Apoptosis inducing agents for the treatment of cancer and immune and autoimmune diseases

Patent metadata

Field	Value
Publication number	US-11897864-B2
Application number	US-202217938835-A
Country	US
Kind code	B2
Filing date	Oct 7, 2022
Priority date	May 26, 2009
Publication date	Feb 13, 2024
Grant date	Feb 13, 2024

Abstract

Disclosed are compounds which inhibit the activity of anti-apoptotic Bcl-2 proteins, compositions containing the compounds and methods of treating diseases during which is expressed anti-apoptotic Bcl-2 protein.

First claim

What is claimed is:

1. A compound having Formula (II)

or a therapeutically acceptable salt thereof, wherein:
n is 0;
A 1 is C(A 2 );
A 2 , D 1 , and E 1 are H;
B 1 is NHR 1 ;
Y 1 is NO 2 ;
R 1 is methyl, which is substituted with one heterocycloalkyl;
Z 2 is piperazinyl;
L 1 is methylene;
Z 3 is cycloalkenyl substituted with R 57A and R 57 ;
R 57A is spiroalkyl; and
R 57 is phenyl substituted with one Cl.

2. The compound of claim 1 , or the therapeutically acceptable salt thereof, wherein the one heterocycloalkyl is tetrahydropyranyl.

3. The compound of claim 1 , or the therapeutically acceptable salt thereof, wherein the one heterocycloalkyl is 1,4-dioxanyl.

4. The compound of claim 1 , or the therapeutically acceptable salt thereof, wherein R 57A is C 2 -C 5 -spiroalkyl.

5. The compound of claim 1 , or the therapeutically acceptable salt thereof, wherein Z 3 is cyclohexenyl.

6. The compound of claim 5 , or the therapeutically acceptable salt thereof, wherein R 57A is C 2 -C 5 -spiroalkyl.

7. The compound of claim 6 , or the therapeutically acceptable salt thereof, wherein the one heterocycloalkyl is 1,4-dioxanyl.

8. The compound of claim 1 , or the therapeutically acceptable salt thereof, wherein the compound is:
4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide.

9. A compound having Formula (II)

or a therapeutically acceptable salt thereof, wherein:
n is 0;
A 1 is C(A 2 );
A 2 , D 1 , and E 1 are H;
B 1 is OR 1 or NHR 1 ;
Y 1 is NO 2 ;
R 1 is methyl, which is substituted with one R 10 ;
R 10 is cycloalkyl or heterocycloalkyl;
wherein R 10 is unsubstituted or substituted with one or two of independently selected from cycloalkyl, heterocycloalkyl, alkyl, alkoxy, OH, or F;
Z 2 is piperazinyl;
L 1 is methylene;
Z 3 is cycloalkenyl substituted with R 57A and R 57 ;
R 57A is spiroalkyl; and
R 57 is phenyl substituted with one Cl.

10. The compound of claim 9 , or the therapeutically acceptable salt thereof, wherein B 1 is OR 1 .

11. The compound of claim 9 , or the therapeutically acceptable salt thereof, wherein B 1 is NHR 1 .

12. The compound of claim 9 , or the therapeutically acceptable salt thereof, wherein R 10 is cycloalkyl.

13. The compound of claim 9 , or the therapeutically acceptable salt thereof, wherein R 10 is cyclohexyl.

14. The compound of claim 9 , or the therapeutically acceptable salt thereof, wherein R 10 is heterocycloalkyl.

15. The compound of claim 9 , or the therapeutically acceptable salt thereof, wherein R 10 is tetrahydropyranyl.

16. The compound of claim 9 , or the therapeutically acceptable salt thereof, wherein R 10 is 1,4-dioxanyl.

17. The compound of claim 9 , or the therapeutically acceptable salt thereof, wherein R 57A is C 2 -C 5 -spiroalkyl.

18. The compound of claim 9 , or the therapeutically acceptable salt thereof, wherein Z 3 is cyclohexenyl.

19. The compound of claim 18 , or the therapeutically acceptable salt thereof, wherein R 57A is C 2 -C 5 -spiroalkyl.

20. The compound of claim 19 , or the therapeutically acceptable salt thereof, wherein B 1 is OR 1 .

21. The compound of claim 19 , or the therapeutically acceptable salt thereof, wherein B 1 is NHR 1 .

22. The compound of claim 21 , or the therapeutically acceptable salt thereof, wherein R 10 is cycloalkyl.

23. The compound of claim 22 , or the therapeutically acceptable salt thereof, wherein R 10 is cyclohexyl.

24. The compound of claim 21 , or the therapeutically acceptable salt thereof, wherein R 10 is heterocycloalkyl.

25. The compound of claim 24 , or the therapeutically acceptable salt thereof, wherein R 10 is tetrahydropyranyl.

26. The compound of claim 24 , or the therapeutically acceptable salt thereof, wherein R 10 is 1,4-dioxanyl.

27. The compound of claim 9 , or the therapeutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
trans-4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide.

Assignees

• Abbvie Inc
• Genentech Inc
• Walter & Eliza Hall Inst Medical Res

Inventors

• Bruncko Milan
• Ding Hong
• Doherty George A
• Elmore Steven W
• Hasvold Lisa A
• Hexamer Laura
• Kunzer Aaron R
• Song Xiaohong
• Souers Andrew J
• Sullivan Gerard M
• Tao Zhi-Fu
• Wang Gary T
• Wang Le
• Wang Xilu
• Wendt Michael D
• Mantei Robert
• Hansen Todd M

Classifications

• C07D401/12 Primary

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

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• C07D209/82

  Carbazoles; Hydrogenated carbazoles · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D403/12

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