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(12) United States Patent (10) Patent No.: US 9.260,425 B2 D0 Et Al USOO9260425B2 (12) United States Patent (10) Patent No.: US 9.260,425 B2 D0 et al. (45) Date of Patent: Feb. 16, 2016 (54) PYRAZOLO3,4-CIPYRIDINE COMPOUNDS WO 2006/042102 A2 4/2006 AND METHODS OF USE WO 2010/022081 A1 2, 2010 WO 2012 O78777 A1 6, 2012 (75) Inventors: Steven Do, San Jose, CA (US); Huiyong Hu, San Mateo, CA (US); Aleksandr OTHER PUBLICATIONS Kolesnikov, San Francisco, CA (US); Dong et al., “QSAR study of Akt protein kinase B (PKB) inhibitors Wendy Lee, San Ramon, CA (US); using support vector machine” Eur J Med Chem. 44(10):4090-7 Vickie H. Tsui, San Francisco, CA (US); (2009). Xiaojing Wang, Foster City, CA (US); Muddassar et al., “Elucidation of binding mode and three dimen Zhaoyang Wen, San Francisco, CA (US) sional quantitative structure-activity relationship studies of a novel series of protein kinase B/Akt inhibitors' J Mol Model. 15(2): 183-92 (73) Assignee: Genetech, Inc., South San Francisco, (Feb. 2009). CA (US) Ohi et al., CAS Registry, Database Accession No. 2003:972059. “Preparation of pyrazole derivatives as JNK inhibitors'. (*) Notice: Subject to any disclaimer, the term of this PCT ISR and Written Opinion of the ISA for PCT/EP2012/065643. patent is extended or adjusted under 35 Wang et al., “Discovery of novel pyrazolo 1.5-alpyrimidines as U.S.C. 154(b) by 0 days. potent pan-Pim inhibitors by structure- and property-based drug design” Bioorg Med Chem Lett. 23(11):3149-53 (Jun. 2013). (21) Appl. No.: 13/571,595 Zhu et al., “Design and synthesis of pyridine-pyrazolopyridine-based inhibitors of protein kinase B/Akt' Bioorg Med Chem. 15(6):2441 (22) Filed: Aug. 10, 2012 52 (2007). (65) Prior Publication Data * cited by examiner US 2013/OO3990.6 A1 Feb. 14, 2013 Primary Examiner — Samira Jean-Louis Related U.S. Application Data (74) Attorney, Agent, or Firm — Tony W. Peng (60) Provisional application No. 61/522,857, filed on Aug. 12, 2011. (57) ABSTRACT (51) Int. C. Pyrazolo 3,4-cpyridine compounds of Formula I, including CO7D 47L/04 (2006.01) Stereoisomers, geometric isomers, tautomers, and pharma CO7D 23/00 (2006.01) ceutically acceptable salts thereof, wherein R' and Rare as (52) U.S. C. defined herein, are useful for inhibiting Pim kinase, and for CPC ............ C07D 471/04 (2013.01); C07D 231/00 treating disorders such as cancer mediated by Pim kinase. (2013.01) Methods of using compounds of Formula I for invitro, in situ, (58) Field of Classification Search and in vivo diagnosis, prevention or treatment of Such disor CPC ............................ C07D 471/04: CO7D 231/00 ders in mammalian cells, or associated pathological condi See application file for complete search history. tions, are disclosed. (56) References Cited U.S. PATENT DOCUMENTS R2 R! 5,604.240 A 2f1997 Chambers et al. N N 7,429,609 B2 9, 2008 Ohi et al. 2005/02O8582 A1* 9/2005 Ohi et al. ....................... 435.7.1 Na2NN N H FOREIGN PATENT DOCUMENTS EP 1510516 A1 3, 2005 WO 02/14317 A2 2, 2002 WO 02/20013 A2 3, 2002 14 Claims, No Drawings US 9,260,425 B2 1. 2 PYRAZOLO3.4-CIPYRIDINE COMPOUNDS Macdonald et al. (2006) Cell Biol vol. 7 pp. 1: Aho et al. AND METHODS OF USE (2004) FEBS Letters vol. 571 (1-3) pp. 43-9:Tamburini et al. (2009) Blood vol. 114 (8) pp. 1618-27). Pim kinase may CROSS REFERENCE TO RELATED affect cell survival since phosphorylation of Bad increases APPLICATIONS Bcl-2 activity and therefore promotes cell survival. Likewise, phosphorylation of eIF4E-BP1 by mTOR or Pim kinases This non-provisional application filed under 37 CFRS1.53 causes depression of eIF4E, promoting mRNA translation (b), claims the benefit under 35 USC S119(e) of U.S. Provi and cellular growth. In addition, Pim-1 has been recognized sional Application Ser. No. 61/522,857 filed on 12 Aug. 2011, to promote cell cycle progression through phosphorylation of which is incorporated by reference in its entirety. 10 CDC25A, p21, and Cdc25C (Mochizuki et al. (1999) J Biol Chemvol. 274 (26) pp. 18659-66; Bachmann et al. (2006) Int FIELD OF THE INVENTION J BiochemCell Biol vol.38 (3) pp. 430-43; Wang et al. (2002) The invention relates generally to pyrazolo 3,4-cpyridine Biochim Biophys Acta vol. 1593 (1) pp. 45-55. compounds for treating disorders mediated by Pim kinase 15 Pim kinases show Synergy in transgenic mouse models (Pim-1, Pim-2, and/or Pim-3) inhibitors, thus useful as cancer with c-Myc-driven and Akt-driven tumors (Verbeek et al. therapeutics. The invention also relates to compositions, (1991) Mol Cell Biol vol. 11 (2) pp. 1176-9: Allen et al. more specifically pharmaceutical compositions comprising Oncogene (1997) Vol. 15 (10) pp. 1133-41; Hammerman et these compounds and methods of using the same, either alone al. (2005) Blood vol. 105 (11) pp. 4477-83). Pim Kinases are or in combination, to treat various forms of cancer and hyper involved in transforming activity of oncogenes identified in proliferative disorders, as well as methods of using the com acute myeloid leukemia (AML) including Flt3-ITD, BCR pounds for in vitro, in situ, and in vivo diagnosis or treatment abl, and Tel-Jak2. Expression of these oncogenes in BaF3 of mammalian cells, or associated pathological conditions. cells results in upregulation of Pim-1 and Pim-2 expression, resulting in IL-3 independent growth, and Subsequent Pim BACKGROUND OF THE INVENTION 25 inhibition results in apoptosis and cell growth arrest (Adam et Pim kinases are family of three highly-related serine and al. (2006) Cancer Research vol. 66 (7) pp. 3828-35). Pim threonine protein kinases encoded by the genes Pim-1, Pim-2, overexpression and dysregulation has also been noted as a and Pim-3. The gene names are derived from the phrase frequent event in many hematopoietic cancers, including leu Proviral Insertion, Moloney, frequent integration sites for 30 kemias and lymphoma (Amson et al. (1989) Proc Natl Acad murine moloney virus wherein the insertions lead to overex Sci USA vol. 86 (22) pp. 8857-61); Cohen et al. (2004) Leuk pression of Pim kinases and either denovo T-cell lymphomas, Lymphoma vol. 45 (5) pp. 951-5; Hittmann et al. (2006) or dramatic acceleration of tumorigenesis in a transgenic Leukemia vol. 20 (10) pp. 1774-82) as well as multiple Myc-driven lymphoma model (Cuypers et al. (1984) Cell, myeloma (Claudio et al. (2002) Blood vol. 100 (6) pp. 2175 vol.37 (1) pp. 141-50; Selten et al. (1985) EMBO.J. vol.4 (7) 35 86. Pim 1 has been shown to be overexpressed and correlated pp. 1793-8; van der Lugt et al. (1995) EMBO J. vol. 14 (11) to prostate cancer progression (Cibull et al. (2006) J Clin pp. 2536-44: Mikkers et al. (2002) Nature Genetics, vol. 32 Pathol vol. 59 (3) pp. 285-8: Dhanasekaran et al. (2001) (1) pp. 153-9; van Lohuizen et al. (1991) Cell, vol. 65 (5) pp. Nature vol. 412 (6849) pp. 822-6). Pim 1 expression increases 737-52). These experiments reveal synergy with the onco in mouse models with disease progression (Kim et al. (2002) gene c-Myc, and Suggest that inhibition of the Pim kinases 40 Proc Natl AcadSci USA vol. 99 (5) pp. 2884-9). Pim-1 has may have therapeutic benefit. been reported to be the most highly overexpressed mRNA in Mouse genetics Suggests that antagonizing Pim kinases the Subset of human prostate tumor samples which have a may have an acceptable safety profile; a Pim 1-/-: Pim-2-/-, c-Myc-driven genesignature (Ellwood-Yen et al. (2003) Can Pim-3-/- mouse knockout is viable although slightly smaller cer Cell vol. 4 (3) pp. 223-38). Pim-3 has been also been than wild type littermates (Mikkers et al. (2004) Mol Cell 45 Biol vol. 24 (13) pp. 6104-154). The three genes give rise to shown to be overexpressed and to have a functional role in six protein isoforms including a protein kinase domain, and pancreatic cancer and hepatocellular carcinoma (Li et al. apparently without recognizable regulatory domains. All six (2006) Cancer Research vol. 66 (13) pp. 6741-7: Fujii et al. isoforms are constitutively active protein kinases that do not (2005) Int J. Cancer, vol. 114 (2) pp. 209-18). require post-translational modification for activity, thus Pim 50 Beyond oncology therapeutic and diagnostic applications, kinases are regulated primarily at the transcriptional level Pim kinases could play an important role in normal immune (Qianet al. (2005) J Biol Chem, vol. 280 (7) pp. 6130-7). Pim system function and Pim inhibition could be therapeutic for a kinase expression is highly inducible by cytokines and number of different immunologic pathologies including growth factors receptors and Pims are direct transcriptional targets of the Stat proteins, including Stat3 and Stats. Pim-1, 55 inflammation, autoimmune conditions, allergy, and immune for example, is required for the 130-mediated Stat3 prolifera Suppression for organ transplantation (Aho et al. Expression tion signal (Aksoy et al. (2007) Stem Cells, vol. 25 (12) pp. of human Pim family genes is selectively up-regulated by 2996-3004; Hirano et al. (2000) Oncogene vol. 19 (21) pp. cytokines promoting T helper type 1, but not Thelper type 2, 2548-56; Shirogane et al. (1999) Immunity vol. 11 (6) pp. cell differentiation. Immunology (2005) vol. 116 (1) pp. 709-19). 60 82-8). Pim kinases function in cellular proliferation and survival pathways parallel to the PI3k/Akt/mTOR signaling axis (Hammerman et al. (2005) Blood vol. 105 (11) pp.
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