Amorphous solid form of a bet protein inhibitor

Abstract

The present invention relates to an amorphous solid form of (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one, and processes for its preparation, which is an inhibitor of BET proteins such as BRD2, BRD3, BRD4, and BRD-t and is useful in the treatment of various diseases such as cancer.

1 - 34 . (canceled) 
     
     
         35 . A method of treating myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in a patient, comprising administering to the patient a therapeutically effective amount of a solid form of (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one which is an amorphous solid. 
     
     
         36 - 60 . (canceled) 
     
     
         61 . The method of  claim 35  further comprising administering to the patient one or more additional therapeutic agents. 
     
     
         62 . The method of  claim 61 , wherein the solid form of (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one and the one or more additional therapeutic agents are administered sequentially. 
     
     
         63 . The method of  claim 61 , wherein the solid form of (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one and the one or more additional therapeutic agents are administered simultaneously. 
     
     
         64 . The method of  claim 61 , wherein the one or more additional therapeutic agents is selected from chemotherapeutics, anti-inflammatory agents, steroids, immunosuppressants, Bcr-Abl inhibitors, Flt-3 inhibitors, RAF inhibitors, FAK inhibitors, JAK kinase inhibitors, and epigenetic regulators. 
     
     
         65 . The method of  claim 61 , wherein the one or more additional therapeutic agents is a JAK kinase inhibitor. 
     
     
         66 . The method of  claim 65 , wherein the JAK kinase inhibitor is selective for JAK1. 
     
     
         67 . The method of  claim 65 , wherein the JAK kinase inhibitor is selective for JAK1 and JAK2. 
     
     
         68 . The method of  claim 65 , wherein the JAK kinase inhibitor is ruxolitinib. 
     
     
         69 . The method of  claim 61 , wherein the one or more additional therapeutic agents is a chemotherapeutic agent. 
     
     
         70 . The method of  claim 69 , wherein the chemotherapeutic agent is selected from abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate. 
     
     
         71 . The method of  claim 35 , wherein the solid is an amorphous powder. 
     
     
         72 . The method of  claim 35 , wherein the solid has an XRPD pattern substantially as shown in  FIG. 1 . 
     
     
         73 . The method of  claim 35 , wherein the solid has a DSC thermogram characterized by an exothermic peak at about 213° C. 
     
     
         74 . The method of  claim 35 , wherein the solid has a DSC thermogram substantially as shown in  FIG. 2 . 
     
     
         75 . The method of  claim 35 , wherein the solid has a purity greater than about 98%. 
     
     
         76 . The method of  claim 35 , wherein the solid has a purity greater than about 99%.