# US 10,308,663 B2 · Inhibitors of PTP4A3 for the treatment of cancer

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,308,663 B2
- Document ID: US10308663B2
- Status: Granted
- Kind: B2
- Application number: 15/737,062
- Filed: 2016-06-16
- Published: 2018-06-21
- Granted: 2019-06-04
- Earliest claimed: 2015-06-16
- Assignees: University of Virginia Patent Foundation; University of Pittsburgh—Of the Commonwealth System of Higher Education
- Applicants: John S. Lazo; Elizabeth R. Sharlow; Kelley E. McQueeney; Peter Wipf; Joseph M. Salamoun
- Inventors: John S. Lazo; Elizabeth R. Sharlow; Kelley E. McQueeney; Peter Wipf; Joseph M. Salamoun
- Web page: https://patentgrep.com/patent/US10308663B2

## CPC

- C07D 495/04: Ortho-condensed systems
- A61K 31/4365: the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 35/00: Antineoplastic agents
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention provides protein tyrosine phosphatase inhibitor compounds, Their pharmaceutical compositions, uses, and methods of use, such as in the treatment of various cancers, and process for making the compounds. Also disclosed is an improved synthesis of protein tyrosine phosphatase inhibitor and precursor compound thienopyridone (5).

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 3

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.

### Claim 4

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.

### Claim 5 (depends on 4)

The method according to claim 4, 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, and —C1-12 alkyl.

### Claim 6 (depends on 5)

The method according to claim 5, wherein R4 is H or C1-12 alkyl.

### Claim 7 (depends on 6)

The method according to claim 6, wherein the compound is:

### Claim 8 (depends on 4)

The method according to claim 4, wherein the cancer is selected from the group consisting of colorectal cancer, breast cancer, ovarian cancer, cervical cancer, lung cancer, liver cancer, stomach cancer, and stromal cancer.

### Claim 9

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.

### Claim 10 (depends on 9)

The method according to claim 9, wherein the protein tyrosine phosphatase is protein tyrosine phosphatase 4A.

### Claim 11 (depends on 10)

The method according to claim 10, wherein the protein tyrosine phosphatase 4A is protein tyrosine phosphatase 4A3.

### Claim 12

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.