Imidazo[4,5-c]quinolin-2-one Compounds and Their Use in Treating Cancer

• US 20180141943A1
• Filed: 11/27/2017
• Published: 05/24/2018
• Est. Priority Date: 09/17/2015
• Status: Active Grant

• Current Assignee: Astrazeneca Limited Astrazeneca UK Limited
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Barlaam, Bernard Christophe, Pike, Kurt Gordon, Eatherton, Andrew John, Hunt, Thomas Anthony
• Granted Patent: US 10,457,679 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The specification generally relates to compounds of Formula (I):

• • and pharmaceutically acceptable salts thereof, where R¹, R², R³, R⁴ and R⁵ have any of the meanings defined herein. The specification also relates to the use of compounds of Formula (I) and salts thereof to treat or prevent ATM mediated disease, including cancer. The specification further relates to pharmaceutical compositions comprising to substituted imidazo[4,5-c]quinolin-2-one compounds and pharmaceutically acceptable salts thereof; kits comprising such compounds and salts; methods of manufacture of such compounds and salts; and intermediates useful in such manufacture.

Claims

1. A compound of Formula (I):

2. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, where R¹ and R² are both methyl;

or R¹ and R² together with the nitrogen atom to which they are bonded form an azetidinyl, pyrrolidinyl or piperidinyl ring.

3. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or claim 2, where R¹ and R² together with the nitrogen atom to which they are bonded form an azetidinyl, pyrrolidinyl or piperidinyl ring.

4. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of the preceding claims, where R³ is hydro.

5. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of the preceding claims, where R⁴ is methyl.

6. The compound of Formula (I), or a pharmaceutically acceptable salt thereof as claimed in any one of the preceding claims, where R⁵ is fluoro.

7. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, where:

R¹ is methyl;

R² is methyl;

or R¹ and R² together with the nitrogen atom to which they are bonded form an azetidinyl, pyrrolidinyl or piperidinyl ring;

R³ is hydro or fluoro;

R⁴ is methyl; and

R⁵ is hydro or fluoro.

8. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, where the compound is selected from the group consisting of:

8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;

7-Fluoro-1-isopropyl-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinolin-2-one;

8-[6-[3-(azetidin-1-yl)propoxy]-3-pyridyl]-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;

1-Isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one;

8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;

1-isopropyl-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinolin-2-one;

8-[6-[3-(Azetidin-1-yl)propoxy]-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;

8-[2-Fluoro-6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;

8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;

8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;

8-[2-fluoro-6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;

7-fluoro-8-[2-fluoro-6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;

7-fluoro-8-[2-fluoro-6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;

8-[6-[3-(azetidin-1-yl)propoxy]-2-fluoro-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;

8-[6-[3-(azetidin-1-yl)propoxy]-2-fluoro-3-pyridyl]-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;

8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-isopropyl-3H-imidazo[4,5-c]quinolin-2-one; and

7-Fluoro-1-isopropyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-3H-imidazo[4,5-c]quinolin-2-one.

9. A pharmaceutical composition which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 8, and at least one pharmaceutically acceptable excipient.

12. The method according to claim 15, where the compound of Formula (I) is administered simultaneously, separately or sequentially with radiotherapy.

13. The method according to claim 15, where the compound of Formula (I) is administered simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from the group consisting of doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan and bleomycin.

15. A method for treating cancer in a warm-blooded animal in need of such treatment, which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 8 or claims 18-21.

16. The method according to claim 15, wherein the compound of Formula (I) is 7-Fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one.

17. The method according to claim 15, wherein the cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, acute myeloid leukaemia, head and neck squamous cell carcinoma, breast cancer, triple negative breast cancer, hepatocellular carcinoma, small cell lung cancer and non-small cell lung cancer.

10. (canceled)

11. (canceled)

14. (canceled)

18. A crystalline form (Form B) of 7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one.

19. The crystalline form (Form B) of 7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one, according to claim 18, which has an X-ray powder diffraction pattern with at least two specific peaks at about 2-theta=3.4 and 11.7°

(plus or minus 0.2°

2-theta).

20. The crystalline form (Form B) of 7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one, according to claim 18, which has an X-ray powder diffraction pattern with specific peaks at 2-theta=3.4, 11.7, 13.1, 13.5, 17.5, 18.1, 19.0, 22.7, 23.4 and 24.0°

(plus or minus 0.2°

2-theta).

21. The a crystalline form (Form B) of 7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one, according to claim 18, which has a differential scanning calorimetry thermogram having an endotherm peak at about 145.8°

C. (plus or minus 5°

C.) with an onset of about 144.7°

C. (plus or minus 5°

C.).