Inosine monophosphate dehydrogenase inhibitory phosphonate compounds
The invention is related to phosphorus substituted IMPDH inhibitory compounds, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.
1. A method for inhibiting IMPDH in vitro comprising contacting a sample in need of such treatment with a conjugate or a pharmaceutically acceptable salt or solvate thereof wherein the conjugate is a compound of formula:
[DRUG]−( A 0 ) nn
wherein:
DRUG is a compound of formula 501:
wherein:
nn is 1, 2, or 3;
A 0 is A 1 , A 2 or W 3 with the proviso that the conjugate includes at least one A 1 ;
Y 1 is independently O, S, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R x )(R x ));
Y 2 is independently a bond, O, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), N(N(R x )(R x )),—S(O) M2 —, or —S(O) M2 —S(O) M2 —; and when Y 2 joins two phosphorous atoms Y 2 can also be C(R 2 )(R 2 );
R x is independently H, R 1 , R 2 , W 3 , a protecting group, or the formula:
wherein:
R y is independently H, W 3 , R 2 or a protecting group;
R 1 is independently H or alkyl of 1 to 18 carbon atoms;
R 2 is independently H, R 1 , R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups or taken together at a carbon atom, two R 2 groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 R 3 groups;
R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d ;
R 3a is F, Cl, Br, I, —CN, N 3 or —NO 2 ;
R 3b is Y 1 ;
R 3c is —R x , —N(R x )(R x ), —SR x , —S(O)R x , —S(O) 2 R x , —S(O)(OR x ), —S(O) 2 (OR x ), —OC(Y 1 )R x , —OC(Y 1 )OR x , —OC(Y 1 )(N(R x )(R x )), —SC(Y 1 )R x , —SC(Y 1 )OR x , —SC(Y 1 )(N(R x )(R x )), —N(R x )C(Y 1 )R x , —N(R x )C(Y 1 )OR x , or —N(R x )C(Y 1 )(N(R x )(R x ));
R 3d is —C(Y 1 )R x , —C(Y 1 )OR x or —C(Y 1 )(N(R x )(R x ));
R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;
W 3 is W 4 or W 5 ;
W 4 is R 5 , —C(Y 1 )R 5 , —C(Y 1 )W 5 , —SO M2 R 5 , or —SO M2 W 5 ;
W 5 is carbocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
W 6 is W 3 independently substituted with 1, 2, or 3 A 3 groups;
M2 is 0, 1 or 2;
M12a is 1,2,3,4,5,6,7,8,9,10,11 or 12;
M12b is 0,1,2,3,4,5,6,7,8,9,10,11 or 12;
M1a, M1c, and M1d are independently 0 or 1; and
M12c is 0,1,2,3,4,5,6,7,8,9,10,11 or 12.
2. A method of treating Hepatitis C in a mammal, comprising administering a conjugate or a pharmaceutically acceptable salt or solvate thereof, to the mammal wherein the conjugate is a compound of formula:
[DRUG]−( A 0 ) nn
wherein:
DRUG is a compound of formula 501:
wherein:
nn is 1, 2, or 3;
A 0 is A 1 , A 2 or W 3 with the proviso that the conjugate includes at least one A 1 ;
Y 1 is independently O, S, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R x )(R x ));
Y 2 is independently a bond, O, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), N(N(R x )(R x )), —S(O) M2 —, or —S(O) M2 —S(O) M2 —; and when Y 2 joins two phosphorous atoms Y 2 can also be C(R 2 )(R 2 );
R x is independently H, R 1 , R 2 , W 3 , a protecting group, or the formula:
wherein:
R y is independently H, W 3 , R 2 or a protecting group;
R 1 is independently H or alkyl of 1 to 18 carbon atoms;
R 2 is independently H, R 1 , R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups or taken together at a carbon atom, two R 2 groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 R 3 groups;
R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d ;
R 3a is F, Cl, Br, I, —CN, N 3 or —NO 2 ;
R 3b is Y 1 ;
R 3c is —R x , —N(R x )(R x ), —SR x , —S(O)R x , —S(O) 2 R x , —S(O)(OR x ), —S(O) 2 (OR x ), —OC(Y 1 )R x , —OC(Y 1 )OR x , —OC(Y 1 )(N(R x )(R x )), —SC(Y 1 )R x , —SC(Y 1 )OR x ,—SC(Y 1 )(N(R X )(R x )), —N(R x )C(Y 1 )R x , —N(R x )C(Y 1 )OR x , or —N(R x )C(Y 1 )(N(R x )(R x ));
R 3d is —C(Y 1 )R x , —C(Y 1 )OR x or —C(Y 1 )(N(R x )(R x ));
R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;
W 3 is W 4 or W 5 ;
W 4 is R 5 , —C(Y 1 )R 5 , —C(Y 1 )W 5 , —SO M2 R 5 , or —SO M2 W 5 ;
W 5 is carbocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
W 6 is W 3 independently substituted with 1, 2, or 3 A 3 groups;
M2 is 0, 1 or 2;
M12a is 1,2,3,4,5,6,7,8,9,10,11 or 12;
M12b is 0,1,2,3,4,5,6,7,8,9,10,11 or 12;
M1a, M1c, and M1d are independently 0 or 1; and
M12c is 0,1,2,3,4,5,6,7,8,9,10,11 or 12.
3. The method of claim 1 wherein each A 3 is of the formula:
4. The method of claim 1 wherein each A 3 is of the formula:
wherein Y 2b is O or N(R x ).
5. The method of claim 1 wherein each A 3 is of the formula:
6. The method of claim 1 wherein each A 3 is of the formula:
7. The method of claim 1 wherein each A 3 is of the formula:
wherein Y 2b is O or N(R x ).
8. The method of claim 1 wherein each A 3 is of the formula:
wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R 2 groups.
9. The method of claim 1 wherein each A 3 is of the formula:
wherein:
Y 1a is O or S;
Y 2b is O or N(R 2 ); and
Y 2c is O, N(R y ) or S.
10. The method of claim 1 wherein A 0 is of the formula:
wherein each R is independently alkyl.
11. The method of claim 2 wherein each A 3 is of the formula:
12. The method of claim 2 wherein each A 3 is of the formula:
wherein Y 2b is O or N(R x ).
13. The method of claim 2 wherein each A 3 is of the formula:
14. The method of claim 2 wherein each A 3 is of the formula:
15. The method of claim 2 wherein each A 3 is of the formula:
wherein Y 2b is O or N(R x ).
16. The method of claim 2 wherein each A 3 is of the formula:
wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R 2 groups.
17. The method of claim 2 wherein each A 3 is of the formula:
wherein:
Y 1a is O or S;
Y 2b is O or N(R 2 ); and
Y 2c is O, N(R y ) or S.
18. The method of claim 2 wherein A 0 of the formula:
wherein each R is independently alkyl.