US00823228OB2 (12) United States Patent (10) Patent No.: US 8,232,280 B2 Honigberg et al. (45) Date of Patent: *Jul. 31, 2012 (54) INHIBITORS OF BRUTON'S TYROSINE 2006, 00794.94 A1 4, 2006 Santi et al. KNASE 2006.0167090 A1 7/2006 Uckun et al. 2007/0281907 A1 12/2007 Watkins 2008/0076921 A1 3/2008 Honigberg et al. (75) Inventors: Lee Honigberg, San Francisco, CA 2008/0108.636 A1 5/2008 Honigberg et al. (US); Erik Verner, Belmont, CA (US); 2008. O139582 A1 6/2008 Honigberg et al. Zhengying Pan, Austin, TX (US) 2010/00042702009/O181987 A1 7/20091/2010 Honigberg 2010.0022561 A1 1/2010 Honigber (73) Assignee: Pharmacyclics, Inc., Sunnyvale, CA 2010.0041677 A1 2/2010 E. US (US) FOREIGN PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this WO WO-97-2816.1 8, 1997 patent is extended or adjusted under 35 W. w86.68 A: 238, U.S.C. 154(b) by 0 days. WO WO-01-19829 A2 3, 2001 This patent is Subject to a terminal dis- WO WO-01-019829WO-01-19829 A3 3, 2001 claimer. WO WO-01-25238 A2 4/2001 WO WO-01-41754 6, 2001 (21) Appl. No.: 13/011,258 WO WO-01-44258 A1 6, 2001 WO WO-02-387.97 A2 5, 2002 1-1. WO WO-02-080926 10, 2002 (22) Filed: Jan. 21, 2011 WO WO-03-000187 1, 2003 O O WO WO-2004-096.253 11, 2004 (65) Prior Publication Data WO WO-2004-100868 A2 11/2004 WO WO-2004-100868 A3 11 2004 US 2011 FO184OO1 A1 Jul. 28, 2011 WO WO-2005-005429 1, 2005 O O WO WO-2005-O 14599 2, 2005 Related U.S. Application Data WO WO-2005-074603 8, 2005 (60) Continuation of application No. 12/356,498, filed O W. W23:59: 838. Jan. 20, 2009, which is a division of application No. WO WO-2008-03921.8 4/2008 1 1/617,645, filed on Dec. 28, 2006, now Pat. No. WO WO-2008-054827 A2 S/2008 7,514,444. OTHER PUBLICATIONS (60) Provisional application No. 60/826,720, filed on Sep. Arnold, L.D. et al., “Pyrrolo[2,3-dipyrimidines Containing an 22, 2006, provisional application No. 60/828,590, Extended 5-Substituent as Potent and Selective Inhibitors of lok 1.” filed on Oct. 6, 2006. 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(56) References Cited Fruman, D.A., "Xid-like Phenotypes: A B Cell Signalosome Takes Shape.” Immunity 13: 1-3 (Jul. 2000). U.S. PATENT DOCUMENTS 6,326,469 B1 12/2001 Ullrich et al. (Continued) 6,506,769 B2 1/2003 Snow et al. 6,660,744 B1 12/2003 Hirst et al. Primary Examiner — Jeffrey Murray 6,753,348 B2 6, 2004 Uckun et al. (74) Attorney, Agent, or Firm — Wilson Sonsini Goodrich & 6,770,639 B2 8, 2004 Snow et al. Rosati 6,921,763 B2 7/2005 Hirst et al. 7,332,497 B2 2/2008 Hirst et al. 7.514,444 B2 * 4/2009 Honigberg et al. ...... 514,263.22 (57) ABSTRACT 7,718,662 B1 5, 2010 Chen Disclosed herein are pyrazolo 3,4-dipyrimidines that form 7,732,454 B2 * 6/2010 Verner ....................... 514,262.1 7,741,330 B1 6, 2010 Chen covalent bonds with Bruton's tyrosine kinase (Btk). Also 7,825,118 B2 * 1 1/2010 Honigberg et al. ........... 514,249 described are irreversible inhibitors of Btk. 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