3-Substituted-4-Oxo-3,4-Dihydro-Imidazo[5,1-d]1,2,3,5-Tetrazine-8-Carboxylic Acid Amides and Their Use

Abstract

The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain 3-substituted-4-oxo-3,4-dihydro-imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid amide (collectively referred to herein as 3TM compounds). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit cell proliferation, and in the treatment of proliferative disorders such as cancer, etc., and methods of preparing such compounds.

1 - 303 . (canceled) 
     
     
         304 . A compound of the following formula or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 (a) -Q is independently a group of the following formula: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 -J 9 - is independently saturated aliphatic C 1-4 alkylene; 
 t is independently 1 or 2; and 
 —R SO  is independently saturated aliphatic C 1-4 alkyl, phenyl, or benzyl, wherein said phenyl and benzyl are independently optionally substituted with one or more substituents selected from —F, —Cl, —Br, —I, —R SOR , —CF 3 , —OH, —OR SOR , and —OCF 3 , wherein each —R SOR  is independently saturated aliphatic C 1-4 alkyl; or 
 (b) -Q is independently a group of the following formula: 
 
       
         
           
           
               
               
           
         
       
       wherein —R YNE  is independently aliphatic C 2-6 alkynyl, and is optionally substituted; or
 (c) -Q is independently a group of the following formula: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 -J 6 - is independently saturated aliphatic C 1-4 alkylene; 
 —R O  is independently —H or —R OO ; 
 —R OO  is independently saturated aliphatic C 1-4 alkyl, phenyl, benzyl, or —Si(R SI ) 3 ; 
 each —R SI  is independently saturated aliphatic C 1-4 alkyl; 
 with the proviso that -Q is not —CH 2 —O—CH 3 , —CH 2 —O—CH 2 CH 3 , or —CH 2 CH 2 —O—CH 3 ; or 
 (d) -Q is independently a group of the following formula: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 —Ar 1  is independently phenyl or C 5-6 heteroaryl, and is optionally substituted; 
 -J 1 - is independently saturated aliphatic C 1-4 alkylene; 
 with the proviso that -Q is not benzyl, para-methoxy-benzyl, or furan-2-yl-methyl; or 
 (e) -Q is independently a group of the following formula: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 —Cy 2  is independently:
 saturated C 3-7 cycloalkyl and is optionally substituted, or 
 non-aromatic C 3-7 heterocyclyl and is optionally substituted; 
 
 -J 2 - is independently a covalent bond or saturated aliphatic C 1-4 alkylene; 
 with proviso that -Q is not cyclohexyl; or 
 (f) -Q is independently a group of the following formula: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 -J 3 - is independently saturated aliphatic C 1-4 alkylene; and 
 either: 
 —R N3A  is independently —H or —R N3C ; 
 —R N3B  is independently —H or —R N3D ; 
 —R N3C  is independently saturated aliphatic C 1-4 alkyl; 
 —R N3D  is independently saturated aliphatic C 1-4 alkyl; 
 or: 
 —R N3A  and —R N3B , taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly one ring heteroatom which is nitrogen, or having exactly two ring heteroatoms, which are nitrogen and oxygen, or nitrogen and nitrogen; or 
 (g) -Q is independently a group of the following formula: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 -J 4 - is independently saturated aliphatic C 1-4 alkylene; and 
 —R S  is independently saturated aliphatic C 1-4 alkyl; or 
 (h) -Q is independently a group selected from groups of the following formulae: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 -J 5 - is independently saturated aliphatic C 1-4 alkylene, and is optionally substituted with one or more substituents independently selected from —OH and —OR EER , wherein 
 each —R EER  is independently saturated aliphatic C 1-4 alkyl; 
 —R E  is independently —H or —R EE ; 
 —R F  is independently —R EE ; 
 —R EE  is independently saturated aliphatic C 1-4 alkyl; 
 with the proviso that -Q is not —CH 2 C(═O)OH or —CH 2 C(═O)OCH 2 CH 3 ; or 
 (i) -Q is independently —CH(CH 3 ) 2 ; or 
 (j) -Q is independently a group of the following formula: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 -J 6A - is independently saturated aliphatic C 1-4 alkylene; and 
 —R AC  is independently saturated aliphatic C 1-4 alkyl; or 
 (k) -Q is independently a group of the following formula: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 R X  is independently saturated aliphatic C 1-6 hydrocarbyl; 
 n is independently 1, 2, 3, 4, or 5; and 
 each —X is independently —F, —Cl, —Br, or —I; 
 with the proviso that -Q is not: —CH 2 Cl, —CH 2 CF 3 , —CH 2 CH 2 Cl, —CH 2 CH 2 Br, —CH 2 CH 2 CH 2 Cl, or —CH 2 CHClCH 2 Cl; or 
 (l) -Q is independently a group of the following formula: 
 
       
         
           
           
               
               
           
         
       
       wherein -J 7 - is independently saturated aliphatic C 1-4 alkylene; or
 (m) -Q is independently a group of the following formula: 
 
       
         
           
           
               
               
           
         
       
       wherein -J 8 - is independently saturated aliphatic C 1-4 alkylene; or
 (n) -Q is independently a group of the following formula: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 -J 10 - is independently saturated aliphatic C 1-4 alkylene; 
 each —R PR  is independently saturated aliphatic C 1-4 alkyl, phenyl, or benzyl, wherein said phenyl and benzyl are independently optionally substituted with one or more substituents selected from —F, —Cl, —Br, —I, —R PRR , —CF 3 , —OH, —OR PRR , and —OCF 3 , wherein each —R PRR  is independently saturated aliphatic C 1-4 alkyl; or 
 (o) -Q is independently a group of the following formula: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 -J 11 - is independently saturated aliphatic C 1-4 alkylene; and 
 —R NCAR  is independently —H or —R CAR ; 
 each —R CAR  is independently saturated aliphatic C 1-4 alkyl, phenyl, benzyl, fluorenyl, or —CH 2 -fluorenyl, wherein said phenyl, benzyl, and fluorenyl are independently optionally substituted with one or more substituents selected from —F, —Cl, —Br, —I, —R CARR , —CF 3 , —OH, —OR CARR , and —OCF 3 , wherein each —R CARR  is independently saturated aliphatic C 1-4 alkyl; or 
 (p) -Q is independently a group of the following formula: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 -J 12 - is independently saturated aliphatic C 1-4 alkylene; and 
 —R IMR  is independently —H or —R IMR ; 
 each —R IMR  is independently saturated aliphatic C 1-4 alkyl, phenyl, or benzyl, wherein said phenyl and benzyl are independently optionally substituted with one or more substituents selected from —F, —Cl, —Br, —I, —R IMRR , —CF 3 , —OH, —OR IMRR , and —OCF 3 , wherein each —R IMRR  is independently saturated aliphatic C 1-4 alkyl. 
 
     
     
         305 . A compound according to  claim 304 , wherein -Q is a group of the following formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 —Ar 1  is independently phenyl, and is optionally substituted; 
 -J 1 - is independently saturated aliphatic C 1-4 alkylene; 
 
       with the proviso that -Q is not benzyl, or para-methoxy-benzyl. 
     
     
         306 . A compound according to  claim 304 , wherein -Q is a group of the following formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 -J 6 - is independently saturated aliphatic C 1-4 alkylene; 
 —R O  is independently —H or —R OO ; 
 —R OO  is independently saturated aliphatic C 1-4 alkyl; 
 
       with the proviso that -Q is not —CH 2 —O—CH 3 , —CH 2 —O—CH 2 CH 3 , or —CH 2 CH 2 —O—CH 3 . 
     
     
         307 . A compound according to  claim 304 , wherein -Q is a group of the following formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 —Cy 2  is independently:
 saturated C 3-7 cycloalkyl and is optionally substituted; 
 
 -J 2 - is independently a covalent bond or saturated aliphatic C 1-4 alkylene; 
 
       with proviso that -Q is not cyclohexyl. 
     
     
         308 . A compound according to  claim 304 , wherein -Q is independently —CH(CH 3 ) 2 . 
     
     
         309 . A compound according to  claim 304 , wherein -Q is independently a group of the following formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R X  is independently saturated aliphatic C 1-6 hydrocarbyl; 
 n is independently 1, 2, 3, 4, or 5; and 
 each —X is independently —F, —Cl, —Br, or —I; 
 
       with the proviso that -Q is not: —CH 2 Cl, —CH 2 CF 3 , —CH 2 CH 2 Cl, —CH 2 CH 2 Br, —CH 2 CH 2 CH 2 Cl, or —CH 2 CHClCH 2 Cl. 
     
     
         310 . A pharmaceutical composition comprising a compound according to  claim 304 , and a pharmaceutically acceptable carrier or diluent. 
     
     
         311 . A method of treatment of a proliferative condition comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to  claim 304 . 
     
     
         312 . A method of treatment of cancer comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to  claim 304 . 
     
     
         313 . A method of treatment of lung cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, renal cancer, prostate cancer, esophageal cancer, squamous carcinoma of the head or neck, or glioma comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to  claim 304 . 
     
     
         314 . A method of inhibiting cell proliferation, inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting the cell with an effective amount of a compound according to  claim 304 . 
     
     
         315 . A method for the preparation of a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       comprising the step of reacting a compound of Formula (II) or a salt, hydrate, or solvate thereof: 
       
         
           
           
               
               
           
         
       
       with a compound of the formula R—X, wherein: —R is a group having: from 1 to 15 carbon atoms; at least one hydrogen atom; from 0 to 6 atoms selected from N, O, S, F, Cl, Br, I, and P; and at least one non-aromatic carbon atom; —X is a halogen atom; and —X is attached to said non-aromatic carbon atom; 
       under conditions suitable to form said compound of Formula (I).