TLR7 / TLR8 agonists for use in trifunctional radiopharmaceutical compounds

Abstract

Provided herein are compounds of Formula I, Formula II, and Formula III as defined herein, methods of use in activating immune cells, radiotherapy and the treatment of PMSA-sensitive cancers.

Description

TLR7 / TLR8 AGONISTS FOR USE IN TRIFUNCTIONAL RADIOPHARMACEUTICAL COMPOUNDS CROSS-REFERENCE TO RELATED PATENT APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application 63 / 664,619, filed June 26, 2024, the entirety of which is incorporated herein by reference. FIELD OF THE TECHNOLOGY The present disclosure relates generally to new TLR7 / TLR8 agonists. These agonists, e.g., compounds of Formulas I-III, may be used alone or in a targeted therapy, e.g., used as part of trifunctional radiopharmaceutical compounds. The present also relates to pharmaceutical compositions comprising the foregoing compounds and methods of activating immune cells and treating cancers, such as PMSA-expressing cancers. BACKGROUND Toll-like receptor (TLR) 7 and TLR8 play an important role in the immune response to viral infection. Accordingly, a need exists for new TLR7 / TLR8 agonists that can be used in activating immune cells and treating cancers. SUMMARY OF THE INVENTION In one aspect, the present technology provides compounds of Formula I, Formula II, and Formula III,or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of two or more thereof,wherein A at each occurrence is independently a bicyclic C4-12cycloalkyl group or a bicyclic C4-12heterocyclyl group wherein the heterocyclyl group contains one or two heteroatoms selected from O, N, or S; B is a C4-12heterocyclyl group wherein the heterocyclyl group contains two N atoms; Xais C or N; when Xais C, one of Xband Xcis NR4and the other is CR5, or when Xais N, one of Xband Xcis N and the other is CR5; Yaand Ybare independently absent or selected from a C1-6alkylene or C1-6heteroalkylene group wherein the heteroalkylene contains 1, 2 or 3 heteroatoms, each independently selected from N, O, and S; R1is selected from the group consisting of H, a C1-6alkyl group, an N-protecting group, and a radiotherapy moiety optionally comprising M, wherein M is a radioisotope selected from177Lu,90Y,225Ac,47Sc,212Pb,149Tb,58mCo, or67Cu; R2is selected from the group consisting of a hydroxyl, halogen, CN, NO2, NRa2, NHCORa, OC(O)Ra, SRa, SO2Ra, SO2NHRa,NHSO2Ra, C(O)ORa, C(O)NRa2, and substituted and unsubstituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocyclyl groups; R3is absent or is selected from the group consisting of -Z-T-R6, -Z-T-U-T-R6, -Z-R7, -Z-Het -Z-Het’-R6, and -Z-Het’-T-R6; R4and R5are independently selected from the group consisting of H and a C1-6alkyl group; R6is selected from the group consisting of H, and a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl group; R7is selected from CN or a substituted or unsubstituted nitrogen-containing heterocyclyl group; R8and R9are independently selected from a C1-6alkyl group; Raat each occurrence is independently selected from the group consisting of H and substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl groups; U is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more -O- groups; T is selected from the group consisting of O, S(O)0-2, S(O)2-NR10a, C(R6a), C(R6a)-O, O-C(O)-O, Q-N(R8a), -C(R6a)-N(R8a), -O-C(R6a)-N(R8a)-, -C(R6a)-N(OR9a)-, and a substituted or unsubstituted nitrogen-containing heterocyclyl group having 5-9 ring members; Het is a substituted or unsubstituted heterocyclyl group; Het’ is a substituted or unsubstituted heterocyclylen group; Q is selected from the group consisting of a bond, -C(R6a)-, -C(R6a)-C(R6a)-, -S(O)2-, - C(R6a)-N(R8a)-W-, -S(O)2-N(R8a)-, -C(R6a)-O-, and -C(R6a)-N(OR9a)-; Z is selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene; wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more -O- groups; and n is 0, 1, 2, 3, or 4;provided that the compound of Formula III is notIn another aspect, the present technology provides a pharmaceutical composition comprising a compound as described herein and a pharmaceutically acceptable carrier or excipient. In another aspect, the present technology provides a vaccine adjuvant comprising a compound as described herein. In another aspect, the present technology provides a method of activating an immune cell comprising TLR7 and / or TLR8, the method comprising administering an effective amount of a compound as described herein to the immune cell. BRIEF DESCRIPTION OF THE DRAWINGS FIGS.1A-1C: FIG.1A shows general procedure for complexation of a compound of the present technology with a radioisotope. FIG.1B is a schematic showing the general conditions of the Cathepsin B assay used to confirm enzyme mediated release of an illustrative TLR 7 / 8 agonist (Compound 10) of the present technology. FIG.1C shows HPLC monitoring and identification of Cathepsin B mediated scission products. t1 / 2of Compound 10 payload release = 4.2 h. LCMS confirmed compound 10 ([M+H]+calcd for C21H28N5 is 350.2345 and found to be 350.2). LCMS confirmed metabolite M3 ([M+H]+calcd for C69H103LuN13O22is 1640.6748 and found to be 1640.61).FIG.2 shows a representativenatLu-RIMS-3 displacement assay curve to determine Ki for human PSMA. FIGS.3A-3D: FIG.3A is a scheme showing radiolabeling of an illustrative compound of the present technology, RIMS-3 with177LuCl3 to generate [177Lu]Lu-RIMS-3 (also referred to herein as “177Lu-RIMS-3”). FIG.3B shows an HPLC analysis of another illustrative embodiment of the present technology,natLu-RIMS-3 and177Lu-RIMS-3 after radiolabeling, demonstrating radiochemical purity and quantitative radiolabeling. FIG.3C shows an HPLC analysis of another illustrative embodiment of the present technology, [177Lu]Lu-RIMS-4 (also referred to herein as “177Lu-RIMS-4”), demonstrating radiochemical purity; and FIG. 3D also shows an HPLC analysis of another illustrative embodiment of the present technology, [177Lu]Lu-RIMS-5 (also referred to herein as “177Lu-RIMS-5”), demonstrating radiochemical purity. FIG.4 is a graph showing the stability of177Lu-RIMS-3, an illustrative embodiment of the present technology, as evaluated by radio-HPLC in phosphate-buffered saline at 37 °C. FIG.5 is a graph showing internalization of177Lu-RIMS- 3 in RM1-PGLS (human PSMA-positive, green fluorescent protein-positive and luciferase-positive) cells. at 2 h, 24 h and 72 h incubation times.177Lu-RIMS-1 and177Lu-PSMA-617 data shown for comparison. FIG.6 is a graph showing quantification of metabolite m3 and177Lu-RIMS-3 in the urine at the 2h timepoint in C57BL / 6J mice bearing RM1-PGLS (human PSMA-positive, green fluorescent protein-positive and luciferase-positive) tumors, administered177Lu- RIMS-3. FIGS.7A-7C provides urine metabolite identification at the 2 h timepoint in C57BL / 6J mice bearing RM1- PGLS (human PSMA-positive, green fluorescent protein-positive and luciferase-positive) tumors administered177Lu-RIMS-3 (n=4). Only 2 radioactive metabolites are present, cathepsin cleaved product m3 and177Lu-RIMS-3.FIG.8 are in vitro dose response curves of various illustrative compounds of the present technology, showing them functioning as TLR7 agonists activating human TLR7 (hTLR7), human TLR8 (hTLR8) and mouse TLR7 (mTLR7) against HEK293 reporter cells transfected with human TLR7 (or human TLR8 or mouse TLR7) and an inducible SEAP (secreted embryonic alkaline phosphatase) reporter gene. EC50 values are tabulated in Table 1. FIG.9 shows structures of177Lu labelled PSMA targeting compounds, used in the Examples of the present disclosure, including177Lu-RIMS-5,177Lu-RIMS-3, comparative compounds177Lu-RIMS-1 and177Lu- RIMS-4, and a control compound,177Lu-PMSA-617, which lacks a TLR7 / 8 agonist. FIG.10 shows flow cytometry analysis of RM1-PGLS (human PSMA-positive, green fluorescent protein-positive and luciferase-positive) cells before implantation into C57BL / 6J mice for in vivo studies. Population distribution is representative of outcomes for different splitting’s. Data shown for stained with anti-hPSMA-APC. Two distinct populations are observed. A high hPSMA expressing (~90%) and a low hPSMA expressing subpopulation (10%). FIGS.11A-11C show biodistribution of177Lu-RIMS-3 (FIG.11A),177Lu-RIMS-1 (FIG. 11A) and177Lu-PSMA-617 (FIG.11A),177Lu-RIMS-4 (FIG.11B) and177Lu-RIMS-5 (FIG. 11C) at 2, 24, 72 and 144 h in C57BL / 6J mice bearing a RM1-PGLS (human PSMA-positive, green fluorescent protein-positive and luciferase-positive) tumor (n = 5 per group). FIG.12 shows Kaplan−Meier survival curves for each treatment cohort (n=10 per cohort) in C57BL / 6J mice bearing a RM1-PGLS (hPSMA+) tumor. High SA= 1.62 mCi @ 0.29 mCi / nmol, 0.1 mg / kg TLR 7 / 8 agonist. Medium SA= 1.62 mCi @ 0.058 mCi / nmol, 0.5 mg / kg TLR 7 / 8 agonist. Low SA= 1.62 mCi @ 0.029 mCi / nmol, 1.0 mg / kg TLR 7 / 8 agonist. Murine anti-PD-1 (or anti-CTLA-4) was administered at 10mg / kg via intraperitoneal injection on 1, 4, 8 12 days after administration of177Lu-RIMS-3.FIG.13 shows plots of the relative tumor volume change after administration of treatment to C57BL / 6J mice bearing a RM1-PGLS (hPSMA+) tumor (n = 10 per group). Each line represents 1 animal. Animals demonstrating complete tumor eradication were rechallenge byreimplantation with 0.1 x 106RM1-PGLS cells suspended in Matrigel (1:1). Lack of tumorgrowth after reimplantation with RM1-PGLS cells is indicative of generation of a protective immune response. High SA= 1.62 mCi @ 0.29 mCi / nmol, 0.1 mg / kg TLR 7 / 8 agonist. Medium SA= 1.62 mCi @ 0.058 mCi / nmol, 0.5 mg / kg TLR 7 / 8 agonist. Low SA= 1.62 mCi @ 0.029 mCi / nmol, 1.0 mg / kg TLR 7 / 8 agonist. Murine anti-PD-1 (or anti-CTLA-4) was administered at 10mg / kg via intraperitoneal injection on 1, 4, 812 days after administration of177Lu-RIMS-3. Treatment was administered as a single tail vein injection on day 0. FIGS.14A-14C show plots of the relative tumor volume change after administration of treatment to C57BL / 6J mice bearing a RM1-PGLS (hPSMA+) tumor (n = 10 per group). Each line represents 1 animal. High SA= 1.62 mCi @ 0.29 mCi / nmol, 0.1 mg / kg TLR 7 / 8 agonist. Low SA= 1.62 mCi @ 0.029 mCi / nmol, 1.0 mg / kg TLR 7 / 8 agonist. Treatment was administered as a single tail vein injection on day 0. FIG.15 shows the relative body weight of mice during treatment with177Lu-RIMS-1,177Lu-RIMS-4 and177Lu-RIMS-5 at high SA (1.62 mCi @ 0.29 mCi / nmol, 0.1 mg / kg TLR 7 / 8 agonist) and low SA (1.62 mCi @ 0.029 mCi / nmol, 1.0 mg / kg TLR 7 / 8 agonist) dosing. FIGS.16A-16C show the results of alpha therapy comparing225Ac-RIMS-5 vs225Ac- PSMA-617. FIG.16A shows that225Ac-RIMS-5 cures 5 / 10 animals with no tumor growth after reimplantation with RM1-PGLS cells. This suggests225Ac-RIMS-5 generates a tumor specific protective immune response vs the225Ac-PSMA-617 treatment group (FIG.16B) which cured 1 mouse, however, after rechallenging with RM1-PGLS there was tumor growth, and the animal had to be euthanized. FIG.16C shows225Ac-RIMS-5 is well tolerated with mice gaining weight after treatment vs225Ac-PSMA-617 treated animals which have transient body weight loss and slower to recover. Dosing:225Ac-RIMS-5 (40kBq, 0.7kBq / nmol, 1.0mg / kg TLR7 agonist),225Ac-PSMA-617 (40kBq, 0.7kBq / nmol).FIGS.17A-17B shows the results of therapy comparing90Y-RIMS-5 vs90Y-PSMA-617. FIG.17A shows that90Y-RIMS-5 cures 3 / 10 of the animals treated. FIG.17B shows that90Y- PSMA-617 does not cure any treated animals. Dosing:90Y-RIMS-5 (9MBq, 0.16 MBq / nmol, 1.0mg / kg TLR7 agonist),225Ac-PSMA-617 (9MBq, 0.16 MBq / nmol) FIG.18 shows the biodistribution of90Y-RIMS-5 in C57BL / 6J mice bearing RM1-PGLS (hPSMA+) tumors. Dosing:90Y-RIMS-5 (9MBq, 0.16 MBq / nmol, 1.0mg / kg TLR7 agonist). FIG.19 shows the biodistribution of225Ac-RIMS-5 in C57BL / 6J mice bearing RM1- PGLS (hPSMA+) tumors. Dosing:225Ac-RIMS-5 (40kBq, 0.7kBq / nmol, 1.0mg / kg TLR7 agonist). DETAILED DESCRIPTION Various embodiments are described hereinafter. It should be noted that the specific embodiments are not intended as an exhaustive description or as a limitation to the broader aspects discussed herein. One aspect described in conjunction with a particular embodiment is not necessarily limited to that embodiment and can be practiced with any other embodiment(s). Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this specification pertains. Definitions As used herein and in the appended claims, singular articles such as “a” and “an” and “the” and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. As used herein, “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the termwhich are not clear to persons of ordinary skill in the art, given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term¾for example, “about 10 wt.%” would be understood to mean “9 wt.% to 11 wt.%.” It is to be understood that when “about” precedes a term, the term is to be construed as disclosing “about” the term as well as the term without modification by “about”¾for example, “about 10 wt.%” discloses “9 wt.% to 11 wt.%” as well as disclosing “10 wt.%.” The phrase “and / or” as used in the present disclosure will be understood to mean any one of the recited members individually or a combination of any two or more thereof¾for example, “A, B, and / or C” would mean “A, B, C, both A and B, both A and C, both B and C, or the combination of A, B, and C.” Generally, reference to a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Compounds comprising radioisotopes such as tritium, C14, P32and S35are thus within the scope of the present technology. Procedures for inserting such labels into the compounds of the present technology will be readily apparent to those skilled in the art based on the disclosure herein. In general, “substituted” refers to an organic group as defined below (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non- hydrogen or non-carbon atoms. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Thus, a substituted group is substituted with one or more substituents, unless otherwise specified. In some embodiments, a substituted group is substituted with 1, 2, 3, 4, 5, or 6 substituents. Examples of substituent groups include: halogens (i.e., F, Cl, Br, and I); hydroxyls; alkoxy, alkenoxy, aryloxy, aralkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyls (oxo); carboxylates; esters; urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyls; sulfonamides; sulfates; phosphates; amines; N-oxides; hydrazines;hydrazides; hydrazones; azides (-N3); amides; ureas; amidines; guanidines; enamines; imides; imines; nitro groups (-NO2); nitriles (-CN); and the like. Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups may also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below. Alkyl groups include straight chain and branched chain alkyl groups having (unless indicated otherwise) from 1 to 12 carbon atoms, and typically from 1 to 10 carbons or, in some embodiments, from 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Alkyl groups may be substituted or unsubstituted. Examples of straight chain alkyl groups include groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Representative substituted alkyl groups may be substituted one or more times with substituents such as those listed above, and include without limitation haloalkyl (e.g., trifluoromethyl), hydroxyalkyl, thioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidinealkyl, guanidinealkyl, alkoxyalkyl, carboxyalkyl, and the like. Alkenyl groups include straight and branched chain alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Alkenyl groups may be substituted or unsubstituted. Alkenyl groups have from 2 to 12 carbon atoms, and typically from 2 to 10 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, the alkenyl group has one, two, or three carbon-carbon double bonds. Examples include, but are not limited to vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, among others. Representative substituted alkenyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with substituents such as those listed above for alkyl.Alkynyl groups include straight and branched chain alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms. Alkynyl groups may be substituted or unsubstituted. Alkynyl groups have from 2 to 12 carbon atoms, and typically from 2 to 10 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, the alkynyl group has one, two, or three carbon-carbon double bonds. Examples include, but are not limited to ethynyl, -C≡C(CH3) and -C≡ C-CH(CH3)2among others. Representative substituted alkynyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with substituents such as those listed above for alkyl. Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Aryl groups herein include monocyclic, bicyclic and tricyclic ring systems. Aryl groups may be substituted or unsubstituted. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, fluorenyl, phenanthrenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups. In some embodiments, aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6-10 carbon atoms in the ring portions of the groups. In some embodiments, the aryl groups are phenyl or naphthyl. The phrase “aryl groups” includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like). Representative substituted aryl groups may be mono-substituted (e.g., tolyl) or substituted more than once. For example, monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with substituents such as those listed above. Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above. Aralkyl groups may be substituted or unsubstituted. In some embodiments, aralkyl groups contain 7 to 16 carbon atoms, 7 to 14 carbon atoms, or 7 to 10 carbon atoms. Substituted aralkyl groups may be substituted at the alkyl, the aryl or both the alkyl and aryl portions of the group. Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkylgroups such as 4-indanylethyl. Representative substituted aralkyl groups may be substituted one or more times with substituents such as those listed above. Heterocyclyl groups include aromatic (also referred to as heteroaryl) and non-aromatic carbon-containing ring compounds containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. In some embodiments, the heterocyclyl group contains 1, 2, 3 or 4 heteroatoms. In some embodiments, heterocyclyl groups include mono-, bi- and tricyclic rings having 3 to 16 ring members, whereas other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 14 ring members. Heterocyclyl groups encompass aromatic, partially unsaturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl groups. The phrase “heterocyclyl group” includes fused ring species including those comprising fused aromatic and non-aromatic groups, such as, for example, benzotriazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. However, the phrase does not include heterocyclyl groups that have other groups, such as alkyl, oxo or halo groups, bonded to one of the ring members. Rather, these are referred to as “substituted heterocyclyl groups”. Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolonyl (including 1,2,,4-oxazol- 5(4H)-one-3-yl), isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxathiane, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl, homopiperazinyl, quinuclidyl, indolyl, indolinyl, isoindolyl, azaindolyl (pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzthiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolizinyl,quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups. Representative substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed above. Heteroaryl groups are aromatic carbon-containing ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl, imidazopyridinyl (azabenzimidazolyl), pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups include fused ring compounds in which all rings are aromatic such as indolyl groups and include fused ring compounds in which only one of the rings is aromatic, such as 2,3- dihydro indolyl groups. Although the phrase “heteroaryl groups” includes fused ring compounds, the phrase does not include heteroaryl groups that have other groups bonded to one of the ring members, such as alkyl groups. Rather, heteroaryl groups with such substitution are referred to as “substituted heteroaryl groups.” Representative substituted heteroaryl groups may be substituted one or more times with various substituents such as those listed above. Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heterocyclyl group as defined above. Substituted heterocyclylalkyl groups may be substituted at the alkyl, the heterocyclyl or both the alkyl and heterocyclyl portions of the group. Representative heterocyclyl alkyl groups include,but are not limited to, morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazol-4-yl-methyl, pyridin-3- yl-methyl, tetrahydrofuran-2-yl-ethyl, and indol-2-yl-propyl. Representative substituted heterocyclylalkyl groups may be substituted one or more times with substituents such as those listed above. Heteroaralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above. Substituted heteroaralkyl groups may be substituted at the alkyl, the heteroaryl or both the alkyl and heteroaryl portions of the group. Representative substituted heteroaralkyl groups may be substituted one or more times with substituents such as those listed above. Groups described herein having two or more points of attachment (i.e., divalent, trivalent, or polyvalent) within the compound of the present technology are designated by use of the suffix, “ene.” For example, divalent alkyl groups are alkylene groups, divalent alkenyl groups are alkenylene groups, and so forth. Substituted groups having a single point of attachment to a compound or polymer of the present technology are not referred to using the “ene” designation. Thus, e.g., chloroethyl is not referred to herein as chloroethylene. Alkoxy groups are hydroxyl groups (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of a substituted or unsubstituted alkyl group as defined above. Alkoxy groups may be substituted or unsubstituted. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like. Examples of branched alkoxy groups include but are not limited to isopropoxy, sec-butoxy, tert- butoxy, isopentoxy, isohexoxy, and the like. Examples of cycloalkoxy groups include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. Representative substituted alkoxy groups may be substituted one or more times with substituents such as those listed above. The term “amide” (or “amido”) includes C- and N-amide groups, i.e., -C(O)NR71R72, and –NR71C(O)R72groups, respectively. R71and R72are independently hydrogen, or a substituted orunsubstituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. Amido groups therefore include but are not limited to carbamoyl groups (- C(O)NH2) (also referred to as “carboxamido groups”) and formamido groups (-NHC(O)H). In some embodiments, the amide is –NR71C(O)-(C1-5 alkyl) and the group is termed “alkanoylamino.” The term “amine” (or “amino”) as used herein refers to –NR75R76groups, wherein R75and R76are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. In some embodiments, the amine is NH2, alkylamino, dialkylamino, arylamino, or alkylarylamino. In other embodiments, the amine is NH2, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino. It will be understood that amines may exist in protonated forms in certain aqueous solutions or mixtures and are examples of charged functional groups herein. The term “carboxyl” or “carboxylate” as used herein refers to a –COOH group or its ionized salt form. As such, it will be understood that carboxyl groups are examples of charged functional groups herein. The term “ester” as used herein refers to –COOR70and –C(O)O-G groups. R70is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. G is a carboxylate protecting group. As used herein, the term “protecting group” refers to a chemical group that exhibits the following characteristics: 1) reacts selectively with the desired functionality in good yield to give a protected substrate that is stable to the projected reactions for which protection is desired; 2) is selectively removable from the protected substrate to yield the desired functionality; and 3) is removable in good yield by reagents compatible with the other functional group(s) present or generated in such projected reactions. Carboxylate protecting groups are well known to one of ordinary skill in the art. An extensive list of protecting groups for the carboxylate group functionality may be found in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons,New York, NY, (3rdEdition, 1999). Which can be added or removed using the procedures set forth therein and which is hereby incorporated by reference in its entirety and for any and all purposes as if fully set forth herein. The term “guanidine” refers to –NR90C(NR91)NR92R93, wherein R90, R91, R92and R93are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein. It will be understood that guanidines may exist in protonated forms in certain aqueous solutions or mixtures and are examples of charged functional groups herein. The term “hydroxyl” as used herein can refer to –OH or its ionized form, –O–. A “hydroxyalkyl” group is a hydroxyl-substituted alkyl group, such as HO-CH2-. The term “imidazolyl” as used herein refers to an imidazole group or the salt thereof. An imidazolyl may be protonated in certain aqueous solutions or mixtures, and is then termed an “imidazolate.” The term “phosphate” as used herein refers to –OPO3H2or any of its ionized salt forms, – OPO3HR84or –OPO3R84R85wherein R84and R85are independently a positive counterion, e.g., Na+, K+, ammonium, etc. As such, it will be understood that phosphates are examples of charged functional groups herein. The term “pyridinyl” refers to a pyridine group or a salt thereof. A pyridinyl may be protonated in certain aqueous solutions or mixtures, and is then termed a “pyridinium group”. The term “sulfate” as used herein refers to –OSO3H or its ionized salt form, –OSO3R86wherein R86is a positive counterion, e.g., Na+, K+, ammonium, etc. As such, it will be understood that sulfates are examples of charged functional groups herein. The term “thiol” refers to –SH groups, while “sulfides” include –SR80groups, “sulfoxides” include –S(O)R81groups, “sulfones” include –SO2R82groups, and “sulfonyls” include –SO2OR83. R80, R81, and R82are each independently a substituted or unsubstituted alkyl,cycloalkyl, alkenyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein. In some embodiments the sulfide is an alkylthio group, -S-alkyl. R83includes H or, when the sulfonyl is ionized (i.e., as a sulfonate), a positive counterion, e.g., Na+, K+, ammonium or the like. As such, it will be understood that sulfonyls are examples of charged functional groups herein. Urethane groups include N- and O-urethane groups, i.e., -NR73C(O)OR74and – OC(O)NR73R74groups, respectively. R73and R74are independently a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. R73may also be H. The terms “preventing” and “prophylaxis” as used herein refer to administering a pharmaceutical compound or medicament or a composition including the pharmaceutical compound or medicament to a subject before a disease, disorder, or condition fully manifests itself, to forestall the appearance and / or reduce the severity of one or more symptoms of the disease, disorder, or condition. The person of ordinary skill in the art recognizes that the term “prevent” is not an absolute term. In the medical art it is understood to refer to the prophylactic administration of a drug to diminish the likelihood or seriousness of a disease, disorder or condition, or a symptom thereof, and this is the sense that such terms are used in this disclosure. Salts, including pharmaceutically acceptable salts of the disclosed compounds are within the scope of the present technology. When the compound has a basic group, such as, for example, an amine group, pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, sulfuric acid, and phosphoric acid), organic acids (e.g. formic acid, acetic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid). When the compound of the present technology has an acidic group, such as for example, a carboxylic acid group, it can form salts with metals, such as alkali and earth alkali metals (e.g., Na+, Li+, K+, Ca2+, Mg2+, Zn2+), ammonia or organic amines (e.g., dicyclohexylamine, trimethylamine, triethylamine, pyridine,picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e.g., arginine, lysine and ornithine). Such salts can be prepared in situ during isolation and purification of the compounds or by separately reacting the purified compound in its free base or free acid form with a suitable acid or base, respectively, and isolating the salt thus formed. “Treating” within the context of the instant technology, means alleviation, in whole or in part, of symptoms associated with a disorder or disease, or slowing, inhibition or halting of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder in a subject at risk for developing the disease or disorder. For example, within the context of treating cancer, successful treatment may include reduction or eradication of a tumor or tumors from the body; clinical benefit; an alleviation of symptoms, such as a reduction or elimination of nausea, loss of appetite, unexplained weight loss, tiredness, unexplained itching, bone pain, chills, night sweats, chronic abdominal pain, blood in stool, jaundice and the like. As used herein, an “effective amount” of a compound of the present technology refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with a disorder or disease, or slows or halts of further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disease or disorder in a subject at risk for developing the disease or disorder. Those skilled in the art are readily able to determine an effective amount. For example, one way of assessing an effective amount for a particular disease state is by simply administering a compound of the present technology to a patient in increasing amounts until progression of the disease state is decreased or stopped or reversed. Those of skill in the art will appreciate that compounds of the present technology may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism and / or stereoisomerism. As the formula drawings within the specification and claims can represent only one of the possible tautomeric, conformational isomeric, stereoisomeric or geometric isomeric forms, it should be understood that the technology encompasses any tautomeric, conformational isomeric, stereoisomeric and / or geometric isomeric forms of the compounds having one or more of the utilities described herein, as well as mixtures of these various different forms.Stereoisomers of compounds (also known as optical isomers) include all chiral, diastereomeric, and racemic forms of a structure, unless the specific stereochemistry is expressly indicated. Thus, compounds disclosed herein include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology. “Tautomers” refers to isomeric forms of a compound that are in equilibrium with each other. The presence and concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, imines may exhibit the following isomeric forms, which are referred to as tautomers of each other:Because of the limits of representing compounds by structural formulas, it is to be understood that all chemical formulas of the compounds described herein represent all tautomeric forms of compounds and are within the scope of the present technology. Compounds In one aspect, the present technology provides compounds of Formula I and Formula II,or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of two or more thereof, wherein A at each occurrence is independently a bicyclic C4-12cycloalkyl group or a bicyclic C4-12heterocyclyl group wherein the heterocyclyl group contains one or two heteroatoms selected from O, N, or S; Xais C or N; when Xais C, one of Xband Xcis NR4and the other is CR5, or when Xais N, one of Xband Xcis N and the other is CR5;Yaand Ybare independently absent or selected from a C1-6alkylene or C1-6heteroalkylene group wherein the heteroalkylene contains 1, 2 or 3 heteroatoms, each independently selected from N, O, and S; R1is selected from the group consisting of H, a C1-6alkyl group, an N-protecting group, and a radiotherapy moiety optionally comprising M, wherein M is a radioisotope selected from177Lu,90Y,225Ac,47Sc,212Pb,149Tb,58mCo, or67Cu; R2is selected from the group consisting of a hydroxyl, halogen, CN, NO2, NRa2, NHCORa, OC(O)Ra, SRa, SO2Ra, SO2NHRa,NHSO2Ra, C(O)ORa, C(O)NRa2, and substituted and unsubstituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocyclyl groups; R3is absent or is selected from the group consisting of -Z-T-R6, -Z-T-U-T-R6, -Z-R7, -Z-Het -Z-Het’-R6, and -Z-Het’-T-R6; R4and R5are independently selected from the group consisting of H and a C1-6alkyl group; R6is selected from the group consisting of H, and a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl group; R7is selected from CN or a substituted or unsubstituted nitrogen-containing heterocyclyl group; R8and R9are independently selected from a C1-6alkyl group; Raat each occurrence is independently selected from the group consisting of H and substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl groups; U is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylenegroups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more -O- groups; T is selected from the group consisting of O, S(O)0-2, S(O)2-NR10a, C(R6a), C(R6a)-O, O- C(O)-O, Q-N(R8a), -C(R6a)-N(R8a), -O-C(R6a)-N(R8a)-, -C(R6a)-N(OR9a)-, and a substituted or unsubstituted nitrogen-containing heterocyclyl group having 5-9 ring members; Het is a substituted or unsubstituted heterocyclyl group; Het’ is a substituted or unsubstituted heterocyclylen group; Q is selected from the group consisting of a bond, -C(R6a)-, -C(R6a)-C(R6a)-, -S(O)2-, - C(R6a)-N(R8a)-W-, -S(O)2-N(R8a)-, -C(R6a)-O-, and -C(R6a)-N(OR9a)-; Z is selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene; wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more -O- groups; and n is 0, 1, 2, 3, or 4. In another aspect, the present technology provides compounds of Formula III,or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of two or more thereof, wherein B is a C4-12heterocyclyl group wherein the heterocyclyl group contains two N atoms;Yais absent or selected from a C1-6alkylene or C1-6heteroalkylene group wherein the heteroalkylene contains 1, 2 or 3 heteroatoms, each independently selected from N, O, and S; R1is selected from the group consisting of H, a C1-6alkyl group, an N-protecting group, and a radiotherapy moiety optionally comprising M, wherein M is a radioisotope selected from177Lu,90Y,225Ac,47Sc,212Pb,149Tb,58mCo, or67Cu; R8and R9are independently selected from a C1-6alkyl group; and provided that the compound is notIn any embodiments of the compounds of Formula III, R1may be selected from the group consisting of a C1-6alkyl group, an N-protecting group, and a radiotherapy moiety optionally comprising M, wherein M is a radioisotope selected from177Lu,90Y,225Ac,47Sc,212Pb,149Tb,58mCo, or67Cu. In any embodiments of the compounds of Formula III, R1may be a radiotherapy moiety optionally comprising M, wherein M is a radioisotope selected from177Lu,90Y,225Ac,47Sc,212Pb,149Tb,58mCo, or67Cu. In any embodiments of the compounds of Formula III, B may be a bicyclic C4-12heterocyclyl group containing two N atoms. In any embodiments of the compounds of FormulaIII, B may be a monocyclic C4-6heterocyclyl group containing two N atoms. For example, B may be selected fromIn any embodiments of the compounds of Formula I and Formula II, A may be a spirobicyclic C5-12cycloalkyl group or a spirobicyclic C4-12heterocyclyl group. In any embodiments, A may be a spirobicyclic C5-10cycloalkyl group or a spirobicyclic C4-10heterocyclyl group. For example, A may be selected fromIn any embodiments, A may be a bridged bicyclic C5-10cycloalkyl group or a bridged bicyclic C4-10heterocyclyl group. For example, A may be selected fromIn any embodiments of the compounds of Formula I and Formula II, A may be a fused bicyclic C4-12cycloalkyl group or a fused bicyclic C4-12heterocyclyl group. In any embodiments, A may be a fused bicyclic C5-10cycloalkyl group or a fused bicyclic C5-10heterocyclyl group.For example, A may be selected fromIn any embodiments, the compound may be a compound of Formula I. In any embodiments, Xamay be N. In any embodiments, Xbis N. In any embodiments, Xcmay be CR4. In any embodiments, Xbmay be CR4. In any embodiments, Xcmay be N. In any embodiments, Xamay be C. In any embodiments, Xbmay be CR4and Xcmay be NR3. In any embodiments, Xbmay be NR3and Xcmay be CR4. In any embodiments, R4may be H. In any embodiments, R5may be H. In any embodiments of the compounds of Formulas I-III, Yamay be a C1-6alkylene group. In any embodiments, Yamay be a methylene group. In any embodiments, Ybmay be a C1- 6 alkylene group. In any embodiments, Ybmay be a methylene group. In any embodiments, Yamay be a C1-6heteroalkylene group. In any embodiments, Yamay be -NH(CH2)1-5-. In any embodiments, Ybmay be a C1-6heteroalkylene group. In any embodiments, Ybmay be - NH(CH2)1-5-. In any embodiments, Yamay be absent. In any embodiments, Ybmay be absent. In any embodiments of the compounds of Formulas I-III, R1may be an N-protecting group. In any embodiments, R1may be Boc, Fmoc, Cbz, Alloc, or Troc. In any embodiments, R1may be H. Compounds of Formulas I-III where R1is H may be used as is for activation of immune cells as a TLR7 / 8 agonists or may be used to prepare trifunctional radiopharmaceutical compounds.Thus, in any embodiments of the compounds of Formulas I-III, R1may be a radiotherapy moiety optionally comprising M, wherein M is a radioisotope selected from177Lu,90Y,225Ac,47Sc,212Pb,149Tb,58mCo, or67Cu. In any embodiments, the radiotherapy moiety may include a chelating moiety for chelating a radioisotope M, a cancer antigen targeting agent, and a releasable linker that links the radiotherapy moiety to the TLR7 / 8 agonist. In any embodiments, the cancer antigen targeting agent may be a prostate-specific membrane antigen (PMSA) targeting antigen. In any embodiments, the releasable linker may be a cathepsin B-releasable peptide that is cleaved in the presence of cathepsin B. In any embodiments, R1may be the radiotherapy moiety selected from structure A or structure B,In any embodiments, R1may be the radiotherapy moiety of structure A. Structure A is a radiotherapy moiety in which the radioisotope M is not present, but which can chelate M when present. In any embodiments, R1may be the radiotherapy moiety of structure B. R2may also be other radiotherapy moieties known in the art Structure B is a radiotherapy moiety in which the radioisotope M is present and chelated to the polycarboxylic acid and amine groups as shown in the structure. In any embodiments of compounds of Formula I, the compound may bear 0, 1, 2, 3, or 4 R2groups. In any embodiments, n may be 0, 1 or 2. In any embodiments, n may be 1 or 2. In any embodiments, n may be 1. In any embodiments, R2at each occurrence may be independently a C1-6haloalkyl, a quinolinyl group or C(O)O-(C1-6alkyl). In any embodiments of compounds of Formula I, R3may be absent. In any embodiments, R3may be -Z-Het. In some embodiments, Z is a bond. In some embodiments, Het may be a quinolinyl group. In any embodiments, R6may be H. In any embodiments, R7may be H. In any embodiments, the compound may be a compound of Formula II or Formula III. In any embodiments, R8may be methyl. In any embodiments, R9may be propyl, butyl, or pentyl. Pharmaceutical Compositions In another aspect, the present technology provides pharmaceutical compositions including a compound as described herein (such as but not limited to a compound of Formula I, Formula II and / or Formula III) and a pharmaceutically acceptable carrier or excipient (including but not limited to any of those described herein). For example, in any embodiments, the pharmaceutical composition may include a compound of Formula I, Formula II and / or Formula III, wherein R2may be H. In any embodiments the pharmaceutical composition may include a compound of Formula I, Formula II and / or Formula III, wherein R2may be a radiotherapy moiety of structure A. In any embodiments of the pharmaceutical compositions herein, R2may be a radiotherapy moiety of structure B.In another aspect, the present technology provides a vaccine adjuvant including a compound as described herein (such as but not limited to a compound of Formula I, Formula II and / or Formula III). In any such embodiments of the vaccine adjuvant, the compound is a compound of Formula I, Formula II and / or Formula III, and R2is H. The instant technology also provides for compositions and medicaments including a compound disclosed herein and a pharmaceutically acceptable carrier. Such compositions may be prepared by mixing one or more compounds of the present technology, pharmaceutically acceptable salts thereof or stereoisomers thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like. The compounds and compositions of the present technology may be used to prepare formulations and medicaments that activate an immune cell and / or treat certain cancers as disclosed herein. Such compositions can be in the form of, for example, granules, powders, tablets, capsules, creams, ointments, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. The instant compositions can be formulated for various routes of administration, for example, by oral, parenteral, topical, injection, rectal, nasal, vaginal, or via implanted reservoir. Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneally, intramuscular, intrathecal, intracranial, and intracerebroventricular injections. The following dosage forms are given by way of example and should not be construed as limiting the instant technology. For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds disclosed herein, or pharmaceutically acceptable salts or stereoisomers thereof, with at least one additive such as a starch or other additive. Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Optionally, oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers,sweeteners, flavoring agents or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the art. Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water. Pharmaceutical formulations and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these. Pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration. As noted above, suspensions may include oils. Such oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water may also be used in suspension formulations. Injectable dosage forms generally include aqueous suspensions or oil suspensions, which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents. Typically, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides. For injection, the pharmaceutical formulation and / or medicament may be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations may optionallycontain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these. Compounds of the present technology also may be formulated as a composition for topical administration (e.g., vaginal cream). These formulations may contain various excipients known to those skilled in the art. Suitable excipients may include, but are not limited to, cetyl esters wax, cetyl alcohol, white wax, glyceryl monostearate, propylene glycol monostearate, methyl stearate, benzyl alcohol, sodium lauryl sulfate, glycerin, mineral oil, water, carbomer, ethyl alcohol, acrylate adhesives, polyisobutylene adhesives, and silicone adhesives. The composition may be in the form of a vaginal cream containing the composition of matter as set forth herein present in a nonliquefying base. The nonliquefying base may contain various inactive ingredients such as, for example, cetyl esters wax, cetyl alcohol, white wax, glyceryl monostearate, propylene glycol monostearate, methyl stearate, benzyl alcohol, sodium lauryl sulfate, glycerin, and mineral oil. Such composition may be formulated similar to PREMARIN® Vaginal Cream made commercially available by Wyeth-Ayerst Laboratories. Dosage units for rectal administration may be prepared in the form of suppositories which may contain the composition of matter in a mixture with a neutral fat base, or they may be prepared in the form of gelatin-rectal capsules which contain the active substance in a mixture with a vegetable oil or paraffin oil. Compounds of the present technology may be administered to the lungs by inhalation through the nose or mouth. Suitable pharmaceutical formulations for inhalation include solutions, sprays, dry powders, or aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. Formulations for inhalation administration contain as excipients, for example, lactose, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate. Aqueous and nonaqueous aerosols are typically used for delivery of inventive compounds by inhalation.Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of the compound together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions. A nonaqueous suspension (e.g., in a fluorocarbon propellant) can also be used to deliver compounds of the present technology. Aerosols containing compounds for use according to the present technology are conveniently delivered using an inhaler, atomizer, pressurized pack or a nebulizer and a suitable propellant, e.g., without limitation, pressurized dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, nitrogen, air, or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be controlled by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. Delivery of aerosols of the present technology using sonic nebulizers is advantageous because nebulizers minimize exposure of the agent to shear, which can result in degradation of the compound. For nasal administration, the pharmaceutical formulations and medicaments may be a spray, nasal drops or aerosol containing an appropriate solvent(s) and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. For administration in the form of nasal drops, the compounds may be formulated in oily solutions or as a gel. For administration of nasal aerosol, any suitable propellant may be used including compressed air, nitrogen, carbon dioxide, or a hydrocarbon based low boiling solvent. Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in theinstant present technology. Such excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference. The formulations of the present technology may be designed to be short-acting, fast- releasing, long-acting, and sustained-releasing as described below. Thus, the pharmaceutical formulations may also be formulated for controlled release or for slow release. The instant compositions may also comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a prolonged storage and / or delivery effect. Therefore, the pharmaceutical formulations and medicaments may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants may employ known inert materials such as silicones and biodegradable polymers. Specific dosages may be adjusted depending on conditions of disease, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant technology. A therapeutically effective amount of a compound of the present technology may vary depending upon the route of administration and dosage form. Effective amounts of such compounds typically fall in the range of about 0.01 up to about 100 mg / kg / day, or about 0.05 to about 50 mg / kg / day, and more typically in the range of about 0.1 up to 5 mg / kg / day or 10 mg / kg / day. Typically, the compound or compounds of the instant technology are selected to provide a formulation that exhibits a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic effects and can be expressed as the ratio between LD50 and ED50. The LD50 is the dose lethal to 50% of the population and the ED50 is the dosetherapeutically effective in 50% of the population. The LD50 and ED50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals. Methods of Use In still another aspect, the present technology provides a method of activating an immune cell comprising TLR7 and / or TLR8, the method comprising administering an effective amount of a compound as described herein (including but not limited to a compound of Formula I, Formula II and / or Formula III) to the immune cell. In any embodiments, the immune cell may be in vitro. In any embodiments of the methods, the immune cell may be in vivo. In any embodiments of the present methods, the administering step may include administering an effective amount of the compound to a subject in need of immune cell activation. In any embodiments of the method, the subject has a PMSA-expressing cancer. In any embodiments, the compound includes a radiotherapy moiety, e.g., with a PMSA targeting antigen. In any embodiments of the present methods, the cancer may be selected from the group consisting of non-Hodgkin’s lymphoma, pancreatic cancer, multiple myeloma, colorectal cancer, renal and mammary carcinomas, skin cancer, and / or cervical intraepithelial neoplasia. In any embodiments, the methods may further include administering an effective amount of a checkpoint inhibitor simultaneously or sequentially with the compound of the present technology. In still another aspect, the present technology provides methods of treatment comprising administering an effective amount of a compound described herein, wherein the compound is a compound of Formula I, II or III and R2is a radiotherapy moiety, to a subject suffering from a cancer susceptible to radioimmunotherapy. In any embodiments, the cancer may be a PMSA- expressing cancer. In any embodiments, the radiotherapy moiety has structure B. In any embodiments of the methods, the subject may be a human, suffering, e.g., from a cancer selected from the group consisting of non-Hodgkin’s lymphoma, pancreatic cancer, multiple myeloma, colorectal cancer, renal and mammary carcinomas, skin cancer, and / or cervical intraepithelial neoplasia. In any embodiments of the methods, M of the radiotherapy moiety may be177Lu.

[0001] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure. The present technology is further illustrated by the following examples, which should not be construed as limiting in any way. EXAMPLES Abbreviations AA Amino acid ADPA Adipic acid Boc Tert-butyloxycarbonyl Ci Curie DIEA N,N-diisopropylethylamine DMF Dimethylformamide DMSO Dimethyl sulfoxide DPBS Dulbecco’s phosphate buffered saline EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide ESI-MS Electrospray ionization mass spectrometry Et2O Diethyl ether FDA Food and Drug Administration Fmoc fluorenylmethoxycarbonyl HPLC High performance liquid chromatography ICP-OES Inductively coupled plasma - optical emission spectrometry MALDI Matrix assisted laser desorption / ionizationMBq Megabecquerels Mtt 4-Methyltrityl Nap Naphthyl NHS N-Hydroxysuccinimide PyBOP (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate RtRetention time SPPS Solid-phase peptide synthesis tBu Tert-butyl TFA Trifluoroacetic acid TIS Triisopropylsilane WA Wang resin Amino acids are abbreviated using their conventional 3-letter codes. Materials: All starting materials were purchased from Macrocyclics, TCI America, Acros Organics, Alfa Aesar, Sigma-Aldrich or MedChemExpress and used without further purification. Fmoc-protected amino acids were purchased from Bachem. Wang resin was purchased from Millipore Sigma. Purity analysis of all compounds employed in biological experiments was determined by HPLC analysis of the nonradioactive or Radio-HPLC for the radioactive complex species. Purity as determined by HPLC is reported individually for each compound, and representative HPLC traces employed for purity analysis are provided.177Lu was produced and obtained from the Missouri University Research Reactor, Research Park Drive, Columbia Missouri. General Methods of Characterization Mass spectrometry: Low-resolution ESI mass spectrometry was carried out at the Department of Chemistry UW-Madison University with an Thermo Q Exactive PlusTM spectrometer. High-resolution ESI mass spectrometry was carried out at the Department of Chemistry UW-Madison University Mass Spectrometry Facility Paul Bender Chemical Instrumentation Center (CIC) with an Thermo Q Exactive PlusTM spectrometer. MALDI-TOF / TOF-MS was carried out at the Department of Chemistry UW-Madison University Mass Spectrometry Facility Paul Bender Chemical Instrumentation Center (CIC) with a Bruker ULTRAFLEX™ III spectrometer. NMR spectra (1H,13C) were collected at Chemistry NMR Facility Paul Bender Chemistry Instrumentation Center on a 500 MHz Callisto–Bruker Avance-500 instrument with DCH cryoprobe at 25 °C and processed using MestreNova software. Chemical shifts are reported as parts per million (ppm). Inductively coupled plasma spectroscopy (ICP) was performed on an Agilent Technologies ICP-OES (Model 5110). A 10-point standard with respect to gallium or copper was used and lines of best fit were found with R2of 0.999. UV-vis spectra were collected with a NanoDrop 1 C instrument (AZY1706045). High-Performance Liquid Chromatography (HPLC): Semi-Preparative HPLC was carried out using a Shimadzu HPLC-20AR equipped with a binary gradient, pump, UV-vis detector, and manual injector on a Phenomenex Luna C18 column (250 mm × 21.2 mm, 100 Å, AXIA packed). Method A (Preparative Purification Method). A = 0.1% TFA in water, B = 0.1% TFA in MeCN. Gradient: 0-5 min: 95% A; 5-24 min: 5-95% B gradient. Analytical HPLC analysis was carried out using a Shimadzu HPLC-20AR equipped with a binary gradient, pump, UV-vis detector, autoinjector, and Laura radio-detector on a Phenomenex Luna C18 column (150 mm × 3 mm, 100 Å). Method B (Analytical HPLC analysis). A = 0.1% TFA in water, B = 0.1% TFA in MeCN with a flow rate of 0.8 mL / min, UV detection at 220 and 270 nm. Gradient 0-2 min: 5% B; 2-14 min 5-95% B; 14-16 min 95% B; 16-16.5 min 95-5% B; 16.5-20 min 5% B. Method C (Analytical HPLC analysis). A = 0.1% FA in water, B = 0.1% FA in MeCN with a flow rate of 0.8 mL / min, UV detection at 220 and 270 nm. Gradient 0-3 min: 5% B; 3-10 min 5- 95% B; 10-13 min 95% B; 13-13.5 min 95-5% B; 13.5-16 min 5% B. Radio-HPLC analysis was carried out using a Shimadzu HPLC-20AR equipped with a binary gradient, pump, UV-vis detector, autoinjector, and Laura radio-detector on a Phenomenex Luna C18 column (150 mm ×3 mm, 100 Å). Method D (Radioanalysis). A = 0.1% TFA in water, B = 0.1% TFA in MeCN with a flow rate of 0.8 mL / min. Gradient 0-2 min: 5% B; 2-14 min 5-95% B; 14-16 min 95% B; 16-16.5 min 95-5% B; 16.5-20 min 5% B. Method E (LC-MS analysis). A = 0.1% FA in water, B = 0.1% FA in MeCN with a flow rate of 0.8 mL / min, UV detection at 220 and 270 nm. Gradient 0-3 min: 5% B; 3-10 min 5-95% B; 10-13 min 95% B; 13-13.5 min 95-5% B; 13.5-16 min 5% B. Method F (LC-MS analysis). A = 0.1% NH4CH3CO2in water, B = 0.1% NH4CH3CO2in MeCN with a flow rate of 0.8 mL / min, UV detection at 220 and 270 nm. Gradient 0-3 min: 5% B; 3-10 min 5-95% B; 10-13 min 95% B; 13-13.5 min 95-5% B; 13.5-16 min 5% B. In vitro and in vivo Biological Methods Cell Lines: RM1-PGLS (hPSMA+) cells were generated by stably transducing parental mouse prostate cancer cells RM1 with human PSMA (hPSMA) and display heterogeneous hPSMA expression with a hPSMA-low and hPSMA-high subpopulation, verified by flow cytometry using anti-hPSMA-APC (REA408, Miltenyi) and REA control (S)-APC (REA293, Miltenyi) prior to implantation in C57BL / 6j mice. Cells were maintained in RPMI 1640 with 5 % FBS at 37 ºC and 5 % CO2.Mycoplasma contamination was excluded using the Venor®GeM Mycoplasma detection kit (Sigma-Aldrich). PC-3 PiP cells (hPSMA+) were maintained in DMEM with 5% FBS at 37 °C and 5% CO2. Radioactive Displacement Assay: Inhibition constants (Ki) ofnatLu-RIMS-3 to PSMA were measured by in vitro competition binding assays using18F-DCFPyL as the radioligand. The 2.17 mCi of18F-DCFPyL in 0.5mL was obtained with the specific activity at 21287 mCi / µmol.natLu labelled compound were dissolved in 10 % DMSO in H2O and 10 concentrations were prepared ranging from 10−13to 10−5M. PC-3 PiP cells were plated onto a 24-well plate for 24 h (500,000 / well). Growth medium was removed and replaced with DPBS buffer. After 1 h,18F- DCFPyL (30 µCi) was added to each well (in triplicate) containing varied concentrations (0.5 mM–0.05 nM) ofnatLu-RIMS-3. Nonspecific binding was determined by adding 10 mMnatLu- PSMA-617 and subtracting measured residually bound activity from total binding valuesobtained for subsequent samples. The assay mixtures were incubated for 1 h at 37°C followed by 2 washes with cold DPBS buffer. A trypsin solution (0.25%, 500 mL) was then added to each well to harvest the cells. Radioactivity was measured by γ-counting. Specific binding was calculated as the difference between total binding and nonspecific binding. The Ki was determined by nonlinear regression analysis using GraphPad Prism software (Mol. Pharm.2021, 18 (12), 4511-4519). Cell Internalization Assay: RM1-PGLS (hPSMA+) cells (105) were incubated with 2.1 MBq of177Lu-RIMS-3 (4.1 MBq / nmol) for 2, 24 or 72 h at 37 ºC in PBS. To strip cell surface of non-internalized compounds, cells were washed 3 times with 500 μL of PBS. To collect the internalized fraction, cells were lysed with 0.1 M NaOH. Radioactivity was quantified by gamma counting, and the internalization was expressed as %IA (injected activity) per 105cells. Cathepsin Mediated Release Assay of TLR 7 / 8 Agonist Payload: The concentration ofnatLu-RIMS-3 were determined via ICP-OES analysis. Cathepsin B from bovine spleen (1.12 mg,≥ 10 units / mg protein) was dissolved in 0.4 mL of 25 mM NaOAc / 1 mM EDTA buffer (pH 5.0).A 60 μL aliquot (20 μg) of this stock solution was activated with 12 μL of 30 mM DTT / 15 mM EDTA (pH 5.0) solution at room temperature for 20 minutes. To this solution, 40 μL of 25 mM NaOAc / 1 mM EDTA (pH 5.0, preincubated at 37 °C) was added, followed by the addition of 0.2 μmol ofnatLu-RIMS-3 in 50 μL of H2O, resulting in an approximate enzyme-to-substrate ratio of 1:400. The samples were incubated at 37 °C, and 10 μL aliquots were removed at various timepoints for HPLC analysis. Stability of177Lu-RIMS-3: The stability for177Lu-RIMS-3 was evaluated by radio- HPLC for radiolytic degradation and decomplexation at relevant time point concentrations for dose preparation, storage, and administration.177Lu-RIMS-3 was radio-labeled with a specific activity of 3.8 MBq / nmol and diluted in PBS. An 0.1 mL aliquot was taken, stored at room temperature, and tested for stability by radio-HPLC at 2, 6, 12, 24, 48 and 72 h.Biodistribution Study: All animal experiments were conducted according to the guidelines of the Institutional Animal Care and Use Committee (IACUC) at UW-Madison. C57BL / 6J mice (5 weeks, The Jackson Laboratory) were implanted subcutaneously on the rightshoulder with 0.1 x 106RM1-PGLS (hPSMA+) cells suspended in Matrigel (1:1). When thetumors reached 24−150 mm3(day 5) the mice were randomized based on tumor volumes into 4 groups (5 mice per group) for single dose compound administration. The mice were anesthetized with isoflurane, and 1.9-2.5 MBq of177Lu-RIMS-3,177Lu-RIMS-1,177Lu-RIMS-4 or177Lu- RIMS-5 at 4.0 MBq / nmol specific activity was intravenously injected using a tail vein catheter. At 2, 24, 72 and 144 h, mice were sacrificed, and select organs were harvested. Radioactivity was quantified by gamma counting, and the radioactivity associated with each organ was expressed as % ID / g. Urine (50 μL) was collected from the177Lu-RIMS-3,177Lu-RIMS-4 and177Lu-RIMS-5 cohorts at 2 h and analyzed by radio-HPLC for metabolites. Therapy Study: C57BL / 6J mice (5 weeks, The Jackson Laboratory) were implantedsubcutaneously on the right shoulder with 0.1 x 106RM1-PGLS (hPSMA+) cells suspended inMatrigel (1:1). When the tumors reached 24−150 mm3(day 5) the mice were randomized based on tumor volumes into 6 groups (10 mice per group) for single dose compound administration of177Lu-RIMS-3 at differing total administered radioactivity and specific activity or in combination with immune checkpoint inhibitors murine anti-PD-1 and murine anti-CTLA4. Group 1, 2 and 3 received177Lu-RIMS-3; group 4 received177Lu-RIMS-3 with anti-PD1; group 5 received177Lu- RIMS-3 with anti-CTLA4; and group 6 was vehicle. Group 1 received 60 MBq with a specific activity of 10.73 MBq / nmol which corresponds to 0.1 mg / kg of TLR 7 / 8 agonist. Group 2 received 60 MBq with a specific activity of 2.15 MBq / nmol which corresponds to 0.5 mg / kg of TLR 7 / 8 agonist. Group 3 received 60 MBq with a specific activity of 1.07 MBq / nmol which corresponds to 1.0 mg / kg of TLR 7 / 8 agonist. Group 4 received 60 MBq with a specific activity of 2.15 MBq / nmol which corresponds to 0.5 mg / kg of TLR 7 / 8 agonist, followed by Intraperitoneal (IP) injection of anti-PD-1 at 10 mg / kg on 1, 4, 8, 12 days after. Group 5 received 60 MBq with a specific activity of 2.15 MBq / nmol which corresponds to 0.5 mg / kg of TLR 7 / 8agonist, followed by Intraperitoneal (IP) injection of anti-CTLA-4 at 10 mg / kg on 1, 4, 8, 12 days after. Tumor volumes and body weights were recorded every 2-3 days. Example 1: Preparations of Compounds of Formula (I)Scheme 1. Synthesis of 1-((3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2-butyl-1H- imidazo[4,5-c]quinolin-4-amine compound 10. Preparation of 3:To 1(Bioorg. Med. Chem.11 (2003) 2541–2550) (318 mg, 1.3 mmol) in 10 mL of dichloromethane under Ar was added DIPEA (0.38 mL, 2.2 mmol) followed by 2 (250.0 mg, 1.1 mmol) and refluxed for 18 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (hexanes:ethyl acetate 5:1 to 3:1) to give 3 (379.9 mg,0.87 mmol, 79.9 %).1H NMR (600 MHz, MeOD) δ 8.20 (d, J = 8.5 Hz, 1H), 7.74 (m, 2H), 7.56 (p, J = 4.2 Hz, 1H), 3.34 (s, 2H), 3.05 (s, 2H), 1.58 (s, 6H), 1.38 (s, 9H);13C NMR (150 MHz, MeOD) δ 158.4, 147.0, 146.4, 143.2, 133.1, 129.4, 128.7, 127.8, 123.4, 121.0, 79.8, 49.6, 46.1, 42.4, 39.9, 28.7. HRESIMS [M + Na]+calcd for C21H25ClN4O4Na 455.14565, found 455.14523. Preparation of 4:To 3 (379.9 mg, 0.87 mmol) in 10 mL of ethyl acetate was added 10% Pd / C (200 mg) and exposed to H2(balloon) and allowed to stir at room temperature for 24 h. The reaction mixture was then filtered and concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 95:5) to give 4 (312 mg, 0.77 mmol, 89.0 %).1H NMR (600 MHz, DMSO-d6) δ 8.02 (m, 1H), 7.69 (m, 1H), 7.39 (m, 2H), 6.70 (t, J = 6.0 Hz, 1H), 5.29 (t, J = 7.0, 1H), 5.01 (s, 2H), 3.36 (d, J = 6.9 Hz, 2H), 2.93 (d, J = 6 Hz, 2H), 1.42 (s, 6H), 1.33 (s, 9H);13C NMR (150 MHz, DMSO-d6) δ 155.6, 141.0, 140.9, 137.0, 128.0, 127.9, 125.6, 124.8, 122.6, 122.1, 77.2, 48.7, 47.5, 41.3, 39.8, 38.7, 28.2. HRESIMS [M + H]+calcd for C21H28ClN4O2403.1901, found 403.18916. Preparation of 6:To 4 (395.6 mg, 0.98 mmol) in 10 mL of tetrahydrofuran under Ar was added DIPEA (0.25 mL, 1.4 mmol) followed by 5 (141.0 mg, 1.1 mmol) and allowed to stir at room temperature for 24 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 97.5:2.5) to give 6 (199.2 mg, 0.40 mmol, 41.7 %).1H NMR (600 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.24 (d, J = 7.9 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.66 (t, J = 6.7 Hz, 1H), 7.48 (t, J = 8.4 Hz, 1H), 6.75 (t, J = 6 Hz, 1H), 6.24 (t, J = 6.1 Hz, 1H), 3.57 (d, J = 6 Hz, 2H), 2.95 (d, J = 6 Hz, 2H), 2.37 (t, J = 7.3 Hz, 2H), 1.61 (quin, J = 7.5 Hz, 2H), 1.49 (s, 6H), 1.38 (m, 2H), 1.34 (s, 9H), 0.91 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 172.3, 155.6, 151.5, 150.1, 145.8, 129.9, 128.0, 124.9, 122.9, 120.3, 110.4, 77.3, 48.5, 46.4, 41.2, 39.1, 38.7, 35.0, 28.1, 27.0, 21.9, 13.7; HRESIMS [M + H]+calcd for C26H36ClN4O3487.247045 found 487.24889. Preparation of 7:To 6 (100.0 mg, 0.20 mmol) in 30 mL of ethanol under Ar was added 5M NaOH (1mL, 0.005 mol) and allowed to stir at room temperature for 6 h. The reaction mixture was then diluted with 100 mL of water and the aqueous phase was extracted three times with methylene chloride (100 mL). The combined organic extracts were washed with 50 mL of brine then dried with MgSO4and concentrated using a rotary evaporator. The crude mixture was purified using flash column chromatography (dichloromethane:methanol 97.5:2.5) to give 7 (25.7 mg, 0.055 mmol, 27.4 %).1H NMR (600 MHz, MeOD) δ 8.37 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.65 (m, 2H), 4.85 (s, 2H), 4.81 (bs, 1H), 2.96 (m, 4H), 1.88 (m, 2H), 1.57 (s, 6H), 1.52 (sex, J = 7.6 Hz, 2H), 1.34 (s, 9H), 1.01 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, MeOD) δ 158.48, 158.43, 144.7, 143.9, 136.5, 133.8, 129.8, 129.0, 127.7, 122.2, 118.6, 79.8, 50.4, 47.7,42.1, 40.7, 39.7, 31.0, 28.6, 27.7, 23.5, 14.1; HRESIMS [M + H]+calcd for C26H34ClN4O2469.236480 found 469.23844. Preparation of 9:To 7 (96.1 mg, 0.20 mmol) under Ar was added 8 (3.6 mL, 22.7 mmol) and heated to 140 °C under reflux conditions for 2 h. The reaction mixture was dissolved with 250 mL of dichloromethane and washed three times with 1M HCl (100mL) then washed with 50 mL of brine followed by drying with MgSO4and concentrated using a rotary evaporator. The crude mixture was purified using flash column chromatography (dichloromethane:methanol 95:5) to give 9 (55.3 mg, 0.092 mmol, 46.1 %).1H NMR (600 MHz, DMSO-d6) δ 8.12 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 9.6 Hz, 1H), 7.37 (t, J = 6.9 Hz, 1H), 7.20 (m, 2H), 6.76 (t, J = 6.0 Hz, 1H), 6.69 (t, J = 6.0 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 8.4, 2.4 Hz, 1H), 4.67 (d, J = 6.0 Hz, 2H), 3.85 (s, 3H), 3.71 (s, 3H), 3.50 (2H, under H2O peak), 2.88 (m, 2H), 2.83 (m, 2H), 1.81 (m, 2H), 1.49 (s, 6H), 1.44 (m, 2H), 1.30 (s, 9H), 0.94 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 159.4, 157.8, 155.6, 153.2, 150.1, 144.6, 132.0, 128.8, 126.8, 126.3, 126.2, 120.6, 120.4, 120.1, 114.9, 104.2, 98.2, 77.3, 55.4, 55.1, 49.1, 45.6, 40.9, 39.1, 38.5, 38.3, 29.3, 28.1, 25.9, 21.9, 13.8; HRESIMS [M + H]+calcd for C35H46N5O4600.3550 found 600.35567. Preparation of 1-((3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2-butyl-1H- imidazo[4,5-c]quinolin-4-amine compound 10:To 9 (25.0 mg, 0.041 mmol) under Ar was added 0.5 mL of dichloromethane followed by trifluoroacetic acid (0.1 mL, 1.3 mmol) and allowed to stir at room temperature for 26 h. The reaction mixture was then concentrated under reduced pressure and loaded on a 10 g reversed phase sep-pak (which had been washed with 100 mL of acetonitrile followed by 100 mL of water). Once loaded the column was eluted with water, 8:2, 7:3, 6:4, 5:5, 4:6 and 3:7 (H2O:MeCN, acidified to 0.01M using HCl) in 20 mL fractions. The fraction eluted with 7:3 H2O:MeCN contained 10 as confirmed by LCMS. This fraction was concentrated under reduced pressure and lyophilized overnight to yield 10 as the HCl salt (11.0 mg, 0.026 mmol, 63.5 %). HRESIMS [M + H]+calcd for C21H28N5350.2345 found 350.23422.Scheme 2. Synthesis of 1-((4-(aminomethyl)bicyclo[2.2.2]octan-1-yl)methyl)-2-butyl-1H- imidazo[4,5-c]quinolin-4-amine compound 17. Preparation of 12:To 1 (301.7 mg, 1.24 mmol) in 15 mL of dichloromethane under Ar was added DIPEA (0.43 mL, 2.48 mmol) followed by 11 (250.0 mg, 0.93 mmol) and stirred at room temperature for 90 min. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (hexanes:ethyl acetate 5:1 to 2:1) to give 12 (428.3 mg, 0.90 mmol, 96.7 %).1H NMR (600 MHz, MeOD) δ 8.19 (d, J = 8.4 Hz, 1H), 7.73 (m, 2H), 7.56 (m, 1H), 6.46 (t, J = 6 Hz, 1H, -NH-), 2.99 (s, 2H), 2.76 (d, J = 6.3 Hz, 2H), 1.45-1.43 (m, 6H), 1.41 (m, 9H),1.38-1.37 (m, 6H);13C NMR (150 MHz, MeOD) δ 158.7, 147.1, 147.0, 143.4, 133.2, 129.4, 128.7, 127.8, 123.7, 120.9, 79.7, 61.5, 54.6, 50.5, 50.4, 34.7, 33.9, 29.7, 29.5, 28.7. HRESIMS [M + H]+calcd for C24H34ClN4O4475.2112, found 475.21018. Preparation of 13:To 12 (341.0 mg, 0.72 mmol) in 3 mL of ethyl acetate was added 10% Pd / C (100 mg) and exposed to H2(balloon) and allowed to stir at room temperature for 3 h. The reaction mixture was then filtered and concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 95:5) to give 13 (290.6 mg, 0.65 mmol, 90.6 %) .1H NMR (600 MHz, MeOD) δ 7.89 (d, J = 10.1 Hz, 1H), 7.70 (d, J = 9.8 Hz, 1H), 7.40 (m, 2H), 6.43 (t, J = 6.6 Hz, 1H, -NH-), 2.95 (s, 2H), 2.75 (d, J = 6.3 Hz, 2H), 1.47-1.44 (m, 6H), 1.41 (s, 9H), 1.36-1.34 (m, 6H) ;13C NMR (150 MHz, MeOD) δ 158.6, 143.2, 142.9, 140.8, 129.1, 128.5, 127.7, 126.6, 124.0, 122.8, 79.6, 57.6, 50.7, 50.6, 34.8, 33.9, 29.9, 29.8, 28.8. HRESIMS [M + H]+calcd for C24H34ClN4O2445.2370, found 445.23635. Preparation of 14:To 13 (280 mg, 0.63 mmol) in 6 mL of tetrahydrofuran under Ar was added DIPEA (0.16 mL, 0.94 mmol) followed by 5 (114.0 mg, 0.945 mmol) and allowed to stir at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 97.5:2.5) to give 14 (129.6 mg, 0.24 mmol, 38.9 %).1H NMR (600 MHz, MeOD) δ 9.50 (s, 1H, -NH-), 8.21 (d, J = 8.7 Hz, 1H), 7.73, (d, J = 8.4 Hz, 1H), 7.67 (t, J = 8.1 Hz, 1H), 7.50 (t, J = 8.4 Hz, 1H), 6.71 (t, J = 6.4 Hz, 1H, -NH-), 5.76 (t, J = 5.7 Hz, 1H, -NH-), 3.27 (d, J = 5.7 Hz, 2H), 2.65 (d, J = 6.3 Hz, 2H), 2.36 (t, J = 7.3 Hz, 2H), 1.62 (p, J = 7.3 Hz, 2H), 1.40-1.34 (m, 8H), 1.35 (s, 9H), 1.28-1.25 (m, 6H), 0.92 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, MeOD) δ 172.3, 155.9, 151.3, 150.6, 145.9, 129.9, 128.1, 124.9, 123.3, 120.2, 110.7, 77.2, 55.1, 49.1, 35.0, 33.5, 32.6, 28.4, 28.3, 28.2, 27.2, 22.0, 13.8. HRESIMS [M + H]+calcd for C29H42ClN4O3529.2945 found 529.29419. Preparation of 15:To 14 (470.0 mg, 0.88 mmol) in 30 mL of ethanol under Ar was added 5M NaOH (4.3mL, 0.021 mol) and allowed to stir at room temperature for 72 h. The reaction mixture was then diluted with 100 mL of water and the aqueous phase was extracted three times with methylene chloride (100 mL). The combined organic extracts were washed with 50 mL of brine then dried with MgSO4and concentrated using a rotary evaporator. The crude mixture was purified using flash column chromatography (dichloromethane:methanol 95:5) to give 15 (45.3 mg, 0.088 mmol, 10.1 %).1H NMR (600 MHz, DMSO-d6) δ 8.59 (d, J = 7.9 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.67 (m, 2H), 6.64 (t, J = 6.3 Hz, 1H), 4.81 (d, J = 15.4 Hz, 1H), 4.29 (d, J = 15.6 Hz, 1H), 3.00 (q, J = 16.7, 8.2 Hz, 2H), 2.57 (m, 2H), 1.80 (quin, J = 7.8 Hz, 2H), 1.45-1.35 (m, 8H), 1.31 (s, 9H), 1.18 (m, 6H), 0.92 (t, J = 7.4 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ162.7, 158.1, 156.3, 143.6, 142.9, 136.3, 133.1, 129.6, 127.9, 126.5, 122.4, 118.3, 77.6, 54.2, 49.3, 36.2, 32.5, 30.3, 29.3, 28.6, 27.6, 22.3, 14.2; HRESIMS [M + H]+calcd for C29H40ClN4O2511.283431 found 511.28341. Preparation of 16:To 15 (45.3 mg, 0.088 mmol) under Ar was added 8 (3.6 mL, 22.7 mmol) and heated to 120 °C for 1 h. The reaction mixture was dissolved with 150 mL of dichloromethane and washed with saturated NH4Cl (50mL) then dried with MgSO4and concentrated using a rotary evaporator. The crude mixture was purified using flash column chromatography (dichloromethane:methanol 95:5) to give 16 (23.9 mg, 0.037 mmol, 42.4 %).1H NMR (600 MHz, DMSO-d6) δ 8.2 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.19 (t, J = 6.8 Hz, 1H), 6.76 (t, J = 6.1 Hz, 1H), 6.64 (t, J = 6.3 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 8.3, 2.4 Hz, 1H), 4.66 (m, 2H), 4.17 (d, J = 15.4 Hz, 1H), 3.84 (s, 3H), 3.71 (s, 3H), 2.90 (m, 2H), 2.58 (m, 2H), 1.76 (sex, J = 7.4 Hz, 2H), 1.46-1.35 (m, 8H), 1.32 (s, 9H), 1.19 (t, J = 8.04 Hz, 6H), 0.91 (t, J = 7.4 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 159.5, 157.8, 155.8, 154.6, 150.1, 144.8, 132.8, 128.9, 127.0, 126.5, 126.0, 121.1, 120.4, 120.1, 115.6, 104.2, 98.2, 77.2, 55.4, 55.1, 53.4, 48.9, 38.3, 35.5, 32.1, 30.2, 28.9, 28.29, 28.25, 27.1, 21.9, 13.8; HRESIMS [M + H]+calcd for C38H52N5O4642.401382 found 642.40432. Preparation of 1-((4-(aminomethyl)bicyclo[2.2.2]octan-1-yl)methyl)-2-butyl-1H- imidazo[4,5-c]quinolin-4-amine compound 17:To 16 (19.0 mg, 0.029 mmol) under Ar was added 2.0 mL of dichloromethane followed by trifluoroacetic acid (0.5 mL, 6.5 mmol) and allowed to stir at room temperature for 24 h. The reaction mixture was then concentrated under reduced pressure and loaded on a 10 g reversed phase sep-pak (which had been washed with 100 mL of acetonitrile followed by 100 mL of water). Once loaded the column was eluted with water, 8:2, 7:3, 6:4, 5:5, 4:6 and 3:7 ( H2O:MeCN, acidified to 0.01M using HCl) in 20 mL fractions. The fraction eluted with 7:3 H2O:MeCN contained 17 as confirmed by LCMS. This fraction was concentrated under reduced pressure and lyophilized overnight to yield 17 as the HCl salt (9.4 mg, 0.020 mmol, 69.8 %).1H NMR (600 MHz, MeOD, Formic Acid Salt) δ 8.39 (d, J = 9.6 Hz, 1H), 7.75 (d, J = 9.6 Hz, 1H), 7.60 (t, J = 8.2 Hz, 1H), 7.46 (t, J = 8.2 Hz, 1H), 4.83 (d, J = 15.7 Hz, 1H), 4.33 (d, J = 16.2 Hz, 1H), 3.03 (t, J = 7.6 Hz, 2H), 2.61 (s, 2H), 1.90 (sex, J = 7.9 Hz, 2H), 1.63-1.43 (m, 8H), 1.45 (t, J = 14.6 Hz, 6H), 1.01 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, MeOD, Formic Acid Salt) δ 158.1, 150.4, 137.5, 136.2, 129.0, 125.4, 123.8, 122.4, 120.9, 114.6, 54.2, 48.4, 36.0, 30.4, 30.3, 29.2, 28.1, 28.0, 22.5, 13.3. HRESIMS [M + H]+calcd for C24H34N5392.2814 found 392.28088.Scheme 3. Synthesis of 1-((6-(aminomethyl)spiro[3.3]heptan-2-yl)methyl)-2-butyl-1H- imidazo[4,5-c]quinolin-4-amine compound 24. Preparation of 19:To 1 (279.5 mg, 1.15 mmol) in 15 mL of dichloromethane under Ar was added DIPEA (0.40 mL, 2.30 mmol) followed by 18 (250.0 mg, 0.85 mmol) and stirred at room temperature for 23 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (hexanes:ethyl acetate 2:1) to give 19 (334.7 mg, 0.73 mmol, 85.4 %).1H NMR (600 MHz, MeOD) δ 8.15 (d, J = 8.4 Hz, 1H), 7.66 (m, 2H), 7.47 (ddd, J = 2.8 Hz, 1H), 3.18 (d, J = 6.5 Hz, 2H), 2.98 (d, J = 7.0 Hz, 2H), 2.48 (p, J = 7.6 Hz, 1H), 2.22 (p, J = 7.6 Hz,1H), 2.16 (m, 1H), 2.06 (m, 2H), 1.93 (m, 1H), 1.69 (m, 2H), 1.62 (m, 2H), 1.39 (s, 9H);13C NMR (150 MHz, MeOD) δ 158.4, 146.6, 145.8, 143.2, 132.8, 129.1, 128.0, 127.6, 123.2, 120.7, 79.6, 50.5, 46.5, 40.0, 39.68, 39.61, 39.3, 37.3, 30.9, 30.8, 28.7. HRESIMS [M + Na]+calcd for C23H29ClN4O4Na 483.1769, found 483.17596. Preparation of 20:To 19 (270.0 mg, 0.58 mmol) in 3 mL of ethyl acetate was added 10% Pd / C (100 mg) and exposed to H2(balloon) and allowed to stir at room temperature for 3 h. The reaction mixture was then filtered and concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 95:5) to give 20 (229.3 mg, 0.53 mmol, 91.7 %). 1H NMR (600 MHz, DMSO-d6) δ 7.99 (m, 1H), 7.67 (m, 1H), 7.40 (m, 2H), 6.72 (t, J = 5.8 Hz, 1H), 5.18 (1H), 5.0 (2H), 3.22 (t, J = 6.7 Hz, 2H), 2.85 (t, J = 6.7 Hz, 2H), 2.25 (quin, J = 7.8 Hz, 1H), 2.14 (quin, J = 7.5 Hz, 1H), 1.94 (m, 2H), 1.85 (m, 2H), 1.64 (dd, J = 7.5, 3.7 Hz, 1H), 1.59 (m, 2H), 1.54 (dd, J = 7.3, 4.0 Hz, 1H), 1.34 (s, 9H);13C NMR (150 MHz, DMSO-d6) δ 155.7, 140.9, 140.7, 136.6, 128.5, 127.9, 125.6, 125.0, 123.0, 122.0, 77.2, 52.4, 45.1, 39.1, 38.9, 38.4, 38.1, 35.8, 30.5, 29.5, 28.2. HRESIMS [M + H]+calcd for C23H34ClN4O2431.2214, found 431.22026. Preparation of 21:To 20 (220 mg, 0.51 mmol) in 5 mL of tetrahydrofuran under Ar was added DIPEA (0.13 mL, 0.76 mmol) followed by 5 (92.5 mg, 0.767 mmol) and allowed to stir at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 97.5:2.5) to give 21 (67.5 mg, 0.13 mmol, 25.7 %).1H NMR (600 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.24 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.65 (t, J = 6.7 Hz, 1H), 7.47 (t, J = 8.4 Hz, 1H), 6.75 (t, J = 5.8 Hz, 1H), 6.57 (t, J = 5.8 Hz, 1H) 3.42 (t, J = 5.8 Hz, 2H), 2.87 (t, J = 6.6 Hz, 2H), 2.44 (quin, J = 7.6 Hz, 1H), 2.31 (t, J = 7.3 Hz, 2H), 2.16 (quin, J = 7.6 Hz, 1H), 2.05 (m, 1H), 1.97 (m, 2H), 1.89 (m, 1H), 1.66 (m, 2H), 1.60 (m, 4H), 1.37 (m, 2H), 1.35 (s, 9H), 0.91 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 172.6, 155.7, 152.3, 149.5, 145.6, 129.8, 128.0, 124.9, 122.5, 120.1, 108.8, 77.2, 50.8, 45.1, 38.9, 38.6, 38.4, 38.1, 35.8, 35.0, 29.6, 29.5, 28.2, 27.0, 22.0, 13.7; HRESIMS [M + H]+calcd for C28H40ClN4O3515.2789 found 515.27802. Preparation of 22:To 21 (57.0 mg, 0.11 mmol) in 10 mL of ethanol under Ar was added 5M NaOH (0.55 mL, 2.75 mmol) and allowed to stir at room temperature for 24 h. The reaction mixture was thendiluted with 100 mL of water and the aqueous phase was extracted three times with methylene chloride (100 mL). The combined organic extracts were washed with 50 mL of brine then dried with MgSO4and concentrated using a rotary evaporator. The crude mixture was purified using flash column chromatography (dichloromethane:methanol 97.5:2.5) to give 22 (14.2 mg, 0.028 mmol, 25.9 %).1H NMR (600 MHz, DMSO-d6) δ 8.29 (m, 1H), 8.05 (m, 1H), 7.71 (m, 2H), 6.73 (t, J = 5.9 Hz, 1H), 4.65 (d, J = 6.7 Hz, 2H), 2.98 (t, J = 7.2 Hz, 2H), 2.85 (t, J = 7.3 Hz, 2H), 2.17 (t, J = 8.0 Hz, 1H), 2.13 (dd, J = 15.0, 7.5 Hz, 1H), 2.03 (m, 1H), 1.96-1.81 (m, 6H), 1.77 (t, J = 8.7 Hz, 1H), 1.61 (dd, J = 11.3, 7.2 Hz, 1H), 1.57 (dd, J = 12.2, 4.5 Hz, 1H), 1.47 (sex, J = 7.6 Hz, 2H), 1.32 (s, 9H), 0.96 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 156.2, 155.7, 143.0, 142.3, 134.7, 132.8, 129.2, 127.5, 126.8, 120.9, 117.2, 77.2, 49.3, 48.4, 44.9, 38.4, 38.1, 37.7, 37.1, 35.7, 30.0, 29.5, 29.2, 28.2, 26.4, 21.9, 17.2, 13.8; HRESIMS [M + H]+calcd for C28H38ClN4O2497.267781 found 497.26946. Preparation of 23:To 22 (14.0 mg, 0.028 mmol) under Ar was added 8 (0.42 mL, 2.81 mmol) and heated to 120 °C for 1 h. The reaction mixture was dissolved with 50 mL of dichloromethane and washed with saturated NH4Cl (50mL) then dried with MgSO4and concentrated using a rotary evaporator. The crude mixture was purified using flash column chromatography (dichloromethane:methanol 95:5) to give 23 (7.6 mg, 0.012 mmol, 42.8 %).1H NMR (600 MHz, MeOD) δ 7.97 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.50 (t, J = 7.0 Hz, t, 1H), 7.33 (t, J = 7.0 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.46 (dd, J = 8.2, 2.3 Hz, 1H), 4.76 (s, 2H), 4.51 (d, J = 6.6 Hz, 2H), 3.84 (s, 3H), 3.76 (s, 3H), 2.96 (d, J = 7.0 Hz, 2H), 2.91(dd, J = 7.5, 0 Hz, 2H), 2.74 (quin, J = 8.1 Hz, 1H), 2.23 (quin, J = 7.6 Hz, 1H), 2.12 (m, 1H), 2.05 (m, 1H), 2.00 (m, 2H), 1.87-1.78 (m, 4H), 1.68 (dd, J = 11.4, 3.9 Hz, 1H), 1.63 (dd, J = 11.6 Hz, 1H), 1.48 (sex, J = 7.5 Hz, 2H), 1.39 (s, 9H), 0.99 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, MeOD) δ 170.0, 162.2, 160.1, 158.6, 155.7, 151.0, 134.3, 131.3, 128.6, 127.1, 125.9, 123.6, 121.7, 119.7, 115.8, 105.3, 99.3, 79.7, 55.9, 55.7, 50.9, 46.5, 41.2, 40.0, 39.6, 39.1, 38.6, 37.3, 31.7, 31.0, 30.9, 28.7, 28.0, 23.5, 14.2; HRESIMS [M + H]+calcd for C37H50N5O4628.385732 found 628.38765. Preparation of 1-((6-(aminomethyl)spiro[3.3]heptan-2-yl)methyl)-2-butyl-1H-imidazo[4,5- c]quinolin-4-amine compound 24:To 23 (7.0 mg, 0.011 mmol) under Ar was added 0.5 mL of dichloromethane followed by trifluoroacetic acid (0.1 mL, 1.3 mmol) and allowed to stir at room temperature for 24 h. The reaction mixture was then concentrated under reduced pressure and loaded on a 10 g reversed phase sep-pak (which had been washed with 100 mL of acetonitrile followed by 100 mL of water). Once loaded the column was eluted with water, 8:2, 7:3, 6:4, 5:5, 4:6 and 3:7 (H2O:MeCN, acidified to 0.01M using HCl) in 20 mL fractions. The fraction eluted with 7:3 H2O:MeCN contained 24 as confirmed by LCMS. This fraction was concentrated under reduced pressure and lyophilized overnight to yield 24 as the HCl salt (2.5 mg, 0.0055 mmol, 50.4 %). 1H NMR (600 MHz, DMSO-d6) δ 8.35 (bs, 2H), 7.97 (d, J = 8.3 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.40 (t, J = 8.2 Hz, 1H), 7.24 (t, J = 8.2 Hz, 1H), 6.53 (bs, 2H), 4.54 (d, J = 6.7 Hz, 2H), 2.90 (t, J = 7.3 Hz, 2H), 2.69 (bs, 2H), 2.67 (m, 1H), 2.27 (quin, J = 7.6 Hz, 1H), 2.05 (m, 2H), 1.96 (m, 1H), 1.92 (m, 1H), 1.86 (t, J = 8.7 Hz, 1H), 1.80 (m, 3H), 1.71 (dd, J = 11.4, 7.5 Hz,1H), 1.67 (dd, J = 11.6, 7.6 Hz, 1H), 1.46 (sex, J = 7.5 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 153.7, 152.1, 144.9, 132.8, 126.84, 126.7, 126.57, 121.54, 120.6, 115.3, 49.4, 44.4, 40.8, 40.5, 38.7, 38.3, 37.8, 36.2, 30.6, 30.2, 26.8, 22.4, 14.3; HRESIMS [M + H]+calcd for C23H32N5378.2658 found 378.26467. Preparations of Compounds of Formula (II)Scheme 4. Synthesis of 5-(4-(((3-aminobicyclo[1.1.1]pentan-1-yl)amino)methyl)-2- methoxybenzyl)-N4-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine compound 28.Preparation of 27:To 25 (US20220242871) (50.0 mg, 0.13 mmol) in 3.5 mL of dichloromethane under Ar was added thionyl chloride (0.058 mL, 0.81 mmol) dropwise after which the ice bath was removed and the reaction mixture allowed to stir at room temperature for 45 min. The reaction mixture was then diluted with 25 mL of methylene chloride and washed with NaHCO3then dried with MgSO4and concentrated using a rotary evaporator. To the benzyl chloride intermediate was added 2.5 mL of N,N-dimethylformamide under Ar followed by DIPEA (0.070 mL, 0.40 mmol) and 26 (53.6 mg, 0.27 mmol) and allowed to stir at 50 °C for 18 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography(dichloromethane:methanol 9:1) to give 27 (48.2 mg, 0.087 mmol, 67.4 %). HRESIMS [M + H]+calcd for C30H44N7O3550.3506 found 550.34970. Preparation of 5-(4-(((3-aminobicyclo[1.1.1]pentan-1-yl)amino)methyl)-2-methoxybenzyl)- N4-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine compound 28:To 27 (32.0 mg, 0.058 mmol) under Ar was added 2.0 mL of dichloromethane followed by trifluoroacetic acid (0.5 mL, 6.5 mmol) and allowed to stir at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and loaded on a 10 g reversed phase sep-pak (which had been washed with 100 mL of acetonitrile followed by 100 mL of water). Once loaded the column was eluted with water, 8:2, 7:3, 6:4, 5:5, 4:6 and 3:7 (H2O:MeCN, acidified to 0.01M using HCl) in 20 mL fractions. The fraction eluted with 8:2 H2O:MeCN contained 28 as confirmed by LCMS. This fraction was concentrated under reduced pressure and lyophilized overnight to yield 28 as the HCl salt (26.4 mg, 0.050 mmol, 87.2 %). HRESIMS [M + H]+calcd for C25H36N7O 450.2981 found 450.29709Scheme 5. Synthesis of (((S)-5-((S)-2-((1S,4S)-4-(((S)-2-(6-(((S)-1-(((S)-1-((4-(((((3-((4-amino-2-butyl- 1H-imidazo[4,5-c]quinolin-1-yl)methyl)bicyclo[1.1.1]pentan-1- yl)methyl)carbamoyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2- yl)amino)-6-oxohexanamido)-6-(2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1- yl)acetamido)hexanamido)methyl)cyclohexane-1-carboxamido)-3-(naphthalen-2-yl)propanamido)- 1-carboxypentyl)carbamoyl)-L-glutamic acid (“RIMS-3”). Preparation of 31:To 29 (103.9 mg, 0.15 mmol) in 1.5 mL of DMF under Ar was added DIPEA (.096 mL, 0.55 mmol) followed by 10 (60 mg, 0.14 mmol) and allowed to stir at room temperature for 24 h. The reaction mixture was then concentrated under reduced pressure and purified using flashchromatography (dichloromethane:methanol 9:1) to give 31 (86.5 mg, 0.097 mmol, 69.4 %). Rt (Method B): 5.91 min. HRESIMS [M + H]+calcd for C52H59N8O6891.4558 found 891.45556. Preparation of 32:To 31 (79.3 mg, 0.088 mmol) in 5.0 mL of DMF was added diethylamine (.026 mL, 0.25 mmol) and allowed to stir at room temperature for 1 h. The reaction mixture was washed three times with hexanes and the DMF layer was concentrated under reduced pressure. The crude mixture was dissolved in 0.5 mL of dimethyl sulfoxide and loaded on a 10 g reversed phase sep- pak (which had been washed with 100 mL of acetonitrile followed by 100 mL of water). Once loaded the column was eluted with water, 8:2, 7:3, 6:4, 5:5, 4:6 and 3:7 (H2O:MeCN, acidified to 0.01M using HCl) in 20 mL fractions. The fraction eluted with 8:2 H2O:MeCN contained 32 as confirmed by LCMS. This fraction was concentrated under reduced pressure and lyophilized overnight to yield 32 as the HCl salt (24.1 mg, 0.034 mmol, 38.8 %). Rt (Method B): 5.91 min. HRESIMS [M + H]+calcd for C37H49N8O4669.3877 found 669.38787. Preparation of (((S)-5-((S)-2-((1S,4S)-4-(((S)-2-(6-(((S)-1-(((S)-1-((4-(((((3-((4-amino-2-butyl- 1H-imidazo[4,5-c]quinolin-1-yl)methyl)bicyclo[1.1.1]pentan-1- yl)methyl)carbamoyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1- oxobutan-2-yl)amino)-6-oxohexanamido)-6-(2-(4,7,10-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecan-1-yl)acetamido)hexanamido)methyl)cyclohexane-1-carboxamido)-3- (naphthalen-2-yl)propanamido)-1-carboxypentyl)carbamoyl)-L-glutamic acid (“RIMS-3”):To 32 (6.9 mg, 0.0097 mmol) in 0.5 mL of DMF was added diisopropylethylamine (0.024 mL, 0.14 mmol) followed by 30 (30.0 mg, 0.022 mmol, Mol. Pharmaceutics.2022, 19, 3217−3227) in 1 mL of DMF dropwise over 5 min and allowed to stir at room temperature for 48 h. After all starting materials were converted, the solvent was evaporated. The crude product was purified by reversed phase semi-preparative HPLC to yield RIMS-3 (8.0 mg, 0.0041 mmol, 42.3 %). RIMS-3 was characterized by analytical HPLC (Method B) and MS measurements. Rt(Method B): 8.22 min. MALDI-TOF [M + H]+calcd for C99H138N19O231949.02130, found 1949.9. The structure of RIMS-3 is provided again below for convenience:Scheme 6. (((S)-5-((S)-2-((1S,4S)-4-(((S)-2-(6-(((S)-1-(((S)-1-((4-(((4-(4-((2-amino-4-(pentylamino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-3-methoxybenzyl)piperazine-1- carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-6- oxohexanamido)-6-(2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1- yl)acetamido)hexanamido)methyl)cyclohexane-1-carboxamido)-3-(naphthalen-2-yl)propanamido)- 1-carboxypentyl)carbamoyl)-L-glutamic acid (“RIMS-4”). Preparation of 33:To 29 (8.68 mg, 0.013 mmol) in 2.0 mL of DMF under Ar was added DIPEA (.006 mL, 0.035 mmol) followed by comparator compound (5.1 mg, 0.0099 mmol) and allowed to stir at room temperature for 90 min. The reaction mixture was then concentrated under reducedpressure and purified using flash chromatography (dichloromethane:methanol 9:1) to give 33 (7.26 mg, 0.0074 mmol, 74.9 %). ESIMS [M + H]+calcd for C55H67N10O7979.51942 found 979.51856. Preparation of 34:To 33 (11.9 mg, 0.012 mmol) in 1.0 mL of DMF was added diethylamine (.004 mL, 0.038 mmol) and allowed to stir at room temperature for 1 h. The reaction mixture was washed three times with hexanes and the DMF layer was concentrated under reduced pressure. The crude mixture was dissolved in 0.2 mL of dimethyl sulfoxide and loaded on a 10 g reversed phase sep- pak (which had been washed with 100 mL of acetonitrile followed by 100 mL of water). Once loaded the column was eluted with water, 8:2, 7:3, 6:4, 5:5, 4:6 and 3:7 (H2O:MeCN, acidified to 0.01M using HCl) in 20 mL fractions. The fraction eluted with 8:2 H2O:MeCN contained 34 as confirmed by LCMS. This fraction was concentrated under reduced pressure and lyophilized overnight to yield 34 as the HCl salt (7.5 mg, 0.0094 mmol, 78.3 %). ESIMS [M + H]+calcd for C40H57N10O5757.45134 found 757.45011. Preparation of (((S)-5-((S)-2-((1S,4S)-4-(((S)-2-(6-(((S)-1-(((S)-1-((4-(((4-(4-((2-amino-4- (pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-3-methoxybenzyl)piperazine-1- carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-6- oxohexanamido)-6-(2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)hexanamido)methyl)cyclohexane-1-carboxamido)-3-(naphthalen-2-yl)propanamido)- 1-carboxypentyl)carbamoyl)-L-glutamic acid (“RIMS-4”):To 34 (19.9 mg, 0.025 mmol) in 1.0 mL of DMF was added diisopropylethylamine (0.072 mL, 0.41 mmol) followed by 30 (73.4 mg, 0.0526 mmol, Mol. Pharmaceutics.2022, 19, 3217−3227) in 1 mL of DMF dropwise over 5 min and allowed to stir at room temperature for 48 h. After all starting materials were converted, the solvent was evaporated. The crude product was purified by reversed phase semi-preparative HPLC to yield RIMS-4 (10.0 mg, 0.0049 mmol, 19.6 %). RIMS-4 was characterized by analytical HPLC (Method B) and MS measurements. Rt (Method B): 8.12 min. MALDI-TOF [M + H]+calcd for C101H146N21O24 2037.08496, found 2037.7. The structure of RIMS-4 is provided again below for convenience:Scheme 7. (((S)-5-((S)-2-((1S,4S)-4-(((S)-2-(6-(((S)-1-(((S)-1-((4-(((((4-((4-amino-2-butyl-1H- imidazo[4,5-c]quinolin-1-yl)methyl)bicyclo[2.2.2]octan-1- yl)methyl)carbamoyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2- yl)amino)-6-oxohexanamido)-6-(2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1- yl)acetamido)hexanamido)methyl)cyclohexane-1-carboxamido)-3-(naphthalen-2-yl)propanamido)- 1-carboxypentyl)carbamoyl)-L-glutamic acid (“RIMS-5”).Preparation of 35: To 29 (25.6 mg, 0.037 mmol) in 2.0 mL of DMF under Ar was added DIPEA (.018 mL, 0.102 mmol) followed by 17 (13.4 mg, 0.028 mmol) and allowed to stir at room temperature for 90 min. The reaction mixture was then concentrated under reduced pressure and purified usingflash chromatography (dichloromethane:methanol 9:1) to give 35 (20.5 mg, 0.022 mmol, 78.5 %).1H NMR (600 MHz, MeOD) δ 8.55 (s, 1H), 8.28 (d, J = 8.3 Hz, 1H), 7.67 (m, 3H), 7.55 (m, 3H), 7.50 (d, J = 8.2 Hz, 2H), 7.28 (m, 2H), 7.21 (m, 2H), 7.19 (d, J = 8.5 Hz, 2H), 6.78 (t, -NH, J = 6.3 Hz, 1H), 4.63 (d, J = 15.4 Hz, 1H), 4.50 (q, J = 7.0 Hz, 1H), 4.29 (m, 2H), 4.15 (d, J = 15.7 Hz, 1H), 4.09 (t, J = 6.9 Hz, 1H), 3.96 (d, J = 6.8 Hz, 1H), 2.89 (m, 2H), 2.71 (m, 2H), 2.10 (sex, J = 6.8 Hz, 1H), 1.84 (m, 2H), 1.44 (m, 4H), 1.41 (d, J = 7.2 Hz, 6H), 1.35 (m, 3H), 1.24 (t, J = 7.8 Hz, 6H), 0.97 (t, J = 7.3 Hz, 6H), 0.94 (d, J = 6.8 Hz, 3H);13C NMR (150 MHz, MeOD) δ 174.0, 172.8, 169.9, 159.3, 159.0, 158.7, 150.7, 145.2, 145.0, 142.4, 139.3, 137.3, 136.2, 134.0, 130.2, 129.4, 128.7, 128.1, 128.0, 126.13, 126.11, 125.8, 125.2, 123.5, 120.9, 120.8, 120.2, 115.0, 67.9, 66.9, 62.2, 55.4, 51.0, 50.8, 48.3, 37.1, 33.4, 31.8, 30.9, 30.6, 29.5, 28.8, 23.4, 19.7, 18.6, 18.0, 14.3; HRESIMS [M + H]+calcd for ESIMS [M + H]+calcd for C55H65N8O6 933.50271 found 933.50216. Preparation of 36:To 35 (20.5 mg, 0.022 mmol) in 1.0 mL of DMF was added diethylamine (.0068 mL, 0.066 mmol) and allowed to stir at room temperature for 1 h. The reaction mixture was washed three times with hexanes and the DMF layer was concentrated under reduced pressure. The crude mixture was dissolved in 0.2 mL of dimethyl sulfoxide and loaded on a 10 g reversed phase sep- pak (which had been washed with 100 mL of acetonitrile followed by 100 mL of water). Once loaded the column was eluted with water, 8:2, 7:3, 6:4, 5:5, 4:6 and 3:7 (H2O:MeCN, acidified to 0.01M using HCl) in 20 mL fractions. The fraction eluted with 8:2 H2O:MeCN contained 36 as confirmed by LCMS. This fraction was concentrated under reduced pressure and lyophilized overnight to yield 36 as the HCl salt (15.2 mg, 0.02 mmol, 92.4 %).1H NMR (600 MHz, MeOD,Formic Acid Salt) δ 8.53 (s, 1H), 8.38 (d, J = 9.6 Hz, 1H), 7.73 (d, J = 8.4 hz, 1H), 7.58 (t, J = 8.4 Hz, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.45 (t, J = 7.0 Hz, 1H), 7.28 (d, J = 8.7 Hz, 2H), 4.97 (s, 2H), 4.79 (d, J = 15.9 Hz, 1H), 4.53 (q, J = 7.1 Hz, 1H), 4.27 (d, J = 16.8 Hz, 1H), 3.60 (d, J = 5.7 Hz, 1H), 3.01 (t, J = 7.6 Hz, 2H), 2.77 (s, 2H), 2.18 (sex, J = 6.9 Hz, 1H), 1.89 (m, 2H), 1.57- 1.43 (m, 9H), 1.46 (d, J = 7.2 Hz, 3H), 1.35 (t, J = 7.9 Hz, 6H), 1.07 (d, J = 6.9 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H), 1.00 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, MeOD, Formic Acid Salt) δ 172.7, 170.6, 169.9, 159.1, 158.8, 151.4, 139.3, 137.0, 134.2, 129.7, 129.5, 126.3, 124.5, 123.3, 122.4, 121.0, 115.8, 67.0, 59.8, 55.4, 51.1, 50.9, 40.4, 37.2, 33.5, 31.9, 31.3, 30.7, 29.6, 28.9, 23.4, 19.0, 18.1, 17.8, 14.2. ESIMS [M + H]+calcd for C40H55N8O4711.43463 found 711.43303. Preparation of (((S)-5-((S)-2-((1S,4S)-4-(((S)-2-(6-(((S)-1-(((S)-1-((4-(((((4-((4-amino- 2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl)bicyclo[2.2.2]octan-1- yl)methyl)carbamoyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1- oxobutan-2-yl)amino)-6-oxohexanamido)-6-(2-(4,7,10-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecan-1-yl)acetamido)hexanamido)methyl)cyclohexane-1-carboxamido)-3- (naphthalen-2-yl)propanamido)-1-carboxypentyl)carbamoyl)-L-glutamic acid (“RIMS-5”):To 36 (6.4 mg, 0.0085 mmol) in 0.5 mL of DMF was added diisopropylethylamine (0.024 mL, 0.14 mmol) followed by 30 (25.1 mg, 0.018 mmol, Mol. Pharmaceutics.2022, 19,3217−3227) in 1 mL of DMF dropwise over 5 min and allowed to stir at room temperature for 48 h. After all starting materials were converted, the solvent was evaporated. The crude product was purified by reversed phase semi-preparative HPLC to yield RIMS-5 (8.3 mg, 0.0042 mmol, 49.0 %). RIMS-5 was characterized by analytical HPLC (Method B) and MS measurements. Rt (Method B): 8.50 min.1H NMR (600 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.30 (d, J = 9.4 Hz, 1H), 8.26 (bs, 1H), 8.07 (m, 1H), 7.94 (m, 2H), 7.87 (m, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.76 (t, J = 8.1 Hz, 2H), 7.66 (s, 1H), 7.64 (d, J = 9.6 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.45 (m, 3H), 7.38 (d, J = 7.6 Hz, 1H), 7.28 (t, J = 8.2 Hz, 1H), 7.22 (d, J = 8.6 Hz, 2H), 7.05 (t, J = 6.3 Hz, 1H), 6.33 (d, J = 8.2 Hz, 2H), 4.88 (s, 2H), 4.69 (d, J = 15.3 Hz, 1H), 4.51 (q, J = 8.7 Hz, 1H), 4.36 (quin, J = 7.0 Hz, 1H), 4.20 (bs, 1H), 4.17 (m, 2H), 4.09 (q, J = 7.9 Hz, 1H), 4.02 (q, J = 7.9 Hz, 1H), 3.62- 3.16 (m, 21H), 3.11-2.88 (m, 22H), 2.79 (m, 2H), 2.66 (d, J = 7.0 Hz, 3H), 2.23 (q, J = 6.4 Hz, 2H), 2.19 (m, 1H), 2.14-2.07 (m, 3H), 2.05 (m, 1H), 1.97 (quin, J = 6.7 Hz, 1H), 1.89 (sex, J = 6.3 Hz, 1H), 1.76 (m, 3H), 1.64 (m, 2H), 1.57 (m, 2H), 1.44 (m, 9H), 1.36 (m, 8H), 1.29 (d, J = 7.1 Hz, 4H), 1.20 (m, 12H), 1.02 (q, J = 10.6 Hz, 1H), 0.91 (t, J = 7.3 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H), 0.83 (d, J = 6.7 Hz, 3H), 0.79 (m, 2H);13C NMR (150 MHz, DMSO-d6) δ 174.99. 174.91, 174.6, 173.9, 172.4, 172.0, 171.8, 171.1, 171.05, 171.02, 163.3, 157.3, 156.4, 155.6, 151.0, 138.6, 134.0, 132.8, 131.9, 131.7, 128.5, 127.8, 127.44, 127.40, 127.28, 127.25, 127.0, 125.88, 125.80125.3, 121.6, 121.4, 118.9, 114.7, 64.8, 57.6, 55.5, 53.7, 53.5, 52.4, 52.0, 49.4, 49.1, 44.5, 43.6, 40.0, 38.3, 38.1, 36.8, 35.6, 34.9, 34.8, 32.0, 31.7, 30.3, 30.2, 29.5, 29.4, 28.8, 28.7, 28.5, 28.3, 28.2, 27.9, 27.1, 25.0, 24.9, 22.9, 22.5, 21.8, 19.2, 18.2, 17.8; MALDI-TOF [M + H]+calcd for C101H144N19O231991.0682, found 1991.353. The structure of RIMS-5 is provided again below for convenience:Scheme 8. Synthesis of imidazoquinoline-like compounds. Preparation of tert-butyl ((3S,3aR,6S,6aR)-6-((2-chloro-3-nitroquinolin-4- yl)amino)hexahydrofuro[3,2-b]furan-3-yl)carbamate compound 38A:To 1 (300 mg, 1.23 mmol) in 5 mL of dichloromethane under Ar was added DIPEA (0.62 mL, 3.7 mmol) followed by 37A (200 mg, 0.8 mmol) and stirred at room temperature for 23 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (hexanes:ethyl acetate 2:1) to give 38A (259.7 mg, 0.57 mmol, 72.0 %).1H NMR (600 MHz, MeOD) δ 8.20 (d, J = 8.5 Hz, 1H), 7.69 (m, 2H), 7.52 (ddd, J = 2.9 Hz, 1H), 4.6 (m, 2H), 4.02 (m, 1H), 3.97 (m, 1H), 3.94 (m, 2H), 3.92 (t, J = 4.2 Hz, 1H), 3.74 (dd, J = 9.4, 2.7 Hz, 1H), 1.39 (s, 9H);13C NMR (150 MHz, MeOD) δ 157.5, 146.9, 144.5, 142.8, 133.1, 129.3, 128.0, 123.6, 120.8, 88.1, 80.4, 73.4, 73.2, 72.3, 71.4, 62.1, 58.6, 28.6. HRESIMS [M + H]+calcd for C20H24ClN4O6451.137889 found 451.14009. Preparation of tert-butyl 6-(((2-chloro-3-nitroquinolin-4-yl)amino)methyl)-2- azaspiro[3.3]heptane-2-carboxylate compound 38B:To 1 (300 mg, 1.23 mmol) in 5 mL of dichloromethane under Ar was added DIPEA (0.62 mL, 3.7 mmol) followed by 37B (200 mg, 0.88 mmol) and stirred at room temperature for 23 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (hexanes:ethyl acetate 2:1) to give 38B (311.6 mg, 0.72 mmol, 82.8 %).1H NMR (600 MHz, DMSO-d6) δ 8.45 (d, J = 8.5 Hz, 1H), 7.78 (m, 2H), 7.73 (m, -NH-, 1H), 7.60 (ddd, J = 4.8 Hz, 1H), 3.81 (bs, 2H), 3.72 (bs, 2H), 3.11 (m, 2H), 2.46 (m, 1H), 2.23 (m, 2H), 1.85 (m, 2H), 1.32 (s, 9H);13C NMR (150 MHz, DMSO-d6) δ 155.3, 145.2, 144.2, 140.9, 131.9, 128.4, 126.5, 126.2, 122.9, 119.5, 78.2, 48.4, 35.9, 33.7, 28.7, 27.9. HRESIMS [M + H]+calcd for C21H26ClN4O4433.163709 found 433.16465. Preparation of tert-butyl (3-(((2-chloro-3-nitroquinolin-4-yl)amino)methyl)bicyclo [3.2.0]heptan-6-yl)carbamate compound 38C:To 1 (300 mg, 1.23 mmol) in 5 mL of dichloromethane under Ar was added DIPEA (0.62 mL, 3.7 mmol) followed by 37C (200 mg, 0.83 mmol) and stirred at room temperature for 23 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (hexanes:ethyl acetate 2:1) to give 38C (271.9 mg, 0.60 mmol, 73.3 %).1H NMR (600 MHz, MeOD) δ 8.33 (d, J = 8.5 Hz, 1H), 7.80 (m, 2H), 7.61 (dd, J = 2.6 Hz, 1H), 3.55 (m, 1H), 3.26 (dd, J = 7.3 Hz, 1H), 2.74-2.59 (m, 4H), 2.05 (m, 1H), 1.92 (m, 2H), 1.73 (dd, J = 6.0 Hz, 2H), 1.41 (s, 9H), 1.37 (m, 1H);13C NMR (150 MHz, MeOD) δ 157.6, 147.0, 145.8, 143.4, 133.1, 129.4, 127.9, 123.4, 122.4, 121.0, 79.9, 50.1, 49.4, 40.9, 37.9, 37.6, 37.5, 33.7, 33.6, 28.7. HRESIMS [M + H]+calcd for C22H28ClN4O4447.179359 found 447.17961. Preparation of tert-butyl ((4-(((2-chloro-3-nitroquinolin-4-yl)amino)methyl)-2- oxabicyclo[2.2.2]octan-1-yl)methyl)carbamate compound 38F:To 1 (300 mg, 1.23 mmol) in 5 mL of dichloromethane under Ar was added DIPEA (0.62 mL, 3.7 mmol) followed by 37F (200 mg, 0.73 mmol) and stirred at room temperature for 23 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (hexanes:ethyl acetate 2:1) to give 38F (297.6 mg, 0.62 mmol, 85.5 %).1H NMR (600 MHz, DMSO-d6) δ 8.43 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 3.6 Hz, 2H), 7.64 (m, 1H), 7.37 (t, J = 6.3 Hz, -NH-CH2-, 1H), 6.51 (t, J = 6.3 Hz, -NH-CH2-, 1H), 3.62 (s, 2H), 2.91 (d, J = 6.3 Hz, 2H), 2.87 (d, J = 6.3 Hz, 2H), 1.60 (m, 2H), 1.51 (m, 6H), 1.32 (s, 9H);13C NMR (150MHz, DMSO-d6) δ 155.7, 145.4, 145.1, 141.0, 132.2, 128.5, 127.0, 126.7, 123.3, 119.6, 77.4, 70.9, 70.5, 49.0, 47.4, 34.0, 28.1, 27.9, 26.8. HRESIMS [M + H]+calcd for C23H30ClN4O5 477.189924 found 477.19014. Preparation of tert-butyl ((6-(((2-chloro-3-nitroquinolin-4-yl)amino)methyl)-5- oxaspiro[3.4]octan-2-yl)methyl)carbamate compound 38D:To 1 (300 mg, 1.23 mmol) in 5 mL of dichloromethane under Ar was added DIPEA (0.62 mL, 3.7 mmol) followed by 37D (200 mg, 0.73 mmol) and stirred at room temperature for 23 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (hexanes:ethyl acetate 2:1) to give 38D (315.7 mg, 0.66 mmol, 90.7 %).1H NMR (600 MHz, MeOD) δ 8.11 (d, J = 8.4 Hz, 1H), 7.67 (m, 2H), 7.49 (p, J = 4.2 Hz, 1H), 4.15 (m, 1H), 3.29 (dd, J = 4.0 Hz, 1H), 3.17 (dd, J = 7.6 Hz, 1H), 3.0 (m, 2H), 2.08=1.86 (m, 8H), 1.58 (m, 1H), 1.38 (s, 9H);13C NMR (150 MHz, MeOD) δ 158.4, 146.7, 145.7, 143.0, 132.9, 129.3, 128.2, 127.7, 123.2, 120.5, 81.5, 79.7, 78.2, 49.6, 46.3, 40.7, 40.0, 37.3, 29.1, 28.7, 27.5. HRESIMS [M + H]+calcd for C23H30ClN4O5477.189924 found 477.19077. Preparation of tert-butyl (4-(((2-chloro-3-nitroquinolin-4-yl)amino)methyl)bicyclo [2.2.2]octan-1-yl)carbamate compound 38E:To 1 (300 mg, 1.23 mmol) in 5 mL of dichloromethane under Ar was added DIPEA (0.62 mL, 3.7 mmol) followed by 37E (200 mg, 0.78 mmol) and stirred at room temperature for 23 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (hexanes:ethyl acetate 2:1) to give 38E (304.8 mg, 0.66 mmol, 84.8 %).1H NMR (600 MHz, DMSO-d6) δ 8.44 (d, J = 8.0 Hz, 1H), 7.83 (q, J = 9.6 Hz, 1H), 7.82 (d, J = 2.1 Hz, 2H), 7.66 (m, 1H), 7.33 (t, J = 6.3 Hz, 1H), 6.33 (bs, 1H), 2.85 (d, J = 6.2 Hz, 2H), 1.69 (m, 6H), 1.43 (m, 6H), 1.33 (s, 9H);13C NMR (150 MHz, DMSO-d6) δ 154.1, 145.4, 145.2, 141.0, 132.3, 128.5, 126.8, 123.3, 119.6, 77.0, 54.9, 52.2, 49.0, 32.7, 29.6, 28.6, 28.2; HRESIMS [M + H]+calcd for C23H30ClN4O4461.195010 found 461.19531. Preparation of tert-butyl 5-(((2-chloro-3-nitroquinolin-4- yl)amino)methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate compound 38G:To 1 (300 mg, 1.23 mmol) in 5 mL of dichloromethane under Ar was added DIPEA (0.62 mL, 3.7 mmol) followed by 37G (200 mg, 0.83 mmol) and stirred at room temperature for 23 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (hexanes:ethyl acetate 2:1) to give 38G (283.4 mg, 0.634 mmol, 76.4 %).1H NMR (600 MHz, DMSO-d6) δ 8.48 (d, J = 8.4 Hz, 1H), 7.86 (t, J = 5.5 Hz, 1H), 7.81 (m, 1H), 7.81 (d, J = 6.3 Hz, 1H), 7.64 (m, 1H), 3.30 (m, 2H), 3.12 (t, J = 7.2 Hz, 2H), 3.08 (m, 2H), 2.53 (bs, 2H), 2.30 (m, 1H), 1.99 (m, 2H), 1.36 (s, 9H), 1.02 (m, 2H);13C NMR (150 MHz, DMSO- d6) δ 153.6, 145.2, 144.2, 141.0, 132.1, 128.5, 126.7, 126.2, 122.9, 119.5, 78.1, 59.7, 51.4, 48.4, 41.7, 35.9, 28.1, 20.7, 14.0; HRESIMS [M + H]+calcd for C22H28ClN4O4447.179359 found 447.17941. Preparation of tert-butyl ((3S,3aR,6S,6aR)-6-((3-amino-2-chloroquinolin-4- yl)amino)hexahydrofuro[3,2-b]furan-3-yl)carbamate compound 39A:To 38A (259.7 mg, 0.57 mmol) in 3 mL of ethyl acetate was added 10% Pd / C (100 mg) and exposed to H2(balloon) and allowed to stir at room temperature for 3 h. The reaction mixture was then filtered and concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 95:5) to give 39A (134.5 mg, 0.31 mmol, 56.1 %). 1H NMR (600 MHz, DMSO-d6) δ 8.02 (m, 1H), 7.73 (m, 1H), 7.44 (m, 2H), 7.20 (d, J = 6.9 Hz, 1H), 5.25 (s, 1H), 5.23 (s, 2H), 4.65 (d, J = 4.1 Hz, 1H), 4.40 (d, J = 5.1 Hz, 1H), 4.07 (m, 1H), 3.94 (dd, J = 9.4, 5.4 Hz, 1H), 3.90 (bs, 1H), 3.80 (dd, J = 9.2, 5.4 Hz, 1H), 3.75 (dd, J = 9.3, 3.3 Hz, 1H), 3.54 (dd, J = 9.3, 3.0 Hz, 1H), 1.37 (s, 9H);13C NMR (150 MHz, DMSO-d6) δ 155.1,141.1, 140.7, 133.8, 130.3, 128.1, 125.8, 125.7, 124.0, 121.9, 86.79, 86.70, 78.0, 72.0, 71.5, 62.2, 57.1, 28.1. HRESIMS [M + H]+calcd for C20H26ClN4O4421.163709 found 421.16442. Preparation of tert-butyl 6-(((3-amino-2-chloroquinolin-4-yl)amino)methyl)-2- azaspiro[3.3]heptane-2-carboxylate compound 39B:To 38B (311.6 mg, 0.72 mmol) in 5 mL of ethyl acetate was added 10% Pd / C (100 mg) and exposed to H2(balloon) and allowed to stir at room temperature for 3 h. The reaction mixture was then filtered and concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 95:5) to give 39B (161.2 mg, 0.40 mmol, 55.6 %).1H NMR (600 MHz, DMSO-d6) δ 7.99 (m, 1H), 7.67 (m, 1H), 7.4 (m, 2H), 5.22 (t, J = 6.7 Hz, 1H), 5.02 (s, 2H), 3.75 (bs, 2H), 3.68 (bs, 2H), 3.20 (t, J = 7.0 Hz, 2H), 2.2 (septet, J = 7.6 Hz, 1H), 2.10 (m, 2H), 1.83 (m, 2H), 1.33 (s, 9H);13C NMR (150 MHz, DMSO-d6) δ 155.3, 140.9, 140.8, 136.4, 128.6, 128.0, 125.7, 125.1, 123.1, 122.0, 78.2, 51.8, 36.2, 33.8, 29.9, 28.0; HRESIMS [M + H]+calcd for C21H28ClN4O2403.189530 found 403.19092. Preparation of tert-butyl (3-(((3-amino-2-chloroquinolin-4-yl)amino)methyl)bicyclo [3.2.0]heptan-6-yl)carbamate compound 39C:To 38C (271.9 mg, 0.60 mmol) in 3 mL of ethyl acetate was added 10% Pd / C (100 mg) and exposed to H2(balloon) and allowed to stir at room temperature for 3 h. The reaction mixture was then filtered and concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 95:5) to give 39C (188.8 mg, 0.45 mmol, 75.5 %).1H NMR (600 MHz, DMSO-d6) δ 8.04 (m, 1H), 7.67 (m, 1H), 7.40 (m, 2H), 7.10 (d, J = 7.0 Hz, 1H), 5.20 (t, J = 6.6 Hz, 1H), 5.06 (s, 2H), 3.42 (bs, 1H), 3.25 (t, J = 6.6 Hz, 2H), 2.53 (m, 2H), 2.00 (m, 1H), 1.78 (dd, J = 12.3, 5.4 Hz, 1H), 1.71 (m, 1H), 1.61 (dd, J = 12.3, 6.4 Hz 1H), 1.38-1.31 (m, 2H), 1.35 (s, 9H), 1.11 (m, 1H);13C NMR (150 MHz, DMSO-d6) δ 154.5, 141.0, 140.8, 137.1, 128.1, 128.0, 125.6, 125.0, 122.8, 122.2, 77.3, 51.9, 48.5, 46.6, 40.6, 36.9, 36.5, 32.4, 32.0, 28.2; HRESIMS [M + H]+calcd for C22H30ClN4O2417.205180 found 417.20681. Preparation of tert-butyl ((4-(((3-amino-2-chloroquinolin-4-yl)amino)methyl)-2- oxabicyclo[2.2.2]octan-1-yl)methyl)carbamate compound 39F:To 38F (297.6 mg, 0.62 mmol) in 5 mL of ethyl acetate was added 10% Pd / C (100 mg) and exposed to H2(balloon) and allowed to stir at room temperature for 3 h. The reaction mixture was then filtered and concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 95:5) to give 39F (226.9 mg, 0.50 mmol, 81.9 %).1H NMR (600 MHz, DMSO-d6) δ 7.96 (m, 1H), 7.69 (m, 1H), 7.41 (m, 2H), 6.53 (t, J = 6.3 MHz, 1H), 5.05 (s, 2H), 4.93 (t, J = 6.9 Hz, 1H), 3.63 (s, 2H), 3.02 (d, J = 6.7 Hz, 2H), 2.87 (d, J = 6.4 Hz, 2H), 1.58 (m, 4H), 1.52 (m, 4H), 1.35 (s, 9H);13C NMR (150 MHz, DMSO-d6) δ 155.7, 144.2, 141.2, 137.3, 128.2, 128.1, 125.7, 125.1, 122.7, 122.2, 77.4, 71.0, 70.9, 53.3, 47.5, 34.3, 28.2, 28.1, 27.1; HRESIMS [M + H]+calcd for C23H32ClN4O3447.215745 found 447.21750. Preparation of tert-butyl ((6-(((3-amino-2-chloroquinolin-4-yl)amino)methyl)-5- oxaspiro[3.4]octan-2-yl)methyl)carbamate compound 39D:To 38D (315.7 mg, 0.66 mmol) in 5 mL of ethyl acetate was added 10% Pd / C (100 mg) and exposed to H2(balloon) and allowed to stir at room temperature for 3 h. The reaction mixture was then filtered and concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 95:5) to give 39D (260.4 mg, 0.58 mmol, 88.3 %).1H NMR (600 MHz, DMSO-d6) δ 8.07 (m, 1H), 7.67 (m, 1H), 7.40 (m, 2H), 6.81 (t, J = 5.8 Hz, 1H), 5.25 (bs, 1H), 5.16 (bs, 2H), 3.97 (quin, J = 6.7 Hz, 1H), 3.20 (m, 2H), 2.95 (m, 2H), 1.97 (m, 2H), 1.85 (m, 4H), 1.78 (m, 2H), 1.60 (m, 1H), 1.36 (s, 9H);13C NMR (150 MHz, DMSO-d6) δ 154.1, 139.2, 139.1, 134.5, 127.0, 126.3, 124.0, 123.6, 121.4, 120.1, 80.1, 77.6,76.3, 75.7, 49.2, 43.5, 37.3, 34.7, 26.6, 26.2, 24.3; HRESIMS [M + H]+calcd for C23H34ClN4O3447.215745 found 447.217981. Preparation of tert-butyl (4-(((3-amino-2-chloroquinolin-4-yl)amino)methyl)bicyclo [2.2.2]octan-1-yl)carbamate compound 39E:To 38E (304.8 mg, 0.66 mmol) in 5 mL of ethyl acetate was added 10% Pd / C (100 mg) and exposed to H2(balloon) and allowed to stir at room temperature for 3 h. The reaction mixture was then filtered and concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 95:5) to give 39E (179.4 mg, 0.41 mmol, 63.1 %).1H NMR (600 MHz, DMSO-d6) δ 7.95 (m, 1H), 7.67 (m, 1H), 7.40 (m, 2H), 6.32 (bs, 1H), 5.01 (s, 2H), 4.86 (t, J = 6.5 Hz, 1H), 2.97 (d, J = 6.5 H, 2H), 1.69 (m, 6H), 1.47 (m, 6H), 1.34 (s, 9H);13C NMR (150 MHz, DMSO-d6) δ 154.6, 141.7, 141.5, 138.4, 128.5, 128.4, 126.2, 125.4, 123.0, 122.9, 77.5, 57.2, 55.3, 49.7, 33.3, 30.3, 29.2, 28.7; HRESIMS [M + H]+calcd for C23H32ClN4O2431.220830 found 431.22077. Preparation of tert-butyl 5-(((3-amino-2-chloroquinolin-4- yl)amino)methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate compound 39G:To 38G (283.4 mg, 0.634 mmol) in 5 mL of ethyl acetate was added 10% Pd / C (100 mg) and exposed to H2(balloon) and allowed to stir at room temperature for 3 h. The reaction mixture was then filtered and concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 95:5) to give 39G (199.8 mg, 0.47 mmol, 75.6 %).1H NMR (600 MHz, DMSO-d6) δ 8.01 (m, 1H), 7.67 (m, 1H), 7.40 (m, 2H), 5.28 (t, J = 6.7 Hz, 1H), 5.00 (s, 1H), 3.41 (t, J = 8.4 Hz, 1H), 3.31 (m, 2H), 3.25 (t, J = 6.9 Hz, 2H), 3.17 (t, J = 6.0 Hz, 1H), 3.06 (dd, J = 10.8, 3.7 Hz, 2H), 2.62 (bs, 1H), 2.12 (m, 1H), 1.96 (m, 1H), 1.57 (m, 1H), 1.46 (m, 1H), 1.36 (s, 9H), 1.04 (m, 1H);13C NMR (150 MHz, DMSO-d6) δ 153.6, 141.0, 136.8, 128.1, 128.0, 125.7, 125.1, 122.8, 122.1, 78.1, 51.9, 51.6, 43.1, 36.3, 36.2, 28.1; HRESIMS [M + H]+calcd for C22H30ClN4O2417.205180 found 417.20518. Preparation of tert-butyl ((6-(((2-chloro-3-pentanamidoquinolin-4-yl)amino)methyl)- 5-oxaspiro[3.4]octan-2-yl)methyl)carbamate compound 40D:To 39D (260.4 mg, 0.58 mmol) in 5 mL of tetrahydrofuran under Ar was added DIPEA (0.15 mL, 0.87 mmol) followed by 5 (0.076 mL, 0.63 mmol) and allowed to stir at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 97.5:2.5) to give 40D (60.0 mg, 0.11 mmol, 19.5 %).1H NMR (600 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.25 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.66 (t, J = 6.7 Hz, 1H), 7.49 (t, J = 8.4 Hz, 1H), 6.81 (t, J = 5.9 Hz, 1H), 6.55 (t, J = 6 Hz, 1H), 4.09 (m, 1H), 3.45 (m, 2H), 2.93 (m, 2H), 2.35 (t, J = 7.4 Hz, 2H), 1.97 (m, 2H), 1.93-1.74 (m, 6H), 1.62 (m, 3H), 1.40 (m, 2H), 1.36 (s, 9H), 0.92 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 172.7, 155.7, 152.0, 149.6, 145.7, 129.9, 128.1, 125.0, 122.6, 120.1, 109.4, 79.3, 77.3, 77.1, 59.7, 49.9, 45.1, 39.5, 36.1, 35.0, 28.2, 28.0, 26.9, 26.0, 22.0, 13.7; HRESIMS [M + H]+calcd for C28H40ClN4O4531.273260 found 531.27486. Preparation of tert-butyl (4-(((2-chloro-3-pentanamidoquinolin-4-yl)amino)methyl) bicyclo[2.2.2]octan-1-yl)carbamate compound 40E:To 39E (179.4 mg, 0.41 mmol) in 5 mL of tetrahydrofuran under Ar was added DIPEA (0.10 mL, 0.61 mmol) followed by 5 (0.053 mmol, 0.45 mmol) and allowed to stir at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 97.5:2.5) to give 40E (60.6 mg, 0.11 mmol, 28.7 %).1H NMR (600 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.22 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.67 (t, J = 6.8 Hz, 1H), 7.49 (t, J = 8.4 Hz, 1H), 6.34 (bs, 1H), 5.83 (t, J = 5.9 Hz, 1H), 3.27 (d, J = 5.8 Hz, 2H), 2.36 (t, J = 7.3 Hz, 2H), 1.70 (m, 6H), 1.61 (quin, J = 7.5 Hz, 2H), 1.43 (m, 6H), 1.38 (sex, J = 7.4 Hz, 2H), 1.34 (s, 9H), 0.92 (t, J = 7.2 Hz, 3H);13CNMR (150 MHz, DMSO-d6) δ 172.2, 151.5, 150.5, 145.9, 129.9, 128.1, 125.0, 123.1, 120.2, 120.1, 110.6, 77.0, 54.5, 49.1, 35.0, 32.7, 29.8, 28.7, 28.2, 27.1, 21.9, 13.7; HRESIMS [M + H]+calcd for C28H39ClN4O3515.278345 found 515.27833. Preparation of tert-butyl ((4-(((2-chloro-3-pentanamidoquinolin-4-yl)amino)methyl)- 2-oxabicyclo[2.2.2]octan-1-yl)methyl)carbamate compound 40F:To 39F (226.9 mg, 0.50 mmol) in 5 mL of tetrahydrofuran under Ar was added DIPEA (0.13 mL, 0.75 mmol) followed by 5 (0.065 mL, 0.55 mmol) and allowed to stir at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 97.5:2.5) to give 40F (98.7 mg, 0.18 mmol, 37.2 %).1H NMR (600 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.23 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 6.9 Hz, 1H), 7.68 (t, J = 6.8 Hz, 1H), 7.52 (t, J = 8.4 Hz, 1H), 6.59 (t, J = 6.3 Hz, 1H), 6.07 (t, J = 6.1 Hz, 1H), 3.58 (s, 2H), 3.31 (d, J = 6.12 Hz, 2H), 2.8 (d, J = 6.3 Hz, 2H), 2.36 (t, J = 7.3 Hz, 2H), 1.61 (quin, J = 7.3 Hz, 2H), 1.56 (m, 2H), 1.50 (m, 6H), 1.36 (sex, J = 7.5 Hz, 2H), 1.35 (s, 9H), 0.92 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 172.3, 155.7, 151.7, 150.2, 145.7, 130.0, 128.1, 125.1, 123.0, 120.3, 110.6, 77.4, 71.0, 70.8, 50.9, 47.4, 35.0, 34.3 ,28.2, 28.0, 27.1, 26.9, 21.9, 13.7 ; HRESIMS [M + H]+calcd for C28H40ClN4O4531.273260 found 531.27481. Preparation of tert-butyl 5-(((2-chloro-3-pentanamidoquinolin-4- yl)amino)methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate compound 40G:To 39G (199.8 mg, 0.47 mmol) in 5 mL of tetrahydrofuran under Ar was added DIPEA (0.12 mL, 0.70 mmol) followed by 5 (0.061 mL, 0.51 mmol) and allowed to stir at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 97.5:2.5) to give 40G (74.6 mg, 0.14 mmol, 31.7 %).1H NMR (600 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.26 (d, J = 7.2 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 6.7 Hz, 1H), 7.49 (t, J = 6.5 Hz, 1H), 6.72 (t, J = 6.0 Hz, 1H), 3.34, (m, 6H), 3.44 (t, J = 6.1 Hz, 2H), 3.09 (d, J = 11.1 Hz, 2H), 2.52 (bs, 1H), 2.33 (t, J = 7.3 Hz, 2H), 1.98 (m, 1H), 1.60 (quin, J = 7.5 Hz, 2H), 1.37 (s, 9H), 1.35 (m, 2H), 1.02 (m, 1H), 0.91 (t, J = 7.2 Hz, 3H) ;13C NMR (150 MHz, DMSO-d6) δ 172.5, 153.6, 152.3, 149.3, 145.6 ,129.9, 128.0, 124.9, 122.4, 120.2, 108.8, 78.1, 50.2, 42.1, 38.6, 36.0, 35.8, 34.9, 28.1, 27.0, 22.0, 13.7; HRESIMS [M + H]+calcd for C27H37ClN4O3501.262695 found 501.26478. Preparation of tert-butyl ((3S,3aR,6S,6aR)-6-((2-chloro-3-pentanamidoquinolin-4- yl)amino)hexahydrofuro[3,2-b]furan-3-yl)carbamate compound 40A:To 39A (134.5 mg, 0.31 mmol) in 3 mL of tetrahydrofuran under Ar was added DIPEA (0.080 mL, 0.46 mmol) followed by 5 (0.040 mL, 0.34 mmol) and allowed to stir at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 97.5:2.5) to give 40A (26.3 mg, 0.052 mmol, 16.8 %). HRESIMS [M + H]+calcd for C25H34ClN4O5505.221334 found 505.22241. Preparation of tert-butyl 6-(((2-chloro-3-pentanamidoquinolin-4-yl)amino)methyl)- 2-azaspiro[3.3]heptane-2-carboxylate compound 40B:To 39B (161.2 mg, 0.40 mmol) in 5 mL of tetrahydrofuran under Ar was added DIPEA (0.10 mL, 0.60 mmol) followed by 5 (0.052 mL, 0.44 mmol) and allowed to stir at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 97.5:2.5) to give 40B (57.6 mg, 0.11 mmol, 29.6 %). HRESIMS [M + H]+calcd for C26H36ClN4O3487.247045 found 487.24856. Preparation of tert-butyl (3-(((2-chloro-3-pentanamidoquinolin-4-yl)amino)methyl) bicyclo[3.2.0]heptan-6-yl)carbamate compound 40C:To 39C (188.8 mg, 0.45 mmol) in 5 mL of tetrahydrofuran under Ar was added DIPEA (0.11 mL, 0.67 mmol) followed by 5 (0.058 mL, 0.49 mmol) and allowed to stir at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 97.5:2.5) to give 40C (51.4 mg, 0.10 mmol, 22.8 %). HRESIMS [M + H]+calcd for C27H38ClN4O3501.262695 found 501.26467. Preparation of tert-butyl (3-((4-chloro-2-propyl-1H-imidazo[4,5-c]quinolin-1- yl)methyl)bicyclo[3.2.0]heptan-6-yl)carbamate compound 41C:To 40C (51.4 mg, 0.10 mmol) in 5 mL of ethanol under Ar was added 5M NaOH (1.0 mL, 5.0 mmol) and allowed to stir at room temperature for 72 h. The reaction mixture was then diluted with 100 mL of water and the aqueous phase was extracted three times with methylene chloride (100 mL). The combined organic extracts were washed with 50 mL of brine then dried with MgSO4and concentrated using a rotary evaporator. The crude mixture was purified usingflash column chromatography (dichloromethane:methanol 95:5) to give 41C (39.8 mg, 0.084 mmol, 84.9 %).1H NMR (600 MHz, DMSO-d6) δ 8.45 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 9.6 Hz, 1H), 7.75 (m, 2H), 7.06 (d, J = 6.8 Hz, 1H), 4.73 (d, J = 5.0 Hz, 2H), 3.17 (m, 1H), 3.00 (t, J = 7.3 Hz, 2H), 2.71 (m, 1H), 2.61 (m, 1H), 2.53 (m, 1H), 1.93 (m, 1H), 1.86 (quin, J = 7.7 Hz, 2H), 1.58 (m, 2H), 1.51-1.43 (m, 3H), 1.29 (s, 9H), 1.22 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H) ;13C NMR (150 MHz, DMSO-d6) δ 156.3, 154.4, 143.0, 142.4, 134.8, 132.9, 129.3, 127.6, 126.9, 121.0, 117.3, 77.4, 48.6, 48.3, 46.3, 40.0, 35.8, 35.6, 31.8, 29.2, 28.2, 26.4, 21.9, 13.8; HRESIMS [M + H]+calcd for C27H35ClN4O2483.252131 found 483.25357. Preparation of tert-butyl ((3S,3aR,6S,6aR)-6-(4-chloro-2-propyl-1H-imidazo[4,5- c]quinolin-1-yl)hexahydrofuro[3,2-b]furan-3-yl)carbamate compound 41A:To 40A (26.3 mg, 0.052 mmol) in 5 mL of ethanol under Ar was added 5M NaOH (0.53 mL, 2.6 mmol) and allowed to stir at room temperature for 72 h. The reaction mixture was then diluted with 100 mL of water and the aqueous phase was extracted three times with methylene chloride (100 mL). The combined organic extracts were washed with 50 mL of brine then dried with MgSO4and concentrated using a rotary evaporator. The crude mixture was purified using flash column chromatography (dichloromethane:methanol 95:5) to give 41A (23.5 mg, 0.049 mmol, 95.6 %).1H NMR (600 MHz, DMSO-d6) δ 8.39 (m, 1H), 8.11 (d, J = 7.5 Hz, 1H), 7.77 (m, 2H), 7.27 (d, J = 6.7 Hz, 1H), 5.63 (bs, 1H), 5.13 (s, 1H), 4.92 (s, 1H), 4.49 (dd, J = 10.6, 8.0 Hz, 1H), 4.31 (dd, J = 10.6, 6.4 Hz, 1H), 4.14 (9.3, 4.7 Hz, 1H), 4.04 (bs, 1H), 3.78 (d, J = 9.3 Hz, 1H), 3.0 (m, 2H), 1.88 (m, 2H), 1.47 (sex, J = 7.3 Hz, 2H), 1.38 (s, 9H), 0.97 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 156.3, 155.0, 143.3, 142.6, 135.2, 132.9, 129.6, 127.6,127.0, 121.2, 117.2, 87.3, 86.6, 78.2, 71.7, 70.0, 57.0, 40.0, 29.7, 28.1, 27.5, 21.9, 13.7; HRESIMS [M + H]+calcd for C25H34ClN4O4487.210660 found 487.21160. Preparation of tert-butyl ((6-((4-chloro-2-propyl-1H-imidazo[4,5-c]quinolin-1- yl)methyl)-5-oxaspiro[3.4]octan-2-yl)methyl)carbamate compound 41D:To 40D (60.0 mg, 0.11 mmol) in 5 mL of ethanol under Ar was added 5M NaOH (1.1 mL, 5.5 mmol) and allowed to stir at room temperature for 72 h. The reaction mixture was then diluted with 100 mL of water and the aqueous phase was extracted three times with methylene chloride (100 mL). The combined organic extracts were washed with 50 mL of brine then dried with MgSO4and concentrated using a rotary evaporator. The crude mixture was purified using flash column chromatography (dichloromethane:methanol 95:5) to give 41D (53.7 mg, 0.10 mmol, 98.0 %).1H NMR (600 MHz, MeOD) δ 8.21 (d, J = 8.6 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.59 (m, 2H), 4.86 (s, 2H), 4.77 (dd, J = 15.6, 2.8 Hz, 1H), 4.53 (dd, J = 15.6, 8.5 Hz, 1H), 4.37 (m, 1H), 3.07 (m, 2H), 2.94 (m, 2H), 2.21 (sep, J = 6.4 Hz, 1H), 2.02 (m, 1H), 1.96 (m, 3H), 1.89 (m, 2H), 1.82 (dd, J = 12.5, 7.5 Hz, 1H), 1.77 (m, 1H), 1.68 (m, 1H), 1.53 (sex, J = 7.4 Hz, 2H), 1.37 (s, 9H), 1.03 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, MeOD) δ 159.2, 158.5, 144.7, 143.8, 136.5, 133.9, 129.8, 128.8, 127.9, 122.0, 118.6, 81.7, 79.7, 78.4, 51.5, 46.3, 40.3, 40.2, 37.4, 30.9, 29.2, 28.7, 28.3, 27.5, 23.7, 14.2; HRESIMS [M + H]+calcd for C28H38ClN4O3513.262695 found 513.26448. Preparation of tert-butyl 6-((2-butyl-4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)- 2-azaspiro[3.3]heptane-2-carboxylate compound 41B:To 40B (57.6 mg, 0.11 mmol) in 5 mL of ethanol under Ar was added 5M NaOH (1.1 mL, 5.5 mmol) and allowed to stir at room temperature for 72 h. The reaction mixture was then diluted with 100 mL of water and the aqueous phase was extracted three times with methylene chloride (100 mL). The combined organic extracts were washed with 50 mL of brine then dried with MgSO4and concentrated using a rotary evaporator. The crude mixture was purified using flash column chromatography (dichloromethane:methanol 95:5) to give 41B (45.2 mg, 0.096 mmol, 87.7 %).1H NMR (600 MHz, MeOD) δ 8.32 (m, 1H), 8.08 (m, 1H), 7.74 (m, 2H), 4.73 (d, J = 6.7 Hz, 2H), 3.88 (s, 2H), 3.79 (s, 2H), 3.08 (m, 2H), 2.83 (quin, J = 8.0 Hz, 1H), 2.28 (m, 2H), 2.12 (m, 2H), 1.89 (quin, J = 7.7 Hz, 2H), 1.52 (sex, J = 7.5 Hz, 2H), 1.39 (s, 9H), 1.03 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, MeOD) δ 158.5, 158.0, 144.9, 144.0, 136.5, 134.1, 130.1, 129.1, 128.3, 122.0, 118.8, 80.9, 50.9, 49.5, 37.3, 35.3, 31.4, 31.1, 28.5, 28.1, 23.5, 14.1; HRESIMS [M + H]+calcd for C26H34ClN4O2469.236480 found 469.23748. Preparation of tert-butyl (4-((2-butyl-4-chloro-1H-imidazo[4,5-c]quinolin-1- yl)methyl)bicyclo[2.2.2]octan-1-yl)carbamate compound 41E:To 40E (60.6 mg, 0.11 mmol) in 5 mL of ethanol under Ar was added 5M NaOH (1.1 mL, 5.5 mmol) and allowed to stir at room temperature for 72 h. The reaction mixture was then diluted with 100 mL of water and the aqueous phase was extracted three times with methylene chloride (100 mL). The combined organic extracts were washed with 50 mL of brine then dried with MgSO4and concentrated using a rotary evaporator. The crude mixture was purified using flash column chromatography (dichloromethane:methanol 95:5) to give 41E (43.7 mg, 0.088 mmol, 80.1 %).1H NMR (600 MHz, DMSO-d6) δ 8.59 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 10.3 Hz, 1H), 7.67 (m, 2H), 6.27 (bs, 1H), 4.81 (d, J = 15.8 Hz, 1H), 4.29 (d, J = 15.7 Hz, 1H), 2.99 (q, J = 8.4 Hz, 2H), 1.79 (m, 2H), 1.61 (m 6H), 1.54 (m, 3H), 1.43 (m, 5H), 1.29 (s, 9H), 0.92 (t, J = 7.2 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 157.6, 143.1, 142.5, 135.8, 132.7, 129.2, 127.4, 126.1, 121.9, 117.8, 77.0, 59.7, 53.4, 48.6, 34.8, 29.8, 29.6, 29.1, 28.2, 27.1, 21.8, 13.7; HRESIMS [M + H]+calcd for C28H38ClN4O2497.267781 found 497.26813. Preparation of tert-butyl ((4-((2-butyl-4-chloro-1H-imidazo[4,5-c]quinolin-1- yl)methyl)-2-oxabicyclo[2.2.2]octan-1-yl)methyl)carbamate compound 41F:To 40F (98.7 mg, 0.18 mmol) in 10 mL of ethanol under Ar was added 5M NaOH (1.80 mL, 9.0 mmol) and allowed to stir at room temperature for 72 h. The reaction mixture was then diluted with 100 mL of water and the aqueous phase was extracted three times with methylene chloride (100 mL). The combined organic extracts were washed with 50 mL of brine then dried with MgSO4and concentrated using a rotary evaporator. The crude mixture was purified using flash column chromatography (dichloromethane:methanol 95:5) to give 41F (74.6 mg, 0.14 mmol, 80.8 %).1H NMR (600 MHz, DMSO-d6) δ 8.59 (d, J = 8.1 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.69 (m, 2H), 6.53 (t, J = 6.4 Hz, 1H), 4.87 (d, J = 16.0 Hz, 1H), 4.37 (d, J = 16.0 Hz, 1H), 3.69 (m, 1H), 3.59 (m, 1H), 2.95 (m, 2H), 2.76 (d, J = 3.9 Hz, 2H), 1.82 (m, 2H), 1.60 (m, 1H), 1.52 (m, 5H), 1.43 (m, 4H), 1.21 (s, 9H), 0.94 (t, J = 7.4 Hz, 3H);13C NMR (150 MHz, DMSO- d6) δ 157.5, 155.7, 143.1, 142.5, 135.7, 132.7, 129.2, 127.5, 126.2, 121.8, 117.7, 77.4, 70.7, 70.5, 59.7, 50.5, 47.2, 36.0, 29.7, 28.1, 27.9, 27.2, 27.1, 26.8, 21.8, 20.7, 14.0, 13.8; HRESIMS [M + H]+calcd for C28H38ClN4O3513.262695 found 513.26295. Preparation of tert-butyl 5-((2-butyl-4-chloro-1H-imidazo[4,5-c]quinolin-1- yl)methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate compound 41G:To 40G (74.6 mg, 0.14 mmol) in 5 mL of ethanol under Ar was added 5M NaOH (1.4 mL, 7 mmol) and allowed to stir at room temperature for 72 h. The reaction mixture was then diluted with 100 mL of water and the aqueous phase was extracted three times with methylene chloride (100 mL). The combined organic extracts were washed with 50 mL of brine then dried with MgSO4and concentrated using a rotary evaporator. The crude mixture was purified using flash column chromatography (dichloromethane:methanol 95:5) to give 41G (54.9 mg, 0.11 mmol, 81.2 %).1H NMR (600 MHz, DMSO-d6) δ 8.33 (m, 1H), 8.06 (m, 1H), 7.72 (m, 2H), 4.70 (d, J = 7.5 Hz, 2H), 3.31 (m, 3H), 3.16 (d, J = 7.8 Hz, 2H), 3.00 (t, J = 7.3 Hz, 2H), 2.44 (m, 2H), 1.89 (bs, 2H), 1.85 (quin, J = 7.6 Hz, 2H), 1.47 (sex, J = 7.5 Hz, 2H), 1.39 (s, 9H), 1.30 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 156.3, 153.6, 143.0, 142.3, 134.7, 132.9, 129.2, 127.5, 126.9, 121.0, 117.3, 78.1, 51.3, 48.9, 42.6, 35.7, 29.2, 28.1, 26.4, 21.8, 13.8; HRESIMS [M + H]+calcd for C27H36ClN4O2483.252131 found 483.25240. Preparation of tert-butyl ((6-((2-butyl-4-((2,4-dimethoxybenzyl)amino)-1H- imidazo[4,5-c]quinolin-1-yl)methyl)-5-oxaspiro[3.4]octan-2-yl)methyl)carbamate compound 42D:To 41D (53.7 mg, 0.10 mmol) under Ar was added 8 (1.5 mL, 10.0 mmol) and heated to 120 °C for 24 h. The reaction mixture was dissolved with 50 mL of dichloromethane and washed with saturated NH4Cl (50mL) then dried with MgSO4and concentrated using a rotary evaporator. The crude mixture was purified using flash column chromatography (dichloromethane:methanol 95:5) to give 42D (48.3 mg, 0.075 mmol, 75.1 %).1H NMR (600 MHz, MeOD) δ 8.39 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.95 (bs, 1H), 7.64 (t, J = 8.1 Hz, 1H), 7.51 (t, J = 8.3 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 2.3 Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H), 4.83 (bs, 1H), 4.74 (dd, J = 15.6, 2.7 Hz, 1H), 4.50 (dd, J = 15.7, 8.8 Hz, 1H), 4.37 (m, 1H), 3.80 (s, 3H), 3.72 (s, 3H), 3.01 (m, 1H), 2.94 (m, 3H), 2.23 (sex, J = 6.5 Hz, 1H), 2.06 (m, 1H), 2.00 (m, 3H), 1.89 (m, 3H), 1.84 (dd, J = 12.5, 7.2 Hz, 1H), 1.77 (t, J = 9.1 Hz, 1H), 1.68 (t, J = 11.0 Hz, 1H), 1.52 (sex, J = 7.4 Hz, 2H), 1.38 (s, 9H), 1.00 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, MeOD) δ 168.1, 162.7, 159.9, 158.6, 158.59, 158.54, 148.7, 131.3, 130.2, 126.0, 125.9, 122.9, 105.6, 99.5, 81.8, 79.8, 79.7, 78.4, 56.0, 55.8, 51.3, 46.4, 40.4, 40.2, 37.3, 30.0, 29.2, 28.7, 28.1, 27.5, 23.5, 14.3 ; HRESIMS [M + H]+calcd for C37H50N5O4644.380646 found 644.38221. Preparation of tert-butyl ((3S,3aR,6S,6aR)-6-(2-butyl-4-((2,4- dimethoxybenzyl)amino)-1H-imidazo[4,5-c]quinolin-1-yl)hexahydrofuro[3,2-b]furan-3- yl)carbamate compound 42A:To 41A (23.5 mg, 0.049 mmol) under Ar was added 8 (0.73 mL, 4.9 mmol) and heated to 120 °C for 24 h. The reaction mixture was dissolved with 50 mL of dichloromethane and washed with saturated NH4Cl (50mL) then dried with MgSO4and concentrated using a rotary evaporator. The crude mixture was purified using flash column chromatography (dichloromethane:methanol 95:5) to give 42A (17.4 mg, 0.028 mmol, 57.5 %). HRESIMS [M + H]+calcd for C34H44N5O6618.328611 found 618.32942. Preparation of tert-butyl (3-((2-butyl-4-((2,4-dimethoxybenzyl)amino)-1H- imidazo[4,5-c]quinolin-1-yl)methyl)bicyclo[3.2.0]heptan-6-yl)carbamate compound 42C:To 41C (39.8 mg, 0.084 mmol) under Ar was added 8 (1.2 mL, 8.4 mmol) and heated to 120 °C for 24 h. The reaction mixture was dissolved with 50 mL of dichloromethane and washedwith saturated NH4Cl (50mL) then dried with MgSO4and concentrated using a rotary evaporator. The crude mixture was purified using flash column chromatography (dichloromethane:methanol 95:5) to give 42C (37.1 mg, 0.060 mmol, 72.0 %).1H NMR (600 MHz, MeOD) δ 8.47 (bs, 1H), 8.23 (d, J = 8.1 Hz, 1H), 7.94 (m, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.50 (dd, J = 8.3, 2.4 Hz, 1H), 4.64 (m, 2H), 3.84 (s, 3H), 3.77 (s, 3H), 3.75 (m, 1H), 2.97 (t, J = 7.5 Hz, 2H), 2.81 (m, 1H), 2.75 (m, 1H), 2.62 (m, 1H), 2.00 (m, 1H), 1.88 (quin, J = 7.6 Hz, 2H), 1.76 (m, 1H), 1.72 (m, 1H), 1.65 (dd, J = 12.7, 6.2 Hz, 1H), 1.56 (dd, J = 12.7, 7.7 Hz, 1H), 1.49 (m, 3H), 1.36 (s, 9H), 1.27 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, MeOD) δ 169.2, 162.6, 160.0, 157.5, 157.1, 149.6, 135.0, 131.5, 129.7, 126.7, 125.4, 122.8, 122.2, 118.3, 115.2, 105.6, 99.5, 80.0, 56.0, 55.8, 50.4, 50.0, 49.5, 41.9, 41.5, 37.4, 37.1, 33.7, 33.3, 30.6, 28.7, 28.1, 23.4, 14.2; HRESIMS [M + H]+calcd for C36H48N5O4614.370081 found 614.37141. Preparation of tert-butyl 6-((2-butyl-4-((2,4-dimethoxybenzyl)amino)-1H- imidazo[4,5-c]quinolin-1-yl)methyl)-2-azaspiro[3.3]heptane-2-carboxylate compound 42B:To 41B (45.2 mg, 0.096 mmol) under Ar was added 8 (1.44 mL, 9.6 mmol) and heated to 120 °C for 24 h. The reaction mixture was dissolved with 50 mL of dichloromethane and washed with saturated NH4Cl (50mL) then dried with MgSO4and concentrated using a rotary evaporator. The crude mixture was purified using flash column chromatography(dichloromethane:methanol 95:5) to give 42B (40.5 mg, 0.067 mmol, 70.4 %).1H NMR (600 MHz, MeOD) δ 8.43 (s, 2H), 8.13 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.64 (t, J = 8.4 Hz, 1H), 7.51 (t, J = 8.3 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 2.3 Hz, 1H), 6.52 (dd, J = 8.2, 2.3 Hz, 1H), 4.64 (d, J = 6.6 Hz, 2H), 3.89 (m, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 3.77 (m, 2H), 2.98 (t, J = 7.4 Hz, 2H), 2.79 (quin, 1H), 2.27 (m, 2H), 2.09 (m, 2H), 1.88 (quin, J = 7.8 Hz, 2H), 1.52 (sex, J = 7.5 Hz, 2H), 1.39 (s, 9H), 1.01 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, MeOD) δ 168.7, 162.7, 160.0, 158.0, 157.2, 149.5, 131.4, 129.8, 126.6, 125.4122.3, 118.1, 115.1, 105.6, 99.5, 80.9, 56.0, 55.8, 50.6, 49.5, 41.9, 40.08, 40.00, 39.94, 39.65, 37.4, 35.3, 31.2, 30.7, 28.5, 28.0, 23.4, 14.2; HRESIMS [M + H]+calcd for C35H46N5O4600.354431 found 600.35535. Preparation of tert-butyl 5-((2-butyl-4-((2,4-dimethoxybenzyl)amino)-1H- imidazo[4,5-c]quinolin-1-yl)methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate compound 42G:To 41G (54.9 mg, 0.11 mmol) under Ar was added 8 (1.65 mL, 11.0 mmol) and heated to 120 °C for 24 h. The reaction mixture was dissolved with 50 mL of dichloromethane and washed with saturated NH4Cl (50mL) then dried with MgSO4and concentrated using a rotary evaporator. The crude mixture was purified using flash column chromatography (dichloromethane:methanol 95:5) to give 42G (40.7 mg, 0.066 mmol, 60.4 %).1H NMR (600MHz, DMSO-d6) δ 7.99 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.80 (bs, 1H), 6.57 (d, J = 2.3 Hz, 1H), 6.42 (dd, J = 8.4, 2.4 Hz, 1H), 4.67 (d, J = 6.2 Hz, 2H), 4.57 (d, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.71 (s, 3H), 3.30 (m, 4H), 3.16 (m, 2H), 2.92 (t, J = 7.4 Hz, 2H), 2.43 (m, 1H), 1.87 (bs, 2H), 1.80 (quin, J = 7.6 Hz, 2H), 1.45 (sex, J = 7.4 Hz, 2H), 1.39 (s, 9H), 1.28 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H); 13C NMR (150 MHz, DMSO-d6) δ 159.9, 158.2, 154.1, 153.6, 150.6, 145.1, 132.1, 129.1, 127.4, 127.1, 126.6, 121.6, 120.5, 115.4, 104.6, 98.7, 78.6, 55.8, 55.6, 51.8, 49.1, 43.2, 36.2, 30.1, 28.6, 26.8, 22.3, 21.5, 19.514.3; HRESIMS [M + H]+calcd for C36H48N5O4614.370081 found 614.36941. Preparation of tert-butyl ((4-((2-butyl-4-((2,4-dimethoxybenzyl)amino)-1H- imidazo[4,5-c]quinolin-1-yl)methyl)-2-oxabicyclo[2.2.2]octan-1-yl)methyl)carbamate compound 42F:To 41F (74.6 mg, 0.14 mmol) under Ar was added 8 (2.1 mL, 14.0 mmol) and heated to 120 °C for 24 h. The reaction mixture was dissolved with 50 mL of dichloromethane and washed with saturated NH4Cl (50mL) then dried with MgSO4and concentrated using a rotary evaporator. The crude mixture was purified using flash column chromatography (dichloromethane:methanol 95:5) to give 42F (48.3 mg, 0.075 mmol, 53.6 %).1H NMR (600 MHz, DMSO-d6) δ 8.22 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 6.9 Hz, 1H), 7.38 (t, J = 8.2 Hz, 1H),7.20 (t, J = 6.9 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 6.80 (t, J = 6.0 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 6.52 (t, J = 11.7 Hz, 1H), 6.42 (dd, J = 8.4 Hz, 1H), 4.71 (bs,1H), 4.67 (t, J = 5.7 Hz, 2H), 4.24 (d, J = 15.9 Hz, 1H), 3.84 (s, 3H), 3.71 (s, 3H), 3.68 (m, 1H), 3.59 (m, 1H), 2.87 (m, 2H), 2.77 (d, J = 2.4 Hz, 2H), 1.78 (sex, J = 9.9 Hz, 2H), 1.61 (m, 1H), 1.52 (m, 5H), 1.41 (m, 4H), 1.32 (s, 9H), 0.92 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 159.5, 157.8, 155.7, 154.5, 150.1, 144.8, 132.7, 128.8, 127.0, 126.6, 126.1, 121.0, 120.5, 120.0, 115.3, 104.2, 98.2, 77.4, 70.9, 70.6, 59.7, 55.4, 55.1, 50.2, 47.3, 38.3, 35.8, 30.1, 28.1, 27.9, 27.3, 27.2, 26.8, 21.9, 13.8; HRESIMS [M + H]+calcd for C37H50N5O5644.380646 found 644.38019. Preparation of tert-butyl (4-((2-butyl-4-((2,4-dimethoxybenzyl)amino)-1H- imidazo[4,5-c]quinolin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)carbamate compound 42E:To 41E (43.7 mg, 0.088 mmol) under Ar was added 8 (1.3 mL, 8.8 mmol) and heated to 120 °C for 24 h. The reaction mixture was dissolved with 50 mL of dichloromethane and washed with saturated NH4Cl (50mL) then dried with MgSO4and concentrated using a rotary evaporator. The crude mixture was purified using flash column chromatography (dichloromethane:methanol 95:5) to give 42E (28.6 mg, 0.045 mmol, 51.8 %).1H NMR (600 MHz, DMSO-d6) δ 8.23 (d, J = 8.3 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 8.2 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 6.77 (bs, 1H), 5.57 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 8.4, 2.4 Hz, 1H), 6.28 (bs, 1H), 4.66 (m, 3H), 4.19 (d, J = 15.6 Hz, 1H), 3.84 (s, 3H), 3.71 (s, 3H), 2.89 (m, 2H),1.77 (sex, J = 8.5 Hz, 2H), 1.62 (m, 6H), 1.54 (m, 3H), 1.43 (m, 3H), 1.39 (quin, J = 7.6 Hz, 2H), 1.30 (s, 9H), 0.93 (t, J = 7.2 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 159.5, 157.8, 154.6, 150.0, 144.8, 132.7, 128.9, 126.9, 126.5, 126.1, 121.1, 120.4, 120.1, 115.5, 104.2, 98.2, 77.0, 55.4, 55.1, 53.0, 48.7, 38.3, 34.7, 30.2, 29.6, 29.2, 28.2, 27.0, 21.9, 13.8; HRESIMS [M + H]+calcd for C37H50N5O4628.385732 found 628.38514. Preparation of 1-((3S,3aR,6S,6aR)-6-aminohexahydrofuro[3,2-b]furan-3-yl)-2-butyl- 1H-imidazo[4,5-c]quinolin-4-amine compound 43A:To 42A (17.4 mg, 0.028 mmol) under Ar was added 1 mL of dichloromethane followed by trifluoroacetic acid (1.0 mL, 13.0 mmol) and allowed to stir at room temperature for 24 h. The reaction mixture was then concentrated under reduced pressure and loaded on to a 5.5 g RediSep Gold® C18 Reversed Phase Column and purified using a gradient from 100% H2O (0.1 % formic acid) to 100% MeCN (0.1 % formic acid) over 30 minutes using a Teledyne Isco CombiFlash purification system. Pure fractions containing the product as verified by LCMS where combined and concentrated under reduced pressure and lyophilized overnight to yield 43A (8.5 mg, 0.018 mmol, 66.4 %).1H NMR (600 MHz, DMSO-d6) δ 8.21 (s, Formic acid, H-C-R, 2H), 8.06 (d, J = 8.16 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.44 (t, J = 6.9 Hz, 1H), 7.28 (t, J = 6.9 Hz, 1H), 6.58 (s, 2H), 5.47 (m, 1H), 5.11 (m, 1H), 4.79 (m, 1H), 4.43 (dd, J = 10.5, 8.1 Hz, 1H), 4.26 (dd, J = 10.4, 6.6 Hz, 1H), 4.10 (dd, J = 9.2, 4.38 Hz, 1H), 3.75 (d, J = 9.1 Hz, 2H), 3.54 (m, 2H), 2.99 (m, 2H), 1.85 (m, 2H), 1.45 (sex, J = 7.3 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 163.9, 153.4, 151.7, 144.9, 132.7, 126.5, 126.4, 121.0, 120.6, 114.5,89.1, 86.7, 73.1, 70.0, 63.2, 57.3, 30.1, 27.3, 22.0, 13.8; HRESIMS [M + H]+calcd for C20H26N5O2368.208102 found 368.20809. Preparation of 1-((2-azaspiro[3.3]heptan-6-yl)methyl)-2-butyl-1H-imidazo[4,5- c]quinolin-4-amine compound 43B:To 42B (40.5 mg, 0.067 mmol) under Ar was added 1 mL of dichloromethane followed by trifluoroacetic acid (1.0 mL, 13.0 mmol) and allowed to stir at room temperature for 24 h. The reaction mixture was then concentrated under reduced pressure and loaded on to a 5.5 g RediSep Gold® C18 Reversed Phase Column and purified using a gradient from 100% H2O (0.1 % formic acid) to 100% MeCN (0.1 % formic acid) over 30 minutes using a Teledyne Isco CombiFlash purification system. Pure fractions containing the product as verified by LCMS where combined and concentrated under reduced pressure and lyophilized overnight to yield 43B (22.7 mg, 0.051 mmol, 77.0 %).1H NMR (600 MHz, DMSO-d6) δ 13.84 (bs, Formic acid, RCOOH, 1H), 12.78 (bs, Formic acid, RCOOH, 1H), 8.64 (bs, Formic acid, H-C-R, 2H), 8.19 (d, J = 8.3 Hz, 1H), 8.13 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.72 (t, J = 8.2 Hz, 1H), 7.57 (t, J = 8.4 Hz, 1H), 6.54 (bs, 2H), 4.65 (d, J = 6.6 Hz, 2H), 3.91 (t, J = 6.06 Hz, 2H), 3.81 (t, J = 5.9 Hz, 2H), 2.98 (t, J = 7.3 Hz, 2H), 2.67 (quin, J = 7.8 Hz, 1H), 2.24 (m, 2H), 2.07 (m, 2H), 1.83 (quin, J = 7.8 Hz, 2H), 1.47 (sex, J = 7.5 Hz, 2H), 0.96 (t, J = 7.44 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 163.5, 157.0, 149.2, 135.2, 129.8, 125.0, 122.2, 118.6, 116.6, 113.1, 57.6, 56.0,49.2, 40.5, 37.2, 35.6, 29.9, 29.6, 26.7, 22.3, 14.2; HRESIMS [M + H]+calcd for C21H28N5 350.233922 found 350.23318. Preparation of 1-((6-aminobicyclo[3.2.0]heptan-3-yl)methyl)-2-butyl-1H- imidazo[4,5-c]quinolin-4-amine compound 43C:To 42C (37.1 mg, 0.060 mmol) under Ar was added 1 mL of dichloromethane followed by trifluoroacetic acid (1.0 mL, 13.0 mmol) and allowed to stir at room temperature for 24 h. The reaction mixture was then concentrated under reduced pressure and loaded on to a 5.5 g RediSep Gold® C18 Reversed Phase Column and purified using a gradient from 100% H2O (0.1 % formic acid) to 100% MeCN (0.1 % formic acid) over 30 minutes using a Teledyne Isco CombiFlash purification system. Pure fractions containing the product as verified by LCMS where combined and concentrated under reduced pressure and lyophilized overnight to yield 43C (14.8 mg, 0.032 mmol, 54.2 %).1H NMR (600 MHz, DMSO-d6) δ 8.38 (bs, 2H), 8.11 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.43 (t, J = 8.4 Hz, 1H), 7.27 (t, J = 8.1 Hz, 1H), 6.52 (bs, 2h), 4.61 (d, J = 4.2 Hz, 2H), 2.93 (t, J = 7.5 Hz, 2H), 2.86 (m, 1H), 2.71 (m, 2H), 2.61 (m, 1H), 1.97 (m, 1H), 1.81 (quin, J = 7.8 Hz, 2H), 1.59 (m, 2H), 1.51 (m, 3H), 1.44 (sex, J = 7.6 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 165.3, 153.2, 151.6, 144.6, 132.4, 126.4, 126.2, 121.1, 120.2, 114.9, 48.5, 48.2, 44.7, 40.0, 35.7, 35.1, 32.1, 30.9, 29.7, 27.4, 21.9, 13.8; HRESIMS [M + H]+calcd for C22H30N5364.249572 found 364.24712.Preparation of 1-((2-(aminomethyl)-5-oxaspiro[3.4]octan-6-yl)methyl)-2-butyl-1H- imidazo[4,5-c]quinolin-4-amine compound 43D:To 42D (48.3 mg, 0.075 mmol) under Ar was added 1 mL of dichloromethane followed by trifluoroacetic acid (1.0 mL, 13.0 mmol) and allowed to stir at room temperature for 24 h. The reaction mixture was then concentrated under reduced pressure and loaded on to a 5.5 g RediSep Gold® C18 Reversed Phase Column and purified using a gradient from 100% H2O (0.1 % formic acid) to 100% MeCN (0.1 % formic acid) over 30 minutes using a Teledyne Isco CombiFlash purification system. Pure fractions containing the product as verified by LCMS where combined and concentrated under reduced pressure and lyophilized overnight to yield 43D (21.3 mg, 0.044 mmol, 58.7 %).1H NMR (600 MHz, DMSO-d6) δ 8.38 (bs, 2H), 8.05 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.43 (t, J = 8.4 Hz, 1H), 7.26 (t, J = 8.3 Hz, 1H), 7.01 (bs, 2H), 4.68 (d, J = 15.4 Hz, 1H), 4.43 (dd, J = 15.6, 8.6 Hz, 1H), 4.28 (m, 1H), 2.93 (dd, J = 8.7, 6.4 Hz, 2H), 2.72 (m, 2H), 2.11 (m, 2H), 2.00 (m, 2H), 1.91 (m, 2H), 1.80 (m, 4H), 1.68 (m, 1H), 1.46 (sex, J = 7.5 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 165.7, 154.3, 151.4, 143.3, 132.7, 126.6, 126.0, 125.1, 121.4, 120.5, 114.6, 79.6, 76.9, 49.5, 43.9, 39.7, 35.7, 29.3, 27.7, 27.5, 24.0, 22.0, 13.8; HRESIMS [M + H]+calcd for C23H32N5O 394.260137 found 394.25950.Preparation of 1-((4-aminobicyclo[2.2.2]octan-1-yl)methyl)-2-butyl-1H-imidazo[4,5- c]quinolin-4-amine compound 43E:To 42E (28.6 mg, 0.045 mmol) under Ar was added 1 mL of dichloromethane followed by trifluoroacetic acid (1.0 mL, 13.0 mmol) and allowed to stir at room temperature for 24 h. The reaction mixture was then concentrated under reduced pressure and loaded on to a 5.5 g RediSep Gold® C18 Reversed Phase Column and purified using a gradient from 100% H2O (0.1 % formic acid) to 100% MeCN (0.1 % formic acid) over 30 minutes using a Teledyne Isco CombiFlash purification system. Pure fractions containing the product as verified by LCMS where combined and concentrated under reduced pressure and lyophilized overnight to yield 43E (15.0 mg, 0.032 mmol, 71.3 %).1H NMR (600 MHz, DMSO-d6) δ 8.35 (s, 2H), 8.29 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.43 (t, J = 7.0 Hz, 1H), 7.27 (t, J = 6.9 Hz, 1H), 7.27 (bs, 2H), 4.74 (d, J = 15.6 Hz, 1H), 4.24 (d, J = 15.7 Hz, 1H), 2.93 (m, 1H), 2.88 (m, 1H), 1.77 (sex, J = 7.9 Hz, 2H), 1.60 (s, 9H), 1.54 (m, 3H), 1.39 (sep, J = 7.2 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 165.4, 155.3, 151.3 ,142.6, 133.7, 126.7126.1 ,124.5121.4, 121.1115.0, 52.6, 49.9, 34.8, 30.3, 28.88, 28.51, 27.0, 21.9, 13.8; HRESIMS [M + H]+calcd for C23H32N5378.265222 found 378.26509. Preparation of 1-((1-(aminomethyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-2-butyl- 1H-imidazo[4,5-c]quinolin-4-amine compound 43F:To 42F (48.3 mg, 0.075 mmol) under Ar was added 1 mL of dichloromethane followed by trifluoroacetic acid (1.0 mL, 13.0 mmol) and allowed to stir at room temperature for 24 h. The reaction mixture was then concentrated under reduced pressure and loaded on to a 5.5 g RediSep Gold® C18 Reversed Phase Column and purified using a gradient from 100% H2O (0.1 % formic acid) to 100% MeCN (0.1 % formic acid) over 30 minutes using a Teledyne Isco CombiFlash purification system. Pure fractions containing the product as verified by LCMS where combined and concentrated under reduced pressure and lyophilized overnight to yield 43F (26.6 mg, 0.054 mmol, 73.2 %).1H NMR (600 MHz, DMSO-d6) δ 8.34 (s, 2H), 8.30 (bs, 2H), 8.28 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.46 (t, J = 8.2 Hz, 1H), 7.28 (t, J = 8.2 Hz, 1H), 4.79 (d, J = 15.9 Hz, 1H), 4.33 (d, J = 16.0 Hz, 1H), 3.75 (m, 1H), 3.65 (m, 1H), 2.93 (m, 1H), 2.88 (m, 1H), 2.64 (s, 2H), 1.79 (sep, J = 8.5 Hz, 2H), 1.71-1.45 (m, 8H), 1.39 (sep, J = 7.5 Hz, 2H), 0.92 (t, J = 7.2 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 165.3, 155.2, 151.3, 142.2, 133.7, 126.9, 126.1, 124.4, 121.4, 121.2, 114.7, 70.9, 68.2, 50.0, 45.4, 35.8, 30.2, 27.7, 26.9, 26.8, 26.7, 21.9, 13.8; HRESIMS [M + H]+calcd for C23H34N5O 394.260137 found 394.25985. Preparation of 2-butyl-1-((octahydrocyclopenta[c]pyrrol-5-yl)methyl)-1H- imidazo[4,5-c]quinolin-4-amine compound 43G:To 42G (40.7 mg, 0.066 mmol) under Ar was added 1 mL of dichloromethane followed by trifluoroacetic acid (1.0 mL, 13.0 mmol) and allowed to stir at room temperature for 24 h. The reaction mixture was then concentrated under reduced pressure and loaded on to a 5.5 g RediSep Gold® C18 Reversed Phase Column and purified using a gradient from 100% H2O (0.1 % formic acid) to 100% MeCN (0.1 % formic acid) over 30 minutes using a Teledyne Isco CombiFlash purification system. Pure fractions containing the product as verified by LCMS where combined and concentrated under reduced pressure and lyophilized overnight to yield 43G (19.7 mg, 0.043 mmol, 65.8 %).1H NMR (600 MHz, DMSO-d6) δ 8.31 (s, 2H), 8.05 (d, J = 6.8 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.47 (t, J = 7.0 Hz, 1H), 7.43 (bs, 1H), 7.32 (t, J = 7.0 Hz, 1H), 4.50 (m, 2H), 3.07 (m, 3H), 2.94 (t, J = 7.4 Hz, 2H), 2.68 (m, 2H), 2.35 (sep, J = 6.0 Hz, 1H), 1.90 (bs, 2H), 1.81 (quin, J = 7.6 Hz, 2H), 1.45 (sex, J = 7.6 Hz, 2H), 1.38 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 164.9, 153.9, 151.2, 141.8, 132.8, 127.0, 126.0, 124.0, 122.1, 120.6, 114.2, 50.3, 48.3, 42.5, 41.0, 35.8, 29.6, 21.9, 13.8; HRESIMS [M + H]+calcd for C22H30N5364.249572 found 364.24898.Scheme 9. Synthesis of pyrrolopyrimidine-like analogues. Preparation of tert-butyl ((3S,3aR,6S,6aR)-6-((4-((2-amino-4-(pentylamino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-3-methoxybenzyl)amino)hexahydrofuro[3,2-b]furan- 3-yl)carbamate compound 44A:To 25 (US20220242871) (50.0 mg, 0.13 mmol) in 3.5 mL of dichloromethane under Ar was added thionyl chloride (0.058 mL, 0.81 mmol) dropwise after which the ice bath was removed and the reaction mixture allowed to stir at room temperature for 45 min. The reaction mixture was then diluted with 25 mL of methylene chloride and washed with NaHCO3then dried with MgSO4and concentrated using a rotary evaporator. To the benzyl chloride intermediate was added 2.5 mL of N,N-dimethylformamide under Ar followed by DIPEA (0.070 mL, 0.40 mmol) and 37A (65.9 mg, 0.27 mmol) and allowed to stir at 50 °C for 18 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 9:1) to give 44A (61.2 mg, 0.10 mmol, 79.1 %).1H NMR (600 MHz, DMSO-d6) δ 8.32 (s, 3H), 7.34 (d, J = 3.0 Hz, 1H), 7.17 (d, J = 6.3 Hz, 1H), 7.05 (s, 1H), 7.00 (t, J = 5.7 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 6.54 (d, J = 7.7 Hz, 1H), 6.09 (d, J = 3 Hz, 1H), 5.48 (s, 2H), 4.39 (m, 2H), 3.82 (s, 3H), 3.79 (m, 1H), 3.74 (m, 2H), 3.69 (q, J = 14.0 Hz, 2H), 3.57 (dd, J = 9.1, 3.3 Hz, 1H), 3.54 (dd, J = 8.9, 2.8 Hz, 1H), 3.43 (q, J = 7.0 Hz, 2H), 3.07 (m, 1H), 1.44 (quin, J = 7.3 Hz, 2H), 1.37 (s, 9H), 1.21 (m, 3H), 1.10 (m, 2H), 0.81 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 165.5, 155.9, 155.1, 1540, 151.6, 142.0, 138.1, 133.8, 126.9, 123.3, 120.3, 110.6, 108.6, 95.0, 86.3, 78.0, 72.0, 71.5, 63.5, 57.0, 55.4, 50.7, 47.1, 40.3, 28.3, 28.1, 21.8, 17.7, 13.8; HRESIMS [M + H]+calcd for C31H46N7O5596.355494 found 596.35400. Preparation of tert-butyl 4-(((4-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl)methyl)-3-methoxybenzyl)amino)methyl)hexahydrocyclopenta[c]pyrrole- 2(1H)-carboxylate compound 44H:To 25 (US20220242871) (50.0 mg, 0.13 mmol) in 3.5 mL of dichloromethane under Ar was added thionyl chloride (0.058 mL, 0.81 mmol) dropwise after which the ice bath was removed and the reaction mixture allowed to stir at room temperature for 45 min. The reaction mixture was then diluted with 25 mL of methylene chloride and washed with NaHCO3then dried with MgSO4and concentrated using a rotary evaporator. To the benzyl chloride intermediate was added 2.5 mL of N,N-dimethylformamide under Ar followed by DIPEA (0.070 mL, 0.40 mmol) and 37H (64.8 mg, 0.27 mmol) and allowed to stir at 50 °C for 18 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 9:1) to give 44H (56.5 mg, 0.095 mmol, 73.5 %).1H NMR (600 MHz, MeOD) δ 8.51 (bs, 3H), 7.35 (d, J = 3.0 Hz, 1H), 7.28 (s, 1H), 7.05 (d, J = 9 Hz, 1H), 6.78 (d, J = 7.7 Hz, 1H), 6.23 (d, J = 3.0 Hz, 1H), 5.54 (s, 2H), 4.19 (s, 2H), 3.95 (s, 3H), 3.52 (t, J = 7.2 Hz, 2H), 3.48 (dd, J = 11.2, 7.0 Hz, 1H), 3.18 (m, 1H), 3.10 (m, 1H), 3.06 (m, 1H), 3.00 (m, 1H), 2.78 (m, 1H), 2.73 (m, 1H), 2.40 (m, 1H), 1.97 (m, 1H), 1.89 (m, 1H), 1.53 (m, 4H), 1.44 (s, 9H), 1.30 (quin, J = 7.4 Hz, 2H), 1.20 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, MeOD) δ 169.7, 158.0, 156.2, 154.5, 153.7, 138.0, 135.3, 129.2, 127.3, 123.6, 113.5, 110.2, 96.1, 80.9, 56.5, 55.7, 52.4, 50.1, 48.3, 43.7, 42.1, 41.3, 31.7, 30.0, 29.9, 29.1, 28.7, 23.4, 18.0, 14.4, 13.1; HRESIMS [M + H]+calcd for C33H50N7O3592.396965 found 592.39717. Preparation of tert-butyl ((6-(((4-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl)methyl)-3-methoxybenzyl)amino)methyl)spiro[3.3]heptan-2- yl)methyl)carbamate compound 47:To 25 (US20220242871) (50.0 mg, 0.13 mmol) in 3.5 mL of dichloromethane under Ar was added thionyl chloride (0.058 mL, 0.81 mmol) dropwise after which the ice bath was removed and the reaction mixture allowed to stir at room temperature for 45 min. The reaction mixture was then diluted with 25 mL of methylene chloride and washed with NaHCO3then dried with MgSO4and concentrated using a rotary evaporator. To the benzyl chloride intermediate was added 2.5 mL of N,N-dimethylformamide under Ar followed by DIPEA (0.070 mL, 0.40 mmol) and 18 (68.6 mg, 0.27 mmol) and allowed to stir at 50 °C for 18 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 9:1) to give 47 (59.1 mg, 0.097 mmol, 75.1 %).1H NMR (600 MHz, MeOD) δ 8.48 (s, 3H), 7.34 (d, J = 3 Hz, 1H), 7.24 (s, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 6.23 (d, J = 3.0 Hz, 1H), 5.54 (s, 2H), 4.13 (s, 2H), 3.94 (s, 3H), 3.51 (m, 3H), 3.46 (m, 1H), 2.52 (quin, J = 7.8 Hz, 1H), 2.25 (m, 2H), 2.12 (m, 2H), 1.95 (m, 1H), 1.80 (dd, J = 11.4, 8.2 Hz, 1H), 1.74 (m, 2H), 1.64 (dd, J = 11.7 Hz, 7.5 Hz, 1H), 1.53 (quin, J = 7.3 Hz, 2H), 1.42 (s, 9H), 1.32 (quin, J = 7.5 Hz, 2H), 1.19 (m, 2H), 1.07 (m, 1H), 0.88 (t, J = 7.2 Hz, 3H);13C NMR (150 MHz, MeOD) δ 169.5, 158.0, 154.5, 153.7, 138.0, 135.3, 134.7, 129.3, 127.3, 123.5, 113.5, 110.2, 96.1, 79.7, 56.4, 55.7, 53.7, 51.8, 46.5, 43.7, 42.1, 40.4, 40.0, 39.4, 38.8, 37.3, 30.0, 28.7, 27.9, 23.4, 14.4, 13.1; HRESIMS [M + H]+calcd for C34H52N7O3606.412615 found 606.41257. Preparation of tert-butyl 6-(((4-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl)methyl)-3-methoxybenzyl)amino)methyl)-2-azaspiro[3.3]heptane-2- carboxylate compound 44B:To 25 (US20220242871) (50.0 mg, 0.13 mmol) in 3.5 mL of dichloromethane under Ar was added thionyl chloride (0.058 mL, 0.81 mmol) dropwise after which the ice bath was removed and the reaction mixture allowed to stir at room temperature for 45 min. The reaction mixture was then diluted with 25 mL of methylene chloride and washed with NaHCO3then dried with MgSO4and concentrated using a rotary evaporator. To the benzyl chloride intermediate was added 2.5 mL of N,N-dimethylformamide under Ar followed by DIPEA (0.070 mL, 0.40 mmol) and 37B (61.1 mg, 0.27 mmol) and allowed to stir at 50 °C for 18 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 9:1) to give 44B (61.2 mg, 0.10 mmol, 81.6 %).1H NMR (600 MHz, MeOD) δ 8.51 (bs, 3H), 7.34 (d, J = 3.0 Hz, 1H), 7.25 (s, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 6.23 (d, J = 3.0 Hz, 1H), 5.54 (s, 2H), 4.13 (s, 2H), 3.94 (s, 3H), 3.79 (bs, 2H), 3.52 (t, J = 7.2 Hz, 2H), 3.02 (d, J = 7.3 Hz, 2H), 2.54 (quin, J = 7.9 Hz, 1H), 2.35 (m, 2H), 1.99 (m, 2H), 1.53 (quin, J = 7.3 Hz, 2H), 1.41 (s, 9H), 1.30 (quin, J = 7.3 Hz, 2H), 1.20 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, MeOD) δ 169.9, 158.0, 154.5, 153.7, 138.0, 135.2, 135.0, 129.3, 127.2, 123.5, 113.4, 110.2, 96.1, 80.9, 56.4, 55.7, 53.3, 51.9, 48.2, 43.7, 42.1, 37.7, 35.8, 30.0, 29.9, 28.6, 27.5, 23.4, 14.4, 13.1; HRESIMS [M + H]+calcd for C32H48N7O3578.381315 found 578.38109. Preparation of tert-butyl (3-(((4-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl)methyl)-3-methoxybenzyl)amino)methyl)bicyclo[3.2.0]heptan-6- yl)carbamate compound 44C:To 25 (US20220242871) (50.0 mg, 0.13 mmol) in 3.5 mL of dichloromethane under Ar was added thionyl chloride (0.058 mL, 0.81 mmol) dropwise after which the ice bath was removed and the reaction mixture allowed to stir at room temperature for 45 min. The reaction mixture was then diluted with 25 mL of methylene chloride and washed with NaHCO3then dried with MgSO4and concentrated using a rotary evaporator. To the benzyl chloride intermediate was added 2.5 mL of N,N-dimethylformamide under Ar followed by DIPEA (0.070 mL, 0.40 mmol) and 37C (64.8 mg, 0.27 mmol) and allowed to stir at 50 °C for 18 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 9:1) to give 44C (53.2 mg, 0.089 mmol, 69.2 %).1H NMR (600 MHz, MeOD) δ 8.50 (bs, 3H), 7.35 (d, J = 3.0 Hz, 1H), 7.29 (s, 1H), 7.06 (d, J = 8.9 Hz, 1H), 6.79 (d, J = 7.7 Hz, 1H), 5.55 (s, 2H), 4.22 (s, 2H), 3.86 (s, 3H), 3.52 (t, J = 7.2 Hz, 3H), 3.0 (m, 2H), 2.7 (m, 1H), 2.6 (m, 1H), 2.56 (sep, J = 6.0 Hz, 1H), 2.06 (m, 1H), 1.91 (dd, J = 12.7, 5.8 Hz, 2H), 1.76 (dd, J = 12.7, 6.1 Hz, 1H), 1.53 (quin, J = 7.2 Hz, 2H), 1.42 (s, 9H), 1.32 (quin, J = 7.3 Hz, 4H), 1.20 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, MeOD) δ 169.6, 158.0, 157.5, 154.4, 153.7, 138.0, 135.3, 134.7, 129.3, 127.4, 123.6, 113.6, 110.2, 96.1, 79.9, 56.5, 55.7, 52.8, 52.3, 48.2, 43.7, 42.1, 38.1, 37.6, 37.5, 30.0, 29.9, 28.7, 23.4, 14.4, 13.1; HRESIMS [M + H]+calcd for C33H50N7O3592.396965 found 592.39591. Preparation of tert-butyl ((3-(((4-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl)methyl)-3-methoxybenzyl)amino)methyl)bicyclo[1.1.1]pentan-1- yl)methyl)carbamate compound 46To 25 (US20220242871) (50.0 mg, 0.13 mmol) in 3.5 mL of dichloromethane under Ar was added thionyl chloride (0.058 mL, 0.81 mmol) dropwise after which the ice bath was removed and the reaction mixture allowed to stir at room temperature for 45 min. The reaction mixture was then diluted with 25 mL of methylene chloride and washed with NaHCO3then dried with MgSO4and concentrated using a rotary evaporator. To the benzyl chloride intermediate was added 2.5 mL of N,N-dimethylformamide under Ar followed by DIPEA (0.070 mL, 0.40 mmol) and 2 (61.1 mg, 0.27 mmol) and allowed to stir at 50 °C for 18 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 9:1) to give 46 (69.9 mg, 0.12 mmol, 93.1 %).1H NMR (600 MHz, MeOD) δ 8.47 (s, 3H), 7.34 (d, J = 3.0 Hz, 1H), 7.26 (s, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 6.23 (d, J = 3.0 Hz, 1H), 5.54 (s, 2H), 4.17 (s, 2H), 3.94 (s, 3H), 3.52 (t, J = 7.2 Hz, 2H), 3.09 (s, 4H), 1.73 (s, 6H), 1.54 (quin, J = 7.1 Hz, 2H), 1.42 (s, 9H), 1.31 (sep, J = 7.5 Hz, 2H), 1.19 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, MeOD) δ 169.2, 157.9, 154.5, 153.6, 138.0, 135.2, 134.4, 129.2, 127.3, 123.8, 113.7, 110.2, 96.0, 79.8, 56.4, 55.6, 52.1, 50.5, 48.2, 43.6, 42.2, 42.0, 40.6, 36.6, 30.0, 29.9, 28.7, 23.4, 14.4, 13.1; HRESIMS [M + H]+calcd for C32H48N7O3578.381315 found 578.38038. Preparation of tert-butyl ((4-(((4-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl)methyl)-3-methoxybenzyl)amino)methyl)-2-oxabicyclo[2.2.2]octan-1- yl)methyl)carbamate compound 44F:To 25 (US20220242871) (50.0 mg, 0.13 mmol) in 3.5 mL of dichloromethane under Ar was added thionyl chloride (0.058 mL, 0.81 mmol) dropwise after which the ice bath was removed and the reaction mixture allowed to stir at room temperature for 45 min. The reaction mixture was then diluted with 25 mL of methylene chloride and washed with NaHCO3then dried with MgSO4and concentrated using a rotary evaporator. To the benzyl chloride intermediate was added 2.5 mL of N,N-dimethylformamide under Ar followed by DIPEA (0.070 mL, 0.40 mmol) and 37F (73.0 mg, 0.27 mmol) and allowed to stir at 50 °C for 18 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 9:1) to give 44F (59.4 mg, 0.095 mmol, 73.6 %).1H NMR (600 MHz, MeOD) δ 8.45 (s, 3H), 7.34 (d, J = 3.0 Hz, 1H), 7.28 (s, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.75 (d, J = 7.7 Hz, 1H), 6.23 (d, J = 3.1 Hz, 1H), 5.54 (s, 2H), 4.17 (s, 2H), 3.93 (s, 3H), 3.68 (s, 2H), 3.52 (t, J = 7.3 Hz, 2H), 2.97 (s, 2H), 2.74 (s, 2H), 1.77 (m, 2H), 1.67-1.58 (m, 6H), 1.52 (quin, J = 7.2 Hz, 2H), 1.41 (s, 9H), 1.30 (sex, J = 7.5 Hz, 2H), 1.19 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, MeOD) δ 169.1, 158.4, 157.9, 154.5, 153.6, 138.0, 135.3, 134.4, 129.1, 127.3, 123.9, 113.7, 110.1, 96.0, 80.0, 72.5, 71.8, 56.5, 55.6, 54.0, 53.0, 48.6, 48.2, 42.0, 32.7, 30.0, 29.9, 28.9, 28.7, 28.2, 23.4, 14.4; HRESIMS [M + H]+calcd for C34H52H7O4622.407530 found 622.40614. Preparation of 5-(4-((((2-(aminomethyl)-5-oxaspiro[3.4]octan-6- yl)methyl)amino)methyl)-2-methoxybenzyl)-N4-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4- diamine compound 44D:To 25 (US20220242871) (50.0 mg, 0.13 mmol) in 3.5 mL of dichloromethane under Ar was added thionyl chloride (0.058 mL, 0.81 mmol) dropwise after which the ice bath was removed and the reaction mixture allowed to stir at room temperature for 45 min. The reaction mixture was then diluted with 25 mL of methylene chloride and washed with NaHCO3then dried with MgSO4and concentrated using a rotary evaporator. To the benzyl chloride intermediate was added 2.5 mL of N,N-dimethylformamide under Ar followed by DIPEA (0.070 mL, 0.40 mmol) and 37D (73.0 mg, 0.27 mmol) and allowed to stir at 50 °C for 18 h. The reaction mixture was then concentrated under reduced pressure and purified using flash chromatography (dichloromethane:methanol 9:1) to give 44D (66.6 mg, 0.10 mmol, 82.5 %).1H NMR (600 MHz, MeOD) δ 8.50 (s, 3H), 7.35 (d, J = 3.0 Hz, 1H), 7.25 (s, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 5.55 (s, 2H), 4.19 (m, 2H), 3.95 (s, 3H), 3.52 (t, J = 7.2 Hz, 2H), 3.06 (m, 3H), 2.82 (dd, J = 12.7, 9.8 Hz, 1H), 2.10 (m, 2H), 1.96-1.89 (m, 6H), 1.62 (dd, J = 12.6, 7.3 Hz, 1H), 1.53 (quin, J = 7.1 Hz, 2H), 1.41 (s, 9H), 1.30 (sex, J = 7.3 Hz, 2H), 1.19 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, MeOD) δ 169.7, 158.7, 158.0, 154.5, 153.7, 138.0, 135.3, 129.3, 127.2, 123.6, 113.4, 110.2, 96.1, 82.1, 79.8, 75.2, 56.5, 55.7.52.9, 52.0, 48.3, 43.7, 42.1, 40.5, 37.3, 30.0, 29.9, 29.6, 28.7, 23.4, 14.4, 13.1; HRESIMS [M + H]+calcd for C34H52N7O4622.407530 found 622.40592. Preparation of 5-(4-((((3S,3aR,6S,6aR)-6-aminohexahydrofuro[3,2-b]furan-3- yl)amino)methyl)-2-methoxybenzyl)-N4-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine compound 45A:To 44A (61.2 mg, 0.10 mmol) under Ar was added 1 mL of dichloromethane followed by trifluoroacetic acid (1.0 mL, 13.0 mmol) and allowed to stir at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and loaded on to a 5.5 g RediSepGold® C18 Reversed Phase Column and purified using a gradient from 100% H2O (0.1 % formic acid) to 100% MeCN (0.1 % formic acid) over 30 minutes using a Teledyne Isco CombiFlash purification system. Pure fractions containing the product as verified by LCMS where combined and concentrated under reduced pressure and lyophilized overnight to yield 45A (46.4 mg, 0.079 mmol, 79.1 %).1H NMR (600 MHz, DMSO-d6) δ 8.28 (s, 3H), 7.7 (bs, 2H), 7.35 (d, J = 3.0 Hz, 1H), 7.12 (t, J = 5.6 Hz, 1H), 7.05 (s, 1H), 6.82 (d, J = 7.7 Hz, 1H), 6.55 (d, J = 7.7 Hz, 1H), 6.11 (d, J = 2.9 Hz, 1H), 5.49 (s, 2H), 4.53 (s, 2H), 3.85 (dd, J = 10.2, 4.9 Hz, 1H), 3.82 (s, 3H), 3.78 (dd, J = 9.3, 5.2 Hz, 1H), 3.70 (m, 3H), 3.60 (m, 2H), 3.42 (q, J = 5.7 Hz, 2H), 3.11 (t, J = 4.8 Hz, 1H), 1.45 (quin, J = 7.2 Hz, 2H), 1.21 (sex, J = 7.3 Hz, 2H), 1.10 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 164.9, 156.0, 153.6, 151.7, 141.8, 137.4, 133.9, 127.0, 123.4, 120.3, 110.6, 108.6, 94.9, 86.7, 84.9, 72.2, 70.2, 63.3, 55.8, 55.4, 50.7, 47.1, 40.4, 28.3, 21.8, 13.8; HRESIMS [M + H]+calcd for C26H38N7O3496.303065 found 496.30360. Preparation of 5-(2-methoxy-4-((((octahydrocyclopenta[c]pyrrol-4- yl)methyl)amino)methyl)benzyl)-N4-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine compound 45H:To 44H (56.5 mg, 0.095 mmol) under Ar was added 1 mL of dichloromethane followed by trifluoroacetic acid (1.0 mL, 13.0 mmol) and allowed to stir at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and loaded on to a 5.5 g RediSep Gold® C18 Reversed Phase Column and purified using a gradient from 100% H2O (0.1 % formic acid) to 100% MeCN (0.1 % formic acid) over 30 minutes using a Teledyne Isco CombiFlash purification system. Pure fractions containing the product as verified by LCMS where combined and concentrated under reduced pressure and lyophilized overnight to yield45H (40.7 mg, 0.069 mmol, 73.5 %).1H NMR (600 MHz, DMSO-d6) δ 8.30 (s, 3H), 7.32 (d, J = 3.0 Hz, 1H), 7.26 (bs, 1H), 7.09 (s, 1H), 6.84 (d, J = 7.7 Hz, 1H), 6.79 (bs, 1H), 6.51 (d, J = 7.7 Hz, 1H), 6.07 (d, J = 3.0 Hz, 1H), 5.47 (s, 2H), 3.83 (s, 3H), 3.74 (q, J = 10.5 Hz, 2H), 3.39 (q, J = 6.9 Hz, 3H), 3.24 (bs, 1H), 2.73 (m, 3H), 2.61 (m, 2H), 2.52 (m, 1H), 2.10 (bs, 1H), 1.63 (m, 2H), 1.45 (m, 3H), 1.31 (m, 1H), 1.22 (sex, J = 7.5 Hz, 2H), 1.09 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 165.2, 155.8, 154.7, 151.4, 140.2, 133.6, 126.9, 124.1, 120.5, 110.8, 108.9, 95.8, 55.5, 52.3, 50.9, 48.6, 47.0, 45.2, 43.5, 41.6, 40.7, 40.2, 29.6, 28.37, 28.36, 27.5, 21.8, 13.8; HRESIMS [M + 2H]2+calcd for C28H43N7O 246.675906 found 246.67517. Preparation of 5-(4-((((6-(aminomethyl)spiro[3.3]heptan-2- yl)methyl)amino)methyl)-2-methoxybenzyl)-N4-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4- diamine compound 49:To 47 (59.1 mg, 0.097 mmol) under Ar was added 1 mL of dichloromethane followed by trifluoroacetic acid (1.0 mL, 13.0 mmol) and allowed to stir at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and loaded on to a 5.5 g RediSep Gold® C18 Reversed Phase Column and purified using a gradient from 100% H2O (0.1 % formic acid) to 100% MeCN (0.1 % formic acid) over 30 minutes using a Teledyne Isco CombiFlash purification system. Pure fractions containing the product as verified by LCMS where combined and concentrated under reduced pressure and lyophilized overnight to yield 49 (43.5 mg, 0.072 mmol, 75.1 %).1H NMR (600 MHz, DMSO-d6) δ 7.78 (bs, 3H), 7.53 (bs, 2H), 7.43 (t, J = 5.7 Hz, 1H), 7.39 (d, J = 3.1 Hz, 1H), 7.24 (s, 1H), 6.95 (d, J = 7.8 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.20 (d, J = 3.0 Hz, 1H), 5.55 (s, 2H), 4.06 (m 2H), 3.83 (s, 3H), 3.62 (m, 2H), 3.45 (q, J = 5.7 Hz, 2H), 3.13 (dd, J = 7.3, 4.2 Hz, 1H), 2.89 (q, J = 7.0 Hz, 2H), 2.78 (quin, J =7.5 Hz, 2H), 2.44 (quin, J = 7.9 Hz, 1H), 2.31 (quin, J = 7.8 Hz, 1H), 2.13 (m, 1H), 2.00 (m, 1H), 1.95 (m, 1H), 1.77 (m, 2H), 1.69 (m, 2H), 1.47 (quin, J = 7.1 Hz, 2H), 1.12 (m, 2H), 0.82 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 172.2, 156.1, 152.5, 151.8, 134.1, 133.3, 127.2, 125.7, 122.1, 112.3, 108.5, 95.1, 55.5, 53.5, 51.4, 49.7, 47.1, 43.8, 41.7, 40.5, 38.7, 38.3, 38.1, 37.5, 28.3, 27.4, 21.8, 13.8, 12.3; HRESIMS [M + 2H]2+calcd for C29H45N7O 253.683731 found 253.68285. Preparation of 5-(4-((((2-azaspiro[3.3]heptan-6-yl)methyl)amino)methyl)-2- methoxybenzyl)-N4-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine compound 45B:To 44B (61.2 mg, 0.10 mmol) under Ar was added 1 mL of dichloromethane followed by trifluoroacetic acid (1.0 mL, 13.0 mmol) and allowed to stir at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and loaded on to a 5.5 g RediSep Gold® C18 Reversed Phase Column and purified using a gradient from 100% H2O (0.1 % formic acid) to 100% MeCN (0.1 % formic acid) over 30 minutes using a Teledyne Isco CombiFlash purification system. Pure fractions containing the product as verified by LCMS where combined and concentrated under reduced pressure and lyophilized overnight to yield 45B (46.4 mg, 0.081 mmol, 81.6 %).1H NMR (600 MHz, DMSO-d6) δ 8.31 (s, 3H), 7.33 (d, J = 3.0 Hz, 1H), 7.05 (bs, 2H), 6.98 (s, 1H), 6.81 (d, J = 9.3 Hz 1H), 6.58 (bs, 1H), 6.47 (d, J = 7.9 Hz, 1H), 6.05 (s, 1H), 5.4 (s, 2H), 3.84 (s, 3H), 3.60 (s, 2H), 3.37 (q, J = 6.7 Hz, 2H), 2.67 (d, J = 7.2 Hz, 2H), 2.24 (m, 2H), 1.83 (m, 2H), 1.50 (dd, J = 6.1, 2.6 Hz, 1H), 1.40 (m, 3H), 1.21 (sex, J = 7.5 Hz, 2H), 1.09 (m, 4H), 0.80 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 165.0, 155.7, 155.3, 151.3, 140.0, 133.5, 126.7, 124.0, 120.7, 110.8, 109.1, 96.1, 60.0, 58.3, 55.4, 55.1, 47.0, 44.5, 40.5, 40.0, 35.9, 34.2, 29.0, 28.33, 28.32, 21.8, 13.8; HRESIMS [M + 2H]2+calcd for C27H41N7O 239.668081 found 239.66727.Preparation of 5-(4-((((6-aminobicyclo[3.2.0]heptan-3-yl)methyl)amino)methyl)-2- methoxybenzyl)-N4-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine compound 45C:To 44C (53.2 mg, 0.089 mmol) under Ar was added 1 mL of dichloromethane followed by trifluoroacetic acid (1.0 mL, 13.0 mmol) and allowed to stir at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and loaded on to a 5.5 g RediSep Gold® C18 Reversed Phase Column and purified using a gradient from 100% H2O (0.1 % formic acid) to 100% MeCN (0.1 % formic acid) over 30 minutes using a Teledyne Isco CombiFlash purification system. Pure fractions containing the product as verified by LCMS where combined and concentrated under reduced pressure and lyophilized overnight to yield 45C (35.9 mg, 0.061 mmol, 69.2 %).1H NMR (600 MHz, DMSO-d6) δ 8.35 (bs, 3H), 7.28 (d, J = 2.8 Hz, 1H), 7.08 (s, 1H), 6.82 (d, J = 7.7 Hz, 1H), 6.46 (d, J = 7.8 Hz, 2H), 6.46 (bs, 1H), 6.22 (bs, 1H), 6.01 (d, J = 3.0 Hz, 1H), 5.42 (s, 2H), 3.84 (s, 3H), 3.35 (q, J = 7.0 Hz, 2H), 3.10 (bs, 1H), 2.69 (m, 1H), 2.63 (m, 1H), 2.52 (m, 2H), 2.32 (m, 1H), 2.09 (m, 1H), 2.32 (m, 1H), 2.09 (m, 1H), 1.76 (m, 1H), 1.72 (dd, J = 12.7, 5.8 Hz, 1H), 1.61 (dd, J = 12.7, 6 Hz, 1H), 1.40 (quin, J = 7.3 Hz, 2H), 1.20 (sex, J = 7.3 Hz, 2H), 1.15-1.06 (m, 4H), 0.81 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 165.3, 156.4, 155.6, 151.0, 141.3, 133.1, 126.7, 124.2, 120.3, 110.5, 109.4, 97.1, 55.4, 52.7, 52.6, 48.2, 46.8, 43.8, 40.0, 38.5, 36.8, 36.1, 32.5, 29.9, 28.4, 28.3, 21.9, 13.8; HRESIMS [M + 2H]2+calcd for C28H43N7O 246.675906 found 246.67583. Preparation of 5-(4-((((3-(aminomethyl)bicyclo[1.1.1]pentan-1- yl)methyl)amino)methyl)-2-methoxybenzyl)-N4-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4- diamine compound 48:To 46 (69.9 mg, 0.12 mmol) under Ar was added 1 mL of dichloromethane followed by trifluoroacetic acid (1.0 mL, 13.0 mmol) and allowed to stir at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and loaded on to a 5.5 g RediSep Gold® C18 Reversed Phase Column and purified using a gradient from 100% H2O (0.1 % formic acid) to 100% MeCN (0.1 % formic acid) over 30 minutes using a Teledyne Isco CombiFlash purification system. Pure fractions containing the product as verified by LCMS where combined and concentrated under reduced pressure and lyophilized overnight to yield 48 (63.6 mg, 0.11 mmol, 93.1 %).1H NMR (600 MHz, DMSO-d6) δ 8.34 (s, 3H), 7.50 (bs, 2H), 7.34 (d, J = 3.0 Hz, 1H), 7.13 (s, 1H), 6.90 (bs, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.50 (d, J = 7.7 Hz, 1H), 6.80 (d, J = 3.0 Hz, 1H), 5.49 (s, 2H), 3.83 (s, 3H), 3.81 (s, 2H), 3.40 (q, J = 5.5 Hz, 2H), 2.87 (s, 2H), 2.67 (s, 2H), 1.66 (s, 6H), 1.43 (quin, J = 7.3 Hz, 2H), 1.21 (sex, J = 7.5 Hz, 2H), 1.09 (m, 2H), 0.80 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 165.7, 155.8, 154.5, 151.5, 139.5, 133.7, 126.8, 124.5, 121.0, 111.2, 109.8, 95.5, 55.4, 51.6, 49.3, 48.1, 47.0, 40.2, 37.9, 36.8, 28.3, 21.8, 13.8; HRESIMS [M + 2H]2+calcd for C27H41N7O 239.668081 found 239.66719. Preparation of 5-(4-((((1-(aminomethyl)-2-oxabicyclo[2.2.2]octan-4- yl)methyl)amino)methyl)-2-methoxybenzyl)-N4-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4- diamine compound 45F:To 44F (59.4 mg, 0.095 mmol) under Ar was added 1 mL of dichloromethane followed by trifluoroacetic acid (1.0 mL, 13.0 mmol) and allowed to stir at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and loaded on to a 5.5 g RediSep Gold® C18 Reversed Phase Column and purified using a gradient from 100% H2O (0.1 % formic acid) to 100% MeCN (0.1 % formic acid) over 30 minutes using a Teledyne Isco CombiFlash purification system. Pure fractions containing the product as verified by LCMS where combined and concentrated under reduced pressure and lyophilized overnight to yield 45F (42.9 mg, 0.069 mmol, 73.6 %).1H NMR (600 MHz, DMSO-d6) δ 8.3 (s, 3H), 7.33 (d, J = 3.0 Hz, 1H), 7.33 (bs, 2H), 7.04 (s, 1H), 6.79 (d, J = 9.3 Hz, 1H), 6.77 (bs, 1H), 6.48 (d, J = 7.7 Hz, 1H), 6.07 (d, J = 3.0 Hz, 1H), 5.46 (s, 2H), 3.82 (s, 3H), 3.63 (d, J = 3.6 Hz, 4H), 3.39 (q, J = 5.5 Hz, 2H), 2.71 (s, 2H), 2.18 (s, 2H), 1.74 (m, 2H), 1.57-1.46 (m, 6H), 1.42 (quin, J = 7.2 Hz, 2H), 1.20 (sex, J = 7.4 Hz, 2H), 1.08 (m, 2H), 0.82 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, DMSO- d6) δ 165.5, 158.8, 154.8, 151.4, 142.2, 133.6, 126.7, 123.5, 120.0, 110.1, 108.9, 95.7, 71.8, 68.5, 55.4, 54.7, 53.2, 47.0, 45.7, 40.1, 32.4, 28.35, 28.32, 28.0, 27.2, 21.8, 13.8; HRESIMS [M + 2H]2+calcd for C29H45N7O2261.681188 found 261.68045. Preparation of 5-(4-((((2-(aminomethyl)-5-oxaspiro[3.4]octan-6- yl)methyl)amino)methyl)-2-methoxybenzyl)-N4-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4- diamine compound 45D:To 44D (66.6 mg, 0.10 mmol) under Ar was added 1 mL of dichloromethane followed by trifluoroacetic acid (1.0 mL, 13.0 mmol) and allowed to stir at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and loaded on to a 5.5 g RediSep Gold® C18 Reversed Phase Column and purified using a gradient from 100% H2O (0.1 % formic acid) to 100% MeCN (0.1 % formic acid) over 30 minutes using a Teledyne IscoCombiFlash purification system. Pure fractions containing the product as verified by LCMS where combined and concentrated under reduced pressure and lyophilized overnight to yield 45D (50.6 mg, 0.0825 mmol, 82.5 %).1H NMR (600 MHz, DMSO-d6) δ 7.87 (bs, 3H), 7.54 (s, 2H), 7.43 (t, J = 5.6 Hz, 1H), 7.40 (d, J = 3.12 Hz, 1H), 7.26 (s, 1H), 6.97 (d, J = 7.8 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.20 (d, J = 3.0 Hz, 1H), 5.56 (s, 2H), 4.14 (m, 3H), 3.84 (s, 3H), 3.61 (m, 2H), 3.13 (m, 2H), 2.97 (m, 1H), 2.83 (m, 3H), 2.13 (m, 2H), 2.01 (m, 2H), 1.87 (m, 4H), 1.58 (m, 1H), 1.48 (quin, J = 7.2 Hz, 2H), 1.12 (m, 2H), 0.83 (t, J = 7.3 Hz, 3H);13C NMR (150 MHz, DMSO-d6) δ 156.1, 152.6, 151.8, 136.1, 134.2, 133.0, 127.2, 125.8, 122.3, 112.5, 108.5, 95.1, 79.8, 73.7, 55.5, 53.5, 50.6, 50.1, 47.1, 44.1, 41.7, 40.5, 35.6, 28.3, 23.9, 18.0, 16.7, 13.8, 12.3; HRESIMS [M + 2H]2+calcd for C29H45N7O2261.681188 found 261.68038. Example 2 - Synthesis and Characterization of Coordination Complexes General Complexation Protocol The general scheme is shown in FIG.1A. A 5 mg aliquot of RIMS-3 was dissolved in 10 % DMSO in H2O (500 µL). Two equivalents of thenatLuCl3were added to the solution and the complexation was carried out for 20 min at 80 ºC. Full complexation was confirmed by LCMS. The product was isolated as a pale solid following complexation and purification using a Sep-Pak Plus C18 short cartridge and characterized using mass spectrometry and HPLC chromatography. Yield fornatLu-RIMS-3: (1.0 mg, 0.00047 mmol, 45 %). Rt(Method B): 8.21 min. HRESIMS [M+H]+calc. for C98H135LuN19O232120.93860, found 2121.0. The concentration was determined using ICP-OES. Example 3 - Cathepsin B Cleavage Assay EvaluatingnatLu-RIMS-3 Cathepsin B cleavage ofnatLu-RIMS-3 (Example 2) was assessed using the general procedure given above (see also FIG.1B). HPLC monitoring results of the disappearance ofnatLu-RIMS-3 and the appearance of Compound 10 and metabolite M3 over time are shown in FIG.1C. Example 4 – Synthesis and Characterization of Radiochemical ComplexesPreparation of177Lu-RIMS-3,177Lu-RIMS-4 and177Lu-RIMS-5. 177Lu-RIMS-3,177Lu-RIMS-4 and177Lu-RIMS-5 were synthesized using the general radiolabeling protocol used to generatenatLu-RIMS-3 (Example 2). (See FIG.3A) The product was characterized using radio-HPLC chromatography. Rt (Method D): 9.92 min (177Lu-RIMS-3), 9.45 min (177Lu-RIMS-4) and 9.68 min (177Lu-RIMS-5). SA: 0.1 mCi / nmol, RCY: 99 %, RCP: 99 %.177LuCl3was received in 0.05 M HCl (38 MBq) (Missouri University Research Reactor) with a specific activity of 148 MBq / mL. The177LuCl3solution was mixed with two-thirds of its volume with Chelex resin-treated water. RIMS-3, RIMS-4 or RIMS-5 was dissolved in DMSO to make a 10 nmol stock solution of which 0.02 mL of the stock was added to an Eppendorf tube and 0.08 mL of 0.4 M ammonium acetate at pH 5.5 was added. Next, the177LuCl3solution (512 MBq, 10 µL) was added and heated at 80 °C. After 20 min of incubation, 5 μL from each solution was removed and injected onto a radio-HPLC to confirm complexation. The radiolabeled compounds were diluted with sterile PBS pH 7.4 and ready for in vitro or in vivo studies. FIG.3B (177Lu-RIMS-3) FIG.3C (177Lu-RIMS-4) FIG.3D (177Lu-RIMS-5) shows the HPLC analysis demonstrating radiochemical purity and quantitative radiolabeling. The stability of the radiolabeled compound over time was assessed in PBS per the HPLC procedure given above, and the results shown in FIG.4 for177Lu-RIMS-3. Example 5 - Internalization of177Lu-RIMS-3 in Syngeneic Mouse Prostate Cancer Cells and Quantitation of Cleavage Products Therein. A cell internalization study was carried out per the procedure given above to compare behavior of177Lu-RIMS-3 in Syngeneic Mouse Prostate Cancer Cells versus known compound177Lu-RIMS-1 and the comparative compound,177Lu-PSMA-617 (i.e., no TLR7 / 8 agonist). Results (FIG.5) show that177Lu-RIMS-3 internalized as well or better than177Lu-RIMS-1, and that the compound without the TLR7 / 8 agonist was only poorly taken up by the prostate cancer cells.Additionally, the amounts of M3 (structurally the same as m1 and m4) cleavage product and177Lu-RIMS-3,177Lu-RIMS-1,177Lu-RIMS-4 in urine of mice in a Syngeneic Mouse Model of Prostate Cancer were quantitated as shown in FIG.6 (Figure 13). RadioHPLC traces of the urine at the 2h time point from individual mice administered177Lu-RIMS-3 (FIG.7A),177Lu- RIMS-4 (FIG.7B) and177Lu-RIMS-5 (FIG.7C) shows intact drug and metabolite. Example 6 - In Vitro Activity of Compounds Towards Human TLR7 / TLR8 and Mouse TLR7 General Procedure The activity of the TLR7 agonists to activate human TLR7 (or hTLR7), human TLR8 (or hTLR8) and mouse TLR7 (or mTLR7) was evaluated on HEK293 reporter cells transfected with human TLR7 (or human TLR8 or mouse TLR7) and an inducible SEAP (secreted embryonic alkaline phosphatase) reporter gene. The SEAP reporter gene is placed under the control of the IFN-β minimal promoter fused to five NF-kB and AP-1 binding sites. Stimulation with a TLR7 agonist activates NF-κΒ and AP-I which induces the production of SEAP. Levels of SEAP was determined with HEK-Blue Detection medium. HEK293-humanTLR7, HEK293-mouseTLR7 and HEK293-humanTLR8 reporter cell lines were maintained in manufacture recommended culture medium with required supplemental antibiotics. On the day of assay, the cells were collected using and counted. In a 96-well plate (200 μL total volume) containing the appropriate number of cells, 20 μL of the ligand at the determined concentration was added to the wells. The 96-well plates were cultured at 37°C in a CO2incubator for 24 hours after which the optical density was measured at 630nm based on the HEK-Blue™ detection medium changes to a purple / blue color in the presence of secreted SEAP. Non-linear regression analysis was used to fit the data using GraphPad Prism. There result was reported in Table 1 as EC50 (the midpoint of the curve, or concentration at which 50% of the maximum effect was observed). Each compound was evaluated in quadruplicate for a given concentration. Results are shown in Table 1 and FIG.8.Table1. Summary of EC50 values of TLR7 / 8 agonists evaluated in HEK293-humanTLR7, HEK293-mouseTLR7 and HEK293-humanTLR8 reporter cell lines.Example 7 - Adult male OLINDA dosimetry estimates for177Lu-PSMA-617,177Lu-RIMS-1, and177Lu-RIMS-3 from a syngeneic mouse model of prostate cancer Methods: C57BL / 6J mice bearing RM1-PGLS(hPSMA+) tumors administered177Lu- PSMA-617,177Lu-RIMS-1 (Mol. Pharmaceutics 2022, 19, 3217−3227), and177Lu-RIMS-3 (structures shown in FIG.9;177Lu-RIMS-3 prepared according to FIG.3A) were sacrificed at time points of 4, 24, 72, and 144 hours post-injection. Subsequently, the organs of interest were surgically extracted and quantified using a gamma counter. Using the measurement data, the mean percent injected dose per gram (%ID / g) was computed for each time point. To derive the extrapolated human %ID, we considered the weights of each mouse and the fitting curve that whole organ mass estimation in mice. The equation is as follows:Subsequently, a %ID curve according to time (hr) was constructed, and the area under the curve was determined using the trapezoidal method to calculate the total disintegration number per injected activity (MBq-hr / MBq). Finally, based on the derived MBq-hr / MBq value, the adult male dosimetry was estimated using OLINDA / EXM version 1.1 (*biodistribution data of blood applied for red marrow, and bone data employed for cortical bone). The assessment of tumor dosimetry was achieved through OLINDA Sphere Self-Dose Interpolation calculations. The extrapolated human adult dosimetry estimation (mSv / MBq) in OLINDA / EXM, derived frommice biodistribution data (%ID / g), is presented in Table 2. Mean absorbed dose estimates (mGy / MBq) within the tumor for mice are displayed in Table 3. Table 2. Human adult dosimetry in OLINDA / EXM extrapolated from mouse biodistribution dataa.177Lu-PSMA-617 (Pluvicto, mSv / MBq), EMA Annexe I (https: / / www.ema.europa.eu / en / documents / product-information / lutathera-epar- product-information_fr.pdf) b.177Lu-PSMA-617 (mSv / MBq), Meyer et al.2022 (https: / / ejnmmires.springeropen.com / articles / 10.1186 / s13550-022-00935-6) c.177Lu-PSMA-617 (mSv / MBq), Kabasakal et al.2015 (https: / / link.springer.com / article / 10.1007 / s00259-015-3125-3) Table 3. Tumor dosimetry by OLINDA sphere self-dose interpolation from mouse biodistribution dataExample 8 – Biodistribution of177Lu-RIMS-3,177Lu-RIMS-4, and177Lu-RIMS-5 in a Syngeneic Mouse Model of Prostate Cancer A flow cytometry analysis of RM1-PGLS (hPSMA+) cells was undertaken before implantation of same into C57BL / 6J mice for in vivo biodistribution studies. Results are shown in FIG.10. The biodistribution of177Lu-RIMS-3,177Lu-RIMS-4, and177Lu-RIMS-5 in a Syngeneic Mouse Model of Prostate Cancer was studied in accordance with the procedure given above. Results are shown in FIGS.11A-11C and in Tables 4-6 below.Table 4. Biodistribution of177Lu-RIMS-3 (% ID / g) in vivo in a syngeneic model of prostate cancer with a RM1-PGLS (hPSMA+) tumour on the right shoulder in C57BL / 6J mice.Table 5. Biodistribution of177Lu-RIMS-4 (% ID / g) in vivo in a syngeneic model of prostate cancer with a RM1-PGLS (hPSMA+) tumour on the right shoulder in C57BL / 6J mice.Table 6. Biodistribution of177Lu-RIMS-5 (% ID / g) in vivo in a syngeneic model of prostate cancer with a RM1-PGLS (hPSMA+) tumour on the right shoulder in C57BL / 6J mice.Example 9 –177Lu-RIMS-3 Administered as a Monotherapy and in Combination with Immune Checkpoint Inhibitors in a Syngeneic Mouse Model of Prostate Cancer A study of the efficacy of177Lu-RIMS-3 as a monotherapy and in combination with immune checkpoint inhibitors in a syngeneic mouse model of prostate cancer was undertaken according the general procedure given above (“Therapy Study”).177Lu-RIMS-3 with low, medium and high levels of specific activity (“SA”) were assessed. Survival curves in Fig.12 show that177Lu-RIMS-3 with medium SA in combination with an anti-CTLA4 or anti-PD1 provided the best survival outcomes. Reimplantation of the tumors in the mice at about 80 days out demonstrated a durable immune response as shown in FIG. 13. Example 10 –177Lu-RIMS-1,177Lu-RIMS-4, and177Lu-RIMS-5 Administered as a Monotherapy in a Syngeneic Mouse Model of Prostate Cancer A study of the efficacy of177Lu-RIMS-1,177Lu-RIMS-4, and177Lu-RIMS-5, respectively, as a monotherapy in a syngeneic mouse model was undertaken as follows. C57BL / 6J male mice (5 weeks, The Jackson Laboratory) were implanted subcutaneously on the right shoulder with 0.1 × 106RM1-PGLS (hPSMA+) cells suspended in Matrigel (1:1). When the tumors reached 24−150 mm3(day 5) the mice were randomized into 6 groups (10 mice per group) for single dose compound administration of177Lu-RIMS-1,177Lu-RIMS-4 and177Lu-RIMS-5 via tail vein injection at the following doses:• High SA (high levels of specific activity): 60 MBq total administered radioactivity with a specific activity of 10.73 MBq / nmol which corresponds to 0.1 mg / kg of TLR 7 / 8 agonist; and • Low SA (low levels of specific activity): 60 MBq total administered radioactivity with a specific activity of 1.07 MBq / nmol which corresponds to 1.0 mg / kg of TLR 7 / 8 agonist. Tumor volumes and body weights were recorded every 2-3 days. Results are summarized in FIGS.14A-14C and FIG.15. It was found that177Lu-RIMS-5 outperforms177Lu-RIMS-1 and177Lu-RIMS-4. In particular, the low SA dose of177Lu-RIMS-5 (5 / 10 animals cured) exhibited advantageous result, and it outperformed225Ac-PSMA-617,177Lu-PSMA-617, anti-PD-1 and (anti-PD-1 +225Ac-PSMA-617) therapies. Example 11 –225Ac-RIMS-5 and90Y-RIMS-5 Administered as a Monotherapy in a Syngeneic Mouse Model of Prostate Cancer A study of the efficacy of225Ac-RIMS-5 and90Y-RIMS-5 as a monotherapy in a syngeneic mouse model was undertaken as follows. C57BL / 6J male mice (5 weeks, The Jackson Laboratory) were implanted subcutaneously on the right shoulder with 0.1 × 106RM1-PGLS (hPSMA+) cells suspended in Matrigel (1:1). When the tumors reached 24−150 mm3(day 5) the mice were randomized into 6 groups (10 mice per group) for single dose compound administration of225Ac-RIMS-5 and90Y-RIMS-5 via tail vein injection at the following doses: •225Ac-RIMS-5 (40kBq, 0.7kBq / nmol, which corresponds to 1.0mg / kg TLR7 agonist). 225Ac-PSMA-617 was used as a comparison (40kBq, 0.7kBq / nmol) and •90Y-RIMS-5 (9MBq, 0.16 MBq / nmol, which corresponds to 1.0mg / kg TLR7 agonist), 225Ac-PSMA-617 was used as a comparison (9MBq, 0.16 MBq / nmol). Tumor volumes and body weights were recorded every 2-3 days. Results are summarized in FIGS.16A-16C (225Ac-RIMS-5) and FIGS.17A-17B (90Y-RIMS-5).225Ac-RIMS-5 cured 5 / 10 animals with no tumor growth after reimplantation with RM1-PGLS cells (FIG.16A). Thissuggests225Ac-RIMS-5 generates a tumor specific protective immune response vs the225Ac- PSMA-617 treatment group (FIG.16B) which cured 1 mouse, however, after rechallenging with RM1-PGLS there was tumor growth, and the animal had to be euthanized.225Ac-RIMS-5 was well tolerated with mice gaining weight after treatment compared to225Ac-PSMA-617 treated animals which had transient body weight loss and were slower to recover (FIG. 16C).90Y- RIMS-5 cured 3 / 10 of the treated animals (FIG.17A), whereas90Y-PSMA-617 did not cure any of the treated animals (FIG.17B). Example 12 – Biodistribution of90Y-RIMS-5 and225Ac-RIMS-5 in a Syngeneic Mouse Model of Prostate Cancer The biodistribution of90Y-RIMS-5 and225Ac-RIMS-5 in a Syngeneic Mouse Model of Prostate Cancer was studied in accordance with the procedure given above for the biodistribution studies of177Lu-RIMS-3,177Lu-RIMS-4, and177Lu-RIMS-5. Results are shown in FIG.18 (90Y- RIMS-5) and FIG.19 (225Ac-RIMS-5). Equivalents The present disclosure is not to be limited in terms of the particular embodiments described in this application. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. In addition, where features or aspects of the disclosure are described in terms of Markushgroups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 cells refers to groups having 1, 2, or 3 cells. Similarly, a group having 1-5 cells refers to groups having 1, 2, 3, 4, or 5 cells, and so forth. The present technology may include, but is not limited to, the features and combinations of features recited in the following lettered paragraphs, it being understood that the following paragraphs should not be interpreted as limiting the scope of the claims as appended hereto or mandating that all such features must necessarily be included in such claims: A. A compound of Formula I, Formula II, or Formula III,or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of two or more thereof, wherein A at each occurrence is independently a bicyclic C4-12cycloalkyl group or a bicyclic C4-12heterocyclyl group wherein the heterocyclyl group contains one or two heteroatoms selected from O, N, or S; B is a C4-12heterocyclyl group wherein the heterocyclyl group contains two N atoms; Xais C or N; when Xais C, one of Xband Xcis NR4and the other is CR5, or when Xais N, one of Xband Xcis N and the other is CR5;Yaand Ybare independently absent or selected from a C1-6alkylene or C1-6heteroalkylene group wherein the heteroalkylene contains 1, 2 or 3 heteroatoms, each independently selected from N, O, and S; R1is selected from the group consisting of H, a C1-6alkyl group, an N-protecting group, and a radiotherapy moiety optionally comprising M, wherein M is a radioisotope selected from177Lu,90Y,225Ac,47Sc,212Pb,149Tb,58mCo, or67Cu; R2at each occurrence is independently selected from the group consisting of a hydroxyl, halogen, CN, NO2, NRa2, NHCORa, OC(O)Ra, SRa, SO2Ra, SO2NHRa,NHSO2Ra, C(O)ORa, C(O)NRa2, and substituted and unsubstituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocyclyl groups; R3is absent or is selected from the group consisting of -Z-T-R6, -Z-T-U-T-R6, -Z-R7, -Z-Het -Z-Het’-R6, and -Z-Het’-T-R6; R4and R5are independently selected from the group consisting of H and a C1-6alkyl group; R6is selected from the group consisting of H, and a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl group; R7is selected from CN or a substituted or unsubstituted nitrogen-containing heterocyclyl group; R8and R9are independently selected from a C1-6alkyl group; Raat each occurrence is independently selected from the group consisting of H and substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl groups;U is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more -O- groups; T is selected from the group consisting of O, S(O)0-2, S(O)2-NR10a, C(R6a), C(R6a)-O, O- C(O)-O, Q-N(R8a), -C(R6a)-N(R8a), -O-C(R6a)-N(R8a)-, -C(R6a)-N(OR9a)-, and a substituted or unsubstituted nitrogen-containing heterocyclyl group having 5-9 ring members; Het is a substituted or unsubstituted heterocyclyl group; Het’ is a substituted or unsubstituted heterocyclylene group; Q is selected from the group consisting of a bond, -C(R6a)-, -C(R6a)-C(R6a)-, -S(O)2-, -C(R6a)-N(R8a)-W-, -S(O)2-N(R8a)-, -C(R6a)-O-, and -C(R6a)-N(OR9a)-; Z is selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene; wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more -O- groups; and n is 0, 1, 2, 3, or 4; provided that the compound of Formula III is notB. The compound of paragraph A, wherein A is a spirobicyclic C5-12 cycloalkyl group or a spirobicyclic C4-12heterocyclyl group.C. The compound of paragraph A or B, wherein A is a spirobicyclic C5-10cycloalkyl group or a spirobicyclic C4-10heterocyclyl group. D. The compound of any one of paragraphs A-C, wherein A is selected fromE. The compound of paragraph A, wherein A is a bridged bicyclic C5-10cycloalkyl group or a bridged bicyclic C4-10heterocyclyl group.F. The compound of paragraph A or E wherein A is selected from,G. The compound of paragraph A, wherein A is a fused bicyclic C4-12cycloalkyl group or a fused bicyclic C4-12heterocyclyl group. H. The compound of paragraph A or G, wherein A is a fused bicyclic C5-10cycloalkyl group or a fused bicyclic C5-10heterocyclyl group. I. The compound of any one of paragraphs A, G, or H, wherein A is selected fromJ. The compound of paragraph A, wherein B is a monocyclic C4-6heterocyclyl group containing two N atoms. K. The compound of paragraph A or J, wherein B is selected fromL. The compound of any one of paragraphs A-K, wherein Xais N. M. The compound of any one of paragraphs A-L, wherein Xbis N. N. The compound of any one of paragraphs A-M, wherein Xcis CR4. O. The compound of any one of paragraphs A-L, wherein Xbis CR4. P. The compound of any one of paragraphs A-M or O, wherein Xcis N.Q. The compound of any one of paragraphs A-K, wherein Xais C. R. The compound of paragraph Q, wherein Xbis CR4and Xcis NR3. S. The compound of paragraph Q, wherein Xbis NR3and Xcis CR4. T. The compound of any one of paragraphs A-S, wherein Yais a C1-6alkylene group. U. The compound of any one of paragraphs A-T, wherein Yais a methylene group. V. The compound of any one of paragraphs A-U, wherein Ybis a C1-6alkylene group. W. The compound of any one of paragraphs A-V, wherein Ybis a methylene group. X. The compound of any one of paragraphs A-S, wherein Yais a C1-6heteroalkylene group. Y. The compound of any one of paragraphs A-S or X, wherein Yais -NH(CH2)1-5-. Z. The compound of any one of paragraphs A-S, wherein Ybis a C1-6heteroalkylene group. AA. The compound of any one of paragraphs A-S or Z, wherein Ybis -NH(CH2)1-5-. AB. The compound of any one of paragraphs A-S, V-W, or Z-AA, wherein Yais absent. AC. The compound of any one of paragraphs A-U or X-Y, wherein Ybis absent. AD. The compound of any one of paragraphs A-AC, wherein R1is an N-protecting group. AE. The compound of paragraph AD, wherein R1is Boc, Fmoc, Cbz, Alloc, or Troc. AF. The compound of any one of paragraphs A-AB, wherein R1is H. AG. The compound of any one of paragraphs A-AB, wherein R1is the radiotherapy moiety selected from structure A or structure B,AH. The compound of paragraph AG, wherein R1is the radiotherapy moiety of structure A. AI. The compound of paragraph AG, wherein R1is the radiotherapy moiety of structure B. AJ. The compound of any one of paragraphs A-AI, wherein n is 0, 1 or 2. AK. The compound of any one of paragraphs A-AJ, wherein n is 1 or 2. AL. The compound of paragraph AK, wherein R2is at each occurrence independently selected from a C1-6haloalkyl, a quinolinyl group or C(O)O-(C1-6alkyl). AM. The compound of any one of paragraphs A-AL, wherein R3is absent.AN. The compound of any one of paragraphs A-AM, wherein R3is -Z-Het AO. The compound of paragraph AN, wherein Het is quinolinyl. AP. The compound of any one of paragraphs A-AO, wherein R4is H. AQ. The compound of any one of paragraphs A-AP, wherein R5is H. AR. The compound of any one of paragraphs A-AP, wherein R8is methyl. AS. The compound of any one of paragraphs A-AR, wherein R9is propyl, butyl, or pentyl. AT. The compound of any one of paragraphs A-AS, wherein the compound is of Formula I. AU. The compound of any one of paragraphs A-AS, wherein the compound is of Formula II. AV. The compound of any one of paragraphs A-AS, wherein the compound is of Formula III. AW. A pharmaceutical composition comprising a compound of any one of paragraphs A-AV and a pharmaceutically acceptable carrier or excipient. AX. The pharmaceutical composition of paragraph AV, wherein each R1is H AY. The pharmaceutical composition of paragraph AV, wherein R1is a radiotherapy moiety of structure A. AZ. The pharmaceutical composition of paragraph AV, wherein R1is a radiotherapy moiety of structure B. BA. A vaccine adjuvant comprising a compound of any one of paragraphs A-AU. BB. The vaccine adjuvant of paragraph BA, wherein R1is H.BC. A method of activating an immune cell comprising TLR7 and / or TLR8, the method comprising administering an effective amount of a compound of any one of paragraphs A-AV to the immune cell. BD. The method of paragraph BC, wherein the immune is cell is in vitro. BE. The method of paragraph BC, wherein the administering step comprises administering the effective amount of the compound to a subject in need of immune cell activation. BF. The method of paragraph BE, wherein the subject has a PMSA-expressing cancer. BG. The method of paragraph BF, wherein the cancer is selected from the group consisting of non-Hodgkin’s lymphoma, pancreatic cancer, multiple myeloma, colorectal cancer, renal and mammary carcinomas, skin cancer, and / or cervical intraepithelial neoplasia. BH. The method of any one of paragraphs BE-BG further comprising administering an effective amount of a checkpoint inhibitor simultaneously or sequentially with the compound. BI. A method of treatment comprising administering an effective amount of a compound of any one of paragraphs A-AU, wherein R2is the radiotherapy moiety of structure B, to a subject suffering from a cancer susceptible to radioimmunotherapy. BJ. The method of paragraph BI, wherein the cancer is a PMSA-expressing cancer. BK. The method of paragraph BI or BJ, wherein the subject is suffering from a cancer selected from the group consisting of non-Hodgkin’s lymphoma, pancreatic cancer, multiple myeloma, colorectal cancer, renal and mammary carcinomas, skin cancer, and / or cervical intraepithelial neoplasia. BL. The method of any one of paragraphs BI-BK, wherein the subject is a human. BM. The method of any one of paragraphs BI-BL, wherein M of the radiotherapy moiety is 177Lu.While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated by the following claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I, Formula II, or Formula III,III or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of two or more thereof, wherein A at each occurrence is independently a bicyclic C4-12cycloalkyl group or a bicyclic C4-12heterocyclyl group wherein the heterocyclyl group contains one or two heteroatoms selected from O, N, or S; B is a C4-12heterocyclyl group wherein the heterocyclyl group contains two N atoms; Xais C or N; when Xais C, one of Xband Xcis NR4and the other is CR5, or when Xais N, one of Xband Xcis N and the other is CR5; Yaand Ybare independently absent or selected from a C1-6alkylene or C1-6heteroalkylene group wherein the heteroalkylene contains 1, 2 or 3 heteroatoms, each independently selected from N, O, and S; R1is selected from the group consisting of H, a C1-6alkyl group, an N-protecting group, and a radiotherapy moiety optionally comprising M, wherein M is a radioisotope selected from177Lu,90Y,225Ac,47Sc,212Pb,149Tb,58mCo, or67Cu; R2at each occurrence is independently selected from the group consisting of a hydroxyl, halogen, CN, NO2, NRa2, NHCORa, OC(O)Ra, SRa, SO2Ra, SO2NHRa,NHSO2Ra, C(O)ORa, C(O)NRa2, and substituted and unsubstituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocyclyl groups; R3is absent or is selected from the group consisting of -Z-T-R6, -Z-T-U-T-R6, -Z-R7, -Z-Het -Z-Het’-R6, and -Z-Het’-T-R6;R4and R5are independently selected from the group consisting of H and a C1-6alkyl group; R6is selected from the group consisting of H, and a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl group; R7is selected from CN or a substituted or unsubstituted nitrogen-containing heterocyclyl group; R8and R9are independently selected from a C1-6alkyl group; Raat each occurrence is independently selected from the group consisting of H and substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl groups; U is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more -O- groups; T is selected from the group consisting of O, S(O)0-2, S(O)2-NR10a, C(R6a), C(R6a)-O, O- C(O)-O, Q-N(R8a), -C(R6a)-N(R8a), -O-C(R6a)-N(R8a)-, -C(R6a)-N(OR9a)-, and a substituted or unsubstituted nitrogen-containing heterocyclyl group having 5-9 ring members; Het is a substituted or unsubstituted heterocyclyl group; Het’ is a substituted or unsubstituted heterocyclylene group; Q is selected from the group consisting of a bond, -C(R6a)-, -C(R6a)-C(R6a)-, -S(O)2-, -C(R6a)-N(R8a)-W-, -S(O)2-N(R8a)-, -C(R6a)-O-, and -C(R6a)-N(OR9a)-; Z is selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene; wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more -O- groups; and n is 0, 1, 2, 3, or 4;provided that the compound of Formula III is not2. The compound of claim 1, wherein A is a spirobicyclic C5-12cycloalkyl group or a spirobicyclic C4-12heterocyclyl group.

3. The compound of claim 1 or claim 2, wherein A is a spirobicyclic C5-10cycloalkyl group or a spirobicyclic C4-10heterocyclyl group.

4. The compound of any one of claims 1-3, wherein A is selected from5. The compound of claim 1, wherein A is a bridged bicyclic C5-10cycloalkyl group or a bridged bicyclic C4-10heterocyclyl group.

6. The compound of claim 1 or claim 5 wherein A is selected from7. The compound of claim 1, wherein A is a fused bicyclic C4-12cycloalkyl group or a fused bicyclic C4-12heterocyclyl group.

8. The compound of claim 1 or claim 7, wherein A is a fused bicyclic C5-10cycloalkyl group or a fused bicyclic C5-10heterocyclyl group.

9. The compound of any one of claims 1, 7 or 8, wherein A is selected from10. The compound of claim 1, wherein B is a monocyclic C4-6heterocyclyl group containing two N atoms.

11. The compound of claim 1 or claim 10, wherein B is selected from12. The compound of any one of claims 1-11, wherein Xais N.

13. The compound of any one of claims 1-12, wherein Xbis N.

14. The compound of any one of claims 1-13, wherein Xcis CR4.

15. The compound of any one of claims 1-12, wherein Xbis CR4.

16. The compound of any one of claims 1-13 or 15, wherein Xcis N.

17. The compound of any one of claims 1-11, wherein Xais C.

18. The compound of claim 17, wherein Xbis CR4and Xcis NR3.

19. The compound of claim 17, wherein Xbis NR3and Xcis CR4.

20. The compound of any one of claims 1-19, wherein Yais a C1-6alkylene group.

21. The compound of any one of claims 1-20, wherein Yais a methylene group.

22. The compound of any one of claims 1-21, wherein Ybis a C1-6alkylene group.

23. The compound of any one of claims 1-22, wherein Ybis a methylene group.

24. The compound of any one of claims 1-19, wherein Yais a C1-6heteroalkylene group.

25. The compound of any one of claims 1-19 or 24, wherein Yais -NH(CH2)1-5-.

26. The compound of any one of claims 1-19, wherein Ybis a C1-6heteroalkylene group.

27. The compound of any one of claims 1-19 or 26, wherein Ybis -NH(CH2)1-5-.

28. The compound of any one of claims 1-19, 22-23, or 26-27, wherein Yais absent.

29. The compound of any one of claims 1-21 or 24-25, wherein Ybis absent.

30. The compound of any one of claims 1-29, wherein R1is an N-protecting group.

31. The compound of claim 30, wherein R1is Boc, Fmoc, Cbz, Alloc, or Troc.

32. The compound of any one of claims 1-28, wherein R1is H.

33. The compound of any one of claims 1-28, wherein R1is the radiotherapy moiety selected from structure A or structure B,34. The compound of claim 33, wherein R1is the radiotherapy moiety of structure A.

35. The compound of claim 33, wherein R1is the radiotherapy moiety of structure B.

36. The compound of any one of claims 1-35, wherein n is 0, 1 or 2.

37. The compound of any one of claims 1-36, wherein n is 1 or 2.

38. The compound of claim 37, wherein R2is at each occurrence independently selected from a C1-6haloalkyl, a quinolinyl group or C(O)O-(C1-6alkyl).

39. The compound of any one of claims 1-38, wherein R3is absent.

40. The compound of any one of claims 1-39, wherein R3is -Z-Het 41. The compound of claim 40, wherein Het is quinolinyl.

42. The compound of any one of claims 1-41, wherein R4is H.

43. The compound of any one of claims 1-42, wherein R5is H.

44. The compound of any one of claims 1-42, wherein R8is methyl.

45. The compound of any one of claims 1-44, wherein R9is propyl, butyl, or pentyl.

46. The compound of any one of claims 1-45, wherein the compound is of Formula I.

47. The compound of any one of claims 1-45, wherein the compound is of Formula II.

48. The compound of any one of claims 1-45, wherein the compound is of Formula III.

49. A pharmaceutical composition comprising a compound of any one of claims 1-48 and a pharmaceutically acceptable carrier or excipient.

50. The pharmaceutical composition of claim 48, wherein each R1is H 51. The pharmaceutical composition of claim 48, wherein R1is a radiotherapy moiety of structure A.

52. The pharmaceutical composition of claim 48, wherein R1is a radiotherapy moiety of structure B.

53. A vaccine adjuvant comprising a compound of any one of claims 1-47.

54. The vaccine adjuvant of claim 53, wherein R1is H.

55. A method of activating an immune cell comprising TLR7 and / or TLR8, the method comprising administering an effective amount of a compound of any one of claims 1-48 to the immune cell.

56. The method of claim 55, wherein the immune is cell is in vitro.

57. The method of claim 55, wherein the administering step comprises administering the effective amount of the compound to a subject in need of immune cell activation.

58. The method of claim 57, wherein the subject has a PMSA-expressing cancer.

59. The method of claim 58, wherein the cancer is selected from the group consisting of non- Hodgkin’s lymphoma, pancreatic cancer, multiple myeloma, colorectal cancer, renal and mammary carcinomas, skin cancer, and / or cervical intraepithelial neoplasia.

60. The method of any one of claims 57-59 further comprising administering an effective amount of a checkpoint inhibitor simultaneously or sequentially with the compound.

61. A method of treatment comprising administering an effective amount of a compound of any one of claims 1-47, wherein R2is the radiotherapy moiety of structure B, to a subject suffering from a cancer susceptible to radioimmunotherapy.

62. The method of claim 61, wherein the cancer is a PMSA-expressing cancer.

63. The method of claim 61 or claim 62, wherein the subject is suffering from a cancer selected from the group consisting of non-Hodgkin’s lymphoma, pancreatic cancer, multiple myeloma, colorectal cancer, renal and mammary carcinomas, skin cancer, and / or cervical intraepithelial neoplasia.

64. The method of any one of claims 61-63, wherein the subject is a human.

65. The method of any one of claims 61-64, wherein M of the radiotherapy moiety is177Lu.

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