PURINONE COMPOUNDS AS KINASE INHIBITORS

• US 20130197014A1
• Filed: 04/30/2012
• Published: 08/01/2013
• Est. Priority Date: 01/31/2012
• Status: Active Grant

• Current Assignee: Pharmacyclics LLC (Abbvie Incorporated)
• Original Assignee: Pharmacyclics Incorporated (Abbvie Incorporated)
• Inventors: CHEN, Wei, LOURY, David J.
• Granted Patent: US 8,501,724 B1
• Time in Patent Office: Days
• US Class Current: 514/263.22
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 473/34 : attached in position 6, e.g. adenine

Abstract

Disclosed herein are compounds that form covalent bonds with Bruton'"'"'s tyrosine kinase (Btk). Also described are irreversible inhibitors of Btk. In addition, reversible inhibitors of Btk are also described. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.

Claims

1. A compound of Formula (I) having the structure:

2. The compound of claim 1, wherein L_a is —

O—

, or —

OCH₂—

.

3. The compound of claim 2, wherein Ar is phenyl.

4. The compound of claim 3, wherein R₃ is

5. The compound of claim 4, wherein Z is C(═

O), NHC(═

O), N(CH₃)C(═

O), or S(═

O)₂.

6. The compound of claim 5, wherein R₆, R₇, and R₈ are H.

7. The compound of claim 5, wherein R₆ and R₈ are H;

and R₇ is L-J-W.

8. The compound of claim 7, wherein L is a bond, substituted or unsubstituted C₁-C₆ alkylene, or substituted or unsubstituted C₃-C₆ cycloalkylene;

and J is a bond, substituted or unsubstituted C₁-C₆ alkylene, substituted or unsubstituted C₃-C₆ cycloalkylene, substituted or unsubstituted C₁-C₆ heteroalkylene, substituted or unsubstituted C₂-C₇ heterocycloalkylene, substituted or unsubstituted C₆-C₁₂ arylene, or substituted or unsubstituted C₃-C₁₂ heteroarylene.

9. The compound of claim 8, wherein L is a bond;

J is —

CH₂—

; and

W is NR₂₅R₂₆.

10. The compound of claim 9, wherein R₂₅ is H, substituted or unsubstituted C₁-C₆ alkyl, or substituted or unsubstituted C₃-C₆ cycloalkyl;

and R₂₆ is substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted C₃-C₁₂ heteroaryl.

30. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof, and a pharmaceutically acceptable excipient.

11. A compound of Formula (II) having the structure:

12. The compound of claim 11, wherein L_a is —

O—

.

13. The compound of claim 12, wherein Ar is phenyl.

14. The compound of claim 13, wherein Z is C(═

O), NHC(═

O), N(CH₃)C(═

O), or S(═

O)₂.

15. The compound of claim 14, wherein R₆ and R₈ are H;

and R₇ is T-W.

16. The compound of claim 15, wherein T is a bond, substituted or unsubstituted C₁-C₆ alkylene, or substituted or unsubstituted C₃-C₆ cycloalkylene.

17. The compound of claim 16, wherein T is —

CH₂—

; and

W is NR₂₅R₂₆.

18. The compound of claim 17, wherein R₂₅ is H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆ cycloalkyl;

and R₂₆ is substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted C₃-C₁₂ heteroaryl.

19. The compound of claim 18, wherein R₂₅ is —

CH₃; and

R₂₆ is substituted or unsubstituted C₃-C₆ cycloalkyl.

20. A compound of Formula (III) having the structure:

21. The compound of claim 20, wherein A is phenyl.

22. The compound of claim 21, wherein R₃ is

23. The compound of claim 22, wherein Z is C(═

O), NHC(═

O), N(CH₃)C(═

O), or S(═

O)₂.

24. The compound of claim 23, wherein R₆, R₇, and R₈ are H.

25. The compound of claim 23, wherein R₆ and R₈ are H;

and R₇ is L-J-W.

26. The compound of claim 25, wherein L is a bond, substituted or unsubstituted C₁-C₆ alkylene, or substituted or unsubstituted C₃-C₆ cycloalkylene;

and J is a bond, substituted or unsubstituted C₁-C₆ alkylene, substituted or unsubstituted C₃-C₆ cycloalkylene, substituted or unsubstituted C₁-C₆ heteroalkylene, substituted or unsubstituted C₂-C₇ heterocycloalkylene, substituted or unsubstituted C₆-C₁₂ arylene, or substituted or unsubstituted C₃-C₁₂ heteroarylene.

27. The compound of claim 26, wherein L is a bond;

J is —

CH₂—

; and

W is NR₂₅R₂₆.

28. The compound of claim 27, wherein R₂₅ is H, substituted or unsubstituted C₁-C₆ alkyl, or substituted or unsubstituted C₃-C₆ cycloalkyl;

and R₂₆ is substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted C₃-C₁₂ heteroaryl.

29. The compound of claim 28, wherein R₂₀ is H, halogen, —

CN, —

CF₃, or substituted or unsubstituted C₁-C₆alkyl.