LLS compounds for treatment of cancer

Patent metadata

Field	Value
Publication number	US-10844052-B2
Application number	US-201716091098-A
Country	US
Kind code	B2
Filing date	Apr 4, 2017
Priority date	Apr 4, 2016
Publication date	Nov 24, 2020
Grant date	Nov 24, 2020

Abstract

The present invention provides benzamidazole compounds and methods of using the compounds as galectin-1 inhibitors.

First claim

What is claimed is:

1. A compound having the formula:

wherein
R 1 is selected from the group consisting of C 1-6 alkyl, —NR 1a R 1b , C 3-10 cycloalkyl, C 3-8 heterocycloalkyl, C 6-12 aryl, and C 5-12 heteroaryl, wherein the aryl is optionally substituted with 1-4 R 1c groups;
R 1a and R 1b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
R 2 is selected from the group consisting of, —NR 2a R 2b , C 5-12 heteroaryl and C 1-6 alkyl-C 5-12 heteroaryl, wherein the heteroaryl is optionally substituted with C 1-6 hydroxyalkyl;
R 2a and R 2b are each independently selected from the group consisting of C 1-6 alkyl, C 1-6 hydroxyalkyl, and C 1-6 alkyl-OC(O)CH 3 , or are combined with the nitrogen to which they are attached to form a C 3-8 heterocycloalkyl having 0 to 2 additional heteroatoms selected from the group consisting of N, O, and S, wherein the C 3-8 heterocycloalkyl is optionally substituted with 1 to 4 R 2c groups;
each R 1c and R 2c is independently selected from the group consisting of C 1-6 alkyl, halogen, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 6-12 aryl;
R 3 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-12 aryl, and C 5-12 heteroaryl, wherein the heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 0 to 4 R 3a groups
each R 3a is independently selected from the group consisting of C 1-6 alkyl, halogen, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-12 aryl, C 5-12 heteroaryl, and —SO 2 —C 6-12 aryl;
R 4 is selected from the group consisting of —C(O)R 4a , —C(O)OR 4a and —C(O)NR 4a R 4b ;
each R 4a and R 4b is independently selected from the group consisting of hydrogen and C 1-6 alkyl;
each R 5 and R 6 is independently selected from the group consisting of hydrogen and C 1-6 alkyl;
R 7 is selected from the group consisting of hydrogen and C 1-6 alkyl-C 6-12 aryl, optionally substituted with 1-4 R 7a groups, each R 7a is independently selected from the group consisting of C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;
X 1 is C 1-6 alkylene;
X 2 is absent or selected from the groups consisting of C 1-6 alkylene, —C(O)CH(NH 2 )CH 2 — and —C(O)CH(NH 2 )CH(OH)—;
the subscripts n and m are each independently integers from 0 to 3; and
the subscript q is an integer from 0 to 4;

or pharmaceutically acceptable salts thereof.

2. The compound of claim 1 , wherein
R 1 selected from the group consisting of C 1-6 alkyl, —NH 2 , C 3-10 cycloalkyl, C 3-8 heterocycloalkyl, C 6-12 aryl, and C 5-12 heteroaryl, wherein the aryl is optionally substituted with 1-4 R 1c groups; and
each R 1c is independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

3. The compound of claim 1 , wherein R 2a and R 2b are each independently selected from the group consisting of —CH 2 CH 2 OH and —CH 2 CH 2 OC(O)CH 3 .

4. The compound of claim 1 , wherein
R 2a and R 2b are combined with the nitrogen to which they are attached to form a C 3-8 heterocycloalkyl having from 0 to 2 additional heteroatoms selected from the group consisting of N, O, and S, wherein the heterocycloalkyl is optionally substituted with 1 to 4 R 2c groups; and
each R 2c is independently C 1-6 alkyl.

5. The compound of claim 1 , wherein
R 3 is selected from the group consisting of hydrogen, C 3-8 cycloalkyl, C 6-12 aryl, and C 5-12 heteroaryl, wherein the aryl and heteroaryl are optionally substituted with 1 to 4 R 3a groups; and
each R 3a is independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 5-12 heteroaryl, and —SO 2 —C 6-12 aryl.

6. The compound of claim 1 , having the formula:

wherein q is an integer from 0 to 4.

7. The compound of claim 1 , having the formula:

8. The compound of claim 1 , wherein
R 1 is selected from the group consisting of C 1-6 alkyl, —NH 2 , C 3-8 heterocycloalkyl, C 6-12 aryl, and C 5-12 heteroaryl, wherein the aryl is optionally substituted with 1-4 R 1c groups; and
each R 1c is independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

9. The compound of claim 1 , wherein
R 2a and R 2b are each independently selected from the group consisting of —CH 2 CH 2 OH and —CH 2 CH 2 OC(O)CH 3 , or are combined with the nitrogen to which they are attached to form a C 3-8 heterocycloalkyl having from 0 to 2 additional heteroatoms selected from the group consisting of N, O, and S, wherein the heterocycloalkyl is optionally substituted with 1 to 4 R 2c groups;
each R 2c is independently C 1-6 alkyl;
R 3 is selected from the group consisting of hydrogen, C 3-8 cycloalkyl, C 6-12 aryl, and C 5-12 heteroaryl, wherein the aryl and heteroaryl are optionally substituted with 1 to 4 R 3a groups;
each R 3a is independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 5-12 heteroaryl, and —SO 2 —C 6-12 aryl;
X 1 is C 1-6 alkylene; and
X 2 is absent or selected from the groups consisting of C 1-6 alkylene, and —C(O)CH(NH 2 )CH 2 —;

or pharmaceutically acceptable salts thereof.

10. The compound of claim 1 , wherein the compound is selected from the group consisting of:

Assignees

• Univ California

Inventors

• Lam Kit S
• Liu Ruiwu
• Shih Tsung-Chieh

Classifications

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D403/10

  linked by a carbon chain containing aromatic rings · CPC title

• C08G73/18 Primary

  Polybenzimidazoles · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C08L79/04

  Polycondensates having nitrogen-containing heterocyclic rings in the main chain; Polyhydrazides; Polyamide acids or similar polyimide precursors · CPC title