METHODS OF SYNTHESIZING SUBSTITUTED PURINE COMPOUNDS
The present invention provides an efficient process for the synthesis of (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol and hydrates thereof and methods for treating disorders in which DOT1-mediated protein methylation plays a part, such as cancer and neurological disorders, by administering these compounds and pharmaceutical compositions to subjects in need thereof. The present invention also provides novel crystalline forms of (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol and hydrates thereof (Form A, Form B, and Form C), characterized by a unique X-ray diffraction pattern and Differential Scanning Calorimetry profile, as well as a unique crystalline structure.
1 - 5 . (canceled)
6 . A method of treating or preventing cancer comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline form of (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl) (isopropyl)amino)methyl) tetrahydrofuran-3,4-diol:
or a pharmaceutically acceptable salt or solvate thereof, wherein the crystalline form is characterized by an XRPD pattern comprising at least four peaks selected from the group consisting of about 16.5, 20.5, 5.2, 14.2, 18.0, 10.4, 12.3, 10.0, 22.7, and 20.9°2θ using Cu Kα radiation.
7 . The method of claim 6 , wherein the crystalline form is characterized by an XRPD pattern comprising at least five peaks selected from the group consisting of about 16.5, 20.5, 5.2, 14.2, 18.0, 10.4, 12.3, 10.0, 22.7, and 20.9°2θ using Cu Kα radiation.
8 . The method of claim 6 , wherein the crystalline form is characterized by an XRPD pattern comprising at least six peaks selected from the group consisting of about 16.5, 20.5, 5.2, 14.2, 18.0, 10.4, 12.3, 10.0, 22.7, and 20.9°2θ using Cu Kα radiation.
9 - 11 . (canceled)
12 . The method of claim 6 , wherein the crystalline form is characterized by an XRPD pattern comprising peaks at about 16.5, 20.5, 5.2, 14.2, 18.0, 10.4, 12.3, 10.0, 22.7, and 20.9°θ2 using Cu Kα radiation.
13 - 16 . (canceled)
17 . A method of treating or preventing cancer comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline form of (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl) (isopropyl)amino)methyl) tetrahydrofuran-3,4-diol:
or a pharmaceutically acceptable salt or solvate thereof, wherein the crystalline form is characterized by an XRPD pattern comprising at least four peaks selected from the group consisting of about 5.5, 16.9, 16.6, 18.8, 14.3, 12.7, 21.8, 20.0, 10.0, and 11.0°2θ using Cu K radiation.
18 . The method of claim 17 , wherein the crystalline form is characterized by an XRPD pattern comprising at least five peaks selected from the group consisting of about 5.5, 16.9, 16.6, 18.8, 14.3, 12.7, 21.8, 20.0, 10.0, and 11.0°2θ using Cu Kα radiation.
19 . The method of claim 17 , wherein the crystalline form is characterized by an XRPD pattern comprising at least six peaks selected from the group consisting of about 5.5, 16.9, 16.6, 18.8, 14.3, 12.7, 21.8, 20.0, 10.0, and 11.0°θ2 using Cu Kα radiation.
20 - 22 . (canceled)
23 . The method of claim 17 , wherein the crystalline form is characterized by an XRPD pattern comprising peaks at about 5.5, 16.9, 16.6, 18.8, 14.3, 12.7, 21.8, 20.0, 10.0, and 11.0°2θ using Cu Kα radiation.
24 - 27 . (canceled)
28 . A method of treating or preventing cancer comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline form of (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl) (isopropyl)amino)methyl) tetrahydrofuran-3,4-diol:
or a pharmaceutically acceptable salt or solvate thereof, wherein the crystalline form is characterized by an XRPD pattern comprising at least four peaks selected from the group consisting of about 16.9, 5.7, 14.5, 22.2, 19.1, 20.0, 11.3, 12.9, 10.0, and 23.7°2θ using Cu K radiation.
29 . The method of claim 28 , wherein the crystalline form is characterized by an XRPD pattern comprising at least five peaks selected from the group consisting of about 16.9, 5.7, 14.5, 22.2, 19.1, 20.0, 11.3, 12.9, 10.0, and 23.7°2θ using Cu Kα radiation.
30 . The method of claim 28 , wherein the crystalline form is characterized by an XRPD pattern comprising at least six peaks selected from the group consisting of about 16.9, 5.7, 14.5, 22.2, 19.1, 20.0, 11.3, 12.9, 10.0, and 23.7°θ2 using Cu Kα radiation.
31 - 33 . (canceled)
34 . The method of claim 28 , wherein the crystalline form is characterized by an XRPD pattern comprising peaks at about 16.9, 5.7, 14.5, 22.2, 19.1, 20.0, 11.3, 12.9, 10.0, and 23.7°2θ using Cu Kα radiation.
35 - 60 . (canceled)
61 . The method of claim 6 , wherein the cancer is hematological cancer.
62 . The method of claim 6 , wherein the cancer is leukemia.
63 . The method of claim 6 , wherein the cancer is acute myeloid leukemia, acute lymphocytic leukemia, or mixed lineage leukemia.
64 . The method of claim 17 , wherein the cancer is hematological cancer.
65 . The method of claim 17 , wherein the cancer is leukemia.
66 . The method of claim 17 , wherein the cancer is acute myeloid leukemia, acute lymphocytic leukemia, or mixed lineage leukemia.
67 . The method of claim 28 , wherein the cancer is hematological cancer.
68 . The method of claim 28 , wherein the cancer is leukemia.
69 . The method of claim 28 , wherein the cancer is acute myeloid leukemia, acute lymphocytic leukemia, or mixed lineage leukemia.