Inhibitors of bruton's tyrosine kinase

• US 9,624,201 B2
• Filed: 12/10/2014
• Issued: 04/18/2017
• Est. Priority Date: 12/13/2013
• Status: Active Grant

• Current Assignee: Chugai Seiyaku Kabushiki Kaisha (Roche Holding AG)
• Original Assignee: Chugai Seiyaku Kabushiki Kaisha (Roche Holding AG), Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Lopez-Tapia, Francisco Javier, So, Sung-Sau, Qiao, Qi, Dominique, Romyr
• Primary Examiner(s): Coughlin, Matthew
• Assistant Examiner(s): Chen, Po-Chih
• Application Number:
  US15/102,315
• Publication Number:
  US 20160318907A1
• Time in Patent Office: 860 Days
• Field of Search: None
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• 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 25/16 Anti-Parkinson drugs
• 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 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 31/04 Antibacterial agents
• 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 5/38 of the suprarenal hormones
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• 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 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings

Abstract

This application discloses compounds according to generic Formula (I): wherein all variables are defined as described herein, which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with excessive Btk activity. The compounds are useful for the treatment of oncological, auto-immune, and inflammatory diseases caused by aberrant B-cell activation. Also disclosed are compositions containing compounds of Formula (I) and at least one carrier, diluent or excipient.

Claims

1. A compound of Formula I,

2. The compound of claim 1, wherein X is methyl and R⁵ is heteroaryl, optionally substituted with one or more R^5′

.

3. The compound of claim 1, wherein R⁵ is thiophenyl, optionally substituted with one or more R^5′

.

4. The compound of claim 1, wherein R⁵ is pyridyl, optionally substituted with one or more R^5′

.

5. The compound of claim 1, wherein R¹ is F and R² is F.

6. The compound of claim 1, wherein R¹ is H and R² is cyano.

7. The compound of claim 1, wherein R⁵ is —

C(═

O)R^5′

.

8. The compound of claim 7, wherein R^5′

is morpholinyl, piperidinyl, loweralkyl-piperidinyl, or lower alkoxy.

9. The compound of claim 8, wherein R¹ is F and R² is F.

10. The compound of claim 8, wherein R¹ is H and R² is cyano.

11. The compound of claim 1, wherein R⁵ is phenyl or benzyl, optionally substituted with one or more R^5′

.

12. The compound of claim 1, wherein R⁵ is lower alkyl, optionally substituted with one or more R^5′

.

13. The compound of claim 11, wherein R¹ is F and R² is F.

14. The compound of claim 11, wherein R¹ is H and R² is cyano.

15. The compound of claim 12, wherein R¹ is F and R² is F.

16. The compound of claim 12, wherein R¹ is H and R² is cyano.

17. The compound of claim 1, selected from the group consisting of:

{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(4-bromo-1H -indol-2-yl)-methanone;

{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(4-phenyl-1H -indol-2-yl)-methanone;

{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(4-thiophen-3-yl-1H-indol-2-yl)-methanone;

{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(4-pyrazol-1-yl-1H-indol-2-yl)-methanone;

{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(4-thiophen-2-yl-1H-indol-2-yl)-methanone;

{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-[4-(morpholine-4-carbonyl)-1H-indol-2-yl]-methanone;

{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-[4-(1-methyl-1H-pyrazol-4-yl)-1H-indol-2-yl]-methanone;

{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(4-pyridin-2-yl-1H-indol-2-yl)-methanone;

{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(4-benzyl-1H -indol-2-yl)-methanone;

{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-[4-(1H-pyrazol-4-yl)-1H-indol-2-yl]-methanone;

3-(2-{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazole-4-carbonyl}-1H-indol-4-yl)-benzonitrile;

{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-[4-(3-chloro-phenyl)-1H-indol-2-yl]-methanone;

3-(2-{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazole-4-carbonyl}-1H-indol-4-ylmethyl)-benzonitrile;

3-(4-{5-Amino-4-[4-(1H-pyrazol-4-yl)-1H-indole-2-carbonyl]-pyrazol-1-yl}-3-methyl -phenoxy)-benzonitrile;

3-(4-{5-Amino-4-[4-(morpholine-4-carbonyl)-1H-indole-2-carbonyl]-pyrazol-1-yl}-3-methyl-phenoxy)-benzonitrile;

3-(4-{5-Amino-4-[4-(4-methyl-piperazine-1-carbonyl)-1H-indole-2-carbonyl]-pyrazol-1-yl}-3-methyl-phenoxy)-benzonitrile;

3-(4-{5-Amino-4-[4-(3-methoxy-benzyl)-1H-indole-2-carbonyl]-pyrazol-1-yl}-3-methyl -phenoxy)-benzonitrile;

2-{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazole-4-carbonyl}-1H -indole-4-carboxylic acid methyl ester;

{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(4-morpholin-4-ylmethyl-1H-indol-2-yl)-methanone;

3-{4-[5-Amino-4-(4-cyanomethyl-1H-indole-2-carbonyl)-pyrazol-1-yl]-3-methyl-phenoxy}-benzonitrile; and

2-{5-Amino-1-[4-(3-cyano-phenoxy)-2-methyl-phenyl]-1H-pyrazole-4-carbonyl}-1H -indole-4-carboxylic acid methylamide.

18. A pharmaceutical composition, comprising the compound of claim 1, admixed with at least one pharmaceutically acceptable carrier, excipient or diluent.

19. A method for treating an inflammatory and/or autoimmune condition, mediated by Bruton'"'"'s Tyrosine Kinase, comprising the step of administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1.

20. A method for treating an inflammatory condition mediated by Bruton'"'"'s Tyrosine Kinase, comprising the step of administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1.

21. A method for treating rheumatoid arthritis, comprising the step of administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1.

22. A method for treating asthma, comprising the step of administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1.