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.

What is claimed is: 
     
         1 . A solid form of the compound (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. 
     
     
         2 . The solid form of  claim 1  wherein the solid is an amorphous powder. 
     
     
         3 . The solid form of  claim 1  having an XRPD pattern substantially as shown in  FIG.  1   . 
     
     
         4 . The solid form of  claim 1  having a DSC thermogram 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   . 
     
     
         6 . The solid form of  claim 1  having a purity greater than about 98%. 
     
     
         7 . The solid form of  claim 1  having a purity greater than about 99%. 
     
     
         8 . A method for preparing (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 1-(S)) in the form of an amorphous powder comprising precipitating Compound 1-(S) from an aqueous solution comprising Compound 1-(S). 
     
     
         9 . The method of  claim 8  wherein the precipitating comprises acidifying the aqueous solution. 
     
     
         10 . The method of  claim 9  wherein the aqueous solution has a pH of about 10-14. 
     
     
         11 . The method of  claim 9  wherein the aqueous solution has a pH of about 12-13. 
     
     
         12 . The method of  claim 9  wherein the acidifying comprises adding an acid to the aqueous solution. 
     
     
         13 . The method of  claim 12  wherein the acid comprises HCl. 
     
     
         14 . The method of  claim 9  wherein the acidifying results in a final pH of the aqueous solution of about 1-5. 
     
     
         15 . The method of  claim 9  wherein the acidification results in a final pH of the aqueous solution of about 2-4. 
     
     
         16 . A method for preparing (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 1-(S)) in the form of an amorphous powder, comprising:
 a) dissolving Compound 1-(S) in a solvent system comprising water and a base to form a basic aqueous solution; and   b) adding an acid to the basic aqueous solution to precipitate the Compound 1-(S) as an amorphous powder.   
     
     
         17 . The method of  claim 16  wherein the step of adding converts the basic solution to an acidic solution having a pH below about 7. 
     
     
         18 . The method of  claim 16  wherein the base comprises NaOH. 
     
     
         19 . The method of  claim 16  wherein the solvent system comprises water and a base is substantially free of organic solvent. 
     
     
         20 . The method of  claim 16  wherein the basic aqueous solution has a pH of about 12-13. 
     
     
         21 . The method of  claim 16  wherein the acid comprises HCl. 
     
     
         22 . The method of  claim 16  wherein adding the acid lowers the pH of the aqueous solution to about 2-4. 
     
     
         23 . 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 prepared by the method of  claim 8 . 
     
     
         24 . A pharmaceutical composition comprising the solid form of  claim 1  and at least one pharmaceutically acceptable carrier. 
     
     
         25 . A solid oral dosage form comprising the solid form of  claim 1 . 
     
     
         26 . The dosage form of  claim 25  which is in the form of a pill, tablet, or capsule. 
     
     
         27 . A method of inhibiting a BET protein comprising contacting the BET protein with the solid form of  claim 1 . 
     
     
         28 . A method of treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of the solid form of  claim 1 . 
     
     
         29 . A method of treating a solid tumor in a patient, comprising administering to the patient a therapeutically effective amount of the solid form of  claim 1 . 
     
     
         30 . A method of treating colorectal cancer, lung cancer, pancreatic cancer, prostate cancer, or breast cancer in a patient, comprising administering to the patient a therapeutically effective amount of the solid form of  claim 1 . 
     
     
         31 . A method of treating lymphoma in a patient, comprising administering to the patient a therapeutically effective amount of the solid form of  claim 1 . 
     
     
         32 . The method of  claim 31  wherein the lymphoma is diffuse large B-cell lymphoma (DLBCL). 
     
     
         33 . A method of treating leukemia in a patient, comprising administering to the patient a therapeutically effective amount of the solid form of  claim 1 . 
     
     
         34 . The method of  claim 33  wherein the leukemia is acute myeloid leukemia (AML), chronic myeloid leukemia (CML), atypical chronic myeloid leukemia (aCML), or chronic myelomonocytic leukemia (CMML). 
     
     
         35 . A method of treating myelodysplastic syndrome (MDS), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), myelofibrosis (MF), multiple myeloma (MM), or refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T) in a patient, comprising administering to the patient a therapeutically effective amount of the solid form of  claim 1 . 
     
     
         36 . A method of treating NUT midline carcinoma in a patient, comprising administering to the patient a therapeutically effective amount of the solid form of  claim 1 . 
     
     
         37 . The method of  claim 28  further comprising administering to the patient one or more additional therapeutic agents. 
     
     
         38 . A compound wherein the compound is 5-nitro-3-(pyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-ol (Compound 1x) or a salt thereof. 
     
     
         39 . A compound wherein the compound is 7-iodo-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 4x) or a salt thereof. 
     
     
         40 . A method for preparing (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 1-(S)), comprising:
 reacting 7-iodo-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 4x) with (3,5-dimethylisoxazol-4-yl)boronic acid in the presence of a palladium complex to afford 7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 1); and   separating the S enantiomer of Compound 1 using chiral column chromatography to afford Compound 1-(S).   
     
     
         41 . A method for preparing 7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 1), comprising reacting 7-iodo-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 4x) with (3,5-dimethylisoxazol-4-yl)boronic acid in the presence of a palladium complex. 
     
     
         42 . The method of  claim 40  wherein the reacting is carried out in the presence of an aqueous CsF solution and an organic solvent. 
     
     
         43 . The method of  claim 40  wherein the palladium complex is dichlorobis(p-dimethylamino phenylditbutylphosphine)palladium(II). 
     
     
         44 . The method of  claim 43  wherein the organic solvent is n-butanol. 
     
     
         45 . The method of  claim 40  wherein Compound 4x is prepared by reacting 4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 3x) with N-iodosuccinimide. 
     
     
         46 . A method for preparing 7-iodo-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 4x), comprising reacting 4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 3x) with N-iodosuccinimide. 
     
     
         47 . The method of  claim 45  wherein the reacting is carried out in the presence of an organic solvent and an acid. 
     
     
         48 . The method of  claim 47  wherein the organic solvent is N,N-dimethyl-acetamide. 
     
     
         49 . The method of  claim 47  wherein the acid is sulfuric acid. 
     
     
         50 . The method of  claim 49  wherein the amount of sulfuric acid is about 0.1-0.5 molar equivalent of Compound 3x. 
     
     
         51 . The method of  claim 50  wherein the amount of sulfuric acid is about 0.3 molar equivalent of Compound 3x. 
     
     
         52 . The method of  claim 45  wherein Compound 3x is prepared by reacting 3-(pyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-amine (Compound 2x) with N,N-carbonyldiimidazole in the presence of an organic solvent. 
     
     
         53 . The method of  claim 52  wherein the organic solvent is ethyl acetate. 
     
     
         54 . The method of  claim 52  wherein Compound 2x is prepared by reacting 5-nitro-3-(pyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-ol (Compound 1x) with hydrogen in the presence of palladium on carbon and an organic solvent. 
     
     
         55 . The method of  claim 54  wherein the organic solvent is methanol. 
     
     
         56 . The method of  claim 54  wherein Compound 1x is prepared by reacting 2-bromo-1-pyridin-2-ylethanone hydrobromide with 2-amino-nitrophenol in the presence of a base and an organic solvent. 
     
     
         57 . A method for preparing 5-nitro-3-(pyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-ol (Compound 1x), comprising reacting 2-bromo-1-pyridin-2-ylethanone hydrobromide with 2-amino-nitrophenol in the presence of a base and an organic solvent. 
     
     
         58 . The method of  claim 56  wherein the base is K 2 CO 3 . 
     
     
         59 . The method of  claim 56  wherein the organic solvent is acetonitrile. 
     
     
         60 . A method for preparing Compound 1-(S), comprising
 1) reacting 2-bromo-1-pyridin-2-ylethanone hydrobromide with 2-amino-nitrophenol in the presence of a base and an organic solvent to afford 5-nitro-3-(pyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-ol (Compound 1x);   2) reacting Compound 1x with hydrogen in the presence of palladium on carbon and an organic solvent to afford 3-(pyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-amine (Compound 2x);   3) reacting Compound 2x with N,N-carbonyldiimidazole in the presence of an organic solvent to afford 4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 3x);   4) reacting Compound 3x with N-iodosuccinimide to afford 7-iodo-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 4x);   5) reacting Compound 4x with (3,5-dimethylisoxazol-4-yl)boronic acid in the presence of a palladium complex to afford 7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (Compound 1); and   6) separating the S enantiomer of Compound 1 using chiral column chromatography to afford Compound 1-(S).