Pyran dervatives as CYP11A1 (cytochrome P450 monooxygenase 11A1) inhibitors

Patent metadata

Field	Value
Publication number	US-12030871-B2
Application number	US-202117367849-A
Country	US
Kind code	B2
Filing date	Jul 6, 2021
Priority date	Dec 22, 2016
Publication date	Jul 9, 2024
Grant date	Jul 9, 2024

Abstract

Compounds of formula (I)

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 23 , R 24 , L, A and B are as defined in claim 1 , or pharmaceutically acceptable salts thereof are disclosed. The compounds of formula (I) possess utility as cytochrome P450 monooxygenase 11A1 (CYP11A1) inhibitors. The compounds are useful as medicaments in the treatment of steroid receptor, particularly androgen receptor, dependent diseases and conditions, such as prostate cancer.

First claim

The invention claimed is:

1. A compound which is
5-((1-(Oxetan-3-ylsulfonyl)piperidin-4-yl)methoxy)-2-((5-(trifluoromethyl)-isoindolin-2-yl)¬methyl)-4H-pyran-4-one;
5-((1-(Methylsulfonyl)piperidin-4-yl)methoxy)-2-((5-(trifluoromethyl)¬iso-indolin-2-yl)methyl)-4H-pyran-4-one;
2-(Isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one;
2-((5-Fluoroisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)-methoxy)-4H-pyran-4-one;
5-((1-(Cyclopropylsulfonyl)piperidin-4-yl)methoxy)-2-(isoindolin-2-yl-methyl)-4H-pyran-4-one;
5-((1-(Ethylsulfonyl)piperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one;
5-((1-(Ethylsulfonyl)piperidin-4-yl)methoxy)-2-((5-fluoroisoindolin-2-yl)-methyl)-4H-pyran-4-one;
5-((1-(Cyclopropylsulfonyl)piperidin-4-yl)methoxy)-2-((5-fluoroisoindolin-2-yl)methyl)-4H-pyran-4-one;
5-((1-(Ethylsulfonyl)-4-methylpiperidin-4-yl)methoxy)-2-(isoindolin-2-yl-methyl)-4H-pyran-4-one;
2-(1-Isoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one;
5-((1-(Methylsulfonyl)piperidin-4-yl)methoxy)-2-((5-(trifluoromethoxy)-isoindolin-2-yl)methyl)-4H-pyran-4-one;
2-(Isoindolin-2-ylmethyl)-5-((1-(pyrrolidine-1-carbonyl)piperidin-4-yl)-methoxy)-4H-pyran-4-one;
5-((1-Butyrylpiperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one;
5-((1-(2,2-Difluoropropanoyl)piperidin-4-yl)methoxy)-2-(isoindolin-2-yl-methyl)-4H-pyran-4-one;
5-((1-(2,2-Difluoropropanoyl)piperidin-4-yl)methoxy)-2-((5-fluoroisoindolin-2-yl)methyl)-4H-pyran-4-one;
2-((5-Fluoroisoindolin-2-yl)methyl)-5-((1-propionylpiperidin-4-yl)methoxy)-4H-pyran-4-one;
4-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N-di-methylpiperidine-1-sulfonamide;
4-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N-methyl-piperidine-1-carboxamide;
4-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N-iso-propylpiperidine-1-carboxamide;
4-(((6-((5-Fluoroisoindolin-2-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N-dimethylpiperidine-1-sulfonamide;
2-(Isoindolin-2-ylmethyl)-5-((4-(oxetan-3-ylsulfonyl)benzyl)oxy)-4H-pyran-4-one;
2-((5-Chloroisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)-methoxy)-4H-pyran-4-one;
5-((1-Propionylpiperidin-4-yl)methoxy)-2-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-4-one;
N-(tert-Butyl)-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)-methyl)piperidine-1-carboxamide;
2-(Isoindolin-2-ylmethyl)-5-((1-pivaloylpiperidin-4-yl)methoxy)-4H-pyran-4-one;
5-((1-Acetylpiperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one;
2-(Isoindolin-2-ylmethyl)-5-((1-propionylpiperidin-4-yl)methoxy)-4H-pyran-4-one;
2-(Isoindolin-2-ylmethyl)-5-((1-((2-methoxyethyl)sulfonyl)piperidin-4-yl)-methoxy)-4H-pyran-4-one;
2-(Isoindolin-2-ylmethyl)-5-((1-(isopropylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one;
5-((1-(Isobutylsulfonyl)piperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one;
5-((1-Isobutyrylpiperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one;
2-(Isoindolin-2-ylmethyl)-5-((1-(2,2,2-trifluoroacetyl)¬pipe¬ri¬din-4-yl)methoxy)-4H-pyran-4-one;
or a tautomer or a pharmaceutically acceptable salt thereof.

2. A method for treating a steroid receptor dependent condition or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 .

3. The method according to claim 2 , wherein the steroid receptor is an androgen receptor.

4. The method according to claim 2 , wherein the steroid receptor dependent disease is cancer.

5. The method according to claim 4 , wherein the cancer is prostate cancer.

6. The method according to claim 5 , wherein the prostate cancer is castration-resistant prostate cancer (CRPC).

7. The method according to claim 2 further comprising administering a glucocorticoid and/or a mineralocorticoid and, optionally, one or more anti-cancer agent.

8. A method according to claim 7 , wherein the one or more anti-cancer agents is selected from the group consisting of a non-steroidal androgen receptor antagonist;
a steroidogenesis inhibitor;
a chemotherapeutic agent;
an antiestrogen;
an epigenetic modulator;
an mTOR inhibitor;
an AKT inhibitor;
a radiopharmaceutical;
a GnRH/LHRH analogue;
a PI3K inhibitor; and
a CDK4/6 inhibitor.

9. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

10. A pharmaceutical combination comprising a compound according to claim 1 and one or more active ingredients selected from the group consisting of:
a glucocorticoid;
a mineralocorticoid;
a non-steroidal androgen receptor antagonist;
a steroidogenesis inhibitor;
a chemotherapeutic agent;
an antiestrogen;
an epigenetic modulator;
a mTOR inhibitor;
an AKT inhibitor;
a radiopharmaceutical;
a GnRH/LHRH analogue;
a PI3K inhibitor; and
a CDK4/6 inhibitor.

11. A compound having the structure

12. A pharmaceutically acceptable salt of a compound having the structure

13. A pharmaceutical composition comprising the compound of claim 11 and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition comprising the compound of claim 11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

15. A pharmaceutical combination comprising the compound of claim 11 or a pharmaceutically acceptable salt thereof and one or more active ingredients selected from the group consisting of:
a glucocorticoid;
a mineralocorticoid;
a non-steroidal androgen receptor antagonist;
a steroidogenesis inhibitor;
a chemotherapeutic agent;
an antiestrogen;
an epigenetic modulator;
a mTOR inhibitor;
an AKT inhibitor;
a radiopharmaceutical;
a GnRH/LHRH analogue;
a PI3K inhibitor; and
a CDK4/6 inhibitor.

16. A pharmaceutical combination comprising the compound of claim 11 and one or more active ingredients selected from the group consisting of:
a glucocorticoid;
a mineralocorticoid;
a non-steroidal androgen receptor antagonist;
a steroidogenesis inhibitor;
a chemotherapeutic agent;
an antiestrogen;
an epigenetic modulator;
a mTOR inhibitor;
an AKT inhibitor;
a radiopharmaceutical;
a GnRH/LHRH analogue;
a PI3K inhibitor; and
a CDK4/6 inhibitor.

17. A compound having the structure

or a pharmaceutically acceptable salt thereof.

18. A method for treating a steroid receptor dependent condition or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 17 .

19. The method according to claim 18 , wherein the steroid receptor is an androgen receptor.

20. The method according to claim 18 , wherein the steroid receptor dependent disease is cancer.

21. The method according to claim 20 , wherein the cancer is prostate cancer.

22. The method according to claim 21 , wherein the prostate cancer is castration-resistant prostate cancer (CRPC).

23. The method according to claim 18 , further comprising administering a glucocorticoid and/or a mineralocorticoid and, optionall

Assignees

• Orion Corp

Inventors

• Din Belle David
• Mäkelä Mikko
• Passiniemi Mikko
• Pietikäinen Pekka
• Rummakko Petteri
• Tiainen Eija
• Vaismaa Matti
• Wohlfahrt Gerd

Classifications

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• C07D491/056

  with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring · CPC title

• C07D451/02

  containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof · CPC title