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 method of preparing Compound I-13:
wherein the method comprises steps of:
reacting Intermediate II-1 or a salt thereof and Intermediate III-1:
to provide Compound I-13; and
preparing Intermediate II-1 or a salt thereof by contacting ((S)—N—((S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methyl propane-2-sulfinamide:
with a suitable acid to provide Intermediate II-1 or a salt thereof.
2. The method of claim 1 , further comprising a step of contacting a compound:
with a suitable reducing agent to provide ((S)—N—((S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methyl propane-2-sulfinamide.
3. The method of claim 2 , further comprising a step of combining 3-acetyl-6-chloroquinolin-2(1H)-one:
and:
to provide the compound:
4. The method of claim 3 , further comprising a step of combining:
and:
to provide 3-acetyl-6-chloroquinolin-2(1H)-one.
5. The method of claim 1 , further comprising 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.
6. The method of claim 5 , further comprising 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.
7. The method of claim 6 , further comprising 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.
8. The method of claim 7 , further comprising 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.
9. The method of claim 1 , wherein the suitable acid is HCl.
10. The method of claim 2 , wherein the suitable reducing agent is NaBH 4 .
11. The method of claim 5 , wherein the suitable methylating agent is MeI.
12. The method of claim 6 , wherein the suitable base is K 2 CO 3 .
13. The method of claim 8 , wherein the suitable oxidizing agent is m-CPBA.
14. A composition comprising Compound I-13:
obtained by a process comprising steps of:
(i) reacting Intermediate II-1 or a salt thereof and Intermediate III-1:
to provide Compound I-13; and
(ii) preparing Intermediate II-1 or a salt thereof from ((S)—N—((S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methyl propane-2-sulfinamide:
15. The composition of claim 14 , wherein the process further comprises obtaining ((S)—N—((S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methyl propane-2-sulfinamide from a compound:
16. The composition of claim 15 , wherein the process further comprises obtaining the compound:
from 3-acetyl-6-chloroquinolin-2(1H)-one.
17. The composition of claim 16 , wherein the process further comprises obtaining 3-acetyl-6-chloroquinolin-2(1H)-one from:
18. The composition of claim 14 , wherein the process further comprises obtaining Intermediate III-1 from 5-fluoro-6-oxo-1,6-dihydropyridine-2-carbonitrile.
19. The composition of claim 18 , wherein the process further comprises obtaining 5-fluoro-6-oxo-1,6-dihydropyridine-2-carbonitrile from 6-cyano-3-fluoropyridin-2-yl acetate.
20. The composition of claim 19 , wherein the process further comprises obtaining 6-cyano-3-fluoropyridin-2-yl acetate from 2-cyano-5-fluoropyridine-1-oxide.
21. The composition of claim 20 , wherein the process further comprises obtaining 2-cyano-5-fluoropyridine-1-oxide from 5-fluoropicolinonitrile.