Pyrazolopyrimidine derivatives as tyrosine kinase inhibitors

• US 9,376,438 B2
• Filed: 05/16/2012
• Issued: 06/28/2016
• Est. Priority Date: 05/17/2011
• Status: Active Grant

• Current Assignee: Principia Biopharma Inc. (Sanofi )
• Original Assignee: Principia Biopharma Inc. (Sanofi )
• Inventors: Goldstein, David Michael, Brameld, Kenneth Albert
• Primary Examiner(s): Moore, Susanna
• Application Number:
  US14/117,927
• Publication Number:
  US 20140221398A1
• Time in Patent Office: 1,504 Days
• US Class Current: 1/1
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• 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: C07D 487/04 Ortho-condensed systems

Abstract

The present disclosure provides compounds of Formula (I)and pharmaceutically acceptable salts that are tyrosine kinase inhibitors,in particular BLK, BMX, EGFR, HER2, HER4, ITK, Jak3, TEC, Btk, and TXK and are therefore useful for the treatment of diseases treatable by inhibition of tyrosine kinases such as cancer and inflammatory diseases such as arthritis, and the like. Also provided are pharmaceutical compositions containing such compounds and pharmaceutically acceptable salts and processes for preparing such compounds and pharmaceutically acceptable salts.

Claims

1. A compound of Formula (I):

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein:

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein:

4. The compound of claim 2 or a pharmaceutically acceptable salt thereof wherein L is O, S, NH, N(methyl), NHCO, CONH, or NHCONH.

5. The compound of claim 3 or a pharmaceutically acceptable salt thereof wherein L is O, S, NH, N(methyl), NHCO, CONH, or NHCONH.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R³ and R⁴ are independently hydrogen, methyl, fluoro, methoxy, chloro, trifluoromethyl, or trifluoromethoxy.

7. The compound of claim 4 or a pharmaceutically acceptable salt thereof wherein R³ and R⁴ are independently hydrogen, methyl, fluoro, methoxy, chloro, trifluoromethyl, or trifluoromethoxy.

8. The compound of claim 5 or a pharmaceutically acceptable salt thereof wherein R³ and R⁴ are independently hydrogen, methyl, fluoro, methoxy, chloro, trifluoromethyl, or trifluoromethoxy.

9. The compound of claim 6 or a pharmaceutically acceptable salt thereof wherein R⁶ and R⁷ are independently hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, trifluoromethoxy, or cyano.

10. The compound of claim 7 or a pharmaceutically acceptable salt thereof wherein R⁵ is hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, trifluoromethoxy or cyano;

R¹ is formula (a)

11. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein R⁵ is hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, trifluoromethoxy, or cyano;

R¹ is formula (a)

12. The compound of claim 7 or a pharmaceutically acceptable salt thereof wherein R⁵ is hydrogen, alkyl, hydroxy, alkoxy, halo, haloalkyl, or haloalkoxy;

R¹ is formula (b)

13. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein R⁵ is hydrogen, alkyl, hydroxy, alkoxy, halo, haloalkyl, or haloalkoxy;

R¹ is formula (b);

14. The compound of claim 12 or a pharmaceutically acceptable salt thereof wherein X^a is O;

R^c′

is ethyl, propyl, cyclopropyl, or alkyl substituted with hydroxyl, alkoxy, alkylamino or dialkylamino;

P is alkylene; and

Q is a bond.

15. The compound of claim 13 or a pharmaceutically acceptable salt thereof wherein X^a is O;

R^c′

is ethyl, propyl, cyclopropyl, or alkyl substituted with hydroxyl, alkoxy, alkylamino or dialkylamino;

P is alkylene; and

Q is a bond.

16. The compound of claim 9 or a pharmaceutically acceptable salt thereof wherein the

17. The compound of claim 14 or a pharmaceutically acceptable salt thereof wherein the

18. The compound of claim 15 or a pharmaceutically acceptable salt thereof wherein the

19. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable excipient.

20. A method of treating chronic lymphocytic leukemia or mantle cell lymphoma in a patient which method comprises administering to the patient in need thereof, a pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable exciplent.