Substituted pyrrolo[2,3-b]pyrazines as JAK3 inhibitors
The present disclosure provides compounds of formula (I) wherein the variables are as defined herein that are JAK3 inhibitors and therefore useful for the treatment of diseases treatable by inhibition of JAK3 such as cancer and inflammatory diseases. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
Z 1 is N;
R 1 is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, cyano, or cycloalkyl;
R 2 is hydrogen, alkyl, cycloalkyl, halo, cyano, acyl, aminocarbonyl, phenyl or heteroaryl, wherein each of phenyl and heteroaryl is optionally substituted with one, two or three substituents independently chosen from alkyl, alkoxy, halo, haloalkyl, and haloalkoxy;
Ar is phenyl;
R 3 is attached to the phenyl ring at the meta position with respect to the
group and is -(alkylene) n -Y—CH═CHR c ;
n is 0 or 1;
Y is —NR a CO—, —NR a SO 2 —, —CO—, or —SO 2 —;
R a is hydrogen or alkyl;
R c is hydrogen, alkyl, -alkylNH 2 , -alkylNHalkyl, or -alkylN(alkyl) 2 ;
R 4 is hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkoxy, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkoxy, aminoalkyl, or aminoalkoxy, wherein
the heterocyclylalkyl is optionally substituted with one or two substitutents independently chosen from alkyl, halo, hydroxyalkyl, and alkoxyalkyl;
the heterocyclyloxy is optionally substituted with one or two substitutents independently chosen from alkyl, halo, hydroxyalkyl, and alkoxyalkyl;
the heterocyclylalkoxy is optionally substituted with one or two substitutents independently chosen from alkyl, halo, hydroxyalkyl, and alkoxyalkyl; and
R 5 is hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, or cyano.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, alkyl, cycloalkyl, halo, cyano, acyl, or aminocarbonyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is acyl.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is aminocarbonyl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —CONHR′, where R′ is isopropyl, isobutyl, or tert-butyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, or haloalkoxy.
7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, or trifluoromethoxy.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkoxy, heterocvclylalkyl, heterocyclyloxy, heterocyclylalkoxy, aminoalkyl, or aminoalkoxy, wherein
the heterocyclylalkyl is optionally substituted with one or two substitutents independently chosen from alkyl, halo, hydroxyalkyl, and alkoxyalkyl;
the heterocyclyloxy is optionally substituted with one or two substitutents independently chosen from alkyl, halo, hydroxyalkyl, and alkoxyalky; and
the heterocyclylalkoxy is optionally substituted with one or two substitutents independently chosen from alkyl, halo, hydroxyalkyl, and alkoxyalkyl.
9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydroxyalkoxy, alkoxyalkoxy, heterocyclyloxy, heterocyclylalkoxy, or aminoalkoxy, wherein
the heterocyclyloxy is optionally substituted with one or two substitutents independently chosen from alkyl, halo, hydroxyalkyl, and alkoxyalkyl; and
the heterocyclylalkoxy is optionally substituted with one or two substitutents independently chosen from alkyl, halo, hydroxyalkyl, and alkoxyalkyl.
10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 4 is attached to the carbon meta to the carbon substituted with the R 3 group.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R c is hydrogen.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R c is methyl.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R c is -alkylNH 2 , -alkylNHalkyl, or -alkylN(alkyl) 2 .
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is —NHCO—.
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1.
18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein alkylene is methylene.
19. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
20. A method of inhibiting Janus kinase 3 activity in a patient in need thereof, said method comprising administering to the patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
21. The method of claim 20 , wherein the patient suffers from a disease chosen from an autoimmune disease, an inflammatory disease, and cancer.
22. The method of claim 21 , wherein the cancer is cutaneous T-cell lymphoma or natural killer T-cell lymphoma.
23. The method of claim 21 , wherein the compound is administered optionally in combination with one or more anticancer or anti-inflammatory agents.
24. A compound chosen from:
N-(3-(7-pivaloyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)phenyl)acrylamide;
2-(3-acrylamidophenyl)-N-(tert-butyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide; and
N-(tert-butyl)-2-(3-(4-(dimethylamino)but-2-enamido)phenyl)-5H-pyrrolo[2,3-b]-pyrazine-7-carboxamide,
an E or Z stereoisomer of any of the foregoing compounds, or
a pharmaceutically acceptable salt thereof.