Deuterated baricitinib
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 Ia:
or a pharmaceutically acceptable salt thereof, wherein:
each of Y 1a , Y 1b , Y 2a and Y 2b is hydrogen or each of Y 1a , Y 1b , Y 2a and Y 2b is deuterium; X 1 and X 2 are the same and selected from hydrogen and deuterium; Z 1 and Z 2 are the same and selected from hydrogen and deuterium; and
R is selected from —CH 3 , —CH 2 D, —CHD 2 , and —CD 3 ;
provided that when Y 1a , Y 1b , Y 2a , Y 2b , X 1 and X 2 are each hydrogen, and R is —CH 3 , then at least one of Z 1 or Z 2 is deuterium.
2. The compound of claim 1 , wherein X 1 and X 2 are hydrogen.
3. The compound of claim 1 , wherein X 1 and X 2 are deuterium.
4. The compound of claim 1 , wherein each of Y 1a and Y 1b is hydrogen, and each of Y 2a and Y 2b is hydrogen.
5. The compound of claim 1 , wherein each of Y 1a and Y 1b is deuterium, and each of Y 2a and Y 2b is deuterium.
6. The compound of claim 1 , wherein R is CH 3 or CD 3 .
7. The compound of claim 1 , wherein each of Z 1 and Z 2 is hydrogen.
8. The compound of claim 1 , wherein each of Z 1 and Z 2 is deuterium.
9. The compound of claim 1 , wherein X 1 and X 2 are the same; and the compound is selected from any of the compounds set forth below:
Cmpd #
Y 1a = Y 1b
Y 2a = Y 2b
Z 1 = Z 2
X 1 = X 2
R
100
D
D
D
H
CH 3
101
D
D
D
H
CD 3
102
D
D
D
D
CH 3
103
D
D
D
D
CD 3
108
H
H
D
H
CH 3
109
H
H
D
H
CD 3
110
H
H
D
D
CH 3
111
H
H
D
D
CD 3
112
D
D
H
H
CH 3
113
D
D
H
H
CD 3
114
D
D
H
D
CH 3
115
D
D
H
D
CD 3
120
H
H
H
H
CD 3
121
H
H
H
D
CH 3
122
H
H
H
D
CD 3
or a pharmaceutically acceptable salt thereof.
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 inhibiting at least one of JAK1 and JAK2 kinase in a cell, comprising contacting the cell with a compound of claim 1 .
12. A method of treating a disease selected from rheumatoid arthritis, psoriasis, myeloproliferative disorders, transplant rejection, and dry eye, in a subject in need of such treatment, the method comprising administering to the subject in need of such treatment a compound of claim 1 .
13. The method of claim 12 , wherein the disease to be treated is selected from rheumatoid arthritis and psoriasis.
14. The method of claim 13 , comprising the additional step of co-administering methotrexate to the subject.
15. A method of treating a disease selected from rheumatoid arthritis, psoriasis, myeloproliferative disorders, transplant rejection, and dry eye, in a subject in need of such treatment, the method comprising administering to the subject in need of such treatment a compound of claim 10 .
16. The method of claim 15 , wherein the disease to be treated is selected from rheumatoid arthritis and psoriasis.
17. The method of claim 16 , comprising the additional step of co-administering methotrexate to the subject.
18. The method of claim 12 , wherein the myeloproliferative disorders are selected from chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia and primary myelofibrosis.
19. The method of claim 15 , wherein the myeloproliferative disorders are selected from chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia and primary myelofibrosis.