Inhibitors of PTP4A3 for the treatment of cancer
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).
1. A compound according to Formula III or a pharmaceutically acceptable salt thereof:
wherein
R 4 is selected from the group consisting of H, —OH, —OC 1-4 alkyl, —OR a , trifluoroC 1-4 alkoxy, —SC 1-4 alkyl, —SR a , —SO 2 —C 1-4 alkyl, —SO 2 R a , —SOC 1-4 alkyl, —SOR a , —SO 2 NHR b , —NR C R d , halo, —C 1-12 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 3-6 cycloalkyl, phenyl, benzyl, monocyclic heteroaryl optionally substituted with R b , —C 4-7 heterocycloalkyl containing one or two of O, S, and N, —OC(O)R b , —OC(O)R b , —P(O)(OR b ) 1-2 , —P(S)(OR b ) 1-2 , —P(O)(NR C R d ) 1-2 , —P(S)(NR C R d ) 1-2 , —O(CH 2 —CH 2 —O) 1-4 CH 3 , —CN, —NO 2 , —C(O)C 1-4 alkyl, and —C(O)—R b ,
R a is selected from the group consisting of —C 3-6 cycloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, phenyl, benzyl, and monocyclic heteroaryl, wherein the phenyl, benzyl, or monocyclic heteroaryl is optionally substituted with R b ;
R b in each instance is independently selected from the group consisting of H, halo, —OH, —COOH, —C 1-12 alkyl, phenyl, benzyl, and monocyclic heteroaryl, wherein the phenyl, benzyl, or monocyclic heteroaryl is optionally substituted with —C 2-6 alkenyl, —C 2-6 alkynyl, trifluoroC 1-4 alkoxy, —OC 1-4 alkyl, —O(CH 2 —CH 2 —O) 1-4 CH 3 , —O-phenyl, —O-benzyl, —NC 1-4 alkyl, —N-phenyl, and —N-benzyl, or —N-monocyclic heteroaryl;
R C and R d are each independently selected from the group consisting of H, —C 1-4 alkyl, —C(O)—C 1-4 alkyl, —SO 2 —R a , —SO 2 —C 1-4 alkyl, phenyl, benzyl, and monocyclic heteroaryl, wherein the phenyl, benzyl, or monocyclic heteroaryl is optionally substituted with R b ,
or R C and R d 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.
2. The compound according to claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
3. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to Formula III or a pharmaceutically acceptable salt thereof:
wherein
R 4 is selected from the group consisting of H, —OH, —OC 1-4 alkyl, —OR a , trifluoroC 1-4 alkoxy, —SC 1-4 alkyl, —SR a , —SO 2 —C 1-4 alkyl, —SO 2 R a , —SOC 1-4 alkyl, —SOR a , —SO 2 NHR b , —NR C R d , halo, —C 1-12 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 3-6 cycloalkyl, phenyl, benzyl, monocyclic heteroaryl optionally substituted with R b , —C 4-7 heterocycloalkyl containing one or two of O, S, and N, —OC(O)R b , —OC(O)R b , —P(O)(OR b ) 1-2 , —P(S)(OR b ) 1-2 , —P(O)(NR C R d ) 1-2 , —P(S)(NR C R d ) 1-2 , —O(CH 2 —CH 2 —O) 1-4 CH 3 , —CN, —NO 2 , —C(O)C 1-4 alkyl, and —C(O)—R b ,
R a is selected from the group consisting of —C 3-6 cycloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, phenyl, benzyl, and monocyclic heteroaryl, wherein the phenyl, benzyl, or monocyclic heteroaryl is optionally substituted with R b ;
R b in each instance is independently selected from the group consisting of H, halo, —OH, —COOH, —C 1-12 alkyl, phenyl, benzyl, and monocyclic heteroaryl, wherein the phenyl, benzyl, or monocyclic heteroaryl is optionally substituted with —C 2-6 alkenyl, —C 2-6 alkynyl, trifluoroC 1-4 alkoxy, —OC 1-4 alkyl, —O(CH 2 —CH 2 —O) 1-4 CH 3 , —O-phenyl, —O-benzyl, —NC 1-4 alkyl, —N-phenyl, and —N-benzyl, or —N-monocyclic heteroaryl;
R C and R d are each independently selected from the group consisting of H, —C 1-4 alkyl, —C(O)—C 1-4 alkyl, —SO 2 —R a , —SO 2 —C 1-4 alkyl, phenyl, benzyl, and monocyclic heteroaryl, wherein the phenyl, benzyl, or monocyclic heteroaryl is optionally substituted with R b ,
or R C and R d 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.
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
R 4 is selected from the group consisting of H, —OH, —OC 1-4 alkyl, —OR a , trifluoroC 1-4 alkoxy, —SC 1-4 alkyl, —SR a , —SO 2 —C 1-4 alkyl, —SO 2 R a , —SOC 1-4 alkyl, —SOR a , —SO 2 NHR b , —NR C R d , halo, —C 1-12 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 3-6 cycloalkyl, phenyl, benzyl, monocyclic heteroaryl optionally substituted with R b , C 4-7 heterocycloalkyl containing one or two of O, S, and N, —OC(O)R b , —OC(O)R b , —P(O)(OR b ) 1-2 , —P(S)(OR b ) 1-2 , —P(O)(NR C R d ) 1-2 , —P(S)(NR C R d ) 1-2 , —O(CH 2 —CH 2 —O) 1-4 CH 3 , —CN, —NO 2 , —C(O)C 1-4 alkyl, and —C(O)—R b ,
R a is selected from the group consisting of —C 3-6 cycloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, phenyl, benzyl, and monocyclic heteroaryl, wherein the phenyl, benzyl, or monocyclic heteroaryl is optionally substituted with R b ;
R b in each instance is independently selected from the group consisting of H, halo, —OH, —COOH, —C 1-12 alkyl, phenyl, benzyl, and monocyclic heteroaryl, wherein the phenyl, benzyl, or monocyclic heteroaryl is optionally substituted with —C 2-6 alkenyl, —C 2-6 alkynyl, trifluoroC 1-4 alkoxy, —OC 1-4 alkyl, —O(CH 2 —CH 2 —O) 1-4 CH 3 , —O-phenyl, —O-benzyl, —NC 1-4 alkyl, —N-phenyl, and —N-benzyl, or —N-monocyclic heteroaryl;
R C and R d are each independently selected from the group consisting of H, —C 1-4 alkyl, —C(O)—C 1-4 alkyl, —SO 2 —R a , —SO 2 —C 1-4 alkyl, phenyl, benzyl, and monocyclic heteroaryl, wherein the phenyl, benzyl, or monocyclic heteroaryl is optionally substituted with R b ,
or R C and R d 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.
5. The method according to claim 4 , wherein R 4 is selected from the group consisting of H, —OH, —OC 1-4 alkyl, —OR a , trifluoroC 1-4 alkoxy, —SC 1-4 alkyl, —SR a , —SO 2 —C 1-4 alkyl, —SO 2 R a , —SOC 1-4 alkyl, —SOR a , —SO 2 NHR b , —NR C R d , halo, and —C 1-12 alkyl.
6. The method according to claim 5 , wherein R 4 is H or C 1-12 alkyl.
7. The method according to claim 6 , wherein the compound is:
8. 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.
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
R 4 is selected from the group consisting of H, —OH, —OC 1-4 alkyl, —OR a , trifluoroC 1-4 alkoxy, —SC 1-4 alkyl, —SR a , —SO 2 —C 1-4 alkyl, —SO 2 R a , —SOC 1-4 alkyl, —SOR a , —SO 2 NHR b , —NR C R d , halo, —C 1-12 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 3-6 cycloalkyl, phenyl, benzyl, monocyclic heteroaryl optionally substituted with R b , —C 4-7 heterocycloalkyl containing one or two of O, S, and N, —OC(O)R b , —OC(O)R b , —P(O)(OR b ) 1-2 , —P(S)(OR b ) 1-2 , —P(O)(NR C R d ) 1-2 , —P(S)(NR C R d ) 1-2 , —O(CH 2 —CH 2 —O) 1-4 CH 3 , —CN, —NO 2 , —C(O)C 1-4 alkyl, and —C(O)—R b ,
R a is selected from the group consisting of —C 3-6 cycloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, phenyl, benzyl, and monocyclic heteroaryl, wherein the phenyl, benzyl, or monocyclic heteroaryl is optionally substituted with R b ;
R b in each instance is independently selected from the group consisting of H, halo, —OH, —COOH, —C 1-12 alkyl, phenyl, benzyl, and monocyclic heteroaryl, wherein the phenyl, benzyl, or monocyclic heteroaryl is optionally substituted with —C 2-6 alkenyl, —C 2-6 alkynyl, trifluoroC 1-4 alkoxy, —OC 1-4 alkyl, —O(CH 2 —CH 2 —O) 1-4 CH 3 , —O-phenyl, —O-benzyl, —NC 1-4 alkyl, —N-phenyl, and —N-benzyl, or —N-monocyclic heteroaryl;
R C and R d are each independently selected from the group consisting of H, —C 1-4 alkyl, —C(O)—C 1-4 alkyl, —SO 2 —R a , —SO 2 —C 1-4 alkyl, phenyl, benzyl, and monocyclic heteroaryl, wherein the phenyl, benzyl, or monocyclic heteroaryl is optionally substituted with R b ,
or R C and R d 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.
10. The method according to claim 9 , wherein the protein tyrosine phosphatase is protein tyrosine phosphatase 4A.
11. The method according to claim 10 , wherein the protein tyrosine phosphatase 4A is protein tyrosine phosphatase 4A3.
12. A process for preparing a compound of formula 5:
comprising
(a) contacting a compound of formula 1:
with CO(OCCl 3 ) 2 , and then subjecting the product to Friedel-Crafts cyclization by contacting the product with FeCl 3 to yield a compound of formula 2:
(b) contacting the compound of formula 2 with Br 2 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(PPh 3 ) 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 HNO 3 /acetic acid, then hydrogenating the product under H 2 in the presence of Pd/C to yield the compound of formula 5.