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:
Y 1 , Y 2 , Y 3 , Y 4 , Z 1 , Z 2 , Z 3 , Z 4 , W 1 and W 2 are each independently selected from hydrogen and deuterium;
provided that if Y 1 , Y 2 , Y 3 , Y 4 , Z 1 , Z 2 , Z 3 , Z 4 , and W 1 are each hydrogen, then W 2 is deuterium.
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):
TABLE 1
Y 1 = Y 2 =
Z 1 = Z 2 =
Cmpd #
Y 3 = Y 4
Z 3 = Z 4
W 1 = W 2
101
H
H
D
102
H
D
H
103
H
D
D
104
D
H
H
105
D
H
D
106
D
D
H
107
D
D
D
or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium in Formula I is present at its natural isotopic abundance.
9. The compound of claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
10. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
11. A method of treating a disease selected from chronic myeloproliferative neoplasms (MPNs), primary myelofibrosis (PMF) post-polycythemia vera (PV) or post-essential thrombocythemia (ET), comprising administering to a subject in need of such treatment a compound of claim 1 .
12. A method of inhibiting a member of the MK family of kinases in a cell, comprising contacting the cell with a compound of claim 1 .
13. The compound of claim 2 , wherein Z 1 , Z 2 , Z 3 and Z 4 are each hydrogen.
14. The compound of claim 3 , wherein Z 1 , Z 2 , Z 3 and Z 4 are each hydrogen.
15. The compound of claim 2 , wherein Z 1 , Z 2 , Z 3 and Z 4 are each deuterium.
16. The compound of claim 3 , wherein Z 1 , Z 2 , Z 3 and Z 4 are each deuterium.
17. The compound of claim 2 , wherein W 1 and W 2 are each hydrogen.
18. The compound of claim 3 , wherein W 1 and W 2 are each hydrogen.
19. The compound of claim 4 , wherein W 1 and W 2 are each hydrogen.
20. The compound of claim 5 , wherein W 1 and W 2 are each hydrogen.
21. The compound of claim 1 , wherein the deuterium incorporation at each designated deuterium atom is at least 90%.
22. The compound of claim 1 , wherein the deuterium incorporation at each designated deuterium atom is at least 95%.
23. The compound of claim 1 , wherein the deuterium incorporation at each designated deuterium atom is at least 97%.