Methods for treating diseases associated with abnormal ACVR1 expression and ACVR1 inhibitors for use in the same
Methods for treating a disease in a subject in need thereof by administering an ACVR1 inhibitor having the following formula (I) are disclosed: including stereoisomers, tautomers, pharmaceutically acceptable salts and prodrugs thereof, wherein R 1 , R 2 , R 3 , and R 4 are as defined herein. Subjects that may benefit from treatment may have mutations in their ACVR1 gene. Various diseases may be treated using the described methods, including cancers (e.g., diffuse intrinsic pontine glioma (DIPG)) and genetic disorders (e.g., fibrodysplasia ossificans progressiva (FOP)).
1. Form A of N 4 -(2,2′-bipyridin-3-yl)-N 2 -(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,4-diamine anhydrous hydrochloric acid salt characterized by an x-ray diffraction pattern (XRPD) comprising one or more 2θvalues selected from: 13.53, 16.14, 17.67, 18.38, 24.96, and 28.18.
2. The Form A of claim 1 , wherein the form is substantially free from impurities.
3. The Form A of claim 1 , wherein the form is characterized by an XRPD selected from the group consisting of:
(a) an XRPD comprising two or more of the listed 2θ values;
(b) an XRPD comprising three or more of the listed 2θ values;
(c) an XRPD comprising four or more of the listed 2θ values;
(d) an XRPD comprising five or more of the listed 2θ values; and
(e) an XRPD comprising each of the six listed 2θ values.
4. The Form A of claim 1 , further characterized by one or more 2θ values selected from: 6.71, 19.25, 23.98, and 29.60.
5. The Form A of claim 4 , wherein the form is characterized by an XRPD selected from the group consisting of:
(a) an XRPD comprising two or more of the listed 2θ values;
(b) an XRPD comprising three or more of the listed 2θ values; and
(c) an XRPD comprising each of the four listed 2θ values.
6. Form A of N 4 -(2,2′-bipyridin-3-yl)-N 2 -(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,4-diamine anhydrous hydrochloric acid salt characterized by an x-ray diffraction pattern (XRPD) substantially the same as FIG. 12 .
7. Form A of N 4 -(2,2′-bipyridin-3-yl)-N 2 -(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,4-diamine anhydrous hydrochloric acid salt characterized by an endotherm at one or more of 196.2° C., 214.8° C., and 274.0° C.
8. The Form A of claim 7 , further characterized by a peak endotherm at one or more of 198.9° C., 218.0° C., and 275.9° C.
9. The Form A of claim 8 , further characterized by an onset temperature of 274.0° C.
10. The Form A of claim 9 , further characterized by weight loss of 1.7% up to 150° C.
11. Form A of N 4 -(2,2′-bipyridin-3-yl)-N 2 -(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,4-diamine anhydrous hydrochloric acid salt characterized by a TGA-DSC thermogram substantially the same as FIG. 15 .