Selective BTK irreversible inhibitors
The invention provides a series of conformationally stable and selective, irreversible kinase inhibitors, and methods of using the kinase inhibitors. The effect of atropisomerism on kinase selectivity was assessed, finding improved selectivity compared to rapidly interconverting parent compounds. The compounds herein are atropisomers having increased kinase selectivity and are for use in treating conditions that benefit from selective BTK kinase inhibition.
1. An atropisomer compound of Formula I:
or salt thereof;
wherein
G 1 is aryloxy, halo, hydroxy, alkyl, alkoxy, amino, amido, or phenyl;
G 2 is amino, halo, hydroxy, alkyl, alkoxy, arylnoxy, amido, or phenyl;
G 3 and G 4 are independently H, halo, hydroxy, alkyl, alkoxy, or amino;
Q is C or N;
X and Y taken together form an atropisomerism rotational blocking moiety; and
R 1 is a buttressing substituent wherein the buttressing substituent comprises a ring heteroatom and an electrophile;
wherein the atropisomer is atropisomerically stable; and
wherein the selectivity of the atropisomer is modulated compared to a corresponding rapidly interconverting parent kinase inhibitor, wherein the atropisomerism rotational blocking moiety of the atropisomer in combination with the buttressing substituent produces a barrier to rotation of at least 10 kcal/mol, and the atropisomeric purity of the atropisomer has a half-life of at least 8 hours, thereby stabilizing atropisomerism of the atropisomer having modulated kinase selectivity.
2. The compound of claim 1 wherein R 1 is a nitrogen heterocycle wherein the nitrogen heterocycle is substituted with a Michael acceptor.
3. The compound of claim 2 wherein R 1 is:
wherein R 2 is H, halo, nitro, or —(C 1 -C 6 )alkyl.
4. The compound of claim 1 wherein X is —(C 1 -C 6 )alkyl, halo, hydroxy, —O(C 1 -C 6 )alkyl, or amino.
5. The compound of claim 1 wherein Q is C and Y is —(C 1 -C 6 )alkyl, halo, hydroxy, —O(C 1 -C 6 )alkyl, or amino, wherein —(C 1 -C 6 )alkyl is optionally substituted;
or Q is N and Y is lone pair.
6. The compound of claim 1 wherein G 1 is OPh, or —(C═O)NR a heteroaryl wherein R a is H or —(C 1 -C 6 )alkyl.
7. The compound of claim 1 wherein G 2 is NH 2 .
8. The compound of claim 1 wherein G 3 is H and G 4 is H, F, or CH 3 .
9. The compound of claim 1 wherein the compound is an atropisomer having an (R a )-configuration in reference to the bond joining the phenyl moiety to the 5-membered heterocyclic ring of Formula I.
10. The compound of claim 1 wherein the compound is an atropisomer having an (S a )-configuration in reference to the bond joining the phenyl moiety to the 5-membered heterocyclic ring of Formula I.
11. The compound of claim 1 wherein the compound of Formula I is a compound of Formula II, Formula IIB, or Formula V:
or salt thereof;
wherein
G 1 is aryloxy or amido;
G 4 is H, halo, hydroxy, alkyl, alkoxy, or amino;
R 1 is:
wherein R 2 is H, halo, nitro, or —(C 1 -C 6 )alkyl;
X is halo alkyl, alkoxy, or amino;
Y is halo alkyl, alkoxy, or amino; and
Z is acyl.
12. The compound of claim 11 wherein X and Y are CH 3 .
13. The compound of claim 11 wherein G 1 is OPh or —(C═O)NHpyridyl.
14. The compound of claim 11 wherein Z is:
15. The compound of claim 11 wherein the compound is:
or salt thereof.
16. A pharmaceutical composition comprising the compound of claim 1 in combination with a pharmaceutically acceptable diluent, carrier, or excipient.
17. A method for the treatment of blood cancer in a subject in need thereof comprising administering an effective amount of an atropisomer of claim 1 , thereby treating the cancer.
18. The method of claim 17 wherein the atropisomer is selective for BTK kinase over other kinases.