IRE1 small molecule inhibitors

Patent metadata

Field	Value
Publication number	US-11634403-B2
Application number	US-202117175940-A
Country	US
Kind code	B2
Filing date	Feb 15, 2021
Priority date	Nov 10, 2017
Publication date	Apr 25, 2023
Grant date	Apr 25, 2023

Abstract

Provided herein are small molecule inhibitors for the targeting or IRE1 protein family members. Binding may be direct or indirect. Further provided herein are methods of using IRE1 small molecule inhibitors for use in treating or ameliorating cancer in a subject. Moreover, IRE1 small molecule inhibitors described herein are for the treatment of cancer, where the cancer is a solid or hematologic cancer.

First claim

What is claimed is:

1. A compound of Formula (I), or a pharmaceutically acceptable salt:

wherein,
each Z is independently N or CR 1 , provided that at least one Z is N;
each R 1 is independently halogen, —OR 8 , or C 1 -C 4 alkyl;
R 3 is C 1 -C 4 alkyl, or —O—C 1 -C 4 alkyl;
R 4 is halogen, or C 1 -C 4 alkyl;
each R 5 is independently H, halogen, or C 1 -C 4 alkyl;
each R 2 is independently H, or C 1 -C 4 alkyl;
R 6 is H, or C 1 -C 4 alkyl;
R 7 is C 3 -C 6 cyclooalkylalkyl, C 1 -C 4 alkyl, —CH 2 CF 3 , —CH 2 -cyclopropyl, or —CH 2 CH 2 OCH 3 ;
each R 8 is C 1 -C 4 alkyl;
each R 9 is C 1 -C 4 alkyl;
R A1 and R A2 are each independently H, halogen, —OR 9 , C 1 -C 4 alkyl, or C 1 -C 4 fluoroalkyl; provided that both R A1 and R A2 , are not H;
n is 1,2,3, or 4; and
q is 1, 2, 3, or 4.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, thereof, wherein R 7 is methyl, ethyl, —CH 2 CF 3 , —CH 2 -cyclopropyl, or —CH 2 CH 2 OCH 3 .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is C 1 -C 4 alkyl.

4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 6 is methyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is H.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently H, or C 1 -C 4 alkyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —OR 8 .

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is Cl, F, Br, methyl, or ethyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A1 is H, or C 1 -C 4 alkyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A2 is H, or C 1 -C 4 alkyl.

12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R A2 is ethyl.

13. The compound of claim 1 having Formula (Id*), or a pharmaceutically acceptable salt thereof:

14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein:
R 3 is C 1 -C 3 alkyl;
R A1 is hydrogen, or C 1 -C 3 alkyl;
R A2 is C 1 -C 3 alkyl, or hydrogen; and
R 4 is chlorine or C 1 -C 3 alkyl.

15. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein:

is

16. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein:
each R 5 is independently hydrogen, chlorine, fluorine, or —CH 3 ;
R 4 is chlorine or —CH 3 ;
R 3 is —CH 3 , or —CH 2 CH 3 ;
R A1 is —CH 3 ; and
R A2 is hydrogen, —CH 3 , —CH 2 CH 3 , or —OCH 3 .

17. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein each R 5 is hydrogen;
R 4 is chlorine; and
each R 2 is hydrogen.

18. A compound, or a pharmaceutically acceptable salt thereof, selected from:
2-chloro-N-(5-(8-ethyl-2-(((18,4r)4-(methylamino)cyclohexyl)amino)quinazolin-6yl)-3-fluoro-6-methoxypyridin-2yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((11,4r)-4(dimethylamino)cyclohexyl)amino)8-ethylquinazolin-6-yl)-3-fluoro 6-methoxypyridin-2yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((18,4s)-4(dimethylamino)cyclohexyl) amino)8-ethylquinazolin-6-yl)-3-fluoro 6-methoxypyridin-2 yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((15,4s)-4 (dimethylamino)-4 methylcyclohexyl) amino)-8 ethylquinazolin-6-yl)-3-fluoro-6 methoxypyridin-2 yl) benzenesulfonamide;
2-chloro-N-(5-(2-(((11,4r)-4 (dimethylamino)cyclohexyl)amino)8-methylquinazolin-6-yl)-3 fluoro-6-methoxypyridin-2 yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((15,4s)-4 (dimethylamino)cyclohexyl)amino)8-methylquinazolin-6-yl)-3 fluoro-6-methoxypyridin-2 yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((11,4r)-4 (dimethylamino)cyclohexyl)amino)8-fluoroquinazolin-6-yl)-3-fluoro 6-methoxypyridin-2 yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((18,4r)-4 (dirnethylamino)cyclohexyl)amino)8-fluoroquinazolin-6-yl)-3-fluoro 6-methylpyridin-2 yl)benzenesulfonamide; and
2-chloro-N-(5-(2-(((11,4r)-4 (dimethylamino)cyclohexyl)amino)8-ethyl-7-fluoroquinazolin-6-yl)3-fluoro-6-methylpyridin-2yl)benzenesulfonamide.

19. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

20. A method of treating cancer, comprising administering to a subject in need thereof a compound of claim 1 , wherein the cancer is a solid or hematologic cancer.

21. A pharmaceutical composition comprising a compound according to claim 18 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

22. A method of treating cancer, comprising administering to a subject in need thereof a compound of claim 18 , wherein the cancer is a solid or hematologic cancer.

Assignees

• Univ Cornell

Inventors

• Vacca Joseph P
• Li Dansu
• Bettigole Sarah Elizabeth

Classifications

• C07D401/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title

• C07D217/22

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring · CPC title

• C07D413/04

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

• C07D403/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D403/04

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