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

A compound represented by formula I:

• or a pharmaceutically acceptable salt or prodrug thereof, wherein:
• X1 and X2 are each independently selected from the group consisting of:
• H, OH, halogen, CN, CO2H, CO2C1-6alkyl, 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, C2-6alkynyl, 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 substituents 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;
• 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;
• Each x is independently 0, 1, or 2;
• Y1 is selected from the group consisting of a bond, a C1-6 alkylene group, and a C2-6 alkenylene group, wherein said alkylene group and said alkenylene group are optionally substituted with one or more substituents independently selected from (a) 1-12 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 or more substituents independently selected from (a) 1-21 halogen atoms, (b) one substituent selected from Ar1 and Het1, and (c) 1-2 substituents independently selected from OH, CN, CO2H, CO2C1-6 alkyl, CO2C2-6 alkenyl, OC1-3alkyleneOC1-3alkyl, OC1-6alkyl, OC2-6 alkenyl, OC(O)C1-6alkyl, OC(O)C2-6alkenyl, C(O)C1-6alkyl, C(O)C2-6alkenyl, Aryl, C(O)Aryl, OC(O)Aryl, OAryl, CO2Aryl, S(O)xC1-6alkyl, S(O) C2-6alkenyl, S(O)xAryl, S(O)2NR1R2, C(O)NR1R2, NR1R2, and a 5-6-membered heterocycle having 1-2 heteroatoms selected from N, S and O in the ring, 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 CO2H, CF2CO2H, P(O)(OR5)2, and SO2R4, and (b) 1-3 groups independently selected from R3;
• Ar1 is phenyl or napthyl, wherein phenyl 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, SO2R4, and Ar2, and (b) 1-5 groups selected from R3, and wherein naphthyl is optionally substituted with one or more groups independently selected from (a) one group selected from CO2H, CF2CO2H, P(O)(OR5)2, SO2R4, and Ar2, and (b) 1-5 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 independently 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 substituents 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, NO2, CO2C1-10 alkyl, CO2C2-10 alkenyl, OC1-10alkyl, OC2-10 alkenyl, C1-10 alkyl, 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)xCl10alkyl, C1-3alkyleneS(O)xC1-10alkyl, S(O)xC2-10alkenyl, S(O)2NR1R2, C(O)NR1R2, NR1R2, NR1S(O)2R2 NR1C(O)C1-6alkyl, NR1C(O)H, Aryl, and Het, wherein each alkyl group and each alkenyl group of each substituent is optionally substituted with one or more substituents 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, S(O)xAryl, S(O)xC1-3alkyl and phenyl, wherein said phenyl is optionally substituted with 1-3 substituents independently selected from OCH3, OCF3, S(O)2 NR1R2, Br, Cl, and F, wherein the C1-3 alkyl groups of said substituents are optionally substituted with one or more substituents independently selected from (a) 1-7 halogen atoms and (b) 1-2 phenyls which are optionally substituted with 1-3 substituents independently selected from halogen and SO2NR1R2;
• 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, OH, OC1-3 alkyl, C(O)C1-3alkyl, OC(O)C1-3alkyl, CO2H, CO2C1-3alkyl, NR1R2, S(O)xC1-4alkyl and SO2NR1R2, wherein said alkyl groups in said substituents are optionally substituted with 1-7 halogen atoms;
• Het is a 5-10 membered aromatic ring system containing 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, CO2C1-3alkyl, NR1R2, S(O)xC1-4alkyl and SO2NR1R2, 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 alkyl, alkenyl, alkadienyl and alkynyl are respectively saturated, contain one double bond, contain 2 double bonds, or contain one triple bond;
• and
• R4 is phenyl or C1-4 alkyl, wherein said phenyl is optionally substituted with one or more substituents 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 substituents 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.