Aryldifluoromethylphosphonic acids with sulfur-containing substituents as PTP-1B inhibitors

A compound represented by formula I:

• 8
• or a pharmaceutically acceptable salt or prodrug thereof, wherein:
• Each X1 is independently selected from the group consisting of:
• H, OH, halogen, CN, CO2H, CO2C 6alkyl, CO2C2-6alkenyl, OC1-6alkyl, OC2-6alkenyl, C(O)C1-6alkyl, C(O)C2-6alkenyl, OC(O)C1-6alkyl, OC(O)C2-6alkenyl, S(O)xC1-6alkyl, S(O)xC2-6alkenyl, C1-6 alkyl, C2-6alkenyl, S(O)2NR1R2, C(O)NR1R2, and NR1R2, wherein each alkyl group and each alkenyl group in each substituent is optionally substituted with one or more groups independently selected from (a) 1-13 halogen atoms and (b) 1-2 substituents independently selected from OC1-3 alkyl, C(O)C1-3alkyl, OC(O)C1-3alkyl, CO2H, and CO2C1-3alkyl;
• X1, CF2P(O)(OR5)2 and Y1S(O)xR are substituted onto any position of either ring;
• Each x is independently 0, 1, or 2;
• R5 is H;
• R1 and R2 are each independently selected from the group consisting of H and C1-4alkyl, wherein said alkyl substituents are optionally substituted with 1-9 halogen atoms;
• Each halogen is independently selected from I, Cl, Br and F;
• Y1 is selected from the group consisting of a bond, a C1-4 alkylene group, and a C2-4 alkenylene group, wherein said alkylene group and said alkenylene group are optionally substituted with one or more groups selected from (a) 1-8 halogen atoms, and (b) 1-2 substituents independently selected from OH and OC1-4 alkyl, said OC1-4 alkyl being optionally substituted with 1-9 halogen atoms;
• R is selected from the group consisting of C1-10 alkyl, C2-10alkenyl, C2-10alkadienyl, C2-10alkynyl, Ar1, and Het1, wherein said alkyl, alkenyl, alkadienyl, and alkynyl are optionally substituted with one substituent selected from Ar1 and Het1, and are optionally also substituted with one or more groups independently selected from (a) 1-21 halogen atoms, and (b) 1-2 substituents independently selected from OH, CN, CO2H, CO2C1-6 alkyl, CO2C2-6 alkenyl, OC1-6alkyl, OC2-6 alkenyl, OC(O)C1-6alkyl, OC(O)C2-6alkenyl, C(O)C1-6alkyl, C(O)C2-6alkenyl, C(O)Aryl, OC(O)Aryl, OAryl, CO2Aryl, S(O)xC1-6alkyl, S(O)xC2-6alkenyl, S(O)2NR1R2, C(O)NR1R2, and NR1R2, wherein said alkyl groups and said alkenyl groups of said substituents are optionally substituted with 1-13 halogen atoms;
• Het1 is a 5-10 membered aromatic ring system comprising 1 ring or 2 rings fused together and 1-4 heteroatoms selected from O, N, S(O)x, and combinations thereof, and 0-2 carbonyl groups, wherein one of said fused rings is optionally a benzene ring, and said Het1 is optionally substituted with one or more groups independently selected from (a) one group selected from CF2P(O)(OR5)2, CO2H, CF2CO2H, P(O)(OR5)2, and SO2R4, and (b) 1-2 groups independently selected from R3;
• Ar1 is phenyl or naphthyl, optionally substituted with one or more groups independently selected from (a) one group selected from CF2P(O)(OR5)2, CO2H, CF2CO2H, P(O)(OR5)2, SO2R4, and Ar2, and (b) 1-2 groups selected from R3;
• Ar2 is phenyl, naphthyl or a 5-10 membered aromatic ring system comprising 1 ring or 2 rings fused together and 1-4 heteroatoms selected from O, N, S(O)x, and combinations thereof, and 0-2 carbonyl groups, wherein one of said fused rings is optionally a benzene ring, wherein Ar2 is optionally substituted with one or more groups independently selected from (a) one group selected from CF2P(O)(OR5)2, CO2H, CF2CO2H, P(O)(OR5)2, and SO2R4, and (b) 1-2 groups selected from R3;
• R3 is selected from the group consisting of halogen, OH, CN, CO2H, CO2C1-10 alkyl, CO2C2-10 alkenyl, OC1-10alkyl, OC2-10 alkenyl, C1-10alkyl, C2-10 alkenyl, OC(O)C1-10alkyl, OC(O)C2-10alkenyl, C(O)C1-10alkyl, C(O)C2-10alkenyl, C(O)Aryl, OC(O)Aryl, OAryl, CO2Aryl, S(O)xC1-10alkyl, S(O)xC2-10alkenyl, S(O)2NR1R2, C(O)NR1R2, NR1R2, Aryl, and Het, wherein each alkyl group and each alkenyl group of each substituent is optionally substituted with one or more groups independently selected from (a) 1-21 halogen atoms and (b) 1-2 substituents independently selected from OH, OC1-3 alkyl, CO2H, CO2C1-3alkyl, C(O)C1-3alkyl, OC(O)C1-3alkyl, and phenyl, wherein said phenyl is optionally substituted with 1-3 substituents independently selected from OCH3, OCF3, Cl and F, and said C1-3 alkyl groups of said substituents are optionally substituted with one or more groups independently selected from (a) 1-7 halogen atoms and (b) 1-2 phenyls, wherein said phenyls are optionally substituted with 1-3 halogen atoms;
• Aryl is a 6-14 membered aromatic carbocyclic moiety comprising 1 ring or 2-3 fused rings, wherein said Aryl is optionally substituted with 1-3 substituents independently selected from C1-3alkyl, halogen, OC1-3 alkyl, C(O)C1-3 alkyl, OC(O)C1-3alkyl, CO2H, and CO2C1-3alkyl, wherein said alkyl groups in said substituents are optionally substituted with 1-7 halogen atoms;
• Het is a 5-10 membered aromatic ring system comprising 1-4 heteroatoms selected from N, S(O)x, O, and mixtures thereof, and 0-2 carbonyl groups, wherein said Het comprises 1 ring or 2 fused rings, one of which fused rings may be a benzene ring, and said Het is optionally substituted with 1-3 substituents independently selected from C1-3alkyl, halogen, OC1-3 alkyl, C(O)C1-3alkyl, OC(O)C1-3alkyl, CO2H, and CO2C1-3alkyl, wherein said alkyl groups are optionally substituted with 1-7 halogen atoms;
• Alkyl, alkenyl, alkadienyl and alkynyl are linear, branched or cyclic hydrocarbon structures, or combinations thereof containing the indicated number of carbon atoms and substituted as indicated, wherein said alkyl, alkenyl, alkadienyl and alkynyl respectively are saturated, comprise one double bond, comprise 2 double bonds, or comprise one triple bond;
• and
• R4 is phenyl or C1-4 alkyl, wherein said phenyl is optionally substituted with one or more groups independently selected from (a) 1-3 halogen atoms and (b) 1-2 C1-3 alkyl or C1-3alkoxy groups, which are optionally substituted with 1-7 halogen atoms, and said C1-4 alkyl is optionally substituted with one or more groups independently selected from (a) 1-9 halogen atoms and (b) 1-2 C1-3 alkoxy groups, which are optionally substituted with 1-7 halogen atoms.