Compounds and methods for inhibiting fascin

Patent metadata

Field	Value
Publication number	US-9850243-B2
Application number	US-201715437229-A
Country	US
Kind code	B2
Filing date	Feb 20, 2017
Priority date	Feb 20, 2014
Publication date	Dec 26, 2017
Grant date	Dec 26, 2017

Abstract

Provided are compounds, compositions and methods for inhibiting fascin activity or treating a condition or disorder mediated by fascin activity in a subject in need thereof.

First claim

What is claimed:

1. A method of treating a condition or disorder mediated by fascin activity in a subject in need thereof, wherein the condition or disorder is selected from the group consisting of a metastatic cancer, a neuronal disorder, neuronal degeneration, an inflammatory condition, a viral infection, a bacterial infection, lymphoid hyperplasia, Hodgkin's disease and ischemia-related tissue damage, which method comprises administering to the subject a therapeutically effective amount of at least one compound of Formula IV

or tautomer thereof, and/or a pharmaceutically acceptable salt thereof;
wherein
R 2 is 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein the 6- to 10-membered aryl or 5-to 10-membered heteroaryl is optionally substituted with 1 to 4 R 4 , wherein each R 4 is independently selected from the group consisting of lower alkyl, lower haloalkyl, —OH, —OR 7 , —SH, —SR 7 , —NR 10 R 10 halo, cyano, nitro, —COH, —COR 7 , —CO 2 H, —CO 2 R 7 , —CONR 10 R 10 , —OCOR 7 , —OCO 2 R 7 , —OCONR 10 R 10 , —NR 10 COR 10 , —NR 10 CO 2 R 10 , —SOR 7 , —SO 2 R 7 , SO 2 NR 10 R 10 , phenyl (optionally substituted with lower alkyl, halo or lower haloalkyl, or —OH), and —NR 10 SO 2 R 7 ;
each R 3 is independently selected from the group consisting of lower alkyl, lower haloalkyl, —OH, —OR 7 , —SH, —SR 7 , —NR 10 R 10 , halo, cyano, nitro, —COH, —COR 7 , —CO 2 H, —CO 2 R 7 , —CONR 10 R 10 , —OCOR 7 , —OCO 2 R 7 , —OCONR 10 R 10 , —NR 10 COR 10 , —NR 10 CO 2 R 10 , —SOR 7 , —SO 2 R 7 , SO 2 NR 10 R 10 , and —NR 10 SO 2 R 7 ;
m is 0, 1, 2 or 3;
R 7 is lower alkyl; and
each R 10 is independently hydrogen or lower alkyl, or two R 10 together with the atom(s) attached thereto form a 4- to 6-membered ring;
Y is selected from the group consisting of CF 3 , Cl, F and Me;
Provided that the compound is not N-(1-(4-trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide.

2. The method of claim 1 , wherein the condition or disorder is a metastatic cancer.

3. The method of claim 2 , wherein the cancer is selected from the group consisting of a carcinoma, lymphoma, sarcoma, melanoma, astrocytoma, mesothelioma cells, ovarian carcinoma, colon carcinoma, pancreatic carcinoma, esophageal carcinoma, stomach carcinoma, lung carcinoma, urinary carcinoma, bladder carcinoma, breast cancer, gastric cancer, leukemia, lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, renal cancer and prostate cancer.

4. A method of inhibiting fascin expression and/or activity, comprising administering an effective amount of a fascin inhibitor to a cell to thereby inhibit fascin expression or activity in the cell, wherein the fascin inhibitor is a compound of Formula IV

or tautomer thereof, and/or a pharmaceutically acceptable salt thereof;
wherein
R 2 is 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein the 6- to 10-membered aryl or 5-to 10-membered heteroaryl is optionally substituted with 1 to 4 R 4 , wherein each R 4 is independently selected from the group consisting of lower alkyl, lower haloalkyl, —OH, —OR 7 , —SH, —SR 7 , —NR 10 R 10 halo, cyano, nitro, —COH, —COR 7 , —CO 2 H, —CO 2 R 7 , —CONR 10 R 10 , —OCOR 7 , —OCO 2 R 7 , —OCONR 10 R 10 , —NR 10 COR 10 , —NR 10 CO 2 R 10 , —SOR 7 , —SO 2 R 7 , SO 2 NR 10 R 10 , phenyl (optionally substituted with lower alkyl, halo or lower haloalkyl, or —OH), and —NR 10 SO 2 R 7 ;
each R 3 is independently selected from the group consisting of lower alkyl, lower haloalkyl, —OH, —OR 7 , —SH, —SR 7 , —NR 10 R 10 , halo, cyano, nitro, —COH, —COR 7 , —CO 2 H, —CO 2 R 7 , —CONR 10 R 10 , —OCOR 7 , —OCO 2 R 7 , —OCONR 10 R 10 , —NR 10 COR 10 , —NR 10 CO 2 R 10 , —SOR 7 , —SO 2 R 7 , SO 2 NR 10 R 10 , and —NR 10 SO 2 R 7 ;
m is 0, 1, 2 or 3;
R 7 is lower alkyl; and
each R 10 is independently hydrogen or lower alkyl, or two R 10 together with the atom(s) attached thereto form a 4- to 6-membered ring;
Y is selected from the group consisting of CF 3 , Cl, F and Me provided that the compound is not N-(1-(4-trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide.

5. The method of claim 4 , wherein the cell is in an animal or the cell has been removed from an animal.

6. The method of claim 5 , wherein the animal is a mammal.

7. The method of claim 6 , wherein the mammal is a human, and the human suffers from a disease or condition.

8. The method of claim 7 , wherein the disease or condition is selected from the group consisting of a metastatic cancer, a neuronal disorder, neuronal degeneration, an inflammatory condition, a viral infection, a bacterial infection, lymphoid hyperplasia, Hodgkin's disease and ischemia-related tissue damage.

9. The method of claim 7 , wherein the disease or condition is a metastatic cancer.

10. The method of claim 9 , wherein the cancer is selected from the group consisting of carcinoma, lymphoma, sarcoma, melanoma, astrocytoma, mesothelioma cells, ovarian carcinoma, colon carcinoma, pancreatic carcinoma, esophageal carcinoma, stomach carcinoma, lung carcinoma, urinary carcinoma, bladder carcinoma, breast cancer, gastric cancer, leukemia, lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, renal cancer and prostate cancer.

11. The method of claim 1 wherein the condition or disorder is HIV.

12. The method of claim 1 wherein, in the compound of Formula IV, R 2 is 5- or 6-membered heteroaryl optionally substituted with 1 to 4 R 4 .

13. The method of claim 1 wherein, in the compound of Formula IV, R 2 is optionally substituted with 1 to 4 R 4 , and R 2 is selected from the group consisting of furan, benzofuran, pyridine, pyridazine, pyrimidine, pyrazine, thiophene, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, imidazole, pyrrole, and pyrazole.

14. The method of claim 1 wherein, in the compound of Formula IV, R 2 is selected from the group consisting of

15. The method of claim 1 wherein, in the compound of Formula IV, R 4 is not optional and is selected from the group consisting of lower alkyl, halo, lower haloalkyl, —OH, —OR 7 , cyano and phenyl optionally substituted methyl, and wherein R 7 is lower alkyl or lower haloalkyl.

16. The method of claim 1 wherein, in the compound of Formula IV, m is 0.

17. The method of claim 1 wherein, the compound of Formula I is

or tautomer thereof, and/or a pharmaceutically acceptable salt thereof.

18. The method of claim 1 wherein, the compound of Formula I is

or tautomer thereof, and/or a pharmaceutically acceptable salt thereof.

19. The method of claim 1 wherein, the compound of Formula I is

or tautomer thereof, and/or a pharmaceutically acceptable salt thereof.

20. The method of claim 1 wherein, the compound of Formula I is

Assignees

• Univ Cornell
• Novita Pharmaceuticals Inc

Inventors

• Huang Xin-Yun
• Shue Christy Young

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/02

  specific for leukemia · CPC title