6-aryl-4-morpholin-1-ylpyridone compounds useful for the treatment of cancer and diabetes

1. A process for preparing a compound of formula (I)

and pharmaceutically acceptable salts, tautomers, or stereoisomers thereof, wherein

R 1 is aryl or heteroaryl, said aryl and said heteroaryl being mono- or bicyclic and optionally substituted with one or more of R 5 , R 6 , R 7 , and R 8 ;

R 2 , R 3 , and R 4 are independently selected from hydrogen, C 1 -C 3 haloalkyl, and C 1 -C 3 alkyl;

R 5 , R 6 , R 7 , and R 8 are independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, amino, —NHSO 2 R 9 , hydroxy, phenyl, and a monocyclic heteroaryl; and

R 9 is C 1 -C 6 haloalkyl or C 1 -C 3 alkyl;

the process comprising:

reacting a compound of formula (III):

with a deprotecting agent to produce the compound of formula (I),

optionally in the presence of R 2 -I when R 2 is C 1 -C 3 haloalkyl or C 1 -C 3 alkyl;

wherein

R 10 is F, OCH 3 , OC(CH 3 ) 3, or OSiR′R″R′″ and R′, R″, and R′″ are independently aryl or alkyl; and

R 1 , R 3 , and R 4 are defined as above for the compound of formula (I).

2. The process of claim 1 , wherein:

(a) R 10 is F and the deprotecting agent is HCl;

(b) R 10 is OCH 3 and the deprotecting agent is trimethylsilyl iodide (TMSI), HBr, or BBr 3 ;

(c) R 10 is OC(CH 3 ) 3 and the deprotecting agent is trifluoroacetic acid; or

(d) R 10 is OSiR′R″R′ 41 and the deprotecting agent is HCl or tetrabutyl ammonium fluoride.

3. The process of claim 1 , wherein R′, R″, and R′″ are independently phenyl, methyl, or tert-butyl.

4. The process of claim 1 , further comprising:

reacting a compound of formula (II):

with a compound of formula T-R 1 ,

wherein

LG is a leaving group;

T is a boronic acid, a boronic ester, a potassium trifluoroborate, a methyliminodiacetic acid (MIDA) boronate, or a stannane; and

R 1 , R 3 , R 4 , and R 10 are as defined in claim 1 ;

in the presence of a metal catalyst to produce the compound of formula (III).

5. The process of claim 4 , wherein LG is a halogen, an alkylsulfonate, an arylsulfonate, or a haloalkylsulfonate.

6. The process of claim 4 , wherein:

(a) LG is chlorine, bromine, or iodine; or

(b) LG is trifluoromethanesulfonate.

7. The process of claim 4 , wherein the metal catalyst is a palladium catalyst.

8. The process of claim 7 , wherein the palladium catalyst is di-tert-butylphosphinoferrocene palladium (II) dichloride, tetrakis(triphenylphosphine)palladium (0), palladium diphenylphosphinoferrocene dichloride, palladium (II) acetate, or bis(dibenzylideneacetone) palladium (0).

9. The process of claim 4 , further comprising the presence of a ligand.

10. The process of claim 9 , wherein the ligand is triphenylphosphine, tri-tert-butylphosphine, or 2-(dicyclohexylphosphino)biphenyl.

11. The process of claim 4 , further comprising the presence of a base.

12. The process of claim 11 , wherein the base is cesium fluoride, triethylamine, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, or potassium phosphate.

13. The process of claim 1 , wherein R 2 is selected from hydrogen and methyl.

14. The process of claim 1 , wherein R 3 is hydrogen; and R 4 is methyl.

15. The process of claim 1 , wherein le is selected from phenyl, furyl, thienyl, pyridyl, pyrimidinyl, and quinolinyl, each optionally substituted with R 5 and/or R 6 ; and R 5 and R 6 are independently selected from chlorine, fluorine, trifluoromethyl, methyl, phenyl, —NHSO 2 CH 3 , and pyrazolyl.

16. The process of claim 1 , wherein R 1 is selected from

wherein

R 5 and R 6 are independently selected from halogen, C 1 -C 3 alkyl, C 1 -C 6 haloalkyl, phenyl, pyrazolyl, and —NHSO 2 CH 3 .

17. The process of claim 1 , wherein R 1 is a monocyclic aryl or heteroaryl.

18. The process of claim 1 , wherein R 1 is

R 4 is C 1 -C 3 alkyl; and

R 5 and R 6 are independently selected from chlorine, fluorine, and trifluoromethyl.

19. The process of claim 1 , wherein R 1 is selected from

R 2 is hydrogen or methyl;

R 3 is hydrogen;

R 4 is methyl; and

R 5 and R 6 are selected from chlorine, fluorine, trifluoromethyl, methyl, phenyl, pyrazolyl, and —NHSO 2 CH 3 .

20. The process of claim 1 , wherein the compound of formula (I) is selected from the group consisting of:

6-(2-chlorophenyl)-4-morpholino-1 H-pyridin-2-one;

6-(2-chlorophenyl)-1 -methyl-4-morpholino-pyridin-2-one;

6-(2-chlorophenyl)-4-(3-methylmorpholin-4-yl)-1 H-pyridin-2-one;

6-(2-chlorophenyl)-1 -methyl-4-(3-methylmorpholin-4-yl)pyridin-2-one;

4-(3-methylmorpholin-4-yl)-6-(4-methyl-3-pyridyl)-1 H-pyridin-2-one;

4-(3-methylmorpholin-4-yl)-6-pyrimidin-5-yl-1 H-pyridin-2-one;

4-(3-methylmorpholin-4-yl)-6-(2-phenylphenyl)-1 H-pyridin-2-one;

6-(2-chloro-5-fluoro-phenyl)-4-[(3R)-3-methylmorpholin-4-yl]-1 H-pyridin-2-one;

4-[(3R)-3-methylmorpholin-4-yl]-6-(o-tolyl)-1 H-pyridin-2-one;

4-[(3R)-3-methylmorpholin-4-yl]-6-[2-(trifluoromethyl)-3-pyridyl]-1 H-pyridin-2-one;

6-(2-chlorophenyl)-4-[(3R)-3-methylmorpholin-4-yl]-1 H-pyridin-2-one;

4-[(3R)-3-methylmorpholin-4-yl]-6-[2-(trifluoromethyl)phenyl]-1 H-pyridin-2-one;

6-(3-furyl)-4-[(3R)-3-methylmorpholin-4-yl]-1 H-pyridin-2-one;

4-[(3R)-3-methylmorpholin-4-yl]-6-(4-methyl-3-thienyl)-1 H-pyridin-2-one;

N-[2-[4-[(3R)-3-methylmorpholin-4-yl]-6-oxo-1 H-pyridin-2-yl]phenyl]methanesulfonamide;

4-[(3R)-3-methylmorpholin-4-yl]-6-(6-methyl-5-quinolyl)-1 H-pyridin-2-one;

4-[(3R)-3-methylmorpholin-4-yl]-6-[4-(1 H-pyrazol-5-yl)phenyl]-1 H-pyridin-2-one; and

pharmaceutically acceptable salts, tautomers, and stereoisomers thereof.