Prodrugs of carbamate inhibitors of IMPDH

A composition comprising:

• a. a compound of Formula (I):
• 24
• wherein:
• A is either B or is selected from:
• (C1-C6)-alkyl, or (C2-C6)-alkenyl or alkynyl;
• and A optionally comprises up to 2 substituents, wherein:
• the first of said substituents, if present, is selected from R1 or B, and
• the second of said substituents, if present, is R1;
• wherein:
• each R1 is independently selected from 1,2-methylenedioxy, 1,2-ethylenedioxy, (C1-C4)-alkyl, (C2-C4)-alkenyl or alkynyl, or (CH2)n—W1;
• wherein n is 0, 1 or 2;
• R1 is optionally substituted with R5;
• and
• W1 is selected from halogen, CN, NO2, CF3, OCF3, OH, S(C1-C4)-alkyl, SO(C1-C4)-alkyl, SO2(C1-C4)-alkyl, NH2, NH(C1-C4)-alkyl, N((C1-C4)-alkyl)2, N((C1-C4)-alkyl)R8, COOH, C(O)NH2, C(O)NH(C1-C4)-alkyl, C(O)N((C1-C4)-alkyl)2, —C(O)O(C1-C4)-alkyl or O(C1-C4)-alkyl;
• and
• R8 is an amino protecting group;
• B is selected from a monocyclic or a bicyclic, saturated or unsaturated or aromatic, ring system consisting of 5 to 6 members per ring, wherein each ring optionally comprises up to 4 heteroatoms selected from N, O, or S, and wherein a CH2 adjacent to any of said N, O, or S heteroatoms is optionally replaced with C(O);
• and each B optionally comprises up to 3 substituents, wherein:
• the first of said substituents, if present, is selected from R1, R2, R4 or R5, the second of said substituents, if present, is selected from R1 or R4, and
• the third of said substituents, if present, is R1;
• wherein:
• each R2 is independently selected from (C1-C4)-alkyl, or (C2-C4)-alkenyl or alkynyl;
• and each R2 optionally comprises up to 2 substituents, wherein:
• the first of said substituents, if present, is selected from R1, R4 and R5, and
• the second of said substituents, if present, is R1;
• each R4 is independently selected from OR5, OC(O)R6, OC(O)R5, OC(O)OR6, OC(O)OR5, OC(O)N(R6)2, OP(O)(OR6)2, SR6, SR5, S(O)R6, S(O)R5, SO2R6, SO2R5, SO2N(R6)2, SO2NR5R6, SO3R6, C(O)R5, C(O)OR5, C(O)R6, C(O)OR6, NC(O)C(O)R6, NC(O)C(O)R5, NC(O)C(O)OR6, NC(O)C(O)N(R6)2, C(O)N(R6)2, C(O)N(OR6)R6, C(O)N(OR6)R5, C(NOR6)R6, C(NOR6)R5, N(R6)2, NR6C(O)R1, NR6C(O)R6, NR6C(O)R5, NR6C(O)OR6, NR6C(O)OR5, NR6C(O)N(R6)2, NR6C(O)NR5R6, NR6SO2R6, NR6SO2R5, NR6SO2N(R6)2, NR6SO2NR5R6, N(OR6)R6, N(OR6)R5, OP(O)(OR6)N(R6)2, and OP(O) (OR6)2;
• each R5 is a monocyclic or a bicyclic, saturated or unsaturated or aromatic, ring system consisting of 5 to 6 members per ring, wherein each ring optionally comprises up to 4 heteroatoms selected from N, O, or S, and wherein a CH2 adjacent to said N, O or S maybe replaced with C(O);
• and each R5 optionally comprises up to 3 substituents, each of which, if present, is selected from 1,2-methylenedioxy, 1,2-ethylenedioxy, (C1-C4)-alkyl, (C2-C4)-alkenyl or alkynyl, or (CH2)n—W1;
• wherein n is 0, 1 or 2;
• and wherein any R5 heterocyclic ring in R5 is optionally benzofused;
• each R6 is independently selected from H, (C1-C5)-alkyl, or (C2-C5)-alkenyl or alkynyl, and each R6 optionally comprises a substituent that is R5;
• and wherein
• any carbon atom in any A, R2 or R6 is optionally replaced by O, S, SO, SO2, NH, or N(C1-C4)-alkyl;
• D is selected from N(R9)—C(O)—N(R9), C(O)—N(R9), N(R9)—C(O), NR9-C(O)—C(R10)═C(R10);
• each R9 is independently selected from hydrogen, (C1-C4)-alkyl, (C2-C4)-alkenyl or alkynyl, R5-substituted-(C1-C4)-alkyl, or R5-substituted-(C2-C4)-alkenyl or alkynyl;
• wherein
• R9 is optionally substituted with up to 3 substituents independently selected from halo, hydroxy, nitro, cyano or amino;
• each R10 is independently selected from R9, W4-[C1-C4-alkyl], W4-[C2-C4-alkenyl or alkynyl], R5-substituted-[W4-[C1-C4-alkyl]], R5-substituted-[W4-[C2-C4-alkenyl or alkynyl]], O—R5, N(R9)—R5, S—R5, S(O)-R5, S(O)2-R5, S—C(O)H, N(R9)—C(O)H, or O—C(O)H;
• wherein:
• W4 is O, O—C(O), S, S(O), S(O)2, S—C(O), N(R9), or N(R9)—C(O);
• and wherein
• each R10 is optionally and independently substituted with up to 3 substituents independently selected from halo, hydroxy, nitro, cyano or amino;
• Z is C1-C10-alkylene, C2-C10-alkenyl or alkynyl, C1-C10 aryl-substituted alkyl, C2-C10 aryl-substituted alkenyl or alkynyl;
• wherein
• up to 3 carbons may be replaced with —O—, —S—, —S(O)—, —S(O)2—, —NR14;
• wherein
• up to 3 —CH2— groups may be replaced with —C(O)—;
• wherein
• up to 5 hydrogen atoms in any of said alkyl, alkenyl, aryl, or alkynyl are optionally and independently replaced by R13 or R5;
• R13 is halo, —OR14, —N(R14)2, —SR14, —S(O)R14, —S(O)2R14, —S(O)2OR14, —S(O)2N(R14)2, N(R14)S(O)2NR14)2, —OS(O)2N(R14)2, —NR14C(O)R14, —NR14C(O)OR14, —N(R14)C(O)N(R14)2, —N(R14)C(S)N(R14)2, —N(R14)C(NR14)NR14)2, —C(O)R14, —C(O)OR14, —C(O)SR14, —C(O)N(R14)2, —C(NR14)N(R14)2, —C(S)OR14, —C(S)N(R14)2, —N(R14)p(O)(OR14)2, —OP(O)(OR14)2;
• R14 is H, C1-C5-alkyl, C2-C5-alkenyl or alkynyl, aryl, or C1-C5 alkyl-aryl;
• wherein
• up to 3 hydrogen atoms in R14 are optionally and independently replaced with a substituent that is R13;
• and wherein
• any NR14, taken together with the nitrogen and a carbon adjacent to the nitrogen, optionally forms a 5-7 membered ring, wherein said ring optionally contains up to three additional heteroatoms selected from O, N, S, or S(O)2;
• Y is —NH(R14);
• RX is (C1-6)-alkyl, wherein up to 4 hydrogen atoms in said alkyl are optionally and independently replaced by R20;
• R20 is independently selected from halo, —OR21, —N(R22)2, —SR21, —S(O)R21, —S(O)2R21, —CN, or;
• R21 is selected from hydrogen, —(C1-6)-straight alkyl, —(C1-6)-straight alkyl-R5, —C(O)—(C1-6)-alkyl which is optionally substituted with R4, —C(O)—R5, or —(C1-6)-straight alkyl—CN;
• each R22 is independently selected from hydrogen, —(C1-C6)-alkyl, —(C1-C6)-alkyl-R5, —(C1-6)-straight alkyl—CN, —(C1-6)-straight alkyl—OH, —(C1-6)-straight alkyl—OR21, —C(O)—(C1-6)-alkyl, —C(O)—R5, —S(O)2-(C1-6)-alkyl, or —S(O)2-R5;
• or two R22 moieties, when bound to the same nitrogen atom, are taken together with said nitrogen atom to form a 3 to 7-membered heterocyclic ring, wherein said heterocyclic ring optionally contains 1 to 3 additional heteroatoms independently selected from N, O, or S;
• RY is selected from hydrogen, —CF3, —(C1-6)-alkyl, —(C1-6)-alkyl-R5, or —R5;
• or wherein RX and RY are optionally taken together with the carbon atom to which they are bound to form a monocyclic or a bicyclic, saturated or unsaturated or aromatic, ring system consisting of 5 to 6 members per ring, wherein each ring optionally comprises up to 4 heteroatoms selected from N, O, or S, and wherein a CH2 adjacent to said N, O or S maybe replaced with C(O);
• wherein 1 to 4 hydrogen atoms in said ring system are optionally replaced by —OC(O)CH3, —O—CH2—C(O)OH, —O—CH2—C(O)O—(C1-C4)-alkyl, —O—CH2—CN, or —O—CH2—C═CH2;
• b. a carrier or adjuvant,
• c. an additional agent selected from an immunosuppressant, an anti-cancer agent, an anti-viral agent or an anti-vascular hyperproliferation agent.