Disubstituted phthalazine hedgehog pathway antagonists

• US 8,273,742 B2
• Filed: 06/15/2010
• Issued: 09/25/2012
• Est. Priority Date: 06/19/2009
• Status: Active Grant

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: Hipskind, Philip Arthur, Patel, Bharvin Kumar, Wilson (nee Takakuwa), Takako
• Primary Examiner(s): Moore, Susanna
• Assistant Examiner(s): Jaisle, Cecilia M
• Application Number:
  US12/815,439
• Publication Number:
  US 20100324048A1
• Time in Patent Office: 833 Days
• Field of Search: 544/237, 514/248
• US Class Current: 514/248
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/14 containing three or more hetero rings

Abstract

The present invention provides novel 1,4-disubstituted phthalazine hedgehog pathway antagonists useful in the treatment of cancer.

Claims

1. A compound of the formula

2. The compound of claim 1 wherein R¹ is methyl, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2 wherein R² is methyl, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3 wherein R³, R⁴, R⁵, R⁶ and R⁷ are independently hydrogen, fluoro, chloro, trifluoromethyl, or methylsulfonyl, or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4 wherein R³, R⁴, R⁵, R⁶ and R⁷ are independently hydrogen, fluoro, or trifluoromethyl, or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 5 wherein R⁴, R⁶ and R⁷ are hydrogen, or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 6 which is 4-fluoro-N-methyl-N-(1-(4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide, or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 7 which is 4-fluoro-N-methyl-N-(1-(4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide hydrochloride.

9. The compound according to claim 1 which is N-(1-(4-(1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)-4-fluoro-N-methyl-2-(trifluoromethyl)benzamide, or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9 which is N-(1-(4-(1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)-4-fluoro-N-methyl-2-(trifluoromethyl)benzamide hydrochloride.

11. The compound according to claim 1 which is 4-fluoro-N-(1-(4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide, or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 11 which is 4-fluoro-N-(1-(4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide hydrochloride.

13. A pharmaceutical composition comprising a compound of the formula

14. The pharmaceutical composition according to claim 13 comprising the compound of the formula

15. The pharmaceutical composition according to claim 14 comprising the compound which is 4-fluoro-N-methyl-N-(1-(4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide, or a pharmaceutically acceptable salt thereof.