6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes

A process for preparing a compound represented by Formula (I):

• wherein
• R1, R2 and R3 are independently selected from the group consisting of hydrogen, C1-C3haloalkyl and C1-C3alkyl;
• A represents
• wherein
• X is selected from the group consisting of CH2, S, SO, SO2, NR5, NCOR5, NCOR9, NCOCH2R9, O, and a bond;
• Y is selected from the group consisting of N, CH and C;
• n is selected from the group consisting of 1, 2, 3 and 4;
• R4 is selected from the group consisting of hydrogen, halogen, COR6, C1-C6alkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C3-C6heterocyclyl, C1-C3cyanoalkyl, C1-C3haloalkyl, aryl and heteroaryl, wherein said aryl and said heteroaryl are optionally substituted with one or more R7;
• R5 is selected from the group consisting of hydrogen, C1-C3fluoroalkyl, C1-C3alkyl, C1-C3alkoxyC1-C3alkyl and C3-C6cycloalkyl;
• R6 is selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl and 1-azetidinyl;
• R7 is selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3haloalkyl, halogen, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C1-C3haloalkoxy and C1-C3alkoxy;
• R9 is selected from the group consisting of C1-C3alkyl, C1-C3alkoxy, C3-C6cycloalkyl, heterocyclyl, phenyl and a monocyclic heteroaryl, wherein said heterocyclyl, said phenyl and said monocyclic heteroaryl are optionally substituted with one or two R8;
• and
• R8 is selected from the group consisting of halogen, C1-C3haloalkyl and C1-C3alkyl;
• and pharmaceutically acceptable salts, stereoisomers and tautomers thereof;
• the process comprising:
• (i) providing a compound represented by Formula (III):
• wherein
• R1, R2, R3, and A are defined as above;
• R10 is selected from the group consisting of F, OCH3, OC(CH3)3, and OSiR′R″R′″;
• and
• R′, R″, and R′″ are each independently aryl or alkyl;
• and
• (ii) converting the compound represented by Formula (III) into the compound represented by Formula (I).

The process of claim 1, wherein the compound is selected from the group consisting of:

• 4-morpholino-6-(2-phenylpyrrolidin-1-yl)-1H-pyridin-2-one;
• 1-methyl-4-morpholino-6-(2-phenylpyrrolidin-1-yl)pyridin-2-one;
• 4-morpholino-6-[(2S)-2-phenylpyrrolidin-1-yl]-1H-pyridin-2-one;
• 4-morpholino-6-[(2R)-2-phenylpyrrolidin-1-yl]-1H-pyridin-2-one;
• 6-(3,6-dihydro-2H-pyran-4-yl)-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;
• 4-(3-methylmorpholin-4-yl)-6-tetrahydropyran-4-yl-1H-pyridin-2-one;
• 6-[2-(3-methoxyphenyl)pyrrolidin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;
• 4-(3-methylmorpholin-4-yl)-6-[2-(3-pyridyl)pyrrolidin-1-yl]-1H-pyridin-2-one;
• 4-(3-methylmorpholin-4-yl)-6-(2-phenylpyrrolidin-1-yl)-1H-pyridin-2-one;
• N,N-dimethyl-1-[4-[(3R)-3-methylmorpholin-4-yl]-6-oxo-1H-pyridin-2-yl]pyrrolidine-2-carboxamide;
• 6-[2-(1-methoxy-1-methyl-ethyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one;
• 6-(2-cyclohexylpyrrolidin-1-yl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one;
• 6-[2-(3-fluorophenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one;
• 6-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one;
• 4-[(3R)-3-methylmorpholin-4-yl]-6-[2-[3-(trifluoromethoxy)phenyl]pyrrolidin-1-yl]-1H-pyridin-2-one;
• 4-[(3R)-3-methylmorpholin-4-yl]-6-[2-[3-(trifluoromethyl)phenyl]pyrrolidin-1-yl]-1H-pyridin-2-one;
• 6-[2-(3-methoxyphenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one;
• 4-[(3R)-3-methylmorpholin-4-yl]-6-(2-phenylpyrrolidin-1-yl)-1H-pyridin-2-one;
• 4-[(3R)-3-methylmorpholin-4-yl]-6-[2-(1-methylpyrazol-4-yl)pyrrolidin-1-yl]-1H-pyridin-2-one;
• 6-[2-(1,5-dimethylpyrazol-3-yl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one;
• 6-[2-(1-ethylpyrazol-3-yl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one;
• 6-[2-(5-methyl-2-furyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one;
• 6-[2-[3-(dimethylamino)phenyl]pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one;
• 4-[(3R)-3-methylmorpholin-4-yl]-6-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;
• 4-[(3R)-3-methylmorpholin-4-yl]-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one;
• 4-[(3R)-3-methylmorpholin-4-yl]-6-(3-phenylmorpholin-4-yl)-1H-pyridin-2-one;
• 4-[(3R)-3-methylmorpholin-4-yl]-6-(1-oxo-1,4-thiazinan-4-yl)-1H-pyridin-2-one;
• 6-(1,1-dioxo-1,4-thiazinan-4-yl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one;
• 6-(4-acetylpiperazin-1-yl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one;
• 4-[(3R)-3-methylmorpholin-4-yl]-6-[(2R)-2-phenyl-1-piperidyl]-1H-pyridin-2-one;
• 4-[(3R)-3-methylmorpholin-4-yl]-6-(4-methyl-2-phenyl-piperazin-1-yl)-1H-pyridin-2-one;
• 4-[(3R)-3-methylmorpholin-4-yl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one;
• 6-(3-cyclopropylmorpholin-4-yl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one;
• 4-[(3R)-3-methylmorpholin-4-yl]-6-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-1H-pyridin-2-one;
• 4-[(3R)-3-methylmorpholin-4-yl]-6-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]-1H-pyridin-2-one;
• 6-[2-(3-chlorophenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one;
• 6-[2-(3-cyclopropylphenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one;
• 4-[(3R)-3-methylmorpholin-4-yl]-6-[2-(2-pyridyl)pyrrolidin-1-yl]-1H-pyridin-2-one;
• 4-[(3R)-3-methylmorpholin-4-yl]-6-(2-thiazol-2-ylpyrrolidin-1-yl)-1H-pyridin-2-one;
• 6-[2-(5-methylisoxazol-3-yl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one;
• 1-methyl-4-[(3R)-3-methylmorpholin-4-yl]-6-[(2R)-2-(trifluoromethyl)-1-piperidyl]pyridin-2-one;
• 4-[(3R)-3-methylmorpholin-4-yl]-6-(8-oxa-5-azaspiro[3.5]nonan-5-yl)-1H-pyridin-2-one;
• 6-[2-(3-methoxyphenyl)-1-piperidyl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one;
• 6-[4-acetyl-2-(trifluoromethyl)piperazin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one;
• 6-[4-(5-fluoropyridine-3-carbonyl)-2-(trifluoromethyl)piperazin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one;
• 6-[4-[2-(4-fluorophenyl)acetyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one;
• 4-[(3R)-3-methylmorpholin-4-yl]-6-[4-(tetrahydrofuran-2-carbonyl)-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;
• 4-[(3R)-3-methylmorpholin-4-yl]-6-[4-methyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;
• and pharmaceutically acceptable salts, tautomers and stereoisomers thereof.

The process of claim 1, wherein:

• (a) when R10 is F, converting the compound of Formula (II) comprises carrying out acidic hydrolysis of the compound of Formula (II);
• (b) when R10 is OCH3, converting the compound of Formula (II) comprises reacting the compound of Formula (II) with trimethylsilyl iodide in a suitable solvent, reacting the compound of Formula (II) with HBr in a suitable solvent, reacting the compound of Formula (II) with BBr3 in a suitable solvent;
• (c) when R10 is OC(CH3)3, converting the compound of Formula (II) comprises reacting the compound of Formula (II) with trifluoroacetic acid in a suitable solvent;
• and
• (d) when R10 is OSiR′R″R′″, converting the compound of Formula (II) comprises reacting the compound of Formula (II) with HCl in a suitable solvent or by reacting the compound of Formula (II) with tetrabutyl ammonium fluoride in tetrahydrofuran.

The process of claim 1, further comprising:

• reacting a compound represented by Formula (II):
• wherein R1, R2, R3, and R10 are defined as in claim 1;
• and
• LG is a leaving group;
• with a coupling partner represented by:
• wherein reaction of the coupling partner with LG produces A.