Inhibitors of PTP4A3 for the treatment of cancer

A pharmaceutical composition comprising a therapeutically effective amount of a compound according to Formula III or a pharmaceutically acceptable salt thereof:

• wherein
• R4 is selected from the group consisting of H, —OH, —OC1-4 alkyl, —ORa, trifluoroC1-4 alkoxy, —SC1-4 alkyl, —SRa, —SO2—C1-4 alkyl, —SO2Ra, —SOC1-4 alkyl, —SORa, —SO2NHRb, —NRCRd, halo, —C1-12 alkyl, —C2-6 alkenyl, —C2-6 alkynyl, —C3-6 cycloalkyl, phenyl, benzyl, monocyclic heteroaryl optionally substituted with Rb, —C4-7 heterocycloalkyl containing one or two of O, S, and N, —OC(O)Rb, —OC(O)Rb, —P(O)(ORb)1-2, —P(S)(ORb)1-2, —P(O)(NRCRd)1-2, —P(S)(NRCRd)1-2, —O(CH2—CH2—O)1-4CH3, —CN, —NO2, —C(O)C1-4 alkyl, and —C(O)—Rb,
• Ra is selected from the group consisting of —C3-6 cycloalkyl, —C2-6 alkenyl, —C2-6 alkynyl, phenyl, benzyl, and monocyclic heteroaryl, wherein the phenyl, benzyl, or monocyclic heteroaryl is optionally substituted with Rb;
• Rb in each instance is independently selected from the group consisting of H, halo, —OH, —COOH, —C1-12 alkyl, phenyl, benzyl, and monocyclic heteroaryl, wherein the phenyl, benzyl, or monocyclic heteroaryl is optionally substituted with —C2-6 alkenyl, —C2-6 alkynyl, trifluoroC1-4 alkoxy, —OC1-4 alkyl, —O(CH2—CH2—O)1-4 CH3, —O-phenyl, —O-benzyl, —NC1-4 alkyl, —N-phenyl, and —N-benzyl, or —N-monocyclic heteroaryl;
• RC and Rd are each independently selected from the group consisting of H, —C1-4 alkyl, —C(O)—C1-4 alkyl, —SO2—Ra, —SO2—C1-4 alkyl, phenyl, benzyl, and monocyclic heteroaryl, wherein the phenyl, benzyl, or monocyclic heteroaryl is optionally substituted with Rb,
• or RC and Rd taken together with the nitrogen to which they are attached represent an optionally substituted monocyclic heterocycloalkyl containing one or more of O, S, and N,
• and a pharmaceutically acceptable vehicle.

A method for treating a subject suffering from cancer, the method comprising administering to the subject a therapeutically effective amount of a compound according to Formula III or a pharmaceutically acceptable salt thereof:

• wherein
• R4 is selected from the group consisting of H, —OH, —OC1-4 alkyl, —ORa, trifluoroC1-4 alkoxy, —SC1-4 alkyl, —SRa, —SO2—C1-4 alkyl, —SO2Ra, —SOC1-4 alkyl, —SORa, —SO2NHRb, —NRCRd, halo, —C1-12 alkyl, —C2-6 alkenyl, —C2-6 alkynyl, —C3-6 cycloalkyl, phenyl, benzyl, monocyclic heteroaryl optionally substituted with Rb, C4-7 heterocycloalkyl containing one or two of O, S, and N, —OC(O)Rb, —OC(O)Rb, —P(O)(ORb)1-2, —P(S)(ORb)1-2, —P(O)(NRCRd)1-2, —P(S)(NRCRd)1-2, —O(CH2—CH2—O)1-4CH3, —CN, —NO2, —C(O)C1-4 alkyl, and —C(O)—Rb,
• Ra is selected from the group consisting of —C3-6 cycloalkyl, —C2-6 alkenyl, —C2-6 alkynyl, phenyl, benzyl, and monocyclic heteroaryl, wherein the phenyl, benzyl, or monocyclic heteroaryl is optionally substituted with Rb;
• Rb in each instance is independently selected from the group consisting of H, halo, —OH, —COOH, —C1-12 alkyl, phenyl, benzyl, and monocyclic heteroaryl, wherein the phenyl, benzyl, or monocyclic heteroaryl is optionally substituted with —C2-6 alkenyl, —C2-6 alkynyl, trifluoroC1-4 alkoxy, —OC1-4 alkyl, —O(CH2—CH2—O)1-4 CH3, —O-phenyl, —O-benzyl, —NC1-4 alkyl, —N-phenyl, and —N-benzyl, or —N-monocyclic heteroaryl;
• RC and Rd are each independently selected from the group consisting of H, —C1-4 alkyl, —C(O)—C1-4 alkyl, —SO2—Ra, —SO2—C1-4 alkyl, phenyl, benzyl, and monocyclic heteroaryl, wherein the phenyl, benzyl, or monocyclic heteroaryl is optionally substituted with Rb,
• or RC and Rd taken together with the nitrogen to which they are attached represent an optionally substituted monocyclic heterocycloalkyl containing one or more of O, S, and N.

A method for inhibiting a protein-tyrosine phosphatase in a cell, comprising contacting the cell with a compound according to Formula III or a pharmaceutically acceptable salt thereof:

• wherein
• R4 is selected from the group consisting of H, —OH, —OC1-4 alkyl, —ORa, trifluoroC1-4 alkoxy, —SC1-4 alkyl, —SRa, —SO2—C1-4 alkyl, —SO2Ra, —SOC1-4 alkyl, —SORa, —SO2NHRb, —NRCRd, halo, —C1-12 alkyl, —C2-6 alkenyl, —C2-6 alkynyl, —C3-6 cycloalkyl, phenyl, benzyl, monocyclic heteroaryl optionally substituted with Rb, —C4-7 heterocycloalkyl containing one or two of O, S, and N, —OC(O)Rb, —OC(O)Rb, —P(O)(ORb)1-2, —P(S)(ORb)1-2, —P(O)(NRCRd)1-2, —P(S)(NRCRd)1-2, —O(CH2—CH2—O)1-4CH3, —CN, —NO2, —C(O)C1-4 alkyl, and —C(O)—Rb,
• Ra is selected from the group consisting of —C3-6 cycloalkyl, —C2-6 alkenyl, —C2-6 alkynyl, phenyl, benzyl, and monocyclic heteroaryl, wherein the phenyl, benzyl, or monocyclic heteroaryl is optionally substituted with Rb;
• Rb in each instance is independently selected from the group consisting of H, halo, —OH, —COOH, —C1-12 alkyl, phenyl, benzyl, and monocyclic heteroaryl, wherein the phenyl, benzyl, or monocyclic heteroaryl is optionally substituted with —C2-6 alkenyl, —C2-6 alkynyl, trifluoroC1-4 alkoxy, —OC1-4 alkyl, —O(CH2—CH2—O)1-4 CH3, —O-phenyl, —O-benzyl, —NC1-4 alkyl, —N-phenyl, and —N-benzyl, or —N-monocyclic heteroaryl;
• RC and Rd are each independently selected from the group consisting of H, —C1-4 alkyl, —C(O)—C1-4 alkyl, —SO2—Ra, —SO2—C1-4 alkyl, phenyl, benzyl, and monocyclic heteroaryl, wherein the phenyl, benzyl, or monocyclic heteroaryl is optionally substituted with Rb,
• or RC and Rd taken together with the nitrogen to which they are attached represent an optionally substituted monocyclic heterocycloalkyl containing one or more of O, S, and N.

A process for preparing a compound of formula 5:

• comprising
• (a) contacting a compound of formula 1:
• with CO(OCCl3)2, and then subjecting the product to Friedel-Crafts cyclization by contacting the product with FeCl3 to yield a compound of formula 2:
• (b) contacting the compound of formula 2 with Br2 in acetic acid to yield a compound of formula 3:
• (c) subjecting the compound of formula 3 to Suzuki-cross coupling by contacting the compound with PhB(OH)2 and Pd(PPh3)4, then aromatizing the cross-coupling product by contacting it with DDQ to yield a compound of formula 4:
• and
• (d) nitrating the compound of formula 4 by contacting the compound with HNO3/acetic acid, then hydrogenating the product under H2 in the presence of Pd/C to yield the compound of formula 5.