US2022340613A1PendingUtilityA1

Cyclic di-nucleotide compounds and methods of use

Assignee: IMMUNESENSOR THERAPEUTICS INCPriority: Mar 18, 2016Filed: Mar 17, 2022Published: Oct 27, 2022
Est. expiryMar 18, 2036(~9.7 yrs left)· nominal 20-yr term from priority
A61K 31/7084C07H 21/02C07H 19/213A61K 45/06C07H 21/00C07H 21/04A61P 35/00A61P 37/02A61P 43/00A61P 31/00A61P 37/04A61K 9/51
70
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Claims

Abstract

Disclosed are cyclic-di-nucleotide cGAMP analogs, methods of synthesizing the compounds, pharmaceutical compositions comprising the compounds thereof, and use of compounds and compositions in medical therapy.

Claims

exact text as granted — not AI-modified
1 - 80 . (canceled) 
     
     
         81 . A method for treating a cancer responsive to activation of the STING pathway by administering a compound, wherein the compound is of Formula Ic: 
       
         
           
           
               
               
           
         
       
       wherein
 Z 12  and Z 15  are N; 
 Z 13 , Z 14 , Z 16  and Z 17  are independently CH or N; 
 R 3  is C 2 alkyl functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, or azido groups; 
 R 4  is hydroxyl; 
 R 9  and R 10  are independently hydroxyl; thiol; C 1-6 alkyl; C 1-6 alkyl functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, or azido groups; C 1-6 alkoxy; C 1-6 alkoxy functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, or azido groups; C 3-5 alkenyl-O—; C 3-5 alkynyl-O—; oligo(ethylene glycol); poly(ethylene glycol); borano (—BH 3   − ); or —NR 7 R 8 ; 
 R 7  and R 8  are independently hydrogen; C 1-6 alkyl; C 1-6 alkyl functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, or azido groups; cyclic —(C 1-6 alkyl)-; cyclic —(C 1-6 alkyl)-functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, or di(C 1-6 alkyl)amino groups; cyclic —(C 1-6 oxaalkyl)-; or cyclic —(C 1-6 oxaalkyl)-functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, or di(C 1-6 alkyl)amino groups; 
 
       or is a pharmaceutically acceptable salt thereof. 
     
     
         82 . The method of  claim 81 , wherein Z 13  and Z 16  are CH, and Z 14  and Z 17  are N. 
     
     
         83 . The method of  claim 81 , wherein R 9  and R 10  are independently hydroxyl or thiol. 
     
     
         84 . The method of  claim 81 , wherein R 3  is C 2 alkyl functionalized with one or more thiol, hydroxyl, carboxyl, C 1-6 hydroxyalkoxy, amino, or C 1-6 alkylamino groups. 
     
     
         85 . The method of  claim 81 , wherein R 3  is C 2 alkyl functionalized with one or more halogen, thiol, or hydroxyl. 
     
     
         86 . The method of  claim 81 , wherein the compound is of Formula Ic: 
       
         
           
           
               
               
           
         
       
       wherein
 Z 12  and Z 15  are N; 
 Z 13  and Z 16  are CH; 
 Z 14  and Z 17  are independently CH or N; 
 R 3  is C 2 alkyl functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, or azido groups; 
 R 4  is hydroxyl; 
 R 9  and R 10  are independently hydroxyl or thiol; 
 
       or is a pharmaceutically acceptable salt thereof. 
     
     
         87 . The method of  claim 86 , wherein R 3  is C 2 alkyl functionalized with one or more thiol, hydroxyl, carboxyl, C 1-6 hydroxyalkoxy, amino, or C 1-6 alkylamino groups. 
     
     
         88 . The method of  claim 86 , wherein R 3  is C 2 alkyl functionalized with one or more halogen, thiol, or hydroxyl. 
     
     
         89 . A method for treating a cancer responsive to activation of the STING pathway by administering a compound of Formula Ic: 
       
         
           
           
               
               
           
         
       
       wherein
 Z 12  and Z 15  are N; 
 Z 13 , Z 14 , Z 16  and Z 17  are independently CH or N; 
 R 3  is C 1-6 alkyl functionalized with one or more halogen, thiol, or hydroxyl; 
 R 4  is hydroxyl; 
 R 9  and R 10  are independently hydroxyl; thiol; C 1-6 alkyl; C 1-6 alkyl functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, or azido groups; C 1-6 alkoxy; C 1-6 alkoxy functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, or azido groups; C 3-5 alkenyl-O—; C 3-5 alkynyl-O—; oligo(ethylene glycol); poly(ethylene glycol); borano (—BH 3   − ); or —NR 7 R 8 ; 
 R 7  and R 8  are independently hydrogen; C 1-6 alkyl; C 1-6 alkyl functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, or azido groups; cyclic —(C 1-6 alkyl)-; cyclic —(C 1-6 alkyl)-functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, or di(C 1-6 alkyl)amino groups; cyclic —(C 1-6 oxaalkyl)-; or cyclic —(C 1-6 oxaalkyl)-functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, or di(C 1-6 alkyl)amino groups; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         90 . The method of  claim 89 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
       or is a pharmaceutically acceptable salt thereof. 
     
     
         91 . The method of  claim 89 , wherein the compound is of Formula Ic: 
       
         
           
           
               
               
           
         
       
       wherein
 Z 12  and Z 15  are N; 
 Z 13  and Z 16  are CH; 
 Z 14  and Z 17  are independently CH or N; 
 R 3  is C 1-6 alkyl functionalized with one or more halogen, thiol, or hydroxyl; 
 R 4  is hydroxyl; 
 R 9  and R 10  are independently hydroxyl or thiol; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         92 . The method of  claim 91 , wherein R 3  is C 1 -6alkyl functionalized with hydroxyl. 
     
     
         93 . The method of  claim 91 , wherein R 3  is C 1 -6alkyl functionalized with thiol. 
     
     
         94 . The method of  claim 91 , wherein R 3  is C 1 -6alkyl functionalized with halogen. 
     
     
         95 . A compound, wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or is a pharmaceutically acceptable salt thereof. 
     
     
         96 . The compound of  claim 95 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or is a pharmaceutically acceptable salt thereof. 
     
     
         97 . The compound of  claim 95 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or is a pharmaceutically acceptable salt thereof. 
     
     
         98 . The compound of  claim 95 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or is a pharmaceutically acceptable salt thereof. 
     
     
         99 . The compound of  claim 95 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or is a pharmaceutically acceptable salt thereof. 
     
     
         100 . The compound of  claim 95 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or is a pharmaceutically acceptable salt thereof. 
     
     
         101 . The compound of  claim 95 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or is a pharmaceutically acceptable salt thereof. 
     
     
         102 . The compound of  claim 95 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or is a pharmaceutically acceptable salt thereof. 
     
     
         103 . The compound of  claim 95 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or is a pharmaceutically acceptable salt thereof. 
     
     
         104 . The compound of  claim 95 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or is a pharmaceutically acceptable salt thereof. 
     
     
         105 . The compound of  claim 95 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or is a pharmaceutically acceptable salt thereof. 
     
     
         106 . The compound of  claim 95 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or is a pharmaceutically acceptable salt thereof. 
     
     
         107 . A compound, wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or is a pharmaceutically acceptable salt thereof. 
     
     
         108 . A compound, wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or is a pharmaceutically acceptable salt thereof.

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