Pyridin-2(1H)-one quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
The invention relates to inhibitors of mutant isocitrate dehydrogenase (mt-IDH) proteins with neomorphic activity useful in the treatment of cell-proliferation disorders and cancers, having the Formula: where A, U, W 1 , W 2 , W 3 , R 1 -R 6 , and R 9 are described herein.
1. A composition comprising Compound I-13 obtained by a process comprising a step of reacting Intermediate II-1 or a salt thereof and Intermediate III-1:
2. The composition of claim 1 , wherein the process further comprises obtaining Intermediate III-1 from 5-fluoro-6-oxo-1,6-dihydropyridine-2-carbonitrile.
3. The composition of claim 2 , wherein the process further comprises obtaining 5-fluoro-6-oxo-1,6-dihydropyridine-2-carbonitrile from 6-cyano-3-fluoropyridin-2-yl acetate.
4. The composition of claim 3 , wherein the process further comprises obtaining 6-cyano-3-fluoropyridin-2-yl acetate from 2-cyano-5-fluoropyridine-1-oxide.
5. The composition of claim 4 , wherein the process further comprises obtaining 2-cyano-5-fluoropyridine-1-oxide from 5-fluoropicolinonitrile.
6. The composition of claim 1 , wherein the process further comprises obtaining Intermediate II-1, or a salt thereof, from (R)—N—((S)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide.
7. The composition of claim 6 , wherein the process further comprises obtaining (R)—N—((S)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide from (R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide.
8. The composition of claim 7 , wherein the process further comprises obtaining (R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide from 2,6-dichloroquinoline-3-carbaldehyde.
9. A method of preparing compound I-13:
wherein the method comprises a step of reacting Intermediate II-1, or a salt thereof, and Intermediate III-1:
to form compound I-13.
10. The method of claim 9 , wherein the method further comprises a step of preparing Intermediate III-1:
by a process comprising a step of reacting 5-fluoro-6-oxo-1,6-dihydropyridine-2-carbonitrile:
with a suitable methylating agent to form Intermediate III-1.
11. The method of claim 10 , wherein the method further comprises a step of preparing 5-fluoro-6-oxo-1,6-dihydropyridine-2-carbonitrile:
by a process comprising a step of reacting 6-cyano-3-fluoropyridin-2-yl acetate:
with a suitable base to form 5-fluoro-6-oxo-1,6-dihydropyridine-2-carbonitrile.
12. The method of claim 11 , wherein the method further comprises a step of preparing 6-cyano-3-fluoropyridin-2-yl acetate:
by a process comprising a step of reacting 2-cyano-5-fluoropyridine-1-oxide;
with acetic anhydride to form 6-cyano-3-fluoropyridin-2-yl acetate.
13. The method of claim 12 , wherein the method further comprises a step of preparing 2-cyano-5-fluoropyridine-1-oxide:
by a process comprising a step of reacting 5-fluoropicolinonitrile:
with a suitable oxidizing agent to form 2-cyano-5-fluoropyridine-1-oxide.
14. The method of claim 9 , wherein the method further comprises a step of preparing Intermediate II-1, or a salt thereof:
by a process comprising a step of reacting (R)—N—((S)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide:
with a suitable acid to form Intermediate II-1, or a salt thereof.
15. The method of claim 14 , wherein the method further comprises a step of preparing (R)—N—((S)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide:
by a process comprising a step of reacting (R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide:
with MeMgBr to form (R)—N—((S)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide.
16. The method of claim 15 , wherein the method further comprises a step of preparing (R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide:
by a process comprising a step of reacting 2,6-dichloroquinoline-3-carbaldehyde:
with:
to form (R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide.
17. The method of claim 10 , wherein the suitable methylating agent is MeI.
18. The method of claim 11 , wherein the suitable base is K 2 CO 3 .
19. The method of claim 13 , wherein the suitable oxidizing agent is m-CPBA.
20. The method of claim 14 , wherein the suitable acid is HCl.
21. A composition comprising Compound I-13:
and at least one compound selected from the group consisting of Intermediate II-1 or a salt thereof and Intermediate III-1:
22. The composition of claim 21 comprising Compound I-13 and Intermediate II-1 or a salt thereof.
23. The composition of claim 21 comprising Compound I-13 and Intermediate III-1.
24. The composition of claim 21 comprising Compound I-13, Intermediate II-1 or a salt thereof, and Intermediate III-1.
25. The composition of claim 21 , wherein Compound I-13 is obtained by a process comprising a step of reacting Intermediate II-1 or a salt thereof and Intermediate III-1.