Stimulator of interferon genes (STING) modulators and uses thereof

Abstract

Compounds of the present invention act as stimulator of interferon genes (STING) pathway modulators and are useful in the treatment of a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs, in addition to microbial infections, controlling pathogenic cGAS activity, neurodegeneration, associated autoimmune diseases, inflammatory diseases, neuropathic pain and vaccine adjuvants. The compounds have the following formulae I-IV: (I), (II), (III) and (IV).

Description

NEW STING MODULATORS AND USES THEREOFField of the Invention

[0001] The present invention relates to the field of medicinal chemistry. Specifically, it relates to modulating STING pathway to treat various human and or animal diseases.Background

[0002] The cGAS-STING signalling pathway is a key mediator in human immunity against a panel of diseases including many infectious diseases, inflammatory disorders, several rare diseases, cellular stress and cancer cells. Moreover, it has the capacity to sense and regulate the cellular response towards cytosolic DNA including microbial and host-derived DNAs (Nature Immunology 17, 1142-1149 (2016)). Apart from cytosolic DNA, the cGAS-STING signalling axis has become a promising area of research for developing therapies against various RNA viruses (Fan, Yiyun Michelle, et al. "Crosstalk between RNA viruses and DNA sensors: Role of the cGAS-STING signalling pathway." Reviews in Medical Virology 32.5 (2022): e2343.)

[0003] Since cGAS-STING has as vital role in the innate immune system (Hu, Ying, et al. "Emerging role of the cGAS-STING signaling pathway in autoimmune diseases: Biologic function, mechanisms and clinical prospection." Autoimmunity Reviews (2022): 103155), many inflammatory and autoimmune diseases are associated with the cGAS-STING signalling pathway including: Systemic lupus erythematosus (Arthritis Rheumatol. 69, 800-807 (2017)), Rheumatoid arthritis (Int. Immunopharmacol. 76, 105791 (2019)), STING-associated vasculopathy with onset in infancy (SAVI) (J. Clin. Invest. 124, 5516-5520 (2014)), COP A syndrome (J. Exp. Med. 217, e20200600 (2020)), Aicardi-Goutieres syndrome (AGS) (Immunity 36, 120-131 (2012)), Familial chilblain lupus (Ann. Rheum. Dis. 76, 468-472 (2017)), and acute myocardial infarction (EJMed Chem 244 (2022) 114791), macular degeneration (EJMed Chem 244 (2022) 114791), and colitis (EJMed Chem 244 (2022) 114791).

[0004] The use of STING agonists in treatment of infection diseases is also well documented (EP3060056A2, Motwani M, Pesiridis S, Fitzgerald KA. DNA sensing by the cGAS-STING pathway in health and disease. Nat Rev Genet. 2019;20:657-674; Ahn J, Barber GN. STING signaling and host defense against microbial infection. Exp Mol Med. 2019;51:1-10).

[0005] The role of cGAS-STING signaling pathway inhibitors in controlling neuropathic pain is also reported (Wu, Wenyao, et al. "Pharmacological inhibition of the cGAS-STING signaling pathway suppresses microglial Ml -polarization in the spinal cord and attenuates neuropathic pain." Neuropharmacology 217 (2022): 109206).

[0006] More recently, the discovery of cGAS-STING signalling pathway stimulators opened up a new avenue to cancer immunotherapy, and it is expected to change the map of cancer therapy soon. In this regard, many STING agonists demonstrated clinical efficacy for multiple tumour types (Nature 56 .T136 (2018): 439-443).

[0007] The endogenous ligands of the cGAS-STING signalling pathway are cyclic dinucleotides (CDNs) such as 2'3'-cGAMP, which act as a secondary messenger that signal the presence of cytosolic DNA. Although two CDNs entered clinical trials (ClinicalTrials.gov: NCT03172936 and NCT03010176), natural CDNs suffer from some drawbacks that limit their applications, mainly their high degree of plasma instability (Nat Chem Biol. 10(12): 1043-1048 (2014)). Moreover, CDNs with their two negative charges are unable to passively diffuse across the plasma membrane (Molecular cell 75.2 (2019): 372-381), therefore, non-CDN agonist are considered highly valuable in the field.

[0008] WO2014099824A1 accounts for the synthesis and the use of several cyclic nucleotides such as 2'3-cGAMP, 2'2-cGAMP, 3'2'-cGAMP and 3'3'-GAMP and their use in cancer immunotherapy. Other patents such as WO2017093933A1, US20170037400A1 and CN109843903 addressed the use of CDN in cancer treatment. EP2942357A1, WO2017161349A1, US20140205653A1, WO2017027646A1, CN105228450A,WO2017123657A1, WO2014189805A8, CN105367617A, WO2016096174A1,CN105008381A, WO2017027645A1, AU2020366354 Al; CA3157849 Al; CN114929241 A; EP4045059 Al; JP2023 / 500045 A and US11542293 disclosed oligonucleotides with modified sugar moieties. On the other hand, several patents addressed the pharmaceutical formulations of these cyclic nucleotides (see WO2014099824A1, WO2017186711A1, US20170296655A1, CA2895175A1, CN106667914A, US20150343056A1, WO2017162055A1).

[0009] Several classes of non-cyclic nucleotides (NCN) are already reported. US20200325126 Al, US10975287B2 and ACS Med. Chem. Lett. 2021, 12, 3, 328-330 account for aminobenzimidazole derivatives as STING modulators. The cyclic aminobenzimidazoles and their STING modulating properties are also addressed in W02019069270A1, WO2017175156A1 and WO2019069269A1.

[0010] CN113024563 accounts for immidazopyrimidine analogues of the following formula, in which R6is -CON(R)(Rj), and (R) taken together with R5or R7forms a 5-6 membered heterocyclic ring.

[0011] RU.521 represents another class of benzoimidazole that act as cGAS inhibitors (Vincent, Jessica, et al. Nature communications 8.1 (2017): 750.). Other benzimidazoles with STING agonistic activity are reported in WO2023 / 2246 and EP4129406.

[0012] US20170146519A1 reported 4-(2-chloro-6-fluorobenzyl)-JV-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-27 / -benzo[6][l,4]thiazine-6-carboxamide as a novel hit compound obtained by HTS in vitro screening.

[0014] WO2019219820A1 and W02021009362A1 disclose fused thiophene derivatives, including benzothiophene, thienopyridine and thienopyrimidine derivatives, as STING modulators. Their dimer is disclosed in WO2021009365 Al.

[0015] Benzo [b]thiophen as a STING agonist is also reported by in US20180093964A1,WO2019195124A1 and WO2019027858A1.es of benzothiophene as STING modulators are disclosed in loses a general formula for a two fused ring system with an amide

[0018] WO2018234807A1 discloses another general formula for a two fused ring system with an amide functionality.

[0019] WO2018234808A1 discloses another general formula for a two fused ring system with an amide functionality.

[0020] WO2018234805A1 discloses another general formula for a two fused ring system with an amide functionality.

[0021] WO2020142735 discloses a general formula with a quinoline and quinazoline ring system.

[0022] WO2023 / 18781, WO2020257621 and W02020010155 reported a number of other fused ring systems as STING antagonists and their medical use in a variety of diseases. Specific examples focused on pyrolopyridine with arylurea substituents at position-3.

[0023] PF-06928215 is a pyrolopyrimidine derivative with potent inhibitory activity of cGAS (Hall, Justin, et al. PLoS One 12.9 (2017): e0184843.).PF-06928215

[0024] W02019055750 reported several fused systems with STING antagonist activity, such as the following.

[0025] US20210087180 disclosed several fused systems with STING agonist activity, such as the following.

[0026] WO2021 / 260528 reported isoindole derivatives, including 3-(l-oxoisoindolin-2- yl)piperidine-2, 6-dione derivatives, as STING modulator for treatment or prevention of IKAROS Family Zinc Finger 2 (IKZF2)-dependent diseases. On the other hand, US2023 / 21448, reported indole-based STING agonists.

[0027] WO2017096963A1 discloses the use of STING agonists in Alzheimer’s disease.

[0028] The present invention arises from extensive virtual study of around 115 million conformers of around 8 million compounds, which lead to a number of novel scaffolds that show modulating activity against the STING pathway.Summary of the Invention

[0029] It is therefore an object of the present invention to provide a novel class of compounds having agonistic activity against stimulator of interferon genes (STING).

[0030] The present invention also relates to the preparation, formulation and medical application in a subject of need of treatment with chemical entities illustrated in the following formulae:Wherein:

[0031] A1to A5, are, independently, selected from C, CH. CH2, CRA1, CHRA1, NH, NRA1, NHNH, NHRA1NH, NHNRA2, N R^NR^, O, S, or SO2.

[0032] B1to B6, are, independently, selected from C, CH. CH2, CRB1, CHRB1, NH, NRB1, NHNH, NHRB1NH, NHNRB2, N RB1NRB2, O, S, or SO2.

[0033] RB1and RB2are, independently, selected from H, CN, NO2, -COOH, -COOR1, NH2, NHR1, NR1R2, OH, OR1, an alkyl or cycloalkyl chain with number of C atoms ranging between 1 and 10, including bi cyclo and fused cyclic systems, a phenyl, substituted phenyl with small C- containing substituents or hetero-atom containing group, aryl with hetero-atom or heterocycle, which may be further substituted with C-containing substituents or hetero-atom containing groups.

[0034] B3and B4are part of another ring.

[0035] In another embodiment, A4and B2, and A2and B6can be connected via O, S, NH, NR1or CH2, CHR1, or CRJR2

[0036] R1and R2are, independently, selected from alkyl, preferably with number of carbons between 1 and 4, such as methyl isopropyl, cyclopropyl, t-butyl, cyclobutyl and the like, optionally with one or more heteroatom(s) such as O, N, S, Se, P or a halide.

[0037] RA1and RA2are, independently, selected from H, CN, NO2, -COOH, -COOR1, NH2, NHR1, NR1R2, OH, OR1, an alkyl or cycloalkyl chain with number of C atoms ranging between 1 and 10, including bi cyclo and fused cyclic systems, a phenyl, substituted phenyl with small C- containing substituents or hetero-atom containing group, aryl with hetero-atom or heterocycle, which may be further substituted with C-containing substituents or hetero-atom containing groups.

[0038] RA5is selected from H, alkyl, heteroalkyl or cycloalkyl with number of C atoms ranging between 1 and 6, which might be further substituted with one, or more halogen atom(s), hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, urithanyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, heteroalkyl haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, quaternary ammonium group, and the protected derivatives thereof.

[0039] RX1is selected from OH, OR1, or alkyl, preferably with number of carbons between 1 and 6, such as methyl isopropyl, cyclopropyl, t-butyl, cyclobutyl, pentyl, 2-methylpentyl, cyclopentyl, cyclohexyl and the like. Optionally with one or more heteroatom(s) such as O, N, S, Se, P or a halide.

[0040] In another embodiment, RN2, X1or RX1is connected with A1directly via a covalent bond''Xy or via , in which X2is selected from N, CH or CRX2.

[0041] RX2is selected from CN, NO2, -COOH, -COOR1, NH2, NHR1, NR1R2. OH, OR1, an alkyl or cycloalkyl chain with number of C atoms ranging between 1 and 10, including bi cyclo and fused cyclic systems, a phenyl, substituted phenyl with small C-containing substituents or hetero-atom containing group, aryl with hetero-atom or heterocycle, which may be further substituted with C-containing substituents or hetero-atom containing groups.

[0042] RN2is selected from H, OH, OR1, or alkyl, preferably with number of carbons between 1 and 6, such as methyl isopropyl, cyclopropyl, t-butyl, cyclobutyl, pentyl, 2-methylpentyl, cyclopentyl, cyclohexyl and the like. Optionally with one or more heteroatom(s) such as O, N, S, Se, P or halide.

[0043] RN1is selected from O, NH, NR1, CH2, (CH2)nRN1, CHR1, or CR'R2.

[0044] RN1and RN2may be part of cyclic structure.

[0045] “RN1— Cy” may together represent H, OH, OR1, or alkyl, preferably with number of carbons between 1 and 6, such as methyl isopropyl, cyclopropyl, t-butyl, cyclobutyl, pentyl, 2- methylpentyl, cyclopentyl, cyclohexyl and the like. Optionally with one or more heteroatom(s) such as O, N, S, Se, P or a halide.

[0046] “Cy” is selected from variable cyclic structures.

[0047] In some embodiment, “RN1— Cy” may together represent an atom such as H, or a small group such as OH.RM

[0048] In formula I, “ 'A4” may, optionally, be omitted and A3linked directly with B2.

[0049] ( — ) represents single or double bonds.

[0050] In another embodiment, the present invention relates to symmetric or asymmetric covalently linked dimers, in which any of formulas I to IV can be covalently linked with any other structure belonging to formulas IV to I. The following formulas are used for illustration:Formula I Formula II Formula III Formula IVFormula I Formula II Formula Illi Formula IVFormula I Formula I Formula I Formula II Formula IVFormula II Formula III Formula IV Formula III Formula II

[0051] The disclosed compounds according to the present invention generally show moderate to excellent modulating activity against the STING pathway.

[0052] In a second aspect of the present invention, there is provided a use of compounds of formulas I-IV, or pharmaceutically acceptable salts, solvates or hydrate, in any acceptable polymorph or pseudopolymorph, as STING activators.

[0053] In a third aspect of the present invention, there is provided a use of compounds of formulae I-IV, or pharmaceutically acceptable salts, solvates or hydrate, in any acceptable polymorph or pseudopolymorph, as STING inhibitors.

[0054] In a fourth aspect of the present invention, there is a provided method of treatment or preventing a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs, in addition to microbial infections, controlling pathogenic cGAS activity, neurodegeneration, associated autoimmune diseases, inflammatory diseases, neuropathic pain and vaccine adjuvants.Brief Description of the Drawings

[0055] In order that the invention may be more clearly understood, a preferred embodiment thereof will now be described in detail by way of example, with reference to the accompanying drawings, in which:

[0056] Figure 1 is a molecular docking rendering of example 1, according to the present invention, in STING protein (PDB ID: 6DXL).

[0057] Figure 2 is a molecular docking rendering of example 31, according to the present invention, in STING protein (PDB ID: 6DXL).

[0058] Figure 3 is a molecular docking rendering of example 16, according to the present invention, in STING protein (PDB ID: 6DXL).

[0059] Figure 4 is a molecular docking rendering of example 21, according to the present invention, in STING protein (PDB ID: 6DXL).Description of the Preferred Embodiments

[0060] In the present invention, novel chemical entities useful for modulating the STING pathway are disclosed. The mode of STING modulation may include activation, inhibition, partial activation, partial inhibition, or mixed actions.

[0061] Certain preferred compounds of the present invention are useful in the treatment of a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs, in addition to microbial infections and controlling pathogenic cGAS activity, associated autoimmune diseases, inflammatory diseases, neuropathic pain, and as vaccine adjuvants.

[0062] For the purposes of promoting an understanding of the principles of the present disclosure, reference will now be made to certain preferred embodiments, and specific language will be used to describe the same. It will nevertheless be understood that the exemplary embodiments disclosed herein are not intended as a limitation of the scope of invention described herein.

[0063] In some illustrative embodiments, the present invention comprises compounds having formula I, or pharmaceutically acceptable salts, hydrates, or solvates thereof.

[0064] In the other embodiment, this invention is related to chemical entities represented by the general formula I:formula I, wherein:

[0065] RA4is selected from H, alkyl, heteroalkyl or cycloalkyl with number of C atoms ranging between 1 and 6, which might be further substituted with one, or more halogen atom(s), hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, urithanyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, heteroalkyl haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, quaternary ammonium groups, and the protected derivatives thereof.

[0066] A1to A4, are, independently, selected from C, CH. CH2, CRA1, CHRA1, NH, NRA1, NHNH, NHRA1NH, NHNRA2, N RA1NRA2. O, S, or SO2.

[0067] RA1and R2are, independently, selected from H, CN, NO2, -COOH, -COOR1, NH2, NHR1, NR1R2, OH, OR1, an alkyl or cycloalkyl chain with number of C atoms ranging between 1 and 10, including bi cyclo and fused cyclic systems, a phenyl, substituted phenyl with small C- containing substituents or hetero-atom containing group, aryl with hetero-atom or heterocycle, which may be further substituted with C-containing substituents or hetero-atom containing groups.

[0068] R1and R2are, independently, selected from alkyl, preferably with number of carbons between 1 and 4, such as methyl isopropyl, cyclopropyl, t-butyl, cyclobutyl and the like, optionally with one or more heteroatom(s) such as O, N, S, Se, P or a halide.

[0069] B1to B6, are, independently, selected from C, CH. CH2, CRB1, CHRB1, NH, NRB1, NHNH, NHRB1NH, NHNRB2, N RB1NRB2, O, S, or SO2.

[0070] RB1and RB2are, independently, selected from H, CN, NO2, -COOH, -COOR1, NH2, NHR1, NR1R2. OH, OR1, an alkyl or cycloalkyl chain with number of C atoms ranging between 1 and 10, including bi cyclo and fused cyclic systems, a phenyl, substituted phenyl with small C- containing substituents or hetero-atom containing group, aryl with hetero-atom or heterocycle,which may be further substituted with C-containing substituents or hetero-atom containing groups.

[0071] In another embodiment, B3and B4are part of:Pyrazine or dihydropyrazine:n. Hydroquinone:

[0072] The value of nB6ranges between 0 and 3.

[0073] X1is selected from O atom, NH, or NRX1.

[0074] Rxlis selected from OH, OR1, or alkyl, preferably with number of carbons between 1 and 6, such as methyl isopropyl, cyclopropyl, t-butyl, cyclobutyl, pentyl, 2-methylpentyl, cyclopentyl, cyclohexyl and the like, optionally with one or more heteroatom(s) such as O, N, S,Se, P or a halide.

[0075] RN1is selected from O, NH, NR1, CH2, (CH2)nRN1, CHR1, or CRJR2

[0076] RN2is selected from H, OH, OR1, or alkyl, preferably with number of carbons between 1 and 6, such as methyl isopropyl, cyclopropyl, t-butyl, cyclobutyl, pentyl, 2-methylpentyl, cyclopentyl, cyclohexyl and the like. Optionally with one or more heteroatom(s) such as O, N, S,Se, P or a halide.

[0077] In some embodiments ofRN1and RN2are not directly connected by the N group and may be connected by another N-containing group, such as:

[0078] Further, RN1and RN2may be part of cyclic structure, selected from, but not limited to:

[0079] “RN1— Cy” may together represent H, OH, OR1, or alkyl, preferably with number of carbons between 1 and 6, such as methyl isopropyl, cyclopropyl, t-butyl, cyclobutyl, pentyl, 2- methylpentyl, cyclopentyl, cyclohexyl and the like. Optionally with one or more heteroatom(s) such as O, N, S, Se, P or halide.

[0080] The nitrogen atom inrN2, can be replaced by another atoms, such as C, S or O, in which the S atom can exist in any oxidation state. For example:

[0081] “Cy” is selected from cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, phenyl, heterocyclic or bicyclic structures, all of which may be further substituted (one, two or more) with one, or more halogen atom(s), hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, urithanyl, C-amido, N- amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, heteroalkyl haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, quaternary ammonium group, and the protected derivatives thereof. Preferable examples of “Cy” include, but not limited to: a. 5 -membered rings:b. 6-membered rings:c. Alicyclic structures:d. Fused systems and other cyclic structures:e. In some embodiment “Cy” is part of more complex aromatic structures:RA4^

[0082] In some embodiment, the moiety “a4” is void or does not exist, so the formula will be as follow:sub formula II

[0083] In some other embodiment, themoiety is connected to the other side of the formula as shown in:sub formula 12

[0084] ( — ) represents single or double bonds.

[0085] Certain preferred embodiments of the present invention, related to formula I, include the following examples:Example 7 Example 8Example 9 Example 10Example 15

[0086] Certain preferred embodiments of the present invention, relate to the two sub formulae II and 12, include the following examples:Example 18 Example 19

[0087] In another embodiment, the present invention relates to chemical entities represented by the general formula II:formula II, wherein:

[0088] RA5is selected from H, alkyl, heteroalkyl or cycloalkyl with number of C atoms ranging between 1 and 6, which might be further substituted with one, or more halogen atom(s), hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, urithanyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, heteroalkyl haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, quaternary ammonium group, and the protected derivatives thereof.

[0089] A1to A5, are, independently, selected from C, CH. CH2, CRA1, CHRA1, NH, NRA1, NHNH, NHRA1NH, NHNRA2, N RA1NRA2. O, S, or SO2.

[0090] RA1and R2are, independently, selected from H, CN, NO2, -COOH, -COOR1, NH2, NHR1, NR1R2, OH, OR1, an alkyl or cycloalkyl chain with number of C atoms ranging between 1 and 10, including bi cyclo and fused cyclic systems, a phenyl, substituted phenyl with small C- containing substituents or hetero-atom containing group, aryl with hetero-atom or heterocycle, which may be further substituted with C-containing substituents or hetero-atom containing groups.

[0091] R1and R2are, independently, selected from alkyl, preferably with number of carbons between 1 and 4, such as methyl isopropyl, cyclopropyl, t-butyl, cyclobutyl and the like, optionally with one or more heteroatom(s) such as O, N, S, Se, P or a halide.

[0092] B1to B6, are, independently, selected from C, CH. CH2, CRB1, CHRB1, NH, NRB1, NHNH, NHRB1NH, NHNRB2, N RB1NRB2, O, S, or SO2.

[0093] RB1and RB2are, independently, selected from H, CN, NO2, -COOH, -COOR1, NH2, NHR1, NR1R2. OH, OR1, an alkyl or cycloalkyl chain with number of C atoms ranging between 1 and 10, including bi cyclo and fused cyclic systems, a phenyl, substituted phenyl with small C- containing substituents or hetero-atom containing group, aryl with hetero-atom or heterocycle,which may be further substituted with C-containing substituents or hetero-atom containing groups.

[0094] In another embodiment, B3and B4are part of:n. Hydroquinone:

[0095] In another embodiment, A4and B2, and A2and B6can be connected via O, S, NH, NR1or CH2, CHR1, or CR1R2.

[0096] The value of nA2ranges between 0 and 5.

[0097] The value of nB6ranges between 0 and 3.

[0098] X1is selected from O atom, NH, or NRX1.

[0099] Rxlis selected from OH, OR1, or alkyl, preferably with number of carbons between 1 and 6, such as methyl isopropyl, cyclopropyl, t-butyl, cyclobutyl, pentyl, 2-methylpentyl, cyclopentyl, cyclohexyl and the like. Optionally with one or more heteroatom(s) such as O, N, S, Se, P or a halide.

[0100] In another embodiment, RN2, X1or RX1is connected with A1directly via a covalent bond or via

[0101] X2is selected from N, CH or CRX2.

[0102] RX2is selected from CN, NO2, -COOH, -COOR1, NH2, NHR1, NR1R2. OH, OR1, an alkyl or cycloalkyl chain with number of C atoms ranging between 1 and 10, including bi cyclo and fused cyclic systems, a phenyl, substituted phenyl with small C-containing substituents or heteroatom containing group, aryl with hetero-atom or heterocycle, which may be further substituted with C-containing substituents or hetero-atom containing groups.

[0103] RN2is selected from H, OH, OR1, or alkyl, preferably with number of carbons between 1 and 6, such as methyl isopropyl, cyclopropyl, t-butyl, cyclobutyl, pentyl, 2-methylpentyl, cyclopentyl, cyclohexyl and the like. Optionally with one or more heteroatom(s) such as O, N, S, Se, P or a halide.

[0104] RN1is selected from O, NH, NR1, CH2, (CH2)nRN1, CHR1, or CRXR2.

[0105] RN1and RN2may be part of cyclic structure, selected from, but not limited to:

[0106] “RN1— Cy” may together represent H, OH, OR1, or alkyl, preferably with number of carbons between 1 and 6, such as methyl isopropyl, cyclopropyl, t-butyl, cyclobutyl, pentyl, 2-methylpentyl, cyclopentyl, cyclohexyl and the like, optionally with one or more heteroatom(s) such as O, N, S, Se, P or a halide.

[0107] “Cy” is selected from cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, phenyl, heterocyclic or bicyclic structures, all of which may be further substituted (one, two or more) with one, or more halogen atom(s), hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, urithanyl, C-amido, N- amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, heteroalkyl haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, quaternary ammonium group, and the protected derivatives thereof. Preferable examples of “Cy” include, but not limited to: a.b.c.d.e.

[0108] ( — ) represents single or double bonds.

[0109] Certain preferred embodiments of the present invention, related to formula II, include the following examples:Example 22 Example 23Example 24 Example 25

[0110] In the other embodiment, this invention is related to chemical entities represented by the general formula III:formula III, wherein:

[0111] A1to A4are, independently, N atom, NH, NR1, CH, CH2, CHR1or CR1R2.

[0112] R1and R2are, independently, selected from H, alkyl, heteroalkyl or cycloalkyl with number of C atoms ranging between 1 and 6, which might be further substituted with one, or more halogen atom(s), hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto,alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, urithanyl, C-amido, N-amido, S- sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, heteroalkyl haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, quaternary ammonium group, and the protected derivatives thereof.

[0113] In some embodiments, R1and R2can form an “oxo” group.

[0114] B1is selected from CH2, CHR1, CR1R2. S, O, NH, NR1, C=O, C=S, C=NOH, or C=NOR1.

[0115] L1is selected from:e. Aromatic linkers with 1,4-disubstitution:f. Aromatic linkers with 1,3-disubstitution

[0116] “Cy” is selected from:c. 5-membered rings:d. 6-membered rings:e. Preferred examples of “Cy” include, but are not limited to:

[0117] C1to C6, are, independently, selected from NH, NRY1, NHNH, NHRCYlaNH, NHNRCYa, O, S, CH2, or CHRCYla

[0118] RCYaand RCYlaare, independently, selected from CN, NO2, -COOH, -COOR1, NH2, NHR1, NR1R2, OH, OR1, an alkyl or cycloalkyl chain with number of C atoms ranging between 1 and 10, including bi cyclo and fused cyclic systems, a phenyl, substituted phenyl with small C- containing substituents or hetero-atom containing group, aryl with hetero-atom or heterocycle, which may be further substituted with C-containing substituents or hetero-atom containing groups.

[0119] The value of nL1ranges between 1 and 5.

[0120] B1to B5, are, independently, selected from C, CH. CTh. CRB1, CHRB1, NH, NRB1, NHNH, NHRB1NH, NHNRB2, N RB1NRB2, O, S, or SO2.

[0121] RB1and RB2are, independently, selected from H, CN, NO2, -COOH, -COOR1, NH2, NHR1, NR.1R2. OH, OR1, an alkyl or cycloalkyl chain with number of C atoms ranging between 1 and 10, including bi cyclo and fused cyclic systems, a phenyl, substituted phenyl with small C- containing substituents or hetero-atom containing group, aryl with hetero-atom or heterocycle, which may be further substituted with C-containing substituents or hetero-atom containing groups.

[0122] In another embodiment, B3and B4are part of: a. 1,3-dioxolane:n. Hydroquinone:

[0123] The value of nB5ranges between 0 and 3.

[0124] RN1and RN2are, independently, selected from H, alkyl or cycloalkyl with C number between 1 and 6, such as methyl isopropyl, or cyclopropyl, optionally substituted with one or more halogen atom(s), OH, or OR1.

[0125] In another embodiment, RN2, is connected with L1directly via a covalent bond or via

[0126] X1is selected from N, CH or CRX1.

[0127] RX1is selected from CN, NO2, -COOH, -COOR1, NH2, NHR1, NR.1R2. OH, OR1, an alkyl or cycloalkyl chain with number of C atoms ranging between 1 and 10, including bi cyclo and fused cyclic systems, a phenyl, substituted phenyl with small C-containing substituents or heteroatom containing group, aryl with hetero-atom or heterocycle, which may be further substituted with C-containing substituents or hetero-atom containing groups.

[0128] ( — ) represents single or double bonds.

[0129] Certain preferred embodiments of the present invention, related to formula III, include the following examples:Example 26 Example 27Example 30

[0130] In the other embodiment, this invention is related to chemical entities represented by the general formula IV :formula IV, wherein:

[0131] A1to A4are, independently, N atom, NH, NRA1, CH, CH2, CHRA1or CRA1RA2.

[0132] RA1and RA2are, independently, selected from H, CN, NO2, -COOH, -COOR1, NH2,NHR1, NR1R2, OH, OR1, an alkyl or cycloalkyl chain with number of C atoms ranging between 1 and 10, including bi cyclo and fused cyclic systems, a phenyl, substituted phenyl with small C- containing substituents or hetero-atom containing groups, aryl with hetero-atom or heterocycle, which may be further substituted with C-containing substituents or hetero-atom containing groups.

[0133] R1and R2are, individually, selected from alkyl or cycloalkyl chains with a number of C atoms ranging between 1 and 6, optionally substituted with one or more halogen atom(s).

[0134] B1to B5are, independently, N atom, NH, NRB1, CH, CH2, CHRB1or CRB1RB2.

[0135] RB1and RB2are, independently, selected from H, CN, NO2, -COOH, -COOR1, NH2, NHR1, NR1R2, OH, OR1, an alkyl or cycloalkyl chains with a number of C atoms ranging between1 and 10, including bi cyclo and fused cyclic systems, a phenyl, substituted phenyl with small C- containing substituents or hetero-atom containing groups, aryl with hetero-atom or heterocycle, which may be further substituted with C-containing substituents or hetero-atom containing groups.

[0136] Preferred examples of B1, B2, B3, B4or B5include, but are not limited to:

[0137] The value of nB5ranges between 0 and 4.

[0138] The value of nBranges between 0 and 4.

[0139] L1is selected from:Linear hydrocarbon chains with a number of C atoms ranging between 1 and 10, such as -CH2-, -CH2CH2-, and -CH2CH2CH2CH2-; which might be further branched with other smaller alkyl or cycloalkyl moiety / ies, optionally substituted with one or more halogen atom(s).e. Alicyclic structure, such as, but not limited to:f. Part of aromatic structures:

[0140] The value of nY1ranges between 1 and 6.

[0141] “Cy1” is selected from cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, phenyl, heterocyclic or bicyclic structures, all of which may be further substituted (one, two or more) with one, or more halogen atom(s), hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, urithanyl, C-amido, N- amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, heteroalkyl haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di -substituted amino groups, quaternary ammonium groups, and the protected derivatives thereof. Preferred examples of “Cy1” include, but are not limited to:b. 6-membered rings:c. Alicyclic structure:

[0142] “Cy2” is selected from cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, phenyl, heterocyclic or bicyclic structures, all of which may be further substituted (one, two or more) with one, or more halogen atom(s), hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, urithanyl, C-amido, N- amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, heteroalkyl haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di -substituted amino groups, quaternary ammonium groups, and the protected derivatives thereof. Preferred examples of “Cy2” include, but are not limited to: a. 5 -membered rings:

[0143] In another embodiment, “Cy1” and “Cy2” form a fused ring system, which may include,

[0144] (- — ) represents single or double bonds.

[0145] Certain preferred embodiments of the present invention, related to formula IV, include the following examples:Example 34

[0146] In another embodiment, covalently linked dimers, symmetric or asymmetric, in which any of formulas I to IV can be covalently linked with any other structure belonging to formulas I toIV. The following formulas are used for illustration:Formula I Formula II Formula III Formula IVFormula I Formula II Formula Illi Formula IV

[0147] This concept is further illustrated by the following general formulae:

[0148] All shared variables between formulas I to IV and formulas la to IVa have the same definitions as are described above with reference to formulas I to IV.

[0149] QB, QRA, QRN, QB, QRA, and QRNare independently selected from O, S, NH, CH2, C=O,

[0150] L1, L2and L3, are independently selected from: -(CH2)n3-, -(OCH2CH2)n3-, -(OCH2CH2CH2)n3-, where the value of m is located between 0 and 10, O, NH, NHNH, C=O,

[0151] In another embodiment, L1, L2and L3, are independently selected from:RL'

[0152] RLand RL, are, independently selected from hydrocarbon chain, preferably with 1 to 4 methylene units, which might be optionally substituted with one or more halogen atoms.

[0153] AL1to AL5is CH, CRA[ I. CH2, CHRA". N, NH, N RU I. O, S, C=O, C=NH, or C=S.

[0154] In the case AL4or AL5is C=O, preferably the other AL5or AL4is O, or NH.

[0155] In the case AL4or AL5is C=NH, preferably the other AL5or AL4, and AL3or AL2are O, or NH.

[0156] RAriis selected from a halogen, H, alkyl group with small number of carbons, preferablyI to 3, 0H, NH2, orNO2.

[0157] The value of NLranges between 0 and 6.

[0158] ( — ) represents single or double bonds.

[0159] Certain preferred embodiments of the present invention, related to formula la, include the following examples:Example 35 Example 36

[0160] Certain preferred embodiments of the present invention, related to formula Ila, include the following examples:Example 39

[0161] Certain preferred embodiments of the present invention, related to formula Illa, include the following examples:Example 40 Example 41Example 42

[0162] Certain preferred embodiments of the present invention, related to formula IV a, include the following examples:Example 44Example 45

[0163] Certain preferred embodiments of the present invention, related to asymmetric dimers, include the following examples:Example 46

[0164] In some other embodiments, the present invention comprises a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable diluents, and excipients.

[0165] In some embodiments, the present invention comprises a pharmaceutical composition comprising a compound disclosed herein, in combination with one or more other therapeutically active compounds by the same or different mode of action, and one or more pharmaceutically acceptable diluents, and excipients.

[0166] In some embodiments, the present invention comprises a method for treating a patient of viral infections, or uncontrolled cell growth and spread of abnormal cells occurs, the method comprising the step of administering a therapeutically effective amount of a compound disclosedherein, together with one or more pharmaceutically acceptable diluents, and excipients, to the patient in need of relief from said pathological state.

[0167] In some embodiments, the present invention comprises a method for treating a patient of viral infections, or uncontrolled cell growth and spread of abnormal cells occurs, the method comprising the step of administering a therapeutically effective amount of a compound disclosed herein, in combination with one or more therapeutically effective compounds by the same or different mode of action, together with one or more pharmaceutically acceptable diluents, and excipients, to the patient in need of relief from said pathological state.

[0168] In some embodiments, the present invention comprises a method for treating a patient of pathological conditions mediated by abnormal levels of interferons and related cytokines, the method comprising the step of administering a therapeutically effective amount of a compound disclosed herein, together with one or more pharmaceutically acceptable diluents, and excipients, to the patient in need of relief from said pathological state.

[0169] In some embodiments, the present invention comprises a method for treating a patient of pathological conditions mediated by abnormal levels of interferons and related cytokines, the method comprising the step of administering a therapeutically effective amount of a compound disclosed herein, in combination with one or more therapeutically effective compounds by the same or different mode of action, together with one or more pharmaceutically acceptable diluents, and excipients, to the patient in need of relief from said pathological state.

[0170] Certain preferred compounds described herein may be used alone or in combination with other antimicrobials that may be therapeutically effective by the same or different modes of action. In addition, the compounds described herein may be used in combination with other therapeutics that are administered to treat other symptoms of viral infections, such as compounds administered to relieve pain, allergy, swelling, nausea / vomiting, and the like.

[0171] Certain preferred compounds described herein may be used alone or in combination with other chemotherapeutics or cytotoxic agents that may be therapeutically effective by the same or different modes of action. In addition, the compounds described herein may be used in combination with other therapeutics that are administered to treat other symptoms of uncontrolled cell growth, such as compounds administered to relieve pain, allergy, swelling, nausea / vomiting, and the like.

[0172] Certain preferred compounds described herein may be used alone or in combination with other therapeutics for controlling pathogenic cGAS activity associated autoimmune diseases that may be therapeutically effective by the same or different modes of action. In addition, the compounds described herein may be used in combination with other therapeutics that are administered to treat other symptoms of controlling pathogenic cGAS activity associated autoimmune diseases, such as sleep disorders, depression, anxiety, pain, allergy, swelling, nausea / vomiting, and the like.

[0173] Pathogenic cGAS activity associated autoimmune diseases include systemic lupus erythematosus conditions, familial chilblain lupus, STING-associated vasculopathy with onset in infancy (SAVI), Rheumatoid arthritis, Sjoegren's syndrome, COPA syndrome and Aicardi- Goutieres syndromes.

[0174] Antimicrobial conditions that can be treated with certain preferred compounds disclosed in the present invention include, but are not limited to, viruses of belong to the following families: Herpesviridae, Flaviviridae, Coronaviridae, Papillomaviridae, Adenoviridae, Hepadnaviridae, ortho- and paramyxoviridae and rhabdoviridae.

[0175] As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art.

[0176] As readily recognized by the skilled person, any given group disclosed herein may comprise further hydrogen(s) than the one(s) provided by a R-group, being hydrogen, attached to the group.

[0177] Whenever a group is described as being "unsubstituted or substituted," if substituted, the substituent(s), which may be present one or more times, such as 1, 2, or 3 times, are independently selected from alkyl, heteroalkyl alkenyl, alkynyl, cycloalkyl, heterocycloalkyl cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroalkyl heteroaralkyl, heteroalkyl (heteroalicyclyl)alkyl, heteroalkyl hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S- sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, heteroalkyl haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.

[0178] When a substituent on a group is deemed to be "substituted," the substituent itself is substituted with one or more of the indicated substituents. When the referenced substituent is substituted, it is meant that one or more hydrogen atoms on the referenced substituent may be replaced with a group(s) individually and independently selected from alkyl, heteroalkyl alkenyl, alkynyl, cycloalkyl, heterocycloalkyl cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroalkyl heteroaralkyl, heteroalkyl (heteroalicyclyl)alkyl, heteroalkyl hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, urithanyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, heteroalkyl haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and disubstituted amino groups, quaternary ammonium group, and the protected derivatives thereof.

[0179] A “halogen” designates F, Cl, Br or I. A “halogen substitution” or “halo” substitution designates replacement of one or more hydrogen atoms with F, Cl, Br or I.

[0180] As used herein, the term “alkyl” refers to a saturated monovalent chain of carbon atoms, which may be optionally branched. It is understood that in embodiments that include alkyl, heteroalkyl illustrative variations of those embodiments include lower alkyl, heteroalkyl such as Ci to C9 alkyl, heteroalkyl methyl, ethyl, propyl, 3-methylbutyl, and the like.

[0181] As used herein, "heteroalkyl," by itself or in combination with another term, refers to saturated monovalent chain of carbon atoms, consisting of the stated number of carbon atoms, where one or more carbon atom(s), such as 1, 2, 3 or 4 carbon atom(s), and the associated hydrogen atom(s) have been independently replaced with the same or different heteroatoms selected from nitrogen, oxygen and sulfur. The carbon atom(s) being replace may be in the middle or at the end of the alkyl group. Examples of heteroalkyl include, but are not limited to, -S-alkyl, -O-alkyl, -NH-alkyl, -alkylene-O-alkyl, and the like.

[0182] As used herein, "heterocycloalkyl," by itself or in combination with another term, refers to saturated monovalent cycle of carbon atoms, consisting of the stated number of carbon atoms, where one or more carbon atom(s), such as 1, 2, 3 or 4 carbon atom(s), and the associated hydrogen atom(s) have been independently replaced with the same or different heteroatoms selected from nitrogen, oxygen and sulfur. The carbon atom(s) being replace may be at any position of the cycle. Examples of heterocycloalkyl include, but are not limited to, tetrahydro- 2H-pyran, tetrahydro-2H-thiopyran, -NH-alkyl, -alkylene-O-alkyl, and the like.

[0183] As used herein, "BN”, "AN" or "(CH2)n" in which "N" and "n" are integers refers to the number of units (which may be CH, N, NH, NR and the like) in the relevant group. That is, the group can contain range described in these definitions. Thus, for example, when the value of ns of -(CH2)n- is located between 0 and 10, this refers to the number of methylene units are between 1 to 10, that is, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, - CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2-,CH2CH2CH2CH2CH2CH2CH2CH2-, - CH2CH2CH2CH2CH2CH2CH2CH2CH2-, and - CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-.

[0184] As used herein, the terms “cycloalkyl” refers to a monovalent chain of carbon atoms, a portion of which forms a ring. It is understood that in embodiments that include cycloalkyl, heteroalkyl illustrative variations of those embodiments include lower cylcoalkyl, heteroalkyl such as C3 - Ce cycloalkyl, heteroheteroalkyl cyclopropyl, cyclobutyl, 3-methylcyclohexyl, and the like.

[0185] As used herein, the terms “hetero-atom” or “hetero atom” refer to non-carbon and nonhydrogen atoms such as N, O, S, Se, P, and the like, preferably N, O or S atoms.

[0186] As used herein, the terms “alicyclic structure” or “alicyclic ring” refer to cyclic saturated or partially saturated ring structures, with or without hetero-atom(s), such as cyclohexane, cyclobutene, pyrrolidine, piperidine, piperazine, imidazoline and the like.

[0187] As used herein, the terms “aryl” used alone or as part of a phrase such as “aralkyl” or “alkylaryl” refer to monocyclic, bicyclic or fused ring systems, with at least one aromatic ring, having 5- to 12 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. Examples of aryl rings include but not limited to phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. The term "aryl" may be used interchangeably with the term "aryl ring".

[0188] As used herein, the term “hetero-atom containing group” refers to all chemical moieties that contain one or more hetero-atom, such as cyano, nitro, amino, carboxylate, carbonyl, hydroxy, sulfone, sulfoxide, sulfonamide, oxime, hydrazine and the like.

[0189] As used herein, the term “heterocycle” refers 4-, 5-, 6-, or 7-membered ring having 1 to 4 heteroatoms selected from O, N, and S, or 8-, 9-, or 10-memebered ring having 1 to 6 heteroatoms selected from O, N, and S, or a salt thereof. The scope of heterocycle includes, but is not limitedto, pyridine, pyrimidine, pyridazine, quinazoline, quinoline, indole, pyrole, pyrazole, imidazole, furan, benzofuran, thiophene, benzothiophene, the like and related examples.

[0190] The term "heterocycle" may be used interchangeably with the term “aryl with heteroatom”.

[0191] The term “acyl” refers to the general structure motif R-C=O, in which R is selected from alkyl, heteroalkyl cycloalkyl, heterocycloalkyl alicylic structures, phenyl, aryl, or heterocyclic structure.

[0192] It is understood that each of alkyl, heteroalkyl and cycloalkyl may be optionally substituted with a group independently selected from groups such as halide, alkyl, heteroalkyl halogenated alkyl, heteroalkyl alkoxy, hydroxy, hydroxyalkyl, heteroalkyl carboxylic acid and derivatives thereof, including esters, nitrile, amides, and nitrites, acyloxy, aminoalkyl and dialkylamino, acylamino, thio, and the like, and combinations thereof.

[0193] The term "optionally substituted,” or “optional substituents," as used herein, means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent, the substituents may be the same or different. Moreover, when using the terms “independently,” means that the groups in question may be the same or different. Certain of the herein defined terms may occur more than once in the structure, and upon such occurrence each term shall be defined independently of the other.

[0194] The term “patient” includes human and non-human animals such as companion animals, including horses, dogs, cats and the like, and livestock animals. Livestock animals are animals raised for production of food, textiles, or other animal-based products. The patient to be treated is preferably a mammal, and more preferably, a human being.

[0195] The term “pharmaceutically acceptable diluent" or “pharmaceutically acceptable excipient” are art-recognized and refer to a pharmaceutically acceptable material, composition orvehicle, such as a liquid or solid filler, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof. Each carrier must be “acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient. Some examples of materials which may serve as pharmaceutically acceptable carriers include: sugars, such as lactose and maltose; starches, such as com starch and gelatinized starch; cellulose, and its derivatives, such as carboxymethyl cellulose salt, and hydroxypropylmethyl cellulose; thickening agents such as gelatin and tragacanth; disintegrants such as copovidone; other excipients, such as cocoa butter and suppository waxes and pyrogen- free water for sterile products; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0196] As used herein, the term “administering” includes all means of introducing the compounds and compositions described herein to the patient, including, but are not limited to, topical, oral, intravenous, intramuscular, transdermal, inhalation, buccal, ocular, vaginal, rectal, and the like. The compounds and compositions described herein may be administered in unit dosage forms or formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles.Preparation of Example Compounds

[0197] Certain preferred compounds, according to the present invention, may be prepared according to the following method:

[0198] Synthetic protocol for representative example from Formula I:

[0199] Synthetic protocol for representative example from Formula II:

[0200] Synthetic protocol for representative example from dimer Formula:

[0201] As shown in Figures 1-4, docking results of certain preferred examples in STING protein (PDB ID: 6DXL) showed favourable interactions, in particular, examples 1, 31, 16, and 21, respectively.

[0202] STING binding method: Human STING binding kit was used from Cisbio (c / o Perkin Elmer), Cat #: 64BDSTGPEG Lot #: 05B. Human STING WT ligand was detected in a competitive assay format using a specific 6His antibody labelled with Terbium Cryptate (donor) which binds to human WT protein 6His-tagged and STING WT ligand labelled with d2 (acceptor). The detection principle was based on HTRF® technology: when the dyes are in close proximity, the excitation of the donor with a light source (flash lamp) triggers a Fluorescence Resonance Energy Transfer (FRET) towards the acceptor, which in turn fluoresces at a specific wavelength (665nm). The sample compound competes with the STING WT ligand labelled withd2, and thereby prevents FRET from occurring. The assay is ratiometric, allowing for quantification of the binding strength, by comparing it to the standard curve. Low signal means that the compound binds to STING (i.e. it outcompetes 6Hislabelled STING protein) - no FRET can take place.

[0203] Result of STING binding assay of selected examples:

[0204] The present invention has been described and illustrated with reference to an exemplary embodiment; however, it will be understood by those skilled in the art that various changes may be made, and equivalents may be substituted for elements thereof without departing from the scope of the invention as set out in the following claims. Therefore, it is intended that the invention is not limited to the embodiments disclosed herein.

Claims

What is claimed is:

1. A compound selected from the group consisting of formula I, formula II, formula III, and formula IV:formula III wherein:A1to A5are independently selected from C, CH. CH2, CRA1, CHRA1, NH, NRA1, NHNH, NHRA1NH, NHNRA2, N RA1NRA2, O, S, or SO2in formulas I and II, and are independently selected from N, NH, NR1, CH, CH2, CHR1, or CR1R2in formula III, and are independently selected from N, NH, NRA1, CH, CH2, CHRA1or CRA1RA2in formula IV;B1to B6are independently selected from C, CH. CH2, CRB1, CHRB1, NH, NRB1, NHNH, NHRB1NH, NHNRB2, N RB1NRB2, O, S, or SO2in formulas I to III, and additionally in formula III B1is selected from CHR1, CR1R2, NR1, C=O, C=S, C=NOH, or C=NOR1, and are independently selected from N, NH, NRB1, CH, CH2, CHRB1or CRB1RB2in formula IV; The value of nA2is between 0 and 5;the value of each of nB5and nB6is between 0 and 3 in formulas I to III, and the value of nb5is between 0 and 4 in formula IV;RA1and RA2are independently selected from H, CN, NO2, -COOH, -COOR1, NH2, NHR1, NR1R2, OH, OR1, an alkyl or cycloalkyl chain with number of C atoms ranging between 1 and 10, including bicyclo and fused cyclic systems, a phenyl, substituted phenyl with small C-containing substituents or hetero-atom containing group, aryl with hetero-atom or heterocycle, which are optionally further substituted with C-containing substituents or hetero- atom containing groups;RA4is selected from H, alkyl, heteroalkyl or cycloalkyl with number of C atoms ranging between 1 and 6, which is optionally substituted with one or more halogen atoms, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, urithanyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, heteroalkyl haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, quaternary ammonium groups, and the protected derivatives thereof;RA5is selected from H, alkyl, heteroalkyl or cycloalkyl with number of C atoms ranging between 1 and 6, which are optionally substituted with one or more halogen atoms, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, urithanyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, heteroalkyl haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, quaternary ammonium group, and the protected derivatives thereof;RB1and RB2are independently selected from H, CN, N02, -COOH, -COOR1, NH2, NHR1, NR1R2, OH, OR1, an alkyl or cycloalkyl chain with number of C atoms ranging between 1 and 10, including bicyclo and fused cyclic systems, a phenyl, substituted phenyl with small C-containing substituents or hetero-atom containing group, aryl with hetero-atom or heterocycle, which are optionally substituted with C-containing substituents or hetero-atom containing groups;R1and R2are independently selected from alkyl, with number of carbons between 1 and 4, optionally with one or more heteroatoms in formulas I and II, and are independently selected from alkyl, heteroalkyl, or cycloalkyl with a number of C atoms ranging between 1 and 6, optionally substituted with one or more halogen atoms, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, urithanyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, heteroalkyl haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, quaternary ammonium groups, and the protected derivatives thereof in formula III, and are independently selected from alkyl or cycloalkyl chains with a number of C atoms ranging between 1 and 6, optionally substituted with one or more halogen atoms in formula IV; optionally, R1and R2form an “oxo” group;X1is selected from O, NH, or NRX1in formulas I and II, and is selected from N, CH, or CRX1in formula III;RX1is selected from OH, OR1, or alkyl, with number of carbons between 1 and 6, optionally with one or more heteroatoms in formulas I and II, and is selected from ON, NO2, COOH, COOR1, NH2, NHR1, NR1R2, OH, OR1, an alkyl or cycloalkyl chain with number of C atoms ranging between 1 and 10, including bicyclo and fused cyclic systems, a phenyl, substituted phenyl with small C-containing substituents or hetero-atom containing group, aryl with hetero-atom or heterocycle, which are optionally substituted with C-containing substituents or hetero-atom containing groups in formula III; optionally, in formulas I and II, RN2, X1or RX1is connected with A1directly via a covalent bond or via, in which X2is selected from N, CH or CRX2; optionally, in formula III, RN2is connected with L1directly via a covalent bond or viaRX2is selected from CN, NO2, -COOH, -COOR1, NH2, NHR1, NR1R2, OH, OR1, an alkyl or cycloalkyl chain with number of C atoms ranging between 1 and 10, including bicyclo and fused cyclic systems, a phenyl, substituted phenyl with small C-containing substituents or hetero-atom containing group, aryl with hetero-atom or heterocycle, which are optionally further substituted with C-containing substituents or hetero-atom containing groups;RN1is selected from O, NH, NR1 , CH2, (CH2)nRN1, CHR1, or CR1R2, and RN2is selected from H, OH, OR1, or alkyl, with a number of carbons between 1 and 6, optionally with one or more heteroatoms, except in formula III wherein RN1and RN2are independently selected from H, alkyl or cycloalkyl with C number between 1 and 6, optionally substituted with one or more halogen atoms, OH, or OR1; optionally, RN1and RN2are connected by another N-containing group, C, S (in any oxidation state), or O; optionally, RN1and RN2are part of cyclic structure; optionally, B3and B4are part of a cyclic structure;“Cy”, “Cy1”, and “Cy2” are each a cyclic structure and, optionally, “RN1— Cy” together represent H, OH, OR1, or alkyl, with a number of carbons between 1 and 6, optionally substituted with one or more heteroatoms;RA4^ optionally, “a4” is omitted and, optionally, A3is linked directly with B2; optionally, themoiety is connected instead on the B1to B6ring;L1is a linker consisting of a cyclic or acyclic carbon chain, with number of carbons between 1 and 10, optionally with one or more heteroatoms; and(— -) represents single or double bonds.

2. The compound of claim 1 , wherein the compound is a compound of formula I, wherein:the one or more heteroatoms optionally included in the RN1, RX1and RX2groups are independently selected from the group consisting of: O, N, S, Se, P, or a halide; and“Cy” is selected from cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, phenyl, heterocyclic or bicyclic structures, all of which are optionally substituted with one or more halogen atoms, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, urithanyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, heteroalkyl haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and disubstituted amino groups, quaternary ammonium groups, and the protected derivatives thereof.

3. The compound of claim 2, wherein B3and B4are part of a cyclic structure selected from the group consisting of:y py j- 1 ,4-Dioxane-2, 3-dione:k. Piperazine-I. Piperazine:m. Pyrazine or dihydropyrazine:and n. Hydroquinone:

4. The compound of claim 2, wherein RN1and RN2are connected by a N-containing group selected from the croup consisting of:

5. The compound of claim 2, wherein RN1and RN2are part of a cyclic structure selected from the group consisting of:The compound of claim 2, wherein the N atom ireplaced by a group selected from C, S (in any oxidation state), O,7. The compound of claim 2, wherein “Cy” is selected from the group consisting of: a. 5-membered rings:d. Fused systems and other cyclic structures:

8. The compound of claim 2, wherein the compound is selected from the group consistingExample 15Example 18 Example 19.

9. The compound of claim 1 , wherein the compound is a compound of formula II, and wherein: the one or more heteroatoms optionally included in the RN1, RX1and RX2groups are independently selected from the group consisting of: O, N, S, Se, P, or a halide; and “Cy” is selected from cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, phenyl, heterocyclic or bicyclic structures, all of which are optionally substituted with one or more halogen atoms, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, urithanyl, C-amido, N-amido, S-sulfonamido,N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, heteroalkyl haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and disubstituted amino groups, quaternary ammonium groups, and the protected derivatives thereof.

10. The compound of claim 9, wherein B3and B4are part of a cyclic structure selected from the group consisting of:,m. Pyrazine or dihydropyrazine:n. Hydroquinone:11 . The compound of claim 9, wherein RN1and RN2are part of a cyclic structure selected from the group consisting of:. ib^tbi12. The compound of claim 9, wherein “Cy” is selected from the group consisting of:

13. The compound of claim 9, wherein the compound is selected from the group consisting of:Example 24 Example 25.The compound of claim 1 , wherein the compound is a compound of formula III, and wherein:“Cy” is a 3 to 6-membered ring with each member of the ring independently selected from NH, NRY1, NHNH, NHRCY1aNH, NHNRCYa, O, S, CH2, or CHRCY1a;RCYaand RCY1aare independently selected from CN, NO2, -COOH, -COOR1, NH2, NHR1, NR1R2, OH, OR1, an alkyl or cycloalkyl chain with number of C atoms ranging between 1 and 10, including bicyclo and fused cyclic systems, a phenyl, substituted phenyl with smallC-containing substituents or hetero-atom containing group, aryl with hetero-atom or heterocycle, which are optionally substituted with C-containing substituents or hetero-atom containing groups.

15. The compound of claim 14, wherein L1is a linker selected from the group consisting of:wherein the value of nL1is between 1 and 5.

16. The compound of claim 15, wherein B3and B4are part of a cyclic structure selected from the group consisting of:k. Piperazine-2, 3-dione:m. Pyrazine or dihydropyrazine:and17. The compound of claim 15, wherein the compound is selected from the group consisting of:Example 26 Example 27Example 30.

18. The compound of claim 1 , wherein the compound is a compound of formula IV, and wherein “Cy1” and “Cy2” are independently selected from cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, phenyl, heterocyclic or bicyclic structures, each optionally substituted with one or more halogen atoms, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O- carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, urithanyl, C- amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, heteroalkyl haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, quaternary ammonium groups, and the protected derivatives thereof; and wherein optionally “Cy1” and “Cy2” form a fused ring system.

19. The compound of claim 18, wherein L1is selected from the group consisting of:a. Linear hydrocarbon chains with a number of C atoms ranging between 1 and 10, which are optionally branched with other smaller alkyl or cycloalkyl moiety / ies, and optionally substituted with one or more halogen atoms; b. Amide:c. Hydroxy ester or amide:d. Amino ester or amide:e. Alicyclic structure, such as, but not limited to:f. Part of aromatic structures:wherein the value of nY1is between 1 and 6.

20. The compound of claim 19, wherein B1, B2, B3, B4, and B5are independently selected from the group consisting of:wherein the value of nBranges from 0 to 4.21 . The compound of claim 19, wherein “Cy1” is selected from the group consisting of:

22. The compound of claim 21 , wherein “Cy2” is selected from the group consisting of: a. 5-membered rings:

23. The compound of claim 19, wherein “Cy1” and “Cy2” form a fused ring system selected from the group consisting of:

24. The compound of claim 19, wherein the compound is selected from the group consisting of:Example 31 Example 32Example 33 Example 34.

25. A compound comprising a covalently linked, symmetric or asymmetric dimer of a first compound according to claim 1 with a second compound according to claim 1 by way of one or more linkers, wherein each of the one or more linkers comprises: a Q group linked to the first compound according to claim 1 ; a Q’ group linked to the second compound according to claim 1 ; and an L group linked to both the Q group and the Q’ group; wherein the Q and Q’ groups are independently selected from: O, S, NH, CH2, C=O,wherein the L groups are independently selected from:, ,wherein RLand RLare, independently selected from a hydrocarbon chain, with 1 to 4 C atoms, which is optionally substituted with one or more halogen atoms; wherein each of AL1to AL5is independently selected from CH, CRAL1, CH2, CHRAL1, N,NH, N RAL1, O, S, C=O, C=NH, or C=S; wherein RAL1is selected from a halogen, H, alkyl group with a number of carbons between 1 and 3, OH, NH2, or NO2; and wherein the value of NLis between 0 and 6.

26. The compound of claim 25, wherein the compound is selected from the group consisting of:Example 37 Example 38Example 39Example 40 Example 41Example 46.

27. The use of a compound according to claim 1 or a pharmaceuticaly acceptable salt, solvate, or hydrate, in an acceptable polymorph or pseudopolymorph, as a STING activator.

28. The use of a compound according to claim 1 or a pharmaceuticaly acceptable salt, solvate, or hydrate, in an acceptable polymorph or pseudopolymorph, as a STING inhibitor.

29. A method of treating or preventing, in a patient in need thereof, a condition selected from the group consisting of: uncontrolled growth and spread of abnormal cells, microbial infection, pathogenic cGAS activity, neurodegeneration, autoimmune disease, inflammatory disease, and neuropathic pain, the method comprising the step of administering a therapeutically effective amount of a compound according to claim 1 to the patient.

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