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(10) Patent No.: US 8232280 B2 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. Bioorg. Med. Chem. Ltrs. 10:2167-2170 (2000). Browning, J.L., “B cells move to centre stage: novel opportunities for (51) Int. Cl. autoimmune disease treatment”. Nature Reviews/Drug Discovery AOIN 43/90 (2006.01) vol. 5, Jul. 2006, pp. 564-576. A 6LX3/59 (2006.01) Burchat et al., “Pyrazolo 3,4-dipyrimidines Containing an Extended 3-Substituent as Potent Inhibitors of Lck—a Selectivity Insight.” CO7D 487/00 (2006.01) Bioorg. Med. Chem. Ltrs. 12:1687-1690 (2002). (52) U.S. Cl. ..................................... 514/262.1; 54.4/262 Cohen, M.S. et al., “Structural Bioinformatics-Based Design of (58) Field of Classification Search ........................ None Selective, Irreversible Kinase Inhibitors.” Science, vol.308, May 27, See application file for complete search history. 2005, pp. 1318-1321. Desiderio, S., “Role of Btk in B cell development and signaling.” Curr, Op. in Immunology 1997, 9:534-540. (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. Methods for the 8,008,309 B2 * 8/2011 Honigberg et al. ........ 514,262.1 preparation of the compounds are disclosed. Also disclosed 2002fOO16460 A1 2/2002 Snow et al. are pharmaceutical compositions that include the com 2003, OO40461 A1 2/2003 Mcatee pounds. Methods of using the Btk inhibitors are disclosed, 2003/O125235 A1 7, 2003 Foxwell alone or in combination with other therapeutic agents, for the 2004/OOO6083 A1 1/2004 Hirst et al. 2005, 0008640 A1 1/2005 Waegell et al. treatment of autoimmune diseases or conditions, heteroim 2005/0090499 A1 4/2005 Currie et al. mune diseases or conditions, cancer, including lymphoma, 2005/0101604 A1 5, 2005 Currie et al. and inflammatory diseases or conditions. 2005, 0196851 A1 9, 2005 Uckun 2005/0209255 A1 9, 2005 Jimenez et al. 16 Claims, 8 Drawing Sheets US 8,232.280 B2 Page 2 OTHER PUBLICATIONS Uckun, Fatih M. et al., “BTK as a Mediator of Radiation-Induced Gold, Michael R. “To make antibodies or not: signaling by the B-cell Apoptosis in DT-40 Lymphoma B Cells.” Science vol. 273 No. 5278, antigen receptor.” Trends in Pharmacological Sciences, 23(7):316 pp. 1096-1 100 (1996). 324 (Jul. 2002). Vassilev, A.O. And Uckun, F.M., “Therapeutic Potential of Inhibiting Horwood, Nicole J. et al., “Bruton's Tyrosin Kinase Is Required for Bruton's Tyrosine Kinase, (BTK). Current Pharmaceutical Design, Lipopolysaccharide—induced Tumor Necrosis Factor O. Produc 2004, 10, 1757-1766. tion.” J. Exp. Med. 197(12):1603-1611 (Jun. 2003). Vassilev, Alexei et al., “Bruton's Tyrosine Kinase as an Inhibitor of Iwaki, Shoki et al., “Btk Plays a Crucial Role in the Amplification of the Fas/CD95 Death-inducing Signaling Complex.” J. Biol. Chem. FceRI-mediated Mast Cell Activation by Kit,” J. Biol. Chem. 274(3):1646-1656 (1999). 280(48):40261-40270 (Dec. 2, 2005). Yamamoto, Noriyuki et al., “The Orally Available Spleen Tyrosine Jefferies, Caroline A. et al., “Bruton's Tyrosine Kinase is a Toll? Kinase Inhibitor 2-7-(3,4-Dimethoxyphenyl)-imidazol-2- Interleukin-1 Receptor Domain-binding Protein That Participates in cpyrimidin-5-ylamino-nicotinamide Dihydrochloride (BAY61 Nuclear Factor KBActivation by Toll-like Receptor 4.” J. Biol. Chem. 278:26258-26264 (2003). 3606) Blocks Antigen-Induced Airway Inflammation in Rodents.” J. Kawakami, Yuko et al., “Terreic acid, a quinone epoxide inhibitor of Pharma. and Exp. Therapeutics 306(3): 1174-1181 (2003). Bruton's tyrosine kinase.” PNAS USA96:2227-2232 (1999). Luskova, P. and Draber, P. “Modulation of the Fce Receptor I Sig Kuppers, R., “Mechanisms of B-cell lymphoma pathogenesis.” naling by Tyrosin Kinase Inhibitors: Search for Therapeutic Targets Nature Reviews/Cancer, vol. 5, Apr. 2005, pp. 251-262. of Inflammatory and Allergy Diseases. Curr. Pharmaceutical Design Kurosaki, Tomohiro, “Functional dissection of BCR signaling path 10:1727-1737 (2004). ways.” Curr. Op. Imm. 12:276-281 (2000). PCT/US06/49626 Search Report dated Apr. 9, 2008. Mahajan, S. et al., “Rational Design and Synthesis of a Novel Anti Vippagunta et al., “Crystalline Solids.” Advanced Drug Delivery leukemic Agent Targeting Bruton's Tyrosine Kinase (BTK), LFM Reviews 48:3-26 (2001). A13 O-Cyano-B-Methyl-N-(2,5-Dibromophenyl)Propenamide).” J. Dorwald, F. A. Side Reactions in Organic Synthesis, Wiley:VCH, of Biol. Chem., vol. 274, No. 14, Apr. 2, 1999, pp. 9587-9599. Weinheim p. IX of Preface, Wile-VCH Verlag GmbH & Co. KGaA Mangla, Anita et al., “Pleiotropic consequences of Bruton tyrosin (2005). kinase deficiency in myeloid lineages lead to poor inflammatory EP06850.039 Supplemental Search Report dated Feb. 9, 2010. responses.” Blood 104(4): 1191-1197 (2004). EP06850386.1 Search Report and Written Opinion dated Sep. 10, Niiro, Hiroaki and Clark, Edward A., “Regulation of B-Cell Fate by 2010. Antigen-Receptor Signals.” Nature Reviews 2:945-956 (2002). Ucken et al., “Bruton's tyrosine kinase as a molecular target in Nisitani, S. et al., “In situ detection of activated Bruton's tyrosine kinase in the Ig signaling complex by phosphopeptide-specific treatment of leukemias and lymphomas as well as inflammatory monoclonal antibodies.” PNAS USA96:2221-2226 (1999). disorders and autoimmunity.” Expert Opinion Ther. Patents 20(11):1- Oligino, Thomas J. and Dalrymple, Stacie A., “Targeting B cells for 14 (2010. the treatment of rheumatoid arthritis.” Arthirits Res Ther 5(Suppl. EP10 155834.4 Search Report dated May 19, 2010. 4):S7-S11 (2002). Dorwald et al., Side Reactions in Organic Synthesis, 2005, Wiley: Pan, Z. et al., “Discovery of Selectable Irreversible Inhibitors for VCH. Weinheimp. IX of Preface. Bruton's Tyrosine Kinase.” ChemMedChem 2006, 1, 1-5. Uckun, Fatih M. et al., “The Anti-leukemic Bruton's Tyrosin Kinase Quek, L.S. et al., “A role for Bruton's tyrosine kinase (Btk) in platelet Inhibitor O-cyano-B-hydroxy-3-mehyl-N-(2,5- activation by collagen.” Curr. Biol. 8(20): 1137-1140 (1998). dibromophenyl)Propenamide (LFM-A13)Prevents Fatal Sada, Kiyonao and Yamamura, Hirohei. “Protein-Tyrosine Kinases Thromboembolism.” Leuk. Lymphoma 44(9): 1569-1577 (2003). and Adaptor Proteins in FceRI-Mediated Signaling in Mast Cells.” Uckun, Fatih M. et al., “In Vivo Pharmacokinetic Features, Toxicity Curr. Mol. Med. 3(1):85-94 (2003). Profile, and Chemosensitizing Activity of C-Cyano-B-hydroxy-3- Schaeffer, Edward M. and Schwartzberg, Pamela L., “Tec family methyl-N-(2,5-dibromophenyl)propenamide (LFM-A13), a Novel kinases in lymphocyte signaling and function.
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