Conjugated tlr7 and tlr4 agonists

Abstract

This invention provides covalent conjugates of TLR7 and TLR4 agonists, processes for preparing such compounds and the use of such compounds in medicine.

Description

[0001] CONJUGATED TLR7 AND TLR4 AGONISTS FIELD OF THE INVENTION The present invention provides covalent conjugates of TLR7 and TLR4 agonists, processes for their preparation and their use in therapeutic applications. BACKGROUND OF THE INVENTION The innate immune system, which plays a crucial role in the body's defense against infections and tumors, consists of specialized immune cells (e.g. dendritic cells (DCs), macrophages). These cells possess various pattern recognition receptors (PRRs) including Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene-1-like receptors (RLRs), C-type lectin receptors (CLRs), and stimulator of interferon genes (STING). When activated by pathogen-associated molecular patterns (PAMPs), a diverse set of immunostimulatory molecules, these DCs enhance the uptake and presentation of antigens through the production of inflammatory cytokines, interferons (IFNs), and co-stimulatory molecules. This activation provides crucial initial signals that determine the nature, intensity, and duration of the subsequent adaptive response, whether it be a cellular or humoral response (Gutjahr et al., 2016). TLR4 is expressed on the cell surface and binds bacterial lipopolysaccharide (LPS). This recognition activates NF-κB and AP1 signaling pathways. Several classes of small molecule TLR4 agonists devoid of significant pro-inflammatory activity yet endowed with potent adjuvant activity, such as 1Z105, have been reported (Chan et al., 2013).1Z105 is synthetically easily accessible and is amenable to covalent coupling, hence it has already been used in the construction of triple TLR conjugates and protein conjugates. TLR4 agonists hold great promise as vaccine adjuvants and immunotherapeutics due to their ability to enhance immune responses, activate immune cells, and modulate immune pathways. For example, a detoxified form of LPS, monophosphoryl lipid A (MPLA), has been successfully used as an adjuvant in several vaccines, including human papillomavirus (HPV) vaccine (Cervarix) and other vaccine formulations (vaccines against hepatitis B, influenza, and malaria) (Didierlaurent et al., 2017; Laurens, 2019; Pifferi et al., 2021). TLR7, an intracellular receptor located in endosomes, is responsible for detecting single-stranded RNA. Upon activation, it triggers signaling pathways mediated by IRF7, IRF5, and NF-κB. In humans, TLR7 is predominantly expressed in plasmacytoid dendritic cells (pDCs) and its activation leads to the production of IFNα and IL-12. These cytokines play a crucial role in priming neighboring natural killer (NK) cells, T cells, and DCs. IFN-α enhances the cytotoxic potential of NK cells, while IL-12 boosts IFN-γ secretion from NK cells. Additionally, TLR7 contributes to the maturation and differentiation of DCs, resulting in the generation of DCs with improved co-stimulatory and antigen- presenting abilities (Kobold et al., 2014). Various small molecule TLR7 agonists have been discovered, including imidazoquinolines, purines, 3-deazapurines, and others (Hemmi et al., 2002; Lee et al., 2003; Jones et al., 2011). Imiquimod, a prototypical imidazoquinoline, is an effective topical cream used for treating genital warts, basal cell carcinoma, and actinic keratosis. Within the purine class, 2-substituted 8-hydroxyadenines have demonstrated potent TLR7 agonistic activity (Kurimoto et al., 2004, 2010) and the ability to be covalently conjugated with other molecules (Akinbobuyi et al., 2016). Various studies and patent disclosures have reported purine-like TLR7 agonists and their medical applications (Tran et al., 2011; Nakamura et al., 2013; Akinbobuyi et al., 2015) (WO2006 / 117670; WO2007 / 024707; WO2008 / 004948; WO2010 / 093436; WO2010 / 018134; WO2011 / 134668; WO2012 / 038058; WO2019 / 209811; WO2019 / 035969; WO2019 / 036023; WO2019 / 035971; WO2019 / 197598). During natural infection, pathogens often stimulate multiple innate receptors simultaneously. Similarly, effective live attenuated vaccines, including yellow fever virus vaccine, engage the immune system via synergistic stimulation of several PRRs to achieve a systemic response (Tom et al., 2019). The concept of using multiple agonists for robust activation of the immune system is the future in vaccine adjuvant / immunotherapeutic design. Cross-talk between innate immune receptors permits signal amplification and can be both quantitatively and qualitatively different than the contribution of each individual pathway (Thaiss et al., 2016). Cells treated with an innate immune agonist can become tolerant to restimulation with the same agonist. In case the cells are restimulated with a different agonist, the response may be primed (Pashenkov et al., 2018). Simultaneous activation of distinct innate immune receptors by a mixture of agonists can bypass this tolerance and permits signal amplification, thus leading to a more efficient immune response. The covalent chemical linkage of these agonists can further enhance this response (Tom et al., 2019) as evidenced by several reported dual PRR agonists including TLR2 / TLR9 (Mancini et al., 2014), TLR4 / 9 (Madan-Lala et al., 2017), TLR2 / TLR7 (Gutjahr et al., 2017), NOD2 / TLR2 (Pavot et al., 2014), NOD2 / TLR7 (Gutjahr et al., 2020; Guzelj et al., 2022) and a trimeric adjuvant composed of TLR4, 7 and 9 agonists (Tom et al., 2015), all of which elicited potent and balanced cellular and humoral responses. Conjugation also impacts their toxicity and pharmacokinetic profiles. For example, a chimeric TLR2 / TLR7 agonist proved to be much safer than equal amounts of individual agonists (Gutjahr et al., 2017). In view of the great therapeutic potential of conjugated innate immune agonists, and despite the work that has already been done, there is an ongoing need for new potent compounds capable of eliciting responses from the aforementioned receptors. Thus, this specification discloses novel conjugated compounds that function as both TLR7 and TLR4 agonists, the processes for their preparation and their uses in medicine.

[0002] SUMMARY OF THE INVENTION In accordance with the purpose of this invention, as embodied and described herein, the present application discloses novel compounds that are synthetic TLR7 agonists covalently conjugated to synthetic TLR4 agonists. Further provided are the processes for preparation of such compounds and the uses of such compounds in medicine. In a first aspect, the present invention provides a compound of Formula I: Formula I or a pharmaceutically acceptable salt, racemate, diastereomer, enantiomer, ester or prodrug thereof, wherein: ^ R1is H, halogen, OH, SH, CF3, C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 5-10 membered heterocyclyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkoxy, C1-C6 alkoxy- (C1-C6 alkyl)S-, (C1-C6 alkyl)SO2NH-, (C1-C6 alkyl)C(=O)O-, (C1-C6 alkyl)OC(=O)-, (C1-C6 alkyl)C(=O)-, (C1-C6 alkyl)C(=O)NH-, RaRbN-, or RaRbN(C=O)-, wherein alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R2is independently for each occurrence selected from H, halogen, OH, CHF2, CF3, CH2CF2, carboxy, CN, NO2, C1-C6alkyl, C3-C10cycloalkyl, C1-C6alkoxy, (C1-C6alkyl)C(=O)-, (C6-C10 aryl)C(=O)-, (C1-C6 alkyl)S-, (C1-C6 alkyl)C(=O)O-, (C1-C6 alkyl)OC(=O)-, (C1-C6 alkyl)C(=O)NH-, (C1-C6alkyl)SO2NH-, RaRbN-, and RaRbN(C=O)-, wherein alkyl, alkoxy, aryl, and cycloalkyl may be optionally substituted; ^ Raand Rbare independently from each other selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10aryl, and 5-10 membered heterocyclyl or Ra1and Rb1may together with the nitrogen atom form a 5-6 membered heterocycle, wherein alkyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ X1is a single bond, -O-, -S-, -NRc-, -C(=O)-, or -SO2-; ^ Rcis H, C1-C6alkyl, or C3-C10cycloalkyl; ^ L is a linking group; ^ n is 0, 1, 2, 3, or 4; and ^ R3is a TLR4 agonist selected from the group consisting of: Formula IV, wherein: ^ X2is a single bond, -O-, -S-, -NRd-, -C(=O)- or -SO2-; ^ Rdis H, C1-C6alkyl, or C3-C10cycloalkyl; ^ m is 0, 1, 2, 3, 4, or 5; ^ R4is independently for each occurrence selected from H, halogen, CN, NO2, CF3, C1-C6alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10cycloalkyl, C6-C10aryl, 5-10 membered heterocyclyl, -ORe, -SRe, -C(=O)Re, -C(=O)NRfRg, -C(=O)ORe, -OC(=O)Re, -OC(=O)NRfRg, -NRfR g, -NReC(=O)Re, -SORe, -SO2Re, -SO2NRfRg, and -NReSO2Re, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ Reis independently for each occurrence selected from H, C1-C6alkyl, C3-C10cycloalkyl, C6- C10aryl and 5-10 membered heterocyclyl, wherein alkyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ Rfand Rgare independently from each other selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10aryl and 5-10 membered heterocyclyl or Rgand Rhmay together with the nitrogen atom form a 5-6 membered heterocycle, wherein alkyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R5is H, C1-C6alkyl, or C3-C10cycloalkyl, wherein alkyl and cycloalkyl may be optionally substituted; ^ R6is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C6-C10aryl, or 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R7is C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10cycloalkyl, C6-C10aryl, or 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R8is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C6-C10aryl, or 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R9is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C6-C10 aryl, or 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ Y is -(C1-C4 alkyl)- or -(C1-C4 alkenyl)-; ^ ^ R11is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C6-C10 aryl, or 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R12is independently for each occurrence selected from H, halogen, CN, NO2, CF3, C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C6-C10aryl, 5-10 membered heterocyclyl, -ORh, -SRh, -C(=O)Rh, -C(=O)NRiRj, -C(=O)ORh, -OC(=O)Rh, -OC(=O)NRiRj, -NRiRj, -NRhC(=O)Rh, -SORh, -SO2Rh, -SO2NRiRj, and -NRhSO2Rh, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ Rhis independently for each occurrence selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, C6- C10aryl and 5-10 membered heterocyclyl, wherein alkyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ Riand Rjare independently from each other selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10 aryl and 5-10 membered heterocyclyl or Riand Rjmay together with the nitrogen atom form a 5-6 membered heterocycle, wherein alkyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted. In further aspect, the invention provides a process and intermediates for the preparation of compounds of Formula I or a pharmaceutically acceptable salt, racemate, diastereomer, enantiomer, ester or prodrug thereof. In a further aspect, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, racemate, diastereomer, enantiomer, ester or prodrug thereof, for use in medicine, such as in therapy. In a further aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, racemate, diastereomer, enantiomer, ester or prodrug thereof, and a pharmaceutically acceptable excipient or carrier. In a further aspect, the invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt, racemate, diastereomer, enantiomer, ester or prodrug thereof, in treatment of conditions for which agonism of TLR7 and TLR4 receptors is beneficial. In a further aspect, the invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt, racemate, diastereomer, enantiomer, ester or prodrug thereof in the manufacture of a medicament. In a further aspect, the invention provides a method for treating a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, racemate, diastereomer, enantiomer, ester or prodrug thereof, or a pharmaceutical composition of the present invention. In a further aspect, the invention provides a vaccine comprising a compound of Formula I or a pharmaceutically acceptable salt, racemate, diastereomer, enantiomer, ester or prodrug thereof. The present invention can be further summarized by the following items: 1. A compound having the structure of Formula I: Formula I or a pharmaceutically acceptable salt, racemate, diastereomer, enantiomer, ester or prodrug thereof, wherein: ^ R1is H, halogen, OH, SH, CF3, C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 5-10 membered heterocyclyl, C1-C6alkoxy, C1-C6alkoxy-C1-C6alkyl, C1-C6alkoxy-C1-C6alkoxy, C1-C6alkoxy-(C1-C6 alkyl)S-, (C1-C6 alkyl)SO2NH-, (C1-C6 alkyl)C(=O)O-, (C1-C6 alkyl)OC(=O)-, (C1-C6alkyl)C(=O)-, (C1-C6alkyl)C(=O)NH-, RaRbN-, or RaRbN(C=O)-, wherein alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R2is independently for each occurrence selected from H, halogen, OH, CHF2, CF3, CH2CF2, carboxy, CN, NO2, C1-C6alkyl, C3-C10cycloalkyl, C1-C6alkoxy, (C1-C6alkyl)C(=O)-, (C6-C10 aryl)C(=O)-, (C1-C6 alkyl)S-, (C1-C6 alkyl)C(=O)O-, (C1-C6 alkyl)OC(=O)-, (C1-C6 alkyl)C(=O)NH-, (C1-C6alkyl)SO2NH-, RaRbN-, and RaRbN(C=O)-, wherein alkyl, alkoxy, aryl, and cycloalkyl may be optionally substituted; ^ Raand Rbare independently from each other selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, and 5-10 membered heterocyclyl or Ra1and Rb1may together with the nitrogen atom form a 5-6 membered heterocycle, wherein alkyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ X1is a single bond, -O-, -S-, -NRc-, -C(=O)-, or -SO2-; ^ Rcis H, C1-C6alkyl, or C3-C10cycloalkyl; ^ L is a linking group; ^ n is 0, 1, 2, 3, or 4; and ^ R3is a TLR4 agonist selected from the group consisting of: Formula IV, wherein: ^ X2is a single bond, -O-, -S-, -NRd-, -C(=O)- or -SO2-; ^ Rdis H, C1-C6alkyl, or C3-C10cycloalkyl; ^ m is 0, 1, 2, 3, 4, or 5; ^ R4is independently for each occurrence selected from H, halogen, CN, NO2, CF3, C1-C6alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C6-C10 aryl, 5-10 membered heterocyclyl, -ORe, -SRe, -C(=O)Re, -C(=O)NRfRg, -C(=O)ORe, -OC(=O)Re, -OC(=O)NRfRg, - NRfRg, -NReC(=O)Re, -SORe, -SO2Re, -SO2NRfRg, and -NReSO2Re, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ Reis independently for each occurrence selected from H, C1-C6alkyl, C3-C10cycloalkyl, C6-C10 aryl and 5-10 membered heterocyclyl, wherein alkyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ Rfand Rgare independently from each other selected from H, C1-C6alkyl, C3-C10cycloalkyl, C6-C10 aryl and 5-10 membered heterocyclyl or Rgand Rhmay together with the nitrogen atom form a 5-6 membered heterocycle, wherein alkyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R5is H, C1-C6 alkyl, or C3-C10 cycloalkyl, wherein alkyl and cycloalkyl may be optionally substituted; ^ R6is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C6-C10 aryl, or 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R7is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C6-C10 aryl, or 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R8is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C6-C10 aryl, or 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R9is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C6-C10 aryl, or 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ Y is -(C1-C4 alkyl)- or -(C1-C4 alkenyl)-; ^ ^ R11is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C6-C10 aryl, or 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R12is independently for each occurrence selected from H, halogen, CN, NO2, CF3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C6-C10 aryl, 5-10 membered heterocyclyl, -ORh, -SRh, -C(=O)Rh, -C(=O)NRiRj, -C(=O)ORh, -OC(=O)Rh, -OC(=O)NRiRj, -N RiRj, -NRhC(=O)Rh, -SORh, -SO2Rh, -SO2NRiRj, and -NRhSO2Rh, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ Rhis independently for each occurrence selected from H, C1-C6alkyl, C3-C10cycloalkyl, C6-C10 aryl and 5-10 membered heterocyclyl, wherein alkyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ Riand Rjare independently from each other selected from H, C1-C6alkyl, C3-C10cycloalkyl, C6-C10 aryl and 5-10 membered heterocyclyl or Rgand Rhmay together with the nitrogen atom form a 5-6 membered heterocycle, wherein alkyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted. 2. The compound according to item 1, wherein n is 1. 3. The compound according to item 1 or 2, wherein R1is C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkoxy, (C1-C6 alkyl)S-, or (C1-C6 alkyl)NH-. 4. The compound according to any one of items 1 to 3, wherein R1is n-BuO-. 5. The compound according to any one of items 1 to 4, wherein R2is hydrogen in each instance. 6. The compound according to any one of items 1 to 5, wherein L is selected from the group consisting of an amino acid, a peptide, a non-peptidic polymeric linker and a non-polymeric aliphatic linker. 7. The compound according to item 6, wherein L is a non-polymeric aliphatic linker or a polyethylene glycol chain comprising 2 to 100 repeating ethylene glycol units. 8. The compound according to any one of items 1 to 7, wherein R3is a TLR4 agonist selected from the group consisting of: Formula III. 9. The compound according to item 8, wherein m is 1. 10. The compound according to item 8 or 9, wherein R4is independently for each occurrence selected from H, halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C6-C10 aryl, and 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, and heterocyclyl may be optionally substituted. 11. The compound according to any one of items 8 to 10, wherein R6is C3-C10 cycloalkyl or C6-C10 aryl, wherein cycloalkyl and aryl may be optionally substituted. 12. The compound according to any one of items 8 to 11, wherein R7is C1-C10alkyl, C3-C10cycloalkyl, or C6-C10aryl, wherein alkyl, cycloalkyl, and aryl may be optionally substituted. 13. The compound according to item 12, wherein R7is cyclohexyl. 14. The compound according to any one of items 1 to 7, wherein R3is a TLR4 agonist of Formula IV: Formula IV 15. The compound according to item 14, wherein R8is an optionally substituted C3-C10 cycloalkyl. 16. The compound according to item 14 or 15, wherein R9is C6-C10aryl or 5-10 membered heterocyclyl, wherein aryl and heterocyclyl may be optionally substituted. 17. The compound according to any one of items 14 to 16, wherein R10is 18. The compound according to any one of items 1 to 17, wherein said compound is selected from the group consisting of: 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(2-(2-(2-((4-oxo-3-phenyl-4,5- dihydro-3H-pyrimido[5,4-b]indol-2-yl)thio)acetamido)ethoxy)ethyl)benzamide, 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(2-(2-(2-(2-((4-oxo-3-phenyl-4,5- dihydro-3H-pyrimido[5,4-b]indol-2-yl)thio)acetamido)ethoxy)ethoxy)ethyl)benzamide, 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(2-oxo-1-((4-oxo-3-phenyl-4,5- dihydro-3H-pyrimido[5,4-b]indol-2-yl)thio)-7,10,13-trioxa-3-azahexadecan-16-yl)benzamide, 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(6-(2-((4-oxo-3-phenyl-4,5-dihydro- 3H-pyrimido[5,4-b]indol-2-yl)thio)acetamido)hexyl)benzamide, 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(2-(2-((4-oxo-3-phenyl-4,5-dihydro- 3H-pyrimido[5,4-b]indol-2-yl)thio)acetamido)ethyl)benzamide, 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(4-(2-((4-oxo-3-phenyl-4,5-dihydro- 3H-pyrimido[5,4-b]indol-2-yl)thio)acetamido)cyclohexyl)benzamide, N-(1-(4-(1-(4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)phenyl)-1,12-dioxo-5,8- dioxa-2,11-diazatridecan-13-yl)phenyl)-2-(cyclopentylamino)-2-oxoethyl)-N-(2,3-dihydro-1H- inden-5-yl)-1,5-diphenyl-1H-pyrazole-3-carboxamide, N-(1-(4-(2-(4-((4-(4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)benzoyl)piperazin-1- yl)methyl)piperidin-1-yl)-2-oxoethyl)phenyl)-2-(cyclopentylamino)-2-oxoethyl)-N-(2,3- dihydro-1H-inden-5-yl)-1,5-diphenyl-1H-pyrazole-3-carboxamide, and N-(1-(4-(2-((6-(4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9- yl)methyl)benzamido)hexyl)amino)-2-oxoethyl)phenyl)-2-(cyclopentylamino)-2-oxoethyl)-N- (2,3-dihydro-1H-inden-5-yl)-1,5-diphenyl-1H-pyrazole-3-carboxamide. A process for preparing a compound of Formula I as defined in any one of items 1 to 18 (with the variable groups being as defined in any one of items 1 to 18) which comprises reacting a compound of Formula VI: Formula VI with a compound of Formula VII: Formula VII, or a compound of Formula VIII: Formula VIII with a compound of Formula IX: Formula IX; and optionally thereafter carrying out one or more of the following procedures: ^ removing any protecting groups, ^ forming a pharmaceutically acceptable salt, ^ converting a compound of Formula I into another compound of Formula I. The process according to item 19, which comprises reacting a compound of Formula VI: Formula VI with a compound of Formula VII: Formula VII, and optionally thereafter carrying out one or more of the following procedures: ^ removing any protecting groups, ^ forming a pharmaceutically acceptable salt, ^ converting a compound of Formula I into another compound of Formula I. The process according to item 19, which comprises reacting a compound of Formula VIII: Formula VIII with a compound of Formula IX: Formula IX; and optionally thereafter carrying out one or more of the following procedures: ^ removing any protecting groups, ^ forming a pharmaceutically acceptable salt, ^ converting a compound of Formula I into another compound of Formula I. 22. Compound of any one of items 1 to 18 for use in medicine. 23. Compound of any one of items 1 to 18 for use in treatment of a condition in which agonism of TLR7 and TLR4 receptors is beneficial, wherein the condition is selected from the group consisting of viral infections, bacterial infections, fungal infections, protozoal infections, tumors, cancers and immunological diseases 24. A pharmaceutical composition comprising a compound according to any one of items 1 to 18 and one or more pharmaceutically acceptable excipients or carriers. 25. A vaccine comprising a compound according to any one of items 1 to 18. BRIEF DESCRIPTION OF FIGURES Figure 1 demonstrates the ability of the compounds of the invention to induce cytokine production in human PBMCs. Concentration of tested compounds was 1 µM. Intermediary compound SG43 was used as a TLR7 agonist, while SB19 and SG202 were used as TLR4 agonists. The combinations of SG43 with SB19 or SG202 were used to compare the activity of conjugated compounds against an unconjugated mixture of TLR7 and TLR4 agonists. Figure 2 demonstrates the ability of the compounds of the invention to activate the cytotoxic activity of PBMCs against K562 cancer cells. Concentration of tested compounds was 1 µM. The results are expressed as a ratio against the control (medium). IL-2 (200 U / mL) was used as the positive control. Intermediary compounds SG43, SB19, and their unconjugated mixture were used to compare the compounds of the invention to a TLR7 agonist, TLR4 agonist and their unconjugated mixture, respectively. Figure 3 demonstrates the ability of the compounds of the invention to promote BMDC antigen presentation to CD4+and CD8+T-lymphocytes. The results are expressed as a ratio of T cells that divided during the co-culturing period. Concentration of tested compounds was 1 µM. Intermediary compounds SG43, SB19, and their unconjugated mixture were used to compare the compounds of the invention to a TLR7 agonist, TLR4 agonist and their unconjugated mixture, respectively. DETAILED DESCRIPTION OF THE INVENTION Definitions Throughout the present specification and the accompanying claims, the word “comprise” and variations such as “comprises” and “comprising” are to be interpreted inclusively. That is, these words are intended to convey the possible inclusion of other elements or integers not specifically recited, where the context allows. “Ci-Cj alkyl” means linear or branched alkyl group comprising of i to j carbon atoms. Non-limiting examples of alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl and hexyl. “Ci-Cj alkoxy” means a Ci-Cj alkyl group as defined above linked to an oxygen atom. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, pentoxy and hexoxy. “Ci-Cj alkenyl” means a linear or branched hydrocarbon group comprising of i to j carbon atoms containing at least one carbon-carbon double bond. Asymmetric structures are intended to include all positional and geometrical isomers. Non-limiting examples of alkenyl group include vinyl, propenyl, allyl, but-2-enyl and but-3-enyl. “Ci-Cj alkynyl” means a linear or branched hydrocarbon group comprising of i to j carbon atoms containing at least one carbon-carbon triple bond. Non-limiting examples of alkynyl group include ethynyl, prop-2-ynyl and but-2-ynyl. “Ci-Cj aryl” means a mono-, or bicyclic aromatic carbon-based radical comprising of i to j carbon atoms. Non-limiting examples or aryl group include phenyl and naphthyl. “Ci-Cj cycloalkyl” means a mono-, bi-, or tricyclic, non-aromatic carbon-based radical comprising of i to j carbon atoms that is fully saturated or partially unsaturated. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. “i-j membered heterocycle” means a saturated, partially saturated or unsaturated cycle consisting of one or several rings, comprising of i to j atoms of which one or more ring atoms are selected from nitrogen, oxygen or sulphur wherein a ring sulphur atom may be optionally oxidised to from the S-oxide, a ring nitrogen may be optionally oxidised to from the N-oxide, a ring nitrogen may be optionally quaternized and a -CH2- group may be optionally replaced by a -C(=O)-. Non-limiting examples of heterocyclyl groups include pyrrolidinyl, pyrrolyl, furanyl, thiophenyl, piperidinyl, pyridinyl, pyranyl, morpholinyl, piperazinyl, pyrimidiyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxodiazolyl, benzimidazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, benzotriazolyl and quinolinyl. “i-j membered heterocyclyl” means a saturated, partially saturated or unsaturated cyclic radical consisting of one or several rings, comprising of i to j atoms of which one or more ring atoms are selected from nitrogen, oxygen or sulphur wherein a ring sulphur atom may be optionally oxidised to from the S-oxide, a ring nitrogen may be optionally oxidised to from the N-oxide, a ring nitrogen may be optionally quaternized and a -CH2- group may be optionally replaced by a -C(=O)-. Non- limiting examples of heterocyclyl groups include pyrrolidinyl, pyrrolyl, furanyl, thiophenyl, piperidinyl, pyridinyl, pyranyl, morpholinyl, piperazinyl, pyrimidiyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxodiazolyl, benzimidazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, benzotriazolyl and quinolinyl. At various places in the present specification various aryl, cycloalkyl, and heterocyclyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term "a pyridine ring" or "pyridinyl" may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring. “Specific side chain of an amino acid” means the R group of an amino acid with a generic formula H2NCHRCOOH. This includes but is not limited to the L and D isomers of natural amino acids arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine or tryptophan as well as unnatural amino acids such as homoserine, ornithine, citrulline, phosphoserine, phosphothreonine, phosphotyrosine, isovaline, isoserine, allothreonine or hydroxyproline. The term “peptide” as used herein, refers to an amino acid polymer wherein each amino acid is linked to its neighbor by an amide bond -C(=O)NH-, also called peptide bond. The term “pharmaceutically acceptable” as used herein, refers to those compounds, materials, compositions and / or dosage forms with are, within the scope of sound medical judgement, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problem or complication commensurate with a reasonable benefit / risk ratio. “Pharmaceutically acceptable salts” means a salt of a disclosed compound that does not abrogate the biological effectiveness and retains properties of free bases or free acids, which are not biologically or otherwise undesirable. Where a compound has one or more basic groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. The salt can be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like or organic acid such as acetic acid, tartaric acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, benzoic acid, cinnamic acid, methanesulfonic acid, lactic acid, maleic acid, fumaric acid, succinic acid, and the like. Where a compound has one or more acidic groups, the salt can be formed with the addition of an organic or an inorganic base. Salts derived from inorganic bases include but are not limited to sodium, potassium, lithium, ammonium, calcium, magnesium and zinc salts. Salts derived from organic bases include but are not limited to salts of primary, secondary and tertiary amines, substituted amines, cyclic amines, naturally-occurring amines and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, ethanolamine, lysine, arginine, piperidine, piperazine, choline, betaine, caffeine, choline, and the like. Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. A preferred pharmaceutically acceptable salt is the sodium salt. Other salts that are not deemed pharmaceutically acceptable may be useful in the preparation of compound of Formula I and are included within the scope of this invention, such as those formed with ammonia and trifluoroacetic acid. “Pharmaceutically acceptable esters” means that compounds of Formula I may be derivatised at carboxylic or hydroxy groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl ester and pivaloyloxymethyl esters. Additionally, any physiologically acceptable equivalents of the compounds of Formula I, similar to the metabolically labile esters, which are capable of producing the parent compounds of Formula I in vivo, are within the scope of this invention. The term “optionally substituted” as used herein, refers to a group that may or may not be further substituted with one or more groups (preferably 1, 2, 3 or 4 groups, more preferably 1 or 2 groups). Permissible substituents include but are not limited to OR, SR, NR2, CN, NO2, halogen, oxo, carboxyl, CF3, CH2CF3, CHF2, OCF3, OCHF2, =NR, =N, =NOR, =N-CN, -C(=O)NR2, -NRC(=O)R, -C(=O)R, - OC(=O)R, -C(=O)OR, -NRC(=O)OR, -SO2R, -SO2NR2, -NRSO2R, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C6-C10 aryl, and 5-10 membered heterocyclyl wherein each R is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C6-C10 aryl, or 5-10 membered heterocyclyl and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl and groups containing them may be further optionally substituted, e.g., with one or more groups (preferably 1, 2, 3 or 4 groups, more preferably 1 or 2 groups) selected from OR, SR, NR2, CN, NO2, halogen, oxo, carboxyl, CF3, CH2CF3, CHF2, OCF3, OCHF2, =NR, =N, =NOR, =N-CN, -C(=O)NR2, -NRC(=O)R, -C(=O)R, - OC(=O)R, -C(=O)OR, -NRC(=O)OR, -SO2R, -SO2NR2, and -NRSO2R. The term “administering” as used herein, refers to parenteral, intravenous, intraperitoneal, intramuscular, intertumoral, intralesional, intranasal, subcutaneous or oral administration, administration as a suppository, topical contact, intrathecal administration, or the implantation of a slow-release device, such as a mini-osmotic pump, to the subject. The term “subject” as used herein, refers to an animal or human body. The term “agonist” as used herein, refers to the native ligand of a receptor, to analogues thereof or other ligand that similarly “activate” the receptor, and / or to a positive modulator of the receptor. A TLR4 agonist is any compound that functions to activate TLR4 receptor. A TLR7 agonist is any compound that functions to activate TLR7 receptor. The term “therapeutically effective amount” as used herein, refers to the quantity of a compound of Formula I or a pharmaceutically acceptable salt, racemate, diastereomer, enantiomer, ester or prodrug thereof, which will elicit the desired biological response in an animal or human body. The term “treatment” or “treating” as used herein, includes (i) preventing a pathological condition from occurring; (ii) inhibiting the pathological condition or arresting its development; (iii) relieving the pathological condition and / or diminishing symptoms associated with the pathological condition. “Pharmaceutical composition” means one or more active ingredients, and one or more inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable excipient (pharmaceutically acceptable carrier). “Excipient” refers to compounds administered together with the therapeutic agent, for example, buffering agents, isotonicity modifiers, preservative, stabilizers, anti-adsorption agents, or other auxiliary agents. However, in some cases, one excipient may have dual or triple functions. It will be appreciated by those skilled in the art that certain compounds described herein contain one or more chiral centres. Accordingly, these compounds may exist in, and be isolated in, optically active and racemic forms. Some compounds may exhibit polymorphism. Polymorphs as referred herein includes both crystalline and amorphous forms. It is to be understood that this invention encompasses any racemic, optically active, polymorphic or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possesses the useful properties described herein, it being known in the art how to prepare optically-active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by stereoselective synthesis, by enzymatic resolution, by biotransformation, or by chromatographic separation using a chiral stationary phase). In addition to salt forms, the invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or carboxy groups are bonded to any group that, when administered to a subject, cleaves to form the hydroxy, amine or carboxy groups. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. A prodrug may improve the physical properties of the parent drug and / or it may also improve overall drug efficacy, for example through the reduction of toxicity and unwanted effects of a drug by controlling its absorption, blood levels, metabolic distribution and cellular uptake. Within the present invention it is to be understood that a compound of Formula I or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which possesses the useful properties described herein and is not to be limited merely to any one tautomeric form utilised within the formulae drawings. The formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been possible to show graphically herein. In particular, a compound of Formula IAis the tautomer of a compound of Formula IB. Generally, tautomeric structures have been represented herein in the enol form, as a matter of consistency and convenience. It is also to be understood that certain compounds of Formula I and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated form which possess the useful properties described herein. In the formulae drawings within this specification a bond traversing an aromatic ring between two carbon atoms means that the attached group may be located at any of the positions on the aromatic ring, made available by removal of the hydrogen atom that is implicitly there. By way of illustration, the formula represents . In another illustration, the formula represents

[0003] Conjugates of TLR7 and TLR4 agonists The first aspect of the present invention are conjugated compounds of Formula I: Formula I or a pharmaceutically acceptable salt, racemate, diastereomer, enantiomer, ester or prodrug thereof, wherein: ^ R1is H, halogen, OH, SH, CF3, C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, 5-10 membered heterocyclyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkoxy, C1-C6 alkoxy- (C1-C6alkyl)S-, (C1-C6alkyl)SO2NH-, (C1-C6alkyl)C(=O)O-, (C1-C6alkyl)OC(=O)-, (C1-C6 alkyl)C(=O)-, (C1-C6 alkyl)C(=O)NH-, RaRbN-, or RaRbN(C=O)-, wherein alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R2is independently for each occurrence selected from H, halogen, OH, CHF2, CF3, CH2CF2, carboxy, CN, NO2, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, (C1-C6 alkyl)C(=O)-, (C6-C10aryl)C(=O)-, (C1-C6alkyl)S-, (C1-C6alkyl)C(=O)O-, (C1-C6alkyl)OC(=O)-, (C1-C6alkyl)C(=O)NH-, (C1-C6 alkyl)SO2NH-, RaRbN-, and RaRbN(C=O)-, wherein alkyl, alkoxy, aryl, and cycloalkyl may be optionally substituted; ^ Raand Rbare independently from each other selected from H, C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, and 5-10 membered heterocyclyl or Ra1and Rb1may together with the nitrogen atom form a 5-6 membered heterocycle, wherein alkyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ X1is a single bond, -O-, -S-, -NRc-, -C(=O)-, or -SO2-; ^ Rcis H, C1-C6 alkyl, or C3-C10 cycloalkyl; ^ L is a linking group; ^ n is 0, 1, 2, 3, or 4; and ^ R3is a TLR4 agonist selected from the group consisting of: Formula II, Formula IV, wherein: ^ X2is a single bond, -O-, -S-, -NRd-, -C(=O)- or -SO2-; ^ Rdis H, C1-C6 alkyl, or C3-C10 cycloalkyl; ^ m is 0, 1, 2, 3, 4, or 5; ^ R4is independently for each occurrence selected from H, halogen, CN, NO2, CF3, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C6-C10 aryl, 5-10 membered heterocyclyl, -ORe, -SRe, -C(=O)Re, -C(=O)NRfRg, -C(=O)ORe, -OC(=O)Re, -OC(=O)NRfRg, -NRfR g, -NReC(=O)Re, -SORe, -SO2Re, -SO2NRfRg, and -NReSO2Re, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ Reis independently for each occurrence selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, C6- C10 aryl and 5-10 membered heterocyclyl, wherein alkyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ Rfand Rgare independently from each other selected from H, C1-C6alkyl, C3-C10cycloalkyl, C6-C10 aryl and 5-10 membered heterocyclyl or Rgand Rhmay together with the nitrogen atom form a 5-6 membered heterocycle, wherein alkyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R5is H, C1-C6 alkyl, or C3-C10 cycloalkyl, wherein alkyl and cycloalkyl may be optionally substituted; ^ R6is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C6-C10aryl, or 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R7is C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10cycloalkyl, C6-C10aryl, or 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R8is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C6-C10aryl, or 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R9is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C6-C10aryl, or 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ ^ ^ R11is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C6-C10aryl, or 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R12is independently for each occurrence selected from H, halogen, CN, NO2, CF3, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C6-C10 aryl, 5-10 membered heterocyclyl, -ORh, -SRh, -C(=O)Rh, -C(=O)NRiRj, -C(=O)ORh, -OC(=O)Rh, -OC(=O)NRiRj, -NRiRj, -NRhC(=O)Rh, -SORh, -SO2Rh, -SO2NRiRj, and -NRhSO2Rh, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ Rhis independently for each occurrence selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, C6- C10aryl and 5-10 membered heterocyclyl, wherein alkyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ Riand Rjare independently from each other selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10aryl and 5-10 membered heterocyclyl or Rgand Rhmay together with the nitrogen atom form a 5-6 membered heterocycle, wherein alkyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted. In one embodiment, the present invention provides a subset of compounds of Formula I, of Formula Ic: Formula Ic or a pharmaceutically acceptable salt, racemate, diastereomer, enantiomer, ester or prodrug thereof, wherein R1, R2, R4, R5, R6, X1, L, m, and n are as defined previously. In another embodiment, the present invention provides a subset of compounds of Formula I, of Formula Id: or a pharmaceutically acceptable salt, racemate, diastereomer, enantiomer, ester or prodrug thereof, wherein R1, R2, R4, R5, R6, R7, X1, X2, L, m, and n are as defined previously. In another embodiment, the present invention provides a subset of compounds of Formula I, of Formula Ie: Formula Ie or a pharmaceutically acceptable salt, racemate, diastereomer, enantiomer, ester or prodrug thereof, wherein R1, R2, R8, R9, R10, X1, X2, Y, L, and n are as defined previously. According to certain embodiments, n is 1 or 2. According to certain embodiments, n is 1. According to certain embodiments, R1is hydrogen, C1-C6alkoxy, C1-C6alkoxy-C1-C6alkoxy, (C1-C6alkyl)NH-, C1-C6alkoxy-(C1-C6alkyl)NH-, (C1-C6alkyl)S- or CF3. According to certain embodiments, R1is C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkoxy, or (C1-C6 alkyl)NH-. According to certain embodiments, R1is C1-C6 alkoxy. According to certain embodiments, R1is n-butoxy. According to certain embodiments, R1is C1-C6 alkoxy-C1-C6 alkoxy. According to certain embodiments, R1is CH2O(CH2)2O-. According to certain embodiments, R1is (C1-C6 alkyl)NH-. According to certain embodiments, R1is butylamino. According to certain embodiments, R2is independently for each occurrence selected from H, halogen or C1-C6alkyl. According to certain embodiments, R2is H in each instance. According to certain embodiments, X1is -O-, -NH- or -C(=O)-. According to certain embodiments, X1is -C(=O)-. According to certain embodiments, X1is in para position relative to the (CH2)n group. According to certain embodiments, m is 1 or 2. According to certain embodiments, m is 1. According to certain embodiments, X2is -O-, -NH- or -C(=O)-. According to certain embodiments, X2is -C(=O)-. According to certain embodiments, R4is independently for each occurrence selected from H, halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C6-C10 aryl, and 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, and heterocyclyl may be optionally substituted. According to certain embodiments, at least one R4is halogen. According to certain embodiments, at least one R4is an optionally substituted C1-C10alkyl. According to certain embodiments, at least one R4is an optionally substituted C2-C10 alkenyl. According to certain embodiments, at least one R4is an optionally substituted C2-C10alkynyl. According to certain embodiments, at least one R4is an optionally substituted C6-C10 aryl. According to certain embodiments, at least one R4is an optionally substituted 5-10 membered heterocyclyl. According to certain embodiments, R4is H in each instance. According to certain embodiments, R5is H or an optionally substituted C1-C6 alkyl. According to certain embodiments, R5is H. According to certain embodiments, R5is an optionally substituted C1-C6 alkyl. According to certain embodiments, R5is methyl. According to certain embodiments, R6is C3-C10 cycloalkyl or C6-C10 aryl, wherein cycloalkyl and aryl may be optionally substituted. According to certain embodiments, R6is an optionally substituted C3-C10 cycloalkyl. According to certain embodiments, R6is cyclohexyl. According to certain embodiments, R6is an optionally substituted C6-C10 aryl. According to certain embodiments, R6is phenyl. According to certain embodiments, R7is C1-C10 alkyl, C3-C10 cycloalkyl, or C6-C10 aryl, wherein alkyl, cycloalkyl, and aryl may be optionally substituted. According to certain embodiments, R7is an optionally substituted C1-C10 alkyl. According to certain embodiments, R7is an optionally substituted C3-C10cycloalkyl. According to certain embodiments, R7is cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. According to certain embodiments, R7is cyclohexyl. According to certain embodiments, R7is an optionally substituted C6-C10 aryl. According to certain embodiments, Y is -(C1-C4alkyl)-. According to certain embodiments, Y is -CH2-. According to certain embodiments, Y is -(C1-C4alkenyl)-. According to certain embodiments, Y is -(CH=CH)-. According to certain embodiments, R8is an optionally substituted C3-C10cycloalkyl. According to certain embodiments, R8is cyclopentyl. According to certain embodiments, R9is C6-C10 aryl or 5-10 membered heterocyclyl, wherein aryl and heterocyclyl may be optionally substituted. According to certain embodiments, R9is an optionally substituted C6-C10aryl. According to certain embodiments, R9is an optionally substituted phenyl. According to certain embodiments, R9is indanyl. According to certain embodiments, R9is an optionally substituted 5-10 membered heterocyclyl. According to certain embodiments, R11is an optionally substituted C6-C10aryl. According to certain embodiments, R11is phenyl. According to certain embodiments, R12is an optionally substituted C6-C10aryl. According to certain embodiments, R12is phenyl. According to certain embodiments, R10is , wherein R11and R12are as defined previously. According to certain embodiments, R10is In some preferred embodiments of Formula I: ^ R1is (C1-C6 alkyl)N-, C1-C6 alkoxy, or C1-C6 alkoxy-C1-C6 alkoxy, preferably is butylamino, n-butoxy, or CH2O(CH2)2O-; ^ R2is H in each instance; ^ n is 1; ^ X1is -C(=O)-; preferably is -C(=O)- in para position relative to the (CH2)n group; ^ L is a linking group; ^ R3is as defined herein. In some preferred embodiments of Formula I, R3is a group of Formula II wherein: ^ m is 1; ^ R4is H in each instance; ^ R5is H or C1-C6alkyl, preferably is H or methyl; ^ R6is an optionally substituted C6-C10 aryl, preferably is phenyl. In some preferred embodiments of Formula I, R3is a group of Formula III wherein: ^ m is 1; ^ X2is -O-, -NH- or -C(=O)-, preferably is -C(=O)-; ^ R4is H in each instance; ^ R5is H or C1-C6alkyl, preferably is H or methyl; ^ R6is an optionally substituted C6-C10aryl, preferably is phenyl; ^ R7is an optionally substituted C3-C10cycloalkyl, preferably is C6-C8cycloalkyl, more preferably is cyclohexyl. In some preferred embodiments of Formula I, R3is a group of Formula IV wherein: ^ X2is -O-, -NH- or -C(=O)-, preferably is -C(=O)-; ^ Y is -(C1-C4 alkyl)- or -(C1-C4 alkenyl)-, preferably is -CH2- or -(CH=CH)-; ^ R8is an optionally substituted C3-C10 cycloalkyl, preferably is cyclopentyl; ^ R9is an optionally substituted C6-C10 aryl, preferably is indanyl; ^ R10is . Preferred compounds of Formula I are selected from the group of: 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(2-(2-(2-((4-oxo-3-phenyl-4,5-dihydro- 3H-pyrimido[5,4-b]indol-2-yl)thio)acetamido)ethoxy)ethyl)benzamide, 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(2-(2-(2-(2-((4-oxo-3-phenyl-4,5- dihydro-3H-pyrimido[5,4-b]indol-2-yl)thio)acetamido)ethoxy)ethoxy)ethyl)benzamide, 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(2-oxo-1-((4-oxo-3-phenyl-4,5-dihydro- 3H-pyrimido[5,4-b]indol-2-yl)thio)-7,10,13-trioxa-3-azahexadecan-16-yl)benzamide, 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(6-(2-((4-oxo-3-phenyl-4,5-dihydro-3H- pyrimido[5,4-b]indol-2-yl)thio)acetamido)hexyl)benzamide, 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(2-(2-((4-oxo-3-phenyl-4,5-dihydro-3H- pyrimido[5,4-b]indol-2-yl)thio)acetamido)ethyl)benzamide, 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(4-(2-((4-oxo-3-phenyl-4,5-dihydro-3H- pyrimido[5,4-b]indol-2-yl)thio)acetamido)cyclohexyl)benzamide, N-(1-(4-(1-(4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)phenyl)-1,12-dioxo-5,8-dioxa- 2,11-diazatridecan-13-yl)phenyl)-2-(cyclopentylamino)-2-oxoethyl)-N-(2,3-dihydro-1H-inden-5-yl)- 1,5-diphenyl-1H-pyrazole-3-carboxamide,

[0004] N-(1-(4-(2-(4-((4-(4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)benzoyl)piperazin-1- yl)methyl)piperidin-1-yl)-2-oxoethyl)phenyl)-2-(cyclopentylamino)-2-oxoethyl)-N-(2,3-dihydro-1H- inden-5-yl)-1,5-diphenyl-1H-pyrazole-3-carboxamide, N-(1-(4-(2-((6-(4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)benzamido)hexyl)amino)-2- oxoethyl)phenyl)-2-(cyclopentylamino)-2-oxoethyl)-N-(2,3-dihydro-1H-inden-5-yl)-1,5-diphenyl- 1H-pyrazole-3-carboxamide. Linking Group In certain embodiments of the invention, L is a linking group that functions to covalently connect a TLR7 agonist of Formula V: Formula V to a TLR4 agonist selected from the group of: Formula IV, wherein R1, R2, R4, R5, R6, R7, R8, R9, R10, X1, X2, Y, m, and n are as defined previously. The specific composition of the linking group L is not critical provided the resulting conjugate retains the useful biological properties described herein. Linker type and length can be readily optimized in the context of the other substituents in the conjugated compound by using the assays provided in examples. The selection of a linker component is based on its documented properties of biocompatibility and solubility in aqueous and organic media. According to certain embodiments, the linker L is a non-peptidic polymeric linker. Non-limiting examples of suitable non-peptidic polymeric linkers include polyalkylene oxides (e.g. polyethylene glycol, polypropylene glycol, and the like), polyvinyl alcohol, polyvinylpyrrolidone, and the like, as well as derivative and copolymers thereof. According to certain embodiments, the linker L comprises a polyethylene glycol (PEG) chain. According to certain embodiments, the polyethylene glycol chain comprises from 2 to 100, such as 2 to 50, repeating ethylene glycol units. According to certain embodiments, the polyethylene glycol chain comprises 2, 3, 4, 5, 6, 7, 8, 9 or 10 repeating ethylene glycol units. According to certain embodiments, one or both terminal hydroxy groups on the polyethylene glycol chain may be substituted with groups selected from amine, thiol, azide, carboxy, hydroxyl, N-hydroxysuccinimide and maleimide. According to certain embodiments, the linker L is non-polymeric aliphatic linker, comprising of a divalent, linear or branched, straight or cyclic, saturated or unsaturated, hydrocarbon chain, having from 2 to 100 carbon atoms, wherein the carbon atoms are optionally replaced by a group selected from -O-, -S-, -NH-, -C(=O)-, -OC(=O)-, -N(C1-C6alkyl)-, -NHC(=O)-, -N(C1-C6alkyl)C(=O)-, -S(=O)- or - S(=O)2- and wherein the chain is optionally substituted on carbon with one or more (e.g.1, 2, 3 or 4) substituents. The non-polymeric aliphatic linkers are typically derived from an aliphatic compound having at least two functional groups, capable of reacting with functional groups on the TLR7 and TLR4 agonist moieties (e.g. carboxy, NH2, OH, and the like). According to certain embodiments, the linker L is a divalent radical formed from an amino acid. According to certain embodiments, the linker L is a divalent radical formed from a natural amino acid and stereoisomers thereof. According to certain embodiments, the linker L is a divalent radical formed from a peptide. According to certain embodiments, the peptide includes naturally occurring amino acids, and stereoisomers thereof. According to certain embodiments, the peptide is formed only from naturally occurring amino acids, and stereoisomers thereof. According to certain embodiments, the linker L is a polyproline linker. According to certain embodiments, the linker L is a polyglycine linker. According to certain embodiments, the linker L is -NH-(CH2)2-O-(CH2)2-NH-. According to certain embodiments, the linker L is -NH-(CH2)2-O-(CH2)2-O-(CH2)2-NH-. According to certain embodiments, the linker L is -NH-(CH2)3-O-(CH2)2-O-(CH2)2-O-(CH2)3-NH-. According to certain embodiments, the linker L is -NH-(CH2)6-NH-. According to certain embodiments, the linker L is -NH-(CH2)2-NH-. According to certain embodiments, the linker L is . According to certain embodiments, the linker L is . Therapeutic applications Conjugated compounds of the present invention are TLR7 and TLR4 agonists. Thus, compounds of Formula I or pharmaceutically acceptable salts, racemates, diastereomers, enantiomers, esters or prodrugs thereof are useful in the treatment of conditions for which modulation, especially agonism, of TLR7 and / or TLR4 is beneficial. Immune responses generated by simultaneous activation of both TLR7 and TLR4 lead to the production and activation of pro-inflammatory cytokines. Thus, in one aspect, conjugated compounds of the invention are useful for the treatment of viral, bacterial, fungal, and protozoal infections, tumors or cancers, and immunological diseases. In another aspect, a compound of the invention is useful for the treatment of a viral, bacterial, fungal or protozoal infection. According to certain embodiments, a compound of the invention is useful for the treatment of a viral infection. According to certain embodiments, a compound of the invention is useful for the treatment of a bacterial infection. According to certain embodiments, a compound of the invention is useful for the treatment of a fungal infection. According to certain embodiments, a compound of the invention is useful for the treatment of a protozoal infection. In yet another aspect, conjugated compounds of the invention are useful for the treatment of tumors or cancer including but not limited to carcinomas, sarcomas, lymphomas, leukemia, brain cancer, cancer of the head, cancer of the reproductive system, gastrointestinal cancer, liver cancer, bile duct cancer, kidney cancer, bladder cancer, bone cancer, lung cancer, thyroid cancer, heart cancer, and metastasized cancer. In yet another aspect, conjugated compounds of the invention are useful to treat bacterial, fungal, and protozoal infections including but not limited to infections caused by bacteria of the genus Escherichia, Enterobacter, Salmonella, Staphylococcus, Klebsiella, Proteus, Pseudomonas, Streptococcus, Chlamydia, or fungal infections such as candidiasis, aspergillosis, histoplasmosis, and cryptococcal meningitis. According to certain embodiments, a compound of the invention is useful for the treatment of an immunological disease. In another aspect, the conjugated compounds of the invention are useful as vaccine adjuvants. Accordingly, this specification discloses a compound of Formula I or a pharmaceutically acceptable salt, racemate, diastereomer, enantiomer, ester or prodrug thereof for use in medicine, for immune modulation for the treatment of a disease. Compounds of the present invention can be formulated as pharmaceutical compositions and administered to a subject, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e. orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes. Pharmaceutical compositions comprising a compound of Formula I, may be prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington’s The Science and Practice of Pharmacy. Accordingly, one aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula I and one or more pharmaceutically acceptable excipients. For example, the conjugated compounds of the invention can be formulated for parenteral administration, such as intravenous administration or administration into a body cavity or lumen of an organ. Formulations for injection will commonly comprise a solution of the conjugated compound of the invention dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be employed are water and Ringer’s solution. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter. These formulations can be sterilized by conventional, well known sterilization techniques. The formulations can contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. These compositions can also be used as vaccine adjuvants. Thus, another aspect of the present invention is a vaccine comprising the conjugated compound of the invention. Used as vaccine adjuvants, the compounds of Formula I and pharmaceutical compositions thereof can be administered at the same time and by the same method as the antigen (viral, bacterial, parasitic antigen and the like) against which it is desired to increase the cell immunity reactions (type IV hypersensitivity) or the production of circulating or local antibodies in the immunized subject. Compounds of the present invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in lipid form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. Typical lipids are the phospholipid and phosphatidyl choline, both natural and synthetic. Methods of forming liposomes are known in the art and are described in Prescott’s Methods in Cell Biology, which is incorporated herein by reference. Process Another aspect of the present invention is the process for the manufacture of compounds of Formula I or a pharmaceutically acceptable salt thereof. If not commercially available, the necessary starting materials for the procedures such as those described below may be made by procedures which are selected from standard organic chemistry techniques, techniques which are analogous to the synthesis of knows structurally similar compounds, or techniques, which are analogous to the procedures described in the examples. It will also be appreciated that in some of the reactions mentioned herein it may be necessary / desirable to protect any sensitive groups in compounds. The instances where protection is necessary or desirable are known to those skilled in the art, as are suitable methods for such protection. Example of a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, a silyl group such as trimethylsilyl or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanol or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium of sodium hydroxide. Alternatively, a silyl group such as trimethylsilyl may be removed, for example, by fluoride or by aqueous acid; or an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation in the presence of catalyst such as palladium-on-carbon. A suitable protecting group for an amino group is, for example, any acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric, phosphoric or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on- carbon, or by treatment with a Lewis acid, for example boron tris (trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthalogenyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine or 2- hydroxyethylamine, or with hydrazine. Example of a suitable protecting group for a carboxy group is, for example, an alkyl group, for example a methyl, ethyl or t-butyl group or an aryl group, for example a benzyl group. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an alky group such as a methyl or ethyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an alkyl group such as a t-butyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric, phosphoric or trifluoroacetic acid. An aryl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. Other suitable protecting groups well known to those skilled in the art can be found in “Protective Groups in Organic Synthesis”, 3rdEd. by Greene and Wuts (John Wiley and Sons, 1999), incorporated herein by reference. The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, or they may be removed during a later reaction step or work-up. Thus, the present invention also provides that the compounds of Formula Iand pharmaceutically acceptable salts thereof can be prepared by a process comprising reacting a compound of Formula VI: Formula VI wherein R1, R2, X1, and n are as defined previously, with a compound of Formula VII: Formula VII, wherein R3and L are as defined previously; or a compound of Formula VIII: Formula VIII wherein R1, R2, X1, L and n are as defined previously, with a compound of Formula IX: Formula IX wherein R3is as defined previously; and optionally thereafter carrying out one or more of the following procedures: ^ removing any protecting groups, ^ forming a pharmaceutically acceptable salt, ^ converting a compound of Formula I into another compound of Formula I. Provided by these processes are conjugated compounds of Formula Ic: Formula Ic, Formula Id:

[0005] Formula Id, or Formula Ie Formula Ie, or pharmaceutically acceptable salts, racemates, diastereomers, enantiomers, esters or prodrugs thereof, wherein R1, R2, R4, R5, R6, R7, R8, R9, R10, X1, X2, Y, m, and n are as defined previously.

[0006] Examples METHODS OF SYNTHESIS The present invention is further exemplified, but not limited by, the following examples that illustrate the preparation of compounds of Formula I. The use of these and other examples anywhere in the specification is illustrative only, and in no way limits the scope and meaning of the invention or of any exemplified form. Likewise, the invention is not limited to any particular preferred embodiments described herein. Indeed, many modifications and variations of the invention may be apparent to those skilled in the art upon reading this specification, and can be made without departing from its spirit and scope. The invention is therefore to be limited only by the terms of the appended claims, along with the full scope of equivalents to which the claims are entitled. Unless otherwise stated: ^ evaporation was carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids after filtration; ^ operations were generally carried out at ambient temperature, that is typically between 18 and 26°C and without exclusion of air unless otherwise stated, or a person skilled in the art would otherwise work under an inert atmosphere; ^ flash column chromatography was used to purify compounds and was performed on Merck Silica Gel 60 unless otherwise stated; ^ yields are given for illustration only and are not necessarily the maximum attainable; ^ the structure of the end-products was generally confirmed by NMR and mass spectral techniques; proton NMR spectra is quoted and was determined using a Bruker Avance III 400 MHz spectrometer operating at field strength of 400 MHz. Chemical shifts are reported in part per million downfield from tetramethylsilane as an internal standard and peak multiplicities are shown thus: s, singlet; brs, broad singlet; d, doublet; t, triplet; q, quartet; m, multiplet ^ mass spectra were obtained using a Q TOF Premier mass spectrometer (Micromass, Waters, Manchester, UK) and Exactive Plus Orbitrap mass spectrometer (Thermo Fisher Scientific, Waltham, Massachusetts, USA) ^ each intermediate was generally purified to the standard required for the subsequent stage and was characterized in sufficient detail to confirm that the assigned structure was correct; purity was assessed by high pressure liquid chromatography, thin layer chromatography, or NMR and identity was determined by mass spectrometry and NMR spectroscopy as appropriate. Abbreviations As used herein, the symbols and conventions are consistent with those used in the contemporary scientific literature. Specifically, the following abbreviations are used in the text: Boc2O for di-tert-butyl decarbonate; CDCl3for deuterated chloroform; COMU for (1-cyano-2- ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate; DCC for N,Nʹ-dicyclohexylcarbodiimide; DCM for dichloromethane; DIPEA for N,N- diisopropylethylamine; DMAP for 4-dimethylaminopyridine; DMF for dimethylformamide; DMSO for dimethyl sulfoxide; DMSO-d6for deuterated dimethyl sulfoxide; EDC for N-(3- dimethylaminopropyl)-Nʹ-ethylcarbodiimide hydrochloride; eq for equivalent; g for gram; HCl for hydrochloric acid; HOBt for hydroxybenzotriazole; K2CO3 for potassium carbonate; LPS for lipopolysaccharides; mL for milliliter; mmol for millimole; NaHCO3for sodium hydrogen carbonate; NaOH for sodium hydroxide; Na2SO4 for sodium sulphate; Na2S2O3 for sodium thiosulfate; NH4Cl for ammonium chloride; NMR for nuclear magnetic resonance; PBS for phosphate buffered saline; RPM for revolutions per minute; rt for room temperature; TEA for triethylamine; TFA for trifluoroacetic acid EXAMPLE 1: Compound SB19 Intermediate 1 Ethyl 2-((2-cyanophenyl)amino)acetate: 2-aminobenzonitrile (10.00 g, 84.65 mmol, 1 eq), ethyl bromoacetate (10.00 mL, 88.29 mmol, 1.04 mmol), and sodium bicarbonate (8.34 g, 99.2 mmol, 1.17 eq) were combined in anhydrous EtOH (40 mL) and refluxed for 40 h. After cooling slightly, solution was decanted from precipitate into a prewarmed flask. Further cooling of the decantate yielded crystals, which were then filtered and washed with cold water several times to afford the subject compound as an off-white solid (7,434 g, yield: 43%).1H NMR (400 MHz, DMSO-d6) δ 7.49 (dd, 1H), 7.44 – 7.38 (m, 1H), 6.70 (td, 1H), 6.64 (d, 1H), 6.36 (t, 1H), 4.13 (q, 2H), 4.04 (d, 2H), 1.20 (t, 3H). Intermediate 2 Ethyl 3-amino-1H-indole-2-carboxylate: In a flame-dried flask, a suspension of potassium t- butoxide (1.10 g, 9.793 mmol, 1 eq) in anhydrous THF (10 mL) was stirred under argon. To this solution was added a solution of Intermediate 1 (2.00 g, 9.793 mmol, 1 eq) in anhydrous THF (13 mL) over 45 min and stirred for an additional 2 h. The reaction was then poured into ice water, extracted with EtOAc, and dried over MgSO4. The solvent was concentrated in vacuo to afford the subject compound as an off-white solid (1.10 g, yield: 55%).1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.74 (m, 1H), 7.30 – 7.10 (m, 2H), 6.88 (m, 1H), 5.68 (s, 2H), 4.29 (q, 2H), 1.33 (t, 3H). Intermediate 3 Ethyl 3-(3-phenylthioureido)-1H-indole-2-carboxylate: Intermediate 2 (0.950 g, 4.65 mmol, 1 eq) was dissolved in warm EtOH (7.5 mL). To a solution was added phenyl isothiocyanate (0.612 mL, 5.12 mmol, 1.1 eq) dropwise with stirring. The reaction was refluxed for 20 minutes and then cooled for 1h. Solids were filtered, washed with cold EtOH, and dried overnight to give the subject compound as an off-white solid (0.791 mg, yield: 48%).1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 9.69 (s, 1H), 9.40 (s, 1H), 7.62 – 7.40 (m, 4H), 7.38 – 7.19 (m, 3H), 7.20 – 6.97 (m, 2H), 4.46 – 4.14 (m, 3H), 1.33 (t, 3H). Intermediate 4 3-phenyl-2-thioxo-2,3-dihydro-1H-pyrimido[5,4-b]indol-4(5H)-one: To a flame-dried flask with cold anhydrous EtOH (10 mL) was added cold acetyl chloride (3.3 mL, 45.82 mmol, 5 eq) under argon with stirring. In a separate flame-dried flask charged with argon, Intermediate 3 (3.293 g, 9.16 mmol, 1eq) was dissolved in anhydrous EtOH (130 mL) and added to the acetyl chloride solution. The reaction was refluxed overnight and cooled upon completion. Precipitate was filtered and washed with EtOH to give the subject compound as an off-white solid (1.866 g, yield: 69%).1H NMR (400 MHz, DMSO-d6) δ 13.76 (s, 1H), 12.20 (s, 1H), 8.23 (d, 1H), 7.62 – 7.35 (m, 5H), 7.35 – 7.13 (m, 3H). Compound 5 SB19 2-((4-oxo-3-phenyl-4,5-dihydro-3H-pyrimido[5,4-b]indol-2-yl)thio)acetic acid: In a flame-dried flask, compound 4 (1 g, 3.41 mmol, 1 eq) and KOH (0.765 g, 13.64 mmol, 2 eq) were dissolved in anhydrous EtOH (28 mL) with heat. In a separate flame-dried flask, chloroacetic acid (0.838 mmol, 8.86 mmol, 2.6 eq) was added to anhydrous EtOH (7 mL). Chloroacetic acid solution was then added to the reaction mixture and refluxed for 20 h. The reaction was concentrated by half and acidified with 3 M HCl to pH 4. The solids were collected, washed with water, and dried in vacuo to give compound 5 (0.671 g, yield: 56%).1H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 12.11 (s, 1H), 7.96 (d, 1H), 7.70 – 7.55 (m, 3H), 7.55 – 7.43 (m, 4H), 7.32 – 7.17 (m, 1H), 3.96 (s, 2H). EXAMPLE 2: Compound SG43 Intermediate 6 4-((6-amino-2-chloro-9H-purin-9-yl)methyl)benzonitrile: 2-chloroadenine (1.017 g, 6 mmol, 1.0 eq), potassium carbonate (2.579 g, 18.66 mmol 3.11 eq) and 4-(bromomethyl)benzonitrile (1.625 g, 8.29 mmol 1.38 eq) were suspended in DMSO (22 mL) and stirred at rt for 20 h. The reaction mixture was poured into ethyl acetate (130 mL) and water (90 mL). After mixing thoroughly, the mixture was concentrated in vacuo. The concentrated mixture was cooled in ice and the formed precipitate was filtered, washed with cold water and dried to afford the subject compound (1.737 g, yield: 89%).1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.85-7.83 (m, 4H), 7.42 (d, 2H), 5.45 (s, 2H). Intermediate 7 4-((6-amino-2-butoxy-9H-purin-9-yl)methyl)benzoic acid: Intermediate 6 (1.737 g, 6.10 mmol, 1 eq) was suspended in dry n-butanol (60 mL). A 20% solution of sodium n-butoxide in n-butanol (33.6 mL, 61.01 mmol, 10 eq) was added and the resulting mixture was refluxed with stirring for 20 h. The reflux was paused to cool the mixture. Water (20 mL) was added and the reflux was continued for additional 20 h. The reaction mixture was extracted three times with 80 mL of water. The combined aqueous layers were acidified to pH 3 with concentrated HCI and cooled overnight. The white precipitate obtained was filtered and dried to afford the subject compound (1.605 g, yield: 77%).1H NMR (400 MHz, DMSO-d6) δ 12.69 (br s, 1H), 8.07 (s, 1H), 7.91 (d, 2H), 7.39 (d, 2H), 7.25 (s, 2H), 5.35 (s, 2H), 4.20-4.18 (m, 2H), 1.64-1.61 (m, 2H), 1.39-1.35 (m, 2H), 0.90 (t, 3H). Intermediate 8 4-((6-amino-8-bromo-2-butoxy-9H-purin-9-yl)methyl)benzoic acid: Intermediate 7 (1.605 g, 4.701 mmol, 1 eq) was suspended in acetic acid (60 mL). Sodium acetate (1.928 g, 23.51 mmol, 5 eq) and bromine (1.22 mL, 23.74 mmol, 5.05 eq) were added and the resulting mixture was stirred at rt for 2 h. Aqueous Na2S2O3 was added to the reaction mixture. The precipitate obtained was filtered and washed with cold water and diethyl ether to afford the subject compounds as a yellow powder (1.976 g, yield 100%).1H NMR (400 MHz, DMSO-d6 ) δ 7.92 (d, 2H), 7.44 (brs, 2H), 7.30 (d, 2H), 5.33 (s, 2H), 4.19 (t, 2H), 1.66-1.59 (m, 2H), 1.40-1.35 (m, 2H), 0.91 (t, 3H). Compound 9 SG43 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)benzoic acid: To Intermediate 8 (1.976 g, 4.701 mmol) in methanol (35 mL) was added 10 M aqueous NaOH (35 mL). The mixture was refluxed with stirring for 24 h. The solution was cooled to room temperature and acidified with 6 M HCI solution. After concentrating the mixture in vacuo, the off-white precipitate obtained was filtered and washed with water and diethyl ether to afford the subject compound (1.523 g, yield (brs, 2H), 4.93 tert-Butyl (2-(2-(4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9- yl)methyl)benzamido)ethoxy)ethyl)carbamate: Compound 9 (200 mg, 0.560 mmol, 1 eq) was dissolved in 10 mL DMSO. Tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (380 mg, 1.86 mmol, 3.33 eq) and DIPEA (0.523 mL, 2.99 mmol, 5.33 eq) were dissolved in DCM (1 mL) and added to the stirring solution of Compound 9 in DMSO. After cooling the reaction mixture in ice, COMU (640 mg, 1.49 mmol, 2.66 eq) was added and the mixture was stirred at rt for 3h. Ethyl acetate (40 mL) was added and after cooling in the fridge, 1M NaHCO3solution (30 mL) was added. After concentrating the mixture in vacuo, the mixture was cooled in ice for one hour. The precipitate was filtered and washed with water and diethyl ether to afford the subject compound (160 mg, yield 53%).1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.45 (s, 1H), 7.78 (d, 2H), 7.34 (d, 2H), 6.76 (d, 1H), 6.47 (s, 2H), 4.90 (d, 2H), 4.12 (t, 2H), 3.44 (dt, 6H), 3.06 (d, 2H), 1.70 – 1.51 (m, 2H), 1.33 (s, 12H), 0.89 (t, 3H). Intermediate 11 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(2-(2-aminoethoxy)ethyl)benzamide: Intermediate 10 (160 mg, 0.294 mmol) was added to an ice-chilled stirred mixture of TFA and DCM (1 / 5, 6 mL), and the mixture was allowed to warm to rt. After 3 h, solvent was evaporated in vacuo. The residue was precipitated in diethyl ether, filtered and washed with diethyl ether to afford the subject compound as a brown solid (156 mg, yield: 97 %).1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.43 (t, 1H), 7.93 – 7.50 (m, 4H), 7.36 (d, 2H), 6.51 (s, 2H), 4.91 (s, 2H), 4.13 (t, 2H), 3.60 – 3.30 (m, 6H), 2.98 (m, 2H), 1.73 – 1.48 (m, 2H), 1.48 – 1.21 (m, 2H), 0.90 (t, 3H). Compound 12 SB29 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(2-(2-(2-((4-oxo-3-phenyl-4,5-dihydro- 3H-pyrimido[5,4-b]indol-2-yl)thio)acetamido)ethoxy)ethyl)benzamide: To an ice-chilled stirring solution of Intermediate 11 (100 mg, 0.179 mmol, 1.2 eq) in dry DMF (2 mL) were added DIPEA (0.104 mL, 0.598 mmol, 4 eq), Compound 5 (52 mg, 0.149 mmol, 1 eq) and COMU (77 mg, 0.179 mmol, 1.2 eq). The resulting mixture was stirred at rt for 20 h. Subsequently, ethyl acetate (20 mL) was added and washed with saturated NaHCO3solution (2 × 15 mL) and 1M HCl (2 × 15 mL). The resulting precipitate in organic phase was filtered and dried. The crude compound was purified using Isolera Biotage One Flash Chromatography (0,1% TFA, Acetonitrile, Methanol) to afford the subject compound as a white solid (20 mg, yield: 17 %).1H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 9.97 (s, 1H), 8.44 (s, 1H), 8.33 (s, 1H), 8.03 (d, 1H), 7.78 (d, 2H), 7.60 (d, 3H), 7.53 – 7.38 (m, 3H), 7.33 (d, 2H), 7.24 (d, 1H), 6.46 (s, 2H), 4.88 (s, 2H), 4.11 (t, 2H), 3.91 (s, 2H), 3.47 (s, 3H), 3.39 (s, 2H), 1.66 – 1.54 (m, 2H), 1.40 – 1.31 (m, 2H), 0.88 (t, 3H). EXAMPLE 4: Compound SB95 Intermediate 13 tert-Butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate: A solution of Boc2O (4.365 g, 20 mmol, 1 eq) in DCM (40 mL) was added dropwise to a stirring solution of 1,2-Bis(2-aminoethoxy)ethane (14.821 g, 100 mmol, 5 eq) in DCM (100 mL) at 0 °C. The resulting mixture was stirred at rt for 20 h. Subsequently, the solution was washed with water (3 × 100 mL) and brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to afford the subject compound as a colourless oil (4.370 g, yield: 88%).1H NMR (400 MHz, DMSO-d6) δ 6.72 (m, 1H), 3.53 - 3.44 (m, 4H), 3.41 - 3.30 (m, 4H), 3.05 (q, 2H), 2.64 (t, 2H), 1.36 (s, 9H). Intermediate 14 tert-Butyl (2-(2-(2-(4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9- yl)methyl)benzamido)ethoxy)ethoxy)ethyl)carbamate: Compound 9 (500 mg, 1.399 mmol, 1 eq) was dissolved in DMSO (20mL). Intermediate 13 (1.157 g, 4.659 mmol, 3.33 eq) and DIPEA (1.299 mL, 7.457 mmol, 5.33 eq) were dissolved in DCM (1 mL) and added to the stirring solution of Compound 6 in DMSO. After cooling the reaction mixture in ice, COMU (1.594 g, 3.722 mmol, 2.66 eq) was added and the mixture was stirred at rt for 20h. Ethyl acetate (100 mL) and 1M NaHCO3 solution (75 mL) were added. After concentrating the mixture in vacuo, the mixture was cooled in ice for one hour. The precipitate was filtered and washed with water and diethyl ether to afford the subject compound, which was used for the next step without any further purification. Intermediate 15 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(2-(2-(2- aminoethoxy)ethoxy)ethyl)benzamide: Intermediate 14 (491 mg, 0,84 mmol) was added to an ice- chilled stirred mixture of TFA and DCM (1 / 5, 12 mL), and the mixture was allowed to warm to room temperature. After 3 h, the solvent was evaporated in vacuo. The residue was precipitated in diethyl ether, filtered and washed with diethyl ether to afford the subject compound as a brown solid (492 mg, yield: 98%).1H NMR (400 MHz, DMSO-d6 ) δ 10.07 (s, 1H), 8.48 (t, 1H), 7.82 - 7.75 (m, 4H), 7.35 (d, 2H), 6.52 (m, 2H), 4.91 (s, 2H), 4.13 (t, 2H), 3.63 - 3.49 (m, 8H), 3.46 - 3.33 (m, 2H), 3.03 - 2.88 (m, 2H), 1.67 - 1.56 (m, 2H), 1.43 - 1.30 (m, 2H), 0.90 (t, 3H). Compound 16 SB95 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(2-(2-(2-(2-((4-oxo-3-phenyl-4,5- dihydro-3H-pyrimido[5,4-b]indol-2-yl)thio)acetamido)ethoxy)ethoxy)ethyl)benzamide: To an ice-chilled stirring solution of Intermediate 15 (0.090 g, 0.185 mmol, 1 eq) in DMF (1.5 mL) were added DIPEA (0.129 mL, 0.740 mmol, 4 eq), Compound 5 (71 mg, 0,203 mmol, 1.1 eq) and COMU (0.087 mg, 0.203 mmol, 1 eq). The resulting mixture was stirred at rt for 20 h. Subsequently, ethy acetate (30 mL) was added and washed with 1% citric acid (2 × 25 mL) and saturated NaHCO3solution (2 × 25 mL). The resulting precipitate in organic phase was filtrated and dried to afford the subject compound as a blue solid (35 mg, yield: 23%).1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 8.47 (d, 1H), 8.33 (d, 1H), 8.04 (d, 1H), 7.78 (d, 2H), 7.60 (d, 3H), 7.49 (dd, 5H), 7.33 (d, 2H), 7.24 (t, 2H), 6.57 (s, 1H), 4.90 (s, 2H), 4.12 (t, 2H), 3.91 (s, 2H), 1.60 (t, 2H), 1.36 (q, 2H), 0.89 (t, 3H). *some signals of the linker are under water peak. EXAMPLE 5: Compound SB101 Intermediate 17 tert-Butyl (3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)carbamate: A solution of Boc2O (2.97 g, 14 mmol, 1 eq) in DCM (35 mL) was added dropwise to a stirring solution of 3,3'-((oxybis(ethane- 2,1-diyl))bis(oxy))bis(propan-1-amine) ( 15 g, 68 mmol, 5 eq) in DCM (60 mL) at 0°C. The resulting mixture was stirred at rt for 20 h. Subsequently, DCM was evaporated and saturated NaHCO3 (50 mL) was added to the mixture, which was extracted two times with DCM (2 × 50 mL). Combined organic phases were washed with NaHCO3 (25 mL) and brine (40 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to afford the subject compound as a colourless oil (3.33 g, yield: 74%).z1H NMR (400 MHz, DMSO-d6) δ 6.78 (t, 1H), 3.60 – 3.30 (m, 12H), 3.04 – 2.86 (m, 2H), 2.57 (t, 2H), 1.69 – 1.47 (m, 4H), 1.37 (s, 9H). Intermediate 18 tert-Butyl (1-(4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)phenyl)-1-oxo-6,9,12- trioxa-2-azapentadecan-15-yl)carbamate: Compound 9 (0.250 g, 0.670 mmol, 1 eq) was dissolved in DMSO (8mL). Intermediate 17 (0.746 g, 2.329 mmol, 3.33 eq), DIPEA (0.62 mL, 3.571 mmol, 5.33 eq) and COMU (0.763 g, 1.782 mmol, 2.66 eq) were added to an ice-chilled mixture. The resulting mixture was stirred at rt for 20 h. Ethyl acetate (75 mL) and 1M NaHCO3 solution (50 mL) were added. After concentrating the mixture in vacuo, the mixture was cooled in ice for one hour. The precipitate was filtered and washed with water and diethyl ether to afford the subject compound, which was used for the next step without any further purification. Intermediate 19 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(3-(2-(2-(3- aminopropoxy)ethoxy)ethoxy)propyl)benzamide: Intermediate 18 (0.362 g, 0.549 mmol) was added to an ice-chilled stirred mixture of TFA and DCM (1 / 5, 20 mL), and the mixture was allowed to warm to room temperature. After 4 h, the solvent was evaporated in vacuo. The residue was coevaporated with diethyl ether to afford the subject compound as a brown solid (300 mg, yield: 98%).1H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.41 (t, 1H), 7.77 (d, 2H), 7.35 (d, 2H), 6.56 (s, 2H), 5.31 (s, 2H), 4.91 (s, 2H), 4.14 (t, 2H), 3.55 – 3.26 (m, 12H), 3.00 – 2.77 (m, 4H), 1.76 (t, 4H), 1.69 – 1.51 (m, 2H), 1.36 (h, 2H), 1.09 (t, 2H), 0.90 (t, 3H). Compound 20 SB101 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(2-oxo-1-((4-oxo-3-phenyl-4,5- dihydro-3H-pyrimido[5,4-b]indol-2-yl)thio)-7,10,13-trioxa-3-azahexadecan-16-yl)benzamide: To an ice-chilled stirring solution of Intermediate 19 (0.114 g, 0.204 mmol, 1 eq) in DMF (1.5 mL) were added Compound 5 (0.079 g, 0.224 mmol, 1.1 eq), DIPEA (0.177 mL, 1.018 mmol, 5 eq) and COMU (0.096 g, 0.224 mmol, 1.1 eq). The resulting mixture was stirred at rt for 20 h. Subsequently, ethyl acetate (30 mL) was added and washed with 1M HCl (2 × 20 mL). The resulting precipitate was filtered and purified using Isolera Biotage One Flash Chromatography (0,1% TFA, Acetonitrile, Methanol) to afford the subject compound as a white solid (15 mg, yield: 8%).1H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 9.98 (s, 1H), 8.38 (s, 1H), 8.23 (s, 1H), 8.03 (d, 1H), 7.76 (d, 2H), 7.60 (d, 3H), 7.55 – 7.39 (m, 3H), 7.33 (d, 1H), 7.29 – 7.20 (m, 1H), 6.46 (s, 1H), 4.89 (s, 2H), 4.12 (t, 4H), 3.88 (s, 5H), 1.78 – 1.65 (m, 2H), 1.61 (q, 4H), 1.35 (q, 2H), 0.89 (t, 3H). *some signals for the linker are under water peak. EXAMPLE 6: Compound SB105 Intermediate 21: tert-Butyl (6-aminohexyl)carbamate: A solution of Boc2O (3.756 g, 17 mmol, 1 eq) in DCM (35 mL) was added dropwise to a stirring solution of hexane-1,6-diamine (10 g, 96 mmol, 5 eq) in DCM (65 mL) at 0°C. The resulting mixture was stirred at rt for 20 h. Subsequently, DCM was evaporated and saturated NaHCO3 was added to the mixture, which was extracted two times with DCM (2 × 50 mL). Combined organic phases were washed with NaHCO3 (2 × 25 mL) and brine (40 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to afford the subject compound as a white solid (2.47 g, yield: 67%).1H NMR (400 MHz, DMSO-d6) δ 6.77 (t, 1H), 2.88 (m, 2H), 1.45 – 1.13 (m, 21H). Intermediate 22 tert-butyl (6-(4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9- yl)methyl)benzamido)hexyl)carbamate: Compound 9 (250 mg, 0.670 mmol, 1 eq) was dissolved in DMSO (8mL). Intermediate 21 (0.500 g, 2.329 mmol, 3.33 eq), DIPEA (0.62 mL, 3.571 mmol, 5.33 eq) and COMU (0.763 g, 1.782 mmol, 2.66 eq) were added to an ice-chilled mixture. The resulting mixture was stirred at rt for 20 h. Ethyl acetate (75 mL) and 1M NaHCO3solution (50 mL) were added. After concentrating the mixture in vacuo, the mixture was cooled in ice for one hour. The precipitate was filtered and washed with water and diethyl ether to afford the subject compound, which was used for the next step without any further purification.1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.39 (t, 1H), 7.77 (d, 2H), 7.34 (d, 2H), 6.78 (d, 1H), 6.48 (s, 2H), 4.90 (s, 2H), 4.13 (t, 2H), 3.27 – 3.05 (m, 2H), 2.98 – 2.81 (m, 2H), 1.67 – 1.17 (m, 23H), 0.90 (t, 3H). Intermediate 23 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(6-aminohexyl)benzamide: Intermediate 22 (0.372 g, 0.670 mmol) was added to an ice-chilled stirred mixture of TFA and DCM (1 / 5, 20 mL), and the mixture was allowed to warm to room temperature. After 4 h, the solvent was evaporated in vacuo. The residue was coevaporated with diethyl ether to afford the subject compound as a brown solid (300 mg, yield: 98%), which was used for the next step without any further purification. Compound 24 SB105 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(6-(2-((4-oxo-3-phenyl-4,5-dihydro- 3H-pyrimido[5,4-b]indol-2-yl)thio)acetamido)hexyl)benzamide: To an ice-chilled stirring solution of Intermediate 23 (0.100 g, 0.219 mmol, 1 eq) in DMF (1.5 mL) were added Compound 5 (0.085 g, 0.241 mmol, 1.1 eq), DIPEA (0.191 mL, 1.09 mmol, 5 eq) and COMU (0.103 g, 0.241 mmol, 1.1 eq). The resulting mixture was stirred at rt for 20 h. Subsequently, ethyl acetate (30 mL) was added and washed with 1M HCl (2 × 20 mL), saturated NaHCO3solution (2 × 20 mL) and brine (20 mL). The organic layer was concentrated in vacuo. The crude compound was purified using preparative thin layer silica gel chromatography (5 % MeOH / DCM) and Isolera Biotage One Flash Chromatography (0,1% TFA, Acetonitrile, Methanol) to afford the subject compound as an off-white solid (10 mg, yield: 6%). EXAMPLE 7: Compound SB109 Intermediate 25 tert-Butyl (2-aminoethyl)carbamate: A solution of Boc2O (7.26 g, 33 mmol, 1 eq) in DCM (35 mL) was added dropwise to a stirring solution of ethylenediamine (10 g, 167 mmol, 5 eq) in DCM (60 mL) at 0°C. The resulting mixture was stirred at rt for 20 h. Subsequently, DCM was evaporated and saturated NaHCO3 was added to the mixture, which was extracted three times with DCM (3 × 50 mL). Combined organic phases were washed with NaHCO3 (2 × 25 mL) and brine (40 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to afford the subject compound as a yellow solid (2.927 g, yield: 53%).1H NMR (400 MHz, DMSO-d6) δ 6.75 (t, 1H), 2.91 (dt, 2H), 2.52 (d, 2H), 1.37 (d, 11H). Intermediate 26 tert-Butyl (2-(4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9- yl)methyl)benzamido)ethyl)carbamate: Compound 9 (0.225 g, 0.630 mmol, 1 eq) was dissolved in DMSO (8mL). Intermediate 19 (0.336 g, 2.096 mmol, 3.33 eq), DIPEA (0.58 mL, 3.358 mmol, 5.33 eq) and COMU (0.717 g, 1.676 mmol, 2.66 eq) were added to an ice-chilled mixture. The resulting mixture was stirred at rt for 20 h. Ethyl acetate (75 mL) and 1M NaHCO3solution (50 mL) were added. After concentrating the mixture in vacuo, the mixture was cooled in ice for one hour. The precipitate was filtered and washed with water and hexane to afford the subject compound, which was used for the next step without any further purification.1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.55 – 8.32 (m, 1H), 7.77 (d, 2H), 7.34 (d, 2H), 6.90 (s, 1H), 6.49 (s, 1H), 4.90 (s, 2H), 4.12 (t, 2H), 3.32 – 3.18 (m, 2H), 3.07 (d, 2H), 1.61 (p, 2H), 1.36 (s, 11H), 0.90 (t, 3H). Intermediate 27 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(2-aminoethyl)benzamide: Intermediate 26 (0.260 g, 0.521 mmol.1 eq) was added to an ice-chilled stirred mixture of TFA and DCM (1 / 5, 20 mL), and the mixture was allowed to warm to room temperature. After 3 h, the solvent was evaporated in vacuo. The residue was coevaporated with diethyl ether to afford the subject compound as a brown solid (205 mg, yield: 99%), which was used for the next step without any further purification Compound 28 SB109 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(2-(2-((4-oxo-3-phenyl-4,5-dihydro- 3H-pyrimido[5,4-b]indol-2-yl)thio)acetamido)ethyl)benzamide: To an ice-chilled stirring solution of Intermediate 27 (70 mg, 0.175 mmol, 1 eq) in DMF (1.5 mL) were added, Compound 5 (68 mg, 0.193 mmol, 1.1 eq), DIPEA (0.153 mL, 0.876 mmol, 5 eq) and COMU (82 mg, 0.193 mmol, 1.1 eq). The resulting mixture was stirred at rt for 20 h. Subsequently, ethyl acetate (30 mL) was added and washed with 1M HCl (2 × 20 mL), saturated NaHCO3 solution (2 × 20 mL) and brine (20 mL). The organic layer was concentrated in vacuo. to afford the subject compound as an off-white solid (30 mg, yield: 24%).1H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 10.20 (s, 1H), 8.60 – 8.21 (m, 2H), 8.00 (d, 1H), 7.71 (d, 3H), 7.59 (dd, 4H), 7.55 – 7.41 (m, 6H), 7.30 (d, 2H), 7.18 (t, 2H), 4.91 (s, 2H), 4.15 (t, 2H), 3.90 (s, 3H), 3.32 – 3.18 (m, 4H), 1.61 (p, 2H), 1.42 – 1.26 (m, 2H), 0.88 (t, 3H). EXAMPLE 8: Compound SB94 Intermediate 29 tert-butyl (4-(2-((4-oxo-3-phenyl-4,5-dihydro-3H-pyrimido[5,4-b]indol-2- yl)thio)acetamido)cyclohexyl)carbamate: Compound 5 (0.300 g, 0.854 mmol, 1 eq) was dissolved in DMF (3 mL). tert-butyl (4-aminocyclohexyl)carbamate (0.220 g, 1.02 mmol, 1.2 eq), DIPEA (0.59 mL, 3.416 mmol, 4 eq) and COMU (0.439 g, 1.02 mmol, 1.2 eq) were added to an ice-chilled mixture. The resulting mixture was stirred at rt for 20 h. Subsequently, ethyl acetate (30 mL) was added and washed with 1M HCl (2 × 20 mL), saturated NaHCO3 solution (2 × 20 mL) and brine (20 mL). The organic layer was concentrated in vacuo. Then the ethyl acetate was added again (10 mL) and the resulting precipitate was filtered to afford the subject compound as a blue solid (370 mg, yield: 79 %).1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.21 (d, 1H), 8.06 (d, 1H), 7.82 – 7.33 (m, 7H), 7.26 (t, 1H), 6.71 (d, 1H), 3.87 (s, 2H), 3.24 – 2.99 (m, 1H), 1.76 (d, 4H), 1.37 (s, 9H), 1.15 (m, 4H). Intermediate 30 N-(4-aminocyclohexyl)-2-((4-oxo-3-phenyl-4,5-dihydro-3H-pyrimido[5,4-b]indol-2- yl)thio)acetamide: Intermediate 29 (0.100 g, 0.182 mmol, 1 eq) was added to an ice-chilled stirred mixture of TFA and DCM (1 / 5, 12 mL), and the mixture was allowed to warm to room temperature. After 4 h, the solvent was evaporated in vacuo. The residue was coevaporated with diethyl ether to afford the subject compound, which was used for the next step without any further purification. Compound 31 SB94 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(4-(2-((4-oxo-3-phenyl-4,5-dihydro- 3H-pyrimido[5,4-b]indol-2-yl)thio)acetamido)cyclohexyl)benzamide: Intermediate 30 (0.081 g, 0.182 mmol, 1 eq) was dissolved in DMF (3 mL). Compound 9 (0.078 g, 0.218 mmol, 1.2 eq), DIPEA (0.095 mL, 0.547 mmol, 3 eq) and COMU (0.093, 0.218 mmol, 1.2 eq) were added to an ice-chilled mixture. The resulting mixture was stirred at rt for 20 h. Subsequently, DCM (50 mL) was added and washed with 1% citric acid (2 × 20 mL), saturated NaHCO3 solution (2 × 20 mL) and brine (20 mL). The precipitate in organic phase was filtered to afford the subject compound as a blue solid (65 mg, yield: 45%).1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 0H), 8.16 (d, 1H), 8.08 (d, 1H), 7.95 (s, 1H), 7.75 (d, 2H), 7.60 (d, 2H), 7.56 – 7.41 (m, 3H), 7.33 (d, 2H), 7.27 (t, 1H), 7.16 (d, 1H), 6.61 (s, 2H), 4.97 – 4.84 (m, 2H), 4.13 (d, 2H), 3.88 (s, 1H), 3.71 (s, 1H), 1.80 (d, 3H), 1.61 (d, 2H), 1.36 (d, 5H), 0.90 (q, 3H). EXAMPLE 9: Compound SG202 Intermediate 32 Methyl 2-(4-(2-(cyclopentylamino)-1-(N-(2,3-dihydro-1H-inden-5-yl)-1,5-diphenyl-1H-pyrazole- 3-carboxamido)-2-oxoethyl)phenyl)acetate: A solution of 2,3-dihydro-1H-inden-5-amine (0.133 g, 1 mmol, 1 eq) in dry methanol (2 mL) was added dropwise to a stirred suspension of 1,5-diphenyl- 1H-pyrazole-3-carboxylic acid (0.264 g, 1 mmol, 1 eq), methyl 2-(4-formylphenyl)acetate (0.178 g, 1 mmol, 1 eq) and isocyanocyclopentane (0.107 mL, 1 mmol, 1 eq) in dry methanol (5 mL). The mixture was stirred on rt for 20 h. The mixture was evaporated in vacuo and the residual oil was purified using preparative thin layer silica gel chromatography (66% ethylacetate / hexane) to afford the subject compound as a white solid (570 mg, yield: 81%).1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, 1H), 7.39 – 7.15 (m, 6H), 7.15 – 6.76 (m, 10H), 6.30 (d, 2H), 3.58 (d, 5H), 2.70 (m, 4H), 1.93 (m, 2H), 1.88 – 1.69 (m, 2H), 1.69 – 1.34 (m, 5H), 1.28 (m, 1H). Compound 33 SG202 2-(4-(2-(cyclopentylamino)-1-(N-(2,3-dihydro-1H-inden-5-yl)-1,5-diphenyl-1H-pyrazole-3- carboxamido)-2-oxoethyl)phenyl)acetic acid: Intermediate 32 (0.527 mg, 0.807 mmol, 1 eq) was dissolved in THF (6 mL) and methanol (3 mL).1M NaOH (2.4 mL, 2.421 mmol, 3 eq) was added to a reaction mixture and stirred at rt. After 3 h THF and methanol were evaporated in vacuo and resulting mixture was acidified with 1M HCl to pH 2. Resulting suspension was extracted with ethyl acetate (2 × 20 mL). Combined organic phases were washed with NaCl (20 mL), dried over anhydrous Na2SO4and concentrated in vacuo. The yellow oil was washed with diethyl ether to afford the subject compound as a white solid (257 mg, yield: 40 %).1H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 8.11 (d, 1H), 7.32 (ddd, 6H), 7.01 (d, 10H), 6.22 (s, 2H), 4.03 (d, 1H), 3.47 (s, 2H), 2.82 – 2.61 (m, 4H), 2.08 – 1.67 (m, 4H), 1.67 – 1.17 (m, 6H). EXAMPLE 10: Compound SB146 Compound 34 SB146 N-(1-(4-(1-(4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)phenyl)-1,12-dioxo-5,8-dioxa- 2,11-diazatridecan-13-yl)phenyl)-2-(cyclopentylamino)-2-oxoethyl)-N-(2,3-dihydro-1H-inden-5- yl)-1,5-diphenyl-1H-pyrrole-3-carboxamide: Intermediate 15 (0.080 g, 0.133 mmol, 1.1 eq) was dissolved in DMF (2 mL). Compound 33 (0.070 g, 0.120 mmol, 1 eq), DIPEA (0.063 mL, 0.363 mmol, 3 eq) and COMU (0.062, 0.145 mmol, 1.2 eq) were added to an ice-chilled mixture. The resulting mixture was stirred at rt for 20 h. Subsequently, ethyl acetate (20 mL) was added and washed with 1M HCl (2 × 15 mL), saturated NaHCO3 solution (2 × 15 mL) and brine (20 mL). The organic layer was concentrated in vacuo. The crude compound was purified using Isolera Biotage One Flash Chromatography (0,1% TFA, Acetonitrile, Methanol) to afford the subject compound as an off- white solid (20 mg, yield: 15%).1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.49 (t, 1H), 8.09 (d, 2H), 7.78 (d, 2H), 7.41 – 7.20 (m, 12H), 7.15 – 6.98 (m, 10H), 6.93 (s, 5H), 6.48 (s, 2H), 6.21 (s, 3H), 4.89 (s, 2H), 4.12 (t, 2H), 4.03 (d, 2H), 3.56 – 3.41 (m, 7H), 3.16 (d, 3H), 2.74 (s, 3H), 1.93 (s, 4H), 1.76 (s, 4H), 1.68 – 1.19 (m, 15H), 0.89 (t, 3H). EXAMPLE 11: Compound SB149 Intermediate 35 tert-Butyl 4-((4-(4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)benzoyl)piperazin-1- yl)methyl)piperidine-1-carboxylate: Compound 9 (0.180 g, 0.504 mmol, 1 eq) was dissolved in DMSO (4.5 mL). tert-Butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (0.130 g, 0.458 mmol, 1 eq), DIPEA (0.40 mL, 2.290 mmol, 5 eq) and COMU (0.216 g, 0,504 mmol, 1 eq) were added to an ice-chilled mixture. The resulting mixture was stirred at rt for 20 h. Ethyl acetate (40 mL) and 1M NaHCO3 solution (30 mL) were added. After concentrating the mixture in vacuo, the mixture was cooled in ice for one hour. The precipitate was filtered and washed with water and hexane to afford the subject compound (200 mg, 70%).1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 7.33 (s, 4H), 6.51 (s, 2H), 4.89 (s, 2H), 4.15 (dt, 2H), 3.90 (d, 2H), 3.58 (s, 2H), 2.68 (d, 3H), 2.28 (s, 3H), 2.12 (d, 2H), 1.73 – 1.57 (m, 6H), 1.38 (s, 14H), 0.90 (t, 3H). Intermediate 36 (4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)phenyl)(4-(piperidin-4- ylmethyl)piperazin-1-yl)methanone: Intermediate 35 (0.200 g, 0.321 mmol) was added to an ice- chilled stirred mixture of TFA and DCM (1 / 5, 6 mL), and the mixture was allowed to warm to room temperature. After 3 h, the solvent was evaporated in vacuo. The residue was coevaporated with diethyl ether to afford the subject compound as a brown solid (165 mg, yield: 99%), which was used for the next step without any further purification Compound 37 SB149 N-(1-(4-(2-(4-((4-(4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)benzoyl)piperazin-1- yl)methyl)piperidin-1-yl)-2-oxoethyl)phenyl)-2-(cyclopentylamino)-2-oxoethyl)-N-(2,3-dihydro- 1H-inden-5-yl)-1,5-diphenyl-1H-pyrazole-3-carboxamide: To an ice-chilled stirring solution of Intermediate 36 (0.084 g, 0.160 mmol, 1 eq) in DMF (2 mL) were added, Compound 33 (0.062 g, 0.177 mmol, 1.1 eq), DIPEA (0.84 mL, 0.482 mmol, 3 eq) and COMU (0.076 g, 0.177 mmol, 1.1 eq). The resulting mixture was stirred at rt for 20 h. The solvent was removes in vacuo and the crude compound was purified using preparative thin layer silica gel chromatography (3,3% methanol / DCM) and Isolera Biotage One Flash Chromatography (0,1% TFA, Acetonitrile, Methanol) to afford the subject compound as an off-white solid (30 mg, yield:16%).1H NMR (400 MHz, DMSO- d6) δ 10.02 (s, 1H), 8.08 (d, 1H), 7.45 – 7.20 (m, 11H), 7.20 – 6.76 (m, 11H), 6.48 (s, 2H), 6.20 (s, 2H), 4.89 (s, 2H), 4.33 (d, 1H), 4.13 (t, 2H), 4.09 – 3.91 (m, 1H), 3.75 (s, 1H), 3.59 (s, 4H), 2.74 (t, 4H), 2.26 (s, 4H), 2.08 (dd, 3H), 2.03 – 1.84 (m, 3H), 1.84 – 1.16 (m, 18H), 0.89 (t, 5H). EXAMPLE 12: Compound SB153 Compound 38 SB153 N-(1-(4-(2-((6-(4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)benzamido)hexyl)amino)- 2-oxoethyl)phenyl)-2-(cyclopentylamino)-2-oxoethyl)-N-(2,3-dihydro-1H-inden-5-yl)-1,5- diphenyl-1H-pyrazole-3-carboxamide: To an ice-chilled stirring solution of Intermediate 23 (0.060 g, 0.132 mmol, 1,1 eq) in DMF (1.5 mL) were added Compound 33 (0.075 g, 0.119 mmol, 1 eq), DIPEA (0.083 mL, 0.476 mmol, 4 eq) and COMU (0.057 g, 0.132 mmol, 1.1 eq). The resulting mixture was stirred at rt for 20 h. Subsequently, ethyl acetate (30 mL) was added and washed with 1M HCl (2 × 20 mL), saturated NaHCO3 solution (2 × 20 mL) and brine (20 mL). The organic layer was concentrated in vacuo. The crude compound was purified using Isolera Biotage One Flash Chromatography (0,1% TFA, Acetonitrile, Methanol) to afford the subject compound as an off- white solid (6 mg, yield: 4%).1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.38 (t, 1H), 8.07 (d, 2H), 7.94 (t, 1H), 7.83 – 7.68 (m, 2H), 7.32 (qd, 13H), 7.27 – 6.79 (m, 16H), 6.57 (s, 2H), 6.21 (s, 3H), 4.89 (s, 2H), 4.35 (d, 1H), 4.12 (t, 2H), 4.08 – 3.93 (m, 2H), 3.26 – 3.16 (m, 3H), 2.99 (q, 2H), 2.72 (d, 4H), 2.00 – 1.85 (m, 3H), 1.76 (d, 4H), 1.68 – 1.19 (m, 23H), 0.89 (t, 3H). EXAMPLE 13: PBMC cytokine production assay The TLR4 and TLR7 conjugated compounds of the invention were tested for their ability to induce cytokine production in human primary peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from whole blood by centrifugation with the Ficoll-Paque density gradient solution. After centrifugation, PBMCs were washed twice with PBS and resuspended in medium at 1.5 x 106cells / mL. To perform the assay, PBMCs were seeded on 96-well microtiter plates at 1.5 x 105cells per well and incubated at 37 °C in the presence of the compounds. The compounds were prepared as follows: First, stock solutions of the conjugated compounds were prepared in DMSO at a 1 mM concentration. The working dilutions of the conjugated compounds in medium were then added directly to PBMCs to ensure a 1 µM final concentration. Cell free supernatant were collected after 20 h of incubation and stored at -80 °C until tested. Cytokine concentrations were determined with the LEGENDplex HU Essential Immune Response Panel (Biolegend, San Diego, CA, USA) on an Attune NxT flow cytometer (Thermo Fisher Scientific, Waltham, MA, USA) in accordance with manufacturer’s instructions. Standard curves were generated using recombinant cytokines contained in the kit. The data were analysed using the LEGENDplex Data Analysis Software Suite (BioLegend). The ability of conjugated compounds to induce cytokine production in PBMCs is demonstrated in Figure 1. SB29 and SB146 were the tested conjugated compounds of the invention. Medium was used as a negative control. Intermediary compound SG43 was used as a TLR7 agonist, while SB19 and SG202 were used as TLR4 agonists. The combinations of SG43 with SB19 or SG202 were employed to compare the activity of conjugated compounds against an unconjugated mixture of TLR7 and TLR4 agonists. EXAMPLE 14: PBMC cytotoxicity assay The TLR7 and TLR4 conjugated compounds of the invention were tested for their ability to activate the cytotoxic activity of peripheral blood mononuclear cells (PBMCs) towards cancer cell lines. The main effector fraction of PBMCs in this assay are natural killer (NK) cells, which play an essential role in the innate immune system through their direct cytotoxic activity against aberrant cells, especially tumour cells and virally infected cells. The flow cytometry-based method described hereafter measures the PBMC cytotoxic activity against target cancer cell lines by co-incubating PBMCs and cancer cells, which were pre-labelled by carboxyfluorescein succinimidyl ester (CFSE) to distinguish them from effector cells. Successful activation of effector cells by the tested compounds leads to higher degree of cell death in the target cell population. Chronic myelogenous leukaemia K562 cells were used as target cells in the assay. K562 cells were pre-cultured for at least 10 days before the assay was performed. Immediately prior to the addition of target cells to PBMCs, target cells were stained with CFSE at 2 µM for 15 minutes at 37 °C in the dark. Cells were then washed with medium and resuspended at 2 x 105cells / mL. PBMCs were isolated from whole blood by centrifugation with the Ficoll-Paque density gradient solution. After centrifugation, PBMCs were washed twice with PBS and resuspended in medium at 4 x 106cells / mL. To perform the assay, PBMCs were seeded on 96-well microtiter plates at 4 x 105cells per well and cultured in duplicates at 37 °C for 20 h in the presence of the compounds. The compounds were prepared as follows: First, stock solutions of the conjugated compounds were prepared in DMSO at a 1 mM concentration. The working dilutions of the conjugated compounds in medium were then added directly to PBMCs to ensure a 1 µM final concentration. After incubating the PBMCs in the presence of compounds, 104CFSE-stained K562 cells were added to each well for a final 40:1 ratio of effector cells versus target cells. After 4 h of co-incubation, cells were stained with the SYTOX Blue (Invitrogen) nucleic acid stain and analysed with flow cytometry. Dead (SYTOX Blue stain positive) target cells were gated out of the CFSE positive population, providing the ratio of killed cells within the target cell population. The ability of conjugated compounds to activate the cytotoxic activity of PBMCs against K562 target cells is demonstrated in Figure 2. SB29 and SB101 were the tested conjugated compounds of the invention. Medium was used as a control and the results are given as a ratio versus the control. Intermediary compounds SG43 and SB19 were used as TLR7 and TLR4 agonists, respectively. The combination of SG43 and SB19 was employed to compare the activity of conjugated compounds against an unconjugated mixture of TLR7 and TLR4 agonists. IL-2 (200 U / mL) was used as the positive control. EXAMPLE 15: Antigen presentation of BMDCs to CD4+and CD8+T-lymphocytes The effect of the conjugated compounds of the invention on antigen presentation of mouse bone marrow derived dendritic cells (BMDCs) to T-lymphocytes was examined. After pre-treating BMDCs with selected compounds and ovalbumin (OVA), antigen presentation of OVA to either CD4+or CD8+OVA-specific T-lymphocytes was observed with flow cytometry by detecting the degree of activation and proliferation of affected T-lymphocytes. Bone-marrow cells were isolated from the tibia of C57BL / 6 mice and cultured in Dulbecco’s modified Eagle’s medium supplemented with 10% heat-inactivated fetal bovine serum, 2 mM L- glutamine, 100 U / mL penicillin, 100 µg / mL streptomycin, and 20 ng / mL granulocyte-macrophage colony-stimulating factor for 7 days at 37 °C and 5% CO2. The compounds were prepared as follows: First, stock solutions of the conjugated compounds were prepared in DMSO at a 1 mM concentration. The working dilutions of the conjugated compounds in medium were then added directly to PBMCs to ensure a 1 µM final concentration. CD4+and CD8+T cells were purified from splenocytes of OT II and OT I transgenic mice using CD4+and CD8+T-cell negative selection kits (Miltenyi Biotec, Germany), according to manufacturer instructions. Purified T cells were stained with CFSE and washed. Then, 5 x 104T cells were mixed in triplicate with 104BMDCs per well (pre-treated with compounds [1 µM] or LPS [1 µg / mL] and 50 µg / mL OVA soluble protein for 18 h, and then washed). After 72 h of coincubation (37 °C, 5% CO2), the cells were stained with Fixable viability dye eFluor 780 (eBioscience, Thermo Fisher Scientific, MA, USA), anti-Thy1.2 PE-Cy7 (Biolegend, San Diego, CA, USA), anti-CD8 eFluor450 (eBioscience), anti-CD4 eFluor450 (eBioscience), and anti-CD25 APC antibodies (Biolegend) and analyzed using a Beckman Coulter Cytoflex S flow cytometer (CA, USA) and the FlowJo software (Tree Star, Inc., Ashland, OR, USA). Live Thy1.2+ / CD4+and Thy1.2+ / CD8+were evaluated for CFSE dilution and CD25 expression. Figure 3 demonstrate the ratio of T-lymphocytes that divided during the co-culturing period. Medium was used as a negative control. LPS (1 μg / mL) was used as the positive control. Intermediary compounds SG43 and SB19 were used as TLR7 and TLR4 agonists, respectively. The combination of SG43 and SB19 was employed to compare the activity of conjugated compounds against an unconjugated mixture of TLR7 and TLR4 agonists.

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Claims

CLAIMS 1. A compound having the structure of Formula I:Formula I or a pharmaceutically acceptable salt, racemate, diastereomer, enantiomer, ester or prodrug thereof, wherein: ^ R1is H, halogen, OH, SH, CF3, C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, 5-10 membered heterocyclyl, C1-C6alkoxy, C1-C6alkoxy-C1-C6alkyl, C1-C6alkoxy-C1-C6alkoxy, C1-C6alkoxy-(C1-C6 alkyl)S-, (C1-C6 alkyl)SO2NH-, (C1-C6 alkyl)C(=O)O-, (C1-C6 alkyl)OC(=O)-, (C1-C6alkyl)C(=O)-, (C1-C6alkyl)C(=O)NH-, RaRbN-, or RaRbN(C=O)-, wherein alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R2is independently for each occurrence selected from H, halogen, OH, CHF2, CF3, CH2CF2, carboxy, CN, NO2, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, (C1-C6 alkyl)C(=O)-, (C6-C10 aryl)C(=O)-, (C1-C6 alkyl)S-, (C1-C6 alkyl)C(=O)O-, (C1-C6 alkyl)OC(=O)-, (C1-C6 alkyl)C(=O)NH-, (C1-C6 alkyl)SO2NH-, RaRbN-, and RaRbN(C=O)-, wherein alkyl, alkoxy, aryl, and cycloalkyl may be optionally substituted; ^ Raand Rbare independently from each other selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, and 5-10 membered heterocyclyl or Ra1and Rb1may together with the nitrogen atom form a 5-6 membered heterocycle, wherein alkyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ X1is a single bond, -O-, -S-, -NRc-, -C(=O)-, or -SO2-; ^ Rcis H, C1-C6 alkyl, or C3-C10 cycloalkyl; ^ L is a linking group; ^ n is 0, 1, 2, 3, or 4; and ^ R3is a TLR4 agonist selected from the group consisting of:Formula II,Formula IV, wherein: ^ X2is a single bond, -O-, -S-, -NRd-, -C(=O)- or -SO2-; ^ Rdis H, C1-C6 alkyl, or C3-C10 cycloalkyl; ^ m is 0, 1, 2, 3, 4, or 5; ^ R4is independently for each occurrence selected from H, halogen, CN, NO2, CF3, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C6-C10 aryl, 5-10 membered heterocyclyl, -ORe, -SRe, -C(=O)Re, -C(=O)NRfRg, -C(=O)ORe, -OC(=O)Re, -OC(=O)NRfRg, - NRfRg, -NReC(=O)Re, -SORe, -SO2Re, -SO2NRfRg, and -NReSO2Re, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ Reis independently for each occurrence selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10 aryl and 5-10 membered heterocyclyl, wherein alkyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ Rfand Rgare independently from each other selected from H, C1-C6alkyl, C3-C10cycloalkyl, C6-C10 aryl and 5-10 membered heterocyclyl or Rgand Rhmay together with the nitrogen atom form a 5-6 membered heterocycle, wherein alkyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R5is H, C1-C6 alkyl, or C3-C10 cycloalkyl, wherein alkyl and cycloalkyl may be optionally substituted; ^ R6is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C6-C10aryl, or 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R7is C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10cycloalkyl, C6-C10aryl, or 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R8is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C6-C10aryl, or 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted;^ R9is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C6-C10aryl, or 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ Y is -(C1-C4alkyl)- or -(C1-C4alkenyl)-;^ R11is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C6-C10aryl, or 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ R12is independently for each occurrence selected from H, halogen, CN, NO2, CF3, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C6-C10 aryl, 5-10 membered heterocyclyl, -ORh, -SRh, -C(=O)Rh, -C(=O)NRiRj, -C(=O)ORh, -OC(=O)Rh, -OC(=O)NRiRj, -N RiRj, -NRhC(=O)Rh, -SORh, -SO2Rh, -SO2NRiRj, and -NRhSO2Rh, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ Rhis independently for each occurrence selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10aryl and 5-10 membered heterocyclyl, wherein alkyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted; ^ Riand Rjare independently from each other selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10aryl and 5-10 membered heterocyclyl or Rgand Rhmay together with the nitrogen atom form a 5-6 membered heterocycle, wherein alkyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted.

2. The compound according to claim 1, wherein n is 1.

3. The compound according to claim 1 or 2, wherein R1is C1-C6alkoxy, C1-C6alkoxy-C1-C6alkoxy, (C1-C6alkyl)S-, or (C1-C6alkyl)NH-.

4. The compound according to any one of claims 1 to 3, wherein R1is n-BuO-.

5. The compound according to any one of claims 1 to 4, wherein R2is hydrogen in each instance.

6. The compound according to any one of claims 1 to 5, wherein L is selected from the group consisting of an amino acid, a peptide, a non-peptidic polymeric linker and a non-polymeric aliphatic linker.

7. The compound according to claim 6, wherein L is a non-polymeric aliphatic linker or a polyethylene glycol chain comprising 2 to 100 repeating ethylene glycol units.

8. The compound according to any one of claims 1 to 7, wherein R3is a TLR4 agonist selected from the group consisting of:Formula III.

9. The compound according to claim 8, wherein m is 1.

10. The compound according to claim 8 or 9, wherein R4is independently for each occurrence selected from H, halogen, C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C6-C10aryl, and 5-10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, and heterocyclyl may be optionally substituted.

11. The compound according to any one of claims 8 to 10, wherein R6is C3-C10 cycloalkyl or C6- C10aryl, wherein cycloalkyl and aryl may be optionally substituted.

12. The compound according to any one of claims 8 to 11, wherein R7is C1-C10 alkyl, C3-C10 cycloalkyl, or C6-C10 aryl, wherein alkyl, cycloalkyl, and aryl may be optionally substituted.

13. The compound according to claim 12, wherein R7is cyclohexyl.

14. The compound according to any one of claims 1 to 7, wherein R3is a TLR4 agonist of Formula IV:Formula IV 15. The compound according to claim 14, wherein R8is an optionally substituted C3-C10cycloalkyl.

16. The compound according to claim 14 or 15, wherein R9is C6-C10 aryl or 5-10 membered heterocyclyl, wherein aryl and heterocyclyl may be optionally substituted.

17. The compound according to any one of claims 14 to 16, wherein R10is18. The compound according to any one of claims 1 to 17, wherein said compound is selected from the group consisting of: 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(2-(2-(2-((4-oxo-3-phenyl-4,5- dihydro-3H-pyrimido[5,4-b]indol-2-yl)thio)acetamido)ethoxy)ethyl)benzamide, 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(2-(2-(2-(2-((4-oxo-3-phenyl-4,5- dihydro-3H-pyrimido[5,4-b]indol-2-yl)thio)acetamido)ethoxy)ethoxy)ethyl)benzamide, 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(2-oxo-1-((4-oxo-3-phenyl-4,5- dihydro-3H-pyrimido[5,4-b]indol-2-yl)thio)-7,10,13-trioxa-3-azahexadecan-16-yl)benzamide, 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(6-(2-((4-oxo-3-phenyl-4,5-dihydro- 3H-pyrimido[5,4-b]indol-2-yl)thio)acetamido)hexyl)benzamide, 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(2-(2-((4-oxo-3-phenyl-4,5-dihydro- 3H-pyrimido[5,4-b]indol-2-yl)thio)acetamido)ethyl)benzamide, 4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)-N-(4-(2-((4-oxo-3-phenyl-4,5-dihydro- 3H-pyrimido[5,4-b]indol-2-yl)thio)acetamido)cyclohexyl)benzamide, N-(1-(4-(1-(4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)phenyl)-1,12-dioxo-5,8- dioxa-2,11-diazatridecan-13-yl)phenyl)-2-(cyclopentylamino)-2-oxoethyl)-N-(2,3-dihydro-1H- inden-5-yl)-1,5-diphenyl-1H-pyrazole-3-carboxamide, N-(1-(4-(2-(4-((4-(4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)benzoyl)piperazin-1- yl)methyl)piperidin-1-yl)-2-oxoethyl)phenyl)-2-(cyclopentylamino)-2-oxoethyl)-N-(2,3- dihydro-1H-inden-5-yl)-1,5-diphenyl-1H-pyrazole-3-carboxamide, and N-(1-(4-(2-((6-(4-((6-amino-2-butoxy-8-hydroxy-9H-purin-9- yl)methyl)benzamido)hexyl)amino)-2-oxoethyl)phenyl)-2-(cyclopentylamino)-2-oxoethyl)-N- (2,3-dihydro-1H-inden-5-yl)-1,5-diphenyl-1H-pyrazole-3-carboxamide.

19. A process for preparing a compound of Formula I as defined in any one of claims 1 to 18 (with the variable groups being as defined in any one of claims 1 to 18) which comprises reacting a compound of Formula VI:Formula VI with a compound of Formula VII:Formula VII, or a compound of Formula VIII:Formula VIII with a compound of Formula IX: Formula IX; and optionally thereafter carrying out one or more of the following procedures: ^ removing any protecting groups, ^ forming a pharmaceutically acceptable salt, ^ converting a compound of Formula I into another compound of Formula I.

20. The process according to claim 19, which comprises reacting a compound of Formula VI:Formula VI with a compound of Formula VII: Formula VII, and optionally thereafter carrying out one or more of the following procedures: ^ removing any protecting groups, ^ forming a pharmaceutically acceptable salt, ^ converting a compound of Formula I into another compound of Formula I.

21. The process according to claim 19, which comprises reacting a compound of Formula VIII:Formula VIII with a compound of Formula IX: Formula IX; and optionally thereafter carrying out one or more of the following procedures: ^ removing any protecting groups, ^ forming a pharmaceutically acceptable salt, ^ converting a compound of Formula I into another compound of Formula I.

22. Compound of any one of claim 1 to 18 for use in medicine.

23. Compound of any one of claim 1 to 18 for use in treatment of a condition in which agonism of TLR7 and TLR4 receptors is beneficial, wherein the condition is selected from the group consisting of viral infections, bacterial infections, fungal infections, protozoal infections, tumors, cancers and immunological diseases 24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 and one or more pharmaceutically acceptable excipients or carriers.

25. A vaccine comprising a compound according to any one of claims 1 to 18.

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