Compounds and compositions for treating solid tumors by intratumoral administration

Abstract

The invention provided herein includes pharmaceutical compositions comprising a TLR7 agonist having the structure of Formula (A), aluminum-containing particles, and one or more pharmaceutically acceptable excipient. The invention further provides the use of such compositions in the treatment of solid tumors either alone or in combination with one or more additional pharmaceutical compositions.

1 . A pharmaceutical composition comprising a compound having the structure of Formula (A), or a pharmaceutically acceptable salt thereof, aluminum-containing particles, a buffering agent and one or more pharmaceutically acceptable excipients: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is -L 1 R 4 , -L 1 R 5 , —OL 1 R 4 , —OL 1 R 5 , CH 3 , —C(═O)P(O)(OH) 2  or —C(═O)CF 2 P(O)(OH) 2 ; 
 R 2  is -L 2 R 4 , -L 2 R 6 , -L 2 L 3 L 2 R 6 , -L 2 L 3 R 4 , -L 2 L 3 L 2 R 4 , —OL 2 R 4 , —OR 4 , —OL 2 R 6 , —OL 2 L 3 R 6 , —OL 2 L 3 L 2 R 6 , —OL 2 L 3 R 4 —OL 2 L 3 L 2 R 4  or —OCH 3 ; 
 each R 3  is independently selected from H and fluoro; 
 R 4  is —P(O)(OH) 2 , 
 R 5  is —CF 2 P(O)(OH) 2  or —C(O)OH; 
 R 6  is —CF 2 P(O)(OH) 2  or —C(O)OH; 
 L 1  is C 1 -C 6 alkylene, C 2 -C 6 alkenylene 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 1  are substituted with 0 to 4 fluoro groups; 
 each L 2  is independently selected from C 1 -C 6 alkylene and —((CR 3 R 3 ) p O) q (CH 2 ) p —, wherein the C 1 -C 6 alkylene of L 2  is substituted with 0 to 4 fluoro groups; 
 L 3  is arylene or a 5-6 membered heteroarylene; 
 each p is independently selected from 1, 2, 3, 4, 5 and 6, and 
 q is 1, 2, 3 or 4. 
 
       
     
     
         2 . The pharmaceutical composition of  claim 1  wherein the composition comprises a compound having the structure of Formula (A), or a pharmaceutically acceptable salt thereof, a buffering agent, a pharmaceutically acceptable excipient selected from mannitol and sucrose, wherein the composition has a pH in the range of 6.5 to 9.0, and the aluminum-containing particles are a suspension of aluminum-containing particles. 
     
     
         3 . The pharmaceutical composition of  claim 1  or  claim 2 , wherein the aluminum-containing particles are aluminum hydroxide particles, aluminum oxyhydroxide particles or aluminum hydroxyphosphate particles and the suspension of aluminum-containing particles is a suspension of aluminum hydroxide particles, aluminum oxyhydroxide particles or aluminum hydroxyphosphate particles. 
     
     
         4 . The pharmaceutical composition of any one of  claims 1  to  3 , wherein the aluminum-containing particles are aluminum hydroxide particles, and the suspension of aluminum-containing particles is a suspension of aluminum hydroxide particles. 
     
     
         5 . The pharmaceutical composition of any one of  claims 1  to  4 , wherein the composition comprises a compound having the structure of Formula (A), or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, Tris buffer and mannitol. 
     
     
         6 . The pharmaceutical composition of any one of  claims 1  to  5 , wherein the composition comprises 0.5 to 2 mg/mL of a compound having the structure of Formula (A), or a pharmaceutically acceptable salt thereof, 5-100 mM Tris buffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL. 
     
     
         7 . The pharmaceutical composition of any one of  claims 1  to  6 , wherein the composition comprises 1 mg/mL of a compound having the structure of Formula (A), or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg/mL, and wherein the composition has a pH in the range of 7.0 to 8.0. 
     
     
         8 . The pharmaceutical composition of any one of  claims 1  to  7 , wherein the composition comprises 1 mg/mL of a compound having the structure of Formula (A), or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg/mL, and wherein the composition has a pH in the range of 7.0 to 8.0. 
     
     
         9 . The pharmaceutical composition of any one of  claims 1  to  7 , wherein the composition comprises 1 mg/mL of a compound having the structure of Formula (A), or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg/mL, and wherein the composition has a pH in the range of 7.0 to 8.0. 
     
     
         10 . The pharmaceutical composition of any one of  claims 1  to  7 , wherein the composition comprises 1 mg/mL of a compound having the structure of Formula (A), or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 5.5% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg/mL, and wherein the composition has a pH in the range of 7.0 to 8.0. 
     
     
         11 . The pharmaceutical composition of any one of  claims 1  to  10 , wherein the (w/w) ratio of the weight of compound of Formula A to the weight of aluminum in the suspension of aluminum-containing particles is in the range from 1:1 to 1:20. 
     
     
         12 . The pharmaceutical composition of any one of  claims 1  to  11 , wherein the (w/w) ratio of the weight of compound of Formula A to the weight of aluminum in the suspension of aluminum-containing particles is 1:2. 
     
     
         13 . The pharmaceutical composition of any one of  claims 1  to  12 , wherein the compound having the structure of Formula (A) is:
 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid; 
 3-(5-amino-2-(2-methyl-4-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid; 
 3-(5-amino-2-(4-(4,4-difluoro-4-phosphonobutoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid; 
 3-(5-amino-2-(2-methyl-4-(3-phosphonopropoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid; 
 3-(5-amino-2-(4-(2-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid; 
 3-(5-amino-2-(2-methyl-4-(2-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid; 
 3-(5-amino-2-(2-methyl-4-(2-(2-phosphonoethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid. 
 (3-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)propyl)phosphonic acid; 
 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl dihydrogen phosphate; 
 ((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phosphonic acid; 
 5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluoropentylphosphonic acid; 
 (4-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorobutyl)phosphonic acid; 
 (3-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)-1,1-difluoropropyl)phosphonic acid; 
 3-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)-1,1-difluoropropylphosphonic acid; 
 2-(4-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenyl)-1,1-difluoroethylphosphonic acid; 
 (3-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenyl)phosphonic acid; 
 (2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethyl)phosphonic acid; 
 (6-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)hexyl)phosphonic acid; 
 (6-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorohexyl)phosphonic acid; 
 (4-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)benzyl)phosphonic acid; 
 (2-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)ethyl)phosphonic acid; 
 (5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)pentyl)phosphonic acid, and 
 (4-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)butyl)phosphonic acid. 
 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1,1-difluoro-2-oxoethylphosphonic acid; 
 (E)-(2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)vinyl)phosphonic acid; 
 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)ethylphosphonic acid; 
 (E)-(2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1-fluorovinyl)phosphonic acid, or (5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbonyl)phosphonic acid. 
 
     
     
         14 . The pharmaceutical composition of any one of  claims 1  to  13 , wherein the compound is 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid. 
     
     
         15 . The pharmaceutical composition of any one of  claims 1  to  13 , wherein the compound is 3-(5-amino-2-(2-methyl-4-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid. 
     
     
         16 . The pharmaceutical composition of any one of  claims 1  to  5 , wherein the composition comprises 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, Tris buffer and mannitol. 
     
     
         17 . The pharmaceutical composition of any one of  claims 1  to  5  or  16 , wherein the composition comprises 0.5 to 2 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, 5-100 mM Tris buffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL. 
     
     
         18 . The pharmaceutical composition of any one of  claims 1  to  5  or  16  to  17 , wherein the composition comprises 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg/mL, and wherein the composition has a pH in the range of 7.0 to 8.0. 
     
     
         19 . The pharmaceutical composition of any one of  claims 1  to  5  or  16  to  18 , wherein the composition comprises 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg/mL, and wherein the composition has a pH in the range of 7.0 to 8.0. 
     
     
         20 . The pharmaceutical composition of any one of  claims 1  to  5  or  16  to  18 , wherein the composition comprises 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg/mL, and wherein the composition has a pH in the range of 7.0 to 8.0. 
     
     
         21 . The pharmaceutical composition of any one of  claims 1  to  5  or  16  to  18 , wherein the composition comprises 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 5.5% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg/mL, and wherein the composition has a pH in the range of 7.0 to 8.0. 
     
     
         22 . The pharmaceutical composition of any one of  claims 1  to  5  or  16  to  21 , wherein the (w/w) ratio of the weight of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, to the weight of aluminum in the suspension of aluminum-containing particles is in the range from 1:1 to 1:20. 
     
     
         23 . The pharmaceutical composition of any one of  claims 1  to  5  or  16  to  21 , wherein the (w/w) ratio of the weight of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, to the weight of aluminum in the suspension of aluminum-containing particles is 1:2. 
     
     
         24 . The pharmaceutical composition of any one of  claims 1  to  5  or  16  to  21 , wherein the composition comprises 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, 5-100 mM Tris buffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxide particles, and wherein the (w/w) ratio of the weight of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid to the weight of aluminum in the suspension of particles is 1:20. 
     
     
         25 . The pharmaceutical composition of any one of  claims 1  to  24  further comprising an additional therapeutic agent. 
     
     
         26 . The pharmaceutical composition of  claim 25 , wherein the additional therapeutic agents is a checkpoint inhibitor, a TLR9 agonist, a TLR8 agonist, a TLR7 agonist, a STING agonist or a chemotherapeutic agent. 
     
     
         27 . A pharmaceutical combination comprising:
 a) a first pharmaceutical composition of any one of  claims 1  to  24 , and   b) a second pharmaceutical composition comprising a checkpoint inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2 inhibitor.   
     
     
         28 . A pharmaceutical combination comprising:
 a) a first pharmaceutical composition of any one of  claims 1  to  24 , and   b) a second pharmaceutical composition comprising a PD-1 receptor inhibitor.   
     
     
         29 . A pharmaceutical combination comprising:
 a) a first pharmaceutical composition of any one of  claims 1  to  24 , and   b) a second pharmaceutical composition comprising a PD-L1 inhibitor.   
     
     
         30 . A pharmaceutical combination comprising:
 a) a first pharmaceutical composition of any one of  claims 1  to  24 , and   b) a second pharmaceutical composition comprising an anti-PD-L1 antibody.   
     
     
         31 . A pharmaceutical combination comprising:
 a) a first pharmaceutical composition of any one of  claims 1  to  24 , and   b) a second pharmaceutical composition comprising an anti-PD-1 antibody.   
     
     
         32 . A pharmaceutical combination comprising:
 a) a first pharmaceutical composition of any one of  claims 1  to  24 ,   b) a second pharmaceutical composition comprising a checkpoint inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2 inhibitor, and   c) a third pharmaceutical composition comprising a checkpoint inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2 inhibitor,   wherein the checkpoint of the third composition is different than the checkpoint inhibitor in the second composition.   
     
     
         33 . A pharmaceutical combination comprising:
 a) a first pharmaceutical composition of any one of  claims 1  to  24 ,   b) a second pharmaceutical composition comprising a PD-L1 inhibitor, and   c) a third pharmaceutical composition comprising a CTLA-4 receptor inhibitor.   
     
     
         34 . A pharmaceutical combination comprising:
 a) a first pharmaceutical composition of any one of  claims 1  to  24 ,   b) a second pharmaceutical composition comprising a PD-1 inhibitor, and   c) a third pharmaceutical composition comprising a CTLA-4 receptor inhibitor.   
     
     
         35 . A pharmaceutical combination comprising:
 a) a first pharmaceutical composition of any one of  claims 1  to  24 ,   b) a second pharmaceutical composition comprising an anti-PD-L1 antibody, and   c) a third pharmaceutical composition comprising an anti-CTLA-4 antibody.   
     
     
         36 . A pharmaceutical combination comprising:
 a) a first pharmaceutical composition of any one of  claims 1  to  24 ,   b) a second pharmaceutical composition comprising an anti-PD-1 antibody, and   c) a third pharmaceutical composition comprising an anti-CTLA-4 antibody.   
     
     
         37 . A method for treating a solid tumor by administering to a subject in need thereof a pharmaceutical composition of any one of  claims 1  to  26 , or a pharmaceutical combination of any one of  claims 27  to  36 . 
     
     
         38 . A method for treating a solid tumor by administering to a subject in need thereof a pharmaceutical combination comprising:
 a) a first pharmaceutical composition of any one of  claims 1  to  24 ,   b) a second pharmaceutical composition comprising a checkpoint inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2 inhibitor, and   c) a third pharmaceutical composition comprising a checkpoint inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2 inhibitor,   wherein the checkpoint of the third composition is different than the checkpoint inhibitor in the second composition, and   wherein the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage or by infusion.   
     
     
         39 . A method for treating a solid tumor by administering to a subject in need thereof a pharmaceutical combination comprising:
 a) a first pharmaceutical composition of any one of  claims 1  to  24 , and a   b) a second pharmaceutical composition comprising a checkpoint inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2 inhibitor,   wherein the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition is administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage or by infusion.   
     
     
         40 . The method of any one of  claims 37  to  39 , wherein the solid tumor is head and neck squamous cell carcinoma (HNSCC), melanoma or a visceral tumor. 
     
     
         41 . Use of a pharmaceutical composition of any one of  claims 1  to  26 , or use a pharmaceutical combination of any one of  claims 27  to  36 , in treating a solid tumor. 
     
     
         42 . The use of  claim 41 , wherein the solid tumor is head and neck squamous cell carcinoma (HNSCC), melanoma or a visceral tumor. 
     
     
         43 . A pharmaceutical composition of any one of  claims 1  to  26 , or a pharmaceutical combination of any one of  claims 27  to  36 , for use in treating a solid tumor. 
     
     
         44 . The pharmaceutical composition of  claim 43 , wherein the solid tumor is head and neck squamous cell carcinoma (HNSCC), melanoma or a visceral tumor. 
     
     
         45 . A lyophilisate comprising a compound having the structure of Formula (A), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is -L 1 R 4 , -L 1 R 5 , —OL 1 R 4 , —OL 1 R 5 , CH 3 , —C(═O)P(O)(OH) 2  or —C(═O)CF 2 P(O)(OH) 2 ; 
 R 2  is -L 2 R 4 , -L 2 R 6 , -L 2 L 3 L 2 R 6 , -L 2 L 3 R 4 , -L 2 L 3 L 2 R 4 , —OL 2 R 4 , —OR 4 , —OL 2 R 6 , —OL 2 L 3 R 6 , —OL 2 L 3 L 2 R 6 , —OL 2 L 3 R 4 —OL 2 L 3 L 2 R 4  or —OCH 3 ; 
 each R 3  is independently selected from H and fluoro; 
 R 4  is —P(O)(OH) 2 , 
 R 5  is —CF 2 P(O)(OH) 2  or —C(O)OH; 
 R 6  is —CF 2 P(O)(OH) 2  or —C(O)OH; 
 L 1  is C 1 -C 6 alkylene, C 2 -C 6 alkenylene 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 1  are substituted with 0 to 4 fluoro groups; 
 each L 2  is independently selected from C 1 -C 6 alkylene and —((CR 3 R 3 ) p O) q (CH 2 ) p —, wherein the C 1 -C 6 alkylene of L 2  is substituted with 0 to 4 fluoro groups; 
 L 3  is arylene or a 5-6 membered heteroarylene; 
 each p is independently selected from 1, 2, 3, 4, 5 and 6, and 
 q is 1, 2, 3 or 4. 
 
       
     
     
         46 . The lyophilisate of  claim 45 , wherein the compound is 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid. 
     
     
         47 . A lyophilisate prepared from a solution having a pH between 6.5 and 9.0 and comprising a a compound having the structure of Formula (A), or a pharmaceutically acceptable salt thereof, and a buffering agent: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is -L 1 R 4 , -L 1 R 5 , —OL 1 R 4 , —OL 1 R 5 , CH 3 , —C(═O)P(O)(OH) 2  or —C(═O)CF 2 P(O)(OH) 2 ; 
 R 2  is -L 2 R 4 , -L 2 R 6 , -L 2 L 3 L 2 R 6 , -L 2 L 3 R 4 , -L 2 L 3 L 2 R 4 , —OL 2 R 4 , —OR 4 , —OL 2 R 6 , —OL 2 L 3 R 6 , —OL 2 L 3 L 2 R 6 , —OL 2 L 3 R 4  —OL 2 L 3 L 2 R 4  or —OCH 3 ; 
 each R 3  is independently selected from H and fluoro; 
 R 4  is —P(O)(OH) 2 , 
 R 5  is —CF 2 P(O)(OH) 2  or —C(O)OH; 
 R 6  is —CF 2 P(O)(OH) 2  or —C(O)OH; 
 L 1  is C 1 -C 6 alkylene, C 2 -C 6 alkenylene 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 1  are substituted with 0 to 4 fluoro groups; 
 each L 2  is independently selected from C 1 -C 6 alkylene and —((CR 3 R 3 ) p O) q (CH 2 ) p —, wherein the C 1 -C 6 alkylene of L 2  is substituted with 0 to 4 fluoro groups; 
 L 3  is arylene or a 5-6 membered heteroarylene; 
 each p is independently selected from 1, 2, 3, 4, 5 and 6, and 
 q is 1, 2, 3 or 4. 
 
       
     
     
         48 . The lyophilisate of  claim 47 , wherein the compound is 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid. 
     
     
         49 . A pharmaceutical composition prepared by reconstituting a lyophilisate of any one of  claims 45  to  48  with water and admixing with a suspension of aluminum-containing particles. 
     
     
         50 . The pharmaceutical composition of  claim 49  prepared by reconstituting a lyophilisate of any one of  claims 45  to  48  with water and admixing with a suspension of aluminum-containing particles having an aluminum content of 1 to 4 mg/mL. 
     
     
         51 . The pharmaceutical composition of  claim 49  or  50 , wherein the aluminum-containing particles are aluminum hydroxide particles.