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. unwanted conversion to crystalline forms as evidenced by 0018. After the Compound 1-(S) is dissolved, the highly stability studies (see Example 5) and a relatively high glass basic solution is acidified, which reduces the solubility of transition temperature (see Example 4). Additionally, the Compound 1-(S) and causes it to precipitate out of the amorphous solid form can be reliably prepared in high aqueous solution into a non-crystalline, homogenous pow purity, with little to no unwanted residual organic solvent. der which is amenable to use in the formulation of drug Residual organic solvent can include any solvents that were products. This process does not require the use of any employed during the synthesis of the Solid form, or residues organic solvents, which is advantageous with respect to or impurities present in the starting materials and reagents. scale up and environmental concerns, as well as resulting in 0013. In some embodiments, the solid form of the inven a drug product substantially free from potentially harmful tion is characterized by an XRPD (X-ray power diffraction) organic residue. pattern substantially as shown in FIG. 1. As can be seen in 0019. In some embodiments, the present invention pro the XRPD pattern, no reflections are observed, indicating a vides a method for preparing (4S)-7-(3,5-dimethylisoxazol homogenous amorphous solid form. The XRPD is obtained 4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo 1.5,4-de(1,4)ben from powder diffractometer with X-ray radiation from cop Zoxazin-2(1H)-one (Compound 1-(S)) in the form of an per at 1.054.056 A with K filter and X-ray power at 30 KV. amorphous powder comprising precipitating Compound 15 mA, and the sample powder was dispersed on a Zero 1-(S) from an aqueous Solution comprising Compound background sample holder (see Example 2). 1-(S). 0014. In some embodiments, the solid form of the inven 0020. The aqueous solution is initially basic, having a pH tion is characterized by a DSC (differential scanning calo greater than 7, such as from about 10-14, about 11-13, or rimetry) thermogram Substantially as shown in FIG. 2. As about 12-13. The aqueous solution can be made basic by the can be seen in FIG. 2, the DSC is characterized by an addition of base, such as a strong base. Examples of bases exothermic peak at about 213° C. which is believed to include NaOH, KOH, LiOH, and CSOH. In some embodi correspond to a decomposition event. In some embodiments, ments, the base is NaOH. Precipitation of Compound 1-(S) the DSC is characterized by an exothermic peak with an is carried out by acidification of the basic aqueous solution onset at about 182° C. The DSC is obtained from TA in which Compound 1-(S) is dissolved. The acidification can Instruments Differential Scanning calorimetry, Model Q200 be carried out by addition of acid, Such as a strong acid. with autosampler (see Example 3). Examples of acids include HCl, HBr, HSO, HPO, meth 0.015. In some embodiments, the solid form of the inven anesulfonic acid (CHSOH), and toluenesulfonic acid (pT tion has a glass transition temperature (Tg) of about 106° C. SOH). In some embodiments, the acid is HC1. Acidification The glass transition temperature is determined by modulated may result in an aqueous Solution having a final pH below DSC (MDSC) using TA Instruments Differential Scanning calorimetry, Model Q2000 with autosampler. 7, such as a pH about 1-5, about 1-4, or about 2-4. 0021. In some embodiments, the present invention pro 0016. The solid form of the invention can be prepared in vides a method for preparing (4S)-7-(3,5-dimethylisoxazol high purity. Purity values presented herein indicate the 4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo 1.5,4-de(1,4)ben percentage of the amount of sample that is e.g., Compound Zoxazin-2(1H)-one (Compound 1-(S)) in the form of an 1-(S) (including stereoisomers thereof). Purity values can be amorphous powder, comprising: determined, for example, by HPLC/UV methods. In some embodiments, the amorphous form of the invention has a 0022 a) dissolving Compound 1-(S) in a solvent system purity greater than about 90%, greater than about 95%, comprising water and a base (e.g., a strong base) to form a greater than about 97%, greater than about 98%, greater than basic aqueous solution; about 98.5%, or greater than about 99%. In some embodi 0023 b) adding an acid (e.g., a strong acid) to the basic ments, the amorphous form of the invention is substantially aqueous solution (e.g., in an amount effective to lower the free of impurities, such as decomposition products and/or pH below about 7) to precipitate the Compound 1-(S) as an residual organic solvent. In some embodiments, the primary amorphous powder. US 2017/O121347 A1 May 4, 2017

0024. In one embodiment, the step of adding converts the 0042. 2) reacting Compound 1X with hydrogen in the basic Solution to an acidic solution having a pH below about presence of palladium on carbon and an organic solvent to 7. afford 3-(pyridin-2-yl)-3,4-dihydro-2H-benzob 14ox 0025. In some embodiments, the base comprises NaOH. azin-5-amine (Compound 2x); 0026. In some embodiments, the solvent system compris 0043. 3) reacting Compound 2x with N,N-carbonyldiimi ing water and a base (e.g., a strong base) is Substantially free dazole in the presence of an organic Solvent to afford of organic solvent. 4-pyridin-2-yl-4,5-dihydroimidazo 1,5,4-de(1,4)benzox 0027. In some embodiments, the solvent system compris azin-2(1H)-one (Compound 3X): ing water and a base (e.g., a strong base) is Substantially free 0044 4) reacting Compound 3x with N-iodosuccinimide of any organic molecules, except for Compound 1-(S) and to afford 7-iodo-4-pyridin-2-yl-4,5-dihydroimidazo 1.5,4- stereoisomers thereof. de 1,4-benzoxazin-2(1H)-one (Compound 4x): 0028. In some embodiments, the basic aqueous solution 0045 5) reacting Compound 4x with (3,5-dimethylisox has a pH of about 10-14. azol-4-yl)boronic acid in the presence of a palladium com 0029. In some embodiments, the basic aqueous solution plex to afford 7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl has a pH of about 12-13. 4,5-dihydroimidazo 1,5,4-de(1,4)benzoxazin-2(1H)-one 0030. In some embodiments, the basic aqueous solution (Compound 1); and is filtered prior to adding an acid (e.g., a strong acid). 0046 6) separating the S enantiomer of Compound 1 0031. In some embodiments, the acid comprises HC1. through chiral column chromatography to afford Compound 1-(S). 0032. In some embodiments, adding the acid lowers the 0047. In step 1, 2-bromo-1-pyridin-2-ylethanone hydro pH of the aqueous solution to a pH of about 1-5. bromide is reacted with 2-amino-nitrophenol in the presence 0033. In some embodiments, adding the acid lowers the of a base and an organic solvent to afford 5-nitro-3-(pyridin pH of the aqueous solution to a pH of about 2-4. 2-yl)-3,4-dihydro-2H-benzob 14oxazin-3-ol (Compound 0034. In some embodiments, the present invention pro 1X). In some embodiments, the present invention also pro vides a solid form of Compound 1-(S) which is prepared by vides a method for preparing 5-nitro-3-(pyridin-2-yl)-3,4- any of the methods described herein. dihydro-2H-benzob 14oxazin-3-ol (Compound 1x), 0035. The present invention also provides a compound, comprising reacting 2-bromo-1-pyridin-2-ylethanone hyd wherein the compound is 5-nitro-3-(pyridin-2-yl)-3,4-di robromide with 2-amino-nitrophenol in the presence of a hydro-2H-benzob 14oxazin-3-ol (Compound 1x) or a base and an organic solvent. In some embodiments, the base salt thereof (e.g., a pharmaceutically acceptable salt thereof). is K2CO3. In some embodiments, the organic solvent is Compound 1X or a salt thereof can be prepared in high acetonitrile. purity. Purity values can be determined, for example, by 0048. In step 2, Compound 1x is reacted with hydrogen HPLC/UV methods. In some embodiments, Compound 1X in the presence of palladium on carbon and an organic or a salt thereof has a purity greater than about 90%, greater solvent to afford Compound 2x. In some embodiments, the than about 95%, greater than about 97%, greater than about Solvent is methanol. 98%, or greater than about 99%. 0049. In step 3, Compound 2x is reacted with N.N- 0036. The present invention also provides a compound, carbonyldiimidazole in the presence of an organic solvent to wherein the compound is 7-iodo-4-pyridin-2-yl-4,5-dihy afford Compound 3X. In some embodiments, the organic droimidazo 1,5,4-de(1,4)benzoxazin-2(1H)-one (Com Solvent is ethyl acetate. pound 4X) or a salt thereof (e.g., a pharmaceutically accept 0050. In step 4, Compound 3X is reacted with N-iodo able salt thereof). Compound 4x or a salt thereof can be succinimide (NIS) to afford Compound 4x. In some embodi prepared in high purity. Purity values can be determined, for ments, the present invention provides a method for prepar example, by HPLC/UV methods. In some embodiments, ing 7-iodo-4-pyridin-2-yl-4,5-dihydroimidazo 1,5,4-de1. Compound 4X or a salt thereof has a purity greater than 4benzoxazin-2(1H)-one (Compound 4X), comprising about 90%, greater than about 95%, greater than about 97%, reacting 4-pyridin-2-yl-4,5-dihydroimidazo 1,5,4-de1.4 greater than about 98%, or greater than about 99%. benzoxazin-2(1H)-one (Compound 3x) with N-iodosuccin 0037. In some embodiment, the present invention also imide (NIS). In some embodiments, the reacting is carried provides a method for preparing Compound 1-(S), compris out in the presence of an organic solvent and an acid. In 1ng: some embodiments, the organic solvent is N,N-dimethyl 0038 reacting 7-iodo-4-pyridin-2-yl-4,5-dihydroimidazo acetamide. In some embodiments, the acid is Sulfuric acid. 1,5,4-de(1,4)benzoxazin-2(1H)-one (Compound 4x) with In some embodiments, the amount of Sulfuric acid is about (3,5-dimethylisoxazol-4-yl)boronic acid to afford 7-(3.5- 0.1-0.5 molar equivalent of Compound 3X. In some embodi dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo ments, the amount of sulfuric acid is about 0.1, about 0.2, 1,5,4-de(1,4)benzoxazin-2(1H)-one (Compound 1) in the about 0.3, about 0.4, or about 0.5 molar equivalent of presence of a palladium complex; and Compound 3X. In some embodiments, the amount of Sulfuric 0039 separating the Senantiomer of Compound 1 using acid is about 0.3 molar equivalent of Compound 3X. chiral column chromatography to afford Compound 1-(S). 0051. Using NIS in step 4 provides certain advantages 0040. The present invention also provides a method for over other halogenation reagents, for example, N-bromo preparing Compound 1-(S), comprising the steps of succinimide (NBS). While not wishing to be bound by 0041 l) reacting 2-bromo-1-pyridin-2-ylethanone hyd theory, NIS is believed to improve the regioselectivity of the robromide with 2-amino-nitrophenol in the presence of a resulting product. For example, if NBS is used in this base and an organic solvent to afford 5-nitro-3-(pyridin-2- electrophilic bromination reaction, the ratio of the desired yl)-3,4-dihydro-2H-benzob 14oxazin-3 -ol (Compound (para-) regioisomer to the undesired (ortho-) regioisomer is 1X): about 5 to 1. By comparison, using NIS in step 4 has an US 2017/O121347 A1 May 4, 2017

improved ratio of about 10 to 1. It is believed that because Solvents. The system may also contain acids and/or bases, NBS is more reactive than NIS, NBS generally provides a Such as inorganic acids and/or bases. lower regioselectivity towards electrophilic halogenation 0057 Compounds described herein also include tauto reaction on the activated aromatic Substrate. Another advan meric forms. Tautomeric forms result from the Swapping of tage of using NIS is that the resulting aryliodide compound a single bond with an adjacent double bond together with the provides a faster and clean Suzuki coupling reaction in the concomitant migration of a proton. Tautomeric forms Subsequent step as compared to e.g., the corresponding include prototropic tautomers which are isomeric protona arylbromo compound. tion states having the same empirical formula and total 0052. In step 5, Compound 4x is reacted with (3.5- charge. Example prototropic tautomers include ketone-enol dimethylisoxazol-4-yl)boronic acid in the presence of a pairs, amide-imidic acid pairs, lactam-lactim pairs, amide palladium complex to afford Compound 1. In some embodi imidic acid pairs, enamine-imine pairs, and annular forms ments, the present invention provides a method for prepar where a proton can occupy two or more positions of a ing 7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihy heterocyclic system, for example, 1H- and 3H-imidazole, droimidazo 1,5,4-de(1,4)benzoxazin-2(1H)-one 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and (Compound 1), comprising reacting 7-iodo-4-pyridin-2-yl 1H- and 2H-pyrazole. Tautomeric forms can be in equilib 4,5-dihydroimidazo 1,5,4-de(1,4)benzoxazin-2(1H)-one rium or sterically locked into one form by appropriate (Compound 4x) with (3,5-dimethylisoxazol-4-yl)boronic substitution. acid in the presence of a palladium complex. In some 0.058 Compounds described herein can also include all embodiments, the reacting is carried out in the presence of isotopes of atoms occurring in the intermediates or final an aqueous CSF solution and an organic solvent. In some compounds. Isotopes include those atoms having the same embodiments, the amount of palladium complex is about atomic number but different mass numbers. Compounds of 0.001-0.010 molar equivalent of Compound 4x. In some the invention can also include all isotopes of atoms occur embodiments, the amount of palladium complex is about ring in the intermediates or final compounds. Isotopes 0.001, about 0.002, about 0.003, about 0.004, about 0.005, include those atoms having the same atomic number but about 0.006, about 0.007, about 0.008, about 0.009, or about different mass numbers. For example, isotopes of hydrogen 0.010 molar equivalent of Compound 4x. In some embodi include tritium and deuterium. One or more constituent ments, the palladium complex is dichlorobis(p-dimethyl atoms of the compounds of the invention can be replaced or amino phenylditbutylphosphine)palladium(II). In some Substituted with isotopes of the atoms in natural or non embodiments, the organic solvent is n-butanol. natural abundance. In some embodiments, the compound 0053. Using (3,5-dimethylisoxazol-4-yl)boronic acid includes at least one deuterium atom. For example, one or instead of the corresponding pinacol ester has certain advan more hydrogen atoms in a compound of the present disclo tages, especially on large Scale processes. For example, sure can be replaced or substituted by deuterium. In some boronic acid is usually more reactive than its pinacol ester embodiments, the compound includes two or more deute and thus, less reaction time; (3,5-dimethylisoxazole)boronic rium atoms. In some embodiments, the compound includes acid is commercially available and economically less expen 1, 2, 3, 4, 5, 6, 7 or 8 deuterium atoms. Synthetic methods sive; the boronic acid is a white solid which is easier to for including isotopes into organic compounds are known in handle (e.g., shipping and charging, etc.). the art. 0059 Substitution with heavier isotopes such as deute 0054. In step 6, Compound 1 is purified through chiral rium, may afford certain therapeutic advantages resulting column chromatography to afford Compound 1-(S). Com from greater metabolic stability, for example, increased in pound 1 in acetonitrile is loaded onto the column, which is Vivo half-life or reduced dosage requirements, and hence eluted with acetonitrile. The chiral purity of the fractions containing Compound 1-(S) is determined by chiral HPLC. may be preferred in Some circumstances. (A. Kerekes et.al. After removal of acetonitrile from the fraction containing J. Med. Chem. 2011, 54, 201-210; R. Xu etal. J. Label Compound 1-(S) to afford a crude Compound 1-(S), the Compa. Radiopharm. 2015, 58, 308-312). sample is further purified by dissolving in methanol and 0060. The term, “compound,” as used herein is meant to loaded onto the same chiral column, which is eluted with include all stereoisomers, geometric isomers, tautomers, and methanol. The desired fraction containing Compound 1-(S) isotopes of the structures depicted. Compounds herein iden is collected and the solvent is removed under reduced tified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless oth pressure to afford Compound 1-(S). erwise specified (e.g., in the case of purine rings, unless 0055 As used herein, the term “organic solvent” refers to otherwise indicated, when the compound name or structure carbon-based solvents (i.e., they contain carbon in their has the 9H tautomer, it is understood that the 7H tautomer structure) that are employed to dissolve or disperse one or is also encompassed). more compounds described herein. Examples of organic 0061 The expressions, “ambient temperature' and Solvents include but not limited to acetone, acetic acid, "room temperature,” as used herein, are understood in the acetonitrile, benzene, carbon tetrachloride, chloroform, dim art, and refer generally to a temperature, e.g., a reaction ethyl sulfoxide, methanol, methyl t-butyl ether, methylene temperature, that is about the temperature of the room in chloride, N,N-dimethylformamide, pentane, ethanol, ethyl which the reaction is carried out, for example, a temperature acetate, hexanes, isopropanol, tetrahydrofuran, and toluene. from about 20° C. to about 30° C. 0056. As used herein, the term “solvent system” refers to 0062 Temperature values in connection with DSC, TGA, a system which comprises one or more solvents. The system or other thermal experiments can vary about +3° C. depend may also contain one or more reagents or starting materials ing on the instrument, particular settings, sample prepara used to prepare a particular compound. In some embodi tion, etc. Accordingly, a Solid form reported herein having a ments, the system may contain primary of water or organic DSC thermogram “substantially as shown in any of the US 2017/O121347 A1 May 4, 2017

Figures is understood to accommodate Such variation. Addi TBS (tert-butyldimethylsilyl); tert (tertiary); tt (triplet of tionally, the recitation of temperature values together with triplets); t-Bu (tert-butyl); TFA (trifluoroacetic acid): THF the term “about for peaks or other events in connection with (tetrahydrofuran); Lug (microgram(s)): LL (microliter(s)): LM a thermogram also accommodates such variation. (micromolar); wt % (weight percent). 0063. The phrase “pharmaceutically acceptable' is employed herein to refer to those compounds, materials, Methods of Use compositions, and/or dosage forms which are, within the 0.066 Compound 1-(S) is a BET protein inhibitor and, Scope of sound medical judgment, Suitable for use in contact thus, is useful in treating and/or preventing diseases and with the tissues of human beings and animals without disorders associated with activity of BET proteins. For excessive toxicity, irritation, allergic response, or other example, Compound 1-(S) can inhibit one or more of BET problem or complication, commensurate with a reasonable proteins BRD2, BRD3, BRD4, and BRD-t. In some embodi benefit/risk ratio. ments, Compound 1-(S) selectively inhibits one or more 0064. The present invention also includes salts (e.g., BET proteins over another. “Selective' means that the pharmaceutically acceptable salts) of the compounds compound binds to or inhibits a BET protein with greater described herein. As used herein, 'salts' refers to derivatives affinity or potency, respectively, compared to a reference, of the disclosed compounds wherein the parent compound is such as another BET protein. modified by converting an existing acid or base moiety to its 0067. The solid form of Compound 1-(S) described salt form. Examples of salts include, but are not limited to, herein is therefore useful for treating and/or preventing mineral or organic acid salts of basic residues such as BET-mediated disorders. The term "BET-mediated disor amines; alkali or organic salts of acidic residues such as der” refers to any disease or condition in which one or more carboxylic acids; and the like. The salts of the present of the BET proteins, such as BRD2, BRD3, BRD4 and/or invention include the conventional non-toxic salts of the BRD-t, or a mutant thereof, plays a role, or where the disease parent compound formed, for example, from non-toxic or condition is associated with expression or activity of one inorganic or organic acids. The salts of the present invention or more of the BET proteins. The solid form of Compound can be synthesized from the parent compound which con 1-(S) described herein can be used to treat or lessen the tains a basic or acidic moiety by conventional chemical severity of diseases and conditions where BET proteins, methods. Generally, Such salts can be prepared by reacting such as BRD2, BRD3, BRD4, and/or BRD-t, or a mutant the free acid or base forms of these compounds with a thereof, are known to play a role. Stoichiometric amount of the appropriate base or acid in 0068 Diseases and conditions treatable and/or prevent water or in an organic solvent, or in a mixture of the two: able using the Solid form provided herein include cancer and generally, non-aqueous media like ether, ethyl acetate, alco other proliferative disorders, autoimmune disease, chronic hols (e.g., methanol, ethanol, iso-propanol, or butanol) or inflammatory diseases, acute inflammatory diseases, sepsis, acetonitrile (MeCN) are preferred. Lists of suitable salts are and viral infection. The diseases can be treated by admin found in Remington's Pharmaceutical Sciences, 17" Ed., istering to an individual (e.g., a patient) in need of the (Mack Publishing Company, Easton, 1985), p. 1418, Berge treatment a therapeutically effective amount or dose of a et al., J. Pharm. Sci., 1977, 66(1), 1-19, and in Stahl et al., solid form of Compound 1-(S) described herein, or any of Handbook of Pharmaceutical Salts. Properties, Selection, the embodiments thereof, or a pharmaceutical composition and Use, (Wiley, 2002). In some embodiments, the com thereof. pounds described herein include the N-oxide forms. 0069. In some embodiments, the present invention pro 0065. The following abbreviations may be used herein: vides a method of inhibiting a BET protein comprising AcOH (acetic acid); AcO (acetic anhydride); aq. (aqueous); contacting the BET protein with the solid form provided atm. (atmosphere(s)): Boc (t-butoxycarbonyl); br (broad); herein. Cbz (carboxybenzyl); calc. (calculated); d (doublet); dd 0070. In some embodiments, the present invention pro (doublet of doublets); DCM (dichloromethane); DEAD (di vides a method of treating cancer in a patient, comprising ethyl azodicarboxylate); DIAD (N,N'-diisopropyl azidodi administering to the patient a therapeutically effective carboxylate); DIPEA (N,N-diisopropylethylamine); DMF amount of the solid form provided herein. The cancers can (N,N-dimethylformamide); Et (ethyl); EtOAc (ethyl include adrenal cancer, acinic cell carcinoma, acoustic neu acetate); g (gram(s)): h (hour(s)): HATU (N.N.N',N'-tetram roma, acral lentiginous melanoma, acrospiroma, acute ethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophos eosinophilic leukemia, acute erythroid leukemia, acute lym phate); HCl (hydrochloric acid); HPLC (high performance phoblastic leukemia, acute megakaryoblastic leukemia, liquid chromatography); HZ (hertz); J (coupling constant); acute monocytic leukemia, acute promyelocytic leukemia, LCMS (liquid chromatography—mass spectrometry); m adenocarcinoma, adenoid cystic carcinoma, adenoma, (multiplet); M (molar); mCPBA (3-chloroperoxybenzoic adenomatoid odontogenic tumor, adenosquamous carci acid); MgSO4 (magnesium Sulfate); MS (Mass spectrom noma, adipose tissue neoplasm, adrenocortical carcinoma, etry); Me (methyl); MeCN (acetonitrile); MeOH (metha adult T-cell leukemia/lymphoma, aggressive NK-cell leuke nol); mg (milligram(s)); min. (minutes(s)); mL (milliliter mia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, (s)); mmol (millimole(s)): N (normal); NaHCO (sodium alveolar soft part sarcoma, ameloblastic fibroma, anaplastic bicarbonate); NaOH (sodium hydroxide); NaSO (sodium large cell lymphoma, anaplastic thyroid cancer, angioimmu sulfate); NHCl (ammonium chloride); NH-OH (ammonium noblastic T-cell lymphoma, angiomyolipoma, angiosar hydroxide); nM (nanomolar); NMR (nuclear magnetic reso coma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell nance spectroscopy); OTf (trifluoromethanesulfonate); Pd chronic lymphocytic leukemia, B-cell prolymphocytic leu (palladium); Ph (phenyl); pM (picomolar); POCl (phospho kemia, B-cell lymphoma, basal cell carcinoma, biliary tract ryl chloride); RP-HPLC (reverse phase high performance cancer, bladder cancer, blastoma, bone cancer, Brenner liquid chromatography); S (singlet); t (triplet or tertiary); tumor, Brown tumor, Burkitt's lymphoma, breast cancer, US 2017/O121347 A1 May 4, 2017

brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, adenocarcinoma, adult T-cell leukemia/lymphoma, bladder cartilage tumor, cementoma, myeloid sarcoma, chondroma, cancer, blastoma, bone cancer, breast cancer, brain cancer, chordoma, choriocarcinoma, choroid plexus papilloma, carcinoma, myeloid sarcoma, cervical cancer, colorectal clear-cell sarcoma of the kidney, craniopharyngioma, cuta cancer, esophageal cancer, gastrointestinal cancer, glioblas neous T-cell lymphoma, cervical cancer, colorectal cancer, toma multiforme, glioma, gallbladder cancer, gastric cancer, Degos disease, desmoplastic Small round cell tumor, diffuse head and neck cancer, Hodgkin’s lymphoma, non-Hodg large B-cell lymphoma, dysembryoplastic neuroepithelial kin's lymphoma, intestinal cancer, kidney cancer, laryngeal tumor, dysgerminoma, embryonal carcinoma, endocrine cancer, leukemia, lung cancer, lymphoma, liver cancer, gland neoplasm, endodermal sinus tumor, enteropathy-as Small cell lung cancer, non-small cell lung cancer, mesothe Sociated T-cell lymphoma, esophageal cancer, fetus in fetu, lioma, multiple myeloma, ocular cancer, optic nerve tumor, fibroma, fibrosarcoma, follicular lymphoma, follicular thy oral cancer, ovarian cancer, pituitary tumor, primary central roid cancer, ganglioneuroma, gastrointestinal cancer, germ nervous system lymphoma, prostate cancer, pancreatic can cell tumor, gestational choriocarcinoma, giant cell fibroblas cer, pharyngeal cancer, renal cell carcinoma, rectal cancer, toma, giant cell tumor of the bone, glial tumor, glioblastoma sarcoma, skin cancer, spinal tumor, Small intestine cancer, multiforme, glioma, gliomatosis cerebri, glucagonoma, stomach cancer, T-cell lymphoma, testicular cancer, thyroid gonadoblastoma, granulosa cell tumor, gynandroblastoma, cancer, throat cancer, urogenital cancer, urothelial carci gallbladder cancer, gastric cancer, hairy cell leukemia, noma, uterine cancer, vaginal cancer, or Wilms tumor. hemangioblastoma, head and neck cancer, hemangiopericy 0071. In some embodiments, the present invention pro toma, hematological malignancy, hepatoblastoma, hepatos vides a method of treating a solid tumor in a patient, plenic T-cell lymphoma, Hodgkin’s lymphoma, non-Hodg comprising administering to the patient a therapeutically kin's lymphoma, invasive lobular carcinoma, intestinal effective amount of the solid form provided herein. cancer, kidney cancer, laryngeal cancer, lentigo maligna, 0072. In some embodiments, the present invention pro lethal midline carcinoma, leukemia, leydig cell tumor, lipos vides a method of treating colorectal cancer, lung cancer, arcoma, lung cancer, lymphangioma, lymphangiosarcoma, pancreatic cancer, prostate cancer, or breast cancer in a lymphoepithelioma, lymphoma, acute lymphocytic leuke patient, comprising administering to the patient a therapeu mia, acute myelogenous leukemia, chronic lymphocytic tically effective amount of the solid form provided herein. leukemia, liver cancer, Small cell lung cancer, non-small cell 0073. In some embodiments, the present invention pro lung cancer, MALT lymphoma, malignant fibrous histiocy vides a method of treating lymphoma in a patient, compris toma, malignant peripheral nerve sheath tumor, malignant ing administering to the patient a therapeutically effective triton tumor, mantle cell lymphoma, marginal Zone B-cell amount of the solid form provided herein. In some embodi lymphoma, mast cell leukemia, mediastinal germ cell tumor, ments, the lymphoma is diffuse large B-cell lymphoma medullary carcinoma of the breast, medullary thyroid can (DLBCL). cer, medulloblastoma, melanoma, meningioma, merkel cell 0074. In some embodiments, the present invention pro cancer, mesothelioma, metastatic urothelial carcinoma, vides a method of treating leukemia in a patient, comprising mixed Mullerian tumor, mucinous tumor, multiple administering to the patient a therapeutically effective myeloma, muscle tissue neoplasm, mycosis fungoides, myx amount of the solid form provided herein. In some embodi oid liposarcoma, myxoma, myxosarcoma, nasopharyngeal ments, the leukemia is acute myeloid leukemia (AML). carcinoma, neurinoma, neuroblastoma, neurofibroma, neu chronic myeloid leukemia (CML), atypical chronic myeloid roma, nodular melanoma, ocular cancer, oligoastrocytoma, leukemia (aCML), or chronic myelomonocytic leukemia oligodendroglioma, oncocytoma, optic nerve sheath menin (CMML). gioma, optic nerve tumor, oral cancer, osteosarcoma, ovar 0075. In some embodiments, the present invention pro ian cancer, Pancoast tumor, papillary thyroid cancer, para vides a method of treating myelodysplastic syndrome ganglioma, pinealoblastoma, pineocytoma, pituicytoma, (MDS), myelodysplastic/myeloproliferative neoplasms pituitary adenoma, pituitary tumor, plasmacytoma, polyem (MDS/MPN), myelofibrosis (MF), multiple myeloma bryoma, precursor T-lymphoblastic lymphoma, primary cen (MM), or refractory anemia with ringed sideroblasts asso tral nervous system lymphoma, primary effusion lymphoma, ciated with marked thrombocytosis (RARS-T) in a patient, primary peritoneal cancer, prostate cancer, pancreatic can comprising administering to the patient a therapeutically cer, pharyngeal cancer, pseudomyxoma peritonei, renal cell effective amount of the solid form provided herein. carcinoma, renal medullary carcinoma, retinoblastoma, 0076. In some embodiments, the present invention pro rhabdomyoma, rhabdomyosarcoma, Richter's transforma vides a method of treating NUT midline carcinoma in a tion, rectal cancer, sarcoma, Schwannomatosis, seminoma, patient, comprising administering to the patient a therapeu Sertoli cell tumor, sex cord-gonadal stromal tumor, signet tically effective amount of the solid form provided herein. ring cell carcinoma, skin cancer, Small blue round cell 0077. The diseases treatable using the solid form pro tumors, Small cell carcinoma, Soft tissue sarcoma, Soma vided herein also include MYC dependent cancers wherein to statinoma, Soot wart, spinal tumor, splenic marginal Zone the cancer is associated with at least one of myc RNA lymphoma, squamous cell carcinoma, synovial sarcoma, expression or MYC protein expression. A patient can be Sezary S disease, Small intestine cancer, squamous carci identified for such treatment by determining myc RNA noma, stomach cancer, T-cell lymphoma, testicular cancer, expression or MYC protein expression in the cancerous thecoma, thyroid cancer, transitional cell carcinoma, throat tissue or cells. cancer, urachal cancer, urogenital cancer, urothelial carci 0078 Diseases that can be treated with the solid form noma, uveal melanoma, uterine cancer, Verrucous carci provided herein also include non-cancerous proliferative noma, visual pathway glioma, Vulvar cancer, vaginal cancer, disorders. Examples of proliferative disorders that can be Waldenstrom's macroglobulinemia, Warthin's tumor, and treated include, but are not limited to, benign soft tissue Wilms tumor. In some embodiments, the cancer can be tumors, bone tumors, brain and spinal tumors, eyelid and US 2017/O121347 A1 May 4, 2017

orbital tumors, granuloma, lipoma, meningioma, multiple acute lung injury, ARDS, acute renal, hepatic, cardiac and endocrine neoplasia, nasal polyps, pituitary tumors, prolac gastro-intestinal injury and mortality. For example, the com tinoma, pseudotumor cerebri, Seborrheic keratoses, stomach pounds of the invention can be administered prior to Surgical polyps, thyroid nodules, cystic neoplasms of the pancreas, or other procedures associated with a high risk of sepsis, hemangiomas, Vocal cord nodules, polyps, and cysts, Castle hemorrhage, extensive tissue damage, SIRS or MODS. man disease, chronic pilonidal disease, dermatofibroma, 0082. Other diseases that can be treated with the solid pilar cyst, pyogenic granuloma, and juvenile polyposis Syn form provided herein include viral infections. Examples of drome. viral infections that can be treated include Epstein-Barr 0079. The diseases and conditions that can be treated virus, hepatitis B virus, hepatitis C virus, herpes virus, with the solid form provided herein also include chronic human immunodeficiency virus, human papilloma virus, autoimmune and inflammatory conditions. Examples of adenovirus, poxvirus and other episome-based DNA viruses. autoimmune and inflammatory conditions that can be treated The compounds can therefore be used to treat disease and include acute, hyperacute or chronic rejection of trans conditions such as herpes simplex infections and reactiva planted organs, acute gout, acute inflammatory responses tions, cold Sores, herpes Zoster infections and reactivations, (such as acute respiratory distress syndrome and ischemia/ chickenpox, shingles, human papilloma virus, cervical neo reperfusion injury). Addison's disease, agammaglobuline plasia, adenovirus infections, including acute respiratory mia, allergic rhinitis, allergy, alopecia, Alzheimer's disease, disease, and poxvirus infections such as cowpox and Small appendicitis, atherosclerosis, asthma, osteoarthritis, juvenile poX and African Swine fever virus. In one particular embodi arthritis, psoriatic arthritis, rheumatoid arthriti, Satopic der ment the solid form provided herein is indicated for the matitis, autoimmune alopecia, autoimmune hemolytic and treatment of human papilloma virus infections of skin or thrombocytopenic states, autoimmune hypopituitarism, cervical epithelia. autoimmune polyglandular disease, Behcet’s disease, bull 0083. The diseases and conditions that can be treated ous skin diseases, cholecystitis, chronic idiopathic throm with the solid form provided herein also include conditions bocytopenic purpura, chronic obstructive pulmonary disease that are associated with ischemia-reperfusion injury. (COPD), cirrhosis, degenerative joint disease, depression, Examples of such conditions include, but are not limited to dermatitis, dermatomyositis, eczema, enteritis, encephalitis, conditions such as myocardial infarction, cerebrovascular gastritis glomerulonephritis, giant cell arteritis, Goodpas ischemia (stroke), acute coronary syndromes, renal reperfu ture's syndrome, Guillain-Barre Syndrome, gingivitis, sion injury, organ transplantation, coronary artery bypass Graves disease, Hashimoto's thyroiditis, hepatitis, hypo grafting, cardio-pulmonary bypass procedures and pulmo physitis, inflammatory bowel disease (Crohn's disease and nary, renal, hepatic, gastro-intestinal or peripheral limb ulcerative colitis), inflammatory pelvic disease, irritable embolism. bowel syndrome, Kawasaki disease, LPS-induced endotoxic I0084. The solid form provided herein is also useful in the shock, meningitis, multiple Sclerosis, myocarditis, myasthe treatment of disorders of lipid metabolism via the regulation nia gravis, mycosis fungoides, myositis, nephritis, osteomy of APO-A1 such as hypercholesterolemia, atherosclerosis elitis, pancreatitis, Parkinson's disease, pericarditis, perni and Alzheimer's disease. cious anemia, pneumonitis, primary biliary Sclerosing I0085. The solid form provided herein can also be used for cholangitis, polyarteritis nodosa, psoriasis, retinitis, Scleritis, the treatment of fibrotic conditions such as idiopathic pull Scleracierma, Scleroderma, sinusitis, Sjogren's disease, sep monary fibrosis, renal fibrosis, post-operative stricture, sis, septic shock, Sunburn, systemic lupus erythematosus, keloid formation, Scleroderma and cardiac fibrosis. tissue graft rejection, thyroiditis, type I diabetes, Takayasu's I0086. The solid form of provided herein can also be used arteritis, urethritis, uveitis, vasculitis, vasculitis including to treat ophthalmological indications such as dry eye. giant cell arteritis, vasculitis with organ involvement such as I0087 As used herein, the term “contacting refers to the glomerulonephritis, vitiligo, Waldenstrom macroglobuline bringing together of indicated moieties in an in vitro system mia and Wegener's granulomatosis. or an in vivo system. For example, "contacting a BET 0080. The diseases and conditions that can be treated protein with a compound described herein (e.g., the Solid with the solid form provided herein also include diseases form provided herein) includes the administration of the and conditions which involve inflammatory responses to compound to an individual or patient, such as a human, infections with bacteria, viruses, fungi, parasites or their having a BET protein, as well as, for example, introducing toxins, such as sepsis, sepsis syndrome, septic shock, endo a compound of the invention into a sample containing a toxaemia, Systemic inflammatory response syndrome cellular or purified preparation containing the BET protein. (SIRS), multi-organ dysfunction syndrome, toxic shock Syn I0088. As used herein, the term “individual” or “patient,” drome, acute lung injury, ARDS (adult respiratory distress used interchangeably, refers to any animal, including mam syndrome), acute renal failure, fulminant hepatitis, burns, mals, preferably mice, rats, other rodents, rabbits, dogs, cats, acute pancreatitis, post-Surgical syndromes, sarcoidosis, Swine, cattle, sheep, horses, or primates, and most preferably Herxheimer reactions, encephalitis, myelitis, meningitis, humans. malaria, SIRS associated with viral infections such as influ I0089. As used herein, the phrase “therapeutically effec enza, herpes Zoster, herpes simplex and coronavirus. tive amount” refers to the amount of active compound or 0081. The diseases for which the solid form provided pharmaceutical agent that elicits the biological or medicinal herein are indicated also include diseases associated with a response that is being sought in a tissue, system, animal, systemic inflammatory response syndrome, such as sepsis, individual or human by a researcher, Veterinarian, medical burns, pancreatitis, major trauma, hemorrhage and ischemia. doctor or other clinician. The solid form provided herein can be administered to (0090. As used herein, the term “treating” or “treatment” reduce the incidence of SIRS, the onset of shock, multi refers to one or more of (1) inhibiting the disease; for organ dysfunction syndrome, which includes the onset of example, inhibiting a disease, condition or disorder in an US 2017/O121347 A1 May 4, 2017 individual who is experiencing or displaying the pathology megestrol acetate, melphalan, mercaptopurine, methotrex or symptomatology of the disease, condition or disorder ate, methoXSalen, mitomycin C, mitotane, mitoxantrone, (i.e., arresting further development of the pathology and/or nandrolone phenpropionate, nelarabine, nofetumomab, oxa symptomatology); and (2) ameliorating the disease; for liplatin, paclitaxel, pamidronate, panitumumab, pegaspar example, ameliorating a disease, condition or disorder in an gase, pegfilgrastim, pemetrexed disodium, pentostatin, pipo individual who is experiencing or displaying the pathology broman, plicamycin, procarbazine, quinacrine, rasburicase, or symptomatology of the disease, condition or disorder rituximab, ruXolitinib, Sorafenib, Streptozocin, Sunitinib, (i.e., reversing the pathology and/or symptomatology) Such Sunitinib maleate, tamoxifen, temozolomide, teniposide, tes as decreasing the severity of disease. tolactone, thalidomide, thioguanine, thiotepa, topotecan, 0091. As used herein, the term “preventing or “preven toremifene, to situmomab, trastuzumab, tretinoin, uracil tion” refers to preventing a disease, condition or disorder in mustard, valrubicin, vinblastine, Vincristine, Vinorelbine, an individual who may be predisposed to the disease, Vorinostat, and Zoledronate. condition or disorder but does not yet experience or display 0.095 For treating autoimmune or inflammatory condi the pathology or symptomatology of the disease. tions, the solid form provided herein can be administered in combination with a corticosteroid such as triamcinolone, Combination Therapies dexamethasone, fluocinolone, cortisone, prednisolone, or 0092. The solid form provided herein can be used in flumetholone. combination treatments where the solid form of Compound 0096. For treating autoimmune or inflammatory condi 1-(S) described herein is administered in conjunction with tions, the solid form provided herein can be administered in other treatments such as the administration of one or more combination with an immune Suppressant such as fluocino additional therapeutic agents. The additional therapeutic lone acetonide (Retisert(R), rimexolone (AL-2178, Vexol, agents are typically those which are normally used to treat Alcon), or cyclosporine (Restasis.(R). the particular condition to be treated. The additional thera 0097. For treating autoimmune or inflammatory condi peutic agents can include, e.g., chemotherapeutics, anti tions, the solid form provided herein can be administered in inflammatory agents, steroids, immunosuppressants, as well combination with one or more additional agents selected as Bcr-Abl, Flt-3, RAF, FAK, and JAK kinase inhibitors for from DehydrexTM (Holles Labs), Civamide (Opko), sodium treatment of BET protein-associated diseases, disorders or hyaluronate (Vismed, Lantibio/TRB Chemedia), conditions. The one or more additional pharmaceutical cyclosporine (ST-603, Sirion Therapeutics), ARG 101(T) agents can be administered to a patient simultaneously or (testosterone, Argentis), AGR1012(P) (Argentis), ecabet sequentially. Sodium (Senju-Ista), gefarnate (Santen), 15-(S)-hydroxyei 0093. In some embodiments, the solid form provided cosatetraenoic acid (15(S)-HETE), cevillemine, doxycycline herein can be used in combination with a therapeutic agent (ALTY-0501, Alacrity), minocycline, iDestrinTM (NP50301, that targets an epigenetic regulator. Examples of epigenetic Nascent Pharmaceuticals), cyclosporine A (Nova22007, regulators include the histone lysine methyltransferases, Novagali), oxytetracycline (Duramycin, MOLI1901, Lan histone arginine methyl transferases, histone demethylases, tibio), CF101 (2S,3S4R,5R)-3,4-dihydroxy-5-6-(3-iodo histone deacetylases, histone acetylases, and DNA methyl phenyl)methylaminolpurin-9-yl)-N-methyl-oxolane-2-car transferases. Histone deacetylase inhibitors include, e.g., bamyl, Can-Fite Biopharma), voclosporin (LX212 or Vorinostat. LX214, Lux Biosciences), ARG103 (Agentis), RX-10045 0094 For treating cancer and other proliferative diseases, (synthetic resolvin analog, Resolvyx), DYN15 (Dyanmis the compounds of the invention can be used in combination Therapeutics), rivoglitazone (DE011, Daiichi Sanko), TB4 with chemotherapeutic agents, or other anti-proliferative (RegeneRx), OPH-01 (Ophtalmis Monaco), PCS101 (Peri agents. The compounds of the invention can also be used in cor Science), REV1-31 (Evolutec), Lacritin (Senju), rebam combination with medical therapy such as Surgery or radio ipide (Otsuka-Novartis), OT-551 (Othera), PAI-2 (Univer therapy, e.g., gamma-radiation, neutron beam radiotherapy, sity of Pennsylvania and Temple University), pilocarpine, electron beam radiotherapy, proton therapy, brachytherapy, tacrolimus, pimecrolimus (AMS981, Novartis), loteprednol and systemic radioactive isotopes. Examples of Suitable etabonate, rituximab, diduafosol tetrasodium (INS365, chemotherapeutic agents include any of abarelix, aldesleu Inspire), KLS-0611 (Kissei Pharmaceuticals), dehydroepi kin, alemtuzumab, alitretinoin, allopurinol, altretamine, androsterone, anakinra, efalizumab, mycophenolate Sodium, anastroZole, arsenic trioxide, asparaginase, azacitidine, etanercept (Embrel(R), hydroxychloroquine, NGX267 (Tor bevacizumab, bexarotene, bleomycin, bortezombi, bort rey Pines Therapeutics), or thalidomide. eZomib, buSulfan intravenous, buSulfan oral, calusterone, 0098. In some embodiments, the solid form provided capecitabine, carboplatin, carmustine, cetuximab, chloram herein can be administered in combination with one or more bucil, cisplatin, cladribine, clofarabine, cyclophosphamide, agents selected from an antibiotic, antiviral, antifungal, cytarabine, dacarbazine, dactinomycin, dalteparin Sodium, anesthetic, anti-inflammatory agents including steroidal and dasatinib, daunorubicin, decitabine, denileukin, denileukin non-steroidal anti-inflammatories, and anti-allergic agents. diftitox, dexraZOxane, docetaxel, doxorubicin, dromo Examples of Suitable medicaments include aminoglycosides stanolone propionate, eculizumab, epirubicin, erlotinib, Such as amikacin, gentamycin, tobramycin, Streptomycin, estramustine, etoposide phosphate, etoposide, exemestane, netilmycin, and kanamycin; fluoroquinolones such as cip filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, rofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxa gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin cin, levofloxacin, and enoxacin, naphthyridine, Sulfona acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, mides; polymyxin; chloramphenicol; neomycin; ifosfamide, imatinib meSylate, interferon alfa 2a, irinotecan, paramomycin; colistimethate; bacitracin; Vancomycin, tet lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leu racyclines; rifampin and its derivatives (“rifampins'); prolide acetate, levamisole, lomustine, meclorethamine, cycloserine; beta-lactams; cephalosporins; amphotericins; US 2017/O121347 A1 May 4, 2017

fluconazole; flucytosine; natamycin; miconazole; ketocon (also known as MK-3475), pidilizumab, SHR-1210, or azole; corticosteroids; diclofenac; flurbiprofen; ketorolac: AMP-224. In some embodiments, the anti-PD-1 monoclonal Suprofen; cromolyn; lodoxamide; levocabastin, naphazo antibody is nivolumab or pembrolizumab. line; antazoline; pheniramine; or azalide antibiotic. (0103. In some embodiments, the inhibitor of an immune 0099. Other examples of agents, one or more of which the checkpoint molecule is an inhibitor of PD-L1, e.g., an solid form provided herein may also be combined with anti-PD-L1 monoclonal antibody. In some embodiments, the include: a treatment for Alzheimer's Disease such as done anti-PD-L1 monoclonal antibody is BMS-935559, pezil and rivastigmine; a treatment for Parkinson's Disease MEDI4736, MPDL3280A (also known as RG7446), or Such as L-DOPA/carbidopa, entacapone, ropinirole, MSB0010718C. In some embodiments, the anti-PD-L1 pramipexole, bromocriptine, pergolide, trihexyphenidyl, and monoclonal antibody is MPDL3280A or MEDI4736. amantadine; an agent for treating multiple Sclerosis (MS) 0104. In some embodiments, the inhibitor of an immune such as beta interferon (e.g., Avonex(R) and RebifR), glati checkpoint molecule is an inhibitor of CTLA-4, e.g., an ramer acetate, and mitoxantrone; a treatment for asthma anti-CTLA-4 antibody. In some embodiments, the anti Such as albuterol and montelukast; an agent for treating CTLA-4 antibody is ipilimumab. Schizophrenia Such as Zyprexa, risperdal, seroquel, and 0105. In some embodiments, the inhibitor of an immune haloperidol; an anti-inflammatory agent such as a corticos checkpoint molecule is an inhibitor of LAG3, e.g., an teroid, such as dexamethasone or prednisone, a TNF blocker, anti-LAG3 antibody. In some embodiments, the anti-LAG3 IL-1 RA, azathioprine, cyclophosphamide, and Sulfasala antibody is BMS-98.6016. Zine; an immunomodulatory agent, including immunosup pressive agents, such as cyclosporin, tacrolimus, rapamycin, Formulation, Dosage Forms, and Administration mycophenolate mofetil, an interferon, a corticosteroid, 0106 When employed as pharmaceuticals, the solid form cyclophosphamide, azathioprine, and SulfaSalazine; a neu provided herein can be administered in the form of phar rotrophic factor Such as an acetylcholinesterase inhibitor, an maceutical compositions. In some embodiments, the present MAO inhibitor, an interferon, an anti-convulsant, an ion invention provides a pharmaceutical composition compris channel blocker, riluzole, or an anti-Parkinson's agent; an ing the solid form provided herein and at least one pharma agent for treating cardiovascular disease such as a beta ceutically acceptable carrier. These compositions can be blocker, an ACE inhibitor, a diuretic, a nitrate, a calcium prepared in a manner well known in the pharmaceutical art, channel blocker, or a statin; an agent for treating liver and can be administered by a variety of routes, depending disease such as a corticosteroid, cholestyramine, an inter upon whether local or systemic treatment is desired and feron, and an anti-viral agent; an agent for treating blood upon the area to be treated. Administration may be topical disorders such as a corticosteroid, an anti-leukemic agent, or (including transdermal, epidermal, ophthalmic and to a growth factor, or an agent for treating immunodeficiency mucous membranes including intranasal, vaginal and rectal disorders such as gamma globulin. delivery), pulmonary (e.g., by inhalation or insufflation of 0100. In some embodiments, the solid form provided powders or aerosols, including by nebulizer, intratracheal or herein can be used in combination with one or more thera intranasal), oral or parenteral. Parenteral administration peutic agents selected from: Janus kinase inhibitors (e.g., includes intravenous, intra-arterial, Subcutaneous, intraperi ruxolitinib, tofacitinib, baricitinib, CYT387, GLPG0634, toneal intramuscular or injection or infusion; or intracranial, lestaurtinib, pacritinib, TG 101348), Pim kinase inhibitors, e.g., intrathecal or intraventricular, administration. Parent PI3 kinase inhibitors (including PI3K-delta selective and eral administration can be in the form of a single bolus dose, broad spectrum PI3K inhibitors). MEK inhibitors, cyclin or may be, for example, by a continuous perfusion pump. dependent kinase inhibitors, b-RAF inhibitors, mTOR Pharmaceutical compositions and formulations for topical inhibitors, proteasome inhibitors (e.g., bortezomib, carfil administration may include transdermal patches, ointments, Zomib), HDAC-inhibitors (e.g., panobinostat, Vorinostat), lotions, creams, gels, drops, Suppositories, sprays, liquids DNA methyl transferase inhibitors, dexamethasone, mel and powders. Conventional pharmaceutical carriers, aque phalan, and immunomodulators such as lenolidomide and ous, powder or oily bases, thickeners and the like may be pomalidomide. In some embodiments, the Janus kinase necessary or desirable. inhibitor is selective for JAK1. In some embodiments, the 0107 This invention also includes pharmaceutical com Janus kinase inhibitor is selective for JAK1 and JAK2. positions which contain, as the active ingredient, the Solid 0101. In some embodiments, the solid form provided form provided herein, in combination with one or more herein can be used in combination with one or more immune pharmaceutically acceptable carriers (excipients). In some checkpoint inhibitors. Exemplary immune checkpoint embodiments, the present invention provides a Solid oral inhibitors include inhibitors against immune checkpoint dosage form comprising the solid form provided herein. In molecules such as CD27, CD28, CD40, CD122, OX40, Some embodiments, the dosage form is in the form of a pill, GITR, CD137, ICOS, A2AR, B7-H3, B7-H4, BTLA, tablet, or capsule. In some embodiments, the composition is CTLA-4, Indoleamine 2,3-dioxygenase (IDO), LAG3, Suitable for topical administration. In making the composi TIM3, VISTA, PD-1, PD-L1 and PD-L2 In some embodi tions of the invention, the active ingredient is typically ments, the solid form provided herein can be used in mixed with an excipient, diluted by an excipient or enclosed combination with one or more agents selected from KIR within Such a carrier in the form of for example, a capsule, inhibitors, TIGIT inhibitors, LAIR 1 inhibitors, CD160 Sachet, paper, or other container. When the excipient serves inhibitors, 2B4 inhibitors and TGFR beta inhibitors. as a diluent, it can be a solid, semi-solid, or liquid material, 0102. In some embodiments, the inhibitor of an immune which acts as a vehicle, carrier or medium for the active checkpoint molecule is an inhibitor of PD-1, e.g., an anti ingredient. Thus, the compositions can be in the form of PD-1 monoclonal antibody. In some embodiments, the anti tablets, pills, powders, lozenges, Sachets, cachets, elixirs, PD-1 monoclonal antibody is nivolumab, pembrolizumab Suspensions, emulsions, Solutions, syrups, aerosols (as a US 2017/O121347 A1 May 4, 2017

Solid or in a liquid medium), ointments containing, for about 30 mg to about 35 mg, about 35 mg to about 40 mg. example, up to 10% by weight of the active compound, soft about 40 mg to about 45 mg, or about 45 mg to about 50 mg and hard gelatin capsules, Suppositories, sterile injectable of Compound 1-(S). Solutions, and sterile packaged powders. 0114. In some embodiments, the compositions of the 0108. The compositions can be formulated as a solution invention contain from about 50 mg to about 500 mg of the or a Suspension. Suitable excipients include methyl cellulose solid form provided herein. One having ordinary skill in the (MC), citrate, and D-O-Tocopherol polyethylene glycol art will appreciate that this embodies Compound 1-(S) and 1000 succinate or Vitamin E polyethylene glycol succinate compositions thereof containing about 50 mg to about 100 (TPGS). In some embodiments, the concentration of Com mg, about 100 mg to about 150 mg, about 150 mg to about pound 1-(S) is from about 0.1-5.0 mg/mL, about 0.5-3.0 200 mg, about 200 mg to about 250 mg, about 250 mg to mg/mL, or about 0.5-2.5 mg/mL. The concentration of about 300 mg, about 350 mg to about 400 mg. or about 450 Compound 1-(S) is about 0.5 mg/mL or about 2.5 mg/mL. mg to about 500 mg of Compound 1-(S). 0109. In some embodiments, the composition is a solu 0.115. In some embodiments, the compositions of the tion, comprising about 0.5 mg/mL of Compound 1-(S) with invention contain from about 500 mg to about 1,000 mg of about 0.5% MC in water. In some embodiments, the com the solid form provided herein. One having ordinary skill in position is a Suspension, comprising about 2.5 mg/mL of the art will appreciate that this embodies Compound 1-(S) Compound 1-(S) with about 0.5% MC in water. In some and compositions thereof containing about 500 mg to about embodiments, the composition is a solution, comprising 550 mg, about 550 mg to about 600 mg, about 600 mg to about 0.5 mg/mL of Compound 1-(S) with about 0.5% MC about 650 mg, about 650 mg to about 700 mg, about 700 mg in about 50 mM citrate. In some embodiments, the compo to about 750 mg, about 750 mg to about 800 mg, about 800 sition is a suspension, comprising about 2.5 mg/mL of mg to about 850 mg, about 850 mg to about 900 mg, about Compound 1-(S) with about 0.5% MC in about 50 mM 900 mg to about 950 mg. or about 950 mg to about 1, 000 citrate. In some embodiments, the composition is a solution, mg of Compound 1-(S). comprising about 2.5 mg/mL of Compound 1-(S) with about 0116. The active compound may be effective over a wide 0% TPGS in about 50 mM citrate. dosage range and is generally administered in a pharmaceu 0110. In preparing a formulation, Compound 1-(S) can be tically effective amount. It will be understood, however, that milled to provide the appropriate particle size prior to the amount of the compound actually administered will combining with the other ingredients. Compound 1-(S) may usually be determined by a physician, according to the be milled using known milling procedures such as wet relevant circumstances, including the condition to be treated, milling to obtain a particle size appropriate for tablet for the chosen route of administration, the actual compound mation and for other formulation types. Finely divided administered, the age, weight, and response of the individual (nanoparticulate) preparations of Compound 1-(S) can be patient, the severity of the patient’s symptoms, and the like. prepared by processes known in the art, e.g., see Interna 0117 For preparing solid compositions such as tablets, tional App. No. WO 2002/000196. Compound 1-(S) is mixed with a pharmaceutical excipient 0111. Some examples of suitable excipients include lac to form a solid preformulation composition containing a tose, dextrose. Sucrose, Sorbitol, mannitol, starches, gum homogeneous mixture of Compound 1-(S). When referring acacia, calcium phosphate, alginates, tragacanth, gelatin, to these preformulation compositions as homogeneous, calcium silicate, microcrystalline cellulose, polyvinylpyr Compound 1-(S) is typically dispersed evenly throughout rolidone, cellulose, water, syrup, and methyl cellulose. The the composition so that the composition can be readily formulations can additionally include: lubricating agents Subdivided into equally effective unit dosage forms such as Such as talc, magnesium Stearate, and mineral oil; wetting tablets, pills and capsules. This solid preformulation is then agents; emulsifying and Suspending agents; preserving subdivided into unit dosage forms of the type described agents such as methyl- and propylhydroxy-benzoates; above containing from, for example, about 0.1 to about 1000 Sweetening agents; and flavoring agents. The compositions mg of Compound 1-(S). of the invention can be formulated so as to provide quick, 0118. The tablets or pills of the present invention can be sustained or delayed release of the active ingredient after coated or otherwise compounded to provide a dosage form administration to the patient by employing procedures affording the advantage of prolonged action. For example, known in the art. the tablet or pill can comprise an inner dosage and an outer 0112 The compositions can be formulated in a unit dosage component, the latter being in the form of an dosage form, each dosage containing from about 5 to about envelope over the former. The two components can be 1,000 mg (1g), more usually about 100 mg to about 500 mg. separated by an enteric layer which serves to resist disinte of the solid form provided herein. The term “unit dosage gration in the stomach and permit the inner component to forms’ refers to physically discrete units suitable as unitary pass intact into the duodenum or to be delayed in release. A dosages for human Subjects and other mammals, each unit variety of materials can be used for such enteric layers or containing a predetermined quantity of active material cal coatings, such materials including a number of polymeric culated to produce the desired therapeutic effect, in associa acids and mixtures of polymeric acids with Such materials as tion with a Suitable pharmaceutical excipient. shellac, cetyl alcohol, and cellulose acetate. 0113. In some embodiments, the compositions of the 0119 The liquid forms in which Compound 1-(S) and invention contain from about 5 mg to about 50 mg of the compositions thereof can be incorporated for administration solid form provided herein. One having ordinary skill in the orally or by injection include aqueous Solutions, Suitably art will appreciate that this embodies Compound 1-(S) and flavored syrups, aqueous or oil Suspensions, and flavored compositions thereof containing about 5 mg to about 10 mg. emulsions with edible oils such as cottonseed oil, Sesame oil, about 10 mg to about 15 mg, about 15 mg to about 20 mg. coconut oil, or peanut oil, as well as elixirs and similar about 20 mg to about 25 mg, about 25 mg to about 30 mg. pharmaceutical vehicles. US 2017/O121347 A1 May 4, 2017

0120 Compositions for inhalation or insufflation include buffer solution containing about 0.1 to about 10% w/v of the Solutions and Suspensions in pharmaceutically acceptable, compound for parenteral administration. Some typical dose aqueous or organic solvents, or mixtures thereof, and pow ranges are from about 1 ug/kg to about 1 g/kg of body weight ders. The liquid or Solid compositions may contain Suitable per day. In some embodiments, the dose range is from about pharmaceutically acceptable excipients as described Supra. 0.01 mg/kg to about 100 mg/kg of body weight per day. The In some embodiments, the compositions are administered by dosage is likely to depend on Such variables as the type and the oral or nasal respiratory route for local or systemic effect. extent of progression of the disease or disorder, the overall Compositions can be nebulized by use of inert gases. Nebu health status of the particular patient, the relative biological lized solutions may be breathed directly from the nebulizing efficacy of the compound selected, formulation of the excipi device or the nebulizing device can be attached to a face ent, and its route of administration. Effective doses can be masks tent, or intermittent positive pressure breathing extrapolated from dose-response curves derived from in machine. Solution, Suspension, or powder compositions can vitro or animal model test systems. be administered orally or nasally from devices which deliver 0.125. The compositions of the invention can further the formulation in an appropriate manner. include one or more additional pharmaceutical agents such 0121 Topical formulations can contain one or more as a chemotherapeutic, Steroid, anti-inflammatory com conventional carriers. In some embodiments, ointments can pound, or immunosuppressant, examples of which are listed contain water and one or more hydrophobic carriers selected hereinabove. from, for example, liquid paraffin, polyoxyethylene alkyl Kits ether, propylene glycol, white Vaseline, and the like. Carrier 0.126 The present invention also includes pharmaceutical compositions of creams can be based on water in combina kits useful, for example, in the treatment or prevention of tion with glycerol and one or more other components, e.g., BET protein-associated diseases or disorders, such as can glycerinemonostearate, PEG-glycerinemonostearate and cer, which include one or more containers containing a cetylstearyl alcohol. Gels can be formulated using isopropyl pharmaceutical composition comprising a therapeutically alcohol and water, suitably in combination with other com effective amount of the solid form provided herein, or any of ponents such as, for example, glycerol, hydroxyethyl cellu the embodiments thereof. Such kits can further include, if lose, and the like. In some embodiments, topical formula desired, one or more of various conventional pharmaceutical tions contain at least about 0.1, at least about 0.25, at least kit components, such as, for example, containers with one or about 0.5, at least about 1, at least about 2, or at least about more pharmaceutically acceptable carriers, additional con 5 wt % of Compound 1-(S). The topical formulations can be tainers, etc., as will be readily apparent to those skilled in the Suitably packaged in tubes of for example, 100 g which are art. Instructions, either as inserts or as labels, indicating optionally associated with instructions for the treatment of quantities of the components to be administered, guidelines the select indication, e.g., psoriasis or other skin condition. for administration, and/or guidelines for mixing the compo 0122) The amount of Compound 1-(S) and compositions nents, can also be included in the kit. thereof administered to a patient will vary depending upon I0127. The invention will be described in greater detail by what is being administered, the purpose of the administra way of specific examples. The following examples are tion, Such as prophylaxis or therapy, the state of the patient, offered for illustrative purposes, and are not intended to limit the manner of administration, and the like. In therapeutic the invention in any manner. Those of skill in the art will applications, compositions can be administered to a patient readily recognize a variety of non-critical parameters which already Suffering from a disease in an amount Sufficient to can be changed or modified to yield essentially the same cure or at least partially arrest the symptoms of the disease results. and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of EXAMPLES the attending clinician depending upon factors such as the Example 1 severity of the disease, the age, weight and general condition Preparation of Amorphous Solid Form of of the patient, and the like. Compound 1-(S) 0123. The compositions administered to a patient can be in the form of pharmaceutical compositions described 0128 above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous Solutions can be packaged for use as is, or lyophilized, the Scheme 1 lyophilized preparation being combined with a sterile aque O ous carrier prior to administration. It will be understood that Br use of certain of the foregoing excipients, carriers, or sta N bilizers will result in the formation of pharmaceutical salts. HBr 0.124. The therapeutic dosage of Compound 1-(S) can 2N vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the ON judgment of the prescribing physician. The proportion or MeCN concentration of Compound 1-(S) in a pharmaceutical com K2CO3 HN step 1 position can vary depending upon a number of factors 2 including dosage, chemical characteristics (e.g., hydropho bicity), and the route of administration. For example, Com OH pound 1-(S) can be provided in an aqueous physiological US 2017/O121347 A1 May 4, 2017 12

-continued -continued O 21 NO H 21 Y-y N N H/10% Pd-C N -- N A, N HO MeOH, <30° C., 16-24 h. N (S) step 2 aq. NaOH O -e- O step 7 1x 21 NH2 2 f H N N O-N N CDI EtOAc, 20-35°C., 1-2 h Compound 1-(S) Step 3 O -- O p Na

2x 21 Y-y O N N N (S) 21 )-y aq. HCI -e- N N NIS, cat. H2SO4 O -e- N DMF/HOAc, 0° C.-rt step 4 a f O O-N 3x (HO)2B

O 2 21 NH f O-N Sa N (1.5 equiv) -e- N Pd-132 (0.5%) CsE (2 equiv) O n-butanol water reflux, 2-3 h I step 5 Compound 1-(S) 4x Amorphous Powder O Preparation of Starting Material 2-bromo-1-pyridin-2-yle 21 )-y thanone hydrobromide N N N purification I0129 Bromine (Br, 198 g. 1240 mmol) dissolved in -- acetic acid (100 mL) was added slowly to a mixture of 1-(pyridin-2-yl)ethanone (150 g, 1238 mmol) in acetic acid O (1500 mL) at rt. The red reaction solution was heated to 105° C. for 1 hour to give an off-white slurry. The mixture was stirred for 1 hour at rt, cooled in a water bath (caution acetic acid freezes), filtered, then the solids were washed with O-N acetic acid (150 mL) and ethyl acetate (250 mL). The solid O was suspended in acetic acid (1500 mL) and heated to 105° C. for 1 h (note: material did not completely dissolve). The 21 )- reaction was allowed to cool to rt in a water bath. The S. N precipitate was filtered, washed with acetic acid 100 mL and N Chiral separation ethyl acetate 300 mL, and dried under house vacuum at rt to -e- give crude 2-bromo-1-pyridin-2-ylethanone hydrobromide step 6 (305 g, 87%) as an off-white powder, which was used in the O Subsequent step without further purification. Step 1: 5-nitro-3-(pyridin-2-yl)-3,4-dihydro-2H-benzob.1, 4-oxazin-3-ol (1x) O-N 0.130) 2-Bromo-1-pyridin-2-ylethanone hydrobromide (135 g, 480 mmol) was suspended in acetonitrile (1700 mL) Compound 1 at rt and potassium carbonate (135 g, 977 mmol) was added. The reaction was stirred for 1 h and then was heated to 60° US 2017/O121347 A1 May 4, 2017

C. and 2-amino-3-nitrophenol (67.5 g., 438 mmol) was with MTBE (20 mL), water (2x25 mL), and MTBE (20 mL). added slowly portionwise as a solid over 30 minutes. The The wet cake was dried on the filter for at least 3 hours, and reaction became a dark red slurry. This mixture was stirred then dried at 20-60° C. under vacuum to afford 4-pyridin at 60° C. for an additional 1 h. The reaction was diluted with 2-yl-4,5-dihydroimidazo 1.5,4-de(1,4)benzoxazin-2(1H water (6500 mL) and stirred vigorously for 1 h to give a )-one (3x, 9.92 g, 89% yield) as off-white solids. "H NMR precipitate. The solids were collected and washed with water (400 MHz, DMSO-d) & 10.91 (s, 1H), 8.51 (d. J=4.1 Hz, and dried to give the product as a dark brown Solid 134 g. 1H), 7.74 (td, J=7.7, 1.8 Hz, 1H), 7.29 (dd, J=6.8, 4.9 Hz, The solid was suspended in ethyl acetate (2500 mL) and 1H), 7.01 (d. J=7.9 Hz, 1H), 6.85 (t, J=8.0 Hz, 1H), 6.67 (d. heated to 75° C. in an oil bath to dissolve the product. To the J=7.7 Hz, 1H), 6.52 (d. J=8.1 Hz, 1H), 5.48 (s, 1H), 4.75 (dd, reaction mixture was added activated charcoal (40 g). The J=11.5, 19 Hz, 1H), 4.39 (dd, J=11.5, 3.1 Hz, 1H) ppm; "C mixture was stirred for 30 minutes and filtered hot through NMR (101 MHz, DMSO-d) 8157.24, 153.53, 150.04, 141. celite to give a yellow-red solution. The solution was 07, 137.90, 128.65, 123.64, 121.75, 121.41, 118.18, 107.10, concentrated in vacuo to give a crystalline residue. This was 103.33, 70.89, 54.55 ppm, C.H.N.O. (MW: 253.26), triturated with ethyl ether, filtered and the solids were LCMS (EI) m/e 254 (M'+H). washed with ethyl ether to give the crude desire product, Step 4. 7-Iodo-4-pyridin-2-yl-4,5-dihydroimidazo 1,5,4-de 5-nitro-3-(pyridin-2-yl)-3,4-dihydro-2H-benzob 14ox 1,4-benzoxazin-2(1H)-one (4x) azin-3-ol (1x, 100 g, 83%) as a yellow orange crystalline I0133) A solution of 4-pyridin-2-yl-4,5-dihydroimidazo1, Solid. The mother liquor was concentrated to give an addi 5,4-de(1,4)benzoxazin-2(1H)-one (3x, 25 g, 0.0987 mole) tional 10.0 g of the crude desired product as a yellow orange in N,N-dimethyl-acetamide (DMF, 300 ml) was stirred at solid. The crude desired product was directly utilized in the 15-30°C. for 15 minutes. N-Iodosuccinimide (NIS, 24.43 g, Subsequent reactions without further purification. 0.1086 mole, 1.10 equiv) was charged to the reaction Step 2. 3-(Pyridin-2-yl)-3,4-dihydro-2H-benzob 14ox mixture and the resulting reaction mixture was stirred at azin-5-amine (2x) 15-30°C. for 12-60 hours until the starting material 4-pyri 0131 A Parr reactor (18 L) was charged with 5-nitro-3- din-2-yl-4,5-dihydroimidazo 1,5,4-de(1,4)benzoxazin-2 (pyridin-2-yl)-3,4-dihydro-2H-benzob 14oxazin-3-ol (1H)-one (3x) was less than 10% by HPLC. Sulfuric acid (1x, 1000 g, 3.918 mol), methanol (7 L) and 10% palladium (H, SO 1.58 mL, 0.003 mole, 0.30 equiv) was then added on carbon (97 g. 50% wet) at ambient temperature. After a while maintaining the batch at 15-30° C. The reaction standard nitrogen purge, the vessel was charged with hydro mixture was stirred at 15-30°C. until starting material (3X) gen (65 psi) and stirred for 16 hours maintaining the internal was less than 2%. The reaction mixture was then cooled to temperature between 20-25°C. The vessel was recharged 5-15° C. before an 1 Naqueous sodium hydroxide (55.3 ml, with hydrogen 8 times. Once the reaction was complete, the 0.0553 mole, 0.56 equiv) solution was added to adjust the vessel was purged again with nitrogen and the resultant dark reaction mixture pH to 4 to 7 while maintaining the reaction solution was filtered through a pad of celite (300 g). The temperature below 35° C. The resulting mixture was con celite filter cake was washed with methanol (6 L) and the tinuing to stir at 15-35°C. for at least 30 minutes and water combined filtrates were concentrated under reduced pres (50 mL) was added at 15-35°C. The resulting mixture was sure. Toluene (8L) was added and evaporated under reduced stirred at ambient temperature until a precipitate was pressure to remove water. The residue was purified over observed. An additional amount of water (250 mL) was silica gel (SiO, Kg), eluting with a gradient of 50 to 100% added to the mixture and the resulting Suspension was stirred ethyl acetate in n-heptane. The solids were triturated with at ambient temperature for at least 1 hour before the solid methyl tent-butyl ether (MTBE, 1 L) and filtered to give the was filtered. The filter cake was washed sequentially with first crop of the desired product (2x, 447 g) as off-white to water (300 mL) and MTBE (175 mL). The wet cake was yellow solids. The filtrates were re-chromatographed and dried on the filter to afford 7-iodo-4-pyridin-2-yl-4,5-dihy triturated with MTBE to give the second crop of the desired droimidazo[1,5,4-de(1,4)benzoxazin-2(1H)-one (4x, 31.4 product (2x, 145 g) as off-white to yellow solids. The total g, 84% yield) as yellow to brown solids. "H NMR (400 amount of desired product (2x) isolated was 592 g (66.5% MHz, DMSO-d) 811.03 (s, 1H), 8.50 (m. 1H), 7.76 (td, yield, 99% purity). H NMR (300 MHz, DMSO-d) 88.60 J=7.7, 1.8 Hz, 1H), 7.31 (dd, J=6.8, 4.9 Hz, 1H), 7.22 (d. 8.56 (m, 1 H).7.83 -7.76 (m, 1 H), 7.5-7.47 (m, 1 H), J=7.9 Hz, 1H), 7.10 (d. J=7.9 HZ, 1H), 6.57 (t, J=8.2 Hz, 7.34-7.29 (m, 1 H), 6.42-6.36 (m, 1 H), 6.28-6.24 (m, 1 H), 1H), 5.51 (s, 1H), 4.86 (dd, J=11.5, 1.8 Hz, 1H), 4.46 (dd. 6.10-6.06 (m, 1 H), 5.15-5.13 (m, 1 H) 4.69 (s. 2 H), J=11.5, 3.1 Hz, 1H) ppm: 'C NMR (101 MHz, DMSO-d) 4.58-4.54 (m. 1 H), 4.29-4.24 (m. 1 H), 4.14-4.08 (m. 1 H): 8.156.85, 153.09, 150.04, 140.99, 138.00, 129.81, 128.78, CHNO (MW: 227.26), LCMS (EI) m/e 228 (M+H). 123.77, 121.59, 118.69, 105.93, 71.85, 70.86, 54.37 ppm; Step 3. 4-Pyridin-2-yl-4,5-dihydroimidazo 1,5,4-de(1.4 CHINO, (MW: 379.15), LCMS (EI) m/e380 (M+H). benzoxazin-2(1H)-one (3x) Step 5. 7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- 0132 A suspension of 3-(pyridin-2-yl)-3,4-dihydro-2H dihydroimidazo 1,5,4-de(1,4)benzoxazin-2(1H)-one benzob 14oxazin-5-amine (2x, 10 g, 0.044 mole, 1.0 (Compound 1) equiv) in ethyl acetate (120 mL) was heated to 40-50° C. and 0.134 1-Butanol (93.5 mL) was degassed by bubbling stirred at 40-50° C. until a solution was obtained. The nitrogen for 5 minutes, then 7-iodo-4-pyridin-2-yl-4,5-dihy resulting solution was gradually cooled down to 15-30° C. droimidazo[1,5,4-de(1,4)benzoxazin-2(1H)-one (4x, 9.74 before N,N-carbonyldiimidazole (CDI, 8.55g, 0.0528 mole, g, 0.026 mol), (3,5-dimethylisoxazol-4-yl)boronic acid 1.2 equiv) was added. The resulting reaction mixture was (4.71 g, 0.033 mole, 1.3 equiv), aqueous CsP solution (10.54 stirred at 15-40° C. for at least 30 minutes and the desired g in 16.6 mL of HO, 0.069 mole, 2.7 equiv) and dichlorobis product (3x) precipitated out during the reaction. When (p-dimethylamino phenylditbutylphosphine)palladium(II) HPLC showed the reaction was complete ((2x)s0.5%), the (Pd-132) (0.091 g, 0.00013 mole, 0.005 equiv) were charged solids were collected by filtration and washed sequentially to the reactor with nitrogen bubbling. The resulting reaction US 2017/O121347 A1 May 4, 2017 mixture was further degassed by bubbling nitrogen for 15 methanol, the pure desired product, (4S)-7-(3,5-dimethyl minutes before it was heated to 85-95° C. and stirred at isoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo 1,5,4-de 85-95° C. for 1-2hour. When HPLC indicated reaction 1,4-benzoxazin-2(1H)-one (Compound 1-(S), 2300 g, completion, the reaction mixture was cooled to 15-30° C. 41.8% for two separations), was obtained as light yellow oil, Then EtOAc (50 mL) and water (35 mL) were added, and which was solidified under vacuum at ambient temperature. the resulting mixture was stirred at ambient temperature for This material was used directly in the Subsequent process 30 minutes. The phases were separated, and the organic steps to manufacture amorphous Compound 1-(S) free base phase was concentrated under vacuum. The residue was drug Substance. transferred to a reactor with EtOAc and treated with an Step 7... (4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl aqueous solution of L-cysteine. The resulting mixture was 4,5-dihydroimidazo 1,5,4-de(1,4)benzoxazin-2(1H)-one heated to 60-70° C. for 1 hour before being gradually cooled (amorphous Compound 1-(S)) to 15-30°C. The two phases were separated and the organic phase was filtered through celite. The filter cake was washed 0.136. A suspension of (4S)-7-(3,5-dimethylisoxazol-4- with EtOAc. The organic phase was transferred to the yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de(1,4)benzo reactor mixture with an additional amount of aqueous L-cys Xazin-2(1H)-one (Compound 1-(S), 42.86 g., 0.123 mole) in teine solution and the resulting mixture was heated to 60-70° water (429 mL) was cooled to 0-5°C. A 1 Maqueous NaOH C. for 1 hour before being cooled down to 15-30°C. The two solution (123 mL, 0.123 mole, 1.0 equiv) was then added to phases were separated; the organic phase was filtered the Suspension while maintaining the internal temperature at through celite and the filter cake was washed with EtOAc. 0-5° C. The reaction mixture (at pH 12-13) was then The organic phase was then washed with water and concen gradually warmed to 10-25°C. and stirred at 10-25°C. until trated to afford 7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2- a clear Solution was obtained. The Solution was polish yl-4,5-dihydroimidazo 1.5,4-de(1,4)benzoxazin-2(1H)-one filtered, and rinsed through the filter with a 0.25 M aqueous (Compound 1, 8.95 g, 98.8% yield) as yellow to brown NaOH solution (20 mL, 0.005 mole, 0.04 equiv). The solids. "H NMR (400 MHz, DMSO-d) 811.00 (s, 1H), 8.49 filtered solution was then cooled to 0-5° C. before being (m. 1H), 7.76 (td, J=7.7, 1.8 Hz, 1H), 7.29 (ddd, J=7.5, 4.8, treated with an 1 M aqueous HCl solution (128 mL, 0.128 0.9 Hz, 1H), 7.11 (d. J=8.0 Hz, 1H), 6.79 (m, 2H), 5.52 (t, mole, 1.04 equiv) at 0-5°C. The final pH of the reaction J=2.3 Hz, 1H), 4.76 (dd, J=11.4, 2.0 Hz, 1H), 4.43 (dd. mixture was 2-4. The solid product was gradually precipi J=11.4, 3.1 Hz, 1H), 2.20 (s, 3H), 2.03 (s, 3H) ppm: 'C tated out during acidification and the resulting Suspension NMR (101 MHz, DMSO-d) 8166. 13, 159.55, 157.12, 153. was gradually warmed to ambient temperature and stirred at 56, 149.97, 138.81, 137.90, 128.45, 123.70, 123.31, 121.56, ambient temperature for 1-2 hours. The solid was collected 118.66, 112.14, 108.91, 103.56, 71.07, 54.37, 11.98, 10.90 by filtration and washed sequentially with purified water and ppm, CHNO (MW: 348.36), LCMS (EI) m/e 349 n-heptane. The wet cake was dried by pulling vacuum on the (M+H). filter for 3-10 hours and further dried under vacuum at Step 6. (4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl 30-40° C. to afford (4S)-7-(3,5-dimethylisoxazol-4-yl)-4- pyridin-2-yl-4,5-dihydroimidazo 1.5,4-de(1,4)benzoxazin 4,5-dihydroimidazo 1,5,4-de(1,4)benzoxazin-2(1H)-one 2(1H)-one (amorphous Compound 1-(S), 38.8 g. 90.6% (Compound 1-(S)) yield) as white to off-white amorphous powder. "H NMR 0135) In an 8x50 mm Simulated Moving Bed (SMB) (400 MHz, DMSO-d) 811.00 (s, 1H), 8.49 (m. 1H), 7.76 separation unit, the columns packed with 20-micron Chiral (td, J=7.7, 1.8 Hz, 1H), 7.29 (ddd, J-7.5, 4.8, 0.9 Hz, 1H), pak AS chiral stationary phase (CSP) were installed. The 7.11 (d. J=8.0 Hz, 1H), 6.79 (m, 2H), 5.52 (t, J=2.3 Hz, 1H), columns and the SMB system were then flushed with 4.76 (dd, J=11.4, 2.0 Hz, 1H), 4.43 (dd, J=11.4, 3.1 Hz, 1H), acetonitrile. A solution of 7-(3,5-dimethylisoxazol-4-yl)-4- 2.20 (s, 3H), 2.03 (s, 3H) ppm; "C NMR (101 MHz, pyridin-2-yl-4,5-dihydroimidazo 1.5,4-de(1,4)benzoxazin DMSO-d) 8166.13, 159.55, 157.12, 153.56, 149.97, 138. 2(1H)-one (Compound 1, 5500 g) in acetonitrile was then 81,137.90, 128.45, 123.70, 123.31, 121.56, 118.66, 112.14, loaded onto the chiral columns installed in the SMB unit. 108.91, 103.56, 71.07, 54.37, 11.98, 10.90 ppm; The chiral columns were then eluted with acetonitrile. The fractions containing the desired Compound 1-(S) and meet CHNO (MW: 348.36), LCMS (EI) m/e 349 (M+H). ing the chiral purity criterion as determined by chiral HPLC were collected and combined for concentration under Example 2 reduced pressure. After removal of acetonitrile, the crude desired product, (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyri X-Ray Powder Diffraction (XRPD) of Amorphous din-2-yl-4,5-dihydroimidazo 1,5,4-de(1,4)benzoxazin-2 Compound 1-(S) (1H)-one (Compound 1-(S), 2500 g, 45.5%) was obtained for further purification. The fractions containing the unde 0.137 Amorphous Compound 1-(S) was characterized by sired (R)-enantiomer as determined by chiral HPLC, were XRPD. The X-Ray Power Diffraction (XRPD) was obtained collected and combined for concentration under reduced from Rigaku MiniFlex X-ray Powder Diffractometer pressure to afford the crude undesired product, for other use. (XRPD). The general experimental procedures for XRPD The crude Compound 1-(S) obtained from the chiral sepa were: (1) X-ray radiation from copper at 1.054.056 A with ration was then dissolved in methanol and the resulting K filter; (2) X-ray power at 30 KV, 15 mA; and (3) the methanol solution was loaded onto the same chiral columns sample powder was dispersed on a Zero-background sample installed in the same SMB unit. The chiral columns were holder. The general measurement conditions for XRPD eluted with methanol. The fractions containing the desired were: Start Angle 3 degrees; Stop Angle 45 degrees; Sam product and meeting the chemical purity criterion as deter pling 0.02 degrees; and Scan speed 2 degree/min. The mined by HPLC and chiral HPLC were collected, combined XRPD pattern displays an amorphous halo as shown in FIG. for concentration under reduced pressure. After removal 1. US 2017/O121347 A1 May 4, 2017

Example 3 TABLE 1. Water Purity Purity Differential Scanning Calorimetry (DSC) of Time content 220 nm 254 nm Solid Form Amorphous Compound 1-(S) Conditions (weeks) (%) (%) (%) (XRPD) 50° C. O 1.67 98.22 97.10 Amorphous 0138 Amorphous Compound 1-(S) was characterized by Open vial 1 O.69 98.12 97.11 Not measured DSC. The DSC was obtained from TA Instruments Differ 2 O43 98.23 97.11 Amorphous ential Scanning calorimetry, Model Q200 with autosampler. 40° C.;75% RH O 1.67 98.22 97.10 Amorphous The DSC instrument conditions were as follows: 30-350° C. Open vial 1 3.39 98.22 97.10 Not measured at 10°C/min: Tzero aluminum sample pan and lid; and 2 2.64 98.18 97.10 Amorphous nitrogen gas flow at 50 mL/min. The DSC thermogram is shown in FIG. 2. The DSC thermogram revealed one exo thermic event at an onset temperature of 181.7°C. with a Example 6 peak temperature of 213.4° C. which corresponds to the decomposition of the compound. The endothermic event Formulation of Amorphous Compound 1-(S) below 100° C. is believed to be due to dehydration. No 0144. Amorphous Compound 1-(S) was formulated as melting point was observed due to the amorphous nature of described in the table below. Table 2 indicates the target the compound. concentration, final pH, solubility, and Some observation of the resulting formulations. Example 4 TABLE 2 Determination of Glass Transition Temperature of Target Amorphous Compound 1-(S) Concentration Final Solubility Vehicle (mg/mL) pH (mg/mL) Observations 0.139. The glass transition temperature (Tg) was deter 0.5% MC in water O.S 6.76 >O.S Solution mined to be 105.8° C. by modulated DSC (MDSC) using TA 2.5 7.87 O.842 Suspension O.S90 MC in O.S 3.00 >O.S Solution Instruments Differential Scanning calorimetry, Model 50 mM citrate, pH 2.5 3.03 1.15 Suspension Q2000 with autosampler. The MDSC instrument conditions 3.0 were as follows: modulation temperature amplitude: +1°C.; 10% TPGS in 2.5 3.07 >2.5 Solution modulation: 60 second; ramp rate: 2° C./min: temperature 50 mM citrate, pH range: 10-150° C.: Tzero aluminum sample pan and lid; and 3.0 nitrogen gas flow at 50 mL/min. The MDSC thermogram is MC = methyl cellulose; shown in FIG. 3. TPGS = D-O-tocopherol polyethylene glycol 1000 succinate or Vitamin E polyethylene glycol succinate, Example 5 (0145 Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications Stability of Amorphous Compound 1-(S) are also intended to fall within the scope of the appended claims. Each reference cited in the present disclosure, 0140. Amorphous Compound 1-(S) has been found to be including all patent, patent applications, and publications, is physically stable under elevated temperature and humidity. incorporated herein by reference in its entirety. Table 1 indicates the conditions/time to which the amor What is claimed is: phous form was subjected and provides the measured water 1. A solid form of the compound (4S)-7-(3,5-dimethyl content (Karl-Fischer analysis) and purity (by HPLC/UV). isoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo 1,5,4-de The HPLC/UV instrument was Agilent HPLC 1100 with an 1,4-benzoxazin-2(1H)-one which is an amorphous Solid. Agilent Zorbax SB-C18, 3.5um, 4.6x150 mm column. The 2. The solid form of claim 1 wherein the solid is an HPLC conditions were as follows: column temperature: 40 amorphous powder. C.; mobile phase A (MPA): 0.05% (v/v) trifluoroacetic acid 3. The solid form of claim 1 having an XRFD pattern (TFA) in water; mobile phase B (MPB): 0.05% (v/v) TFA in substantially as shown in FIG. 1. acetonitrile; and flow rate: 1 mL/min. 4. The solid form of claim 1 having a DSC thermogram 0141. The gradient conditions were as follows: characterized by an exothermic peak at about 213° C. 5. The solid form of claim 1 having a DSC thermogram substantially as shown in FIG. 2. Time (minute) % MPA % MPB 6. The solid form of claim 1 having a purity greater than about 98%. O 67 23 2O 67 23 7. The solid form of claim 1 having a purity greater than 25 2O 8O about 99%. 25.1 67 23 8. A method for preparing (4S)-7-(3,5-dimethylisoxazol 30 67 23 4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo 1.5,4-de(1,4)ben Zoxazin-2(1H)-one (Compound 1-(S)) in the form of an amorphous powder comprising precipitating Compound 0142. Injection: 5 LL 1-(S) from an aqueous Solution comprising Compound 0143 Detection: UV 220 nm, 254 nm. 1-(S). US 2017/O121347 A1 May 4, 2017

9. The method of claim 8 wherein the precipitating 33. A method of treating leukemia in a patient, comprising comprises acidifying the aqueous Solution. administering to the patient a therapeutically effective 10. The method of claim 9 wherein the aqueous solution amount of the solid form of claim 1. has a pH of about 10-14. 34. The method of claim 33 wherein the leukemia is acute 11. The method of claim 9 wherein the aqueous solution myeloid leukemia (AML), chronic myeloid leukemia has a pH of about 12-13. (CML), atypical chronic myeloid leukemia (aCML), or 12. The method of claim 9 wherein the acidifying com chronic myelomonocytic leukemia (CMML). prises adding an acid to the aqueous solution. 35. A method of treating myelodysplastic syndrome 13. The method of claim 12 wherein the acid comprises (MDS), myelodysplastic/myeloproliferative neoplasms HC1. (MDS/MPN), myelofibrosis (MF), multiple myeloma 14. The method of claim 9 wherein the acidifying results (MM), or refractory anemia with ringed sideroblasts asso in a final pH of the aqueous solution of about 1-5. ciated with marked thrombocytosis (RARS-T) in a patient, 15. The method of claim 9 wherein the acidification comprising administering to the patient a therapeutically results in a final pH of the aqueous Solution of about 2-4. effective amount of the solid form of claim 1. 16. A method for preparing (4S)-7-(3,5-dimethylisoxazol 36. A method of treating NUT midline carcinoma in a 4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo 1.5,4-de(1,4)ben patient, comprising administering to the patient a therapeu Zoxazin-2(1H)-one (Compound 1-(S)) in the form of an tically effective amount of the solid form of claim 1. amorphous powder, comprising: 37. The method of claim 28 further comprising adminis a) dissolving Compound 1-(S) in a solvent system com tering to the patient one or more additional therapeutic prising water and a base to form a basic aqueous agents. Solution; and b) adding an acid to the basic aqueous solution to pre 38. A compound wherein the compound is 5-nitro-3- cipitate the Compound 1-(S) as an amorphous powder. (pyridin-2-yl)-3,4-dihydro-2H-benzob 14oxazin-3-ol 17. The method of claim 16 wherein the step of adding (Compound 1x) or a salt thereof. converts the basic solution to an acidic solution having a pH 39. A compound wherein the compound is 7-iodo-4- below about 7. pyridin-2-yl-4,5-dihydroimidazo 1.5,4-de(1,4)benzoxazin 18. The method of claim 16 wherein the base comprises 2(1H)-one (Compound 4x) or a salt thereof. NaOH. 40. A method for preparing (4S)-7-(3,5-dimethylisoxazol 19. The method of claim 16 wherein the solvent system 4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo 1.5,4-de(1,4)ben comprises water and a base is substantially free of organic Zoxazin-2(1H)-one (Compound 1-(S)), comprising: solvent. reacting 7-iodo-4-pyridin-2-yl-4,5-dihydroimidazo 1.5.4- 20. The method of claim 16 wherein the basic aqueous de 1,4-benzoxazin-2(1H)-one (Compound 4x) with solution has a pH of about 12-13. (3,5-dimethylisoxazol-4-yl)boronic acid in the pres 21. The method of claim 16 wherein the acid comprises ence of a palladium complex to afford 7-(3.5 -dimeth HC1. ylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazol, 22. The method of claim 16 wherein adding the acid 5,4-de(1,4)benzoxazin-2(1H)-one (Compound 1); and lowers the pH of the aqueous solution to about 2-4. separating the Senantiomer of Compound 1 using chiral 23. A solid form of (4S)-7-(3,5-dimethylisoxazol-4-yl)-4- column chromatography to afford Compound 1-(S). pyridin-2-yl-4,5-dihydroimidazo 1.5,4-de(1,4)benzoxazin 41. A method for preparing 7-(3,5-dimethylisoxazol-4- 2(1H)-one prepared by the method of claim 8. yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de(1,4)benzo 24. A pharmaceutical composition comprising the Solid Xazin-2(1H)-one (Compound 1), comprising reacting form of claim 1 and at least one pharmaceutically acceptable 7-iodo-4-pyridin-2-yl-4,5-dihydroimidazo 1.5,4-de1.4 carrier. benzoxazin-2(1H)-one (Compound 4x) with (3,5-dimethyl 25. A solid oral dosage form comprising the solid form of isoxazol-4-yl)boronic acid in the presence of a palladium claim 1. complex. 26. The dosage form of claim 25 which is in the form of 42. The method of claim 40 wherein the reacting is carried a pill, tablet, or capsule. out in the presence of an aqueous CSF solution and an 27. A method of inhibiting a BET protein comprising organic solvent. contacting the BET protein with the solid form of claim 1. 43. The method of claim 40 wherein the palladium 28. A method of treating cancer in a patient, comprising complex is dichlorobis(p-dimethylamino phenylditbutyl administering to the patient a therapeutically effective phosphine)palladium(II). amount of the solid form of claim 1. 44. The method of claim 43 wherein the organic solvent 29. A method of treating a solid tumor in a patient, is n-butanol. comprising administering to the patient a therapeutically 45. The method of claim 40 wherein Compound 4x is effective amount of the solid form of claim 1. prepared by reacting 4-pyridin-2-yl-4,5-dihydroimidazol, 30. A method of treating colorectal cancer, lung cancer, 5,4-de(1,4)benzoxazin-2(1H)-one (Compound 3X) with pancreatic cancer, prostate cancer, or breast cancer in a N-iodosuccinimide. patient, comprising administering to the patient a therapeu 46. A method for preparing 7-iodo-4-pyridin-2-yl-4,5- tically effective amount of the solid form of claim 1. dihydroimidazo 1,5,4-de(1,4)benzoxazin-2(1H)-one 31. A method of treating lymphoma in a patient, com (Compound 4x), comprising reacting 4-pyridin-2-yl-4,5- prising administering to the patient a therapeutically effec dihydroimidazo 1,5,4-de(1,4)benzoxazin-2(1H)-one tive amount of the solid form of claim 1. (Compound 3X) with N-iodosuccinimide. 32. The method of claim 31 wherein the lymphoma is 47. The method of claim 45 wherein the reacting is carried diffuse large B-cell lymphoma (DLBCL). out in the presence of an organic solvent and an acid. US 2017/O121347 A1 May 4, 2017

48. The method of claim 47 wherein the organic solvent 59. The method of claim 56 wherein the organic solvent is N,N-dimethyl-acetamide. is acetonitrile. 49. The method of claim 47 wherein the acid is sulfuric acid. 60. A method for preparing Compound 1-(S), comprising 50. The method of claim 49 wherein the amount of 1) reacting 2-bromo-1-pyridin-2-ylethanone hydrobro Sulfuric acid is about 0.1-0.5 molar equivalent of Compound mide with 2-amino-nitrophenol in the presence of a 3X. base and an organic solvent to afford 5-nitro-3-(pyri 51. The method of claim 50 wherein the amount of din-2-yl)-3,4-dihydro-2H-benzob 14oxazin-3-ol sulfuric acid is about 0.3 molar equivalent of Compound 3x. (Compound 1X): 52. The method of claim 45 wherein Compound 3x is prepared by reacting 3-(pyridin-2-yl)-3,4-dihydro-2H-benzo 2) reacting Compound 1X with hydrogen in the presence b1.4loxazin-5-amine (Compound 2x) with N.N-carbonyl of palladium on carbon and an organic solvent to afford diimidazole in the presence of an organic solvent. 3-(pyridin-2-yl)-3,4-dihydro-2H-benzob 14oxazin 53. The method of claim 52 wherein the organic solvent 5-amine (Compound 2x): is ethyl acetate. 3) reacting Compound 2x with N.N-carbonyldiimidazole 54. The method of claim 52 wherein Compound 2x is in the presence of an organic solvent to afford 4-pyri prepared by reacting 5-nitro-3-(pyridin-2-yl)-3,4-dihydro din-2-yl-4,5-dihydroimidazo[1,5,4-de(1,4)benzox 2H-benzob.1,4-oxazin-3-ol (Compound 1x) with hydro azin-2(1H)-one (Compound 3x); gen in the presence of palladium on carbon and an organic solvent. 4) reacting Compound 3x with N-iodosuccinimide to 55. The method of claim 54 wherein the organic solvent afford 7-iodo-4-pyridin-2-yl-4,5-dihydroimidazo 1.5, is methanol. 4-de(1,4)benzoxazin-2(1H)-one (Compound 4x): 56. The method of claim 54 wherein Compound 1x is 5) reacting Compound 4x with (3,5-dimethylisoxazol-4- prepared by reacting 2-bromo-1-pyridin-2-ylethanone hyd yl)boronic acid in the presence of a palladium complex robromide with 2-amino-nitrophenol in the presence of a to afford 7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl base and an organic solvent. 4.5-dihydroimidazo[1,5,4-de(1,4)benzoxazin-2(1H)- 57. A method for preparing 5-nitro-3-(pyridin-2-yl)-3,4- one (Compound 1); and dihydro-2H-benzob.1,4-oxazin-3-ol (Compound 1x), comprising reacting 2-bromo-1-pyridin-2-ylethanone hyd 6) separating the S enantiomer of Compound 1 using robromide with 2-amino-nitrophenol in the presence of a chiral column chromatography to afford Compound base and an organic solvent. 1-(S). 58. The method of claim 56 wherein the base is KCO,