Interferon gene stimulatory factor agonists

Abstract

The present disclosure provides stimulator of interferon genes (STING) modulators and their use in treating STING-associated diseases, disorders, or conditions.

Description

[Background technology]

[0001] Stimulator of interferon genes (STING), also known as transmembrane protein 173 (TMEM173) and MPYS / MITA / ERIS, is an endoplasmic reticulum-associated protein that binds to cyclic dinucleotides or cytoplasmic DNA to induce cytokine production. STING is an innate immune adaptor protein that enables signaling from cytoplasmic receptors to the transcription factor interferon regulatory factor 3. Initiation of these pathways leads to the expression of type I interferons and proteins associated with antiviral and antitumor immunity. Compounds capable of inducing STING-dependent cellular processes are effective in inhibiting viral replication, enhancing vaccine efficacy, and promoting immune responses against cancer cells. Summary of the Invention

[0002] In some aspects, the presently disclosed subject matter comprises:

[0003] [ka]

[0004] n is 1 or 2, and X is S, O, or NR x , and C.R. x1 R x2 Selected from R x , R x1 , and R x2 are each independently selected from H and C1-C4 alkyl, and A is

[0005] [ka]

[0006] R1 is H or C1-C4 alkyl, R2 is selected from -OR4, -NR5R6, and -NO2, and R4 is H or C1-C 20and R and R are each independently H or C-C alkyl, each R can be the same or different and each is halogen, each R can be the same or different and each is halogen, and (i) when X is S, A is 2,4,6-trifluorophenyl, n is 2, and R is F at positions 2 and 6 of ring B, then R cannot be H or C alkyl, or (ii) when X is S, A is 2,4,6-trifluorophenyl, n is 2, and R is F at position 2 of ring B, then R cannot be C alkyl, and pharmaceutically acceptable salts thereof.

[0007] In certain embodiments, the compound of formula (I) is a compound of formula (I').

[0008] [ka]

[0009] In some embodiments, the compound of formula (I') is a compound of formula (Ia).

[0010] [ka]

[0011] In some embodiments, the compound of formula (Ia) is a compound of formula (Ia-i).

[0012] [ka]

[0013] In certain embodiments of compounds of Formula (Ia-i), R2 is -OR4. In certain embodiments, R1 is H. In other embodiments, R1 is C1-C4 alkyl.

[0014] In some embodiments, the compound of formula (Ia) is a compound of formula (Ia-ii).

[0015] [ka]

[0016] In certain embodiments of compounds of Formula (Ia-ii), R2 is -OR4. In certain embodiments, R1 is H. In other embodiments, R1 is C1-C4 alkyl.

[0017] In some embodiments, the compound of formula (Ia) is a compound of formula (Ia-iii).

[0018] [ka]

[0019] In some embodiments of a compound of Formula (Ia-iii), R2 is -OR4. In some embodiments, R1 is H. In other embodiments, R1 is C1-C4 alkyl.

[0020] In some embodiments of compounds of Formula (I), R2 is -NR5R6 or -NO2. In some embodiments of compounds of Formula (Ia), R2 is -NR5R6 or -NO2.

[0021] In some embodiments, the compound of formula (I) is a compound of formula (Ib).

[0022] [ka]

[0023] In certain embodiments, the compound of formula (Ib) is a compound of formula (Ib-i).

[0024] [ka]

[0025] In some embodiments of compounds of Formula (Ib-i), R2 is -OR4. In some embodiments of compounds of Formula (Ib-i), R1 is H. In other embodiments of compounds of Formula (Ib-i), R1 is C1-C4 alkyl.

[0026] In some embodiments, the compound of formula (Ib) is a compound of formula (Ib-ii).

[0027] [ka]

[0028] In some embodiments of compounds of Formula (Ib-ii), R2 is -OR4. In some embodiments of compounds of Formula (Ib-ii), R1 is H. In other embodiments of compounds of Formula (Ib-ii), R1 is C1-C4 alkyl.

[0029] In some embodiments, the compound of formula (Ib) is a compound of formula (Ia-iii).

[0030] [ka]

[0031] In some embodiments of a compound of Formula (Ib-iii), R2 is -OR4. In some embodiments of a compound of Formula (Ib-iii), R1 is H. In other embodiments of a compound of Formula (Ib-iii), R1 is C1-C4 alkyl. In some embodiments of a compound of Formula (Ib), R2 is -NR5R6 or -NO2. In some embodiments of a compound of Formula (Ib), R2 is -NR5R6 or -NO2.

[0032] In another aspect, the presently disclosed subject matter provides a method of modulating stimulator of interferon genes (STING), the method comprising contacting a cell with a compound of Formula (I), Formula (Ia), Formula (I-ai-iii), Formula (Ib), and Formula (I-bi-iii).

[0033] In other aspects, the presently disclosed subject matter provides methods of activating or stimulating STING, the methods comprising contacting a cell with a compound of Formula (I), Formula (Ia), Formulas (I-ai-iii), Formula (Ib), and Formulas (I-bi-iii).

[0034] In another aspect, the presently disclosed subject matter provides a method for treating a STING-associated disease, disorder, or condition, the method comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula (I), Formula (Ia), Formulas (I-ai-iii), Formula (Ib), and Formulas (I-bi-iii).

[0035] In certain aspects, the disease, disorder, or condition is selected from cancer, a bacterial infection, a viral infection, a fungal infection, a parasitic infection, an immune-mediated disease, a central nervous system disease, a peripheral nervous system disease, a neurodegenerative disease, a mood disorder, a sleep disorder, a cerebrovascular disease, a peripheral arterial disease, and a cardiovascular disease.

[0036] In particular aspects, the disease, disorder, or condition is cancer, hi more particular aspects, the cancer is selected from colon cancer, aerodigestive squamous cell carcinoma, lung cancer, brain cancer, liver cancer, gastric cancer, sarcoma, leukemia, lymphoma, multiple myeloma, ovarian cancer, uterine cancer, breast cancer, melanoma, prostate cancer, bladder cancer, pancreatic cancer, and renal cancer.

[0037] In some embodiments, the methods of the present disclosure further comprise administering a second therapeutic agent, hi certain embodiments, the second therapeutic agent is selected from an antiviral agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-cancer vaccine, and a hormone therapy.

[0038] In certain embodiments, the second therapeutic agent is selected from a B7 costimulatory molecule, interleukin-2, interferon-g, GM-CSF, a CTLA-4 antagonist, an IDO inhibitor or an IDO / TDO inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, an OX-40 ligand, a LAG3 inhibitor, a CD40 ligand, a 41BB / CD137 ligand, a CD27 ligand, bacillus Calmette-Guerin (BCG), liposomes, alum, Freund's complete or incomplete adjuvant, a TLR agonist, and detoxified endotoxin.

[0039] Certain aspects of the subject matter of the present disclosure have been described above; other aspects that are covered in whole or in part by the subject matter of the present disclosure will become apparent as the specification proceeds, as fully described herein below and in connection with the accompanying examples and figures.

[0040] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application will be provided by the Office upon request and payment of the necessary fee.

[0041] Thus, to describe the subject matter of the present disclosure in general terms, reference will now be made to the accompanying drawings, which are not necessarily drawn to scale. [Brief explanation of the drawings]

[0042] [Figure 1] THF luciferase activity is shown for compounds INI-3067, INI-3069, INI-3070, and INI-3071. [Figure 2] Luciferase activity of THF STING KO cells is shown for compounds INI-3067, INI-3069, INI-3070, and INI-3071. [Figure 3] Luciferase activity in THF TRIF / MAVS KO cells is shown for compounds INI-3067, INI-3069, INI-3070, and INI-3071. [Figure 4] 1 shows the THF luciferase activity of compounds INI-3077, INI-3078, INI-3079, INI-3080, INI-3067, and INI-3069. [Figure 5] Figure 1 shows the THF STING KO luciferase activity of compounds INI-3077, INI-3078, INI-3079, and INI-3080. [Figure 6] Figure 1 shows the THF STING-alone luciferase activity of compounds INI-3077, INI-3078, INI-3079, INI-3080, INI-3081, and INI-3067. [Figure 7] 1 shows the THF luciferase activity of compounds INI-3067, INI-3111, INI-3112, INI-3069, and INI-3110. [Figure 8] Figure 1 shows the THF STING-alone luciferase activity of compounds INI-3067, INI-3110, INI-3111, INI-3112, and INI-3069. [Figure 9] Figure 1 shows the THF STING KO luciferase activity of compounds INI-3110, INI-3111, INI-3112 and IFNβ plate 3. [Figure 10] Figure 1 shows the THF luciferase activity of compounds INI-3071, INI-3105, INI-3106, INI-3107, INI-3108, and INI-3109. [Figure 11] Figure 1 shows the THF STING KO luciferase activity of compounds INI-3105, INI-3106, INI-3107, INI-32018, INI-3109, and IFNβ plate 1. [Figure 12] Figure 1 shows the THF STING-alone luciferase activity of compounds INI-3071, INI-3105, INI-3106, INI-3107, INI-3108, INI-3109, and INI-3069. [Figure 13] 1 shows the THF luciferase activity of compounds INI-3070, INI-3074, INI-3071, and INI-3075. [Figure 14] Figure 1 shows the THF STING KO luciferase activity of compounds INI-3074, INI-3075, and IFNβ. [Figure 15] THF STING-only luciferase activity is shown for compounds INI-3070, INI-3074, INI-3071, and INI-3075. [Figure 16] Figure 1 shows the THF luciferase activity of compounds INI-3076, INI-3082, INI-3083, INI-3084, INI-3085, INI-3086, and INI-3069. [Figure 17] THF STING KO luciferase activity is shown for compounds INI-3076, INI-3082, INI-3083, INI-3084, INI-3085, and IFNβ. [Figure 18] THF STING-only luciferase activity is shown for compounds INI-3076, INI-3082, INI-3083, INI-3084, INI-3085, and INI-3086. [Figure 19] THF luciferase activity is shown for compounds INI-3087, INI-3088, INI-3089, INI-3090, INI-3091, INI-3092, and INI-3069. [Figure 20] Figure 1 shows the THF STING-alone luciferase activity of compounds INI-3087, INI-3088, INI-3089, INI-3090, INI-3091, and INI-3092. [Figure 21] Figure 1 shows the THF STING KO luciferase activity of compounds INI-3087, INI-3088, INI-3089, INI-3090, INI-3091, INI-3092, and IFNβ. [Figure 22] Figure 1 shows the THF STING luciferase activity of compounds INI-3087, INI-3088, INI-3089, INI-3090, INI-3091, and INI-3092. [Figure 23]Figure 1 shows the THF luciferase activity of compounds INI-3093, INI-3094, INI-3095, INI-3096, INI-3103, INI-3104, and INI-3069. [Figure 24] Figure 1 shows the THF STING-alone luciferase activity of compounds INI-3093, INI-3094, INI-3095, INI-3096, INI-3103, and INI-3104. [Figure 25] Figure 1 shows the THF STING KO luciferase activity of compounds INI-3093, INI-3096, INI-3103, INI-3104, and IFNβ. DETAILED DESCRIPTION OF THE INVENTION

[0043] The presently disclosed subject matter is described more fully below with reference to the accompanying figures, which illustrate some, but not all, embodiments of the invention. Like numbers refer to like elements throughout. The presently disclosed subject matter may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. Indeed, many modifications and other embodiments of the presently disclosed subject matter will come to mind to one skilled in the art to which the presently disclosed subject matter pertains having the benefit of the teachings presented in the foregoing descriptions and the associated figures. Therefore, it should be understood that the presently disclosed subject matter is not to be limited to the particular embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims.

[0044] (I. Stimulator of Interferon Genes (STING) Agonists)

[0045] A. Representative Compounds of Formula (I) In some embodiments, the presently disclosed subject matter comprises:

[0046] [ka]

[0047] n is 1 or 2, X is S, O, NR x , and C.R. x1 R x2 Selected from R x , R x1 , and R x2 are each independently selected from H and C1-C4 alkyl; A is as follows:

[0048] [ka]

[0049] R1 is H or C1-C4 alkyl, R2 is selected from -OR4, -NR5R6, and -NO2, and R4 is H or C1-C 20 and R and R are each independently H or C-C alkyl, each R can be the same or different and each is halogen, each R can be the same or different and each is halogen, and (i) when X is S, A is 2,4,6-trifluorophenyl, n is 2, and R is F at positions 2 and 6 of ring B, then R cannot be H or C alkyl, or (ii) when X is S, A is 2,4,6-trifluorophenyl, n is 2, and R is F at position 2 of ring B, then R cannot be C alkyl, and pharmaceutically acceptable salts thereof.

[0050] Furthermore, the structure generally represented by the formula:

[0051] [ka]

[0052] As used herein, the term "ring structure" refers to a ring structure having a substituent R group, where the R group may or may not be present, and when present, one or more R groups may each be substituted on one or more available carbon atoms of the ring structure. The presence or absence of an R group and the number of R groups are determined by the value of the variable "n", which is generally an integer ranging from 0 to the number of carbon atoms on the ring that can be substituted. When there are multiple R groups, each R group is substituted on an available carbon of the ring structure instead of another R group. For example, the above structure where n is 2 includes, but is not limited to, the following group of compounds:

[0053] [ka]

[0054] A dashed line representing a bond in a cyclic ring structure indicates that the bond may or may not be present in the ring, i.e., that the ring structure is selected from the group consisting of saturated, partially saturated, and unsaturated ring structures.

[0055] JPEG2025526390000016.jpg8134

[0056] As used herein, the term "alkyl" refers to a group derived from an alkane by removing a hydrogen atom from any carbon atom and having the formula -C n H 2n+1 The alkyl group obtained by removing a hydrogen atom from the terminal carbon atom of an unbranched alkane has the formula -H(CH2) n RCH2, R2CH (R≠H), and R3C (R≠H) groups form a subclass of normal alkyl (n-alkyl) groups having the formula: RCH2, R2CH (R≠H), and R3C (R≠H) groups are primary, secondary, and tertiary alkyl groups, respectively.

[0057] The number of carbon atoms designated for the alkyl group (i.e., C1-C 10means 1 to 10 carbons, including 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbons). In certain embodiments, the term "alkyl" refers to C1-C6, inclusive, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbons. 20 An alkyl group can be linear (i.e., "straight chain") or branched. More specifically, as used herein, the term "C1-C4 alkyl" refers to an alkyl group having 1, 2, 3, or 4 carbon atoms. Representative C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. "Branched" refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl, or propyl, is attached to a linear alkyl chain. "Lower alkyl" refers to an alkyl group having from 1 to about 8 carbon atoms (i.e., C 1-8 It refers to an alkyl group having a radical (alkyl).

[0058] In some embodiments, an alkyl group can be substituted. As used herein, the term "substituted alkyl" includes an alkyl group, as defined herein, in which one or more atoms of the alkyl group are replaced with another atom or functional group, including, for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, cyano, and mercapto.

[0059] As used herein, the terms "halo," "halide," or "halogen" refer to fluoro, chloro, bromo, and iodo groups. In some embodiments, the halogen is F. In some embodiments, the halogen is Cl.

[0060] In certain embodiments, the compound of formula (I) is a compound of formula (I').

[0061] [ka]

[0062] In certain embodiments, the compound of formula (I') is a compound of formula (Ia).

[0063] [ka]

[0064] In certain embodiments, the compound of formula (Ia) is a compound of formula (Ia-i).

[0065] [ka]

[0066] In certain embodiments of a compound of Formula (Ia-i), R2 is -OR4. In certain embodiments, R1 is H. In such embodiments, the compound of Formula (Ia-i) is selected from:

[0067] [ka]

[0068] In certain embodiments of compounds of Formula (Ia-i), R1 is C1-C4 alkyl, and in such embodiments, the compound of Formula (Ia-i) is selected from:

[0069] [ka]

[0070] In certain embodiments, the compound of Formula (Ia) is a compound of Formula (Ia-ii).

[0071] [ka]

[0072] In certain embodiments of a compound of Formula (Ia-ii), R2 is -OR4. In certain embodiments, R1 is H. In such embodiments, the compound of Formula (Ia-ii) is selected from:

[0073] [ka]

[0074] In some embodiments of the compound of Formula (Ia-ii), R1 is C1-C4 alkyl. In such embodiments, the compound of Formula (Ia-ii) is selected from:

[0075] [ka]

[0076] In certain embodiments, the compound of Formula (Ia) is a compound of Formula (Ia-iii):

[0077] [ka]

[0078] In certain embodiments of a compound of Formula (Ia-iii), R2 is -OR4. In some embodiments, R1 is H. In such embodiments, the compound of Formula (Ia-iii) is selected from:

[0079] [ka]

[0080] In certain embodiments of the compound of Formula (Ia-iii), R1 is C1-C4 alkyl. In such embodiments, the compound of Formula (Ia-iii) is selected from:

[0081] [ka]

[0082] In some embodiments of a compound of Formula (I), R2 is -NR5R6 or -NO2. In some embodiments of a compound of Formula (Ia), R2 is -NR5R6 or -NO2. In such embodiments, the compound of Formula (Ia) is selected from:

[0083] [ka]

[0084] In certain embodiments, the compound of Formula (I) is a compound of Formula (Ib).

[0085] [ka]

[0086] In certain embodiments, the compound of formula (Ib) is a compound of formula (Ib-i).

[0087] [ka]

[0088] In some embodiments of a compound of Formula (Ib-i), R2 is -OR4. In some embodiments of a compound of Formula (Ib-i), R1 is H. In such embodiments, the compound of Formula (Ib-i) is selected from:

[0089] [ka]

[0090] In some embodiments of the compound of Formula (Ib-i), R1 is C1-C4 alkyl. In such embodiments, the compound of Formula (Ib-i) is selected from:

[0091] [ka]

[0092] In certain embodiments, the compound of Formula (Ib) is a compound of Formula (Ib-ii).

[0093] [ka]

[0094] In some embodiments of a compound of Formula (Ib-ii), R2 is -OR4. In some embodiments of a compound of Formula (Ib-ii), R1 is H. In such embodiments, the compound of Formula (Ib-ii) is selected from:

[0095] [ka]

[0096] In some embodiments of the compound of Formula (Ib-ii), R1 is C1-C4 alkyl. In such embodiments, the compound of Formula (Ib-ii) is selected from:

[0097] [ka]

[0098] In certain embodiments, the compound of Formula (Ib) is a compound of Formula (Ia-iii).

[0099] [ka]

[0100] In some embodiments of a compound of Formula (Ib-iii), R2 is -OR4. In some embodiments of a compound of Formula (Ib-iii), R1 is H. In such embodiments, the compound of Formula (Ib-iii) is selected from:

[0101] [ka]

[0102] In some embodiments of the compound of Formula (Ib-iii), R1 is C1-C4 alkyl. In such embodiments, the compound of Formula (Ib-iii) is selected from:

[0103] [ka]

[0104] In some embodiments of a compound of Formula (Ib), R2 is -NR5R6 or -NO2. In some embodiments of a compound of Formula (Ib), R2 is -NR5R6 or -NO2. In such embodiments, the compound of Formula (Ib) is selected from:

[0105] [ka]

[0106] Throughout the specification and claims, a particular chemical formula or name is intended to encompass all tautomers, homologs, optical isomers and stereoisomers, as well as racemic mixtures where such isomers and mixtures exist.

[0107] Certain compounds of the present disclosure may have asymmetric carbon atoms (optical or chiral centers) or double bonds, and enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, and individual isomers, which may be defined in terms of absolute stereochemistry as (R)- or (S)-, or D- or L-, of amino acids, are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include compounds known in the art to be too unstable to synthesize and / or isolate. The present disclosure is intended to include compounds in racemic, scale, and optically pure form. Optically active (R)- and (S)-isomers, or D- and L-isomers, can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0108] Unless otherwise stated, structures depicted herein are intended to include all stereochemical forms of the structure, i.e., the R and S configurations of each asymmetric center. Accordingly, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0109] It will be apparent to one of ordinary skill in the art that certain compounds of the present disclosure may exist as tautomers, and all such tautomers of the compounds are within the scope of the present disclosure. As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0110] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures in which hydrogen is replaced by deuterium or tritium, or a carbon is replaced by a C- or C-enriched carbon are within the scope of this disclosure.

[0111] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain unnatural proportions of atomic isotopes, such as tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.

[0112] In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Furthermore, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0113] The term "protecting group" refers to a chemical moiety that blocks some or all of the reactive moieties of a compound, preventing them from participating in a chemical reaction until the protecting group is removed. For example, the moieties are listed and described in T.W. Greene, P.G.M. Buts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons (1999). When different protecting groups are used, it can be advantageous to be able to remove each (different) protecting group in a different manner. Protecting groups that are cleaved under completely different reaction conditions allow for different removal of such protecting groups. For example, protecting groups can be removed by acid, base, and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal, and tert-butyldimethylsilyl can be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with the acid-labile, hydrogenolysis-removable Cbz group and the base-labile Fmoc group. Carboxylic acid and hydroxy reactive moieties can be blocked with base labile groups such as methyl, ethyl, acetyl, etc. in the presence of amines blocked with acid labile groups such as tert-butyl carbamate, or carbamates that are stable to both acid and base but removable by hydrolysis.

[0114] Carboxylic acid and hydroxy reactive moieties can also be blocked with hydrolytically removable protecting groups such as benzyl groups, while amine groups capable of hydrogen bonding with acids can be blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties can be blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while coexisting amino groups can be blocked with fluoride-labile silyl carbamates.

[0115] Allyl-blocking groups are useful when acid- and base-protecting groups are present. This is because acid-blocking groups are stable and can be subsequently removed by metal or π-acid catalysts. For example, allyl-blocked carboxylic acids can be deprotected by palladium(O)-catalyzed reactions in the presence of acid-labile t-butyl carbamate or base-labile acetate amine protecting groups. Another form of protecting group is a resin to which a compound or intermediate can be attached. As long as the residue is attached to the resin, the functional group is blocked and cannot react. Once released from the resin, the functional group becomes reactive.

[0116] Common blocking / protecting groups include, but are not limited to, the following moieties:

[0117] [ka]

[0118] B. Methods of Treating STING-Related Diseases, Disorders, or Conditions In some embodiments, the presently disclosed subject matter provides a method of modulating stimulator of interferon genes (STING), the method comprising contacting a cell with a compound of Formula (I), Formula (Ia), Formulas (I-ai-iii), Formula (Ib), and Formulas (I-bi-iii).

[0119] As used herein, the term "contacting" refers to placing under conditions that result in direct physical bonding, including contact between solid and solid, liquid and liquid, liquid and solid, or liquid or solid and cell or tissue, whether in vitro or in vivo. Contacting can occur with isolated cells or tissues in vitro or by administration to a subject in vivo.

[0120] In some embodiments, the presently disclosed subject matter provides a method of activating or stimulating STING, the method comprising contacting a cell with a compound of Formula (I), Formula (Ia), Formulas (I-ai-iii), Formula (Ib), and Formulas (I-bi-iii).

[0121] In some embodiments, the compounds of the present disclosure may be "STING modulators." As used herein, the term "STING modulator" refers to an agent that can either activate or downregulate the STING pathway. A "STING modulator" may be an agonist or an antagonist.

[0122] As used herein, the term "agonist" and its grammatical variations refer to an agent, such as a small molecule or protein, that binds to a protein and causes, enhances, or increases (to a statistically significant extent) a specific biological effect of the protein. In certain embodiments, an agonist activates a receptor. Activation can be full, partial, or inverse. Full agonists are highly potent, producing a full response while occupying a relatively low percentage of the receptor. Partial agonists are less potent than full agonists, producing submaximal activation even when occupying the entire receptor, and therefore fail to produce a maximal response regardless of the applied concentration. Inverse agonists produce the opposite effect of an agonist, but bind to the same receptor binding site as an agonist. Agonists can be naturally occurring compounds or artificially synthesized compounds.

[0123] For example, an agonist of a STING pathway protein is a compound that enhances the natural activity (either upstream or downstream) of a STING pathway protein. In particular, in some embodiments, compounds of the present disclosure activate STING-mediated signaling in human cells.

[0124] In some embodiments, the subject matter of the present disclosure provides a "STING antagonist." As used herein, the term "STING antagonist" refers to a compound disclosed herein that inhibits the STING pathway. In some embodiments, the STING antagonist directly interacts with the STING protein. In some embodiments, the STING antagonist interacts with downstream components of the STING pathway, such as cyclic GMP-AMP synthase (cGAS), TBK1, IRF3, or IFN-β. In some embodiments, the STING antagonist reduces the level or activity of one or more components of the STING pathway, such as STING, cyclic GMP-AMP synthase (cGAS), TBK1, IRF3, and / or IFN-β.

[0125] In some embodiments, the presently disclosed subject matter provides a method for treating a STING-associated disease, disorder, or condition, the method comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula (I), Formula (Ia), Formulas (I-ai-iii), Formula (Ib), and Formulas (I-bi-iii).

[0126] In certain embodiments, the disease, disorder, or condition is selected from cancer, a bacterial infection, a viral infection, a fungal infection, a parasitic infection, an immune-mediated disease, a central nervous system disease, a peripheral nervous system disease, a neurodegenerative disease, a mood disorder, a sleep disorder, a cerebrovascular disease, a peripheral arterial disease, and a cardiovascular disease.

[0127] In particular embodiments, the disease, disorder, or condition is cancer, hi more particular embodiments, the cancer is selected from colon cancer, aerodigestive squamous cell carcinoma, lung cancer, brain cancer, liver cancer, gastric cancer, sarcoma, leukemia, lymphoma, multiple myeloma, ovarian cancer, uterine cancer, breast cancer, melanoma, prostate cancer, bladder cancer, pancreatic cancer, and renal cancer.

[0128] In some embodiments, the methods of the present disclosure further comprise administering a second therapeutic agent, hi certain embodiments, the second therapeutic agent is selected from an antiviral agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-cancer vaccine, and a hormone therapy.

[0129] In certain embodiments, the second therapeutic agent is selected from a B7 costimulatory molecule, interleukin-2, interferon-g, GM-CSF, a CTLA-4 antagonist, an IDO inhibitor or an IDO / TDO inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, an OX-40 ligand, a LAG3 inhibitor, a CD40 ligand, a 41BB / CD137 ligand, a CD27 ligand, bacillus Calmette-Guerin (BCG), liposomes, alum, Freund's complete or incomplete adjuvant, a TLR agonist, and detoxified endotoxin.

[0130] In more specific embodiments, the CTLA-4 antagonist is ipilimumab or tremilimumab.

[0131] In more specific embodiments, the IDO inhibitor or IDO / TDO inhibitor is epacadostat or GDC-o919.

[0132] In more specific embodiments, the PD-1 inhibitor is selected from nivolumab, pembrolizumab, pidilizumab, AMP-224, and MDX-1106.

[0133] In more specific embodiments, the PD-L1 inhibitor is selected from durvalumab, avelumab, and atezolizumab.

[0134] In more specific embodiments, the TLR agonist is selected from poly I:C, MPL, LPS, bacterial flagellin, imiquimod, resiquimod, loxoribine, and CpG dinucleotides.

[0135] As used herein, the term "treatment" can include reversing, alleviating, inhibiting the progression of, preventing, or reducing the likelihood of a disease, disorder, or condition to which the term applies, or one or more symptoms or signs of the disease, disorder, or condition. Prevention refers to not causing a disease, disorder, condition, or its symptoms or signs, or worsening of its severity. Thus, the compounds of the present disclosure can be administered prophylactically to prevent or reduce the occurrence or recurrence of a disease, disorder, or condition.

[0136] While the "subject" treated by many embodiments of the disclosed methods is desirably a human subject, it should be understood that the methods described herein are effective on all vertebrate species intended to be encompassed by the term "subject." Accordingly, a "subject" can include a human subject for medical purposes, such as treatment of an existing condition or disease or prophylactic treatment to prevent the onset of a condition or disease, or an animal subject for medical, veterinary, or developmental purposes. Suitable animal subjects include mammals, including, but not limited to, primates such as humans, monkeys, and apes; bovines, such as cows and oxen; ovines, such as goats; caprines, such as pigs and domestic pigs; equines, such as horses, donkeys, and zebras; felines, including wild and domestic cats; canines, including dogs; lagomorphs, including rabbits, hares, and the like; rodents, including mice, rats, and the like. The animal may be a transgenic animal. In some embodiments, the subject is a human, including, but not limited to, a fetal, neonatal, infant, juvenile, or adult subject. Additionally, a "subject" can also include a patient suffering from or suspected of suffering from a condition or disease. Thus, the terms "subject" and "patient" are used interchangeably herein. The term "subject" also refers to an organism, tissue, cell, or collection of cells from a subject.

[0137] Generally, an "effective amount" of an active agent or drug delivery device refers to the amount necessary to elicit a desired biological response. As one skilled in the art would understand, the effective amount of an agent or device can vary depending on factors such as the desired biological endpoint, the agent being delivered, the composition of the pharmaceutical composition, the target tissue, and the like.

[0138] The term "combination" is used in the broadest sense and means that a subject is administered at least two agents, more specifically, a compound described herein and at least one other therapeutic agent. More specifically, the term "combination" refers to the simultaneous administration of two (or more) active agents, for example, to treat a single medical condition. As used herein, the active agents can be administered in combination in a single dosage form, simultaneously in separate dosage forms, or in separate dosage forms that are administered alternately or sequentially on the same or different days. In one embodiment of the presently disclosed subject matter, the active agents are administered in combination in a single dosage form. In another embodiment, the active agents are administered in separate dosage forms (e.g., when it is desired to vary the amount of one agent while maintaining the amount of the other). The single dosage form may include an additional active agent for the treatment of a medical condition.

[0139] Additionally, the compounds described herein may be administered alone or in combination with one or more therapeutic agents to enhance the stability of the compound, in certain embodiments facilitate administration of pharmaceutical compositions containing them, increase dissolution or dispersion, increase inhibitory activity, provide adjunctive therapy, or the like, including other active ingredients, alone or in combination with other therapeutic agents. Advantageously, such combination therapy may require lower doses of conventional therapeutic agents, thereby avoiding potential toxicity and side effects that may occur when those agents are used as monotherapies.

[0140] The timing of administration of the compound described herein and at least one additional therapeutic agent can be changed, as long as the beneficial effect of the combination of these drugs is achieved.Therefore, the term "in combination" refers to administering the compound described herein and at least one additional therapeutic agent simultaneously, sequentially, or in combination.Therefore, the subject who is administered the combination of the compound described herein and at least one additional therapeutic agent can administer the compound and at least one additional therapeutic agent simultaneously (i.e., simultaneously) or at different times (i.e., sequentially, in any order, on the same day or different days), as long as the combined effect of both drugs is achieved in the subject.

[0141] When administered sequentially, the agents may be administered within 1, 5, 10, 30, 60, 120, 180, 240 minutes, or more of each other. In other embodiments, sequentially administered agents may be administered within 1, 5, 10, 15, 20 days, or more of each other. When a compound described herein and at least one additional therapeutic agent are administered simultaneously, they may be administered to a subject as separate pharmaceutical compositions, each containing either the compound or the at least one additional therapeutic agent, or they may be administered to a subject as a single pharmaceutical composition containing both agents.

[0142] When administered in combination, the effective concentration of each agent that induces a particular biological response may be lower than the effective concentration when each agent is administered alone, thereby reducing the dosage of one or more agents compared to the dosage required when the agent is administered as a single agent. The effects of multiple agents are not necessarily additive or synergistic, but may be additive. Agents may be administered multiple times.

[0143] In some embodiments, administering two or more agents in combination can result in a synergistic effect. As used herein, the terms "synergy," "synergistic," "synergistically," and derivatives thereof, such as "synergistic effect" or "synergistic combination" or "synergistic composition," refer to a situation in which the biological activity of a combination of a compound described herein and at least one additional therapeutic agent is greater than the sum of the biological activities of each agent when administered individually.

[0144] Synergy can be expressed in terms of the "synergy index (SI)," which can generally be determined from the ratio determined by the method described in F.C. Kull et al., Applied Microbiology 9, 538 (1961), according to the following formula: Q a / Q A +Q b / Q B = Synergy Index (SI)

[0145] Q A is the concentration of component A acting alone to produce the endpoint relative to component A, Q a is the concentration of component A in the mixture that produced the endpoint, Q B is the concentration of component B acting alone to produce the endpoint relative to component B, Q b is the concentration of component B in the mixture that produced the endpoint. Generally, Q a / Q A and Q b / Q BA sum greater than 1 indicates antagonism, a sum equal to 1 indicates additive action, and a sum less than 1 demonstrates synergy. The lower the SI, the greater the synergistic effect exhibited by that particular mixture. Thus, a "synergistic combination" exhibits greater activity than would be expected based on the observed activity of the individual components when used alone. Furthermore, a "synergistically effective amount" of a component refers to the amount of that component needed to elicit a synergistic effect, for example, with another therapeutic agent present in the composition.

[0146] C. Pharmaceutical Compositions and Administration In another aspect, the present disclosure provides pharmaceutical compositions comprising one of the compounds described herein, alone or in combination with one or more additional therapeutic agents in a pharmaceutically acceptable excipient. Those skilled in the art will recognize that pharmaceutical compositions include pharmaceutically acceptable salts of the compounds. Pharmaceutically acceptable salts are generally well known to those skilled in the art and include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituent moieties found on the compounds described herein. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent, or by ion exchange, replacing one base counterion (base) in the ionic complex with another. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts.

[0147] When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent, or by ion exchange, whereby one acidic counterion (acid) in the ionic complex is replaced by another acid. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate acid, diphosphoric acid, sulfuric acid, monohydrogensulfate acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, trifluoroacetic acid (TFA), and the like. Also included are salts of amino acids, such as arginic acid, and salts of organic acids, such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0148] Thus, pharmaceutically acceptable salts suitable for use in the presently disclosed subject matter include, for example, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolic acid arsanilate, hexylresorcinate, hydrabamine, hydrobromide, Examples of suitable salts include, but are not limited to, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, acetate, succinate, sulfate, tannate, tartrate, or teoclate. These salts are described in Lippincott, Williams & Wilkins (2000). For therapeutic and / or diagnostic applications, the compounds of the present disclosure may be formulated for various modes of administration, including systemic, topical, or local administration. Techniques and formulations are generally described in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000).

[0149] These agents may be formulated into liquid or solid dosage forms and administered systemically or locally, depending on the specific condition being treated. The agents may be delivered, for example, in time-release or sustained-release forms, as known to those skilled in the art. Formulation and administration techniques are described in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000). Suitable routes of administration include oral, buccal, inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration, parenteral administration, including intramuscular, subcutaneous, and intramedullary injection, as well as intrathecal, direct intraventricular, intravenous, intraarticular, intrasternal, intrasynovial, intrahepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injection, or other modes of administration.

[0150] For injection, the agent of the present invention can be prepared and diluted in an aqueous solution such as Hank's solution, Ringer's solution, or physiologically compatible buffer such as physiological saline buffer. For such transmucosal administration, a penetrant appropriate to the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art.

[0151] It is within the scope of the present disclosure to use a pharmaceutically acceptable inert carrier to formulate the compounds disclosed herein into dosages suitable for systemic administration for the practice of the present disclosure. By appropriately selecting the carrier and employing an appropriate manufacturing method, the compositions of the present disclosure, particularly those formulated as solutions, can be administered parenterally, such as by intravenous injection. The compounds can be easily formulated into dosages suitable for oral administration using pharmaceutically acceptable carriers well known in the art. With such carriers, the compounds of the present disclosure can be formulated into tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral ingestion by a treatment subject (e.g., a patient).

[0152] For nasal or inhalation delivery, the agents of the present disclosure may also be formulated by methods known to those skilled in the art, and may include, for example, but not limited to, solubilizing, diluting, or dispersing agents such as saline, preservatives such as benzyl alcohol, absorption enhancers, and fluorocarbons.

[0153] In certain embodiments, the compound of Formula (I-III) is administered intranasally in a form selected from the group consisting of a nasal spray, nasal drops, powder, granules, sachets, tablets, aerosols, pastes, creams, gels, ointments, salves, foams, pastes, lotions, creams, oil suspensions, emulsions, solutions, patches, and sticks.

[0154] As used herein, the term "administration by the intranasal route" refers to administration via the nasal structure. The small molecule compounds of formula (I) of the present disclosure have been found to be much more effective in penetrating the brain and peripheral nervous system when administered intranasally.

[0155] As used herein, the term "peripheral nervous system" includes the part of the nervous system that comprises the nerves and ganglia outside the brain and spinal cord. The peripheral nervous system connects the central nervous system to the limbs and organs and acts as a communication relay between the brain and the extremities. The small molecule compounds of formula (I) of the present disclosure can access the peripheral nervous system via the blood.

[0156] Intranasal administration generally allows active drugs to avoid first-pass metabolism, thereby improving the bioavailability of the active drug. Such delivery can offer several advantages over other drug delivery methods, including, but not limited to, increased onset of action, reduced dosage requirements, enhanced efficacy, and improved safety profiles of the active drug. For example, tablet dosage forms enter the bloodstream through the gastrointestinal tract, whereby the drug is degraded by gastric acid, bile, digestive enzymes, and other first-pass metabolic effects. As a result, tablet formulations often require larger doses and generally have a delayed onset of action. Nasal administration of drugs can also promote compliance, especially for pediatric patients, elderly patients, patients with neurodegenerative diseases, or other patients who have difficulty swallowing, such as patients suffering from nausea or swallowing disorders, such as those undergoing chemotherapy.

[0157] Intranasal ("in" or "IN") administration of drugs to a subject can facilitate delivery of drugs to the brain and / or peripheral nervous system. Such administration is non-invasive and offers several advantages, including avoidance of first-pass clearance in the liver, rapid onset of action, frequent self-administration, and easy dose adjustment. Small molecules have the additional advantage of intracellular absorption through the nasal epithelium, after which these molecules can enter the CNS directly via olfactory or trigeminal nerve-related pathways and be transported directly to the brain upon intranasal administration.

[0158] For intranasal delivery, the pharmaceutical composition may contain, in addition to the active ingredient, a suitable pharmaceutically acceptable carrier, including excipients and adjuvants that facilitate the processing of the active compound into a formulation that can be used as a medicine.The medicaments of the present disclosure may be formulated by methods known to those skilled in the art, and may include, but are not limited to, solubilizing, diluting, or dispersing agents such as saline, preservatives such as benzyl alcohol, absorption enhancers, and fluorocarbons.Formulations optimized for intranasal delivery may include the addition of penetration enhancers (mucoadhesives, nanoparticles, etc.) and the use in combination with intranasal drug delivery devices (e.g., devices that target the upper nasal cavity and provide controlled particle dispersion with aerosolized particles).

[0159] In particular, polymer-based nanoparticles including chitosan, maltodextrin, polyethylene glycol (PEG), polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), and PAMAM dendrimers, gels including poloxamers, and lipid-based formulations including glycerol monocaprate (Capmul™), a mixture of mono-, di-, and triglycerides, mono- and di-fatty acid esters of PEG (Labrafil™), palmitic acid, glycerol monostearate, and phospholipids may be used for intranasal administration of the compounds of formula (I) of the present disclosure.

[0160] The compounds of formula (I) disclosed in the present invention can also be administered intranasally via mucoadhesives. Mucoadhesion is generally defined as adhesion between two substances, at least one of which is a mucosal surface. More specifically, mucoadhesion is the interaction between a mucinous surface and a synthetic or natural polymer. Mucoadhesive dosage forms can be designed to enable long-term retention at the application site and can control the drug release rate to improve therapeutic outcomes. Application of dosage forms to mucosal surfaces can be beneficial for drug molecules that are not suitable for oral administration, such as those that undergo acid degradation or extensive first-pass metabolism. Mucoadhesive materials suitable for use in the nasal administration of the compounds of formula (I) disclosed herein include, but are not limited to, soluble cellulose derivatives such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose (MC), carboxymethylcellulose (CMC), and insoluble cellulose derivatives such as ethylcellulose, microcrystalline cellulose (MCC), starch (e.g., Amioca®), polyacrylates such as polyacrylic acid (e.g., Carbopol® 974P), polycarbophil, hyaluronic acid, functionalized mucoadhesive polymers such as Amberlite resin, and chitosan (2-amino-2-deoxy-(1→4)-β-d-glucopyranan) preparations and derivatives thereof.

[0161] In some embodiments, the formulation also includes a penetration enhancer. As used herein, the term "penetration enhancer" refers to a substance that facilitates delivery of a drug through mucosal tissue. This term includes chemical enhancers that, when applied to mucosal tissue, make the tissue more permeable to the drug. Permeability enhancers include, but are not limited to, dimethyl sulfoxide (DMSO), hydrogen peroxide (H2O2), propylene glycol, oleic acid, cetyl alcohol, benzalkonium chloride, sodium lauryl sulfate, isopropyl myristate, Tween 80, dimethylformamide, dimethylacetamide, sodium lauroyl sarcosinate, sorbitan monolaurate, methylsulfonylmethane, azone, terpenes, phosphatidylcholine-dependent phospholipase C, triacylglycerol hydrolase, acid phosphatase, phospholipase A2, concentrated saline (e.g., PBS and NaCl), polysorbate 80, polysorbate 20, sodium dodecanoate (C12), sodium caprate (C10) and / or sodium palmitate (C16), tert-butylcyclohexanol (TBCH), and α-terpinol.

[0162] In some embodiments, intranasal administration is achieved via a ViaNase™ device (Kurve Technology, Inc.).

[0163] Pharmaceutical compositions suitable for use in the present disclosure include compositions containing the active ingredient in an amount effective to achieve its intended purpose. Determination of an effective amount is within the capabilities of one of ordinary skill in the art, especially in light of the detailed disclosure provided herein. Generally, compounds according to the present disclosure are effective over a wide dosage range. For example, for adult treatment, dosages of 0.01-1000 mg, 0.5-100 mg, 1-50 mg per day, 5-40 mg per day, etc. are examples of dosages that may be used. Dosages are not limited to 10-30 mg per day. The exact dosage will depend on the route of administration, the dosage form of the compound, the subject being treated, the subject's body weight, the bioavailability of the compound, the adsorption, distribution, metabolism, and excretion (ADME) toxicity of the compound, and the preference and experience of the attending physician.

[0164] These pharmaceutical compositions may contain, in addition to the active ingredient, a suitable pharmaceutically acceptable carrier, including excipients and adjuvants that facilitate the processing of the active compound into a preparation that can be used as a medicine. Preparations formulated for oral administration may be in the form of tablets, sugar-coated tablets, capsules, or solutions.

[0165] Oral pharmaceutical preparations can be obtained by combining active compounds with solid excipients, grinding the resulting mixture as needed, adding suitable excipients as needed, and then processing the granulated mixture to obtain tablets or sugar-coated tablet cores.Suitable excipients are, in particular, fillers such as sugars including lactose, sucrose, mannitol, or sorbitol, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (CMC), and / or cellulose preparations such as polyvinylpyrrolidone (PVP: povidone).If necessary, disintegrants can be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate.

[0166] The core of the sugar-coated tablet is provided with a suitable coating.For this purpose, concentrated sugar solutions are used, which may contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures as needed.For identification or to characterize different combinations of dosages of active compounds, dyes or pigments may be added to the tablet or sugar-coated tablet coating.

[0167] Pharmaceuticals that can be used for oral administration include push-fit capsules made of gelatin and sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules may contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally, a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oils, liquid paraffin, or liquid polyethylene glycol (PEG). Additionally, stabilizers may be added.

[0168] Following long-standing patent law convention, the terms "a," "an," and "the" refer to "one or more" when used in this application, including the claims. Thus, for example, a reference to "a subject" includes a plurality of subjects unless the context clearly dictates otherwise (e.g., a plurality of subjects).

[0169] Throughout this specification and claims, the terms "comprises," "comprises," and "comprising" are used in a non-exclusive sense unless the context otherwise requires. Similarly, the term "comprises" and its grammatical variations are intended to be non-limiting, and the recitation of items in a list does not exclude other similar items that may be substituted for or added to the listed items.

[0170] For purposes of this specification and the appended claims, unless otherwise indicated, all numbers expressing quantities, sizes, dimensions, proportions, shapes, formulations, parameters, percentages, quantities, properties, and other numerical values used in the specification and claims are to be understood as being modified in all instances by the term "about," even if the value, amount, or range does not explicitly state otherwise. Accordingly, unless otherwise indicated, the numerical parameters set forth in the following specification and appended claims are not, and need not be, exact, but may be approximate and / or may be made larger or smaller as necessary to reflect tolerances, conversion factors, rounding, measurement error, and the like, as well as other factors known to those of ordinary skill in the art, depending upon the desired properties sought to be obtained by the subject matter of the present disclosure. For example, the term "about" when referring to a value can be meant to encompass variations in some embodiments of ±100%, in some embodiments of ±50%, in some embodiments of ±20%, in some embodiments of ±10%, in some embodiments of ±5%, in some embodiments of ±1%, in some embodiments of ±0.5%, and in some embodiments of ±0.1% from the specified amount, as appropriate for practicing the disclosed methods or using the disclosed compositions.

[0171] Furthermore, the term "about," when used in connection with one or more numerical values or numerical ranges, is understood to refer to all such numerical values, including all numerical values within the range, and modifies that range by extending the boundaries above and below the numerical values set forth. The recitation of numerical ranges by endpoints includes all numbers contained within that range, including, for example, integers and fractions thereof (e.g., recitation of 1 to 5 includes 1, 2, 3, 4, 5, as well as fractions thereof such as 1.5, 2.25, 3.75, 4.1, etc.), and any range within that range. [Example]

[0172] The following examples are included to provide guidance to those skilled in the art for practicing representative embodiments of the presently disclosed subject matter. Given this disclosure and the general level of skill in the art, those skilled in the art will appreciate that the following examples are intended to be merely illustrative and that numerous changes, modifications, and variations can be adopted without departing from the scope of the presently disclosed subject matter. The synthetic descriptions and specific examples below are for illustrative purposes only and should not be construed in any way as limiting the ability to prepare the disclosed compounds by other methods. [Example]

[0173] (Synthesis of Compounds of Formula (I))

[0174] [ka]

[0175] (Methylation (Synthesis of Compound 1)) To a stirred solution of the core molecule (1.0 eq.) in MeOH (10 mL), 2-3 drops of H2SO4 were added, and the mixture was refluxed for 3 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated, diluted with water, extracted with DCM, and the organic layer was washed with brine and dried over anhydrous MgSO4. The organics were evaporated under reduced pressure to give the crude product, which was used in the next step without further purification.

[0176] (Allylation (synthesis of compound 2)) To a stirred solution of compound 1 (1.0 eq.) in DMF (10 mL) was added NaH (2.0 eq.), followed by the addition of substituted allylic bromide (1.2 eq.), and the mixture was stirred at room temperature for 0.5–1 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc, and the organic layer was washed with brine and dried over anhydrous MgSO4. The organics were evaporated under reduced pressure to give the crude product, which was used in the next step without further purification.

[0177] (Ester Hydrolysis (Synthesis of Compound 3)) Method 1: To a stirred solution of compound 2 (1 mmol) in a mixture of MeOH and dioxane (1:2; 9 mL) was added 1.6% NaOH (3 mL) at room temperature. The reaction was stirred for 2 hours. After completion of the reaction, water was added. The aqueous solution was acidified with 7% HCl and then extracted with EtOAc. The organic layer was dried and evaporated to dryness to give the crude product. This crude product was used in the next step without further purification.

[0178] Method 2: To a stirred solution of compound 2 (1 mmol) in EtOH (20 mL) was added 1 M NaOH (10 mL) at room temperature. The reaction was stirred for 2 hours. After the reaction was complete, water was added. The aqueous solution was acidified with 1 M HCl and then extracted with EtOAc. The organic layer was dried and evaporated to dryness to give the crude product. This crude product was used in the next step without further purification.

[0179] (Amidation (Synthesis of Compound 4)) To a stirred solution of carboxylic acid 3 (1 eq.) in a suitable solvent, such as DCM or DMF (10 mL), was added amine (1.3 eq.) and a coupling reagent, i.e., HATU (2.0 eq.), followed by dropwise addition of TEA (2.0 eq.). The mixture was stirred at room temperature for 2–3 h. When TLC indicated the reaction was complete, the reaction mixture was diluted with ice-cold water and extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure to give the crude material, which was purified by column chromatography using a mixture of EtOAc in heptane as the eluent to give the compound (70–80% yield). Addition of the crude product to ice-cold water precipitated some of the compound. The precipitate was collected using filtration techniques. After washing with water three times, the product was purified using column chromatography.

[0180] (Deprotection Reaction (Synthesis of 5)) The corresponding compound 4 (1 eq.) was dissolved in dry dichloromethane using a hot-dried three-neck round-bottom flask equipped with a magnetic stirrer. The solution was cooled to approximately -20 °C using ice and acetone, and then boron tribromide solution (1 M in CHCl, 3 eq.) was added dropwise. After the addition of the deprotecting agent, the ice bath was removed and the reaction mixture was allowed to warm to room temperature and stirred for 1–4 h. The reaction was quenched by adding ice-cold water (60 mL, very slowly), and the product was extracted with dichloromethane (20 mL). The combined organic phases were dried over sodium sulfate, and the solvent was evaporated under vacuum. Finally, the product was purified by column chromatography using a mixture of ethyl acetate and heptane to give the corresponding hydroxylated compound.

[0181] (Alkylation (Synthesis of 6)) To a solution of compound 5 (1 eq.) in ACN (10 mL) was added K2CO3 (5.0 eq.), followed by alkyl bromide (1.2 eq.), and the mixture was refluxed for 2–3 h. When TLC showed the reaction was complete, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure to give the crude material, which was purified by column chromatography using a mixture of EtOAc in heptane as the eluent to give the compound.

[0182] Representative compounds of formula (I) are shown in Table 1.

[0183] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Example]

[0184] (THF luciferase activity)

[0185] STING molecules were screened to investigate the specificity of the human STING pathway. The THF-ISRE, THF-ISRE STING knockout (KO), and THF-ISRE TRIF / MAVS KO cell lines contain an inducible luciferase reporter construct that signals upon IRF3 activation. The THF-ISRE STING KO cell line only utilizes the TRIF / MAVS pathway to activate IRF3. The THF-ISRE TRIF / MAVS KO cell line only utilizes the STING pathway for IRF3 activation. Luciferase activity was determined by measuring luminescence.

[0186] The three cell lines were maintained in T-75 flasks containing DMEM / high glucose (Cytiva™, Logan, UT), Pen / Strep / glutamine (Hyclone™, Logan, UT), and 10% heat-inactivated FBS (Hyclone™, Logan, UT).

[0187] For the primary screen, THF-ISRE cells were seeded at a density of 15,000 cells / well in opaque, flat-bottom 96-well tissue culture plates. The cells were cultured for 36 hours and then treated with compounds formulated in DMSO (Sigma™, St. Louis, MO). Prior to treatment, the cell culture medium was changed to 2% FBS in DMEM containing antibiotics. Compounds were serially diluted in two-fold increments starting at 50 μM and ending at 0.391 μM. Luciferase activity was measured after 18 hours by adding the Steady-Glo Luciferase Assay System (Promega™, Madison, WI) at a 1:1 ratio and reading the luminescence on a plate reader. Compounds that showed luciferase activity underwent secondary screening.

[0188] In the secondary screen, we used the same procedure as above with THF-ISRE STING KO cells and THF-ISRE TRIF / MAVS KO cells. Compounds specific for human STING showed luciferase activity in THF-ISRE TRIF / MAVS KO cells alone.

[0189] Initial screening demonstrated that representative compounds of Formula (I), INI-3067, INI-3069, INI-3070, and INI-3071, exhibited positive luciferase activity. Referring to Figure 1, secondary screening in THF TRIF / MAVS KO cells demonstrated that INI-3067, INI-3069, INI-3070, and INI-3071 use the STING pathway for luciferase activity.

[0190] FIG. 2 shows the THF luciferase activity of compounds INI-3077, INI-3078, INI-3079, INI-3080, INI-3067, and INI-3069.

[0191] Figure 3 shows the luciferase activity of THF STING alone for compounds INI-3077, INI-3078, INI-3079, INI-3080, INI-3081, and INI-3067.

[0192] FIG. 4 shows the THF luciferase activity of compounds INI-3067, INI-3111, INI-3112, INI-3069, and INI-3110.

[0193] FIG. 5 shows the THF luciferase activity of compounds INI-3071, INI-3105, INI-3106, INI-3107, INI-3108, and INI-3109.

[0194] FIG. 6 shows the THF luciferase activity of compounds INI-3070, INI-3074, INI-3071, and INI-3075.

[0195] FIG. 7 shows the THF luciferase activity of compounds INI-3076, INI-3082, INI-3083, INI-3084, INI-3085, INI-3086, and INI-3069.

[0196] Figure 8 shows the THF STING luciferase activity of compounds INI-3076, INI-3082, INI-3083, INI-3084, INI-3085, and INI-3086.

[0197] FIG. 9 shows the THF luciferase activity of compounds INI-3087, INI-3088, INI-3089, INI-3090, INI-3091, INI-3092, and INI-3069.

[0198] Figure 10 shows the luciferase activity of THF STING alone for compounds INI-3087, INI-3088, INI-3089, INI-3090, INI-3091, and INI-3092.

[0199] FIG. 11 shows the THF luciferase activity of compounds INI-3093, INI-3094, INI-3095, INI-3096, INI-3103, INI-3104, and INI-3069.

[0200] Figure 12 shows the luciferase activity of THF STING alone for compounds INI-3093, INI-3094, INI-3095, INI-3096, INI-3103, and INI-3104.

[0201] (References) All publications, patent applications, patents, and other references mentioned herein are indicative of the level of ordinary skill in the art to which the subject matter of this disclosure pertains. All publications, patent applications, patents, and other references are incorporated herein by reference to the same extent as if each individual publication, patent application, patent, and other reference were specifically and individually indicated to be incorporated by reference. Although numerous patent applications, patents, and other references are referenced herein, it should be understood that such reference does not constitute an admission that any of these documents form part of the general knowledge in the art. [Prior art documents] [Non-patent literature]

[0202] [Non-Patent Document 1] DCPryde, S. Middya, M. Banerjee, R. Shrivastava, S. Basu, R. Ghosh, DBYadav, A. Surya, The discovery of potent small molecule activators of human STING, Eur. J. Med. Chem., 209, 112869 (2021). [Non-patent document 2] M. Banerjee, S. Middya, R. Shrivastava, S. Basu, R. Ghosh, DCPryde, et al., G10 is a direct activator of human STING, PLoS ONE 15(9), e0237743(2020). [Patent documents]

[0203] [Patent Document 1] U.S. Patent Application Publication No. 2020 / 0138827, SMALL MOLECULE MODULATORS OF HUMAN STING, Banerjee et al., published May 7, 2020. [Patent Document 2] U.S. Patent Application Publication No. 2017 / 0146519, STING AGONISTS AND METHODS OF SELECTED STING AGONISTS, DeFilippis et al., published May 25, 2017.

[0204] Although the foregoing subject matter has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will understand that certain changes and modifications may be practiced within the scope of the appended claims.

Claims

【Request 1】 【Chemical 1】 n is 1 or 2; X is S, O, NR ｘ , and C.R. ｘ１ R ｘ２ and R ｘ , R ｘ１ , and R ｘ２ are each independently H and C １ -C ４ alkyl, A is, 【Chemistry 2】 and R １ is H or C １ -C ４ is alkyl, R ２ is -OR ４ , -NR ５ R ６ , and -NO ２ and R ４ is H or C １ -C ２０ alkyl, and R ５ and R ６ are each independently H or C １ -C ４ is alkyl, Each R ３ can be the same or different and are each halogen; (i) X is S, A is 2,4,6-trifluorophenyl, n is 2, R ３ is F at the 2- and 6-positions of ring B, R ４ is H or C １ or (ii) X is S, A is 2,4,6-trifluorophenyl, n is 2, and R ３ is F at the 2-position of ring B, R ４ is C １ It cannot be an alkyl Compounds of formula (I) and pharmaceutically acceptable salts thereof.

2. The compound of formula (I) is 【Chemistry 3】 The compound of claim 1 which is a compound of formula (I').

3. The compound of formula (I') is 【Chemistry 4】 3. The compound of claim 2, which is a compound of formula (Ia).

4. The compound of formula (Ia) is 【Chemistry 5】 The compound according to claim 3, which is a compound of formula (Ia-i).

5. R ２ is -OR ４ 5. The compound of claim 4, wherein:

6. R １ The compound of claim 5 , wherein is H.

7. The compound of formula (Ia-i) is 【Chemistry 6】 7. The compound of claim 6, selected from:

8. R １ is C １ -C ４ The compound of claim 5, wherein the compound is alkyl.

9. The compound of formula (Ia-i) is 【Chemistry 7】 9. The compound of claim 8 selected from:

10. The compound of formula (Ia) is 【Chemistry 8】 The compound according to claim 3, which is a compound of formula (Ia-ii).

11. R ２ is -OR ４ 11. The compound of claim 10, wherein:

12. R １ is H.

13. The compound of formula (Ia-ii) is 【Chemistry 9】 13. The compound of claim 12, selected from:

14. R １ is C １ -C ４ The compound of claim 11 , wherein the compound is alkyl.

15. The compound of formula (Ia-ii) is 【Chemistry 10】 15. The compound of claim 14, selected from:

16. The compound of formula (Ia) is 【Chemistry 11】 The compound according to claim 3, which is a compound of formula (Ia-iii).

17. R ２ is -OR ４ 17. The compound of claim 16, wherein:

18. R １ is H.

19. The compound of formula (Ia-iii) is 【Chemistry 12】 19. The compound of claim 18, selected from:

20. R １ is C １ -C ４ 18. The compound of claim 17, wherein the compound is alkyl.

21. The compound of formula (Ia-iii) is 【Chemistry 13】 21. The compound of claim 20 selected from:

22. R ２ is -NR ５ R ６ or - NO ２ 3. The compound of claim 2, wherein:

23. R ２ is -NR ５ R ６ or - NO ２ 5. The compound of claim 4, wherein:

24. The compound of formula (Ia) is 【Chemistry 14】 24. The compound of claim 23 selected from:

25. The compound of formula (I') is 【Chemistry 15】 3. The compound of claim 2, which is a compound of formula (Ib).

26. The compound of formula (Ib) is 【Chemistry 16】 The compound according to claim 25, which is a compound of formula (Ib-i).

27. R ２ is -OR ４ 27. The compound of claim 26, wherein:

28. R １ is H.

29. The compound of formula (Ib-i) is 【Chemistry 17】 29. The compound of claim 28, selected from:

30. R １ is C １ -C ４ 28. The compound of claim 27, wherein the compound is alkyl.

31. The compound of formula (Ib-i) is 【Chemistry 18】 31. The compound of claim 30, selected from:

32. The compound of formula (Ib) is 【Chemistry 19】 The compound according to claim 25, which is a compound of formula (Ib-ii).

33. R ２ is -OR ４ 33. The compound of claim 32, wherein:

34. R １ is H.

35. The compound of formula (Ib-ii) is 【Chemistry 20】 35. The compound of claim 34, selected from:

36. R １ is C １ -C ４ 36. The compound of claim 35, which is alkyl.

37. The compound of formula (Ib-ii) is 【Chemical 21】 37. The compound of claim 36, selected from:

38. The compound of formula (Ib) is 【Chemical 22】 The compound of claim 25, which is a compound of formula (Ia-iii).

39. R ２ is -OR ４ 39. The compound of claim 38, wherein:

40. R １ is H.

41. The compound of formula (Ib-iii) is 【Chemical 23】 41. The compound of claim 40, selected from:

42. R １ is C １ -C ４ 42. The compound of claim 41, which is alkyl.

43. The compound of formula (Ib-iii) is 【Chemistry 24】 43. The compound of claim 42, selected from:

44. R ２ is -NR ５ R ６ or - NO ２ 26. The compound of claim 25, wherein:

45. R ２ is -NR ５ R ６ or - NO ２ 27. The compound of claim 26, wherein:

46. The compound of formula (I-b) is 【Chemistry 25】 46. The compound of claim 45, selected from:

47. 47. A method of modulating stimulator of interferon genes (STING), comprising contacting a cell with a compound of any one of claims 1 to 46.

48. A method of activating or stimulating STING, comprising contacting a cell with a compound described in any one of claims 1 to 46.

49. A method for treating a disease, disorder, or condition associated with STING, comprising administering a therapeutically effective amount of a compound described in any one of claims 1 to 46 to a subject in need of such treatment.

50. 50. The method of claim 49, wherein the disease, disorder, or condition is selected from cancer, a bacterial infection, a viral infection, a fungal infection, a parasitic infection, an immune-mediated disease, a central nervous system disease, a peripheral nervous system disease, a neurodegenerative disease, a mood disorder, a sleep disorder, a cerebrovascular disease, a peripheral arterial disease, and a cardiovascular disease.

51. 51. The method of claim 50, wherein the disease, disorder, or condition is cancer.

52. 52. The method of claim 51, wherein the cancer is selected from colon cancer, aerodigestive squamous cell carcinoma, lung cancer, brain cancer, liver cancer, gastric cancer, sarcoma, leukemia, lymphoma, multiple myeloma, ovarian cancer, uterine cancer, breast cancer, melanoma, prostate cancer, bladder cancer, pancreatic cancer, and renal cancer.

53. 50. The method of claim 49, further comprising administering a second therapeutic agent.

54. 54. The method of claim 53, wherein the second therapeutic agent is selected from an antiviral agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-cancer vaccine, and a hormone therapy.

55. 54. The method of claim 53, wherein the second therapeutic agent is selected from a B7 costimulatory molecule, interleukin-2, interferon-g, GM-CSF, a CTLA-4 antagonist, an IDO inhibitor or an IDO / TDO inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, an OX-40 ligand, a LAG3 inhibitor, a CD40 ligand, a 41BB / CD137 ligand, a CD27 ligand, bacillus Calmette-Guerin (BCG), liposomes, alum, Freund's complete or incomplete adjuvant, a TLR agonist, and detoxified endotoxin.

56. 56. The method of claim 55, wherein the CTLA-4 antagonist is ipilimumab or tremilimumab.

57. 56. The method of claim 55, wherein the IDO inhibitor or IDO / TDO inhibitor is epacadostat or GDC-o919.

58. 56. The method of claim 55, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, pidilizumab, AMP-224, and MDX-1106.

59. The method of claim 55, wherein the PD-1 inhibitor is durvalumab, avelumab, or atezolizumab.

60. 56. The method of claim 55, wherein the TLR agonist is selected from poly I:C, MPL, LPS, bacterial flagellin, imiquimod, resiquimod, loxoribine, and CpG dinucleotides.

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