Macrocyclic inhibitors of JAK
The present invention relates to the use of novel macrocyclic compounds of Formula I, wherein the variables Q, Q 1 , Q 2 , Q 3 , and Q 4 are defined as described herein, which inhibit JAK and are useful for the treatment of auto-immune and inflammatory diseases.
1. A compound of Formula I
wherein:
Q is phenyl or heteroaryl, optionally substituted with one or more Q′;
Q′ is halogen, hydroxy, lower alkyl, lower haloalkyl, lower hydroxyalkyl, amino, lower alkoxy, or lower haloalkoxy;
Q 1 is O or C(Q 1′ ) 2 ;
each Q 1′ is independently H, halogen, hydroxy, lower alkyl, lower haloalkyl, lower hydroxyalkyl, amino, lower alkoxy, or lower haloalkoxy;
Q 2 is (C(Q 2′ ) 2 ) n , N(Q 2″ ), or C(Q 2′ ) 2 C(Q 2′ ) 2 ;
each Q 2′ is independently H, halogen, hydroxy, lower alkyl, lower haloalkyl, lower hydroxyalkyl, amino, lower alkoxy, or lower haloalkoxy;
or Q 2″ and Q 3′ together form a heterocyclic ring;
n is 2, 3, 4, or 5;
Q 3 is O, N(Q 3′ ), C(Q 3′ ) 2 , carbocyclyl, or heterocyclyl;
each Q 3′ is independently H, halogen, hydroxy, lower alkyl, lower haloalkyl, lower hydroxyalkyl, amino, lower alkoxy, phenyl, benzyl, or lower haloalkoxy;
or both Q 3′ together form a spirocyclic carbocyclic or heterocyclic ring; and
Q 4 is C(═O) or S(═O) 2 ;
with the proviso that when Q 2 is N(Q 2″ ), then Q 3 is not N(Q 3′ );
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein Q is pyridine.
3. The compound of claim 2 , wherein Q 4 is C(═O).
4. The compound of claim 3 , wherein Q 3 is C(CH 3 ) 2 or C(CH 3 )(CH 2 CH 3 ).
5. The compound of claim 4 , wherein Q 1 is CH 2 .
6. The compound of claim 5 , wherein Q 2 is C(CH 2 )n.
7. The compound of claim 6 , wherein n is 2.
8. The compound of claim 6 , wherein n is 3.
9. The compound of claim 6 , wherein n is 4.
10. The compound of claim 4 , wherein Q 1 is O.
11. The compound of claim 10 , wherein Q 2 is C(CH 2 )n.
12. The compound of claim 11 , wherein n is 3.
13. The compound of claim 11 , wherein n is 4.
14. A compound of Formula II
wherein:
each of Z 1 , Z 2 , Z 3 , and Z 4 are independently C(Z′) or N;
each Z′ is independently H, halogen, hydroxy, lower alkyl, lower haloalkyl, lower hydroxyalkyl, amino, lower alkoxy, or lower haloalkoxy;
Q 1 is O or C(Q 1′ ) 2 ;
each Q 1′ is independently H, halogen, hydroxy, lower alkyl, lower haloalkyl, lower hydroxyalkyl, amino, lower alkoxy, or lower haloalkoxy; Q 2 is (C(Q 2′ ) 2 ) n , N(Q 2″ ), or C(Q 2′ ) 2 C(Q 2′ ) 2 ;
each Q 2′ is independently H, halogen, hydroxy, lower alkyl, lower haloalkyl, lower hydroxyalkyl, amino, lower alkoxy, or lower haloalkoxy;
or Q 2″ and Q 3′ together form a heterocyclic ring;
n is 2, 3, 4, or 5;
Q 3 is O, N(Q 3′ ), C(Q 3′ ) 2 , carbocyclyl, or heterocyclyl;
each Q 3′ is independently H, halogen, hydroxy, lower alkyl, lower haloalkyl, lower hydroxyalkyl, amino, lower alkoxy, phenyl, benzyl, or lower haloalkoxy;
or both Q 3′ together form a spirocyclic carbocyclic or heterocyclic ring; and with the proviso that when Q 2 is N(Q 2″ ), then Q 3 is not N(Q 3′ );
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 14 , wherein Z 1 is N, Z 2 is CH, Z 3 is CH, and Z 4 is CH.
16. The compound of claim 15 , wherein Q 3 is C(CH 3 ) 2 or C(CH 3 )(CH 2 CH 3 ).
17. The compound of claim 16 , wherein Q 1 is CH 2 .
18. The compound of claim 17 , wherein Q 2 is C(CH 2 )n.
19. The compound of claim 18 , wherein n is 2.
20. The compound of claim 18 , wherein n is 3.
21. The compound of claim 18 , wherein n is 4.
22. The compound of claim 16 , wherein Q 1 is O.
23. The compound of claim 22 , wherein Q 2 is C(CH 2 )n.
24. The compound of claim 23 , wherein n is 3.
25. The compound of claim 23 , wherein n is 4.
26. A compound selected from the group consisting of:
27. A pharmaceutical composition comprising the compound of claim 1 , admixed with at least one pharmaceutically acceptable carrier, excipient or diluent.
28. The pharmaceutical composition of claim 27 , further comprising an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, and an agent for treating immunodeficiency disorders.
29. A method for treating rheumatoid arthritis comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 .
30. A method for treating asthma comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 .