Benzonapthyridine compositions and uses thereof

Abstract

The present invention generally relates to compositions comprising benzonapthyridine small molecule immune potentiators (SMIPs) that are capable of stimulating or modulating an immune response in a subject that has had pre- or post-exposure to a pathogen such as hemorrhagic fever virus. Also provided are methods of preparing and using the SMIP compositions of the invention.

1 : A method of (i) potentiating an immune response to a hemorrhagic fever virus, comprising administering to a subject a pharmaceutically effective amount of a composition comprising a benzonapthyridine TLR7 agonist or salt, solvate, or derivative thereof, (ii) treating a subject who has been exposed to a hemorrhagic fever virus, comprising administering to said subject a pharmaceutically effective amount of a composition comprising a benzonapthyridine TLR7 agonist or salt, solvate, or derivative thereof, (iii) for inducing an immune response to a hemorrhagic fever virus, comprising administering to said subject an immunogenic composition comprising: (a) a benzonapthyridine TLR7 agonist or salt, solvate, or derivative thereof, and (b) an antigen derived from a hemorrhagic fever virus, (iv) inducing an immune response to a hemorrhagic fever virus, comprising administering to said subject an immunogenic composition comprising: (a) a benzonapthyridine TLR7 agonist or salt, solvate, or derivative thereof: (b) an antigen derived from a hemorrhagic fever virus; and (c) an adjuvant, or (v) inducing an immune response to a hemorrhagic fever virus, comprising administering to said subject an immunogenic composition comprising a benzonapthyridine TLR7 agonist or salt, solvate, or derivative thereof. 
     
     
         2 - 13 . (canceled) 
     
     
         14 : An immunogenic composition comprising: (i) (a) benzonapthyridine compound, or salt, solvate, or derivative thereof, having the structure of: 
       
         
           
           
               
               
           
         
         wherein: 
         R 3  is H, halogen, C 1 -C 6 alkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cycloalkyl, or C 3 -C 8 heterocycloalkyl groups of R 3  are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —R 7 , —OR 8 , —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —N(R 9 ) 2 , —C(O)N(R 9 ) 2 , —S(O) 2 R 8 , —S(O) 2 N(R 9 ) 2  and —NR 9 S(O) 2 R 8 ; 
         R 4  and R 5  are each independently selected from H, halogen, —C(O)OR 7 , —C(O)R 7 , —C(O)N(R 11 R 12 ), —N(R 11 R 12 ), —N(R 9 ) 2 , —NHN(R 9 ) 2 , —SR 7 , —(CH 2 ) n OR 7 , —(CH 2 ) n R 7 , -LR 8 , -LR 10 , —OLR 8 , —OLR 10 , C 1 -C 6 alkyl, C 1 -C 8 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl groups of R 4  and R 5  are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —NO 2 , —R 7 , —OR 8 , —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —N(R 9 ) 2 , —P(O)(OR 8 ) 2 , —OP(O)(OR 8 ) 2 , —P(O)(OR 10 ) 2 , —OP(O)(OR 10 ) 2 , —C(O)N(R 9 ) 2 , —S(O) 2 R 8 , —S(O)R 8 , —S(O) 2 N(R 9 ) 2 , and —NR 9 S(O) 2 R 8 ; 
         or R 3  and R 4 , or R 4  and R 5 , when present on adjacent ring atoms, can optionally be linked together to form a 5-6 membered ring, wherein the 5-6 membered ring is optionally substituted with R 7 ; 
         each L is independently selected from a bond, —(O(CH 2 ) m ) t —, C 1 -C 6 alkyl, C2-C 6 alkenylene and C 2 -C 6 alkynylene, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenylene and C 2 -C 6 alkynylene of L are each optionally substituted with 1 to 4 substituents independently selected from halogen, —R 8 , —OR 8 , —N(R 9 ) 2 , —P(O)(OR 8 ) 2 , —OP(O)(OR 8 ) 2 , —P(O)(OR 10 ) 2 , and —OP(O)(OR 10 ) 2 ; 
         R 7  is selected from H, C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 3 -C 8 heterocycloalkyl groups of R 7  are each optionally substituted with 1 to 3 R 13  groups, and each R 13  is independently selected from halogen, —CN, -LR 9 , -LOR 9 , —OLR 9 , -LR 10 , -LOR 10 , —OLR 10 , -LR 8 , -LOR 8 , —OLR 8 , -LSR 8 , -LSR 10 , -LC(O)R 8 , —OLC(O)R 8 , -LC(O)OR 8 , -LC(O)R 10 , -LOC(O)OR 8 , -LC(O)NR 9 R 11 , -LC(O)NR 9 R 8 , -LN(R 9 ) 2 , -LNR 9 R 8 , -LNR 9 R 10 , -LC(O)N(R 9 ) 2 , -LS(O) 2 R 8 , -LS(O)R 8 , -LC(O)NR 8 OH, -LNR 9 C(O)R 8 , -LNR 9 C(O)OR 8 , -LS(O) 2 N(R 9 ) 2 , —OLS(O) 2 N(R 9 ) 2 , -LNR 9 S(O) 2 R 8 , -LC(O)NR 9 LN(R 9 ) 2 , -LP(O)(OR 8 ) 2 , -LOP(O)(OR 8 ) 2 , -LP(O)(OR 10 ) 2  and —OLP(O)(OR 10 ) 2 ; 
         each R 8  is independently selected from H, —CH(R 10 ) 2 , C1-C 8 alkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkoxy, wherein the C 1 -C 8 alkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkoxy groups of R 8  are each optionally substituted with 1 to 3 substituents independently selected from —CN, R 11 , —OR 11 , —SR 11 , —C(O)R 11 , —OC(O)R 11 , —C(O)N(R 9 ) 2 , —C(O)OR 11 , —NR 9 C(O)R 11 , —NR 9 R 10 , —NR 11 R 12 , —N(R 9 ) 2 , —OR 9 , —OR 10 , —C(O)NR 11 R 12 , —C(O)NR 11 OH, —S(O) 2 R 11 , —S(O)R 11 , —S(O) 2 NR 11 R 12 , —NR 11 S(O) 2 R 11 , —P(O)(OR 11 ) 2 , and —OP(O)(OR 11 ) 2 ; 
         each R 9  is independently selected from H, —C(O)R 8 , —C(O)OR 8 , —C(O)R 10 , —C(O)OR 10 , —S(O) 2 R 10 , —C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl and C 3 -C 6  cycloalkyl, or each R 9  is independently a C 1 -C 6 alkyl that together with N they are attached to form a C 3 -C 8 heterocycloalkyl, wherein the C 3 -C 8 heterocycloalkyl ring optionally contains an additional heteroatom selected from N, O and S, and wherein the C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 3 -C 8  cycloalkyl, or C 3 -C 8 heterocycloalkyl groups of R 9  are each optionally substituted with 1 to 3 substituents independently selected from —CN, R 11 , —OR 11 , —SR 11 , —C(O)R 11 , —OC(O)R 11 , —C(O)OR 11 , —NR 11 R 12 , —C(O)NR 11 R 12 , —C(O)NR 11 OH, —S(O) 2 R 11 , —S(O)R 11 , —S(O) 2 NR 11 R 12 , —NR 11 S(O) 2 R 11 , —P(O)(OR 11 ) 2 , and —OP(O)(OR 11 ) 2 ; 
         each R 10  is independently selected from aryl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl and heteroaryl, wherein the aryl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl and heteroaryl groups are optionally substituted with 1 to 3 substituents selected from halogen, —R 8 , —OR 8 , -LR 9 , -LOR 9 , —N(R 9 ) 2 , —NR 9 C(O)R 8 , —NR 9 CO 2 R 8 , —CO 2 R 8 , —C(O)R 8  and —C(O)N(R 9 ) 2 ; 
         R 11  and R 12  are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl groups of R 11  and R 12  are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, R 8 , —OR 8 , —C(O)R 8 ,  − OC(O)R 8 , —C(O)OR 8 , —N(R 9 ) 2 , —NR 8 C(O)R 8 , —NR 8 C(O)OR 8 , —C(O)N(R 9 ) 2 , C 3 -C 8 heterocycloalkyl, —S(O) 2 R 8 , —S(O) 2 N(R 9 ) 2 , —NR 9 S(O) 2 R 8 , C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy; 
         or R 11  and R 12  are each independently C 1 -C 6 alkyl and taken together with the N atom to which they are attached form an optionally substituted C 3 -C 8 heterocycloalkyl ring optionally containing an additional heteroatom selected from N, O and S; 
         each R A  is independently selected from halogen, —R 8 , —R 7 , —OR 7 , —OR 8 , —R 10 , —OR 10 , —SR 8 , —NO 2 , —CN, —N(R 9 ) 2 , —NR 9 C(O)R 8 , —NR 9 C(S)R 8 , —NR 9 C(O)N(R 9 ) 2 , —NR 9 C(S)N(R 9 ) 2 , —NR 9 CO 2 R 8 , —NR 9 NR 9 C(O)R 8 , —NR 9 NR 9 C(O)N(R 9 ) 2 , —NR 9 NR 9 CO 2 R 8 , —C(O)C(O)R 8 , —C(O)CH 2 C(O)R 8 , —CO 2 R 8 , —(CH 2 ) n CO 2 R 8 , —C(O)R 8 , —C(S)R 8 , —C(O)N(R 9 ) 2 , —C(S)N(R 9 ) 2 , —OC(O)N(R 9 ) 2 , —OC(O)R 8 , —C(O)N(OR 8 )R 8 , —C(NOR 8 )R 8 , —S(O) 2 R 8 , —S(O) 3 R 8 , —SO 2 N(R 9 ) 2 , —S(O)R 8 , —NR 9 SO 2 N(R 9 ) 2 , —NR 9 SO 2 R 8 , —P(O)(OR 8 ) 2 , —OP(O)(OR 8 ) 2 , —P(O)(OR 10 ) 2 , —OP(O)(OR 10 ) 2 , —N(OR 8 )R 8 , —CH═CHCO 2 R 8 , —C(═NH)—N(R 9 ) 2 , and —(CH 2 ) n NHC(O)R 8 ; or two adjacent R A  substituents form a 5-6 membered ring that contains up to two heteroatoms as ring members; 
         n is, independently at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7 or 8; 
         each m is independently selected from 1, 2, 3, 4, 5 and 6, and 
         t is 1, 2, 3, 4, 5, 6, 7 or 8; 
         and (b) an antigen derived from a hemorrhagic fever virus, or (ii) (a) benzonapthyridine compound, or salt, solvate, or derivative thereof, having the structure of: 
       
       
         
           
           
               
               
           
         
         wherein: 
         R 3  is H, halogen, C 1 -C 6 alkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cycloalkyl, or C 3 -C 8 heterocycloalkyl groups of R 3  are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —R 7 , —OR 8 , —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —N(R 9 ) 2 , —C(O)N(R 9 ) 2 , —S(O) 2 R 8 , —S(O) 2 N(R 9 ) 2  and —NR 9 S(O) 2 R 8 ; 
         R 4  and R 5  are each independently selected from H, halogen, —C(O)OR 7 , —C(O)R 7 , —C(O)N(R 11 R 12 ), —N(R 11 R 12 ), —N(R 9 ) 2 , —NHN(R 9 ) 2 , —SR 7 , —(CH 2 ) n OR 7 , —(CH 2 ) n R 7 , -LR 8 , -LR 10 , —OLR 8 , —OLR 10 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl groups of R 4  and R 5  are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —NO 2 , —R 7 , —OR 8 , —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —N(R 9 ) 2 , —P(O)(OR 8 ) 2 , —OP(O)(OR 8 ) 2 , —P(O)(OR 10 ) 2 , —OP(O)(OR 10 ) 2 , —C(O)N(R 9 ) 2 , —S(O) 2 R 8 , —S(O)R 8 , —S(O) 2 N(R 9 ) 2 , and —NR 9 S(O) 2 R 8 ; 
         or R 3  and R 4 , or R 4  and R 5 , when present on adjacent ring atoms, can optionally be linked together to form a 5-6 membered ring, wherein the 5-6 membered ring is optionally substituted with R 7 ; 
         each L is independently selected from a bond, —(O(CH 2 ) m ) t —, C 1 -C 6 alkyl, C 2 -C 6 alkenylene and C 2 -C 6 alkynylene, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenylene and C 2 -C 6 alkynylene of L are each optionally substituted with 1 to 4 substituents independently selected from halogen, —R 8 , —OR 8 , —N(R 9 ) 2 , —P(O)(OR 8 ) 2 , —OP(O)(OR 8 ) 2 , —P(O)(OR 10 ) 2 , and —OP(O)(OR 10 ) 2 ; 
         R 7  is selected from H, C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 3 -C 8 heterocycloalkyl groups of R 7  are each optionally substituted with 1 to 3 R 13  groups, and each R 13  is independently selected from halogen, —CN, -LR 9 , -LOR 9 , —OLR 9 , -LR 10 , -LOR 10 , —OLR 10 , -LR 8 , -LOR 8 , —OLR 8 , -LSR 8 , -LSR 10 , -LC(O)R 8 , —OLC(O)R 8 , -LC(O)OR 8 , -LC(O)R 10 , -LOC(O)OR 8 , -LC(O)NR 9 R 11 , -LC(O)NR 9 R 8 , -LN(R 9 ) 2 , -LNR 9 R 8 , -LNR 9 R 10 , -LC(O)N(R 9 ) 2 , -LS(O) 2 R 8 , -LS(O)R 8 , -LC(O)NR 8 OH, -LNR 9 C(O)R 8 , -LNR 9 C(O)OR 8 , -LS(O) 2 N(R 9 ) 2 , OLS(O) 2 N(R 9 ) 2 , -LNR 9 S(O) 2 R 8 , -LC(O)NR 9 LN(R 9 ) 2 , -LP(O)(OR 8 ) 2 , -LOP(O)(OR 8 ) 2 , LP(O)(OR 10 ) 2  and —OLP(O)(OR 10 ) 2 ; 
         each R 8  is independently selected from H, —CH(R 10 ) 2 , C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkoxy, wherein the C 1 -C 8 alkyl, C 2 -C 8 alkene C 2 -C 8 alkyne, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkoxy groups of R 8  are each optionally substituted with 1 to 3 substituents independently selected from —CN, R 11 , —OR 11 , —SR 11 , —C(O)R 11 , —OC(O)R 11 , —C(O)N(R 9 ) 2 , —C(O)OR 11 , —NR 9 C(O)R 11 , NR 9 R 10 , —NR 11 R 12 , —N(R 9 ) 2 , —OR 9 , —OR 10 , —C(O)NR 11 R 12 , —C(O)NR 11 OH, —S(O) 2 R 11 , —S(O)R 11 , —S(O) 2 NR 11 R 12 , NR 11 S(O) 2 R 11 , —P(O)(OR 11 ) 2 , and —OP(O)(OR 11 ) 2 ; 
         each R 9  is independently selected from H, —C(O)R 8 , —C(O)OR 8 , —C(O)R 10 , —C(O)OR 10 , —S(O) 2 R 10 , —C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl and C 3 -C 6  cycloalkyl, or each R 9  is independently a C 1 -C 6 alkyl that together with N they are attached to form a C 3 -C 8 heterocycloalkyl, wherein the C 3 -C 8 heterocycloalkyl ring optionally contains an additional heteroatom selected from N, O and S, and wherein the C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 3 -C 6 cycloalkyl, or C 3 -C 8 heterocycloalkyl groups of R 9  are each optionally substituted with 1 to 3 substituents independently selected from —CN, R 11 , —OR 11 , —SR 11 , —C(O)R 11 , —OC(O)R 11 , —C(O)OR 11 , —NR 11 R 12 , —C(O)NR 11 R 12 , —C(O)NR 11 OH, —S(O) 2 R 11 , —S(O)R 11 , —S(O) 2 NR 11 R 12 , —NR 11 S(O) 2 R 11 , —P(O)(OR 11 ) 2  and —OP(O)(OR 11 ) 2 ; 
         each R 10  is independently selected from aryl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl and heteroaryl, wherein the aryl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl and heteroaryl groups are optionally substituted with 1 to 3 substituents selected from halogen, —R 8 , —OR 8 , -LR 9 , -LOR 9 , —N(R 9 ) 2 , —NR 9 C(O)R 8 , —NR 9 CO 2 R 8 , —CO 2 R 8 , —C(O)R 8  and —C(O)N(R 9 ) 2 ; 
         R 11  and R 12  are independently selected from H, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl groups of R 11  and R 12  are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, R 8 , —OR 8 , —C(O)R 8 ,  − OC(O)R 8 , —C(O)OR 8 , —N(R 9 ) 2 , —NR 8 C(O)R 8 , —NR 8 C(O)OR 8 , —C(O)N(R 9 ) 2 , C 3 -C 8 heterocycloalkyl, —S(O) 2 R 8 , —S(O) 2 N(R 9 ) 2 , —NR 9 S(O) 2 R 8 , C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy; 
         or R 11  and R 12  are each independently C 1 -C 6 alkyl and taken together with the N atom to which they are attached form an optionally substituted C 3 -C 8 heterocycloalkyl ring optionally containing an additional heteroatom selected from N, O and S; 
         each R A  is independently selected from halogen, —R 8 , —R 7 , —OR 7 , —OR 8 , —R 10 , —OR 10 , —SR 8 , —NO 2 , —CN, —N(R 9 ) 2 , —NR 9 C(O)R 8 , —NR 9 C(S)R 8 , —NR 9 C(O)N(R 9 ) 2 , —NR 9 C(S)N(R 9 ) 2 , —NR 9 CO 2 R 8 , —NR 9 NR 9 C(O)R 8 , —NR 9 NR 9 C(O)N(R 9 ) 2 , —NR 9 NR 9 CO 2 R 8 , —C(O)C(O)R 8 , —C(O)CH 2 C(O)R 8 , —CO 2 R 8 , —(CH 2 ) n CO 2 R 8 , —C(O)R 8 , —C(S)R 8 , —C(O)N(R 9 ) 2 , —C(S)N(R 9 ) 2 , —OC(O)N(R 9 ) 2 , —OC(O)R 8 , —C(O)N(OR 8 )R 8 , —C(NOR 8 )R 8 , —S(O) 2 R 8 , —S(O) 3 R 8 , —SO 2 N(R 9 ) 2 , —S(O)R 8 , —NR 9 SO 2 N(R 9 ) 2 , —NR 9 SO 2 R 8 , —P(O)(OR 8 ) 2 , —OP(O)(OR 8 ) 2 , —P(O)(OR 10 ) 2 , —OP(O)(OR 10 ) 2 , —N(OR 8 )R 8 , —CH═CHCO 2 R 8 , —C(═NH)—N(R 9 ) 2 , and —(CH 2 ) n NHC(O)R 8 ; or two adjacent R A  substituents form a 5-6 membered ring that contains up to two heteroatoms as ring members; 
         n is, independently at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7 or 8; 
         each m is independently selected from 1, 2, 3, 4, 5 and 6, and 
         t is 1, 2, 3, 4, 5, 6, 7 or 8; 
         (b) an antigen derived from a hemorrhagic fever virus; and (c) an adjuvant. 
       
     
     
         15 - 26 . (canceled) 
     
     
         27 : An immunogenic composition comprising: (i) (a) benzonapthyridine compound of Formula (VIII), or salt, solvate, or derivative thereof, having the structure of: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is H, C 1 -C 6 alkyl, —C(R 5 ) 2 OH, -L 1 R 5 , -L 1 R 6 , -L 2 R 5 , -L 2 R 6 , —OL 2 R 5 , or —OL 2 R 6 ; 
 L 1  is —C(O)— or —O—; 
 L 2  is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, arylene, heteroarylene or #CR 4 R 4 ) p O) q (CH 2 ) p —, wherein the C 1 -C 6 alkylene and C 2 -C 6 alkenylene of L 2  are optionally substituted with 1 to 4 fluoro groups; 
 each L 3  is independently selected from C 1 -C 6 alkylene and —((CR 4 R 4 ) p O) q (CH 2 ) p —, wherein the C 1 -C 6 alkylene of L 3  is optionally substituted with 1 to 4 fluoro groups; 
 L 4  is arylene or heteroarylene; 
 R 2  is H or C 1 -C 6 alkyl; 
 R 3  is selected from C 1 -C 4 alkyl, -L 3 R 5 , -L 1 R 5 , -L 3 R 7 , -L 3 L 4 L 3 R 7 , -L 3 L 4 R 5 , -L 3 L 4 L 3 R 5 , —OL 3 R 5 , —OL 3 R 7 , —OL 3 L 4 R 7 , —OL 3 L 4 L 3 R 7 , —OR 8 , —OL 3 L 4 R 5 , —OL 3 L 4 L 3 R 5  and —C(R 5 ) 2 OH; 
 each R 4  is independently selected from H and fluoro; 
 R 5  is —P(O)(OR 9 ) 2 , 
 R 6  is —CF 2 P(O)(OR 9 ) 2  or —C(O)OR 10 ; 
 R 7  is —CF 2 P(O)(OR 9 ) 2  or —C(O)OR 10 ; 
 R 8  is H or C 1 -C 4 alkyl; 
 each R 9  is independently selected from H and C 1 -C 6 alkyl; 
 R 10  is H or C 1 -C 4 alkyl; 
 each p is independently selected from 1, 2, 3, 4, 5 and 6, and 
 q is 1, 2, 3 or 4; 
 
         with the proviso that when R 3  is C 1 -C 4  alkyl or —OR 8 , R 1  is —C(R 5 ) 2 OH, -L 1 R 5 , -L 1 R 6 , -L 2 R 5 , -L 2 R 6 , —OL 2 R 5 , or —OL 2 R 6 , wherein R 6  is —CF 2 P(O)(OR 9 ) 2  and R 7  is —CF 2 P(O)(OR 9 ) 2 ; 
         and (b) an antigen derived from a hemorrhagic fever virus, or (ii) (a) benzonapthyridine compound of Formula (VIII), or salt, solvate, or derivative thereof, having the structure of: 
       
       
         
           
           
               
               
           
         
         wherein:
 R 1  is H C 1 -C 6 alkyl, —C(R 5 ) 2 OH, -L 1 R 5 , -L 1 R 6 , -L 2 R 5 , -L 2 R 6 , —OL 2 R 5 , or —OL 2 R 6 ; 
 L 1  is —C(O)— or —O—; 
 L 2  is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, arylene, heteroarylene or —((CR 4 R 4 ) p O) q (CH 2 ) p —, wherein the C 1 -C 6 alkylene and C 2 -C 6 alkenylene of L 2  are optionally substituted with 1 to 4 fluoro groups; 
 each L 3  is independently selected from C 1 -C 6 alkylene and —((CR 4 R 4 ) p O) q (CH 2 ) p —, wherein the C 1 -C 6 alkylene of L 3  is optionally substituted with 1 to 4 fluoro groups; 
 L 4  is arylene or heteroarylene; 
 R 2  is H or C 1 -C 6 alkyl; 
 R 3  is selected from C 1 -C 4 alkyl, -L 3 R 5 , -L 1 R 5 , -L 3 R 7 , -L 3 L 4 L 3 R 7 , -L 3 L 4 R 5 , -L 3 L 4 L 3 R 5 , —OL 3 R 5 , —OL 3 R 7 , —OL 3 L 4 R 7 , —OL 3 L 4 L 3 R 7 , —OR 8 , —OL 3 L 4 R 5 , —OL 3 L 4 L 3 R 5  and —C(R 5 ) 2 OH; 
 each R 4  is independently selected from H and fluoro; 
 R 5  is —P(O)(OR 9 ) 2 , 
 R 6  is —CF 2 P(O)(OR 9 ) 2  or —C(O)OR 10 ; 
 R 7  is —CF 2 P(O)(OR 9 ) 2  or —C(O)OR 10 ; 
 R 8  is H or C 1 -C 4 alkyl; 
 each R 9  is independently selected from H and C 1 -C 6 alkyl; 
 R 10  is H or C 1 -C 4 alkyl; 
 each p is independently selected from 1, 2, 3, 4, 5 and 6, and 
 q is 1, 2, 3 or 4; 
 
         with the proviso that when R 3  is C 1 -C 4  alkyl or —OR 8 , R 1  is —C(R 5 ) 2 OH, -L 1 R 5 , -L 1 R 6 , -L 2 R 5 , -L 2 R 6 , —OL 2 R 5 , or —OL 2 R 6 , wherein R 6  is —CF 2 P(O)(OR 9 ) 2  and R 7  is —CF 2 P(O)(OR 9 ) 2 ; 
         (b) an antigen derived from a hemorrhagic fever virus; and (c) an adjuvant. 
       
     
     
         28 - 34 . (canceled) 
     
     
         35 : A composition comprising (a) a benzonapthyridine TLR7 agonist or salt, solvate, or derivative thereof for use as a medicament, (b) a benzonapthyridine TLR7 agonist or salt, solvate, or derivative thereof for the treatment of exposure to a hemorrhagic fever virus, (c) a benzonapthyridine TLR7 agonist or salt, solvate, or derivative thereof for potentiating an immune response to a hemorrhagic fever virus, or (d) a benzonapthyridine TLR7 agonist or salt, solvate, or derivative thereof for inducing an immune response to a hemorrhagic fever virus. 
     
     
         36 - 48 . (canceled)