Dihydrochromene derivatives

Patent metadata

Field	Value
Publication number	US-11639357-B2
Application number	US-202016944482-A
Country	US
Kind code	B2
Filing date	Jul 31, 2020
Priority date	Mar 20, 2018
Publication date	May 2, 2023
Grant date	May 2, 2023

Abstract

The present invention relates to the compound of formula (I) wherein R1A, R1B, R1C, and R1D are hydrogen atom, etc., R2A and R2B are hydrogen atom, etc., R3A, R3B, R3C, and R3D are hydrogen atom, etc., L is bond, etc., V is C1-6 alkylene, Q is optionally-substituted imidazole, or a pharmaceutically acceptable salt thereof, as a novel anti-tumor agent that targets CSCs which are thought to be closely involved in the persistent proliferation of malignant tumor, metastasis or recurrence of cancer, and resistance to anti-tumor agents.

First claim

The invention claimed is:

1. A compound of formula (1):

or a pharmaceutically acceptable salt thereof, wherein
R 1A , R 1B , R 1C , and R 1D are each independently hydrogen atom, halogen atom, azide, or cyano, provided that all of R 1A , R 1B , R 1C , and R 1D are not hydrogen atom,
R 2A and R 2B are each independently hydrogen atom or C 1-6 alkyl,
R 3A , R 3B , R 3C , and R 3D are each independently hydrogen atom, halogen atom, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, —CO 2 R 4 ,
—NR 5 R 6 , or —NR 7 COR 8 , or any two of R 3A , R 3B , R 3C , and R 3D may be taken together at the common carbon atom to which they are attached to form=O,
L is bond or —C(O)—,
V is C 1-6 alkylene which may be substituted with 1 to 3 substituents selected independently from the group consisting of fluorine atom, hydroxy, C 1-6 alkoxy, C 3-7 cycloalkyl, 3- to 7-membered saturated heterocyclyl, cyano, and azide,
Q is optionally-substituted imidazole group,
R 4 and R 8 are each independently C 1-3 alkyl, and
R 5 , R 6 , and R 7 are each independently hydrogen atom or

C 1-3 alkyl, or when R 5 and R 6 are both C 1-3 alkyl, they may be combined with the nitrogen atom to which they are attached to form 3- to 6-membered nitrogen-containing saturated heterocyclyl,
provided that the following compounds of formulae (Z-1) and (Z-2):

are excluded.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
Q is imidazole group which may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen atom, cyano, C1-6 alkyl (which may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen atom, cyano, hydroxy, C1-6 alkoxy, —NR5aR6a, and —NR7aCOR8a), C2-6 alkenyl (which may be substituted with 1 to 3 hydroxy groups), —CO2R4a, and —CONR9R10,
R5a, R6a, R7a, R9, and R10 are each independently hydrogen atom or C1-3 alkyl, or
when R5a and R6a are both C1-3 alkyl, they may be combined with the nitrogen atom to which they are attached to foil 3- to 6-membered nitrogen-containing saturated heterocyclyl, and
when R9 and R10 are both C1-3 alkyl, they may be combined with the nitrogen atom to which they are attached to form 3- to 6-membered nitrogen-containing saturated heterocyclyl, and
R4a and R8a are independently C1-3 alkyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R3A, R3B, R3C, and R3D are hydrogen atom.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R2A and R2B are each independently hydrogen atom or C1-3 alkyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R2A and R2B are each independently C1-3 alkyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R2A and R2B are methyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is bond.

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

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is C1-6 alkylene.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is C1-3 alkylene.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is ethylene.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is methylene.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R1A, R1B, R1C, and R1D are each independently hydrogen atom, fluorine atom, or chlorine atom, provided that all of R1A, R1B, R1C, and R1D are not hydrogen atom.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is formula (Q-1) or (Q-2):

wherein
R11A, R11B, R11C, R11D, and R11E are each independently hydrogen atom, halogen atom, cyano, C1-6 alkyl (which may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen atom, cyano, hydroxy, C1-6 alkoxy, —NR5aR6a, and —NR7aCOR8a), C2-6 alkenyl (which may be substituted with 1 to 3 hydroxy groups), —CO2R4a, or —CONR9R10,
R5a, R6a, R7a, R9, and R10 are each independently hydrogen atom or C1-3 alkyl, or
when R5a and R6a are both C1-3 alkyl, they may be combined with the nitrogen atom to which they are attached to form 3- to 6-membered nitrogen-containing saturated heterocyclyl, and
when R9 and R10 are both C1-3 alkyl, they may be combined with the nitrogen atom to which they are attached to form 3- to 6-membered nitrogen-containing saturated heterocyclyl,
R4a and R8a are independently C1-3 alkyl,
R12 is hydrogen atom or C1-6 alkyl, and
asterisk (*) is the binding point to V.

15. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R11A, R11B, R11C, R11D, and R11E are each independently hydrogen atom, cyano, C1-6 alkyl (which may be substituted with 1 to 3 substituents selected independently from the group consisting of fluorine atom, hydroxy, and —NR7aCOR8a), C2-6 alkenyl (which may be substituted with one hydroxy group), or —CO2R4a.

16. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R11 A, R11B, R11C, R11D, and R11E are each independently hydrogen atom, cyano, C1-3 alkyl, or C2-6 alkenyl, wherein the alkyl and the alkenyl may be each independently substituted with one hydroxy group.

17. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R11A, R11B, R11C, R11D, and R11E are each independently hydrogen atom or C1-3 alkyl.

18. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R12 is hydrogen atom.

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein formula (I) is formula (1-A):

20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein formula (I) is formula (1-B):

21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein formula (I) is formula (1-C):

22. The compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein
R1A, R1B, R1C, and R1D are each independently hydrogen atom, fluorine atom, or chlorine atom, provided that all of R1A, R1B, R1C, and R1D are not hydrogen atom,
R2A and R2B are each independently hydrogen atom or C1-3 alkyl,
L is bond or —C(O)—,
V is C1-3 alkylene,
Q is formula (Q-1) or (Q-2):

wherein
R11A, R11B, R11C, R11D, and R11E are each independently hydrogen atom, halogen atom, cyano, C1-6 alkyl (which may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen atom,

Assignees

• Sumitomo Pharma Co Ltd

Inventors

• Ban Hitoshi
• Kamioka Seiji
• Sawayama Yusuke
• Hashizume Miki

Classifications

• A61K31/438

  The ring being spiro-condensed with carbocyclic or heterocyclic ring systems · CPC title

• A61K31/436

  the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D491/20 Primary

  Spiro-condensed systems · CPC title