14 is halo-C 1~6 alkyl. In one embodiment including any of the above, R 14 is C 1~6 alkyl.

[0133] In certain embodiments including any of the above, R 17 is amino-C 1~6 alkyl, C 1~6 alkyl-amino-C 1~6 alkyl, di-C 1~6 alkylamino-C 1~6 alkyl or C 3~10 cycloalkyl-amino-C 1~6 alkyl. In one embodiment including any of the above, R 17 is amino-C 1~6 alkyl. In certain embodiments including any of the above, R 18 is amino-C 1~6 alkyl, C 1~6 alkyl-amino-C 1~6 alkyl, di-C 1~6 alkylamino-C 1~6 alkyl or C 3~10 cycloalkyl-amino-C 1~6 alkyl. In one embodiment including any of the above, R 18 is amino-C 1~6 alkyl.

[0134] In certain embodiments including any of the above, R15 is independently selected from hydrogen and C 1~6 alkyl. In one embodiment including any of the above, R 15 is hydrogen. In one embodiment including any of the above, R 15 is C 1~6 alkyl. In one embodiment including any of the above, R 15 is methyl.

[0135]

[0135] In a specific embodiment including any of the above,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0136]

[0136] In a specific embodiment including any of the above,

Chemical formula

Chemical formula

[0137]

[0137] In a specific embodiment including any of the above,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0138]

[0138] In a specific embodiment including any of the above,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0139]

[0139] In a specific embodiment including any of the above,

Chemical formula

[0140]

[0140] In a specific embodiment including any of the above, [Chemical formula] is [Chemical formula] and R 18 is amino-C 1~6 alkyl, C 1~6 alkyl-amino-C 1~6 alkyl, di-C 1~6 alkylamino-C 1~6 alkyl or C 3~10 cycloalkyl-amino-C 1~6 alkyl. In one embodiment including any of the above, [Chemical formula] is [Chemical formula] It is. In a specific embodiment including any of the above,

Chemical formula

Chemical formula

[0141]

[0141] In a specific embodiment including any of the above,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0142]

[0142] In a specific embodiment including any of the above,

Chemical formula

Chemical formula

[0143]

[0143] In a specific embodiment including any of the above, [Chemistry] is [Chemistry] selected from

[0144]

[0144] In a specific embodiment including any of the above, [Chemistry] is [Chemistry] selected from

[0145]

[0145]

Chem.

Chem.

[0146]

[0146] In certain embodiments including any of the above,

Chem.

Chem.

[0147]

[0147] In certain embodiments including any of the above,

Chem.

Chem.

[0148]

[0148] In certain embodiments including any of the above,

Chem.

Chem.

[0149] In certain embodiments including any of the above,

Chemical formula

Chemical formula

[0150] In certain embodiments including any of the above,

Chemical formula

Chemical formula

[0151] In certain embodiments including any of the above,

Chemical formula

Chemical formula

[0152]

[0152]

Chemical formula

Chemical formula

[0153]

[0153]

Chemical formula

[0154]

[0154] In certain embodiments including any of the above, [Chemical formula] is [Chemical formula] selected from.

[0155]

[0155] In certain embodiments including any of the above, [Chemical formula] is [Chemical formula] selected from.

[0156]

[0156] In certain embodiments including any of the above, [Chemical formula] is [Chemical formula] selected from.

[0157]

[0157] In certain embodiments including any of the above, [Chemical formula] is [Chemical formula] selected from. In certain embodiments including any of the above, [Chemical formula] is [Chemical formula] In certain embodiments including any of the above, [Chemical formula] is [Chemical formula] In certain embodiments including any of the above,

[0158]

[0158] [Chemical formula] Non-limiting examples of include [Chemical formula] include.

[0159]

[0159] In certain embodiments including any of the above, [Chemical formula] is [Chemical formula] selected from, and [Chemical formula] is

Chem.

[0160]

[0160] In certain embodiments including any of the above,

Chem.

Chem.

Chem.

Chem.

[0161]

[0161] In certain embodiments including any of the above,

Chem.

Chem.

Chem.

Chem.

[0162]

[0162] In certain embodiments including any of the above, [Chemistry] is, [Chemistry] selected from, and [Chemistry] is, [Chemistry] selected from.

[0163]

[0163] In certain embodiments including any of the above, [Chemistry] is, [Chemistry] and, [Chemistry] is, [Chemistry] is.

[0164]

[0164] In certain embodiments including any of the above, [Chemistry] is, [Chemistry] and, [Chemistry] is [Chemical formula] .

[0165]

[0165] In a specific embodiment including any of the above, [Chemical formula] is [Chemical formula] , and [Chemical formula] is [Chemical formula] .

[0166]

[0166] In a specific embodiment including any of the above, [Chemical formula] is [Chemical formula] , and [Chemical formula] is [Chemical formula] .

[0167]

[0167] In a specific embodiment including any of the above,

Chem.

Chem.

Chem.

Chem.

[0168]

[0168] In a specific embodiment including any of the above,

Chem.

Chem.

Chem.

Chem.

[0169]

[0169] In a specific embodiment including any of the above,

Chem.

Chem.

[0170]

[0170] In a specific embodiment including any of the above, [Chemical formula] is [Chemical formula] and [Chemical formula] is [Chemical formula] .

[0171]

[0171] In a specific embodiment including any of the above, [Chemical formula] is [Chemical formula] and [Chemical formula] is [Chemical formula] .

[0172] In certain embodiments including any of the above,

Chem.

Chem.

Chem.

Chem.

[0173] In certain embodiments including any of the above,

Chem.

Chem.

Chem.

Chem.

[0174] In one embodiment including any of the above, R 12a and R 12b are each hydrogen. In one embodiment including any of the above, R 12a , R 12b , R 13a and R 13b are each hydrogen. In one embodiment including any of the above, R 12a and R12b is hydrogen respectively, and R 13a and R 13b are C 1~6 alkyl respectively. In one embodiment including any of the above, R 12a and R 12b are hydrogen respectively, and R 13a and R 13b are methyl respectively.

[0175]

[0175] In a specific embodiment including any of the above, R 12a and R 13b are hydrogen respectively, and R 12c and R 12d are joined together to form a C3-C 1~6 cycloalkyl optionally substituted with a substituent selected from halogen, alkoxy, C 3~10 alkyl, C 9a cycloalkyl, hydroxy, cyano, -NR 9b R 10 and -COOR 10 cycloalkyl. In a specific embodiment including any of the above, R 12a and R 13b are hydrogen respectively, and R 12c and R 12d are joined together to form a cyclopropyl optionally substituted with a substituent selected from halogen, alkoxy, C 1~6 alkyl, C 3~10 cycloalkyl, hydroxy, cyano, -NR 9a R 9b and -COOR 10 is formed. In one embodiment including any of the above, R 12a and R 13b are hydrogen respectively, and R 12c and R 12d are joined together to form an unsubstituted cyclopropyl.

[0176]

[0176] In a specific embodiment including any of the above, X 9 , X 10 and X 11 are CR 19and is independently selected from N, R 19 is hydrogen. In certain embodiments including any of the above, X 9 , X 10 and X 11 are CR 19 and are independently selected from N, R 19 is hydrogen, halogen, C 1~6 alkyl and alkoxy. In certain embodiments including any of the above, X 9 , X 10 and X 11 are each CR 19 and R 19 is hydrogen. In certain embodiments including any of the above, X 9 , X 10 and X 11 are each CR 19 and R 19 is hydrogen, 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 selected from. In one embodiment including any of the above, X 9 is N, X 10 and X 11 are CR 19 In one embodiment including any of the above, X 10 is N, X 9 and X 11 are CR 19 In one embodiment including any of the above, X 1 is N, X 10 and X 9 are CR 19 In one embodiment including any of the above, X 9 is N, X 10 is N, and X 11 is CR 19 In one embodiment including any of the above, X 9 is N, X 11is N, and X 10 is CR 19 In one embodiment including any of the above, X 10 is N, X 11 is N, and X 9 is CR 19 is.

[0177]

[0177] In certain embodiments, the STING agonists of the present disclosure are

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

[0178]

[0178] In certain embodiments, the STING agonists of the present disclosure are

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

[0179] Use of the compound and composition

[0179] In one aspect, treatment of a STING-mediated medical disorder or disease is performed in a subject in need thereof using an effective amount of the compound or composition described herein. In one embodiment, the medical disorder or disease is a cell proliferative disorder such as, but not limited to, cancer. In another aspect, induction of an immune response is performed in a subject in need thereof using an effective amount of the compound or composition described herein. In yet another aspect, induction of STING-dependent type I interferon production is performed in a subject in need thereof using an effective amount of the compound or composition described herein. In yet another aspect, induction of STING-dependent cytokine production is performed in a subject in need thereof using an effective amount of the compound or composition described herein.

[0180]

[0180] In one embodiment, an effective amount of the compounds or compositions described herein is used to treat abnormal cell growth, including but not limited to cancer. In certain embodiments, the term “cancer” includes, but is not limited to, the following cancers: epidermoid oral cancer: oral vestibule cancer, lip cancer, oral cancer, pharyngeal cancer, head and neck squamous cell carcinoma (HNSCC); heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, 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, chondroid hamartoma, mesothelioma, non-small cell lung cancer (NSCLC); gastrointestinal: gastric cancer, esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, VIP-producing tumor), small bowel or small intestine (adenocarcinoma, lymphoma, Kaposi sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel or large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyosarcoma), colon, colorectal, colon-rectal, microsatellite stable colorectal cancer (MSS CRC), rectum; urogenital tract: kidney (adenocarcinoma, Wilms tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma), metastatic castration-resistant prostate cancer (mCRPC), muscle-invasive urothelial cancer; liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, hepatocellular adenoma, hemangioma, bile duct; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, Ewing sarcoma, malignant lymphoma (reticulum cell sarcoma), malignant giant cell tumor of bone osteochondroma (exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, gliomatosis, glioma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma);Gynecology: Uterus (endometrial carcinoma), Cervix (cervical cancer, cervical carcinoma, pre-tumor cervical dysplasia), Ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell tumor, Sertoli-Leydig cell tumor, undifferentiated embryonal cell tumor, malignant teratoma), Vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), Vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), Fallopian tube (carcinoma), Breast, triple-negative breast cancer (TNBC), platinum-resistant epithelial ovarian cancer (EOC)); Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative disorders, multiple myeloma (MM), myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma) hairy cell; Lymphatic diseases (e.g., mantle cell lymphoma, Waldenström macroglobulinemia, marginal zone lymphoma and follicular lymphoma); Skin: Malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; Thyroid: Papillary thyroid carcinoma, follicular thyroid carcinoma; Medullary thyroid carcinoma, undifferentiated thyroid cancer, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid carcinoma, pheochromocytoma, paraganglioma; Adrenal: Neuroblastoma; and metastatic melanoma are included.;

[0181]

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

[0182]

[0182] In certain embodiments, the cancer is a solid tumor. As used herein, a solid tumor means an abnormal mass of tissue that does not normally contain cysts or liquid regions. Different types of solid tumors are named for the type of cells that form them. Examples of classes of solid tumors include, but are not limited to, sarcoma, carcinoma and lymphoma. Further 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]

[0183] Non-limiting examples of cancers that can be treated using the compounds described herein include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, angiosarcoma), appendiceal cancer, benign monoclonal gammopathy, biliary tract cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, breast cancer, breast medullary carcinoma), brain tumor (e.g., meningioma, glioma, astrocytoma, oligodendroglioma; gliomatosis), bronchial cancer, carcinoid tumor, cervical cancer, choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, epithelioma, endothelial sarcoma (e.g., Kaposi's 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, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma (OSCC)), laryngeal cancer (e.g., laryngeal carcinoma, pharyngeal carcinoma, nasopharyngeal carcinoma, oropharyngeal carcinoma), hematopoietic cancer, heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immunocyte amyloidosis, kidney cancer (e.g., nephroblastoma also known as 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., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF) also known as agnogenic myeloid metaplasia (AMM), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g., type 1 or type 2 neurofibromatosis (NF), schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), 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., penile and scrotal Paget's disease), pineal tumor,Undifferentiated neuroectodermal tumors (PNT), prostate cancer (e.g., prostatic 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., appendiceal cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovial sarcoma, testicular cancer (e.g., seminoma, embryonal carcinoma of the testis), thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid cancer (PTC), medullary thyroid cancer), Wilms tumor, urethral cancer, vaginal cancer, and vulvar cancer (e.g., Paget's disease of the vulva) are included.

[0184]

[0184] In one embodiment, the cancer is a sarcoma, including but not limited to, for example, Ewing's sarcoma, Kaposi's sarcoma, liposarcoma, rhabdomyosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma (undifferentiated astrocytoma, diffuse astrocytoma, and low-grade astrocytoma), oligodendroglioma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, gliomatosis, pineocytoma, meningioma, meningiosarcoma, neurofibroma, and Schwannoma.

[0185]

[0185] In one embodiment, the cancer is, but is not limited to, a hematopoietic cancer such as leukemia, for example acute lymphoblastic leukemia (ALL), also known as 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 myelogenous 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 tumor 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, e.g., 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, lymphoplasmacytic lymphoma (i.e., Waldenström macroglobulinemia), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL, such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary 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 a mixture of one or more of the above leukemias / lymphomas.Other leukemias and lymphomas include T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, precursor B-cell (Pre-B) ALL, precursor B-cell (Pre-B) lymphoma, 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 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]

[0186] In certain embodiments, the cancers treated with the disclosed compounds are sarcoma, adrenal cancer, adrenocortical carcinoma, bile duct cancer, bone cancer, bone marrow cancer, brainstem glioma, breast cancer (including, but not limited to, triple (estrogen, progesterone, and HER-2) negative breast cancer, double negative breast cancer (where two of estrogen, progesterone, and HER-2 are negative), single negative (where 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), metastatic breast cancer with mesothelioma), colorectal cancer, cutaneous lymphoma, cutaneous melanoma, ductal carcinoma in situ (DCIS), endometrial cancer, epitheloid sarcoma, esophageal cancer, extrahepatic cancer, eye cancer, fallopian tube cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumor (GIST), glioblastoma multiforme (GBM), glioma, hairy cell leukemia, hemangioendothelioma, hypopharyngeal cancer, invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), intestinal cancer, intrahepatic bile duct cancer, invasive / infiltrating (breast cancer, islet cell carcinoma, jaw cancer, kidney cancer, laryngeal cancer, leiomyosarcoma, intramedullary seeding metastasis, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, gliomatosis, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymal, metastatic melanoma, metastatic squamous cell carcinoma of the head and neck, mixed glioma, monodermal teratoma, oral cancer mucinous carcinoma, mucosal melanoma, multiple myeloma, fungating polyposis, myelodysplastic syndrome, nasal cancer, nasopharyngeal cancer, head and neck cancer, neuroblastoma, neuroendocrine tumor (NET), oat cell carcinoma, ocular cancer, ocular melanoma, anaplastic glioma, oral cancer, oral cavitycancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, primary peritoneal cancer of the ovary, sex cord-stromal tumor of the ovary, Paget's disease, pancreatic cancer, papillary carcinoma, 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 cancer, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, osteosarcoma, sarcoma, nasal cavity cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cord cancer, spinal cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsillar cancer, transitional cell carcinoma, fallopian tube cancer, urothelial carcinoma, cancer of undetermined diagnosis, ureter cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, plasma cell myeloma, solitary plasmacytoma of bone, and extramedullary plasmacytoma.

[0187]

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

[0188]

[0188] In an alternative embodiment, an effective amount of the compound or composition described herein is used to effect treatment of a STING-mediated medical disorder or disease in a subject in need thereof, the disorder or disease being a viral infection, such as a double-stranded DNA virus. In certain embodiments, the virus is a virus of the family Herpesviridae, including but not limited to herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), varicella zoster virus (VZV), 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 a virus of the family Papillomaviridae, including but not limited to human papillomavirus (HPV). In an alternative embodiment, the viral infection is an RNA viral infection, such as a virus of the family Flaviviridae, such as flavivirus (e.g., yellow fever virus, West Nile virus, dengue virus, and Zika virus) and Hepacivirus (e.g., hepatitis B and hepatitis C).

[0189]

[0189] The compounds described herein can be administered at a dosage considered appropriate by a skilled physician. In certain embodiments, the dosage is from 0.1 to 1000 mg / kg. In certain embodiments, the dosage is from 0.1 to 900 mg / kg. In certain embodiments, the dosage is from 0.1 to 800 mg / kg. In certain embodiments, the dosage is from 0.1 to 700 mg / kg. In certain embodiments, the dosage is from 0.1 to 600 mg / kg. In certain embodiments, the dosage is from 0.1 to 500 mg / kg. In certain embodiments, the dosage is from 0.1 to 400 mg / kg. In certain embodiments, the dosage is from 0.1 to 300 mg / kg. In certain embodiments, the dosage is from 0.1 to 200 mg / kg. In certain embodiments, the dosage is from 0.1 to 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]

[0190] The dosage can be administered according to a schedule that is considered appropriate by those 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 two divided doses per day. In certain embodiments, the dosage is administered in three divided doses per day. In certain embodiments, the dosage is administered in four divided doses per day.

[0191]

[0191] Administration can be continued for a length of time that is considered appropriate by those skilled in the art. In certain embodiments, the dosage is administered daily for 14 days. In certain embodiments, the dosage is administered daily for 13 days. In certain embodiments, the dosage is administered daily for 12 days. In certain embodiments, the dosage is administered daily for 11 days. In certain embodiments, the dosage is administered daily for 10 days. In certain embodiments, the dosage is administered daily for 9 days. In certain embodiments, the dosage is administered daily for 8 days. In certain embodiments, the dosage is administered daily for 7 days. In certain embodiments, the dosage is administered daily for 6 days. In certain embodiments, the dosage is administered daily for 5 days. In certain embodiments, the dosage is administered daily for 4 days. In certain embodiments, the dosage is administered daily for 3 days. In certain embodiments, the dosage is administered daily for 2 days. In certain embodiments, the dosage is administered for 1 day.

[0192]

[0192] In the dosing regimen, it can be administered daily or periodically according to the judgment of a skilled physician. In certain embodiments, the dosage is administered daily. In certain embodiments, the dosage is administered with an interval between administrations. 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]

[0193] In certain embodiments, the dosage is administered on a weekly basis. In certain embodiments, the dosage is administered twice a week. In certain embodiments, the dosage is administered three times a week.

[0194]

[0194] In certain embodiments, following the judgment of a skilled physician, the dosage is administered for a certain period at the first interval between administrations and then readministered for a certain period after the first interval between administrations, and this administration schedule can be repeated (i.e., periodically or cyclically, for example, after the second, third, etc. intervals between successive administrations of the dosage). For example, in one embodiment, the first dosage is administered for one week, followed by a first interval of one week without administration of the first dosage, then the second dosage is readministered for another week, followed by a second interval of one week without administration of the first or second dosage, etc., and it is administered periodically. Other variations for the first, second, third, etc. dosages, followed by variations for the first, second, third, etc. intervals and combinations thereof are contemplated herein as would be recognized by a skilled physician and the needs of the patient. For example, in one embodiment, the first dosage is administered daily for one week, followed by a first interval of three weeks without administration of the first daily dose, then the second dosage is readministered twice a week for another week, followed by a second interval of four weeks without administration of the first daily dose or the second twice-weekly dose for one week, etc., and it continues periodically.

[0195]

[0195] The compounds can be administered by a route of administration considered appropriate by a skilled physician. In certain embodiments, the dosage is administered orally. Formulations and administration techniques are described in detail below.

[0196] Pharmaceutical Composition

[0196] The compounds described herein can be formulated into pharmaceutical compositions further comprising a pharmaceutically acceptable carrier, diluent, additive, or excipient. In one embodiment, the present disclosure provides a pharmaceutical composition comprising the above-described compound and a pharmaceutically acceptable carrier, diluent, additive, or excipient. In one embodiment, a pharmaceutical composition is provided herein comprising an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents, additives, or excipients.

[0197]

[0197] In accordance with another embodiment, the present specification provides a composition comprising a compound herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition herein comprises a therapeutically effective amount of 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, stereoisomer or salt thereof.

[0198]

[0198] It will also be understood that certain compounds of the present disclosure may exist for therapeutic use in the free form or, where appropriate, as pharmaceutically acceptable derivatives thereof (e.g., salts). In accordance with the present disclosure, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters or any other adducts / leaving groups or derivatives which, when administered to a patient in need thereof, can provide directly or indirectly the compounds described elsewhere herein or their metabolites or residues.

[0199]

[0199] As used herein, the term "pharmaceutically acceptable salt" or "salt" means a salt suitable for use in contact with the tissues of humans and lower animals within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, etc.

[0200]

[0200] Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail in J. Pharmaceutical Sciences 1977, 66, 1-19, incorporated herein by reference by S. M. Berge et al. Pharmaceutically acceptable salts of the compounds herein include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include those formed using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or using organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or using other methods used in the art such as ion exchange, of amino groups. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, 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, etc. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium and N + (C 1~4Examples of such salts include (alkyl)4 salts. In this specification, the quaternization of the basic nitrogen-containing groups of the compounds disclosed herein is also contemplated. Water-soluble, oil-soluble or dispersible products can be obtained by such quaternization. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide ions, hydroxide ions, carboxylate ions, sulfate ions, phosphate ions, nitrate ions, lower alkylsulfonate ions and arylsulfonate ions.

[0201]

[0201] A pharmaceutically acceptable carrier can contain an inert component that does not overly inhibit the biological activity of the compound. A pharmaceutically acceptable carrier should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic, or lacking other undesirable reactions or side effects when administered to a subject. Standard pharmaceutical formulation techniques can be used.

[0202]

[0202] The pharmaceutically acceptable carriers, adjuvants or excipients used herein include any and all solvents, diluents or other liquid excipients, dispersing or suspending aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc., as appropriate for the particular dosage form desired. Remington’s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in the formulation of pharmaceutically acceptable compositions and the known techniques for manufacturing them. The use of such carrier media is contemplated to be within the scope of this specification, except when the conventional carrier media are incompatible with the compounds described herein, for example, by producing undesirable biological effects or by interacting detrimentally with any other component of the pharmaceutically acceptable composition. The term "side effect" as used herein encompasses the unwanted and harmful effects of a therapy (e.g., prophylactic or therapeutic agent). Side effects are always unwanted, but unwanted effects are not necessarily adverse. The harmful effects from a therapy (e.g., prophylactic or therapeutic agent) can be harmful, painful or dangerous. Side effects include, but are not limited to, fever, chill, drowsiness, gastrointestinal toxicity (such as ulceration and erosion of the stomach and intestine), nausea, vomiting, neurotoxicity, nephrotoxicity, kidney toxicity (such as symptoms as papillary necrosis and chronic interstitial nephritis), hepatotoxicity (such as elevation of serum liver enzyme levels), myelotoxicity (such as leukopenia, bone marrow suppression, thrombocytopenia and anemia), dry mouth, metallic taste, prolongation of pregnancy, asthenia, somnolence, pain (such as myalgia, bone pain and headache), alopecia, asthenia, dizziness, extrapyramidal symptoms, akathisia, cardiovascular disorders and sexual dysfunction.

[0203] Examples of substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (human serum albumin), buffering substances (such as tween 80, phosphate, glycine, sorbic acid or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride or zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene - polyoxypropylene - block polymer, methylcellulose, hydroxypropylmethylcellulose, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth gum; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; 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; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen - free water; isotonic saline; Ringer's solution; ethyl alcohol and phosphate buffer solutions and other non - toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring agents and fragrances. Preservatives and antioxidants may also be present in the composition at the discretion of the formulator.

[0204]

[0204] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, transmucosally, vaginally or via an implantable reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intramedullary, intraocular, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally or intravenously. Injectable sterile forms of the compositions of the present invention can be aqueous or oily suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Injectable sterile preparations can be, for example, solutions in 1,3-butanediol, injectable sterile solutions or suspensions in non-toxic parenterally acceptable diluents or solvents. Among the acceptable excipients and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils have conventionally been used as a solvent or suspending medium.

[0205]

[0205] For this purpose, non-irritating fixed oils such as synthetic mono- or diglycerides can be used. Fatty acids such as oleic acid and their glyceride derivatives are useful in the manufacture of injectables as pharmaceutically acceptable natural oils such as olive oil or castor oil, especially in their polyoxyethylenated versions. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and suspensions. Other surfactants commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms, such as Tween, Span and other emulsifying agents or bioavailability enhancers, can also be used for formulation.

[0206]

[0206] The pharmaceutically acceptable compositions of the present invention can be administered orally in an orally acceptable dosage form such as, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also generally used. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifying and suspending agents. Optionally, certain sweetening, flavoring or coloring agents may also be added.

[0207]

[0207] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for rectal or vaginal administration. They can be manufactured by mixing a suitable non-irritating excipient and the active substance that is solid at room temperature but liquid at rectal temperature and thus melts in the rectal or vaginal cavity to release the drug. Such materials include cocoa butter, polyethylene glycol or suppository waxes that are solid at ambient temperature but liquid at body temperature and thus melt in the rectal or vaginal cavity to release the active compound.

[0208]

[0208] The pharmaceutically acceptable compositions of the present invention can also be administered topically, particularly when the target of treatment includes sites or organs that are readily accessible by topical application, such as diseases of the eye, skin or lower gastrointestinal tract. Suitable topical formulations can be readily prepared for each of these sites or organs.

[0209]

[0209] Topical application to the lower gastrointestinal tract can be effected with rectal suppository formulations (see above) or suitable enema formulations. Topical transdermal patches can also be used.

[0210]

[0210] For topical application, the pharmaceutically acceptable compositions can be formulated as suitable ointments containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the 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 compositions can be formulated as suitable lotions or creams containing the 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, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0211]

[0211] For ophthalmic use, the pharmaceutically acceptable compositions can be formulated, for example, as a micronized suspension in isotonic, pH-adjusted sterile saline or other aqueous solutions or preferably as a solution, with or without preservatives such as benzalkonium chloride, in isotonic, pH-adjusted sterile saline or other aqueous solutions. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated as an ointment such as petrolatum. The pharmaceutically acceptable compositions of the invention can also be administered by nasal aerosol or inhalation. Such compositions are manufactured according to techniques well known in the art of pharmaceutical formulation and can be manufactured as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and / or conventional solubilizing or dispersing agents.

[0212]

[0212] In certain embodiments, the compositions of the present disclosure are administered orally. The pharmaceutically acceptable compositions herein can be administered orally in an orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricants such as magnesium stearate are also generally added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifying and suspending agents. Optionally, certain sweetening, flavoring or coloring agents can also be added.

[0213]

[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 compounds herein, the liquid dosage forms can contain inert diluents commonly used in the art such as water or other solvents, solubilizing and emulsifying agents such as ethyl alcohol, isopropyl alcohol, 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 glycol and fatty acid esters of sorbitan and mixtures thereof and the like. In addition to the inert diluents, oral compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

[0214]

[0214] For oral administration, solid dosage forms include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compounds herein are combined with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium silicate, and / or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) dissolution retardants such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include buffering agents.

[0215]

[0215] Solid compositions of the same type can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be manufactured using coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical field. The solid dosage forms can optionally contain opacifying agents. These solid dosage forms can also be dosage forms of compositions that optionally release only the active ingredient in a delayed manner in a specific part of the intestinal tract. Examples of implantable compositions that can be used include polymeric substances and waxes. Solid compositions of the same type can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0216]

[0216] The compounds described herein can be in microencapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be manufactured using coatings and shells such as enteric coatings, release control coatings, and other coatings known in the pharmaceutical art. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms can also include, as a normal practice, additional substances other than the inert diluent, such as tableting lubricants and magnesium stearate, and tableting aids such as microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form can also include buffering agents. They can also optionally contain opacifying agents and can be dosage forms of compositions that, for example, release only the active ingredient in an optionally delayed manner in a specific part of the intestinal tract. Examples of implantable compositions that can be used include polymeric substances and waxes.

[0217]

[0217] The compounds of the present specification are formulated in dosage unit forms for ease of administration and for the uniformity of dosage. The term "dosage unit form" as used herein means a physically discrete drug suitable for the patient to be treated. However, it should be understood that the total daily usage amount of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage levels for a particular patient or organism will vary depending on various factors such as the disease to be 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, the route of administration, and the specific excretion rate of the compound used; the duration of treatment; the drugs used in combination with or simultaneously with the specific compound used; and factors well known in the medical field.

[0218]

[0218] The amount of the compounds of the present disclosure that can be combined with a carrier to manufacture a composition in a single-dose dosage form will vary depending on the host being treated, the particular dosage form, and other factors. The composition should be formulated so that a patient to whom these compositions are administered can be administered a dosage of the compound or inhibitor of 0.01 to 100 mg / kg body weight / day.

[0219] combination

[0219] The compounds or compositions described herein can be administered simultaneously with, before, or following one or more additional therapeutically active agents. Generally, each active agent is administered at the dosage and / or time schedule determined for its respective action. It will further be understood that the additional therapeutically active agents used in this combination can be administered together in a single composition or separately in different compositions. In a particular combination used in a dosing regimen, the compatibility of the additional therapeutically active agent with the compounds of the invention and / or the therapeutic effect of the desired purpose to be achieved is considered. Generally, it is contemplated that the additional therapeutically active agents used in combination are used at levels that do not exceed the levels at which they are used individually. In some embodiments, the levels used in combination will be lower than the levels used individually. Additional therapeutically active agents include, but are not limited to, organic small molecules such as drug compounds (e.g., compounds approved by the Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional therapeutic agent is an anti-cancer agent (e.g., a biological or chemotherapeutic anti-cancer agent).

[0220]

[0220] In one embodiment, the additional active agent is one or more agents selected from the group consisting of STING agonist compounds, antiviral compounds, antigens, adjuvants, anti-cancer agents, CTLA-4, LAG-3 and PD-1 pathway antagonists, lipids, liposomes, peptides, cytotoxic agents, chemotherapeutic agents, immune-modifying substance cell lines, checkpoint inhibitors, vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, smoothen inhibitors, alkylating agents, antitumor antibiotics, anti-metabolites, retinoids, and without limitation, immunomodulators such as anti-cancer vaccines.

[0221]

[0221] In one embodiment, the additional therapeutically active agent is an anti-inflammatory agent. In one aspect of this embodiment, the additional therapeutically active agent is an immune-modifying substance, without limitation, a checkpoint inhibitor such as a PD-1 inhibitor, a PD-Ll inhibitor, a PD-L2 inhibitor, a CTLA-4 inhibitor, a LAG-3 inhibitor, a TIM-3 inhibitor, a V domain Ig suppressor of T cell activation (VISTA) inhibitor, a small molecule, a peptide, a nucleotide, or other inhibitor. In a particular aspect, the immune-modifying substance is an antibody such as a monoclonal antibody.

[0222]

[0222] Examples of PD-1 inhibitors that block the interaction between PD-1 and PD-L1 by binding to the PD-1 receptor and then inhibit immunosuppression include, for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro), and the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.). Examples of PD-1 inhibitors that block the interaction between PD-1 and PD-L1 by binding to the PD-1 receptor and then inhibit immunosuppression include, for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). Examples of CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibit immune suppression include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884, and AGEN2041 (Agenus). Examples of LAG-3 checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima Biomed), LAG525 (Novartis), and the PD-1 and LAG-3 dual inhibitor MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro).

[0223]

[0223] In an alternative embodiment, the PD-1 antagonist as the second therapeutic agent is a monoclonal antibody (mAb) or an antigen-binding fragment thereof, which specifically binds to PD-1 or PD-L1, preferably specifically binds to human PD-1 or human PD-L1. The mAb can be a human antibody, a humanized antibody or a chimeric antibody, and can include a human constant region. In some embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4 constant regions, and in a preferred embodiment, 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]

[0224] In one embodiment, the additional therapeutically effective agent is a cytotoxic agent or a chemotherapeutic agent. Cytotoxic agents that can be used in combination with the compounds or pharmaceutically acceptable salts described herein include, but are not limited to, arsenic trioxide (sold under the trade name TRISENOX®), asparaginase (sold under the trade names ELSPAR® and KIDROLASE®, also known as L-asparaginase and Erwinia L-asparaginase).

[0225]

[0225] Chemotherapeutic agents that can be used in combination with the compounds or pharmaceutically acceptable salts described herein include abiraterone acetate, altretamine, anhydrous vinblastine, 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-L-valyl-L-prolyl-1-L-prolyl-t-butylamide, cacectin, semadotin, chlorambucil, cyclophosphamide, 3’,4’-didehydro-4’deoxy-8’-norvin-norvincaleucoblastine, docetaxel, docetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, daunorubicin, desitabindrastatin, doxorubicin (adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyurea and taxane, ifosfamide, liarozole, lonidamine, lomustine (CCNU), MDV3100, mechlorethamine (nitrogen mustard), melphalan, miboplatin isethionate, lysofylline, selteneef, streptozocin, mitomycin, methotrexate, taxane, nilutamide, nivolumab, onapristone, paclitaxel, pembrolizumab, prednimustine, procarbazine, RPR109881, estramustine phosphate, tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate and vinflunine. Such chemotherapeutic agents can be provided as pharmaceutically acceptable salts, as appropriate.In one embodiment, additional therapeutically effective agents include vascular endothelial growth factor (VEGF) receptor inhibitors, 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), pazopanib, and sunitinib (SUTENT), sorafenib (NEXAVAR), and the like.

[0226]

[0226] In one embodiment, additional therapeutically effective agents include topoisomerase II inhibitors, including but not limited to etoposide (also known as VP-16 and etoposide phosphate, and commercially available under the trade names TOPOSAR, VEPESID, and ETOPOPHOS) and teniposide (also known as VM-26, and commercially available under the trade name VUMON).

[0227]

[0227] In one embodiment, additional therapeutic active agents are alkylating agents, including but not limited to 5-azacitidine (VIDAZA), decitabine (DECOGEN), temozolomide (TEMCAD, TEMODAR, and TEMODAL), dactinomycin (also known as actinomycin-D and commercially available under the trade name COSMEGEN), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard and commercially available under the trade name ALKERAN), altretamine (hexamethylmelamine (HMM) and commercially available under the trade name HEXALEN), carmustine (BCNU), bendamustine (TREANDA), busulfan (BUSULFEX® and MYLERAN®), carboplatin (PARAPLATIN®), lomustine (also known as CCNU and commercially available under the trade name CEENU®), cisplatin (also known as CDDP and commercially available under the trade names PLATINOL® and PLATINOL®-AQ), chlorambucil (LEUKERAN®), cyclophosphamide (CYTOXAN® and NEOSAR®), dacarbazine (DTIC, DIC, and also known as imidazole carboxamide and commercially available under the trade name DTIC-DOME®), altretamine (also known as hexamethylmelamine (HMM) and commercially available under the trade name HEXALEN®), ifosfamide (IFEXR), procarbazine (MATULANE®), mechlorethamine (nitrogen mustard, mustine, and mechlorethamine hydrochloride and commercially available under the trade name MUSTARGEN®), streptozocin (ZANOSAR®), thiotepa (also known as thiophosphoramide, TESPA, and TSPA and commercially available under the trade name THIOPLEX®), and the like. Such alkylating agents can be provided, as appropriate, as pharmaceutically acceptable salts.

[0228] Examples of antitumor antibiotics include, but are not limited to, doxorubicin (commercially available under the trade names ADRIAMYCIN® and RUBEX®), bleomycin (commercially available under the trade name LENOXANE®), daunorubicin (also known as daunorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, commercially available under the trade name CERUBIDINE®), daunorubicin liposome (daunorubicin citrate liposome, commercially available under the trade name DAUNOXOME®), mitoxantrone (also known as DHAD, commercially available under the trade name NOVANTRONE®), epirubicin (commercially available under the trade name ELLENCE™), idarubicin (commercially available under the trade names IDAMYCIN® and IDAMYCIN PFS®), and mitomycin C (commercially available under the trade name MUTAMYCIN®). Such antitumor antibiotics can be provided, as appropriate, as pharmaceutically acceptable salts.

[0229]

[0229] In one embodiment, additional therapeutic active agents are antimetabolites, including but not limited to cladribine (2-chlorodeoxyadenosine, LEUSTATIN®), 5-fluorouracil (ADRUCIL®), 6-thioguanine (PURINETHOL®), pemetrexed (ALIMTA®), cytarabine (also known as arabinosylcytosine (Ara-C) and commercially available under the trade name CYTOSAR-U®), cytarabine liposome (also known as liposomal Ara-C and commercially available under the trade name DEPOCYT™), decitabine (DACOGEN®), hydroxyurea (HYDREA®, DROXIA™ and MYLOCEL™), fludarabine (FLUDARA®), floxuridine (FUDR®), cladribine (also known as 2-chlorodeoxyadenosine (2-CdA) and commercially available under the trade name LEUSTATIN™), methotrexate (also known as amethopterin, methotrexate sodium (MTX) and commercially available under the trade names RHEUMATREX® and TREXALL™) and pentostatin (NIPENT®). Such antimetabolites may be provided as pharmaceutically acceptable salts as appropriate.

[0230]

[0230] In one embodiment, additional therapeutic active agents are retinoids, including but not limited to alitretinoin (PANRETIN®), tretinoin (also known as ATRA and commercially available under the trade name VESANOID®, all-trans retinoic acid), isotretinoin (13-cis-retinoic acid, commercially available under the trade names ACCUTANE®, AMNESTEEM®, CLARAVIS®, CLARUS®, DECUTAN®, ISOTANE®, IZOTECH®, ORATANE®, ISOTRET® and SOTRET®) and bexarotene (TARGRETIN®).

[0231]

[0231] The amount of the additional therapeutic agent present in the compositions of the present disclosure does not exceed the amount that would typically be administered in a composition containing that therapeutic agent as the sole active agent. The amount of the additional therapeutic agent in the compositions of the present disclosure will be in the range of about 50 to 100% of the amount that is typically present in a composition containing that therapeutic agent as the sole active agent.

[0232]

[0232] In certain embodiments, the compounds or pharmaceutically acceptable salts described herein are administered with one or more additional therapeutic agents, such as a vaccine intended to stimulate an immune response. Antigens and adjuvants that can be used with the compounds or pharmaceutically acceptable salts described herein include B7 co-stimulatory molecules, interleukin-2, interferon-y, GM-CSF, CTLA-4 antagonists, OX40 / OX40 ligand, CD40 / CD40 ligand, sargramostim, levamisole, vaccinia virus, Bacillus Calmette-Guerin (BCG), liposomes, alum, Freund's complete or incomplete adjuvant, detoxified endotoxin, mineral oil, surfactants such as lipolecithin, pluronic polyols, polyanions, peptides and oil or hydrocarbon emulsions. The addition of an adjuvant such as aluminum hydroxide or aluminum phosphate can increase the ability of the vaccine to induce, enhance or prolong an immune response. Additional substances such as cytokines, chemokines and bacterial nucleic acid sequences such as CpG, Toll-like receptor (TLR) 9 agonists and additional agonists for TLR2, TLR4, TLR5, TLR 7 , TLR8, TLR9, such as lipoproteins, LPS, monophosphoryl lipid A, lipoteichoic acid, imiquimod, resiquimod and retinoic acid-inducible gene I (RIG-I) agonists such as poly I:C used separately or in combination with the compositions further described are also potential adjuvants. Such antigens and adjuvants as a second therapeutically active agent can optionally be provided as pharmaceutically acceptable salts.

[0233]

[0233] Antiviral compounds that can be used in combination with the compounds described herein or pharmaceutically acceptable salts 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. Such antiviral compounds can be provided, as appropriate, as pharmaceutically acceptable salts.

[0234] Manufactured articles and kits

[0234] Also provided are manufactured articles containing any of the compounds or pharmaceutical compositions described herein. The manufactured article includes a container or packaging material suitable for the compound or pharmaceutical composition. Examples of suitable containers include, but are not limited to, bottles, vials, syringes, intravenous administration bags, or tubes.

[0235]

[0235] Also provided are kits containing any of the compounds or pharmaceutical compositions described herein. The kit can contain the compound or pharmaceutical composition in a suitable container or packaging material, such as, but not limited to, a bottle, vial, syringe, intravenous administration bag, or tube. The kit can include the compound or pharmaceutical composition for administration to an individual in a single-dose form or a multiple-dose form. The kit can further include instructions or a label for administering the compound or pharmaceutical composition to an individual according to any of the methods disclosed herein. The kit can further include an instrument for administering the compound or pharmaceutical composition to an individual, such as, but not limited to, a needle, syringe, tube, or intravenous administration bag. The kit can further include instructions for generating any of the compounds or pharmaceutical compositions described herein.

[0236] Articles are also provided that contain any of the compounds, vaccines, or pharmaceutical compositions described herein. The article includes a container or packaging material suitable for the compound or pharmaceutical composition. The article includes a container or packaging material suitable for the compound, oncolytic virus, or pharmaceutical composition. Examples of suitable containers include, but are not limited to, bottles, vials, syringes, intravenous bags, or tubing.

[0237]

[0237] The present disclosure will be understood in more detail by reference to the following examples. However, these should not be construed as limiting the scope of the present disclosure. The examples and embodiments described herein are for illustrative purposes only, and in view of them, various modifications and variations will be suggested to those skilled in the art and are understood to be within the spirit and scope of the present application and the appended claims.

Examples

[0238] Examples

[0238] The compounds provided herein can be manufactured or synthesized according to techniques that would be considered appropriate by those skilled in the art. Exemplary synthetic schemes are described below.

[0239] Manufacture of Compounds

[0239] The proton nuclear magnetic resonance (NMR) spectrum was obtained using a Bruker Ascend TM 500 MHz spectrometer. The NMR spectrum is reported as follows: chemical shift δ (ppm), multiplicity, coupling constant J (Hz), and integral value. The abbreviations s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad are used throughout. 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 detector (ELSD), and electrospray positive ion (ESI) (column: Agilent Poroshell 120 EC-C18, 2.7 μm, 4.6 × 50 mm). Solvent used: acetonitrile / water containing 0.1% formic acid; flow rate 1 mL / min.

[0240]

[0240] The abbreviations used in the examples include the following.

[0241]

Table 1

[0242]

[0241] For all of the following examples, standard workup and purification methods known to those skilled in the art can be used. Unless otherwise specified, all temperatures are in °C (Celsius). Unless otherwise specified, all reactions are carried out at room temperature. The synthetic methodologies described herein are intended to illustrate the applicable chemistry through the use of specific examples and are not indicative of the scope of the present disclosure.

[0243]

[0242] The symbols and conventions used in these processes, schemes, and examples as used herein are consistent with those used in modern scientific literature, such as the Journal of Biological Chemistry and / or the Journal of the American Chemical Society, regardless of whether specific abbreviations are specifically defined.

[0244]

[0243] For all of the following examples, standard workup and purification methods known to those skilled in the art can be used. Unless otherwise specified, all temperatures are expressed in °C (degrees Celsius). Unless otherwise specified, all methods are carried out at room temperature (「rt」, or 「r.t.」, or 「RT」).

[0245]

[0244] The following synthetic schemes are provided for illustrative purposes only, and not for purposes of limitation. The following examples illustrate various methods for preparing the compounds described herein. It is understood that those skilled in the art can prepare these compounds by combining similar methods or other methods known to those skilled in the art. It is also contemplated that those skilled in the art may be able to prepare these compounds in a similar manner as described below by using appropriate starting materials and making modifications to the synthetic routes as necessary. Generally, starting materials and reagents can be obtained from manufacturing suppliers, or synthesized according to suppliers known to those skilled in the art, or prepared as described herein.

[0246] Example 1: Synthesis of Selective STING Agonists

[0245] The general intermediates of the STING agonist examples described below were prepared according to the following scheme. The intermediates were then used to prepare the STING agonist compounds of the present disclosure.

[0247]

[0246] Scheme 1: Synthesis of Intermediate Compound A:

Chemical formula

[0248]

[0247] 1-Fluoro-2,3-dimethoxybenzene (A2): Methyl iodide (83.1 g, 585.4 mmol) was added dropwise 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 extracted with EtOAc (3 × 1 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 (400 MHz, CDCl3) δ 6.95 (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).

[0249]

[0248] 2-Fluoro-3,4-dimethoxybenzaldehyde (A3): Titanium tetrachloride (63.7 g, 336.1 mmol) in DCM (100 mL) was added dropwise to a stirred solution of compound A2 (35 g, 224.1 mmol) in DCM (200 mL) at -20 °C under a N2 atmosphere. Dichloromethyl methyl ether (28.3 g, 246.5 mmol) in DCM (100 mL) was then added to the reaction. The reaction was then stirred at room temperature for 16 h. 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 pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 7.59 (dd, J = 8.8, 7.7 Hz, 1H), 7.09 (dd, J = 8.9, 1.5 Hz, 1H), 3.93 (s, 3H), 3.83 (s, 3H).

[0250]

[0249] (E)-5-(2-Fluoro-3,4-dimethoxybenzylidene)-2-thiazolidin-4-one (A4): A solution of compound A3 (18.2 g, 98.8 mmol), 2-thiazolidin-4-one (13.1 g, 98.8 mmol), and NaOAc (24.3 g, 296.4 mmol) in acetic acid (200 mL) was stirred at 100 °C overnight. The reaction mixture was cooled to room temperature and slowly added to water (600 mL). A precipitate formed, was filtered, and washed with water (15 mL × 3) to give compound A4 (28 g, 94% yield) as a bright yellow solid, which was used directly without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 7.53 (s, 1H), 7.20 (t, J = 8.4 Hz, 1H), 7.09 (dd, J = 9.0, 1.5 Hz, 1H), 3.91 (s, 3H), 3.82 (s, 3H).

[0251]

[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 in 200 mL of H2O and 200 mL of EtOH), and the reaction mixture was stirred at room temperature overnight. Then the reaction was diluted with water (500 mL) and EtOAc (250 mL). The aqueous phase was recovered, acidified to pH ~3 by adding 1N HCl, extracted with EtOAc (200 mL × 3), and the combined organic layers were concentrated to give compound A5 (18.2, yield: 38.7%) as a yellow solid, which was used directly in the next step. 1 H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H), 7.71 (s, 1H), 7.67 - 7.56 (m, 1H), 7.04 (dd, J = 9.0, 1.7 Hz, 1H), 3.88 (s, 3H), 3.80 (s, 3H).

[0252]

[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 recovered, adjusted to pH ~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 (400 MHz, chloroform-d) δ 8.12 (s, 1H), 7.09 (s, 1H), 3.99 (s, 3H), 3.97 (s, 3H).

[0253]

[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 h. 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 (400 MHz, CDCl3) δ 7.34 - 7.30 (m, 1H), 7.27 (s, 1H), 7.14 - 7.11 (m, 1H), 3.98 (d, J = 0.9 Hz, 3H), 3.94 (s, 3H).

[0254] [

[0253] ] Methyl 4-(4-fluoro-5,6-dimethoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate (A8): 3,3-Dimethyldihydrofuran-2,5-dione (2.8 g, 22.6 mmol) and AlCl3 (1.9 g, 14.7 mmol) in DCM (15 mL) were stirred at 0 °C for 10 minutes. The reaction mixture was stirred at room temperature overnight. Then, the reaction was carefully quenched with water (10 mL) and then extracted with CHCl3 / IPA (3 / 1, v / v, 15 × 3 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 (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.56 (s, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.57 (s, 2H), 1.23 (s, 6H).

[0255] [

[0254] ] Methyl 4-(4-fluoro-5,6-dimethoxybenzo[b]thiophen-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 the combined organic phases were concentrated under reduced pressure and purified by silica gel chromatography to give the desired product A9 (840 mg, 54% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (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)

[0256] [

[0255] ] Methyl 4-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate (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 h. The reaction mixture was quenched with ice-cold water (20 mL) and extracted with CHCl3 / IPA (3 / 1, v / v, 15 mL×3). The combined organic phases were concentrated and the residue was purified by silica gel chromatography to give the desired product A10 (560 mg, yield 67.9%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.52 (d, J = 0.9 Hz, 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).

[0257] [

[0256] ] Methyl 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate (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 extracted with EtOAc (15 mL×3). The combined organic phases were concentrated under reduced pressure and the residue was purified by silica gel chromatography to give the desired product A (260 mg, yield 88%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.59 (s, 1H), 4.15 (t, J = 5.9 Hz, 2H), 3.92 (s, 3H), 3.73 (t, J = 6.5 Hz, 2H), 3.57 (s, 3H), 3.43 (s, 2H), 2.21 (p, J = 6.2 Hz, 2H), 1.24 (s, 6H).

[0258] [

[0257] ] Scheme 2: Synthesis of compound 1: [[Chem.]]

[0259]

[0258] 4-Fluoro-5,6-dimethoxybenzo[b]thiophene-2-carbonyl 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, and then the reaction was concentrated under reduced pressure, and compound 2 was carried over directly to the next step.

[0260]

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

[0261] [

[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. From TLC, it was found that the SM had disappeared. The reaction was slowly added to ice-cold water and extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain a crude product, which was purified by a reverse-phase column to obtain compound 5 (285 mg) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.44 (s, 1H), 4.17 (s, 2H), 3.91 (s, 3H).

[0262] [

[0261] ] 4-(4-Fluoro-5-(3-((4-fluoro-6-methoxy-2-(2-sulfoacetyl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate (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) were 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 at 65 °C overnight. The reaction was cooled to room temperature and purified by preparative HPLC to obtain the desired compound 1 (11 mg) as a white solid. 11H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 9.7 Hz, 2H), 7.54 (d, J = 6.2 Hz, 2H), 4.28 (t, J = 6.1 Hz, 4H), 4.19 (s, 2H), 3.88 (d, J = 3.1 Hz, 6H), 3.37 (s, 2H), 2.10 (p, J = 6.1 Hz, 2H), 1.24 (s, 6H).

[0263]

[0262] Scheme 3: Synthesis of Compound 2:

Chem.

[0264]

[0263] Methyl 4-fluoro-5,6-dimethoxybenzo[b]thiophene-2-carboxylate (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 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 silica gel chromatography to give Compound 2 (10 g) as a solid. 1 1H NMR (400 MHz, chloroform-d) δ 8.04 (s, 1H), 7.07 (s, 1H), 3.98 (d, J = 1.1 Hz, 3H), 3.96 (s, 3H), 3.93 (s, 3H).

[0265]

[0264] Methyl 2-(4-fluoro-5,6-dimethoxybenzo[b]thiophen-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. Then, 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 an aqueous NH4Cl solution, 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 (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.63 (s, 1H), 5.40 (s, 2H), 3.98 (d, J = 1.5 Hz, 3H), 3.94 (s, 3H), 3.87 (s, 3H).

[0266]

[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. Then, the reaction mixture was 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 give compound 4 (4.9 g) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.44 (s, 1H), 4.17 (s, 2H), 3.91 (s, 3H).

[0267]

[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): To a solution of 2-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-2-oxoethane-1-sulfonic acid (4) (4.38 g, 0.013 mol) in DMF (50 mL) were sequentially added methyl 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethylpent-4-enoate (A) (7.57 g, 0.016 mol), Cs2CO3 (13.37 g, 0.04 mol), and NaI (4.1 g, 0.027 mol) at room temperature. 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 give the desired product, Compound 2 (880 mg) as a white solid. 1 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 2H), 7.55 (d, J = 9.0 Hz, 2H), 4.29 (t, J = 6.1 Hz, 4H), 4.21 (s, 2H), 3.89 (d, J = 3.0 Hz, 6H), 3.59 (s, 3H), 3.45 (s, 2H), 2.11 (p, J = 6.1 Hz, 2H), 1.26 (s, 6H).

[0268]

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

Chem.

[0269] [

[0268] ] Methyl 4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylate (3): To a suspension of AlCl3 (10.8 g, 81.4 mmol) in DCM (180 mL) was added methyl 4-fluoro-5,6-dimethoxybenzo[b]thiophene-2-carboxylate 2 (4.4 g, 16.3 mmol) at 0 °C. The reaction mixture was warmed to ambient temperature and stirred for 16 h under a nitrogen atmosphere. From TLC, it was found that the SM was consumed, then the mixture was diluted with water (100 mL), acidified to pH ~2 by adding 1 M 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 afford the desired product 3 (2 g, 47.9%) as a pale yellow solid. LCMS (ESI) = 255.1 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 9.58 - 9.52 (m, 1H), 7.94 (s, 1H), 7.48 (s, 1H), 3.91 (s, 3H), 3.86 (s, 3H).

[0270] [

[0269] ] Methyl 4-fluoro-6-methoxy-5-((triisopropylsilyl)oxy)benzo[b]thiophene-2-carboxylate (4): To a solution of methyl 4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophene-2-carboxylate 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 a nitrogen atmosphere, 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 afford the desired product 4 (2.6 g, 81%) as a pale yellow solid. 11H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.52 (s, 1H), 4.18 (s, 3H), 4.15 (s, 3H), 1.59 - 1.48 (m, 4H), 1.35 (d, J = 7.4 Hz, 18H).

[0271]

[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 then the reaction was stirred for 45 minutes. Thereafter, 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. Then, the reaction was quenched with a saturated aqueous NH4Cl solution (40 mL) at -40 °C and extracted with EtOAc (60 mL × 3). The combined organic layers were 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 pale yellow solid. LCMS (ESI): m / z 505.2 (M+H).

[0272] [

[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). The reaction mixture was stirred at room temperature for 2 h under a nitrogen atmosphere, then the mixture was quenched with water (30 mL), acidified to pH ~3 by addition of 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 pale yellow solid. LCMS (ESI) = m / z 349.1 (M+H).

[0273] [

[0272] ] 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): To a solution of dimethyl (2-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-2-oxoethyl)phosphonate 6 (1.8 g, 5.17 mmol) and methyl 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate (A) (2.4 g, 5.17 mmol) in CH3CN (40 mL) was added Cs2CO3 (5.1 g, 15.50 mmol), and the mixture was stirred at 65 °C for 2 h under a nitrogen atmosphere. The reaction was then 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 pale yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.26 (s, 1H), 7.55 (d, J = 3.4 Hz, 2H), 4.28 (td, J = 6.3, 3.3 Hz, 4H), 4.00 (s, 1H), 3.94 (s, 1H), 3.87 (d, J = 1.8 Hz, 6H), 3.70 (s, 3H), 3.67 (s, 3H), 3.57 (s, 3H), 3.42 (s, 2H), 2.09 (p, J = 6.2 Hz, 2H), 1.24 (s, 6H).

[0274]

[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-oxobutanoate (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 a nitrogen atmosphere. The reaction was cooled to room temperature and 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. 1 1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 2H), 7.54 (s, 1H), 7.50 (s, 1H), 4.31 - 4.22 (m, 4H), 3.87 (d, J = 5.6 Hz, 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).

[0275]

[0274] Scheme 5. Synthesis of Compound 5:

Chem.

[0276]

[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): 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 (3.0 g, 4.12 mmol) in DCM (120 mL) were added N,O-bis(trimethylsilyl)trifluoroacetamide (6.4 g, 24.70 mmol) and iodotrimethylsilane (4.1 g, 20.58 mmol) at 0 °C, and then the mixture was stirred for 1 h under a nitrogen atmosphere. The reaction was concentrated under reduced pressure and the residue was purified by reverse-phase column to give the desired product, Compound 5 (1.69 g, 58.6%) as a pale orange solid. LCMS (ESI) = m / z 699.2 (M-H). 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 2H), 7.54 (d, J = 4.2 Hz, 2H), 4.27 (t, J = 6.1 Hz, 4H), 3.87 (s, 6H), 3.62 - 3.52 (m, 5H), 2.10 (q, J = 6.2 Hz, 2H), 1.24 (s, 6H).

[0277]

[0276] Scheme 6. Synthesis of Compound 6:

Chem.

[0278]

[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-oxobutanoate: 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 (400 MHz, DMSO-d6) δ 8.22 (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 = 20.7 Hz, 2H), 2.05 (m, 2H), 1.24 (s, 6H).

[0279]

[0278] Scheme 7. Synthesis of compound 7:

Chem.

[0280] [

[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 overnight at room temperature. Then, the reaction was 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 silica gel chromatography to give compound 2 (1.33 g) as a solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.43 (s, 1H), 3.90 (s, 3H), 3.80 (s, 3H), 3.32 (s, 3H).

[0281] [

[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. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was added to an ice-cooled 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 (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.40 (s, 1H), 7.57 (dd, J = 16.9, 10.4 Hz, 1H), 7.49 (s, 1H), 6.38 (dd, J = 16.9, 1.9 Hz, 1H), 5.95 (dd, J = 10.3, 1.9 Hz, 1H), 3.92 (s, 3H).

[0282] [

[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) were 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 h. It was found from TLC that the SM had disappeared. The mixture was diluted with water and 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 (400 MHz, DMSO-d6) δ 8.24 (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).

[0283] [

[0282] ] Methyl 4-(5-(3-((2-(3-(dimethoxyphosphoryl)propanoyl)-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) were 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. The reaction mixture was stirred at 65 °C for 2 h. The reaction was diluted with water and 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 5. 11H NMR (400 MHz, chloroform-d) δ 7.93 (s, 2H), 7.05 (s, 2H), 4.39 (d, J = 6.1 Hz, 4H), 3.91 (s, 6H), 3.78 (dd, J = 10.8, 2.5 Hz, 6H), 3.72 (d, J = 2.5 Hz, 3H), 3.32 (d, J = 6.8 Hz, 2H), 2.80 (t, J = 6.7 Hz, 2H), 2.31 - 2.17 (m, 4H), 0.87 (s, 2H).

[0284]

[0283] 4-(4-Fluoro-5-(3-((4-fluoro-2-(3-(hydroxy(methoxy)phosphoryl)propanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (6): To a solution of methyl 4-(5-(3-((2-(3-(dimethoxyphosphoryl)propanoyl)-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 1 M HCl solution, extracted with EtOAc, 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 (M - H)

[0285]

[0284] 4-(4-Fluoro-5-(3-((4-fluoro-6-methoxy-2-(3-phosphonopropanoyl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (Compound 7): To a solution of 4-(4-fluoro-5-(3-((4-fluoro-2-(3-(hydroxy(methoxy)phosphoryl)propanoyl)-6-methoxybenzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate 6 (50 mg, 0.07 mmol) in CH3CN were 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 title compound, Compound 7 (18 mg) as a white solid. LCMS (ESI) = m / z 670.95 (M-H); 1 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.14 (s, 1H), 7.53 (s, 2H), 4.27 (t, J = 6.1 Hz, 4H), 3.87 (s, 6H), 3.30 (s, 2H), 3.24 - 3.20 (m, 2H), 2.59 (t, J = 6.4 Hz, 2H), 2.08 (p, J = 6.2 Hz, 2H), 1.89 (dt, J = 16.3, 7.7 Hz, 2H).

[0286]

[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.

Chem.

[0287]

[0286] Scheme 9. Synthesis of Compound 9:

Chem.

[0288] [

[0287] ] 1-(4-Fluoro-5,6-dimethoxybenzo[b]thiophen-2-yl)-3-methylbut-2-en-1-one (2): 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) were added to a solution of AlCl3 (1.4 g, 10.41 mmol) in DCM (20 mL) at -78 °C. The reaction was stirred at room temperature overnight. Then, the reaction mixture was added to ice water 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 2 (2.18 g) as a solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.55 (s, 1H), 7.11 (s, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 2.19 (d, J = 1.2 Hz, 3H), 2.02 (d, J = 1.3 Hz, 3H).

[0289] [

[0288] ] 1-(4-Fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-3-methylbut-2-en-1-one (3): AlCl3 (6.4 g, 48.3 mmol) was added 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) at 0 °C. The reaction was stirred at room temperature overnight, then the mixture was slowly added to ice-cold 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 (400 MHz, chloroform-d) δ 7.90 (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).

[0290] [

[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) and Cs2CO3 (5.5 g, 16.8 mmol), and the reaction mixture was stirred at 65 °C for 2 h. The reaction was cooled to room temperature, diluted with water, extracted with EtOAc, 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. 1 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 2H), 7.52 (d, J = 9.2 Hz, 2H), 7.09 (s, 1H), 4.27 (t, J = 6.1 Hz, 4H), 3.86 (s, 6H), 3.56 (s, 3H), 2.20 (s, 3H), 2.09 (q, J = 6.3 Hz, 2H), 2.03 (s, 3H), 1.23 (s, 6H).

[0291]

[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) was added TMSOTf (622.3 mg, 2.8 mmol) at 0 °C. 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 enolsilane intermediate was hydrolyzed by stirring the reaction mixture with 3 mL of 1 M HCl for 3 hours. 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 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.12 (s, 1H), 7.53 (d, J = 3.1 Hz, 2H), 4.27 (t, J = 6.1 Hz, 4H), 3.86 (s, 6H), 3.65 (s, 3H), 3.62 (s, 3H), 3.57 (s, 3H), 2.08 (q, J = 6.1 Hz, 2H), 1.23 (s, 12H).

[0292]

[0291] 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 (6): To a solution of 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 (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). The mixture was stirred at room temperature overnight, then 1 M HCl solution was added to acidify the reaction. The mixture was 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.

[0293]

[0292] 4-(4-Fluoro-5-(3-((4-fluoro-6-methoxy-2-(3-methyl-3-phosphonobutanoyl)benzo[b]thiophen-5-yl)oxy)propoxy)-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate (Compound 9): To a solution of 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 6 (63 mg, 0.08 mmol) in DCM were sequentially added BSTFA (85.7 mg, 0.33 mmol) and TMSI (99.9 mg, 0.50 mmol) at 0 °C. The reaction was stirred for 1 hour and then concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the desired compound, compound 9 (25 mg) as a white solid. LCMS (ESI) = m / z 727.05 (M-H); 11H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.00 (s, 1H), 7.50 (s, 2H), 4.26 (t, J = 6.2 Hz, 4H), 3.86 (s, 6H), 3.34 (s, 2H), 3.09 (d, J = 9.3 Hz, 2H), 2.07 (t, J = 6.7 Hz, 2H), 1.22 (s, 12H).

[0294]

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

Chem.

[0295]

[0294] Scheme 11. Synthesis of Compound 11:

Chem.

[0296]

[0295] 4-(4-Fluoro-5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (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) portionwise, and the reaction was stirred at room temperature overnight. The reaction was quenched slowly with ice-cold 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 afford the desired product 2 (1.8 g, 62%) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 12.17 (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 = 6.4 Hz, 2H).

[0297]

[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-oxobutanoate 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 h. The reaction mixture was diluted in 800 mL of water and extracted with EtOAc (400 mL × 3). The combined organic layers were concentrated, and the residue was purified by silica gel chromatography to give the desired product 3 (4.57 g, 81% yield) as a yellow solid. LCMS (ESI) = m / z 326.9 (M+H).

[0298]

[0297] Methyl 4-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-oxobutanoate (4): 4-(4-Fluoro-5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoate 3 (4.5 g, 14 mmol) was added to a suspension of AlCl3 (9.4 g, 70.5 mmol) in DCM (225 mL) at 0 °C. The mixture was warmed to ambient temperature and stirred under a nitrogen atmosphere for 16 h. The mixture was quenched with water (500 mL), acidified to pH ~2 by slowly adding 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 pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.24 (s, 1H), 7.46 (s, 1H), 3.91 s, 3H), 3.60 (s, 3H), 3.37 (t, J = 6.4 Hz, 2H), 2.67 (t, J = 6.3 Hz, 2H).

[0299] [

[0298] ] Methyl 4-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-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) was added NaBH4 (38 mg, 1.33 mmol) portionwise at 0 °C, and the reaction was stirred at room temperature for 1 hour. Then, the reaction was diluted with water (10 mL) and extracted with EtOAc (10 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 5 (220 mg, 54%) as a pale yellow solid. LCMS (ESI) = m / z 314.9 (M+H).

[0300] [

[0299] ] 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): To a solution of methyl 4-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-4-hydroxybutanoate 5 (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 pale yellow solid.

[0301]

[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-oxobutanoate (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. Then, 1 M HCl solution was added to acidify the mixture to pH = 1, and the mixture was extracted with EtOAc (15 mL × 3). 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 pale yellow solid. LCMS (ESI) = m / z 665.2 (M-H).

[0302]

[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-oxobutanoate 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 a nitrogen atmosphere. The mixture was stirred at room temperature overnight. Then, the reaction mixture was concentrated under reduced pressure and 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 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 7.21 (s, 1H), 6.76 (d, J = 16.0 Hz, 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 = 7.2 Hz, 2H), 2.07 (m, 2H), 1.23 (s, 6H).

[0303]

[0302] Scheme 12. Synthesis of Compound 12:

Chem.

[0304]

[0303] (4-Fluoro-5,6-dimethoxybenzo[b]thiophen-2-yl)methanol (2): Lithium aluminum hydride (1 M, 44.9 mL, 45.0 mmol) was added 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) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. It was found from LCMS that the reaction was complete. The reaction mixture was carefully quenched with ice-cold water, acidified to pH ~3 by adding 1N HCl, and extracted with EtOAc (30 × 3 mL). The combined organic phases were concentrated and purified by silica gel column to give the desired product 2 (1.64 g, 45% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.45 (s, 1H), 7.17 (s, 1H), 5.63 (t, J = 5.8 Hz, 1H), 4.69 (dd, J = 5.9, 1.1 Hz, 2H), 3.87 (s, 3H), 3.81 (s, 3H).

[0305]

[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]thiophen-2-yl)methanol 2 (1.64 g, 6.76 mmol) in DCM (40 mL), and the mixture was stirred at room temperature for 16 h. Then, 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 (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.37 (s, 1H), 7.63 (s, 1H), 3.93 (s, 3H), 3.86 (s, 3H).

[0306]

[0305] 4-Fluoro-5-hydroxy-6-methoxybenzo[b]thiophene-2-carbaldehyde (4): Aluminum chloride (6.35 g, 47.62 mmol) was added to a solution of 4-fluoro-5,6-dimethoxybenzo[b]thiophene-2-carbaldehyde 3 (1.43 g, 5.95 mmol) in DCM (60 mL) at 0 °C. The mixture was stirred at room temperature overnight and it was found from LCMS that the reaction was complete. The mixture was slowly added to ice water and extracted with DCM (40 × 3 mL). The organic layer was dried over Na2SO4 and concentrated to obtain a 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 (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.61 (s, 1H), 8.30 (s, 1H), 7.52 (s, 1H), 3.93 (s, 3H).

[0307]

[0306] 4-Fluoro-6-methoxy-5-((4-methoxybenzyl)oxy)benzo[b]thiophene-2-carbaldehyde (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-carbaldehyde 4 (100 mg, 0.44 mmol) in DMF (3 mL), and the reaction was stirred at room temperature overnight. It was found from LCMS that the reaction was complete. The mixture was diluted with water, extracted with EtOAc, the organic layer was dried over Na2SO4 and concentrated to obtain a crude product, which was purified by silica gel column chromatography to give compound 5 (140 mg, 90%). 1 H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.33 (s, H), 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).

[0308] [

[0307] ] t-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-((t-butyldimethylsilyl)oxy)propyl)sulfonyl)benzothiazole (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 for 1 hour under a N2 atmosphere. It was found from LCMS that the reaction was complete, then the mixture was diluted with water and extracted with EtOAc (15 mL × 3). 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 6 (760 mg, 90%) as a white solid.

[0309] [

[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 t-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. It was found from LCMS that the reaction was complete, the mixture was diluted with water and extracted with EtOAc (15 mL × 3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 7 (300 mg, 58%) as a yellow oil.

[0310]

[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 diethyl ether, 30 mL, 30.8 mmol) at 0 °C in THF (3 mL) was added 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). The mixture was stirred overnight. The desired product was indicated by LCMS. The reaction mixture was concentrated and purified by a reverse-phase column to give compound 8 (250 mg, 40%).

[0311]

[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 Dess-Martin periodinane (632 mg, 1.49 mmol) at 0 °C. The reaction was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with EtOAc (15 × 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).

[0312]

[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) were added KH2PO4 (258 mg, 1.90 mmol), 2-methyl-2-butene (166 mg, 2.37 mmol) and NaClO2 (171 mg, 1.90 mmol) at 0 °C. The mixture was stirred at room temperature overnight. Completion of the reaction was indicated by LCMS. The reaction was diluted with water, 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%).

[0313]

[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)acetic acid 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). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water, 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 11 (156 mg, yield 22%). 11H NMR (400 MHz, DMSO-d6) δ 7.38 (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, 4.9 Hz, 1H), 1.40 - 1.31 (m, 1H), 1.06 (dt, J = 8.9, 5.1 Hz, 1H), 0.97 (dt, J = 8.4, 5.3 Hz, 1H).

[0314]

[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) were added HCl (1 drop) and Pd / C (20 mg, 10%). The mixture was stirred at 60 °C overnight under a H2 atmosphere. The reaction mixture was cooled, carefully filtered through celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by preparative TLC to give compound 12 (62 mg, 55% yield) as a yellow solid.

[0315]

[0314] Methyl 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-oxobutanoate (13): To a solution of methyl 2-(2-(4-fluoro-5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)cyclopropyl)acetate 12 (52.6 mg, 0.169 mmol) in CH3CN (2.5 mL) were added methyl 4-(5-(3-bromopropoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate A (93.83 mg, 0.203 mmol) and Cs2CO3 (276.12 mg, 0.847 mmol) at 65 °C for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography to give the desired product 13 (100 mg, 85% yield) as a yellow solid.

[0316]

[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-oxobutanoate (Compound 12): A solution of methyl 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-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 reaction was concentrated and purified by silica gel column chromatography to give the desired product, Compound 12 (80 mg, 64% yield) as a yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.52 (s, 1H), 7.35 (s, 1H), 6.96 (s, 1H), 4.25 (t, J = 6.2 Hz, 2H), 4.20 (t, J = 6.1 Hz, 2H), 3.86 (s, 3H), 3.79 (s, 3H), 3.45 - 3.40 (m, 2H), 2.37 - 2.30 (m, 2H), 2.05 (dp, J = 12.0, 5.7 Hz, 3H), 1.35 (s, 1H), 1.23 (s, 6H), 1.08 - 0.92 (m, 2H). 19 19F NMR (376 MHz, DMSO-d6) δ -134.15, -137.06.

[0317]

[0316] Scheme 13. Synthesis of Compound 13:

Chem.

[0318]

[0317] 4-(6-Methoxynaphthalen-2-yl)-4-oxobutanoate (2): Aluminum chloride (16.84 g, 126.40 mmol) was added portionwise 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) at 0 °C. The mixture was stirred at room temperature overnight. The reaction mixture was then carefully quenched with ice-cold 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 (1.6 g, 10%) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.07 (d, J = 9.0 Hz, 1H), 8.01 - 7.90 (m, 2H), 7.44 (d, J = 2.2 Hz, 1H), 7.29 (dd, J = 8.9, 2.4 Hz, 1H), 3.94 (s, 3H), 3.44 (t, J = 6.3 Hz, 2H), 2.73 (d, J = 12.6 Hz, 2H).

[0319] [

[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) were added K2CO3 (2.11 g, 15.3 mmol) and CH3I (8.3 g, 58.5 mmol) at °C. The mixture was stirred at room temperature for 3 hours. Then, the reaction mixture was diluted with water (300 mL) and 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).

[0320] [

[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. It was found from TLC that the starting material had disappeared. The reaction mixture was diluted with water (10 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 (25 mg, 21%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.57 (s, 1H), 7.99 (d, J = 9.6 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.17 (dd, J = 6.9, 2.3 Hz, 2H), 3.61 (s, 3H), 3.40 (t, J = 6.3 Hz, 2H), 2.69 (t, J = 6.3 Hz, 2H).

[0321]

[0320] 4-(5-(3-((6-(3-Carboxypropanoyl)naphthalen-2-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate (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 pale yellow solid. LCMS (ESI) = m / z 639.1 (M+H).

[0322]

[0321] 4-(5-(3-((6-(3-Carboxypropanoyl)naphthalen-2-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate (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 completion of the reaction was indicated by LCMS. 1 M HCl was added to adjust the pH of the reaction mixture to 1, and the mixture was extracted with EtOAc (5 mL × 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. 11H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 2H), 8.63 (d, J = 1.6 Hz, 1H), 8.27 (s, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.96 (d, J = 10.0 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.55 (s, 1H), 7.45 (s, 1H), 7.27 (dd, J = 8.8, 2.4 Hz, 1H), 4.37 (t, J = 6.0 Hz, 2H), 4.26 (t, J = 6.0 Hz, 2H), 3.83 (s, 3H), 3.39 - 3.34 (m, 4H), 2.63 (t, J = 6.2 Hz, 2H), 2.22 (m, 2H), 1.22 (s, 6H). LCMS (ESI) = m / z 609.2 (M + H).

[0323]

[0322] Scheme 14. Synthesis of Compound 14:

Chem.

[0324]

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

[0325]

[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) were added 3-(benzylthio)propanoyl chloride 2 (900 mg, 4.2 mmol) and AlCl3 (336 mg, 2.52 mmol) at 0 °C under a nitrogen atmosphere. The reaction was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and extracted with DCM (10 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 3 (510 mg, 62%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.84 (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 = 7.2 Hz, 2H), 2.85 (t, J = 7.2 Hz, 2H).

[0326]

[0325] 3-(4-Fluoro-5,6-dimethoxybenzo[b]thiophen-2-yl)-3-oxopropane-1-sulfonic acid (4): To a solution of NCS (684 mg, 5.12 mmol) in CH3CN (5 mL) was added 1M HCl (2 mL, 2 mmol), 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 CH3CN 3 mL was added to the reaction, and the mixture was stirred at room temperature for 1 hour. Thereafter, the mixture was directly concentrated under reduced pressure, and the crude product was purified by a reverse-phase column to give the desired product 4 (445 mg, 62%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.08 (s, 1H), 3.99 (s, 3H), 3.96 (s, 3H), 3.93 (t, J = 7.2 Hz, 2H), 3.45 (t, J = 7.2 Hz, 2H).

[0327] [

[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. Thereafter, the reaction mixture was carefully diluted with water (10 mL) and extracted with EtOAc (10 mL × 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).

[0328] [

[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) were 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 the reaction was 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. 11H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.14 (s, 1H), 7.54 (d, J = 7.7 Hz, 2H), 4.27 (t, J = 6.1 Hz, 4H), 3.87 (d, J = 5.5 Hz, 6H), 3.29 (s, 2H), 2.77 (t, J = 7.5 Hz, 2H), 2.08 (q, J = 6.2 Hz, 2H), 1.23 (s, 6H).

[0329]

[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-oxobutanoate (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. It was found from TLC that the SM had disappeared. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the desired product, Compound 14 (7 mg, 92%) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.14 (s, 1H), 7.53 (d, J = 2.7 Hz, 2H), 4.27 (t, J = 6.1 Hz, 4H), 3.87 (d, J = 4.4 Hz, 6H), 3.35 (s, 2H), 3.29 (t, J = 7.5 Hz, 2H), 2.77 (t, J = 7.5 Hz, 2H), 2.09 (t, J = 6.1 Hz, 2H), 1.23 (s, 6H). LCMS (ESI) = m / z 699 (M-H).

[0330]

[0329] Scheme 15. Synthesis of Compound 15:

Chem.

[0331]

[0330] 1-Fluoronaphthalen-2-ol (2): To a solution of naphthalen-2-ol (2.0 g, 14 mmol) in MeOH (40 mL) were added Selectfluor (2.7 g, 8 mmol) and BMIMPF6 (13.79 g, 48 mmol) at room temperature. Then the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was quenched with ice water (100 mL), extracted with EtOAc (40 mL × 3), 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 1H NMR (400 MHz, chloroform-d) δ 7.96 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.59 - 7.48 (m, 2H), 7.38 (t, J = 7.6 Hz, 1H), 7.23 (t, J = 8.6 Hz, 1H).

[0332]

[0331] 1-Fluoro-2-methoxynaphthalene (3): To a solution of 1-fluoronaphthalen-2-ol 2 (480 mg, 2.96 mmol) in DMF (8 mL) were added K2CO3 (1.02 g, 7.40 mmol) and CH3I (1.05 g, 7.40 mmol) at 0 °C. Then the reaction mixture was stirred at room temperature for 3 h under a nitrogen atmosphere. The mixture was diluted with water (60 mL) and 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)

[0333] [

[0332] ] 4-(5-Fluoro-6-methoxynaphthalen-2-yl)-4-oxobutanoate (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-cold 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 1H NMR (400 MHz, methanol-d4) δ 8.56 (d, J = 6 Hz, 1H), 8.06 - 7.98 (m, 2H), 7.85 (d, J = 9.2 Hz, 1H), 7.51 (t, J = 8.8 Hz, 1H), 4.03 (s, 3H), 3.42 (t, J = 6.4 Hz, 2H), 2.75 (t, J = 6.4 Hz, 2H).

[0334] [

[0333] ] Methyl 4-(5-fluoro-6-methoxynaphthalen-2-yl)-4-oxobutanoate (5): To a solution of 4-(5-fluoro-6-methoxynaphthalen-2-yl)-4-oxobutanoate 4 (300 mg, 1.09 mmol) in DMF (3 mL) were added K2CO3 (450 mg, 3.26 mmol) and CH3I (231 mg, 1.63 mmol) at 0 °C. Then, the mixture was stirred at room temperature for 3 h under a nitrogen atmosphere. The mixture was diluted with water (30 mL) and 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).

[0335]

[0334] Methyl 4-(5-fluoro-6-hydroxynaphthalen-2-yl)-4-oxobutanoate (6): Methyl 4-(5-fluoro-6-methoxynaphthalen-2-yl)-4-oxobutanoate 5 (71 mg, 0.25 mmol) was added to a suspension of AlCl3 (326 mg, 2.5 mmol) in DCM (1 mL) at 0 °C. The reaction mixture was warmed to ambient temperature and stirred for 16 h under a nitrogen atmosphere. The mixture was then quenched with water (10 mL), adjusted to pH 2 by addition of 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 pale yellow solid. LCMS (ESI) = m / z 275.1 (M+H).

[0336]

[0335] 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): Cs2CO3 (92 mg, 0.38 mmol) was added 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), and the mixture was stirred at 65 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product 7 (52 mg, 62%) as a pale yellow solid. LCMS (ESI) = m / z 657.2 (M+H).

[0337]

[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-oxobutanoate (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 overnight at room temperature. 1M HCl was added to adjust the pH of the mixture to 1, and the mixture was extracted with EtOAc (5 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure, and 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 1H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 2H), 8.73 (s, 1H), 8.25 (s, 1H), 8.07 - 7.97 (m, 3H), 7.68 (d, J = 9.2 Hz, 1H), 7.53 (s, 1H), 4.49 (t, J = 6.0 Hz, 2H), 4.26 (t, J = 6.0 Hz, 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).

[0338]

[0337] Scheme 16. Synthesis of Compound 16:

Chem.

[0339]

[0338] 4-(6,7-Dimethoxynaphthalen-2-yl)-4-oxobutanoate (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 min, and then 2,3-dimethoxynaphthalene e (3.0 g, 15.9 mmol) in DCM (15 mL) was slowly added to the suspension. The reaction mixture was stirred at room temperature for 14 h. The reaction mixture was quenched with water (60 mL) and extracted with CHCl3 / IPA (3 / 1, v / v, 40×3 mL). The combined organic phases were concentrated and the residue was purified by silica gel chromatography to afford the desired product 2 (2.8 g, 60% yield) as a dark yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 8.34 (d, J = 1.8 Hz, 1H), 7.87 (dd, J = 8.6, 1.8 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.20 (s, 1H), 7.11 (s, 1H), 3.99 (s, 3H), 3.99 (s, 3H), 3.39 (t, J = 6.7 Hz, 2H), 2.78 (t, J = 6.7 Hz, 2H).

[0340]

[0339] Methyl 4-(6,7-dimethoxynaphthalen-2-yl)-4-oxobutanoate (3): To a solution of 4-(6,7-dimethoxynaphthalen-2-yl)-4-oxobutanoate 2 (2.8 g, 10.40 mmol) in DMF (40 mL) were 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 h. Completion of the reaction was indicated by LCMS. The mixture was extracted with EtOAc (40×3 mL), the organic layer was dried over Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to afford compound 3 (2.7 g, 93%) as a yellow solid.

[0341] [

[0340] ] Methyl 4-(5-fluoro-6,7-dimethoxynaphthalen-2-yl)-4-oxobutanoate (4): To a solution of methyl 4-(6,7-dimethoxynaphthalen-2-yl)-4-oxobutanoate 3 (1 g, 3.3 mmol) in DMF (8 mL) was added Selectfluor (1.7 g, 4.96 mmol) 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), extracted with EtOAc (20 × 3 mL), the combined organic layers were dried over Na2SO4, concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography to afford compound 4 (116 mg, 11%) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 8.37 (t, J = 1.8 Hz, 1H), 8.01 (d, J = 8.7 Hz, 1H), 7.94 (dd, J = 8.8, 1.6 Hz, 1H), 7.08 (d, J = 1.6 Hz, 1H), 4.12 (d, J = 2.0 Hz, 3H), 4.01 (s, 3H), 3.73 (s, 4H), 3.43 (t, J = 6.7 Hz, 2H), 2.82 (t, J = 6.7 Hz, 3H); 19 F NMR (376 MHz, chloroform-d) δ -141.86.

[0342] [

[0341] ] Methyl 4-(5-fluoro-6-hydroxy-7-methoxynaphthalen-2-yl)-4-oxobutanoate (5): A mixture of methyl 4-(5-fluoro-6,7-dimethoxynaphthalen-2-yl)-4-oxobutanoate 4 (110 mg, 0.34 mmol) and AlCl3 (155.9 g, 1.03 mmol) in DCM (5 mL) was stirred at 25 °C for 12 h. Completion of the reaction was indicated by LCMS, and the reaction mixture was quenched with ice water (20 mL) and extracted with CHCl3 / IPA (3 / 1, v / v, 15 mL × 3). The combined organic phases were concentrated and purified by silica gel column chromatography to afford the desired product 5 (88 mg, 83% yield) as a white solid. 11H NMR (400 MHz, chloroform-d) δ 8.38 (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 = 6.7 Hz, 2H), 2.82 (t, J = 6.7 Hz, 2H).

[0343]

[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. Completion of the reaction was indicated by LCMS. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography to give the title product 6 (25 mg, 44% yield) as a white solid. 1 1H NMR (400 MHz, chloroform-d) δ 8.36 (s, 1H), 8.00 - 7.92 (m, 2H), 7.88 (s, 1H), 7.05 (s, 1H), 7.01 (s, 1H), 4.52 (t, J = 6.1 Hz, 2H), 4.40 (t, J = 6.1 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.73 (s, 3H), 3.70 (s, 3H), 3.43 (t, J = 6.7 Hz, 2H), 3.28 (s, 2H), 2.83 (t, J = 6.6 Hz, 2H), 2.28 (t, J = 6.1 Hz, 2H), 1.35 (s, 6H).

[0344]

[0343] 4-(5-(3-((6-(3-Carboxypropanoyl)-1-fluoro-3-methoxynaphthalen-2-yl)oxy)propoxy)-4-fluoro-6-methoxybenzo[b]thiophen-2-yl)-2,2-dimethyl-4-oxobutanoate (Compound 16): Compound 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 (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 h. Completion of the reaction was indicated by LCMS. 1N HCl was added to acidify the reaction mixture to pH ~3 and extracted with EtOAc (15 × 3 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. 1 1H NMR (400 MHz, DMSO-d6) δ 12.13 s, H), 8.61 (s, 1H), 8.23 (s, 1H), 8.02 - 7.85 (m, 2H), 7.51 (s, 2H), 4.41 (t, J = 6.1 Hz, 2H), 4.29 (t, J = 6.1 Hz, 2H), 3.91 (s, 3H), 3.84 (s, 3H), 3.37 (s, 2H), 2.64 (t, J = 6.3 Hz, 2H), 2.13 (d, J = 6.1 Hz, 2H), 1.22 (s, 6H).

[0345]

[0344] Scheme 17. Synthesis of Compound 17:

Chem.

[0346]

[0345] t-Butyl 4-(5-(3-((2-(4-((2-((t-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-oxobutanoate: To a mixture of 4-(5-(3-((2-(4-(t-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-oxobutanoate 1 (77 mg, 0.1 mmol), t-butyl N-(2-sulfamoylethyl)carbamate (46 mg, 0.2 mmol), and DIEA (66 mg, 0.51 mmol, 0.09 mL) in dichloromethane (5 mL) were sequentially added HATU (58.6 mg, 0.15 mmol) and DMAP (12.6 mg, 0.10 mmol). After 2 hours, DBU (23.5 mg, 0.15 mmol, 0.02 mL) was added. The reaction mixture was stirred at room temperature for 21 hours. Completion of the reaction was indicated by LCMS. The reaction was diluted with water, the organic layer was extracted with DCM, and the organic material was concentrated under reduced pressure. The residue was purified by silica chromatography to afford compound 2 (50 mg, 51%). LCMS (ESI) = m / z 955.2 (M+H), 977.2 (M+Na).

[0347]

[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-oxobutanoate (Compound 17): A mixture of Compound 2 (37 mg, 0.04 mmol) in 5% TFA in 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. Completion of the reaction was indicated by LCMS and MTBE was added to the residue and the suspension was reconcentrated. This process was repeated twice. Reverse phase HPLC; purification of the residue over 30 min with 10 - 80% acetonitrile in water containing 0.1% formic acid on a C-18 column. Fractions were combined and lyophilized 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-oxobutanoate Compound 17 as a white powder (20.2 mg, 33%); 1 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H),.14 (s, 1H), 7.52 (d, J = 15.7 Hz, 2H), 6.70 (s, 1H), 4.31 - 4.23 (m, 4H), 3.85 (d, J = 6.9 Hz, 6H), 3.41 (d, J = 72.6 Hz, 2H), 3.21 - 3.06 (m, 4H), 3.00 (t, J = 6.6 Hz, 2H), 2.08 (p, J = 6.0 Hz, 2H), 1.21 (s, 6H), 1.15 (s, 6H). LCMS (ESI) = m / z = 799.2 (M + H).

[0348]

[0347] Scheme 18. Synthesis of Compound 18:

Chem.

[0349]

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

[0350]

[0349] Scheme 19. Synthesis of compound 19:

Chem.

[0351]

[0350] Compound 19 was synthesized in a similar manner using the same method as described above.

[0352]

[0351] Compounds 20, 21, 22, 24, 25, 26, 27, 28, 29, 30 and 31 were synthesized using a method similar to the above.

Chem.

Chem.

[0353]

[0352] Scheme 20. Synthesis of compound 23:

Chem.

[0354]

[0353] 1-Fluoro-2,3-dimethoxy-5-nitrobenzene (2): A solution of 1-fluoro-2,3-dimethoxybenzene (12 g, 76.84 mmol, 1.0 equiv) dissolved in 120 mL of HNO3 at 0 °C was stirred at room temperature for 30 minutes. TLC indicated that the starting material had been consumed. The reaction mixture was poured into water (300 mL) and extracted with EtOAc (150 mL × 3). The combined organic phases were washed with an aqueous NaHCO3 solution, dried over Na2SO4, and concentrated to obtain a crude product, which was purified by silica gel chromatography to give the desired product 2 (11 g, 55%) as a white solid. 11H NMR (400 MHz, DMSO-d6) δ 7.87 - 7.84 (m, 1H), 7.73 - 7.12 (m, 1H), 3.95 (s, 6H).

[0355]

[0354] 3-Fluoro-4,5-dimethoxyaniline (3): Pd / C (20%, 1 g) was added to a solution of 1-fluoro-2,3-dimethoxy-5-nitrobenzene 2 (11 g, 54.68 mmol, 1.0 eq) in IPA (400 mL). The mixture was then stirred at room temperature overnight under a hydrogen atmosphere. TLC indicated 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 1H NMR (400 MHz, DMSO-d6) δ 6.05 (s, 1H), 5.95 (dd, J = 12.8, 2.4 Hz, 1H), 5.11 (s, 2H), 3.70 (s, 3H), 3.60 (s, 3H).

[0356]

[0355] 5-Fluoro-6,7-dimethoxyquinoline (4): A mixture of 4-nitrophenol (6.5 g, 46.80 mmol) and glycerol (23.5 g, 255.6 mmol) was added to a solution of 3-fluoro-4,5-dimethoxyaniline 3 (7.3 g, 42.59 mmol, 1.0 eq) dissolved in H2O (20 mL) and concentrated H2SO4 (18 mL). The reaction mixture was then stirred at 140 °C for 4 h. The mixture was cooled to room temperature and poured into ice-cold water. The mixture was adjusted to pH 8 with aqueous NaHCO3 and extracted with EtOAc (100 mL × 3). The combined organic phases were dried over Na2SO4 and concentrated to give a crude product, which was purified by silica gel chromatography to give the desired product 4 (6.76 g, 76%) as a white solid. 1 1H NMR (400 MHz, chloroform-d) δ 8.80 (dd, J = 4.4, 1.6 Hz, 1H), 8.28 (dd, J = 8.4, 1.6 Hz, 1H), 7.32 (dd, J = 8.4, 4.4 Hz, 1H), 7.28 (d, J = 1.7 Hz, 1H), 4.09 (s, 3H), 4.02 (s, 3H).

[0357] 5-Fluoro-1-hydroxy-6,7-dimethoxyquinolin-1-ium (5): A solution of MCPBA (14 g, 80 mmol) at 0 °C was added to a solution of 5-fluoro-6,7-dimethoxyquinoline 4 (8.4 g, 40 mmol, 1.0 equiv) dissolved in DCM (130 mL). 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 obtain the crude product 5 (9 g, 96%) as a white solid. LCMS [M+1] + =224.1

[0358] 5-Fluoro-6,7-dimethoxyquinoline-2-carbonitrile (6): A mixture of TMSCN (66 g, 204 mmol) and (diacetoxyiodo)benzene (20 g, 204 mmol) was added to a solution of 5-fluoro-1-hydroxy-6,7-dimethoxyquinolin-1-ium 5 (11.4 g, 51.07 mmol, 1.0 equiv) dissolved in DCE (300 mL) 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 obtain the desired product 6 (5.2 g, 44%) as a white solid. 1 H NMR (400 MHz, 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).

[0359] 5-Fluoro-6-hydroxy-7-methoxyquinoline-2-carboxylic acid (7): The mixture was stirred at 110 °C overnight for a solution of 5-fluoro-6,7-dimethoxyquinoline-2-carbonitrile 6 (1 g, 4.31 mmol, 1.0 equiv) dissolved in concentrated HCl (10 mL). The reaction mixture was concentrated under reduced pressure and the crude product was purified by silica gel chromatography to obtain the desired product 7 (820 mg, 80%) as a white solid. 11H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.45 (s, 1H), 4.02 (s, 3H).

[0360]

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

[0361]

[0360] Diethyl 2-(5-fluoro-6-hydroxy-7-methoxyquinoline-2-carbonyl) succinate (9): A solution of potassium bis(trimethylsilyl)amide (KHMDS) (5.8 ml, 5.72 mmol) was added dropwise to a solution of diethyl succinate (554 mg, 6.36 mmol, 1.0 equiv) dissolved in anhydrous THF (15 mL) at -78 °C and stirred at that temperature for 30 min. 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 an aqueous NH4Cl solution (20 mL) at 0 °C and 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 obtain the desired product 9 (720 mg, 54%) as a white solid. 1 1H NMR (400 MHz, chloroform-d) δ 8.39 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.33 (s, 1H), 5.53 (t, J = 7.2 Hz, 1H), 4.06 (s, 3H), 3.70 (s, 3H), 3.66 (s, 3H), 3.11 - 3.03 (m, 2H).

[0362]

[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 for 2 h under a nitrogen atmosphere. Completion of the reaction was indicated by LCMS. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 80 / 1, v / v) to afford the desired product 10 (420 mg, 71%) as a pale yellow solid. LCMS [M+1] + =774.1

[0363]

[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-oxobutanoate (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 6 M HCl (1 mL) at room temperature. The mixture was then stirred at 80 °C overnight. Completion of the reaction was indicated by LCMS. The mixture was concentrated and the crude product was purified by silica gel chromatography (DCM / MeOH = 10 / 1) to afford the desired product, Compound 23 (20 mg, 30%) as a pale yellow solid. 11H NMR (400 MHz, chloroform-d) δ 8.27 (d, J = 8.8 Hz, 1H), 7.92 (d, J =.8 Hz, 1H),.82 (s, 1H), 7.26 (s, 1H), 6.97 (s, 1H) 4.47 (t, J = 6.0 Hz, 2H), 4.31 (t, J = 6.0 Hz, 2H), 3.92 (s, 3H), 3.79 (s, 3H), 3.59 (s, 2H), 3.21 (s, 2H), 2.72 (t, J = 6.7 Hz, 2H), 2.19 - 2.16 (m, 2H), 1.27 (s, 6H).

[0364]

[0363] The following compounds are synthesized according to the above method.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0365] Example 2: In vitro cell-based activity of selective STING agonists

[0364] Specific STING compounds of the present disclosure were evaluated in in vitro cell-based assays.

[0366]

[0365] 293-Dual hSTING-R232 and mSTING cells (Invivogen) were seeded at 25,000 cells / well (50 ul) and co-cultured with STING agonists (2-fold concentration, 50 ul) in a clear half-area 96-well polystyrene plate. 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 ul of the supernatant was added to the QUANTI-Blue detection reagent (Invivogen). After incubation at 37 °C for 1 hour, the plate was read at 640 / 650 nm using an EnVision plate reader (PerkinElmer). Using GraphPad Prism software, the OD values were plotted by logarithm (agonist) vs. response, variable slope, four-parameter curve fit (logarithmic transformation), and the EC 50 value was determined.

[0367]

[0366] Table 1 provides the results for ISG reporter induction in 293 human / mouse reporter cells (「A」 means EC 50 ≤ 50 nM, 「B」 means > 50 nM and < 150 nM, and 「C」 means > 150 nM).

[0368]

Table 2

[0369]

Table 3

[0370] Example 3: Thermal Shift and Surface Plasmon Resonance of Selected STING Agonists

[0367] Based on the published method described in Ramanjulu et al. Nature, 2018, 564, 439, a thermal shift assay procedure was performed. The results are shown in Table 4.

[0371]

Table 4

[0372]

[0368] Based on the published method described in Pan et al., Science, 2020 369, eaba6098, a surface plasmon resonance assay experimental method was performed (where "A" is EC 50 ≦20 nM). The results are shown in Table 3.

[0373]

Table 5

[0374]

[0369] The above-described embodiments and examples are intended to be merely illustrative and non-limiting. Those skilled in the art will be able to recognize or confirm many equivalents of specific compounds, materials, and procedures through routine experimentation. All such equivalents are considered to be within the scope of the appended claims and are encompassed by the appended claims.

Claims

1. Formula I: 【Chemical 1】 (wherein, L １ is C １ to C ６ alkylene, 【Chemical 2】 selected from, L １ Any replaceable carbon in is optionally substituted with one or more substituents selected from halogen, alkoxy, C １～６ alkyl, C １～６ alkylamino, C ３～１０ cycloalkyl, hydroxy, cyano, -NR ９ａ R ９ｂ and -COOR １０ and is optionally substituted with one or more substituents selected from A is, [Chemical Formula 3] selected from, R １ 、 R ２ 、 R ３ 、 R ４ 、 R ５ 、 R ６ 、 R ７ and R ８ are independently selected from hydrogen, halogen, alkoxy, C １～６ alkyl, C ３～１０ cycloalkyl, halo-C １～６ alkyl, hydroxyl-C １～６ alkyl, hydroxy, -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 and are independent of each other, X １ and X ４ is independently selected from -C(O)-, -C(R １２ａ R １２ｂ ), -CH=CH-, and -C(R １２ａ R １２ｂ )(R １３ａ R １３ｂ ), and is X ２ and X ５ is independently selected from - (C(R １２ａ R １２ｂ )) １～６ - and - (C(R １２ａ R １２ｂ )(C(R １３ａ R １３ｂ )) １～３ - and is independently selected from X ３ is - COOR １０ 、 - CONR ９ａ R ９ｂ 、 - C(O)NR ９ａ S(O) ２ R １４ 、 - S(O) ２ OR １０ 、 - SOOR １０ 、 - P(O)(OR １５ ) ２ 、 - OP(O)(OR １５ ) ２ and - P(O)(NR １６ａ R １６ｂ )(OR １５ ) and is selected from X ６ is selected from -C(O)NR ９ａ S(O) ２ R １７ -, -C(O)NR ９ａ R １８ -, -S(O) ２ OH, -S(O)OH, -P(O)(OR １５ ), ２ -, -OP(O)(OR １５ ), ２ and -P(O)(NR １６ａ R １６ｂ )(OR １５ ), and is selected from X ７ is -CH=CH-, C ２ alkynyl or -C(R １２ａ R １２ｃ )(R １３ａ R １３ｃ )-, and X ８ is —COOR １０ —CONR ９ａ R ９ｂ —C(O)NR ９ａ —S(O) ２ R １４ —S(O) ２ OR １０ —S(O)OR １０ —P(O)(OR １５ ) ２ —OP(O)(OR １５ ) ２ and —P(O)(NR １６ａ R １６ｂ )(OR １５ ) and is selected from X ９ , X １０ and X １１ is independently selected from CR １９ and N, Y １ is independently selected from CH ２ , O, NH and S, Y ２ is independently selected from O, NH, and S, R ９ａ and R ９ｂ are independently selected from hydrogen, 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 is independently selected from hydrogen, C １～６ alkyl, C ３～１０ cycloalkyl, aryl, aryl-C １～６ alkyl and heteroaryl, R １１ is independently selected from hydrogen and C １～６ alkyl, R １２ａ 、 R １２ｂ 、 R １３ａ and R １３ｂ are each independently selected from hydrogen and C １～６ alkyl, or R １２ｂ and R １３ｂ are joined together to optionally substituted with a substituent selected from halogen, alkoxy, C １～６ alkyl, C ３～１０ cycloalkyl, hydroxy, cyano, -NR ９ａ R ９ｂ and -COOR １０ to form a C ３ ~C １０ cycloalkyl which is optionally substituted, R １２ｃ and R １３ｃ are joined together to optionally form a C １～６ alkyl, C ３～１０ cycloalkyl, hydroxy, cyano, -NR ９ａ R ９ｂ and -COOR １０ optionally substituted with a substituent selected from C ３ to C １０ cycloalkyl, R １４ is C １～６ alkyl, C ３～１０ cycloalkyl, halo-C １～６ alkyl, amino-C １～６ alkyl, C １～６ alkyl-amino-C １～６ alkyl, di-C １～６ alkylamino-C １～６ alkyl, aryl, aryl-C １～６ selected from alkyl, aryl and heteroaryl, R １５ 、 R １６ａ and R １６ｂ are each independently selected from hydrogen, C １～６ alkyl, and C ３～１０ cycloalkyl, R １７ is amino-C １～６ alkyl, C １～６ alkyl-amino-C １～６ alkyl, di-C １～６ alkylamino-C １～６ alkyl, C ３～１０ cycloalkyl-amino-C １～６ alkyl, aryl, aryl-C １～６ is alkyl or heteroaryl, R １８ 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 cycloalkyl-amino-C １～６ alkyl, C １～６ alkyl, C ３～１０ cycloalkyl, aryl, aryl-C １～６ is alkyl or heteroaryl, and R １９ is independently selected from hydrogen, halogen, alkoxy, C １～６ alkyl, C ３～１０ cycloalkyl, halo-C １～６ alkyl, hydroxyl-C １～６ alkyl, hydroxy, -NR ９ａ R ９ｂ and -COOR １０ and is independently selected from, and each of a and b is an integer independently selected from 0, 1, 2, 3, 4 and 5) a compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

2. Formula II: 【Chemical Formula 4】 (wherein, L １ is C １ to C ６ alkylene, [Chemical Formula 5] selected from, L １ Any replaceable carbon in is optionally substituted with one or more substituents selected from halogen, alkoxy, C １～６ alkyl, C １～６ alkylamino, C ３～１０ cycloalkyl, hydroxy, cyano, -NR ９ａ R ９ｂ and -COOR １０ and is optionally substituted with one or more substituents selected from A is, 【Chemical Formula 6】 selected from, R １ 、 R ２ 、 R ３ 、 R ４ 、 R ５ 、 R ６ 、 R ７ and R ８ are independently selected from hydrogen, halogen, alkoxy, C １～６ alkyl, C ３～１０ cycloalkyl, halo-C １～６ alkyl, hydroxyl-C １～６ alkyl, hydroxy, -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 and are independently selected from X １ and X ４ is independently selected from -C(O)-, -C(R １２ａ R １２ｂ ), -CH=CH-, and -C(R １２ａ R １２ｂ )(R １３ａ R １３ｂ ), and is independently selected from the group consisting of: X ２ and X ５ is independently selected from - (C(R １２ａ R １２ｂ )) １～６ - and - (C(R １２ａ R １２ｂ ))C(R １３ａ R １３ｂ )) １～３ - and is independently selected from X ３ is - COOR １０ 、 - CONR ９ａ R ９ｂ 、 - C(O)NR ９ａ 、 - S(O) ２ R １４ 、 - S(O) ２ OR １０ 、 - SOOR １０ 、 - P(O)(OR １５ ) ２ 、 - OP(O)(OR １５ ) ２ and - P(O)(NR １６ａ R １６ｂ )(OR １５ ) and is selected from X ６ is selected from -C(O)NR ９ａ S(O) ２ R １７ , -C(O)NR ９ａ R １８ , -S(O) ２ OH, -S(O)OH, -P(O)(OR １５ ), ２ , -OP(O)(OR １５ ), ２ and -P(O)(NR １６ａ R １６ｂ )(OR １５ ), and is selected from X ７ is -CH=CH-, C ２ alkynyl or -C(R １２ａ R １２ｃ )(R １３ａ R １３ｃ )-, and X ８ is - COOR １０ 、 - CONR ９ａ R ９ｂ 、 - C(O)NR ９ａ 、 - S(O) ２ R １４ 、 - S(O) ２ OR １０ 、 - SOOR １０ 、 - P(O)(OR １５ ) ２ 、 - OP(O)(OR １５ ) ２ and - P(O)(NR １６ａ R １６ｂ )(OR １５ ) and is selected from X ９ 、 X １０ and X １１ are each independently selected from CR １９ and N, Y １ is independently selected from CH ２ , O, NH and S, Y ２ is independently selected from O, NH, and S, R ９ａ and R ９ｂ are independently selected from hydrogen, 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 is independently selected from hydrogen, C １～６ alkyl, C ３～１０ cycloalkyl, aryl, aryl-C １～６ alkyl and heteroaryl, R １１ is independently selected from hydrogen and C １～６ alkyl, R １２ａ 、 R １２ｂ 、 R １３ａ and R １３ｂ are each independently selected from hydrogen and C １～６ alkyl, or R １２ｂ and R １３ｂ are joined together to optionally substituted with a substituent selected from halogen, alkoxy, C １～６ alkyl, C ３～１０ cycloalkyl, hydroxy, cyano, -NR ９ａ R ９ｂ and -COOR １０ to form a C ３ ~C １０ cycloalkyl optionally substituted with R １２ｃ and R １３ｃ are joined together to optionally substituted with a substituent selected from halogen, alkoxy, C １～６ alkyl, C ３～１０ cycloalkyl, hydroxy, cyano, -NR ９ａ R ９ｂ and -COOR １０ to form C ３ ~C １０ cycloalkyl which is optionally substituted, R １４ is C １～６ alkyl, C ３～１０ cycloalkyl, halo-C １～６ alkyl, amino-C １～６ alkyl, C １～６ alkyl-amino-C １～６ alkyl, di-C １～６ alkylamino-C １～６ alkyl, aryl, aryl-C １～６ selected from alkyl and heteroaryl, R １５ 、 R １６ａ and R １６ｂ are independently selected from hydrogen, C １～６ alkyl and C ３～１０ cycloalkyl, R １７ is amino-C １～６ alkyl, C １～６ alkyl-amino-C １～６ alkyl, di-C １～６ alkylamino-C １～６ alkyl, C ３～１０ cycloalkyl-amino-C １～６ alkyl, aryl, aryl-C １～６ is alkyl or heteroaryl, R １８ 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 cycloalkyl-amino-C １～６ alkyl, C １～６ alkyl, C ３～１０ cycloalkyl, aryl, aryl-C １～６ is alkyl or heteroaryl, and R １９ is independently selected from hydrogen, halogen, alkoxy, C １～６ alkyl, C ３～１０ cycloalkyl, halo-C １～６ alkyl, hydroxyl-C １～６ alkyl, hydroxy, -NR ９ａ R ９ｂ and -COOR １０ and is independently selected from, and each of a and b is an integer independently selected from 0, 1, 2, 3, 4 and 5) a compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

3. Formula III: [Chemical Formula 7] (wherein, L １ is C １ to C ６ alkylene, 【Chemical Formula 8】 selected from, L １ Any replaceable carbon in １～６ is optionally substituted with one or more substituents selected from halogen, alkoxy, C １～６ alkyl, C ３～１０ alkylamino, C ９ａ cycloalkyl, hydroxy, cyano, -NR ９ｂ R ９ｂ and -COOR １０ and is optionally substituted with one or more substituents selected from A is, 【Chemical Formula 9】 selected from, R １ 、R ２ 、R ３ 、R ４ 、R ５ 、R ６ 、R ７ and R ８ are independently selected from hydrogen, halogen, alkoxy, C １～６ alkyl, C ３～１０ cycloalkyl, halo-C １～６ alkyl, hydroxyl-C １～６ alkyl, hydroxy, -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 and are independent of each other, X １ and X ４ is independently selected from -C(O)-, -C(R １２ａ R １２ｂ ), -CH=CH-, and -C(R １２ａ R １２ｂ )(R １３ａ R １３ｂ ), and X ２ and X ５ is independently selected from - (C(R １２ａ R １２ｂ )) １～６ - and - (C(R １２ａ R １２ｂ )(C(R １３ａ R １３ｂ ))) １～３ - and is independently selected from X ３ is - COOR １０ 、 - CONR ９ａ R ９ｂ 、 - C(O)NR ９ａ 、 - S(O) ２ R １４ 、 - S(O) ２ OR １０ 、 - SOOR １０ 、 - P(O)(OR １５ ) ２ 、 - OP(O)(OR １５ ) ２ and - P(O)(NR １６ａ R １６ｂ )(OR １５ ) and is selected from X ６ is selected from -C(O)NR ９ａ S(O) ２ R １７ -C(O)NR ９ａ R １８ -S(O) ２ OH, -S(O)OH, -P(O)(OR １５ ), ２ -OP(O)(OR １５ ), ２ and -P(O)(NR １６ａ R １６ｂ )(OR １５ ), and is selected from X ７ is -CH=CH-, C ２ alkynyl or -C(R １２ａ R １２ｃ )(R １３ａ R １３ｃ )-, and X ８ is - COOR １０ - CONR ９ａ R ９ｂ - C(O)NR ９ａ - S(O) ２ R １４ - S(O) ２ OR １０ - SOOR １０ - P(O)(OR １５ ) ２ - OP(O)(OR １５ ) ２ and - P(O)(NR １６ａ R １６ｂ )(OR １５ ) and is selected from X ９ , X １０ and X １１ are each independently selected from CR １９ and N, Y １ is independently selected from CH ２ , O, NH, and S, Y ２ is independently selected from O, NH, and S, R ９ａ and R ９ｂ are each independently selected from hydrogen, 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 is independently selected from hydrogen, C １～６ alkyl, C ３～１０ cycloalkyl, aryl, aryl-C １～６ alkyl and heteroaryl, R １１ is independently selected from hydrogen and C １～６ alkyl, R １２ａ 、R １２ｂ 、R １３ａ and R １３ｂ are each independently selected from hydrogen and C １～６ alkyl, or R １２ｂ and R １３ｂ are joined together to optionally form a C １～６ alkyl, C ３～１０ cycloalkyl, hydroxy, cyano, -NR ９ａ R ９ｂ and -COOR １０ optionally substituted with a substituent selected from C ３ to C １０ cycloalkyl, R １２ｃ and R １３ｃ are joined together to optionally form a C １～６ alkyl, C ３～１０ cycloalkyl, hydroxy, cyano, -NR ９ａ R ９ｂ and -COOR １０ optionally substituted with a substituent selected from C ３ ~C １０ cycloalkyl, R １４ is C １～６ alkyl, C ３～１０ cycloalkyl, halo-C １～６ alkyl, amino-C １～６ alkyl, C １～６ alkyl-amino-C １～６ alkyl, di-C １～６ alkylamino-C １～６ alkyl, aryl, aryl-C １～６ selected from alkyl, aryl and heteroaryl, R １５ 、 R １６ａ and R １６ｂ are independently selected from hydrogen, C １～６ alkyl and C ３～１０ cycloalkyl, R １７ is amino-C １～６ alkyl, C １～６ alkyl-amino-C １～６ alkyl, di-C １～６ alkylamino-C １～６ alkyl, C ３～１０ cycloalkyl-amino-C １～６ alkyl, aryl, aryl-C １～６ is alkyl or heteroaryl, R １８ 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 cycloalkyl-amino-C １～６ alkyl, C １～６ alkyl, C ３～１０ cycloalkyl, aryl, aryl-C １～６ is alkyl or heteroaryl, and R １９ is independently selected from hydrogen, halogen, alkoxy, C １～６ alkyl, C ３～１０ cycloalkyl, halo-C １～６ alkyl, hydroxyl-C １～６ alkyl, hydroxy, -NR ９ａ R ９ｂ and -COOR １０ and is independently selected from, and each of a and b is an integer independently selected from 0, 1, 2, 3, 4 and 5) a compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

4. Formula Ia: 【Chemical Formula 10】 The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

5. Formula Ib: 【Chemical Formula 11】 The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

6. Formula Ic: 【Chemical Formula 12】 The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

7. Formula Id: 【Chemical 13】 The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

8. Formula IIa: 【Chemical Formula 14】 The compound according to claim 2 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

9. Formula IIb: 【Chemical Formula 15】 The compound according to claim 2 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

10. Formula IIIa: 【Chemical Formula 16】 The compound according to claim 3 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

11. L １ is C １ to C ６ alkylene, 【Chemical 17】 A compound selected from any one of claims 1 to 10.

12. L １ is 【Chemical Formula 18】 The compound according to any one of claims 1 to 10, which is.

13. L １ is 【Chemical Formula 19】 A compound selected from any one of claims 1 to 10.

14. The compound of formula Ia is a compound of formula (Iai), (Iaii), (Iaiii) or (Iaiv): 【Chemical 20】 The compound according to claim 4, which is a compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

15. The compound of formula Ib is a compound of formula (Ibi) or (Ibi): 【Chemical Formula 21】 The compound according to claim 5, which is a compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

16. The compound of formula Ic is a compound of formula (Ici), (Icii), (Iciii), (Iciv): 【Chemical 22】 The compound according to claim 6, which is a compound of formula (Ici), (Icii), (Iciii), (Iciv) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

17. The compound of formula Id is a compound of formula (Idi): 【Chemical 23】 The compound according to claim 7, which is a compound of formula (Idi) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

18. The compound of formula IIa is a compound of formula (IIai): 【Chemical 24】 The compound according to claim 8, which is a compound of formula (IIai) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

19. R １ and R ７ is independently selected from hydrogen and halogen, R ２ is selected from hydrogen and alkoxy, and R ５ is selected from alkoxy, hydroxy and amino-C １～６ alkyl, the compound according to any one of claims 1 to 18.

20. R １ and R ７ are each halogen, and R ２ and R ５ are each alkoxy, the compound according to any one of claims 1 to 18.

21. R １ The compound according to claim 19, wherein R is a halogen.

22. R ７ The compound according to claim 19, wherein R is a halogen.

23. The compound according to claim 21 or 22, wherein the halogen is fluorine.

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

25. R ５ is a compound according to any one of claims 1 to 24 selected from alkoxy and hydrogen.

26. The compound according to any one of claims 1 to 25, wherein the 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. 【Fig. 25】 is 【Chemical 26】 selected from 【Chemical 27】 and represents the point of attachment to the remainder of the compound. The compound according to any one of claims 1 to 28.

30. 【Fig. 28】 is 【Chemical 29】 selected from 【Chemical 30】 and represents the point of attachment to the remainder of the compound. The compound according to claim 29.

31. 【Fig. 31】 is 【Chemical 32】 selected from 【Chemical 33】 and represents the point of attachment to the remainder of the compound. The compound according to claim 29.

32. 【Fig. 34】 is 【Chemical 35】 selected from 【Chemical Formula 36】 and represents the point of attachment to the remainder of the compound. The compound according to claim 29.

33. X ４ is -C(O)-, and X ５ is -CH ２ -, -CH ２ CH ２ -, and -CH ２ C(CH ３ ) ２ -, selected from the group consisting of: a compound according to any one of claims 1 to 4, 6 to 14 or 16 to 32.

34. 【Fig. 37】 is 【Chemical Formula 38】 selected from 【Chemical 39】 and represents the point of attachment to the remainder of the compound. The compound according to any one of claims 1 to 4, 6 to 14 or 16 to 32.

35. 【Figure 40】 is 【Chemical 41】 and 【Chemical 42】 represents the point of attachment to the remainder of the compound. The compound according to any one of claims 1 to 4, 6 to 14 or 16 to 32.

36. 【Chemical Formula 43】 is 【Chemical 44】 and 【Chemical 45】 represents the point of attachment to the remainder of the compound. The compound according to any one of claims 1 to 4, 6 to 14 or 16 to 32.

37. R １７ is amino-C １～６ alkyl, C １～６ alkyl-amino-C １～６ alkyl or di-C １～６ alkylamino-C １～６ alkyl, the compound according to claim 34.

38. R １７ is amino-C １～６ alkyl, the compound according to claim 37.

39. R １８ is amino-C １～６ alkyl, C １～６ alkyl-amino-C １～６ alkyl, di-C １～６ alkylamino-C １～６ alkyl or C １～６ alkyl, and the compound according to claim 36, which is

40. R １８ is amino-C １～６ alkyl, the compound according to claim 39.

41. R １５ is hydrogen, C １～６ alkyl and C ３～１０ cycloalkyl, independently selected, of the compound according to claim 35.

42. R １５ The compound according to claim 41, wherein R is hydrogen.

43. R １５ is C １～６ alkyl, the compound according to claim 41.

44. 【Fig. 46】 is 【Chemical 47】 selected from 【Chemical Formula 48】 and represents the point of attachment to the remainder of the compound. The compound according to any one of claims 1 to 3, 5, 11 to 13, 15 or 19 to 32.

45. 【Fig. 49】 is 【Chemical Formula 50】 selected from 【Chemical 51】 and represents the point of attachment to the remainder of the compound. The compound according to any one of claims 1 to 3, 5, 11 to 13, 15 or 19 to 32.

46. 【Fig. 52】 is 【Chemical Formula 53】 selected from 【Chemical 54】 The compound according to any one of claims 1 to 3, 5, 11 to 13, 15 or 19 to 32, which indicates the binding point to the remaining part of the compound.

47. R １０ is hydrogen, C １～６ alkyl or C ３～１０ cycloalkyl, and is a compound according to any one of claims 1 to 46.

48. R １０ is the compound according to claim 47, which is hydrogen.

49. X ５ is selected from -CH ２ -, -CH ２ CH ２ -, and -CH ２ C(CH ３ ) ２ a compound according to any one of claims 1 to 48

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

51. X ９ is N, and X １０ and X １１ is CR １９ and N, the compound according to claim 50.

52. X １０ is N, and X ９ and X １１ is CR １９ and N, the compound according to claim 50.

53. X １１ is N, and X ９ and X １０ is CR １９ and N, the compound according to claim 50.

54. R １９ is a compound according to any one of claims 50 to 53, independently selected from hydrogen, halogen, C １～６ alkyl and alkoxy.

55. R １９ is hydrogen, the compound according to any one of claims 50 to 53.

56. Y １ is O or N, and Y ２ is O, a compound according to any one of claims 1 to 3, 7, 9 to 13, 17 or 19 to 43.

57. Formula: 【Chemical Formula 55】 The compound according to claim 4, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

58. Formula: 【Chemical Formula 56】 The compound according to claim 57, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

59. Formula: 【Chemical 57】 The compound according to claim 5, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

60. Formula: 【Chemical Formula 58】 The compound according to claim 59, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

61. 【Fig. 59】 【Chemical Formula 60】 【Chemical Formula 61】 【Chemical 62】 The compound according to claim 1, selected from or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

62. 【Chemical Formula 63】 【Chemical Formula 64】 【Chemical Formula 65】 【Chemical Formula 66】 【Chemical Formula 67】 The compound according to claim 1, selected from or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

63. 【Fig. 68】 【Chemical 69】 【Chemical Formula 70】 The compound according to claim 1, selected from or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

64. 【Fig. 71】 The compound according to claim 1, 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 for treating a STING-mediated disease or disorder in a subject in need thereof, the method comprising administering the compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or the pharmaceutical composition according to claim 65.

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

68. The method according to claim 67, wherein the immune response induces STING-dependent type I interferon products in a subject in need thereof.

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

70. A method for treating abnormal cell growth in a subject in need thereof, comprising administering 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.

71. The method according to claim 70, wherein the abnormal cell growth is cancer.

72. The method according to claim 71, wherein the cancer is a solid tumor.

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

74. 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 a STING-mediated disease or disorder in a subject in need thereof.

75. 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 inducing 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 products 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 growth in a subject in need thereof.

79. The use according to claim 78, wherein the abnormal cell growth 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 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, for preparing a medicament for treating a STING-mediated disease or disorder 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 for 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 for 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 said compound.

86. A kit comprising a pharmaceutical composition according to claim 65 and instructions for use of said compound.

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