Pyridine compounds as allosteric SHP2 inhibitors
The present disclosure is directed to inhibitors of SHP2 and their use in the treatment of disease. Also disclosed are pharmaceutical compositions comprising the same.
1. A compound of Formula I-Y1:
or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein:
A is a 5- to 12-membered monocyclic or polycyclic aryl or heteroaryl;
Y 1 is —S— or a direct bond;
Y 2 is —NR a ; wherein the bond on the left side of Y 2 , as drawn, is bound to the pyridine ring and the bond on the right side of the Y 2 moiety, as drawn, is bound to R 3 ;
R 1 is independently, at each occurrence, —H, —C 1 -C 6 alkyl, —OH, halogen, or —NH 2 ;
R 2 is —OH or —C 1 -C 6 alkyl;
R 3 is combined with R a to form a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally substituted with one or more —C 1 -C 6 alkyl, —OH, —NH 2 , —CF 3 , —CHF 2 , or —CH 2 F;
R 4 is —H, or —C 1 -C 6 alkyl, wherein each alkyl is optionally substituted with one or more —OH or halogen;
n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
2. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein Y 1 is —S—.
3. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein Y 1 is a direct bond.
4. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more —C 1 -C 6 alkyl, —OH, —NH 2 —CF 3 , —CHF 2 , or —CH 2 F.
5. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein R 3 and R a together with the atoms to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more —C 1 -C 6 alkyl, —OH, —NH 2 —CF 3 , —CHF 2 , or —CH 2 F.
6. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more —C 1 -C 6 alkyl, —OH, —NH 2 —CF 3 , —CHF 2 , or —CH 2 F.
7. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein A is a monocyclic or polycyclic aryl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein A is a monocyclic or polycyclic heteroaryl.
9. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein R 1 is independently, at each occurrence, —H, —C 1 -C 6 alkyl, halogen, or —NH 2 .
10. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein R 2 is —OH.
11. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein R 2 is —C 1 -C 6 alkyl.
12. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein R 4 is —C 1 -C 6 alkyl, which is optionally substituted with one or more —OH, —NH 2 , halogen, or oxo.
13. The compound of claim 12 , or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein R 4 is —C 1 -C 6 alkyl, which is substituted with one or more —OH.
14. A compound, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, selected from the group consisting of:
15. A compound, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, selected from the group consisting of:
Example
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16. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.