Pyrimidine-2,4,6-trione metalloproteinase inhibitors

Abstract

The present invention relates to pyrimidine-2,4,6-trione metalloproteinase inhibitors of the formula wherein X, Y, A, B and R 1 are as defined in the specification, and to pharmaceutical compositions and methods of treating inflammation, cancer and other disorders.

1 . A compound of the formula  
       
         
           
           
               
               
           
         
         wherein R 1  is (R 2 )—(CH 2 ) n —;  
         n is an integer from one to ten;  
         R 2  is selected from the group consisting of R 3 — and R 3 —O—;  
         R 3  is selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl, (C 1 -C 10 )heteroaryl and (C 1 -C 10 )heterocyclyl; wherein R 3  can be optionally substituted on any carbon atom able to support an additional substituent, by one to three substituents per alkyl moiety or by one to three substituents per ring, independently selected from the group consisting of halo, hydroxy, amino, —CN, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl-NH—, [(C 1 -C 4 )alkyl] 2 —N—, (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl, (C 1 -C 10 )heteroaryl and (C 1 -C 10 )heterocyclyl; wherein said (C 3 -C 8 )cycloalkyl and (C 1 -C 10 )heterocyclyl can also optionally be substituted by oxo; wherein said (C 1 -C 10 )heteroaryl and (C 1 -C 10 )heterocyclyl can optionally be substituted on any ring nitrogen atom able to support an additional substituent by one to two substituents per ring independently selected from the group consisting of (C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl-(C═O)—, (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl, (C 1 -C 10 )heteroaryl and (C 1 -C 10 )heterocyclyl;  
         G is R 6 CH 2 ) p —; wherein G is on any ring carbon atom meta or para to —O—;  
         p is an integer from one to six;  
         wherein R 6  is selected from the group consisting of R 8 —(C═O)—(NR 9 )—, R 8 NH—(C═O)—(NR 9 )—, (R 8 ) 2 N—(C═O)—(NR 9 )—, and R 80 —(C═O)—(NR 9 )—;  
         R 8  is selected from the group consisting of (C 1 -C 4 )alkyl, (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl, (C 1 -C 10 )heteroaryl and (C 1 -C 10 )heterocyclyl; wherein each R 3  can be optionally substituted on any carbon atom able to support an additional substituent, by one to three substituents per alkyl moiety or by one to three substituents per ring, independently selected from the group consisting of F, Cl, Br, CN, OH, (C 1 -C 4 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 4 )alkoxy, and (C 3 -C 8 )cycloalkyloxy; wherein said (C 3 -C 8 )cycloalkyl and (C 1 -C 10 )heterocyclyl can also optionally be substituted by oxo; wherein said (C 1 -C 10 )heteroaryl and (C 1 -C 10 )heterocyclyl can also optionally be substituted on any ring nitrogen atom able to support an additional substituent by one to two substituents per ring independently selected from the group consisting of (C 1 -C 4 )alkyl and (C 1 -C 4 )alkyl-(C═O)—; wherein two of said R 8  can optionally be taken together with the heteroatom to which they are attached to form a three to eight membered ring;  
         R 9  wherever it occurs is independently selected from the group consisting of hydrogen and (C 1 -C 4 )alkyl; wherein said R 8  and R 9  can optionally be taken together with the heteroatoms to which they are attached to form a three to eight membered ring;  
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         2 . A compound according to  claim 1 , wherein n is 2.  
     
     
         3 . A compound according to  claim 1 , wherein R 3  is selected from the group consisting of (C 1 -C 4 )alkyl and (C 1 -C 10 )heterocyclyl.  
     
     
         4 . A compound according to  claim 1 , wherein R 3  is (C 1 -C 4 )alkyl.  
     
     
         5 . A compound according to  claim 1 , wherein R 1  is —(CH 2 ) 2 OCH 2 CH 3 .  
     
     
         6 . A compound according to  claim 1 , wherein p is 1.  
     
     
         7 . A compound according to  claim 1 , wherein G is para to —O—.  
     
     
         8 . A compound according to  claim 1 , wherein R 6  is R 8 —(C═O)—(NR 9 )—.  
     
     
         9 . A compound according to  claim 8  wherein R 6  is selected from the group consisting of —NH(C═O)CH 3 , —NH(C═O)CH 2 CH(CH 3 ) 2 , —NH(C═O)(CH 2 ) 3 CH 3 , —NH(C═O)CH(CH 3 ) 2 , —N H(C═O)CH 2 OCH 3 , —NH(C═O)-cyclobutyl, —NH(C═O)CH(CH 3 )CH 2 CH 3 , —NH(C═O)CH 2 CH 3 , 2-oxo-pyrolidin-1-yl, 2-oxo-piperidin-1-yl, and 2-oxo-azepan-1-yl.  
     
     
         10 . A compound according to  claim 1 , wherein R 6  is R 8 NH—(C═O)—(NR 9 )—.  
     
     
         11 . A compound according to  claim 10 , wherein R 6  is selected from the group consisting of —NH(C═O)NHCH 3 , —NH(C═O)N H(CH 2 ) 2 CH 3 , and —NH(C═O)N(CH 3 ) 2 .  
     
     
         12 . A compound according to  claim 1 , wherein R 6  is (R 8 ) 2 N—(C═O)—(NR 9 )—.  
     
     
         13 . A compound according to  claim 12 , wherein R 6  is selected from the group consisting of N—(C═O)-azetidin-1-yl, 2-oxo-imidazolidin-1-yl, and N—(C═O)-pyrrolidin-1-yl.  
     
     
         14 . A compound according to  claim 1 , wherein R 6  is R 8 O—(C═O)—(NR 9 )—.  
     
     
         15 . A compound according to  claim 14 , wherein R 6  is selected from the group consisting of 2-oxo-oxazolidin-3-yl, CH 3 O—(C═O)—(NH)—, CH 3 (CH 2 ) 2 O—(C═O)—(NH)—, CH 3 CH 2 O—(C═O)—(NH)—, and (CH 3 ) 2 CHO—(C═O)—(NH)—.  
     
     
         16 . A compound according to  claim 1 , wherein R 3  is selected from the group consisting of (C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 10 )heterocycly (C 6 -C 10 )aryl, and (C 1 -C 10 )heteroaryl; wherein R 3  can be optionally substituted on any carbon atom able to support an additional substituent by one to three substituents per alkyl moiety or by one to three substituents per ring, independently selected from the group consisting of halo, hydroxy, amino, —CN, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl-NH—, and [(C 1 -C 4 )alkyl] 2 —N—.  
     
     
         17 . A compound according to  claim 1  selected from the group consisting of: 
 N-(4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-benzyl)-acetamide;    N-(4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-enzyl)-3-methyl-butyramide;    Pentanoic acid 4-{4-[5-(2-ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-benzylamide;    N-(4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-benzyl)-isobutyramide;    N-(4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-benzyl)-2,2-dimethyl-propionamide;    Cyclobutanecarboxylic acid 4-{4-[5-(2-ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-benzylamide;    N-(4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-benzyl)-2-methyl-butyramide;    N-(4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-benzyl)-propionamide;    1-(4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-benzyl)-3-methyl-urea;    1-(4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-troxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-benzyl)-3-propyl-urea;    Azetidine-1-carboxylic acid 4-{4-[5-(2-ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-benzylamide;    3-(4-{4-[5-(2-ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-benzyl)-1,1-dimethyl-urea;    Pyrrolidine-1-carboxylic acid 4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-benzylamide;    5-(2-ethoxy-ethyl)-5-{4-[4-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-phenoxy}-pyrimidine-2,4,6-trione;    5-(2-ethoxy-ethyl)-5-{4-[4-(2-oxo-imidazolidin-1-ylmethyl)-phenoxy]-phenoxy}-pyrimidine-2,4,6-trione;    5-(2-ethoxy-ethyl)-5-{4-[4-(2-oxo-pyrrolidin-1-ylmethyl)-phenoxy]-phenoxy}-pyrimidine-2,4,6-trione;    5-(2-ethoxy-ethyl)-5-{4-[4-(2-oxo-piperidin-1-ylmethyl)-phenoxy]-phenoxy}-pyrimidine-2,4,6-trione;    5-(2-ethoxy-ethyl)-5-{4-[4-(2-oxo-azepan-1-ylmethyl)-phenoxy]-phenoxy}-pyrimidine-2,4,6-trione;    (4-{4-[5-(2-ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-benzyl)-carbamic acid methyl ester;    (4-{4-[5-(2-ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-benzyl)-carbamic acid ethyl ester;    (4-{4-[5-(2-ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-benzyl)-carbamic acid propyl ester;    (4-{4-[5-(2-ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-benzyl)-carbamic acid isopropyl ester; and    Azetidine-1-carboxylic acid 4-{4-[2,4,6-trioxo-5-(tetrahydrofuran-2-ylmethyl)-hexahydro-pyrimidin-5-yloxy]-phenoxy}-benzylamide.    
     
     
         18 . A pharmaceutical composition for the treatment of a condition selected from the group consisting of connective tissue disorders, inflammatory disorders, immunology/allergy disorders, infectious diseases, respiratory diseases, cardiovascular diseases, eye diseases, metabolic diseases, central nervous system (CNS) disorders, liver/kidney diseases, reproductive health disorders, gastric disorders, skin disorders and cancers in a mammal, including a human, comprising an amount of one or more compounds according to  claim 1  effective in such treatment and a pharmaceutically acceptable carrier.  
     
     
         19 . A method for treating a condition selected from the group consisting of connective tissue disorders, inflammatory disorders, immunology/allergy disorders, infectious diseases, respiratory diseases, cardiovascular diseases, eye diseases, metabolic diseases, central nervous system (CNS) disorders, liver/kidney diseases, reproductive health disorders, gastric disorders, skin disorders and cancers in a mammal, including a human, comprising administering to said mammal an amount of one or more compounds according to  claim 1  effective in treating such a condition.