MST1 kinase inhibitors and methods of their use
View Patent ↗Compounds for the inhibition of mammalian Ste20-like kinase 1 (MST1) are disclosed, along with compositions comprising them and methods of their use in the treatment, management or prevention of an inflammatory or autoimmune diseases or disorders. Particular compounds are of the formula:
1. A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
A is aryl or 4-7-membered heterocycle;
D is a 4-7-membered heterocycle;
X is N or CH;
Y 1 and Y 2 are each independently S, N or CH, provided that at least one of Y 1 and Y 2 is N or CH;
each R 1 is independently R 1A , —(R 1B ) n SO p R 1C , —(R 1B ) n SO p N(R 1C ) 2 , —(R 1B ) n NR 1C SO p R 1C , —(R 1B ) n C(O)N(R 1C ) 2 , or —(R 1B ) n NR 1C C(O)R 1C , or optionally substituted C 1-12 hydrocarbyl or 2-12-membered heterocarbyl, which optional substitution is with one or more of R 1A ;
each R 1A is independently amino, alkoxyl, carboxyl, cyano, halo, or hydroxyl;
each R 1B is independently C 1-12 hydrocarbyl optionally substituted with one or more of amino, alkoxyl, carboxyl, cyano, halo, or hydroxyl;
each R 1C is independently hydrogen or optionally substituted C 1-12 hydrocarbyl or 2-12-membered heterocarbyl, which optional substitution is with one or more of amino, alkoxyl, carboxyl, cyano, halo, or hydroxyl;
each R 3A is independently amino, alkoxyl, carboxyl, cyano, halo, or hydroxyl;
m is 0-3;
n is 0 or 1;
p is 0-2; and
q is 0-2.
2. The compound of claim 1 , which is of the formula:
wherein Z is N or CR 1 .
3. The compound of claim 2 , which is of the formula:
wherein Y 1 and Y 2 are each independently N or OH.
4. The compound of claim 2 , which is of the formula:
5. The compound of claim 2 , which is of the formula:
6. The compound of claim 2 , which is of the formula:
wherein:
R is hydrogen or alkyl; and
r is 1 or 2.
7. The compound of claim 2 , which is of the formula:
8. The compound of claim 1 , wherein X is N.
9. The compound of claim 1 , wherein Y 1 is CH.
10. The compound of claim 1 , wherein Y 2 is CH.
11. The compound of claim 2 , wherein Z is N.
12. The compound of claim 2 , wherein Z is CR 1 .
13. The compound of claim 1 , wherein R 1 is —(R 1B ) n SO p R 1C , —(R 1B ) n SO p N(R 1C ) 2 , —(R 1B ) n NR 1C SO p R 1C , —(R 1B ) n C(O)N(R 1C ) 2 , or —(R 1B ) n NR 1C C(O)R 1C .
14. The compound of claim 13 , wherein n=0.
15. The compound of claim 13 , wherein p=2.
16. The compound of claim 13 , which is of the formula:
17. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipients or diluent.