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(12) Patent Application Publication (10) Pub. No.: US 2017/0121347 A1 Chen Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2017/0121347 A1 Chen Et Al US 201701 21347A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0121347 A1 Chen et al. (43) Pub. Date: May 4, 2017 (54) AMORPHOUS SOLID FORM OF A BET Publication Classification PROTEIN INHIBITOR (51) Int. Cl. (71) Applicant: Incyte Corporation, Wilmington, DE C07D 49.8/04 (2006.01) (US) C07D 413/04 (2006.01) (52) U.S. Cl. (72) Inventors: Shili Chen, Newark, DE (US); William CPC ......... C07D 498/04 (2013.01); C07D 413/04 Frietze, Kennett Square, PA (US); (2013.01) Zhongjiang Jia, Kennett Square, PA (US); Pingli Liu, Newark, DE (US); Jiacheng Zhou, Newark, DE (US) (57) ABSTRACT (21) Appl. No.: 15/337,202 The present invention relates to an amorphous solid form of (22) Filed: Oct. 28, 2016 (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihy droimidazo 1.5,4-de(1,4)benzoxazin-2(1H)-one, and pro Related U.S. Application Data cesses for its preparation, which is an inhibitor of BET (60) Provisional application No. 62/248,040, filed on Oct. proteins such as BRD2, BRD3, BRD4, and BRD-t and is 29, 2015. useful in the treatment of various diseases such as cancer. Patent Application Publication May 4, 2017. Sheet 1 of 3 US 2017/O121347 A1 FIGURE 1 XRPD Two-Theta deg) Patent Application Publication May 4, 2017. Sheet 2 of 3 US 2017/O121347 A1 FIGURE 2 DSC 3.3 - f, 8.8 - i \ fiA \ S. ii ' s i \ s St. -- ? . 2S38 \ A- f a36s2.ig 32C N A ---a--- / N Y. ---...------------t-r 88C ------------.Ss. 53.GC-- - 998.g ----------------------------~~--------------------------------------------------------------------------------------------------------------------------------- S8 8. 3. 8G 23. & 33 axis Temperature (°C) Riversa: Wasa, a sires Patent Application Publication May 4, 2017. Sheet 3 of 3 US 2017/O121347 A1 FIGURE 3 MDSC is is 101 22°C \\ y \A 105.80°C()3. Exc is emperature {C} waisa WSAA Stats US 2017/O121347 A1 May 4, 2017 AMORPHOUS SOLID FORM OF ABET mouse model showed dramatically lower levels of inflam PROTEIN INHIBITOR matory cytokines and protection from obesity induced dia betes. Wang et al., Biochem. J., 2009, 425, 71-83; Belkina et FIELD OF THE INVENTION al., J. Immunol. 102838, online publication before print, Feb. 18, 2013. In addition, some viruses make use of these 0001. The present invention relates to an amorphous solid BET proteins to tether their genomes to the host cell form of (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl chromatin, as part of the process of viral replication or use 4,5-dihydroimidazo 1,5,4-de(1,4)benzoxazin-2(1H)-one, BET proteins to facilitate viral gene transcription and repres and processes for its preparation, which is an inhibitor of sion. You et al., Cell, 2004, 117, 349-60; Zhu et al., Cell BET proteins such as BRD2, BRD3, BRD4, and BRD-t and Reports, 2012, 2,807-816. is useful in the treatment of various diseases such as cancer. 0004 Inhibitors of BET proteins are in current develop ment. Exemplary BET protein inhibitors are disclosed in, for BACKGROUND OF THE INVENTION example, U.S. Pat. App. Pub. Nos. 2014/0275030; 2015/ 0002 The BET (Bromodomain and Extra-Terminal) fam 0011540: 2015/0148375; 2015/0148342: 2015/0148372: ily of bromodomain containing proteins comprises 4 pro and 2015/0175604. An example of BET protein inhibitor is teins (BRD2, BRD3, BRD4 and BRD-t) that share a con (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihy served structural organization containing tandem N-terminal droimidazo[1,5,4-de(1,4)benzoxazin-2(1H)-one which is bromodomains capable of binding to acetylated lysine resi described in U.S. Pat. App. Pub. No. 2014/0275030. While dues of histones and other proteins. BRD2, BRD3 and certain inhibitors of BET proteins are in the literature, there BRD4 are ubiquitously expressed while BRD-t is restricted remains a need for new solid forms of these inhibitors to germ cells. BRD proteins play essential, but non-over having Suitable properties useful in the manufacture of safe, lapping roles in regulating gene transcription and controlling effective, high quality drug products. The present invention cell growth. BET proteins are associated with large protein described herein is directed toward this end. complexes including Mediator, PAFc and Super elongation complex that regulate many aspects of gene transcription. SUMMARY OF THE INVENTION BRD2 and BRD4 proteins have been shown to remain in complex with chromosomes during mitosis and are required 0005. The present invention provides, inter alia, a solid to promote transcription of critical genes including cyclin D form, which is an amorphous powder, of the BET protein and c-Myc that initiate the cell cycle. Mochizuki et al., J. inhibiting compound (4S)-7-(3,5-dimethylisoxazol-4-yl)-4- Biol. Chem. 2008, 283, 9040-9048. BRD4 is essential for pyridin-2-yl-4,5-dihydroimidazo 1.5,4-de(1,4)benzoxazin recruiting the protein translational elongation factor B com 2(1H)-one, compositions, methods of use, and methods for plex to the promoters of inducible genes resulting in the preparing the same. phosphorylation of RNA polymerase II and stimulating 0006. The present invention also provides intermediate productive gene transcription and elongation. Jang et al., compounds generated during the preparation of (4S)-7-(3. Mol. Cell, 2005, 19, 523-534. In some instances, a kinase 5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimi activity of BRD4 may directly phosphorylate and activate dazo[1,5,4-de(1,4)benzoxazin-2(1H)-one and methods for RNA polymerase II. Devaiah et al., Proc. Nat. Acad. Sci., preparing these intermediate compounds. USA. 2012, 109, 6927-6932. Cells lacking BRD4 show 0007. The details of one or more embodiments are set impaired progression through cell cycle. BRD2 and BRD3 forth in the description below. Other features, objects, and are reported to associate with histones along actively tran advantages will be apparent from the description and from scribed genes and may be involved in facilitating transcrip the claims. tional elongation. Leroy et al., Mol. Cell, 2008, 30, 51-60. In addition to acetylated histones, BET proteins have been BRIEF DESCRIPTION OF THE DRAWINGS shown to bind selectively to acetylated transcription factors including the RelA subunit of NF-kB and GATA1 thereby 0008 FIG. 1 shows an XRPD pattern for Compound directly regulating the transcriptional activity of these pro 1-(S) amorphous powder. teins to control expression of genes involved in inflamma 0009 FIG. 2 shows a DSC thermogram for Compound tion and hematopoietic differentiation. Huang et al., Mol. 1-(S) amorphous powder. Cell Biol., 2009, 29, 1375-1387: Lamonica et al., Proc. Nat. (0010 FIG. 3 shows a MIDSC thermogram for Com Acad. Sci., USA, 2011, 108, E159-168. pound 1-(S) amorphous powder. 0003. A recurrent translocation involving NUT (nuclear protein in testes) with BRD3 or BRD4 to form a novel fusion DETAILED DESCRIPTION oncogene, BRD-NUT, is found in a highly malignant form of epithelial neoplasia. French et al., Cancer Res., 2003, 63, Solid Form 304-307; French et al., J. Clin. Oncol., 2004, 22, 4135-4139. Selective ablation of this oncogene restores normal cellular 0011. The present invention provides, inter alia, a solid differentiation and reverses the tumorigenic phenotype. Fil form, which is an amorphous solid, of the BET protein ippakopoulos et al., Nature, 2010, 468, 1068-1073. Genetic inhibiting compound (4S)-7-(3,5-dimethylisoxazol-4-yl)-4- knockdown of BRD2, BRD3 and BRD4 has been shown to pyridin-2-yl-4,5-dihydroimidazo 1.5,4-de(1,4)benzoxazin impair the growth and viability of a wide range of hemato 2(1H)-one (see below), referred to herein as “Compound logical and solid tumor cells. Zuber et al., Nature, 2011, 478, 1-(S). In one embodiment, the solid is an amorphous 524-528: Delmore et al., Cell, 2011, 146, 904-917. Aside powder. An alternative name for the same compound is from a role in cancer, BET proteins regulate inflammatory (3S)-6-(3,5-dimethylisoxazol-4-yl)-3-(pyridin-2-yl)-3,4-di responses to bacterial challenge, and a BRD2 hypomorph hydro-5-oxa-12a-diazaacenaphthylen-2(1H)-one. US 2017/O121347 A1 May 4, 2017 impurity in the amorphous form of the invention is water, Compound 1-(S) which can be present, for example, in an amount of less than N about 5%, less than about 3%, less than about 2%, less, than about 1.5%, less than about 1%, or less than about 0.5%. Na2 0017. The solid form of the invention can be made by initially dissolving Compound 1-(S) in water with the aid of s O a base (e.g., a strong base). While not wishing to be bound by theory, it is believed that the base (e.g., strong base) r ( assists dissolution of Compound 1-(S) by deprotonation of O NH the weakly acidic cyclic urea group. In this way, a Sufficient amount of Compound 1-(S) can be dissolved in aqueous Solution for purification. As used herein, the term “aqueous solution” refers to a solvent system comprised primarily of (N water. In some embodiments, the aqueous Solution is free from organic Substances, such as organic Solvents, with the exception of Compound 1-(S). In some embodiments, the 0012. The amorphous solid form of the invention has aqueous solution may contain acids and/or bases, such as several properties making it particularly Suitable for scale up inorganic acids and/or bases. Additionally, the aqueous and formulation. For example, the solid form of the inven Solution may contain one or more salts or ions, such as tion has good stability with respect to decomposition and inorganic salts or ions.
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