MONOCYCLIC AGONISTS OF THE INTERFERON GENE STIMULATOR STING

Abstract

The invention provides compounds having interferon gene stimulator (STING) agonist bioactivity that can be used in the treatment of tumors in patients suffering from this condition. The compounds are of formula (IA), formula (I), and formula (II): (see formulas)(IA)(I)(II), wherein the various substituents are as defined herein. Ring A is a 5- or 6-membered heteroaryl comprising 1, 2, or 3 N atoms, unsubstituted or substituted with 1, 2, or 3 groups as defined herein. The compounds for the practice of a method of the invention can be administered orally for systemic exposure, as well as intratumorally. Antitumor therapy using a compound of formula (I) may further comprise the administration of an effective dose of a drug targeting an immune checkpoint.

Description

MONOCYCLIC AGONISTS OF THE INTERFERON GENE STIMULATOR STING This application claims priority to U.S. Patent No. 62 / 889,669 filed on August 21, 2019. BACKGROUND The cGAS-STING signaling pathway plays a fundamental role in the innate immune response mounted by mammalian host cells to eliminate various DNA and RNA viruses. STING (Interferon Gene Stimulator) is an endoplasmic reticulum (ER) resident signaling protein, partially located in mitochondrial-associated membranes, that is widely expressed in both immune and non-immune cell types. In response to cyclic dinucleotides (CDNs), including the 2'-3' cGAMP produced in response to cytosolic DNA by cyclic GMP-AMP synthase (cGAS), STING translocates to the perinuclear region where it rapidly induces type I interferon (IFN) and pro-inflammatory cytokine production in a TBK1- / IRF3-dependent manner. STING has also been found to bind directly to cytosolic DNA, although the physiological relevance of this direct DNA-sensing activity has not yet been fully characterized. Recent studies have demonstrated that STING plays essential roles in immune responses to tumor cells. Effective tumor-initiated T-cell priming within the tumor microenvironment requires the production of interferon-beta (IFN-β) by resident dendritic cells, and IFN-β expression has been shown to depend on activation of the STING pathway (1). In fact, intratumoral administration of nucleotide-based STING agonists has been shown to induce profound regression of established tumors in syngeneic mouse models (1). Furthermore, activation of the STING pathway has also been shown to contribute significantly to the antitumor effect of radiation, through the IFN-β-mediated immune response within the irradiated tumor microenvironment. BRIEF DESCRIPTION In various forms, the present description provides an interferon gene stimulator (STING) agonist, which can be used in the treatment of tumors. This disclosure provides, in various forms, a compound of formula (IA) or formula (II), or a pharmaceutically acceptable salt thereof, ML / t / ZUZZ / UJ I OOOO IVIA / I IOO where X = S, -N=C(R1)-, or -C(R1)=C(R1). Each R1 is independently H, F, Cl, Ci-Ce alkyl, ethenyl or ethynyl (any of which may be substituted), cyano, alkoxy or haloalkyl. R2 is selected from the group consisting of -C(O)OR, -C(O)NH(O-Ce alkyl) (wherein the alkyl is optionally substituted), optionally substituted C3-C6 cycloalkenyl, and a 3- to 10-membered heterocycle. R is selected from the group consisting of H, optionally substituted alkyl with -((C1C6-alkyl)OC(O)OCi-C6-alkyl) or a 3- to 10-membered heterocyclyl and benzyl, wherein the benzyl can be unsubstituted or substituted with methoxyl or with an acid or isoester. Ring A is a 5- or 6-membered heteroaryl comprising 1, 2, or 3 N atoms, unsubstituted or substituted with 1, 2, or 3 groups independently selected from the set consisting of NH2, unsubstituted or substituted NH-benzyl with methoxyl, cyano, alkylnitrile, haloalkyl, hydroxymethyl, aminomethyl, aminopropyl, carboxamido, alkoxy, In various forms, the compound of formula (IA) is of formula (I): IVIA / I 100 wherein X is S, -N=C(R1)-, or -C(R1)=C(R1)-; R1= each independently H, F, Cl, ethenyl or ethinyl (any of which may be substituted), cyano, alkoxy or haloalkyl; and R is H, alkyl or benzyl, wherein the benzyl may be unsubstituted or substituted with methoxyl or with an acid or isoester such as 1,2,3,4 triazole. In some embodiments, optionally in combination with any other embodiment described herein, ring A comprises any of pyridazinyl, triazolyl, pyrimidiyl or pyridinyl, any of which may be substituted or unsubstituted. More specifically, according to illustrative modalities, a compound of the present description includes any of the specific compounds shown in Table 1 below. Furthermore, according to one embodiment, the present description provides a method for stimulating the expression of interferon genes, comprising administering to a patient an effective dose of an interferon gene stimulator (STING) agonist, comprising a compound described herein, and a method of treating a tumor in a patient, comprising administering to the patient an effective dose of an interferon gene stimulator (STING) agonist, comprising a compound described herein. In addition, a method of the present disclosure may be carried out using an effective dose of any of the specific compounds disclosed in the application; see, for example, Table 1. In various modalities, the method of treating a tumor may further comprise the administration of an effective dose of a compound as described herein by oral or intratumoral administration, or both. In various modalities, the method of treating a tumor may also include administering an effective dose of a compound as described herein, wherein the administration comprises administering the compound to the patient as an antibody-drug conjugate, or in a liposomal formulation. In various modalities, the treatment method for a tumor may further comprise the administration of an effective dose of a compound as described herein, which further comprises the administration of an effective dose of an immune checkpoint target drug. For example, the immune checkpoint target drug may be an anti-PD-L1 antibody, an anti-PD-1 antibody, an anti-CTLA-4 antibody, or an anti-4-1BB antibody. In various modalities, the method of treating a tumor may also include the administration of an effective dose of a compound as described herein, which also includes the administration of ionized radiation or anticancer drugs. DETAILED DESCRIPTION There is considerable interest in the development of STING pathway agonists for various immuno-oncology applications. In particular, STING pathway agonists have significant potential as part of combination therapies involving immune checkpoint-targeted drugs in patients who do not respond to checkpoint blockade alone. We have established a robust platform for identifying nucleotide-free, small-molecule STING agonists. This was established using a primary assay involving a human THP-1 cell line carrying an IRF-inducible indicator with 5 copies of the IFN signaling response element. Counter screens, involving alternative indicator constructs, rodent cell-based assays, and cGAS and STING knockout cell lines, were used to eliminate luciferase artifacts and ensure cross-species reactivity between humans and rodents, as well as pathway selectivity. Biochemical assays, involving cGAS enzyme activity and STING protein binding assays, were used to identify the specific target of the identified hits. "Treatment" or "treatment" within the meaning of this document refers to the relief of symptoms associated with a disorder or disease, or the inhibition of further progression or worsening of those symptoms, or the prevention or prophylaxis of the disease or disorder, or the cure of the disease or disorder. Similarly, as used herein, an effective amount or a therapeutically effective amount of a compound in this disclosure refers to an amount of the compound that relieves, in whole or in part, the symptoms associated with the disorder or condition, or stops or slows the progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition. In particular, a therapeutically effective amount refers to an amount that is effective, at the doses and for the periods of time necessary, to achieve the desired therapeutic result.A therapeutically effective amount is also one in which any toxic or harmful effects of the compounds described herein are not observed. ML / t / ZUZZ / UJ I OOO compensated by the therapeutically beneficial effects. The term "effective amount," when used to describe therapy for an individual suffering from a disorder, refers to the amount or concentration of a compound of the present description that is effective in inhibiting or otherwise acting upon STING in the tissues of the individual in whom STING is involved in the disorder, wherein such inhibition or other action occurs to a degree sufficient to produce a beneficial therapeutic effect. In general, the initial therapeutically effective amount of a compound described herein or one of its pharmaceutically acceptable salts administered is in the range of approximately 0.01 to approximately 200 mg / kg or approximately 0.1 to approximately 20 mg / kg of the patient's body weight per day, with the typical initial range being approximately 0.3 to approximately 15 mg / kg / day. Oral unit-dose forms, such as tablets and capsules, may contain from approximately 0.1 mg to approximately 1000 mg of the compound or a pharmaceutically acceptable salt thereof. In another embodiment, such dosage forms contain from approximately 50 mg to approximately 500 mg of the compound or a pharmaceutically acceptable salt thereof. In yet another embodiment, such dosage forms contain from approximately 25 mg to approximately 200 mg of the compound or a pharmaceutically acceptable salt thereof.In another embodiment, these dosage forms contain from approximately 10 mg to approximately 100 mg of the compound or a pharmaceutically acceptable salt thereof. In yet another embodiment, these dosage forms contain from approximately 5 mg to approximately 50 mg of the compound or a pharmaceutically acceptable salt thereof. In either embodiment, the dosage form may be administered once or twice daily. The term pharmaceutically acceptable salts refers to addition salts of non-toxic inorganic or organic acids and / or bases, see, for example, Lit, et al., Salt Selection for Basic Drugs (1986), Int J. Pharm., 33, 201-217, incorporated here by reference.Representative pharmaceutically acceptable salts include, for example, alkali metal salts, alkaline earth salts, ammonium salts, water-soluble and water-insoluble salts such as acetate salts, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamin, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, ammonium salt of N-methylglucamine, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate,. IVIA / t / ZUZZ / UÓ I IOO einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate, tosylate, triethoidide, and valerate. A pharmaceutically acceptable salt may have more than one charged atom in its structure. In this case, the pharmaceutically acceptable salt may have multiple counterions. Therefore, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions. Standard abbreviations are used for chemical groups such as those that are well known in the field; for example, Me = methyl, Et = ethyl, i-Pr = isopropyl, Bu = butyl, t-Bu = tere-butyl, Ph = phenyl, Bn = benzyl, Ac = acetyl, Bz = benzoyl and the like. Alkyl refers to a linear or branched hydrocarbon chain containing from 1 to approximately 20 carbon atoms. For example, an alkyl group can have from 1 to 10 carbon atoms or from 1 to 6 carbon atoms. The exemplary alkyl includes straight-chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like, and also includes branched-chain isomers of straight-chain alkyl groups, for example, without limitation, -CH(CH3)2, -CH(CH3)(CH2CH3), -CH(CH2CH3)2, -C(CH3)3, -C(CH2CH3)3, -CH2CH(CH3)2, -CH2CH(CH3)(CH2CH3), -CH2CH(CH2CH3)2, -CH2C(CH3)3, -CH2C(CH2CH3)3, -CH(CH3)CH(CH3)(CH2CH3), -CH2CH2CH(CH3)(CH2CH3), -CH2CH2CH(CH3)2, -CH2CH2CH(CH3)(CH2CH3), -CH2CH2CH(CH2CH3)2, -CH2CH2C(CH3)3, -CH2CH2C(CH2CH3)3, -CH(CH3)CH2CH(CH3)2, -CH(CH3)CH(CH3)CH(CH3)2, and the like. Therefore, alkyl groups include primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups.An alkyl group may be unsubstituted or optionally substituted with one or more substituents as described in this document. The term alkoxy or alkoxyl refers to an -O-alkyl group that has the indicated number of carbon atoms. For example, an alkoxy group (Ci-Ce) includes -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-butyl, -O-sec-butyl, -O-tert-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl, -O-hexyl, -O-isohexyl, and -O-neohexyl. The terms halo or halogen or halide, either by themselves or as part of another substituent, mean, unless otherwise stated, an atom of fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine. A haloalkyl group includes mono-haloalkyl groups, poly-haloalkyl groups in which all the halo atoms can be the same or different, and per-haloalkyl groups in which all the hydrogen atoms are replaced by the same or different halogen atoms, such as fluorine and / or chlorine atoms. Examples of haloalkyls include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and the like. Arito groups are cyclic aromatic hydrocarbons that do not contain heteroatoms IVIA / t / ZUZZ / UÓ I ΊΟΟ in the ring. An aromatic compound, as is well known in the art, is a cyclic system of multiple unsaturation containing 4n+2π electrons where n is an integer. Accordingly, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain from approximately 6 to approximately 14 carbons in the ring portions of the groups. Aryl groups may be substituted or unsubstituted, as defined above. Representative substituted aryl groups may be monosubstituted or substituted more than once, such as, but not limited to, phenyl groups substituted at 2, 3, 4, 5 or 6 or naphthyl groups substituted at 2 to 8, which may be substituted with carbon or non-carbon groups such as those listed above. Heterocyclyl groups, or the term heterocyclyl, encompass aromatic and non-aromatic ring compounds containing three or more ring members, one or more of which are heteroatoms such as nitrogen, oxygen, and sulfur. Therefore, a heterocyclyl group can be a cycloheteroalkyl, a heteroaryl, or, if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include from three to approximately twenty ring members, while others have from three to approximately fifteen. A heterocyclyl group designated as C2heterocyclyl can be a five-ring with two carbon atoms and three heteroatoms, a six-ring with two carbon atoms and four heteroatoms, and so on. Similarly, a C4heterocyclyl group can be a five-ring with one heteroatom, a six-ring with two heteroatoms, and so forth.The number of carbon atoms plus the number of heteroatoms are added together to equal the total number of atoms in the ring. Ring sizes can also be expressed by the total number of atoms in the ring; for example, a heterocyclyl group of 3 to 10 members, counting both carbon and non-carbon atoms. A heterocyclyl ring may also include one or more double bonds. A heteroaryl ring is a type of heterocyclyl group. The term heterocyclyl group includes fused ring species, including those comprising fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning of this document.The term also includes polycyclic ring systems, for example, bicyclo- and tricyclo-, containing one or more heteroatoms such as, but not limited to, quinuclidyl. The heterocyclyl groups may be unsubstituted or substituted. Heteroaryl groups are heterocyclic aromatic ring compounds containing 5 or more ring members, one or more of which is a heteroatom such as, among others, N, O, and S; for example, heteroaryl rings can have from 5 to IVIA / I IOO approximately 8-12 ring members. A heteroaryl group is a type of heterocyclyl group that possesses an aromatic electronic structure, which is a multi-unsaturated cyclic system containing 4n+2π electrons where n is an integer. A heteroaryl group designated as a C2-heteroaryl can be a 5-ring (i.e., a 5-membered ring) with two carbon atoms and three heteroatoms, a 6-ring (i.e., a 6-membered ring) with two carbon atoms and four heteroatoms, and so on. Likewise, a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, etc. The number of carbon atoms plus the number of heteroatoms are added together to equal the total number of atoms in the ring. It is also intended that heteroaryl include oxidized S or N, such as sulfinyl, sulfonyl, and nitrogen N-oxide of a tertiary ring.A carbon atom or heteroatom is the attachment point of the heteroaryl ring structure, resulting in a stable compound. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrazinyl, quinaoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxatiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, and indolyl. A heteroaryl group may be unsubstituted or optionally substituted with one or more substituents as described herein. Examples of heteroaryl ring systems described in this document include the structural unit with the formula: IVIA / t / ZUZZ / UÓ I ΊOOO an imidazoyl-pyridazine, which can also be represented as: Similarly, other aryl (e.g., phenyl) and heteroaryl (e.g., pyridyl) ring systems described in this document can be written with the double bonds explicit or with the aryl circle nomenclature, but the meanings are the same. Cycloalkyl groups are groups containing one or more carbocyclic rings, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group may have from 3 to approximately 8–12 members in the ring, while in others the number of carbon atoms in the ring ranges from 3 to 4, 5, 6, or 7. Cycloalkyl groups also include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl and the like. Cycloalkyl groups also include rings substituted with linear or branched alkyl groups as defined above. Cycloalkenyl groups include cycloalkyl groups that have at least one double bond between two carbon atoms. Thus, for example, cycloalkenyl groups include, but are not limited to, cyclohexenyl, cyclopentenyl, and cyclohexadienyl groups. Cycloalkenyl groups can have from 3 to approximately 8–12 ring members, while in other embodiments the number of carbon atoms in the ring ranges from 3 to 5, 6, or 7. Cycloalkyl groups also include polycyclic cycloalkyl groups such as, among others, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, among others, decalinyl and the like, provided they include at least one double bond within the ring. Cycloalkenyl groups also include rings that are substituted with linear or branched alkyl groups as defined above. One or more optional substituents in any group described herein are selected independently of the group consisting of RA, ORA, halo, -N=NRA, NRARB, -(Ci-C6-alqu¡l)NRARB, -C(O)ORA, -C(O)NRARB, -OC(O)RA, and -CN. RA and RB are independently selected from the group consisting of H, -CN, -hydroxy, oxo, CiCe-alkyl, Ci-Ce-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, NH2, -S(0)o-2-(Ci-C6-alkyl), -S(0)o-2-(C6Cio-aryl), -C(O)(Ci-C6-alkyl), -C(O)(C3-Ci4-carbocyclyl), -Ca-Cu-carbocyclyl, -(Ci-C6-alkyl)(C3Ci4-carbocyclyl), Ce-Cw-aryl, 3- to 14-membered heterocycloalkyl and -(Ci-Ce-alkyl)(3- to 4-membered heterocycloalkyl) (wherein the 1-4-membered heterocycloalkyl is independently selected from N, O, and S), and 5- to 10-membered heteroaryl (in where 1-4 heteroaryl members are selected independently of N, O, and S). Each alkyl, alkoxy, alkenyl, alkynyl, aryl, carbocyclyl, heterocycloalkyl fraction,and the heteroaryl of RAy RB is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, NR'2 (where each R' is independently selected from the group consisting of Cr Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ce-Cw-aryl, 3- to 14-membered heterocycloalkyl and -(C1C6-alkyl)-(3- to 14-membered heterocycloalkyl) (where 1-4 ring members are independently selected from N, O, and S), and 5- to 10-membered heteroaryl (where 1-4 heteroaryl members are independently selected from N, O, and S), NHC(O)(OCi-C6-alkyl), -NO2, -CN, oxo, -C(O)OH, -C(O)O(Ci-C6-alkyl), -Ci-C6-alkyl(Ci-C6alkoxy), -C(O)NH2, Ci-Ce-alkyl, -C(O)Ci-C6-alkyl, -OCi-Ce-alkyl, -Si(Ci-C6-alkyl)3, -S(O)o-2(Ci-Ce-alkyl), Ce-Cw-aryl, -(C1-Ce-alkyl)(C6-Cw-aryl), 3-to-14-membered heterocycloalkyl, and (Ci-C6-alkyl)-(3-to-14-membered heterocycle) (where 1-4 heterocycle members are selected independently of N,O, and S), and -O(Ce-Ci4-aryl). Each alkyl, alkenyl, aryl and heterocycloalkyl group described above is optionally substituted with one or more substituents selected from the group consisting of hydroxy, -OC1-C6-alkyl, halo, -NH2, (C1-C6-alkyl)NH2, -C(O)OH, CN and oxo. IVIA / I IOO The compounds described herein may exist in various isomeric forms, including configurational, geometric, and conformational isomers, such as cis or trans conformations. The compounds may also exist in one or more tautomeric forms, including both individual tautomers and mixtures of tautomers. The term IVIA / I IOO is intended to encompass all isomeric forms of a compound of this description, including tautomeric forms. Compounds of this description may also exist in open-chain or cyclic forms. In some cases, one or more of the cyclic forms may result from the loss of water. The specific composition of the open-chain and cyclic forms may depend on how the compound is isolated, stored, or administered. For example, the compound may exist primarily in open-chain form under acidic conditions but cyclize under neutral conditions. All forms are included in this disclosure. The -CO2H substituent can be replaced with bioisosteric replacements such as: either II To OH and the like, where R has the same definition as RA as defined herein. See, for example, The Practice of Medicinal Chemistry (Academic Press: New York, 1996), on page 203. Some compounds described herein may have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. A compound as described herein may exist as an optical isomer or a diastereomer. Accordingly, the disclosure covers compounds and their uses as described herein in the form of their optical isomers, diastereomers, and mixtures thereof, including a racemic mixture. The optical isomers of the compounds described herein may be obtained by known techniques such as asymmetric synthesis, chiral chromatography, simulated moving bed technology, or by chemical separation of stereoisomers using optically active resolving agents. Unless otherwise stated, the term stereoisomer means a stereoisomer of a compound that is substantially free of other stereoisomers of that compound. Thus, a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound.A typical stereomerically pure compound comprises more than 80% by weight of one stereoisomer of the compound and less than 20% by weight of other stereoisomers of the compound; for example, more than 90% by weight of one stereoisomer of the compound and less than 10% by weight of the other stereoisomers of the compound, or more than 95% by weight of one stereoisomer of the compound and less than 5% by weight of the other stereoisomers of the compound, or more than 97% by weight of one stereoisomer of the compound and less than 3% by weight of the other stereoisomers of the compound, or more than 99% by weight of one stereoisomer of the compound and less than 1% by weight of the other stereoisomers of the compound. The stereoisomer described above can be viewed as a composition comprising two stereoisomers present in their respective weight percentages as described herein. If there is a discrepancy between a represented structure and a name given to that structure, then the represented structure prevails. Furthermore, if the stereochemistry of a structure or part of a structure is not indicated, for example, by bold or dashed lines, the structure or part of the structure should be interpreted as encompassing all of its stereoisomers. In some cases, however, where more than one chiral center exists, structures and names may be represented as individual enantiomers to help describe the relative stereochemistry. Those skilled in the technique of organic synthesis will know whether compounds are prepared as individual enantiomers from the methods used to prepare them. As used herein, and unless otherwise specified, the term compound is inclusive because it encompasses a compound or one of its pharmaceutically acceptable salts, stereoisomers, and / or tautomers. Thus, for example, a compound of formula (I), formula (IA), or formula (II) includes a pharmaceutically acceptable salt of a tautomer of the compound. COMPOUNDS This disclosure provides, in various forms, a compound of formula (IA) or IVIA / I IOO formula (II), or a pharmaceutically acceptable salt thereof: R1 / Rlr / V ViR2yXRi HN^ON^O (A)( A ) vy (ia) vj In the formula (ΙΑ), X is S, -N=C(R1)-, or -C(R1)=C(R1)-. In some forms, the compound is a compound of formula (IA). In other forms, the compound is a compound of formula (II). This disclosure provides in various forms, optionally in combination with any other form described herein, a compound of formula (IA) that is a compound of formula (I) or a pharmaceutically acceptable salt thereof: X is S, -N=C(R1)-, or -C(R1)=C(R1)-. Each R1 is independently H, F, Cl, Ci-Ce alkyl, ethenyl or ethynyl (any of which may be substituted), cyano, alkoxy or haloalkyl. R2 is selected from the group consisting of -C(O)OR, -C(O)NH(CrCe alkyl) (where the alkyl is optionally substituted), optionally substituted C3-C6 cycloalkenyl, and 3- to 10-membered heterocycle. For example, in some embodiments, optionally in combination with any other embodiment described herein, R2 is -C(O)OR. R is selected from the group consisting of H, optionally substituted alkyl with -((C1C6-alkyl)OC(O)OCi-C6-alkyl) or 3- to 10-membered heterocyclyl, and benzyl, wherein the benzyl may be unsubstituted or substituted with methoxyl or with an acid or isoester. In various embodiments, R is H, alkyl, or benzyl, wherein the benzyl may be unsubstituted or substituted with methoxyl or with an acid or isoester. Ring A is a 5- or 6-membered heteroaryl comprising 1, 2, or 3 N atoms, either unsubstituted or substituted with 1, 2, or 3 groups selected independently from the group consisting of NH2, NH-benzyl (wherein the benzyl is either unsubstituted or substituted with methoxyl, cyano, alkylnitrile, haloalkyl, hydroxymethyl, aminomethyl, aminopropyl, carboxamido, or alkoxy), ML / t / ZUZZ / UJ I OOOO HN^O EITHER. , and \ , where a wavy line indicates a linking position. In various embodiments, ring A comprises any of pyridazinyl, triazolyl, pyrimidinyl and pyridinyl, any of which may be substituted or unsubstituted as described herein. In additional modalities, this description provides specific examples of compounds and their pharmaceutically acceptable salts, as set out in Table 1 below. The compounds are presented with activity scores derived, in part, from an ISG-LUC activation assay as described herein, and physicochemical characterization data. Table 1: Specific Compounds and Activity Scores. Activity scores are based on potency and efficacy data (+ = EC50 > 20,000 nM; ++ = active, but less potent and effective than the reference compound (EC50 > 1000 nM); +++ = activity comparable to the reference compound (EC50 < 3000 nM); ++++ = more potent and / or effective than the reference compound (EC50 < 900 nM)). Compound no. Structure ISG-LUC activation assay score Analytical data 1 F Ck NH OH Ν^ί II N^JO ++++ 'HNMR (400 MHz, DMSO-¿ / 6)ó 15.91 (s, 1H), 8.92 (d, 8.8 Hz (1H), 8.92 (d, 8.8 Hz, 6.5). 2H), 8.60 (d, 7 = 8.8Hz, 1H), 8.498.37 (m, 1H), 8.32-8.20 (m, 2H), 7.78 (d, J= 10.5 Hz, 1H), 4.54 (s, 1H). MS-ESI: m / z 363.08 observed [M+H]+ 2 O \=O ».-1M / ===1 \- / z Vz I LL O£· >--- 2—' ++ Ή NMR (400 MHz, DMSO-76)ó 13.11 (s,93H), (8.93H), (s,lH), 8.83–8.777 (m, 4H), 8.44 (s, 1H), 8.15–8.10 (m, 1H), 7.62 (s, 1H), 4.68 (t, J = 5.2 Hz, 2H), 3.96 (s, 3H). MS-ESI: m / z 389.22 observed [M+H]+ 3 OK° / r\ W W_ / z u.—# y— 2 2=2 '—' / Γ ++++ 'H NMR (400 MHz, DMSO) δ 8.91-8.82 (m, 39. (H = Hz), J = 8.8. 8.30–8.20 (m, 2H), 8.13 (d, 7=8.6 Hz, 1H), 8.08 (d, 7 = 6.2 Hz, 1H), 5.04 (s, 1H). MS-ESI: m / z 345.46 observed [M+H]+ IVIA / I 100 Compound no. Structure ISG-LUC Activation Assay Score Analytical Data 4 '4CK.NH 0 Ν^Ί II HO | \N^ V +++ 'HNMR (400 MHz, DMSO-í / 6) δ 13.05 (s, 1H), 8.85 (dd, J= 13.6, 7.6 Hz, 1H), 8.60 (d, 7 = 9.2 Hz, 1H (9, H = 8.4), 8.11 (dd, 7= 11.2, 8.8 Hz, 1H), 7.96 (d, 7 = 0.8 Hz, 1H), 7.14 (d, 7 = 0.8 Hz, 1H), 5.55 (1,7 = 5.6 Hz, 1H = 7), 2.H ,4. 3.96 (s, 3H). MS-ESI: m / z 390.46 observed [M+H]+ 5 O^NH 0 II N\^ N ++ Ή NMR (400 MHz, DMSO-í / 6) δ 13.08 (s,lH), 8.83-8.78 (m, 1H), 8.4=Hz (q 8.11 (t, 7 = 9.2 Hz, 1H), 3.96 (s, 3H). MS-ESI: m / z 319.1 observed [M+H]+ 6 FF^J\ CK.NH OH n hn γ O o ++ 'HNMR (400MHz, DMSO-¿ / 6)ó 13.4 (s, 1H), 8.87 (dd, 7 = 7.6 Hz), 1.3, 1H), 8.068.01 (m, 1H), 7.65 (s, 1H), 7.60 (s, 1H), 7.24-7.21 (m, 2H), 6.95 (t,7=6Hz, 1H), 3.43-3.41 (H, 1. 2.3. 3), (s, 3H). MS-ESI: m / z 482.42 observed [M+H]+ Compuesto No. Estructura Testaje de activación ISG-LUC Analytical data 7 οΗ°γΝΗ 0 Yes ' ó ++++ 'HNMR (400 MHz, DMSO-¿ / 6) δ 13.04 (s, 1H), 8.85-8.77 (m, 2H), 8.40 (s, 1H), 8.25-8.24 (m, 1H), 8.09 (dd, 7 = 9.2, 11.2 Hz, 1H), 7.26 (s, 1H), 5.84 (t, 7 =5.2 Hz, 1H), 5.12-5.11 (m, 2H), 3.95 (s, 3H). MS-ESI: m / z 390.23 observed [M+H]+ 8 Q / =\ I U. ά AZ Λ Λ / — / —\ / -z U. o Z=Z ++ 'HNMR (400MHz, DMSO-ófe) δ 12.72 (s, 1H), 8.83 (dd, 7= 14,7.6 Ηζ,ΙΗ), 8.07-8.01 (m, 1H), 7.90 (d, 7 = 9.2 Hz, 1H), 7.204 (s, 2H), 6.91 (d, 7 = 9.2 Hz, 1H), 3.93 (s, 3H). MS-ESI: m / z 309.17 observed [M+H]+ 9 O u. O z=z ++ *H NMR (400 MHz, DMSO-í / ó) δ 13.08 (s, 1H), 8.83 (dd, 7 = 7.6, 13.6 Hz, 1H), 8.41 (d, 7 = 8.8 Hz, 1H), 8.10 (dd, 7 = 8.8, 11.2 Hz, 1H), 8.01 (d, 7=8.8 Hz, 1H), 4.63 (s, 2H), 3.96 (s, 3H). MS-ESI: m / z 333.14 observed [M+H]+ IVIA / I ΊΟΟ Compound no. Structure ISG-LUC Activation Assay Score Analytical Data 10 z=\ z=z O -Π X \ / ° \ O ++ 'HNMR (400 MHz, DMSO-í / 6)ó 13.1 (s, 1H), 9.44-9.67 (dd, =7), 8H 13.6 Hz, 1H), 8.80–8.79 (m, 1H), 8.678.63 (m, 2H) 8.47 (d, J = 9.2 Hz, 1H), 8.10 (dd, J = 8.8, 11.2 Hz, (11.9 Hz, 1H, 1H. 64), (8,7. 64). 3H). MS-ESI: m / z 371.27 observed [M+H]+ 11 O^NH OH r<^NO^NH r° ++ lH NMR (400 MHz, DMSO-úfe) δ 15.83 (s, 1H), 11.17 (s, 1H), 14 = Hz 8.28 (d, J = 9.6 Hz, 1H), 8.24 (d, J = 9.2 Hz, 1H), 7.93–7.87 (m, 1H), 4.22 (q, 7 = 7.2 Hz, 2H), 1.28 (t, 7=7.2 Hz). MS-ESI: m / z 367.24 observed [M+H]+ 12 o \=oo—C z Z=\ -r <rQ z CM X ++ 1H NMR (400 MHz, DMSO) δ 12.87 (s, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.55 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.45 (s, 2H), 7.15 (s, 1H), 3.97 (s, 3H), 3.91 (s, 3H). MS-ESI: m / z 337.44 observado [M+H]+ IVIA / t / ZUZZ / UÓ I ΊΟΟ Compuesto No. Estructura Puntaje de ensayo de activación ISG-LUC Datos analíticos 13 F Ι|ΎΟ NH OH O^NH2 + 'HNMR (400 MHz, DMSO-í / 6) δ 14.33 (s, 1H), 12.97 (s, lH),9.14(s, 1H), 8.64 (dd, 7 = 7.6, 13.2, Hz, 1H), 8.45 (dd, 7= 1.7, 8, Hz, 1H), 8.30 (s, 1H), 8.22 (d, 7 = 8.1 Hz, 1H), 8.02 (t, 7= 10.8 Hz, 1H). MS-ESI: m / z 322.46 observed [M+H]+ 14 FF^ / LO^NH OH H Η,Ν^Αχ \\ / N-NH ++ MS-ESI: m / z 361.47 observed [M+H]+ 15 _z / =\ O -n ^ \ / \ / / / / W ZZ ^—\ / Ή ο=ς o ++++ 1H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.88 (q, 7 = 7.6 Hz, 2H), 8.52-8.45 (m, 2H), 8.13-8.08 (m, 1H), 3.97 (s, 3H). MS-ESI: m / z 360.9 observed [M+H]+ 16 o 5=oo u- O z=z ++ 'H NMR (400 MHz, DMSO-í / 6)ó 13.1 (s, 1H), 9.79 (d,7 = 2Hz, 1H), 8.84 (q, 7 = 5.6 Hz, 1H), 8.70(d, 7= 2 Hz, 2H), 8.14-8.128 (m, 1H), 8.118.10 (m, 1H), 3.953 (s, 3H). IVIA / I 100 Compuesto No. Estructura Puntaje de ensayo de activación ISG-LUC Datos analíticos 5 MS-ESI: m / z 337.3 observado [M+H]+ 10 17 O / =\ z u.—4 \ LL· O Z Z +++ 'HNMR (400 MHz, DMSO-dó) δ 13.06 (s, 1H), 8.84 (dd, 7 = 7.6,13.6 Hz, 1H), 8.40 (d, 7=8.8 Hz, 1H), 8.1 (dd, 7 = 9.2,11.2 Ηζ,ΙΗ), 8.02 (d, 7=8.4 Hz, 1H), 5.85 (t, 7 = 6 Hz, 1H), 4.91 (d,7 = 6Hz, 2H), 3.95 (s, 3H). 15 ΌΗ MS-ESI: m / z 324.42 observado [M+H]+ 20 18 O \=O — i ° —ά / )~z f,—£ / — —\ / ~z Q O Z=Z ++ *H NMR (400 MHz, DMSO-76) δ 12.62 (s, 1H), 9.06 (s, 1H), 8.17 (s, 1H), 7.97 (d, 7 = 9.6 Hz, 1H), 7.59 (s, 2H), 7.06 (d, 7 = 9.2 Hz, 1H), 3.94 (s, 3H). MS-ESI: m / z 341.41 observado [M+H]+ 25 19 / =(1 z=z i o— / 1 o ++ ‘H NMR (400 MHz, DMSO4) δ 15.86 (s, 1H), 9.02 (s, 1H), 8.80-8.77 (m, 1H), 8.60 (d, 7 = 8.8 Hz, 1H), 8.50-8.49 (m, 1H), 8.38 (d, 7=8.8 Hz, 1H), 8.37 (s, 1H), 8.37-7.96 (m, 1H), 3.97 (s, 3H). 30 π o^N 1 MS-ESI: m / z 387.0 observado [M+H]+ IVIA / t / ZUZZ / UÓ I 100 Compuesto No. Estructura Puntaje de ensayo de activación ISG-LUC Datos analíticos 20 / O \=o / ==\ 1 U_—¿ Z Z-Z z OI X ++++ 'HNMR (400 MHz, DMSO-í / 6) δ 12.91 (s, 1H), 8.84 (dd, 7 = 7.6, 13.6 Hz, 1H), 8.69 (d, 7 = 2.8Hz, 1H), 8.06 (dd, J = 8.8, 11.2 Hz, 1H), 7.33 (d, J = 2.8 Hz, 1H), 6.91 (s, 2H), 3.94 (s, 3H). MS-ESI: m / z 309.16 observado [M+H]+ 21 * / O LL. O Z Z ^Z ++ 'HNMR (400MHz, DMSO-d6) δ 16.13 (s, 1H), 9.44 (s, 1H), 8.808.74 (m, 2H), 8.66-8.65 (m, 1H), 8.57 (d,7=8.8 Hz, 1H), 8.39 (d, 8.8 Hz, 1H), 7.96-7.9 (m 1H), 7.68-7.64 (m, 1H). MS-ESI: m / z 357.17 observado [M+H]+ 22 Cl O^NH O A N-N ví 7^0 ++ *H NMR (400 MHz, CDCb) δ 12.58 (s, 1H), 9.11 (s, 1H), 8.57 (s, 1H), 8.46 (s, 1H), 8.18 (s, 1H), 8.12 (s, 1H), 4.02 (s, 3H), 1.70 (s, 9H). 23 Cl Ο^,ΝΗ O N-N Anh Ν ++++ *H NMR (400 MHz, DMSO) δ 13.46 (s, 1H), 12.29 (s, 1H), 9.42- 9.29 (m, 1H), 9.07- 8.94 (m, 1H), 8.32 (s, 2H), 8.228.16 (m, 1H), 7.95 (s, 1H), 3.95 (s, 3H). MS-ESI: m / z 403.36 observado [M+Na]+ IVIA / I 100 Compuesto No. Estructura Puntaje de ensayo de activación ISG-LUC Datos analíticos 24 / —z OZ z_z z / jo o O ++++ 1H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 9.06 (s, 2H), 8.72 (s, 1H), 8.60 (s, 3H), 8.29 (s, 1H), 8.25 (s, 1H), 7.45 (s, 1H), 4.64 (d, J = 4.8 Hz, 2H), 3.97 (s, 3H). MS-ESI: m / z 421.4 observado [M+H]+ 25 O - L'ÁM / Vo 1 )__' O=\ o ++ Ή NMR (400 MHz, DMSO-áfe) δ 12.88 (s, 1H), 9.25 (d, J = 2Hz, 1H), 9.14 (s, 1H), 8.57 (s, 1H), 8.44-8.41 (m, 1H), 8.31 (d, J= 8.4 Hz, 1H), 8.19 (s, 1H), 8.04-8.03 (m, 1H), 7.22 (s, 1H), 3.97 (s, 3H). MS-ESI: m / z 391.27 observado [M+H]+ 26 Cl “<V· O^NH 0 NH2 N \\ ++++ Ή NMR (400 MHz, DMSO-¿ / 6)ó 13.09 (s, 1H), 9.07 (s, 1H), 8.86 (s, 1H), 8.78 (s, 3H), 8.64 (s, 1H), 8.25 (s, 1H), 7.99 (s, 1H), 7.44 (s, 1H), 4.33 (s, 2H), 3.96 (s, 3H). MS-ESI: m / z 421.29 observado [M+H]+ IVIA / I 100 Compuesto No. Estructura Puntaje de ensayo de activación ISG-LUC Datos analíticos 27 N O^NH O li N Br N= / + 'HNMR (400 MHz, DMSO-¿ / 6)ó 13.33 (s, 1H), 9.14 (s, 1H), 8.61-8.54 (m, 2H), 8.39 (d, 7=8.8 Hz, 1H), 7.86 (s, 1H), 4.06 (s,3H), 3.99 (s, 3H). MS-ESI: m / z 475.04 observado [M+H]+ 28 F CI.Á Yy° o. NH OH II N 7 7 N-NH ++ 1H NMR (400 MHz, DMSO-d6) δ 14.46 (s, 1H), 13.61 (s, 1H), 9.04 (d, 7 = 6.8 Hz, 1H), 8.968.94 (m, 1H), 8.44 (d, 7 = 8.8 Hz, 1H), 8.33-8.30 (m, 1H), 7.99 (d, 7 = 9.6 Hz, 1H). MS-ESI: m / z 387.0 observado [M+H]+ 29 F C|^Á Vv° O^NH OH II N^J Λ / N-S ++++ 1H NMR (400 MHz, DMSO-d6) δ 15.67 (s, 1H), 9.95 (s, 1H), 9.42 (s, 1H), 8.97 (d, 7 = 7.2 Hz, 1H), 8.48 (d7=8.8Hz, 1H), 8.37 (d, 7 = 8.8 Hz, 1H), 7.92 (s,7= 10.4 Hz, 1H). MS-ESI: m / z 379.0 observado [M+H]+ IVIA / I 100 Compuesto No. Estructura Puntaje de ensayo de activación ISG-LUC Datos analíticos 30 N II O^NH 0 νΎί 1 N-NH ++++ 'HNMR (400 MHz, DMSO-¿ / 6)ó 15.77 (s, 1H), 13.37 (s, 1H), 9.13 (s, 1H), 8.87 (s,lH), 8.59 (s, 1H), 8.51 (d, 7=8.8Hz, 1H), 8.47 (d, 7-8.8 Hz, 1H), 3.99 (s, 3H). MS-ESI: m / z 384.14 observado [M+H]+ 31 F Ck / L i Ύ° O^NH OH II S' / N= / ++++ 1H NMR (400 MHz, DMSO-d6) δ 15.98 (s, 1H) 8.95 (d, 7 = 7.2 Hz, 1H), 8.78 (d, 7 = 1.6 Hz, 1H), 8.57 (d, 7=8.8 Hz, 1H), 8.43 (d, 7=8.8Hz, 1H), 8.29 (d, 7 = 2Hz, 1H), 7.90 (d, J= 10.4 Hz, 1H). MS-ESI: m / z 379.0 observado [M+H]+ 32 Y * / ° o / w z + Ή NMR (400 MHz, DMSO-dó) δ 16..02 (s, 1H), 9.01 (s, 1H), 8.79 (s, 1H), 8.40 (d, 7=8.8Hz, 1H), 8.35 (d, 7 = 8.8Hz, 1H), 8.16 (s, 1H), 4.04 (s, 3H). MS-ESI: m / z 417.12 observado [M+H]+ 33 Cl Ck Jx T^Y° O^NH OH Π N^J ó NH ++ *H NMR (400 MHz, DMSO-í / ó) δ 15.54 (s, 1H), 13.473 (s, 1H), 9.33 (s, 1H), 8.38, (d, 7 = 8.4 Hz, 1H), 8.32 (d, 7 = 8.8 Hz, 1H), 7.98 (s, 1H), 7.17(d, 7= 2 Hz, 1H). MS-ESI: m / z 379.44 observed [M+H]+. Compuesto No. Estructura Puntaje de ensayo de activación ISG-LUC Datos analíticos 34 Cl “Λ TY0 O. NH O N^% II N ó NH ++++ 'HNMR (400 MHz, DMSO-76)6 13.52 (s, 1H), 12.97 (s, 1H), 9.43 (s, 1H), 8.46 (d, 7 = 8.8Hz, 1H), 8.39 (d, 7=8.8 Hz, 1H), 8.00 (d, 7 = 2Hz, 1H), 7.19 (s, 1H), 3.99 (s, 3H). MS-ESI: m / z 393.14 observado [M+H]+ 35 Z'Z ° ¿ Ύ 1 )= / i o / ++++ 'HNMR (400MHz, DMSO-76)ó 13.44 (s, 1H), 12.10 (s, 1H), 9.31 (s, 1H), 8.84 (d, 7 = 6.4 Hz, 1H), 8.51 (s, 1H), 8.13 (s, 1H), 7.88 (d, 7 = 9.6 Hz, 1H), 4.85 (s, 1H), 3.95 (s,3H). MS-ESI: m / z 353.26 observado [M-H]’ 36 F °yNH HO •A N—N ^~NH N ++ Ή NMR (400 MHz, DMSO-¿ / 6) δ 15.39 (s, 1H), 13.40 (s, 1H), 9.11 (d,7 = 1.9 Hz, 1H), 8.80 (dd, 7 = 7.0, 2.0 Hz, 1H), 8.27 (s, 2H), 7.74 (dd, 7= 10.6, 2.0 Hz, 1H), 4.52 (d, 7= 1.8 Hz, 1H). MS-ESI: m / z 341.06 observado [M+H]+ 37 Cl Xv 0 XI O^N N= / 4 ,NH N +++ 'H NMR (400 MHz, DMSO-í / 6)ó 13.60 (s, 1H), 12.24 (s, 1H), 8.75 (s, 1H), 8.50 (s, 1H), 8.21 (s, 1H), 8.07 (s, 1H), 3.97 (s, 3H). MS-ESI: m / z 382.12 observed [M+H]+. IVIA / I 100 Compound no. Structure ISG-LUC activation assay score Analytical data 38 Cl kk'-k3 O^NH OH II V / N-NH ++++ 'HNMR (400 MHz, DMSO-afe) δ 15.23 (s, 1H), 13.43 (s. 273), (s. 273), (s, 1H), 8.33 (s, 1H), 8.22 (q, 7 = 7.6 Hz, 2H), 4.80 (s, 1H). MS-ESI: m / z 369.15 observed [M+H]+ 39 / =\ / ? kzz^\ / W -7 ZZ Z—<λ IZ Ο-Λ / © ++ 1HNMR (400 MHz, DMSO) δ 12.36 (s, 1H), 8.95 (s, 1H), 8.58 (d, J = 9.2 Hz, J. = 1. 2), 8 8.28 (d, J = 1.9 Hz, 1H), 8.01 (s, 1H), 7.34 (s, 1H), 3.88 (s, 3H), 2.57 (s, 3H). MS-ESI: m / z 344.48 observed [M+H]+ 40 'k O^NH O N'k II n^j JM H2N N ++++ Ή NMR (400 MHz, DMSO) δ 13.21 (s, 1H), 8.87 (dd, J= 1.3.3). 8.63–8.52 (m, 2H), 8.18 (d, 7 = 6.3 Hz, 1H), 8.13 (dd, 7 = 11.2, 8.9 Hz, 1H), 7.75 (s, 1H), 7.56 (d, 7=6.2 H), (3.2 Hz), 3. Hz. MS-ESI: m / z 386.46 observed [M+H]+ IVIA / t / ZUZZ / UÓ I 100 Compuesto No. Estructura Puntaje de ensayo de activación ISG-LUC Datos analíticos 41 I z / ° __ / 1 Zií / zz z- / ^C—-Π 1 \' o=\ O ++++ MS-ESI: m / z 375.42 observado [M+H]+ 42 u- o ZZ ++ 'HNMR (400 MHz, DMSO) Ó 13.08 (s, 1H), 8.85 (dd, 7 = 7.6, 13.6 Hz, 1H), 8.54 (s, 1H), 8.34 (s, 1H) 8.10 (dd, 7 = 9.2, 11.2 Hz, 1H), 7.87 (s, 1H), 7.24 (s, 1H), 3.95 (s, 3H), 2.56 (s, 3H). MS-ESI: m / z 374.28 observado [M+H]+ 43 a \=o / =\ 1 U-—ά / )—Z ZZ V# y-(7 Vz 1 u- O ++ 'HNMR (400MHz, DMSO) δ 12.96 (s, 1H), 8.49-8.78 (m, 2H), 8.34 (d, 7=0.8Hz, 1H). 8.18-8.17 (m, 1H), 8.09 (dd, 7= 8.8, 11.2 Hz, 1H), 7.27-7.26 (m, 1H), 3.94 (s, 3H), 2.82.77 (m, 3H).MS-ESI: m / z 374.25 observado [M+H]+ IVIA / I 100 Compuesto No. Estructura Puntaje de ensayo de activación ISG-LUC Datos analíticos 44 Vo ++++ 1H NMR (400 MHz, DMSO-d6) δ 15.61 (s, 1H), 13.44 (s, 1H), 9.01 (d, 7 = 7.2 Hz, 1H), 8.66 (s, 1H), 8.32 (s, 1H), 8.26 -8.15(m, 2H), 7.70 (d, J = 11.8 Hz, 1H), 6.86 (dd, J = 17.8, 11.1 Hz, 1H), 5.86 (d, J = 17.7 Hz, 1H), 5.47 (d, J= 11.2 Hz, 1H). MS-ESI: m / z 354.53 observado [M+H]+ 45 / =2 O Π z / )—λ / ;—λ —7 z—V- O 1 )__ / oR O ++ 1H NMR (400 MHz, DMSO) δ 12.98 (s, 1H), 9.51-9.50 (m, 1H), 9.20 (d, J = 4.8 Hz, 1H), 8.82 (d, J = 12.4 Hz, 1H), 8.24-8.20 (m, 2H), 3.97 (s, 3H). MS-ESI: m / z 310.43 observado [M+H]+ 46 Vo ++ 1H NMR (400 MHz, DMSO) δ 15.63 (s, 1H), 8.90 (d, 7 = 6.5 Hz, 1H), 8.48 (s, 2H), 8.19 (q, J = 8.8 Hz, 2H), 7.76 (d, J = 10.2 Hz, 1H), 4.53 (s, 1H). MS-ESI: m / z 352.48 observado [M+H]+ 47 Cl Xv O^NH O A O^NH N / 0 V ++ 1H NMR (400 MHz, DMSO) δ 13.03 (s, 1H), 9.07 (s, 1H), 8.43 (s, 1H), 8.35 (s, 1H), 8.22 (s, 1H), 8.11 (t, 7 = 5.6 Hz, 1H), 7.89 (s, 1H), 7.27 (s, 1H), 4.42 (d, 7 = 6 Hz, 2H), 3.96(s, 3H), 3.58(s, 3H). ΜΛ / Ε / ΖΖΖ / υοΊ Ί OS Compound No. Structure ISG-LUC activation assay score MS-ESI analytical data: m / z 479.20 observed [M+H]+ 48 Cl O^NH OAO^NH N i O NH2 vN ++ 'HNMR (400 MHz, DMSO-aphe) δ 9.89 (s, 1H), 9.09 (s, 48). 1H), 8.56(s,1H), 8.44(t,J=1.6Hz,1H),8.24(s,1H),8.O6(s,1H), 4.42(s,2H), 3.96(3H). MS-ESI: m / z 464.26 observed [M+H]+ 49 Cl Cl^2\ Ο^,ΝΗ OH N^A 11 V / N-NH++ *H NMR (400 MHz, DMSO-í / ó) δ 15.75(s,1H), 13.51(s,1H), 9.01(s,1). 1H), 8.50 (s, 1H), 8.25-8.16 (m, 3H), 7.27-7.14 (m, 1H). MS-ESI: m / z 378.41 observed [M+H]+ 50 Cl O^NH OAN^ N-NH ++++ 'HNMR (400 MHz, DMSO-¿ / 6) δ 15.75 (s, 1H), 13.10 (s, lH),9.10(s, 1H), 8.88-8.83 (m,100). 1H), 8.46 (dd, 7 = 9.2, 21.2 Hz, 2H), 8.20 (s, 1H), 3.97 (s, 3H). MS-ESI: m / z 393.44 observed [M+H]+ IVIA / I Compound no. Structure ISG-LUC Activation Assay Score Analytical Data 51 Cl O^NH OH A LÍ.NN^ N-NH ++ 'HNMR (400 MHz, DMSO-¿ / 6)6 15.24-15.16 (m, 1H), 9.07), (s. 4.07), (s. 4.07). 8.20 (s, 1H). MS-ESI: m / z 378.9 observed [M+H]+ 52 Cl CK J\ vv° O^NH OH II N^J 1 / N-NH ++++ 'H NMR (400 MHz, DMSO-í / ó) δ 15.48 (d, 7 = 3.4), ( .3 Hs, 9.31 (d, J= 1.8 Hz, 1H), 8.49 (d, J= 123.8 Hz, 2H), 8.22 (dd, 7 = 6.3, 2.1 Hz, 2H). MS-ESI: m / z 379.33 observed [M+H]+ 53 \ θ' O^NH OH N^Y ll N^JY / N-NH ++ Ή NMR (400 MHz, DMSO-í / ó) δ 15.61 (s, 1H), 1.9.H180), s,1.1.H180 8.51 (s, 1H), 8.20 (7 = 8.8, 16.4 Hz, 2H), 8.07 (s, 1H), 4.59 (s, 1H). MS-ESI: m / z 368.1 observed [M+H]+ ΜΛ / Ε / ΖυΖΖ / υοΊ Ί OS Compuesto No. Estructura Testaje de test de activación ISG-LUC Analytical data 54 FO^NH OH ííj N^N N-7 NA 'HNMR (400 MHz, DMSO-76) δ 12.90 (s, 1H), 9.46 (s, 2H), 8.87 (s, 1H), 8.77 (d, 7 = 6.4 Hz, 1H), 8.21 (s, 1H), 8.01 (d, J = 10 Hz, 1H), 7.39 (s, 1H). MS-ESI: m / z 352.2 observed [M+H]+ 55 O^-NH 0 nX 1H), 8.48 (s, 2H), 7.89 (d, 7 = 10 Hz, 1H), 4.86 (s, 1H), 3.96 (s, 1H). MS-ESI: m / z 366.0 observed [M+H]+ 56 O^NH ON^NX N-NH + 'H NMR (400 MHz, DMSO-í / ó) δ 12.84 (s, 1H), 9.39 (s, 2H), 9.03 (d, 7 = 6.4 Hz, 1H), 8.46 (s, 2H), 7.92 (d, 7 = 9.6 Hz, 1H), 4.88 (s, 1H), 3.98 (s, 3H). MS-ESI: m / z 366.5 observed [M+H]+ ΜΛ / Ε / ΖυΖΖ / υοΊ Ί 00 Compound no. Structure ISG-LUC activation assay score Analytical data 57 Cl 0 HN^O í^N ll XH HN-N ++++ MS-ESI: m / z 376.47 observed [M+H]+ 58 F -vQ, O HN^OH Xíl4+ HN+0 'SOM ++ΓHz 13.44 (s, 1H), 13.11 (s, 1H), 8.88 (dd, J = 13.6, 7.6 Hz, 1H), 8.71 (s, 1H), 8.35 (s, 1H), 8.32 (d, J=8.8H, J. = 18), 8.10 (dd, J = 11.3,9.0 Hz, 1H), 3.96 (s, 3H). MS-ESI: m / z 360.41 observed [M+H]+ 59 0 HN^O f^NH HN'^^N íV I ++++ MS-ESI: m / z 429.48 observed [M+H]+ Compound no. Structure ISG-LUC Activation Assay Score Analytical Data 60 \ oo= / zz O a ++++ MS-ESI: m / z 371.47 observed [M+H]+ 61 ..... 0 HN O m ά γ nh 0 s N—' do HN-5^z8 ++6 O [M+H]+ 62 \ OO=¿ z^ / \_ / V \ '---<( O Π 'TO I ++ MS-ESI: m / z 395.46 observed [M+H]+ 63 FJ\ / F °YV OH HN^O r^N ll \ 7 HN+I [m+ / zO r^N ll \ 7 HN+I observed] m ++ / z-4 MA / E / ZUZZ / Uol Ί OS Compound no. Structure ISG-LUC activation assay score Analytical data 64 Cl A / Ci o^cp OH HN^O fX NN hn4 N ++ MS-ESI: m / z 366.7 observed [M+H]+ 65 4 ZZ o -Π +4 MS-z9+6 observed [m. Cl / L / F °yV OH HN^O ll \ 4 HN-N ++ MS-ESI: m / z 362.44 observed [M+H]+ 67 vX OH HN^O r^N 1 4 / n \ z? HN-N ++ MS-ESI: m / z 362.44 observed [M+H]+ VIA / I ΊΟΟ Compound no. Structure ISG-LUC activation assay score Analytical data 68 N ++++ MS-ESI: m / z 383.46 observed [M+H]+ I 0 HN^O r^N II \ 7 HN-zN 69 0 HN-O f^N II \ +7 m+7 MS-4+N observed [M+H]+ 70 KI OH Hh H \ / CI JJ II ^VN A 7 NN + MS-ESI: m / z 369.47 observed [M+H]+ MA / E / ZUZZ / Uol Ί OS Compuesto No. Estructura Puntaje de ensayo de activación ISG-LUC Datos analíticos 71 N II 1 0 HN..0 r^N II N 7”^ + MS-ESI: m / z 413.49 observado [M+H]+ 72 N II vV OH HN^.0 r^N II \ / ,N HN-N + MS-ESI: m / z 370.49 observado [M+H]+ 73 Cl v> 0 HN.^0 II A N-7 + Ή NMR (400 MHz, DMSO-í / 6) δ 12.99 (s, 1H), 9.07 (s, 1H), 8.80 (s, 1H), 8.47 (d, 7=8.8 Hz, 1H), 8.41 (d, 7 = 8.8 Hz, 1H), 8.21 (s, 1H), 4.05 (s, 3H), 3.98 (s, 3H). MS-ESI: m / z 431.10 observed [M+H]+ IVIA / I 100 Compuesto No. Estructura Puntaje de ensayo de activación ISG-LUC Datos analíticos 74 Cl 0 HN..0 A N—1 NH2 ++ MS-ESI: m / z 449.48 observado [M+H]+ 75 Z-Z 2—4 a— -Π o ++++ 'HNMR (400 MHz, DMSO-dó) δ 8.86-8.74 (m, 1H), 8.64 (d, J = 9.3 Hz, 1H), 8.45 (d, 7 = 9.5 Hz, 1H), 8.28-8.14 (m, 1H), 8.11 (d, 7=8.5 Hz, 1H), 8.04 (d, 7 = 6.3 Hz, 1H), 7.33-7.16 (m, 1H), 5.02 (s, 1H). MS-ESI: m / z 334.76 observado [M+H]+ 76 2=2 O 1 o=\ o ++++ *H NMR (400 MHz, DMSO-í / ó) δ 12.85 (s, 1H), 9.31 (s, 1H), 8.84 (s, 1H), 8.56 (d, 7 = 9.2 Hz, 1H), 8.49 (d, 7 = 8.8 Hz, 1H), 8.24 (s, 1H), 7.28 (s, 1H), 5.14 (s, 1H), 4.46 (q,7 = 6.8 Hz, 2H), 1.39 (t, 7 = 6.8 Hz, 3H) MS-ESI: m / z 397.4 observado [M+H]+ IVIA / I 100 Compuesto No. Estructura Testaje de test de activación ISG-LUC Analytical data 77 Cl wAo O. NH OH II N—J ++++ 'HNMR (400 MHz, DMSO-í / 6) δ 15.47 (s, 1H), 9.25 (d, J= 1.5 Hz, 1H), 8.80 (q, J= 1.2 Hz, 1H), 8.48 (dd, 7 = 9.1, 1.4 Hz, 1H), 8.42 (dd, 7 = 9.2, 1.4 Hz, 1H), 8.21 (q, 7= 1.4 Hz, 1H), 7.26 (q, 7= 1.2 Hz, 1H), 4.81 (d, 7= 1.6Hz, 1H). MS-ESI: m / z 369.44 observed [M+H]+ 78 / ° - / = \ 1 H\ / / z\ / AA V__y \---(7 x\---<7 z / ° ~ ++++ 'H NMR (400 MHz, DMSO-dó) δ 15.88 (s, 1H), 8.99 (s, 1H), 8.84 (d, 7=6 Hz, 2H), 8.60 (d, 7 = 9.2 Hz, 1H), 8.42 (d, 7=8.8 Hz, 1H), 8.24 (d, 7 = 6 Hz, 2H), 8.08 (s, 1H), 4.60 (s, 1H) MS-ESI: m / z 379.1 observed [M+H]+ 79 F ^T ^ Hz, 1H), 8.55 (d, 7 = 9.2 Hz, 1H), 8.44 (s, 1H), 7.90 (d, 7 = 9.8 Hz, 1H), 7.60 (s, 1H), 4.85 (s, 1H). MS-ESI: m / z 352.3 observed [M+H]+ ΜΛ / Ε / ΖυΖΖ / υοΊ Ί OS Compuesto No. Estructura Puntaje de ensayo de activación ISG-LUC Datos analíticos 80 — Z-Z. Z—G λ— O o ++++ ‘HNMR (400 MHz, MeOD) δ 9.93 (s, 1H), 8.90 (d,7 = 9.0 Hz, 1H), 8.57 (s, 1H), 8.50 (d, J = 9.2 Hz, 1H), 8.35 (d, J = 1.7 Hz, 1H), 8.04 (s, 1H), 7.85 (s, 1H), 4.40 (s, 1H). MS-ESI: m / z 350.59 observado [M+H]+ 81 I / ° — f / \ I y o ++++ ‘H NMR (400 MHz, DMSO-í / 6) δ 15.87 (s, 1H), 8.97 (s, 1H), 8.80 (s, 1H), 8.46 (d, 7 = 9.1 Hz, 1H), 8.41 (d, 7 = 9.1 Hz, 1H), 8.21 (s, 1H), 8.06 (s, 1H), 7.26 (s, 1H), 4.61 (s, 1H). MS-ESI: m / z 368.48 observado [M+H]+ 82 Cl C|>A LJL^o N H OH N^i H NJ' ++++ *H NMR (400 MHz, DMSO-í / 6)ó 15.74 (s, 1H), 9.30 (t,7= 1.0 Hz, 1H), 8.81 (d,7= 1.5 Hz, 1H), 8.61-8.36 (m, 2H), 8.22 (d,7= 1.6 Hz, 1H), 7.27 (d, 7 = 2.3 Hz, 1H). MS-ESI: m / z 380.16 observado [M+H]+ IVIA / I 100 Compound no. Structure ISG-LUC activation assay score Analytical data 83 | HO nY II V / N-NH ++++ 'HNMR (400 MHz, DMSO-ί / β) δ 15.91 (s, 1H), 8.50 (s, 2H), 8.47 (d, 7 = 6.8, 1H), 8.20-8.814 (m, 8, 1H), 4.63 (s, 1H). MS-ESI: m / z 404.2 observed [M+H]+ 84 FYYNO^NH N-nh i] NV HN—N ++ Ή NMR (499 MHz, DMSO-ófe) δ 12.79 (s, 1H), 8.96 (d, 7.3=1.8 Hz), 8.32-8.24 (m, 2H), 8.03 (d, 7=10 Hz, 1H), 4.78 (s,lH) MS-ESI: m / z 376.1 observed [M+H]+ 85 ov=° / Y 1 U-——Z^ / ° δ z-z=MMR *DM *++4) 12.84 (s, 1H), 8.94 (d, 7 = 6.4 Hz, 2H), 8.82 (s, 1H), 8.55-8.45 (m, 2H), 8.22 (s, 1H), 7.90 (d, 7= 10 Hz, 7. 1H), 1H), 4.42 (q, 7=6.8Hz, 1H), 1.39 (t, 7 = 6.8 Hz, 3H) MS-ESI: m / z 380.0 observed [M+H]+ IVIA / I 100 Compuesto No. Estructura Puntaje de ensayo de activación ISG-LUC Datos analíticos 86 z=z z—7 y-n 1 λ__' ° y O-( o — / o ++++ 'HNMR (499 MHz, DMSO-76) δ 12.65 (s, 1H), 8.93 (d, J = 6 Hz, 2H), 8.58 (d, 7 = 8.8 Hz, 1H), 8.50 (d, 7 = 9.2 Hz, 1H), 8.27 (s, 1H), 7.94 (d, 7 = 9.6 Hz, 1H), 7.32 (s, 1H), 6.98-6.94 (m, 1H), 4.93 (s, 1H), 4.18 (q, 7 = 7.2 Hz, 2H), 1.64 (d, 7 = 5.2 Hz, 3H), 1.22 (t, 7=7.2 Hz, 3H) MS-ESI: m / z 468.3 observado [M+H]+ 87 F Ο^,ΝΗ OH N^i 1' N—J ++++ 'H NMR (400 MHz, DMSO-í / 6)ó 15.81 (s, 1H), 8.97-8.66 (m, 2H), 8.538.28 (m, 2H), 8.21 (d, 7 = 1.5 Hz, 1H), 7.74 (d, J = 10.4 Hz, 1H), 7.27 (d, 7 = 2.2 Hz, 1H), 2.13 (s,3H). MS-ESI: m / z 366.5 observado [M+H]+ 88 / =\ o / = z^\ / \ / / __ / L H \ Z-Z 2—V / 1 )--' O—Z 1 o ++++ 'HNMR (400MHz, DMSO-¿6)ó 15.84 (s, 1H), 9.05-8.97 (m, 1H), 8.80 (d, 7= 1.4 Hz, 1H), 8.47 (dd, 7=9.0, 1.4 Hz, 1H), 8.41 (dd, 7 = 9.1, 1.4 Hz, 1H), 8.21 (d, 7= 1.6 Hz, 1H), 7.71 (dd, 7= 11.7, 1.4 Hz, 1H), 7.26 (q,7= 1.2 Hz, 1H), 6.97-6.77 (m, 1H), 5.87 (d, 7= 17.6 Hz, 1H), 5.48 (d,7= 11.0 Hz, 1H). MS-ESI: m / z 354.49 observed [M+H]+. IVIA / I 100 Compound No. Structure Activation Assay Score ISG-LUC Analytical Data 89 * / ° i U- — <X Λ— Z r--< / --' --\ / —Z / = / O Z=Z ++++ 'HNMR (400MHz, DMSO-7ó) δ 15.79 (d, J = 2.2 Hz, 1H), 8.94 (dd, J = 7.4, 1.9 Hz, 1H), 8.80 (q, 7 = 1.3 Hz, 1H), 8.43 (qt, 7 = 9.1, 1.4 Hz, 2H), 8.21 (q, 7 = 1.5 Hz, 1H), 7.68 (dd, 7 = 11.7, 2.0 Hz, 1H), 7.26 (d,7= 1.6 Hz, 1H), 6.54 (dd,7= 15.9, 2.2 Hz, 1H), 6.40-6.30 (m, 1H). MS-ESI: m / z 368.49 observado [M+H]+ 90 Π O^NH OH ii N-J +++ ‘H NMR (400 MHz, DMSO-76) δ 15.40 (s, 1H), 9.09 (s, 1H), 8.80 (s, 1H), 8.48-8.41 (m, 2H), 8.21 (s, 1H), 7.27 (s, 1H), 4.62 (s, 1H), 2.57 (s, 3H). MS-ESI: m / z 349.0 observado [M+H]+ 91 ci> An OTo O^NH OH N^i HN— ++ 'HNMR (400MHz, DMSO-í / ó) δ 15.35 (s, 1H), 9.19 (s, 1H), 8.80 (s, 1H), 8.49-8.41 (m, 2H), 8.21 (s, 1H), 7.26 (s, 1H). MS-ESI: m / z 359.1 observed [M+H]+ IVIA / I 100 Compuesto No. Estructura Puntaje de ensayo de activación ISG-LUC Datos analíticos 92 F LkOH O^NH 0 <> (NJ N J ++++ Ή NMR (400 MHz, DMSO-76)ó 15.32 (s, 1H), 9.31 (d, 7 = 8Hz, 1H), 8.80 (s, 1H), 8.50-8.43 (m, 1H), 8.41-8.37 (m, 1H), 8.21 (s, 1H), 7.27 (s, 1H), 4.714 (s, 1H) MS-ESI: m / z 353.2 observado [M+H]+ 93 Z=Z 2—(\ p—Q o +++ ‘H NMR (400 MHz, DMSO-76)ó8.81 (s, 1H), 8.65 (d, 7 = 9.3 Hz, 1H), 8.55 (s, 1H), 8.47 (d,7 = 9.3 Hz, 1H), 8.21 (t, 7 = 1.5 Hz, 1H), 7.33-7.23 (m, 1H), 5.26 (s, 1H). MS-ESI: m / z 351.1 observado [M+H]+ 94 F O^NH °Ύ^ X 0.^0 r^ N V ll ++++ *H NMR (400 MHz, DMSO-76) δ 12.65 (s, 1H), 8.94 (d, 7 = 6.4 Hz, 1H), 8.83 (s, 1H), 8.56 (d,7 = 9.2 Hz, 1H), 8.48 (d, 7 = 9.2 Hz, 1H), 8.24 (s, 1H), 7.87 (d, 7 = 9.6 Hz, 1H), 7.28 (s, 1H), 6.85 (d,7 = 4.8 Hz, 1H), 4.93 (s, 1H), 2.68-2.61 (m, 1H), 2.242.19 (m, 1H), 1.14-1.09 (m, 6H), 1.03-0.87 (m, 6H). MS-ESI: m / z 494.3 observado [M+H]+ IVIA / I 100 Compuesto No. Estructura Puntaje de ensayo de activación ISG-LUC Datos analíticos 95 z^\ z=z o X ^ΖΑ#Λ / Η o o=( o ++++ 'HNMR (400 MHz, DMSO-7ó) δ 12.87 (s, 1H), 9.25 (s, 1H), 8.86 (s, 1H), 8.57 (d, 7 = 9.2 Hz, 1H), 8.50 (d, 7 = 9.2 Hz, 1H), 8.26 (s, 1H), 7.29 (s, 1H), 4.46 (q, 7 = 6.8 Hz, 2H), 2.25 (s, 3H), 1.40 (t, 7 = 6.8 Hz, 3H). MS-ESI: m / z 411.6 observado [M+H]+ 96 o \=o z=z / ° ++ Ή NMR (400 MHz, DMSO-í / ó) δ 12.84 (s, 1H), 8.94 (d, 7 = 6.5 Hz, 1H), 8.87-8.79 (m, 1H), 8.55 (d, 7 = 9.1 Hz, 1H), 8.47 (d, 7 = 9.1 Hz, 1H), 8.288.19 (m, 1H), 7.90 (d,7 = 9.8 Hz, 1H), 7.27 (s, 1H), 5.26 (p, 7 = 6.2 Hz, 1H), 4.87 (s, 1H), 1.38 (d, 7 = 6.2 Hz, 5H). MS-ESI: m / z 394.1 observado [M+H]+ 97 „ o / z \ 7 / —z 0=7 o ++++ 'HNMR (400MHz, DMSO-¿ / 6) δ12.83 (s, 1H), 9.29 (s, 1H), 8.84 (s, 1H), 9.56 (d, 7 = 9.2 Hz, 1H), 8.49 (d, 7=8.8 Hz, 1H), 8.24 (s, 1H), 7.28 (s, 1H), 5.32-5.259 (m, 1H), 5.12 (s, 1H), 1.39 (d,7=6Hz, 6H) MS-ESI: m / z 411.5 observado [M+H]+ MA / E / ZUZZ / Uol Ί OS Compuesto No. Estructura Puntaje de ensayo de activación ISG-LUC Datos analíticos 'HNMR (400 MHz, Cl DMSO-í / 6) δ 13.18 (s, 1H), L1 9.57 (s, 1H), 8.63-8.56 (m, Τϊ 2H), 7.89-7.82 (m, 2H), 98 O^^NH 0 L^^-θ ++++ 7.38 (s, 1H), 4.73 (s, 2H), 3.78-3.73 (m, 4H), 2.97 (m, 2H), 2.68 (s, 3H) ú MS-ESI: m / z 482.3 observado [M+H]+ h 'HNMR (400MHz, Ck AT DMSO-¿6) δ 16.49 (s, 1H), 9.01 (d, J= 1.8 Hz, 1H), O. .NH OH 8.81 (s, 1H), 8.52-8.35 99 +++ (m, 3H), 8.22 (q, J= 1.4 Hz, 1H), 7.26 (s, 1H). II MS-ESI: m / z 369.43 ú observed [M+H]+ M Ή NMR (400 MHz, DMSO-í / ó) δ 16.32 (s, 1H), [1 9.02 (s, 1H), 8.80 (s, 1H), 8.49-8.47 (m, 1H), 8.43- 100 O^^NH OH +++ 8.41 (m, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 7.26 (s, 1H), 4.79 (s, 1H) II N MS-ESI: m / z 359.47 N. observed [M+H]+ o «—N ΜΛ / Ε / ΖυΖΖ / υοΊ Ί OS Compuesto No. Estructura Puntaje de ensayo de activación ISG-LUC Datos analíticos 101 zz O Z---G λ---,---( A / / \ / \ vJ —<\ / )—oz A / / — / —zo—¿ 1 A o ++++ MS-ESI: m / z 385.35 observado [M+H]+ 102 Cl CU / NH ό'Ύ o. ^0 ii l °a N । O LN ++++ Ή NMR (400 MHz, DMSO-76) δ 12.66 (s, 1H), 9.30(s, 1H), 8.85 (s, 1H), 8.58 (d, 7 = 9.2 Hz, 1H), 8.50 (d, 7 = 8.8 Hz, 1H), 8.25 (s, 1H), 7.28 (s, 1H), 7.03-6.99 (m, 1H), 5.18 (s, 1H), 4.19 (q, 7 = 7.2, 2H), 1.64 (d, 7 = 5.6 Hz, 3H), 1.25-1.14 (m, 3H) MS-ESI: m / z 485.6 observed [M+H]+ 103 8.23 (s, 1H), 7.89 (d,7 = 9.6Hz, 1H), 7.28 (s, 1H),4.89 (s, 1H), 4.49 (t, 7=5.2 Hz, 2H), 3.57-3.52 (m, 6H), 2.76 (t, 7 = 5.2 Hz, 4H) MS-ESI: m / z 465.2 observed [M+H]+ ΜΛ / Ε / ΖυΖΖ / υοΊ Ί OS Compuesto No. Estructura Puntaje de ensayo de activación ISG-LUC Datos analíticos 104 \ Cl II 1 Ok / NH OH li 0 N ++++ 'HNMR (400MHz, DMSO-dó) δ 15.54 (s, 1H), 9.19 (s, 1H), 8.82 (s, 1H), 8.47-8.42 (m, 2H), 8.23 (s, 1H), 7.28 (s, lH),2.19(s, 3H) MS-ESI: m / z 383.4 observado [M+H]+ 105 Cl W-™ CL.NH O H -¾¾.. .N 0 N—J ++ Ή NMR (400 MHz, DMSO-6?6) δ 14.06 (s, 1H), 9.44 (s, 1H), 9.01 (s, 1H), 8.86 (s, 1H), 8.52 (dd, 7 = 9.2, 30 Hz, 2H), 8.26 (s, 1H), 7.29 (s, 1H),5.O9 (s, 1H), 4.89 (t, 7=5.2 Hz, 1H), 3.58 (d, 7 = 5.6 Hz, 2H), 3.45 (d, 7 = 5.6 Hz) MS-ESI: m / z 412.3 observado [M+H]+ 106 O...NH O H 0 + 'HNMR (400MHz, DMSO-¿ / 6) δ 13.23 (s, 1H), 8.95-8.94 (m, 1H), 8.98.89 (m, 1H), 8.83 (s, 1H), 8.49 (dd, 7 = 9.2, 27.6 Hz, 2H), 8.23 (s, 1H), 7.86 (d, 7= 10 Hz, 1H), 7.27 (s, 1H), 4.83 (t, 7=6Hz, 1H), 4.78 (s, 1H), 3.56 (dd,7 = 6, 11.6 Hz, 2H), 3.38 (dd, 7= 5.6, 11.6 Hz, 2H) MS-ESI: m / z 395.3 observado [M+H]+ Compuesto No. Estructura Puntaje de test de activación ISG-LUC Analytical data 107 O / ° 2=< / \ TZ \ / z / ^2 / —y—\ / —z 1 / ° z=z ++++ 'HNMR (400 MHz, DMSO-¿Z6)ó 13.07 (s, ÍH), 9.29 (s, 1H), 8.81 (s, 1H), 8.50 (d, 7=8.8 Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.21 (s, 1H), 7.26 (s, 1H), 5.24 (s, 1H), 3.98 (s, 3H). MS-ESI: m / z 373.9 observed [M+H]+ 108 Χν O^ / NH OH N'^NN—NH + 'HNMR (400MHz, DMSO-¿ / 6) δ 9.90 (s, 2H), 9.01 (s, 2H), 8.99-8.98 (m, 1H), 8.14-8.09 (m, 1H), 3.67 (d, 7- 24.8 Hz, 1H) MS-ESI: m / z 352.2 observed [M+H]+ Documentos relacionados [1] Corrales L, Glickman LH, McWhirter SM, Kanne DB, Sivick KE, Katibah GE, Woo SR, Lemmens E, Banda T, Leong JJ, Metchette K, Dubensky TW Jr, Gajewski TF. (2015) Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity. Cell Rep 11: 1018-30. [2] Deng, L. et al. (2014) STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors, Immunity. 41:843. [3] Corrales L, Matson V, Flood B, Spranger S, Gajewski TF. (2017) Innate immune signaling and regulation in cancer immunotherapy. Cell Res 27:96-108. IVIA / E / ZUZZ / UÓ I IOO [4] Corrales L, McWhirter SM, Dubensky TW Jr, Gajewski TF. (2016) The host STING pathway at the interface of cancer and immunity. J Clin Invest. 126: 2404-11. METHODS OF USE This disclosure also provides, in one modality, a method for stimulating interferon gene expression in a human patient. The method comprises administering to the patient an effective dose of a compound or one of its pharmaceutically acceptable salts as described herein. In another embodiment, the present description provides a method for treating a tumor in a patient. The method comprises administering to the patient an effective dose of a compound or one of its pharmaceutically acceptable salts. With respect to combination therapies comprising the administration of a compound of this disclosure and an immune checkpoint-targeting drug, or as combination therapies for the augmentation of existing ionizing radiation-based therapeutic approaches and chemotherapies, such as DNA damage-based chemotherapies, the STING agonists of this disclosure may complement and enhance the effects of these known therapeutic approaches. This is based on recent articles indicating the critical role of STING-dependent micronucleus-mediated tumor elimination using these approaches; see, for example: [5] Mackenzie, KF, et al, (2017), micronucleus cGAS surveillance links genome instability to innate immunity, Nature, 548, 461. [6] Wang, W. et al., (2016), Effector T cells override stroma-mediated chemoresistance in ovarian cancer, Cell, 165, 1092-1105. [7] Charlotte E. Ariyan, et al., January 16, 2018; DOI: 10.1158 / 2326-6066, Strong antitumor responses as a result of local chemotherapy and CTLA-4 blockade, cancerimmunolres.aacrjournals.org on January 31, 2018. [8] Chung Kil Song, et al., www.moleculartherapy.org vol 15 no. 8 August 2007, Chemotherapy enhances CD8+ T cell-mediated antitumor immunity induced by Vaccinia virus vaccination. The compounds described herein may be used in therapeutic combinations with the administration of an effective dose of an immune checkpoint-targeting drug. For example, the immune checkpoint-targeting drug may be an anti-PD-L1 antibody, an anti-PD-1 antibody, an anti-CTLA-4 antibody, or an anti-4-1BB antibody. See, for example: [9] Ager, CR, et al., (2017) Cancer Immunol Res; 5(8), 676.

[10] Fu, J. et al. (2015) Sci Transí Med. 2015 April 15; 7(283): 283ra52. ΜΛ / t / ZUZZ / UÓ 1100 doi: 10.1126 / scitranslmed.aaa4306.

[11] Wang, H., et al. (2017) PNAS, February 14, 2017, vol. 114, no. 7, 1637-1642. PHARMACEUTICAL COMPOSITION The present description provides in another embodiment a pharmaceutical composition comprising a compound or one of its pharmaceutically acceptable salts as described herein in combination with a pharmaceutically acceptable vehicle or excipient. The compositions described herein may be administered orally, topically, parenterally, by inhalation or spray, or rectally in unit-dose formulations. The term parenteral, as used herein, includes subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection, or infusion techniques. Suitable oral compositions as described in this document include, without limitation, tablets, lozenges, pastilles, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. The compositions described herein that are suitable for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions. For example, liquid formulations of the compounds described herein contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives to provide pharmaceutically palatable preparations of the compound or a pharmaceutically acceptable salt thereof. For tablet compositions, the compound or a pharmaceutically acceptable salt thereof mixed with non-toxic, pharmaceutically acceptable excipients is used to manufacture tablets. Examples of such excipients include, without limitation, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin, or acacia; and lubricating agents, such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated using known coating techniques to delay disintegration and absorption in the gastrointestinal tract and thus provide sustained therapeutic action for a desired period of time.For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used. Oral formulations may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, IVIA / t / ZUZZ / UÓ I ΊOOO calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium, for example, peanut oil, liquid paraffin or olive oil. For aqueous suspensions, the compound or one of its pharmaceutically acceptable salts is mixed with suitable excipients to maintain a stable suspension. Examples of such excipients include, but are not limited to, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum. Oral suspensions may also contain dispersing or wetting agents, such as natural phosphatides, for example, lecithin; condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate; condensation products of ethylene oxide with long-chain aliphatic alcohols, for example, heptadecaethylenexycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, such as polyoxyethylsorbitol monooleate; or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more colorants; one or more flavorings; and one or more sweeteners, such as sucrose or saccharin. Oil suspensions can be formulated by suspending the compound or one of its pharmaceutically acceptable salts in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oil suspensions may contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners, such as those described above, and flavoring agents can be added to provide palatable oral preparations. These compositions can be preserved by adding an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for preparing an aqueous suspension by adding water provide the compound or one of its pharmaceutically acceptable salts mixed with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those mentioned above. Additional excipients, such as sweeteners, flavorings, and colorants, may also be present. The pharmaceutical compositions described herein may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example. IVIA / E / ZUZZ / UÓ I 100, for example, olive oil or peanut oil, or a mineral oil, for example, liquid paraffin, or mixtures thereof. Suitable emulsifying agents may be natural gums, for example, gum arabic or tragacanth gum, natural phosphatides, for example, soybean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example, sorbitan monooleate, and condensation reaction products of such partial esters with ethylene oxide, for example, polyoxyethylsorbitan monooleate. Emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. Pharmaceutical compositions may be in the form of a sterile injectable, an aqueous suspension, or an oily suspension. This suspension may be formulated according to known techniques using the appropriate dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic diluent or solvent acceptable to parents, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution.In addition, sterile fixed oils are conventionally used as solvents or suspension mediums. Any soft fixed oil, including synthetic mono- or diglycerides, can be used for this purpose. Furthermore, fatty acids such as oleic acid are used in the preparation of injectables. The compound or one of its pharmaceutically acceptable salts may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compound with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at rectal temperature and will therefore melt in the rectum to release the compound. Exemplary excipients include cocoa butter and polyethylene glycols. Parenteral formulations are administered in a sterile environment. Depending on the vehicle used and the concentration of the compound or one of its pharmaceutically acceptable salts in the formulation, the parenteral formulation may be a suspension or a solution containing the dissolved compound. Adjuvants such as local anesthetics, preservatives, and buffering agents may also be added to parenteral formulations. EXAMPLES IVIA / I 100 The following non-limiting examples are additional modalities to illustrate this disclosure. Tissue culture. Wild-type THP-1 -Lucia ISG (n.ade cat. thpl-isg) and STING KO (n.2de cat. thpd-kostg) cells were purchased from Invivogen and maintained in growth media consisting of RPMI 1640, 2 mM L-glutamine, 25 mM HEPES, 10% heat-inactivated fetal bovine serum (FBS), 1000 units / ml penicillin, 1000 pg / ml streptomycin, 0.25 pg / ml amphotericin B, and 100 pg / ml zeocin, unless otherwise stated. Type 1 interferon stimulation. Poly(dA:dT) and 2'3'-cGAMP were purchased from invivogen and resuspended according to the manufacturer's instructions. ISRE-luciferase assay. THP-1 Lucia ISG cells were resuspended in low serum content culture medium (2% FBS) at a density of 5 x 10⁵ cells / ml and treated with the test article or vehicle (DMSO). Fifty milliliters of cells were seeded into each well of 384-well white Greiner plates and incubated for 24 hours. To assess luciferase indicator expression, 30 milliliters of Quanti-luc detection reagent (Invivogen) were added to each well, and luminescence was read using an Envision plate reader (Perkin Elmer) with an integration time of 0.1 seconds. Viability assay. Cells were resuspended in low serum culture medium at a density of 5 x 10⁵ cells / ml and treated with the test article or vehicle (DMSO). Fifty milliliters of cells were seeded into each well of 384-well white Greiner plates and incubated for 24 hours. To assess luciferase indicator expression, 30 milliliters of CelITiter-Glo detection reagent (Promega) were added to each well, and luminescence was read using an Envision plate reader set with an integration time of 0.1 seconds. Western blot. Cells were solubilized in 1X protein lysis buffer (HEPES 25 mM, pH 7.4, NaCl 300 mM, MgCh 1.5 mM, EGTA 1 mM, P-40 1%, sodium deoxycholate 1%, sodium pyrophosphate 2.5 mM, glycerophosphate 1 mM) with added protease and phosphatase inhibitors (Cell Signaling). Western blotting was performed using Bolt™ 4-12% BisTris gels and the Bolt™ mini transfer system according to the manufacturer's instructions (ThermoFisher Scientific). STING and γ-tubulin antibodies were obtained from Cell Signaling and diluted in 5% BSA and 1X TBS-T buffer (Table 3). Rabbit antl-HRP antibody was diluted in 5% skimmed milk powder, 1X TBS-T buffer, and luminescence signal images were taken using a ChemiDoc Imager (BioRad). Semi-quantitative real-time PCR (qPCR) was used. THP-1 cells were resuspended in low-serum culture medium at a density of 5 x 10⁵ cells / ml and treated with the test article or vehicle (DMSO). 2.5 mL of cells were seeded into each well of a 6-well plate and incubated for 24 hours. RNA was isolated using a kit. RNeasy Plus Mini (Qiagen) and 1 pg of purified RNA were reverse transcribed into cDNA (VILO, cat. no. 11755050, ThermoFisher Scientific). Gene expression was assessed using TaqMan primers and probes listed in Table 4 with TaqMan Universal Mix II (cat. no. 4440038, ThermoFisher) according to the manufacturer's instructions. Gene expression was normalized using the double-delta Ct method and reported as a change in expression. STING Heat Shift Assay (TSA). The c-terminal domains (CTDs) of human and mouse STING were expressed and purified as detailed above (Ouyang, S., Song, X., Wang, Y., Ru, H., Shaw, N., Jiang, Y., Niu, F., Zhu, Y., Qiu, W., Parvatiyar, K., et al. (2012). Structural analysis of the STING adaptor protein reveals a hydrophobic dimer interface and mode of cyclic di-GMP binding. Immunity 36, 1073-1086.). The test article or vehicle controls were added to diluted STING protein (0.22 mg / ml) in 1X Protein Heat Shift Buffer provided in the Protein Heat Shift Dye Kit (catalog no. 4461146, ThermoFisher Scientific). The thermal shift dye was added and mixed before performing a melting curve following the parameters described for the dye kit. Melting temperatures (Tm) were calculated using the Derived method using the Protein Thermal Shift v1.3 software (cat # 4466038, ThermoFisher Scientific). WT STING binding assay (Cisbio, catalog number 64BDSTGPEH). An assay format was optimized to demonstrate the binding of recombinant human STING protein labeled with Terbium Cryptote 6x, His 6x, to the natural ligand, d2-labeled 2',3'cGAMP (the acceptor). Upon proximity of the two dyes, excitation of the donor by the flash lamp of the PHERAstar FSX plate reader triggers fluorescence resonance energy transfer (FRET) to the acceptor, which in turn fluoresces at 665 nm. To evaluate the ability of synthetic small-molecule STING ligands to bind to human STING, a competitive assay format was applied. A 10-point titration of each of the synthetic ligands in 5 µL was transferred to a 384-well plate, followed by 20 µL of assay buffer containing the His 6x-labeled human STING protein and the labeled 2'3'cGAMP ligand and incubated for three hours at room temperature.The raw values ​​obtained from PHERAstar were used to calculate the reported IC50 values ​​(the signal is inversely proportional to the synthetic ligand binding) by curve fitting in Genedata. The percentage of inhibition was calculated based on the maximum amount of binding per synthetic compound versus the maximum binding of unlabeled 2',3' cGAMP, which was used as a control in each assay. YOOO Table 2: Cell signaling antibodies Target Protein Cat. No. Dilution STING 13647 1:1000 γ-tubulin 5S86 1:3000 Rabbit IgG 7074 1:3000 IVIA / I IOO Table 3: Primers / ThermoFisher Scientific Taqman probe Gene Symbol Species Cat. No. Dye IFNB1 human Hs01077958_sl FAM CXCL10 human Hs00171042_ml FAM IFIT3 human Hs01922752_sl FAM B2M human Hs00187842_ml VIC The compounds useful for carrying out a method of the present disclosure can be prepared according to the following procedures in conjunction with ordinary knowledge and skill in organic synthesis, substituting the appropriate reagents as is obvious to the practitioner. Experimental procedures Abbreviations. The following abbreviations are used: tetrahydrofuran (THF), dichloromethane (DCM), Ν,Ν-dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), trifluoroacetic acid (TFA), triethylamine (TEA), diisopropylethylamine (DIPEA), hexafluorophosphate (1 pyridinium 3-oxide hexafluorophosphate, N-[(dimethylamino)-1 H-1,2,3-triazolo-[4,5-b]pyridín-1 -ylmethylene]-N-methylmethane hexafluorophosphate N-oxide (HATU). General examples for the preparation of compounds in this disclosure. Starting materials and intermediates for the compounds described herein may be prepared by applying or adapting the methods described below, their obvious chemical equivalents, or, for example, as described in the literature such as *The Science of Synthesis*, Volumes 1–8, edited by E.M. Carreira et al., Thieme Publishers (2001–2008). Details of reagent and reaction options are also available through structure and reaction searches using commercial computer search engines such as SciFinder (www.cas.org) or Reaxys (www.reaxys.com). PART I: PREPARATION FOR INTERMEDIATE LEVELS Scheme 1: Summary of Intermediate-A: IVIA / t / ZUZZ / UÓ I IOO Step 1: Synthesis of ethyl 6-(pyridin-4-yl)pyridazine-3-carboxylate: To an argon-purged solution of ethyl 6-chloropyridazine-3-carboxylate (4.0 g, 21.4 mmol), 4-(tributylstannyl)pyridine (8.71 g, 23.65 mmol) in 1,4-dioxane (40 mL) was added, and the resulting mixture was stirred at room temperature for 10 min before adding Pd(PPh3)4 (2.48 g, 2.15 mmol). The reaction mixture was stirred at 110 °C for 16 hours. Once complete, the reaction mixture was diluted with acidic solution. The solution was prepared with NaHCO3 (50 mL) and extracted with EtOAc (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to yield ethyl 6-(pyridin-4α)pyridazin-3-carboxylate (2.5 g, 46% yield) as a white solid. 1H NMR (400 MHz, DMSO-cfe): δ 8.84 (m, 2H), 8.58 (d, J= 8.8 Hz, 1H), 8.38 (d, J= 8.8 Hz, 1H), 8.21 (m, 2H), 4.48 (q, J= 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H).LC-MS (ESI+): m / z; 230.14 [M+H]+. Step 2: Synthesis of 6-(pyridin-4-yl)pyridazine-3-carboxylic acid (A): An aqueous solution of lithium hydroxide monohydrate (0.55 g, 13.1 mmol) in water (10 mL) was added to a solution of ethyl 6-(pyridin-4-yl)pyridazine-3-carboxylate (2.5 g, 10.9 mmol) in THF (10 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 5 hours. MeOH (10 mL) was added, and the mixture was stirred at 60 °C for 1 hour. After the reaction was complete, the THF and MeOH were removed under reduced pressure, and the aqueous phase was acidified with 2N HCl (pH 4). The resulting solid was filtered, washed with water, and dried. The mixture was then ground with acetonitrile, filtered, and the filter cake was dried to provide compound A (1.4 g, 53% yield) as a pale brown solid. 1H NMR (400 MHz, DMSO-ds): δ 14.02 (s, 1H), 8.84 (m, 2H), 8.56 (d, J = 8.8 Hz, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.21 (m, 2H). LC-MS (ESI-): m / z; 200.11 [MH]'. Scheme 2: Synthesis of Intermediate-B: ácido pirazol-4-borónico Pd(PPh3)4,clioxano ac. Na2CO3, 90 °C, 1 h Paso 1 MA / E / zUZZ / Uol Ί OO Step 1: Synthesis of ethyl 6-(1H-pyrazol-4-yl)pyridazine-3-carboxylate: Argon gas was purged through a solution of pyrazol-4-boronic acid (4.51 g, 40.31 mmol), Na₂CO₃ (7.1 g, 67.2 mmol), and ethyl 6-chloropyridazine-3-carboxylate (5 g, 26.88 mmol) in 1,4-dioxane (175 mL) and water (25 mL) for 10 min before the addition of Pd(PPhs)₄ (1.55 g, 1.34 mmol). The reaction mixture was stirred at 90 °C for 1 h. After the reaction was complete, it was cooled to room temperature and diluted with EtOAc (250 mL). The sample was then washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield 3.2 g of ethyl 6-(1H-pyrazol-4-yl)pyridazine-3-carboxylate as a whitish solid. LC-MS (ESI+): m / z 219.0 [M+H]+. Step 2: Synthesis of 6-(1-((2-(trimethylyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridazine-3-carboxylate ethyl: NaH (60% w / w) (0.422 g, 17.6 mmol) was added in portions to a stirred solution of ethyl 6-(1H-pyrazol-4-yl)pyridazine-3-carboxylate (3.2 g, 14.67 mmol) in THF (64 mL) and DMF (30 mL) at 0 °C and stirred for 10 min. SEM-CI (2.93 g, 17.61 mmol) was then added, and the reaction mixture was stirred at 0 °C for 30 min. The mixture was then inactivated with a 10% citric acid solution, and the resulting solid was filtered, washed with water (5 mL x 2), and dried. The residue was purified by column chromatography on silica gel (using 0-5% methanol in dichloromethane as eluent) to produce 2.65 g of 6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-1I)pyridazine-3-carboxylate ethyl as a whitish solid. LC-MS (ESI+): m / z-, 349.1 [MH]+. Step 3: Synthesis of 6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrazol-4yl)pyridazine-3-carboxylic acid (B): An aqueous solution of lithium hydroxide monohydrate (0.382 g, 9.13 mmol, in 3 mL of water) was added to a solution of 6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ylethyl)pyridazine-3-carboxylate (2.65 g, 7.61 mmol) in THF (9 mL) at 0 °C and stirred at room temperature for 2 h. After the reaction was complete, the reaction mixture was diluted with water (10 mL) and washed with EtOAc (30 mL x 2). The aqueous layer was acidified using a 2N HCl solution (pH-4) and the resulting solid was filtered, washed with water (2 mL x 2) and dried to yield 1.1 g of B as a whitish solid. 1H NMR (400 MHz, DMSO-oe) δ 13.62 (s, 1H), 8.78 (s, 1H), 8.33 (s, 1H), 8.18-8.13 (m, 2H), 5.51 (s, 2H), 3.61 (t, J = 8.0 Hz, 2H), 0.87 (d, J = 8.0 Hz, 2H), 0.04 (s, 9H). LC-MS (ESI+): m / z 321.0 [M+H]+. IVIA / t / ZUZZ / UÓ I ΊOOO Scheme 3: Intermediate-C Summary: TMS^^ Cl Pd(PPh3)2CI2, CO2Me Cul.TEA, THF 25 °C, 1 h Paso 1 tms CO2Me Paso 2 TBAF, THF 25 °C,1 h PMBN3, CuSO4ascorbato de sodio t-BuOH, H2O 40 °C, 2 h Paso 3 OH ,CO2Me L¡OH-H2On X N V THF, H2OΊ ° °C, 12 h n'' Y N V N-J Paso 4N-^ pmb' PMB c Step 1: Synthesis of methyl 6-((trimethylsilyl)ethynyl)pyridazine-3-carboxylate: To a solution of methyl 6-chloropyridazine-3-carboxylate (1 g, 5.79 mmol) in THF (10 mL) were added ethynyl(trimethyl)silane (4.0 mL, 29.0 mmol), Pd(PPh3)2Cl2 (407 mg, 0.58 mmol), Cul (221 mg, 1.2 mmol) and EtsN (0.807 mL, 5.79 mmol) and the resulting mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the mixture was filtered through a layer of silica gel and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc) to provide methyl 6-((trimethylsilyl)ethynyl)pyridazine-3-carboxylate (500 mg, 37% yield) as a yellow solid. Step 2: Synthesis of methyl 6-ethynylpyridazine-3-carboxylate: To a solution of methyl 6-(trimethylsyl)ethynyl)pyridazine-3-carboxylate (500 mg, 2.13 mmol) in THF (10 mL), TBAF (1 M in THF, 4.27 mL, 4.27 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. Once complete, the reaction mixture was poured into H2O (50 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc) to provide methyl 6-ethynylpyridazina3-carboxylate (260 mg, 75% yield) as a brown solid. Step 3: Synthesis of methyl 6-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)pyridazin-3-carboxylate: To a solution of methyl 6-ethynylpyridazin-3-carboxylate (500 mg, 3.1 mmol) and 1-(azidomethyl)-4-methoxybenzene (1.0 g, 6.2 mmol) in H2O (4 mL) and t-BuOH (16 mL), CUSO4 (98.4 mg, 0.62 mmol) and sodium ascorbate (489 mg, 2.5 mmol) were added. The reaction mixture was purged with nitrogen and stirred at 40 °C for 2 h. After the reaction was complete, it was diluted with EtOAc (50 mL) and H2O (20 mL). The precipitate was filtered and the filter cake was washed with DCM / MeOH 10 / 1 (500 mL). The filtrate was concentrated under reduced pressure to produce methyl 6-(1-(4-methoxybenzyl)-1H-1,2,3-trazol-4-1)pinazine-3-carboxylate (600 mg, 60% yield) as a gray solid. LCMS (ESI+): m / z 325.9 [M+H]+. Step 4: Synthesis of lithium 6-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)pyridazine-3-carboxylate (C): A solution of methyl 6-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)pyridazine-3-carboxylate (250 mg, 0.77 mmol) in THF (2.5 mL) was added to a solution of lithium hydroxide monohydrate (96.7 mg, 2.3 mmol) in water (2.5 mL) at 0 °C. After stirring at room temperature for 12 h, the precipitate was filtered and the filter cake was dried under reduced pressure. The residue was ground with acetonitrile and filtered to give acid C (70.0 mg, 29% yield) as a gray solid. LCMS (ESI+): m / z 312 [M+H]+. PART II: PREPARATION OF EXEMPLARY COMPOUNDS All compounds were prepared using the procedures exemplified below. Example 1: Scheme 4: Synthesis of Compound 1: Step 1: Synthesis of methyl 5-fluoro-2-(6-(pyridin-4-yl)pyridazine-3-carboxamido)-4-((trimethylsilyl)ethynyl)benzoate: To a solution of intermediate C (1.4 g, 7.0 mmol) and DIPEA (6.17 mL, 34.8 mmol) in DCE (30 mL) T3P (50% in EtOAc) (13.29 mL, 20.89 mmol) was added at room temperature, followed by methyl 2-amino-5-fluoro-4-((trimethylsyl)ethynyl)benzoate (1.8 g, 7.0 mmol). The reaction mixture was stirred at 80 °C for 7 h. After the reaction was complete, the volatiles were removed under reduced pressure and saturated NaHCO3 solution (15 mL) was added. The resulting solid was filtered, washed with water, and dried. The residue was purified by column chromatography (ΡΕ / EtOAc) to give methyl 5-fluoro-2-(6-(pyrídin-4-¡l)pyridazine-3carboxamido)-4-((trimethylsil¡l)ethynyl)benzoate (2.2 g, 70% yield) as a pale cream solid.1H NMR (400 MHz, DMSO-de): or 12.96 (s, 1H), 8.98 - 8.84 (m, 1 H), 8.69 (d, J= 8.8 Hz, 2H), 8.52 (m, 1H), 8.26 (m, 1H), 8.24 (m, 2H), 7.92 (m, 1H), 3.97 (s, 3H), 0.29 (s, 9H). LC-MS (ESI-): m / z; 447.28 [MH]'. Step 2: Synthesis of methyl 4-ethynyl-5-fluoro-2-(6-(pyridin-4-yl)pyridazine-3-carboxamido)benzoate: TBAF (1M in THF) (4.9 mL, 4.9 mmol) was added to a stirred solution of methyl 5-fluoro-2-(6-(pyridin-4-yl)pyridazine-3-carboxamido)-4-((trimethylsyl)ethynyl)benzoate (2.2 g, 4.90 mmol) in THF (22 mL) at 0 °C and the resulting mixture was stirred at room temperature for 30 min. After the reaction was complete, saturated acidic NaHCO3 solution (20 mL) was added. The solid was filtered, washed with water, and dried. The residue obtained was purified by column chromatography (DCM / MeOH) to generate methyl 4-ethynyl-5-fluoro-2-(6-(pyridine-4-1)pyridazin-3-carboxamido) benzoate (1.1 g, 60% yield) as a pale orange solid.1H NMR (400 MHz, DMSO-cfe): δ 12.96 (s, 1H), 8.97 (d, J= 6.8 Hz, 1H), 8.86 - 8.84 (m, 2H), 8.68 (d, J = 8.8 Hz, 1H), 8.51 (d, J = 8.8 Hz, 1H), 8.26 - 8.24 (m, 2H), 7.93 (d, J =10.0 Hz, 1H), 4.87 (s, 1H), 3.97 (s, 3H). LCMS: m / z 377.2 [M+H]+. Step 3: Synthesis of lithium 4-ethynyl-5-fluoro-2-(6-(pyridin-4-yl)pyridazine-3-carboxamido)benzoate (1): An aqueous solution of lithium hydroxide monohydrate (33.4 mg, 0.8 mmol) in water (2 mL) was added to a solution of methyl 4-ethynyl-5-fluoro-2-(6-(pyridin-4-yl)pyridazine-3-carboxamido)benzoate (200 mg, 0.5 mmol) in THF (4 mL) at 0 °C and the resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, the resulting solid was filtered, washed with water, and dried. It was then ground with acetonitrile, filtered, and dried to provide compound 1 as the lithium salt (99 mg, 54% yield) as a whitish solid. 1H NMR (400 MHz, DMSO-ok): <5 8.93 (d, J = 6.8 Hz, 1H), 8.85 - 8.83 (m, 2H), 8.61 (d, J = 8.8 Hz, 1H), 8.43 (d, J = 8.8 Hz, 1H), 8.25 - 8.24 (m, 2H), 7.79 (d, J = 10.4 Hz, 1H), 4.52 (s, 1H). LC-MS (ESI+): m / z 363.2 [M+H]+. Procedures analogous to those used for the synthesis of compound 1 were used for the synthesis of compounds 10, 13, 16, 19, 38, 44, 49, 52, 29, 31, 33, 46, 47, 77, 54, 53, 57, 58, IVIA / t / ZUZZ / UÓ I ΊOOO 63, 66, 60, 55, 56, 46, 79, 66, 67, 68, 69, 70, 71, 73, 96, 97, 98, 99, 100, 101, 102, 103, 104, 107,108, 10, 90, 82, 88 and 81 et al. MA / E / ZUZZ / Uol Ί OO Example 2: Scheme 5: Synthesis of compound 2: Boc-glycine, AgNO3(NH4)2S2O8, water 80 °C, 30 min Step 1 imidazole THF, NaH °C, 2 h Step 2 EtOH, NaOAc CO (100 ps¡) 90 °C, 24 h Step 3 Step 1: Synthesis of tert-butyl ((3,6-dichloropyridazin-4-yl)methyl)carbamate: To a suspension of Boc-glycine (20.0 g, 114.2 mmol) in H2O (100 mL) were added 3,6-dichloropyridazine (10.0 g, 67.1 mmol) and silver nitrate (1.1 g, 6.7 mmol), and the resulting mixture was heated to 80 °C. Ammonium sulfate solution (27.6 g, 120.9 mmol) in H2O (40 mL) was added dropwise to the reaction mixture at 80 °C for 30 min. The reaction mixture was then stirred at 80 °C for an additional 30 min. It was then cooled to room temperature and basified with concentrated sodium chloride. ammonium hydroxide (pH 10) was used, and the mixture was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (hexanes / EtOAc) to generate tert-butyl ((3,6-dichloropyridazin-4-yl)methyl)carbamate (15.0 g, 40% yield) as a thick, light red oil.1H NMR (400 MHz, CDCI3): δ 7.49 (s, 1H), 4.38 (d, J= 6.0 Hz, 2H), 1.49 (s, 9H). LC-MS (ESI-): m / z 278.1 [ΜΗ]'. Step 2: Synthesis of tert-butyl ((6-chloro-3-(1H-imidazol-1-yl)pyridazin-4-yl)methyl)carbamate and tert-butyl ((3-chloro-6-(1H-imidazol-1-yl)pyridazin-4-yl)methyl)carbamate: To a solution of imidazole (5.9 g, 86.2 mmol) in THF (200 ml) NaH (60% in mineral oil) (3.5 g, 86.2 mmol) was added at 0 °C and the resulting mixture was stirred for 15 min. tert-butyl ((3,6-dichloropyridazin-4-yl)methyl)carbamate (20.0 g, 72.1 mmol) was added and the reaction mixture was stirred at 60 °C for 2 h. Once the reaction was complete, the mixture was cooled to room temperature, diluted with water (200 mL), and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na₂S₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc) to obtain a mixture of the desired compounds (8.1 g, 36% yield) as a light brown solid, which was used in the next step as a mixture.LC-MS (ESI+): m / zr.t. = 1.24 min, 310.19 [M+H]+y r.t. = 1.28 min, 310.15 [M+H]+. Step 3: Synthesis of ethyl 5-(((tert-butoxycarbonyl)amino)methyl)-6-(1H-imidazol-1yl)pyridazine-3-carboxylate and ethyl 4-(((tert-butoxycarbonyl)amino)methyl)-6-(1H-imidazol-1yl)pyridazine-3-carboxylate: To a solution of a mixture of tert-butyl ((6-chloro-3-(1H-imidazol-1yl)pyridazine-4-1l)methyl)carbamate and tert-butyl ((3-chloro-6-(1H-imidazol-1yl)pyridazine-4-1l)methyl)carbamate compounds (6.5 g, 21.0 mmol) in EtOH (97.5 mL) sodium acetate (3.4 g, 41.9 mmol) was added and the The resulting mixture was purged with argon for 10 minutes. Then, Pd(dppf)Cl2 (0.77 g, 1.0 mmol) was added, and the reaction mixture was stirred under CO2 pressure (68.9476 MPa (100 psi)) at 90 °C for 24 h. It was then cooled to room temperature, and the volatiles were evaporated under reduced pressure. Saturated acidic NaHCO3 solution (100 mL) was added, and the mixture was extracted with EtOAc (100 mL x 3).The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH) to provide a mixture of ethyl 5-(((tert-butoxycarbonyl)amino)methyl)-6-(1H-imidazol-1-yl)pyridazine-3-carboxylate and ethyl 4-(((tert-butoxycarbonyl)amino)methyl)-6-(1H-imidazol-1-yl)pyridazine-3-carboxylate (6.5 g, 89% yield) as a brown solid. LC-MS: m / z rt = 1.36 min, 348.4 [M+H]+ and rt = 1.29 min, 348.3 [M+H]+. Steps 4 and 5: Synthesis of methyl 2-(5-(((tert-butoxycarbonyl)amino)methyl)-6-(1H-imidazol-1yl)pyridazine-3-carboxamido)-4,5-difluorobenzoate and methyl 2-(4-(((tert-butoxycarbonyl)amino)methyl)-6-(1H-imidazol-1-yl)pyridazine-3-carboxamido)-4,5-difluorobenzoate: An aqueous solution of lithium hydroxide monohydrate (0.32 g, 7.7 mmol) in water (12.5 mL) was added to a solution of ethyl 5-(((tert-butoxycarbonyl)amino)methyl)-6-(1H-imidazol-1-yl)pyridazine-3-carboxylate and Ethyl 4-((((tert-butoxycarbonyl)amino)methyl)-6-(1-Himidazol-1-yl)pyridazin-3-carboxylate (2.5 g, 1 / 2 mmol) was added to THF (25 mL) and the resulting mixture was stirred at room temperature for 30 min. After the reaction was complete, the THF was removed under reduced pressure and the aqueous layer was acidified with 3N HCl (pH 4-5). The volatiles were removed by lyophilization to obtain a mixture of the corresponding carboxylic acids. The mixture was dissolved in DMF (41 mL) and 4,5-difluoroanthranilate was added. IVIA / t / ZUZZ / UÓ I ΊOOO of methyl (3.2 g, 17.1 mmol) and DIPEA (7.38 mL, 42.40 mmol). HATU (4.9 g, 12.8 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 80 °C for 7 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with saturated acidic NaHCO3 solution (220 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2S4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH) to produce methyl 2-(5-(((tert-butoxycarbonyl)amino)methyl)-6-(1H-imidazol-1αl)pyridazine-3-carboxamido)-4,5-difluorobenzoate (0.75 g, 21% yield) as a yellow solid and methyl 2-(4-(((tert-butoxycarbonyl)amino)methyl)-6-(1H-imidazol-1-yl)pyridazine-3-carboxamido)-4,5-difluorobenzoate (0.11 g, 3% yield) as a fluffy light brown solid.Compuesto 5-sustituido:1H NMR (400 MHz, DMSO-óe): ó 13.09 (s, 1H), 8.88 - 8.81 (m, 1H), 8.35 (s, 1H), 8.43 (s, 1H), 8.14 - 8.06 (m, 1H), 7.89 - 7.84 (m, 2H), 7.26 (s, 1H), 4.37 (d, J= 6.0 Hz, 2H), 3.95 (s, 3H), 1.40 (s, 9H). LC-MS (ESI+): m / z489.69 [M+H]+. Compuesto 4-sustituido:1H NMR (400 MHz, DMSO-cfe): 5 12.99 (s, 1H), 8.84 - 8.77 (m, 2H), 8.15 - 8.07 (m, 3H), 7.36 (s, 1 H), 7.29 (s, 1 H), 4.79 (d, J = 5.6 Hz, 2H), 3.95 (s, 3H), 1.42 (s, 9H). LC-MS (ESI+): m / z487.3 [M-H]. Step 6: Synthesis of methyl 2-(4-(aminomethyl)-6-(1H-imidazol-1-yl)pyridazine-3-carboxamido)-4,5-difluorobenzoate 2: To a solution of 2-(4-(((tert-butoxycarbonyl)amino)methyl)-6-(1H-imidazol-1-yl)pyridazine-3-carboxamido)-4,5-difluorobenzoate (600 mg, 1.2 mmol) in DCM (0.5 mL) 4M HCl in dioxane (5 mL) was added and the reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, the volatiles were removed under reduced pressure and diethyl ether (10 mL) was added to the residue. The resulting solid was filtered and dried to yield compound 2 (HCl salt) (34 mg, 7% yield) as a whitish solid. 1H NMR (400 MHz, DMSO-όε): δ 13.10 (s, 1H), 9.43 (s, 1H), 8.91 (s, 1H), 8.77-8.83 (m, 4H), 8.44 (s, 1H), 8.10-8.15 (m, 1H), 7.62 (s, 1H), 4.68 (t, J = 5.2 Hz, 2H), 3.96 (s, 3H). LC-MS (ESI+): m / z 389.2 [M+H]+. Compounds 7, 42, 43 and 74 were prepared using procedures analogous to those of the synthesis of compound 2. IVIA / E / ZUZZ / UÓ I IOO Example 3: Scheme 5: Synthesis of compound 3: MA / E / ZUZZ / Uol Ί OS Synthesis of 7-ethynyl-6-fluoro-2-(6-(pyridin-4-1)pyridazin-3-1)-4H-benzo[d][1,3]oxazin-4-one (3): A suspension of compound 1 (36 mg, 0.1 mmol) in 0.5 mL of thionyl chloride was heated under reflux for 2 hours. Then, the excess thionyl was removed under vacuum. 2 mL of anhydrous acetonitrile were added to the solid, and a solution of DIPEA (35 µL, 0.2 mmol) in 2 mL of anhydrous acetonitrile was added at room temperature. After shaking for 30 minutes, the resulting precipitate was isolated and washed with acetonitrile to give the product (28 mg, 80% yield). 1H NMR (400 MHz, DMSO) δ 8.91-8.82 (m, 2H), 8.63 (q, J= 9.0 Hz, 2H), 8.30-8.20 (m, 2H), 8.13 (d, J= 8.6 Hz, 1H), 8.08 (d, J = 6.2 Hz, 1H), 5.04 (s, 1H). MS-ESI: m / z 345.46 observed (M+H)+ Compounds 75, 80, and 93 were prepared using a procedure analogous to that used to synthesize compound 3. Although the present disclosure has been described and exemplified in sufficient detail for those skilled in the art to manufacture and use it, various alternatives, modifications, and improvements will be evident to those skilled in the art without departing from the spirit and scope of the claims. All patents and publications referenced herein are incorporated herein by reference to the same extent as if each individual publication were specifically and individually indicated to be incorporated by reference in its entirety.

Claims

1. A compound of formula (IA) or formula (II): IVIA / I IOO characterized in that X is S, -N=C(R1)-, or -C(R1)=C(R1)-; each R1 is independently H, F, Cl, Ci-Ce alkyl, ethenyl or ethynyl (any of which may be substituted), cyano, alkoxy or; R2 is selected from the group consisting of -C(O)OR, -C(O)NH(Ci-Ce alkyl) (wherein the alkyl is optionally substituted), optionally substituted C3-C6 cycloalkenyl, and 3- to 10-heterocyclyl; R is selected from the group consisting of H, optionally substituted alkyl with -((Cr C6-alkyl)OC(O)OCi-C6-alkyl) or 3- to 10-membered heterocyclyl and benzyl, wherein the benzyl can be unsubstituted or substituted with methoxyl or with an acid or ester;Ring A is a 5- or 6-membered heteroaryl comprising 1, 2, or 3 N atoms, unsubstituted or substituted with 1, 2, or 3 groups independently selected from the group consisting of NH2, NH-benzyl (where the benzyl is unsubstituted or substituted with methoxyl, cyano, alkylnitrile, haloalkyl, hydroxymethyl, aminomethyl, aminopropyl, carboxamido, or alkoxy), NH IVIA / I 100 hn where a wavy line indicates a bonding position; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, characterized in that the compound of formula (IA) is of formula (I): wherein X is S, -N=C(R1)-, or -C(R1)=C(R1)-; each R1 is independently H, F, Cl, ethenyl or ethynyl (any of which may be substituted), cyano, alkoxy or haloalkyl; and R is H, alkyl or benzyl, wherein the benzyl may be unsubstituted or substituted with methoxy or with an acid or isosteric ester.

3. The compound according to claim 1, characterized in that the compound is of formula (II).

4. The compound according to any of claims 1 to 3, characterized in that ring A comprises any of pyridazinil, triazolyl, primidine or pyridinyl, any of which may be substituted or unsubstituted.

5. The compound according to claim 1, characterized because the compound is one selected from the following table: 1 / =\ 2=2 O / / ζ Λ-- / \--¿ / ,___ / α / / / ' / \ '—' ζ —6 ,)— -Π ι Ά_ ο- / 1 Ο 55 Ο^ΝΗ 0 X Ν-ΝΗ 2 r— Ζ 7 Ζ^ / \ / / ,__ / 1 ζ-\\ / / \ ^= / ΖΖ 2—7 / Η Ο=\ Ο 56 XV Ν Η Ο Ν^Ν X Ν-ΝΗ 3 F Ν<_0 ν^Α, >< ο Ν 57 01 αΧ 0 ΝΝ^.0 ιι \ 7 ΝΝ-Ν 4 / Ο ιΖ Ο Ζ=ζ Α Ο7 τ 58 F Ar Ο ΝΝ^Ο ιι Υ / Ν \ 7 ΝΝ-Ν ΙνΙΛ / E / ZUZZ / Uó I 100 5 o \=o u- O 2=2 59 F νΧ 0 ΗΝ..Ο r^N ΗνΆ-ν Jlj 1 6 X,- O^NH OH HN^ °Á y A 60 F νχ 0 ΗΝχ^Ο II Α 7 o Ao / =\ 1 “ \\ / / z zz / — Αζ 11. O \= / \^Z 2 / o—7 61 1 F Xu.,X' ° ην Ο ά á S Ν—' ΗΝ.^Ο 8 o Ao / =\ 1 U. —δ Λ—2 r—Λ £« / — —\ / -ζ U. Ο 2=2 62 Α' 9 0 ΗΝγ° / ^ΟΗ ν^νη V C7 IVIA / I 100 9 o U- O z=z 63 FJ\P OH HN^OP^NH \ii HN-N 10 OV=O ^ρΗ^ρρπτ, u. O z=z \=z 64 Cl pL / C| o^xp^ OH HN^O <ry N-N N 11 ox I / ° yo o '— 65 'o O=¿ ^r?^\=\ Z—TI \ ~y -Z.--Z.O ti 12 I hp / °_ zy—<( pp ^ZZ—ó / )—oz yp “ o=\ o 66 Cl pL / F о^Хх OH HN^OP^NH y / N \¡1 HN-N IOO 13 FF\J\ NH OH [H O' nh2 67 FX^.01 OH HN^O II ЧП HN-N 14 F 'lY0 NH OH R'N II X^n H,N-^Ax \\ / N-NH 68 NO HN^OX^N ll X^N \ 7 HN-N 15 Hil O^,NH 0 AX^N N'R N-NH 69 F 4 O HN^.0 rX^N ll % / N \ 7 HN-N 16 O )=OO ™ u. O z=z 70 N 1 OH HN H x,CI y X^N II ^N XX NN ΜΛ / Ε / ΖυΖΖ / υοΙ Ί OS 17 O Xo U-—6 / O uí O z=z 71 N II 1 aN 0 HNX .0 II N n4 18 O Xo — / =\ 1 Q —ά Λ— Z z-Λ / -- --\ / —Z ó O z=z 72 N II J^CI °vV OH HN^OH 4 / n HN-N 19 '¿VO^NH OH II ΓιΙ oA^ 1 73 Cl 0 HN^O II / 20 I z V=\ O m \\ / / \ xA zz z—vy— ί 1 \' °X / O 74 Cl vX O HN^O i 0 \ 21 Ζ=χ Ζ=Ζ Ο τι ν—yν—y'ζ—υy—-π 1 \ / θ4 1 Ο 75 Ο Χ^ο / Γ~\ / 22 CI ΆΟ^ΝΗ Ο Λ Ν-Ν / Ν 76 \ Cl τ^γΓ°^^ N H 0 N^i 1' N\X N-7 23 CI O ,NH 0 «Λ N-N Xni N 77 CI O^NH OH ii N—υ 24 CI “ΧνΟ\ ,NH 0 nh2^ N—J 78 CI O^NH OH N^ί H O N ΜΛ / Ε / ΖυΖΖ / υοΙ Ί OS CF jL / O\ CU NH 0 O^NH OH 25 N^i 79 λ N—J Ó N—J Cl Cl CI\J X-. <u o^nh o nyo 26 80 h jcn nj nh2 n \\ a n—j cl i ci^j 1,0. λ ml1 s*t o^ nh oh 27 μς^,νπ q 81 n^i>II N=S Br (jl N—JF Cl Cl\ θ'Υ^Ν CU ^NH OH O^NH OH 28 II N 82 N^i li N^l N^J. \\ N- NH ON—J ΊΟΟ 29 F CI.1 NH OH i N^i / < NS '< II N\3 U-—d 2 r-, _ X \__ / \ / / \ / 7 2 / -- d--\ / --\ 1 / ° Z=Z 30 N II ^^1^^ Ο^,ΝΗ 0 II Nf / N-NH 84 F Uv l\í NO^NH N-ÁNH tHN°CI-N N^JS' / 85 2^\ Z=H ° / 1 2—¿ \r— / Y—7 2—y—-n 1 \_ / ° \ o 32 z / / / J o 2 xZ'z z=zz^-o 1 \__' — oZ 1 o 86 Z~V z=-zz— / / y Cl Ck k O^NH OH N'Y π N 4 vN NH 87 F ^^J^O Ck,NH OH N^k N. ON—J 34 Cl vΕ Vr00 N— IIH N—O. Ο^,ΝΗ OH Q y N—J 35 ° ,NH O Λ NN NH N 89 O^NH OH H y N— 36 F ΟγΝΗ HO Λ N—N 4 ,NH N 90 I ykYU O^NH OH N^yZE / I—Z 100 37 / ooo O'z 91 Ck J- >Zn O^NH OH H 4- ,NH N N-7 Cl F 38 ο^,νη oh N^ II 92 z=z OZ— T o= v / N-NH N— 39 / =\ O :— / / o 1 zzz o z / Γ N—J N-7 40 'Á··· O. NH ON^ II n^Z 94 FO^NH O^J\ rZ^NTH \ / N JM IVIA / I 100 41 ζ Μ ζ ° Τ \ Ζ—2—\ γ.— / ζζ Τ y—Π 1 \__7 Ο 95 Cl Ο^ΝΗ 0 II Νχ^ ΍J? Ν— 42 Ο^ΝΗ Ο Tji Ν— 96 y ο ^=° ζ ζ=ζ 43 rA j? Z L ,z L\ T~L / τ\ ^7 z-z z—(z x)— -P 1 \' ° \ O 97 °<ϊ^ΝΗ 0 1 ιι ο N—J 44 O^ΝΗ ΟΗΗ N'^% II N JV / N-ΝΗ 98 CI ' ητ- °^ / ΝΗ 0 fí?^N II ύ IVIA / I 100 45 / =Ζ Ο Ι1 ζ / )—λ η—( —y 'ζ— 1 \__7 O 99 N CI^Á Vr° O^^ΝΗ ΟΗΗ II NJ ο —N 46 F N H ΟΗ V / N-ΝΗ 100 N ύ\° ΟΗ Ν'Α ιι N\ A 0 N 47 CI Ο^,ΝΗ 0 (X Ι,Ν Ο^ΝΗ Ν ^0 101 Ζ=Ζ O 1 Η---( #----\ / ----\ 2^ / Ά # \ / \ —J -ζ.--4 / )--O 1 Ά y — / —ζ ο—4 X χ\ Ο ΙνΙΛ / E / ZUZZ / Uó I 100 48 Cl Xv 0^ NH 0 X y O^NH N i O nh2 102 Cl ΧΧ'Ν Ο^,ΝΗ 0.^ / X, O. XN ii 1 o NO 49 Cl ci^XO^NH OH N / X II NX V / N-NH 103 Xx°—QHX 50 Cl Xv O^NH 0 A / N-NH 104 \ Cl 11 Ϊ 0^. NH OH N^X ii 0 ^N 51 Cl ci^J\ ii ° O^NH OH A II.N nX} N-NH 105 Cl Ο.Ϊ; .ΝΗ 0 X^N ΧχΝ XN—] IVIA / I 100 IVIA / I 100.

6. The compound according to claim 1, characterized in that the compound is one selected from the following table: η----Λ \ / \ # Ά / ^ζ / =^ Λ--\ / —ζ 1= / Ο Ζ=Ζ 77 CI Ο^ΝΗ ΟΗ Ν^ί ι Α Ν— 81 \ Cl Ο^ΝΗ ΟΗ II Α Ν-^ 75 / — 2.=2. 2-—d Λ~ ·Π ο 99 Ν Vr° tK NH OH N^''Y li 0 —N IVIA / E / ZUZZ / UÓ I 100 IVIA / I 100 7. A method of interferon gene stimulation expression in a human patient, characterized in that it comprises administering to the patient an effective dose of a pharmaceutically acceptable compound or salt, therefore, in accordance with claims 1 to 6.

8. A method of treating a tumor in a patient, characterized in that it comprises administering to the patient an effective dose of a pharmaceutically acceptable compound or salt, therefore, in accordance with claims 1 to 6.

9. The method according to claim 7 or 8, characterized in that the administration comprises oral or intratumoral administration, or both.

10. The method according to claim 7 or 8, characterized in that administering comprises administering the compound to the patient as an antibody-drug conjugate or in a liposomal formulation.

11. The method according to claim 7 or 8, further characterized in that it comprises administering an effective dose of a drug targeting an immune checkpoint.

12. The method according to claim 11, characterized in that the drug targeting the immune checkpoint comprises an anti-PD-L1 antibody, an anti-PD-1 antibody, an anti-CTLA-4 antibody, or an anti-4-1 BB antibody.

13. The method according to claim 7 or 8, further characterized in that it comprises administering ionizing radiation or anticancer drugs.

14. A pharmaceutical composition characterized in that it comprises a pharmaceutically acceptable compound or salt thereof according to any of claims 1 to 6 and a pharmaceutically acceptable carrier.

15. A pharmaceutically acceptable compound or salt thereof according to any of claims 1 to 6 for use in an interferon gene stimulation expression method in a human patient.

16. A pharmaceutically acceptable compound or salt thereof according to any of claims 1 to 6 for use in a method of treating a tumor in a patient.

17. The compound for use according to claim 15 or 16, characterized in that the compound is administered to the patient by oral or intratumoral administration, or both.