Deuterated momelotinib
The present invention in one embodiment provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula I are as defined in the specification.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
either:
a. Y 1 , Y 2 , Y 3 , Y 4 , Z 1 , Z 2 , Z 3 , and Z 4 are each deuterium; and W 1 and W 2 are each hydrogen or each deuterium;
or
b. Y 1 , Y 2 , Y 3 and Y 4 are each hydrogen or each deuterium; Z 1 , Z 2 , Z 3 , Z 4 are each hydrogen or each deuterium; and W 1 and W 2 are each deuterium; and
wherein any atom not designated as deuterium in Formula I is present at its natural isotopic abundance; and wherein the deuterium incorporation at each designated deuterium atom is at least 90%.
2. The compound of claim 1 , wherein Y 1 , Y 2 , Y 3 and Y 4 are each hydrogen.
3. The compound of claim 1 , wherein Y 1 , Y 2 , Y 3 and Y 4 are each deuterium.
4. The compound of claim 1 , wherein Z 1 , Z 2 , Z 3 and Z 4 are each hydrogen.
5. The compound of claim 1 , wherein Z 1 , Z 2 , Z 3 and Z 4 are each deuterium.
6. The compound of claim 1 , wherein W 1 and W 2 are each hydrogen.
7. The compound of claim 1 , wherein W 1 and W 2 are each deuterium.
8. The compound of claim 1 , wherein the compound is selected from any one of the compounds (Cmpd) set forth in Table 1 (below):
Cmpd #
Y 1 = Y 2 = Y 3 = Y 4
Z 1 = Z 2 = Z 3 = Z 4
W 1 = W 2
101
H
H
D
103
H
D
D
105
D
H
D
106
D
D
H
107
D
D
D
or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
10. A method of treating a disease selected from chronic myeloproliferative neoplasms (MPNs), primary myelofibrosis (PMF), post-polycythemia vera (PV) and post-essential thrombocythemia (ET), comprising administering to a subject in need of such treatment a compound of claim 1 .
11. A method of inhibiting a member of the JAK family of kinases in a cell, comprising contacting the cell with a compound of claim 1 .
12. The compound of claim 8 wherein the compound is selected from Compound 101; Compound 106; and Compound 107, or a pharmaceutically acceptable salt thereof.
13. The compound of claim 12 wherein the compound is Compound 101, or a pharmaceutically acceptable salt thereof.
14. The compound of claim 12 wherein the compound is Compound 106, or a pharmaceutically acceptable salt thereof.
15. The compound of claim 12 wherein the compound is Compound 107, or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 , wherein the deuterium incorporation at each designated deuterium atom is at least 95%.
17. The compound of claim 1 , wherein the deuterium incorporation at each designated deuterium atom is at least 97%.
18. The compound of claim 13 , wherein the deuterium incorporation at each designated deuterium atom is at least 95%.
19. The compound of claim 14 , wherein the deuterium incorporation at each designated deuterium atom is at least 95%.
20. The compound of claim 15 , wherein the deuterium incorporation at each designated deuterium atom is at least 95%.