Protein tyrosine phosphatase 1B (PTP-1B) inhibitors containing two ortho-substituted aromatic phosphonates

A compound represented by formula I:

• 33
• or a pharmaceutically acceptable salt thereof, wherein:
• R1 and R2 are selected from the group consisting of:
• C1-10alkyl(Ra)0-7, C2-10alkenyl(Ra)0-7, Aryl(Ra)0-3 and Het(Ra)0-3;
• wherein each Ra independently represents a member selected from the group consisting of:
• Aryl, OH, halogen, CN, CO2H, CO2C1-6alkyl, CO2C2-6alkenyl, OC1-10alkyl, C(O)C1-6alkyl, S(O)yC1-6alkyl, C1-6alkyl, C1-6haloalkyl, S(O)yNR3′R4′, wherein y is 0, 1, or 2, C(O)NR3′R4′, NR3′R4′, and Het, wherein each alkyl group in Ra is optionally substituted with 1-7 groups independently selected from halogen, OC1-3 alkyl, CO2H, and CO2C1-3alkyl, and each Het and Aryl in Ra is optionally substituted with 1-3 groups independently selected from C1-3alkyl, halogen, OC1-3 alkyl, CO2H, and CO2C1-3alkyl;
• Aryl is a 6-14 membered carbocyclic aromatic ring system comprising 1-3 phenyl rings, wherein the phenyl rings are fused together when there is more than one aromatic ring;
• Het represents a 5-10 membered aromatic ring system comprising one ring or two fused rings, 1-4 heteroatoms, 0-4 of which are N atoms and 0-2 of which are O or S(O)y wherein y is 0-2, and 0-2 carbonyl groups;
• Y1, Y2, Z1, and Z2 each independently represents —(CR3R4)a—X—(CR3R4)b— wherein a and b are integers 0-2 such that the sum of a and b equals 0, 1, 2, or 3;
• X represents a bond, O, S(O)y, NR3′, C(O), OC(O), C(O)O, C(O)NR3′, NR3′C(O) or —CH═CH—, where y is as previously defined;
• R3 and R4 are independently H, halogen, C1-10alkyl or C1-10haloalkyl;
• R3′ and R4′ are each independently selected from the group consisting of:
• H, C1-6alkyl, C1-6haloalkyl, OH, C(O)C1-6 alkyl, C(O)Aryl, C(O)Het, C(O)C1-6 haloalkyl, Aryl and Het;
• W1 and W2 are each in a position on the aromatic ring adjacent to the —CF2P(O)(OH)2 substituent and are each independently selected from the group consisting of:
• OH, CN, halo, OC6alkyl(Ra)0-7, S(O)yC1-6alkyl(Ra)0-7, with y equal to 0-2, S(O)3H, C1-6alkyl(Ra)0-7, CO2H, CO2C1-6alkyl(Ra)0-7, CO2C2-6 alkenyl(Ra)0-7, C(O)C1-6alkyl(Ra)0-7, C(O)NR3′R4′, S(O)yNR3′R4′, NR3′R4′, Aryl, and Het, wherein R3′ and R4′ are as defined above;
• and
• W1′ and W2′ are optionally present on any remaining position on the aromatic ring and are each independently selected from H and from the same groups as W1 and W2,
• wherein at least one substituent group on the compound of FIG. I is selected from Het.