Patent ID: 7432273

Claim:
A method for inhibiting DHFR 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 505: 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 ; A 1 is: A 2 is: A 3 is: 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.