Purinone Derivatives as Tyrosine Kinase Inhibitors

• US 20160257686A1
• Filed: 01/15/2016
• Published: 09/08/2016
• Est. Priority Date: 11/20/2012
• Status: Abandoned Application

• Current Assignee: Principia Biopharma Inc. (Sanofi )
• Original Assignee: Principia Biopharma Inc. (Sanofi )
• Inventors: OWENS, Timothy D.
• Application Number:
  US14/997,248
• Publication Number:
  US 20160257686A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: C07D 473/34 attached in position 6, e.g. adenine

Abstract

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

Claims

1. A compound of Formula (I):

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

L is O and is attached at the 4-position of the phenyl ring with the carbon atom of the phenyl ring attached to purinone nitrogen being position 1; and

R¹ and R² are independently hydrogen, alkyl, halo, haloalkyl, or alkoxy.

3. The compound or a pharmaceutically acceptable salt of claim 2

wherein R¹ is hydrogen or halo;

and

R² is hydrogen.

4. The compound or a pharmaceutically acceptable salt of claim 2

wherein R¹ and R² are hydrogen.

5. The compound or a pharmaceutically acceptable salt of claim 2 wherein

6. The compound or a pharmaceutically acceptable salt of claim 2 wherein

7. The compound or a pharmaceutically acceptable salt of claim 2 wherein —

X—

is -cycloalkylene-NR^a—

, -(alkynylene)-NR^a—

, -(alkylene)-NR^a—

, -phenylene-NR^a—

(where each R^a is hydrogen, alkyl or cycloalkyl), or

8. The compound or a pharmaceutically acceptable salt of claim 2 wherein —

X—

Y—

is;

9. The compound or a pharmaceutically acceptable salt of claim 2 wherein —

X—

Y—

is;

10. The compound or a pharmaceutically acceptable salt of claim 9 wherein R^c is cycloalkyl.

11. The compound or a pharmaceutically acceptable salt of claim 9 wherein R^c is alkyl.

12. The compound or a pharmaceutically acceptable salt of claim 9 wherein R^c is alkyl substituted with hydroxyl, alkoxy, —

NRR′

(where R is hydrogen, alkyl, alkoxyalkyl, heterocyclyl or cycloalkyl and R′

is hydrogen or alkyl), or heterocycicyl which is optionally substituted with one or two groups independently selected from alkyl.

13. The compound or a pharmaceutically acceptable salt of claim 9 wherein R^c is 3- to 6-membered saturated monocyclic heterocyclyl containing one or two heteroatoms selected from N, O, or S and optionally substituted with one or two substituents selected from hydroxy, alkyl or fluoro.

14. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of claim 1, and a pharmaceutically acceptable excipient.

15. A method of treating an autoimmune disease, inflammatory disease or cancer which method comprises administering to the patient in need thereof, a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of claim 1 optionally in combination with one or more anticancer or anti-inflammatory agents.

16. The method of claim 15 wherein the disease is leukemia or lymphoma.

17. The method of claim 15 wherein the leukemia is chosen from chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), multiple myeloma, mantle cell lymphoma, and B-cell non-Hodgkin lymphoma.

18. The method of claim 15 wherein the disease is arthritis, lupus, Sjogren'"'"'s dry eye, non-Sjogren'"'"'s dry eye, or asthma.

19. A compound selected from: