Thrombopoietin Receptor Agonists

A compound of the Formula

• or the pharmaceutically acceptable salts thereof;
• wherein
• R1 is (C2-C9)heteroaryl or (C2-C9)heterocycloalkyl wherein the heteroaryl or heterocycloalkyl groups are optionally substituted by one to three groups selected from the group consisting of halo, cyano, nitro, carboxy, hydroxy, amino, NH2C(O)—, R3(C1-C6)alkyl, R3(C1-C6)alkoxy, R3(C1-C6)alkoxycarbonyl, R3(C1-C6)alkylthio, R3(C1-C6)alkylsulfinyl, R3(C1-C6)alkylsulfonyl, R3(C1-C6)alkylaminosulfonyl, R3(C1-C6)alkylsulfonylamino, R3(C1-C6)alkylamino, R3(C1-C6)alkylcarboxy, R3(C1-C6)alkyl-NH—C(O)—, amino-C(O)—NH—, R3(C1-C6)alkylamino C(O)—NH—, aminocarbonyl(C1-C6)alkyl, R3(C1-C6)alkylaminocarbonyl(C1-C6)alkyl, amino-C(O)—O—, amino(C1-C6)alkoxycarbonyl, R3(C1-C6)alkylamino-C(O)—O—, R3(C1-C6)alkylamino(C1-C6)alkoxycarbonyl, R3(C1-C6)alkoxy-C(O)—NH—, R3(C1-C6)alkoxy(C1-C6)alkylamino, trifluoromethyl, trifluoromethyl(C1-C6)alkyl, R3(C1-C6)alkyl-CF2, trifluoromethyl[(C1-C6)alkyl]a-(CF2)b—[(C1-C6)alkyl]c- wherein a is 0 or 1, b is 1, 2, 3 or 4, and c is 0 or 1;
• R4R5N—, R4R5N—C(O)—, R4R5N—C(O)—NH—, R4R5N—C(O)—(C1-C6)alkyl and R4R5N—C(O)—O—;
• wherein R3 is one to three groups selected from hydrogen, (C1-C6)alkoxy, hydroxy, carboxy, amino, (C1-C6)alkylamino, R4R5N—, (C1-C6)alkylamino, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl and NH2—C(O)—;
• R4 and R5 are each independently (C1-C6)alkyl optionally substituted by (C1-C6)alkoxy, hydroxy, carboxy, amino, (C1-C6)alkylamino, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl and NH2—C(O)—;
• or R4 and R5 may be taken together with the nitrogen to which they are attached to form a 4 to X membered ring wherein the 6 to 8 membered rings may further optionally contain one to three heteroatoms selected from the group consisting of O, S, S(O), S(O)2, NH or ((C1-C6)alkyl)-N—;
• and the ring so formed is optionally substituted by (C1-C6)alkoxy, hydroxy, carboxy, amino, (C1-C6)alkylamino, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl and NH12—C(O)—;
• A, B, D, F are each independently CH, N or CR6 wherein R1 is halo, cyano, nitro, carboxy, hydroxy, amino, NH2C(O)—, R7(C1-C6)alkyl, R7(C1-C6)alkoxy, R7(C1-C6)alkoxycarbonyl, R7(C1-C6)alkylthio, R7(C1-C6)alkylsulfonyl, R7(C1-C6)alkylsulfonyl, R7(C1-C6)alkylaminosulfonyl, R7(C1-C6)alkylsulfonylamino, R7(C1-C6)alkylamino, R7(C1-C6)alkylcarboxy, R7(C1-C6)alkyl-NH—C(O)—, amino-C(O)—NH—, R7(C1-C6)alkylamino C(O)—NH—, aminocarbonyl(C1-C6)alkyl, R7(C1-C6)alkylaminocarbonyl(C1-C6)alkyl, amino-C(O)—O—, amino(C1-C6)alkoxycarbonyl, R7(C1-C6)alkylamino-C(O)—O—, R7(C1-C6)alkylamino(C1-C6)alkoxycarbonyl, R7(C1-C6)alkoxy-C(O)—NH—, R7(C1-C6)alkoxy(C1-C6)alkylamino, trifluoromethyl, trifluoromethyl(C1-C6)alkyl, R7(C1-C6)alkyl-CF2, trifluoromethyl[(C1-C6)alkyl]a-(CF2))b-[(C1-C6)alkyl]c- wherein a is 0 or 1, b is 1, 2, 3 or 4, and c is 0 or 1;
• R8R9N—, R8R9N—C(O)—, R8R9—C(O)—NH—, R8R9N—C(O)—(C1-C6)alkyl and R8R8R9N—C(O)—O—;
• wherein R7 is one to three groups selected from hydrogen, (C1-C6)alkoxy, hydroxy, carboxy, amino, (C1-C6)alkylamino, R8R9N—, (C1-C6)alkylamino, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl or NH2—C(O)—;
• R8 and R9 are each independently (C1-C6)alkyl optionally substituted by (C1-C6)alkoxy, hydroxy, carboxy, amino, (C1-C6)alkylamino, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl and NH2—C(O)—;
• or R8 and R9 may be taken together with the nitrogen to which they are attached to form a 4 to 8 membered ring wherein the 6 to 8 membered rings may further optionally contain one to three heteroatoms selected from the group consisting of O, S, S(O), S(O)2, NH or ((C1-C6)alkyl)-N—;
• and the ring so formed is optionally substituted by (C1-C6)alkoxy, hydroxy, carboxy, amino, (C1-C6)alkylamino, amino, (C1-C6)alkyl amino, ((C1-C6)alkyl)2amino, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl and NH2—C(O)—;
• W, X and Y are each independently selected from the group consisting of C, CH, CR10, O, S, N, NH and R10(((C1-C6)alkyl)-N;
• Z is C or N;
• wherein R10 is halo, cyano, nitro, carboxy, hydroxy, amino, NH2C(O)—, R11(C1-C6)alkyl, R11(C1-C6)alkoxy, R11(C1-C6)alkoxycarbonyl, R11(C1-C6)alkylthio, R11(C1-C6)alkylsulfinyl, R11(C1-C6)alkylsulfonyl, R11(C1-C6)alkylaminosulfonyl, R11(C1-C6)alkylsulfonylamino, R11(C1-C6)alkylamino, R11(C1-C6)alkylcarboxy, R11(C1-C6)alkyl-N—-C(O)—, amino-C(O)—NH—, R11 (C1-C6)alkylamino C(O)—NH—, aminocarbonyl(C1-C6)alkyl, R11(C1-C6)alkylaminocarbonyl(C1-C6)alkyl, amino-C(O)—O—, amino(C1-C6)alkoxycarbonyl, R11(C1-C6)alkylamino-C(O)—O—, R11(C1-C6)alkylamino(C1-C6)alkoxycarbonyl, R11(C1-C6)alkoxy-C(O)—NH—, R11K(C1-C6)alkoxy(C1-C6)alkylamino, trifluoromethyl, trifluoromethyl(C1-C6)alkyl, R11(C1-C6)alkyl-CF2, trifluoromethyl[(C1-C6)alkyl]a—(CF2)b-[C1-C6)alkyl]c-, wherein a is 0 or 1, b is 1, 2, 3 or 4, and c is 0 or 1;
• R12R13N—, R12R13N—C(O)—, R12R13N—C(O)—NH—, R12R13N—C(O)—(C1-C6)alkyl and R12R13N—C(O)—O—;
• wherein R11 is one to three groups selected from hydrogen, (C1-C6)alkoxy, hydroxy, carboxy, amino, (C1-C6)alkylamino, R12R13N—, (C1-C6)alkylamino, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl and NH2—C(O)—;
• R12 and R13 are each independently (C1-C6)allyl optionally substituted by (C1-C6)alkoxy, hydroxy, carboxy, amino, (C1-C6)alkylamino, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl and NH2—C(O)—;
• or R12 and R13 may be taken together with the nitrogen to which they are attached to form a 4 to 8 membered ring wherein the 6 to 8 membered rings may further optionally contain one to three heteroatoms selected from the group consisting of O, S, S(O), S(O)2, NH or ((C1-C6)alkyl)-N—;
• and the ring so formed is optionally substituted by (C1-C6)alkoxy, hydroxy, carboxy, amino, (C1-C6)alkylamino, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl and NH2—C(O)—;
• and
• R2 is R14(C6-C10)aryl, R14(C2-C9)heteroaryl, R14(C3-C10)cycloalkyl or R14(C2-C9)heterocycloalkyl;
• wherein R14 is one to three groups selected from hydrogen, halo, cyano, nitro, carboxy hydroxy, amino, NH2C(O)—, R15(C1-C6)alkyl, R15(C3-C10)cycloalkyl, R15(C1-C6)alkoxy, R15(C1-C6)alkoxycarbonyl, R15(C1-C6)alkylthio, R15(C1-C6)alkylsulfinyl, R15(C1-C6)alkylsulfonyl, R15(C1-C6)alkylaminosulfonyl, R15(C1-C6)alkylsulfonylamino, R15(C1-C6)alkylamino, R15(C1-C6)alkylcarboxy, R15(C1-C6)alkyl-NH—C(O)—, amino-C(O)—NH—, R15(C1-C6)alkylamino C(O)—NH—, aminocarbonyl(C1-C6)alkyl, R15(C1-C6)alkylaminocarbonyl(C1-C6)alkyl, amino-C(O)—O—, amino(C1-C6)alkoxycarbonyl, R15(C1-C6)alkylamino-C(O)—O—, R15 (C1-C6)alkylamino(C1-C6)alkoxycarbonyl, R15(C1-C6)alkoxy-C(O)—NH—, R15(C1-C6)alkoxy(C1-C6)alkylamino, trifluoromethyl, trifluoromethoxy, trifluoromethyl(C1-C6)alkyl, R15(C1-C6)alkyl-CF2, trifluoromethyl[(C1-C6)alkyl]a-(CF2)b[(C1-C6)alkyl]c-, wherein a is 0 or 1, b is 1, 2, 3 or 4, and c is 0 or 1 R16R17N—, R16R17N—C(O)—, R16R17N—C(O)—NH—, R16R17N—C(O)—(C1-C6)alkyl and R16R17N—C(O)—O—;
• wherein R15 is one to three groups selected from hydrogen, (C1-C6)alkyl, (C3-C10)cycloalkyl, (C1-C6)alkoxy, hydroxy, cyano, carboxy, amino, (C1-C6)alkylamino, R16R17N—, (C1-C6)alkylamino, (C1-C6)alkylthio, (C1-C6) alkylsulfinyl, (C1-C6)alkylsulfonyl and NH2—C(O)—;
• R16 and R17 are each independently (C1-C6)alkyl optionally substituted by (C1-C6)alkoxy, hydroxy, carboxy, amino, (C1-C6)alkylamino, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl and NH2—C(O)—;
• or R16 and R17 may be taken together with the nitrogen to which they are attached to form a 4 to 8 membered ring wherein the 6 to 8 membered rings may further optionally contain one to three heteroatoms selected from the group consisting of O, S, S(O), S(O)2, NH or ((C1-C6)alkyl)-N—;
• and the ring so formed is optionally substituted by (C1-C6)alkoxy, hydroxy, carboxy, amino, (C1-C6)alkylamino, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl and NH2—C(O)—.