Dihydroquinoline-2-one derivatives

Abstract

The invention provides novel compounds having the general formula (I) ##STR00001##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.9, R.sup.10 and R.sup.11 are as described herein, compositions including the compounds and methods of using the compounds.

Claims

1. A Compound of formula (I) ##STR00063## wherein R.sup.1 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; R.sup.2 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; R.sup.3 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; R.sup.4 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; or R.sup.3 and R.sup.4 together with the carbon atoms to which they are attached form a double bond; R.sup.5 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; R.sup.6 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; R.sup.7 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; or R.sup.6 and R.sup.7 together with the carbon atom to which they are attached form a cycloalkyl; R.sup.8 and R.sup.9 together with the nitrogen atom to which they are attached form a heteroaryl substituted with an oxo substituent and one to three substitutents independently selected from H, halogen, cyano, alkyl, haloalkyl, cycloalkyl and halocycloalkyl; R.sup.10 is H, halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; R.sup.11 is H, halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; or pharmaceutically acceptable salts or esters.

2. The compound according to claim 1, wherein R.sup.1 is alkyl.

3. The compound according to claim 1, wherein R.sup.2 is H.

4. The compound according to claim 1, wherein R.sup.3 is H.

5. The compound according to claim 1, wherein R.sup.4 is H.

6. The compound according to claim 1, wherein R.sup.5 is H.

7. The compound according to claim 1, wherein R.sup.6 is H.

8. The compound according to claim 1, wherein R.sup.7 is H.

9. The compound according to claim 1, wherein R.sup.8 and R.sup.9 together with the nitrogen atom to which they are attached form a heteroaryl, substituted with an oxo substituent and one to three substitutents independently selected from H, halogen, cyano, alkyl and haloalkyl.

10. The compound according to claim 1, wherein R.sup.8 and R.sup.9 together with the nitrogen atom to which they are attached form a substituted 2H-pyridinyl, a substituted pyrimidinyl, a substituted thiazolyl or a substituted benzothiazolyl, wherein substituted 2H-pyridinyl, substituted pyrimidinyl, substituted thiazolyl and substituted benzothiazolyl are substituted with an oxo substituent and one to three substitutents independently selected from H, halogen, cyano, alkyl and haloalkyl.

11. The compound according to claim 1, wherein R.sup.8 and R.sup.9 together with the nitrogen atom to which they are attached form oxo-2H-pyridinyl substituted one to three substitutents independently selected from H, halogen, cyano, alkyl and haloalkyl.

12. The compound according to claim 1, wherein R.sup.8 and R.sup.9 together with the nitrogen atom to which they are attached form oxo-2H-pyridinyl substituted one to two substitutents independently selected from H, halogen and alkyl.

13. The compound according to claim 1, wherein R.sup.8 and R.sup.9 together with the nitrogen atom to which they are attached form fluoro-oxo-2H-pyridinyl, chloro-oxo-2H-pyridinyl or methyl-oxo-2H-pyridinyl.

14. The compound according to claim 1, wherein R.sup.10 is H or alkyl.

15. The compound according to claim 1, wherein R.sup.10 is alkyl.

16. The compound according to claim 1, wherein R.sup.11 is H or halogen.

17. The compound according to claim 1, wherein R.sup.11 is halogen.

18. The compound according to claim 1, selected from 1-Methyl-6-[5-(2-oxo-benzothiazol-3-ylmethyl)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one; 6-[5-(5-Fluoro-2-oxo-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one; 1-Methyl-6-[5-(2-oxo-thiazol-3-ylmethyl)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one; 6-[5-(3-Chloro-2-oxo-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one; 6-[5-(3-Fluoro-2-oxo-5-trifluoromethyl-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one; 6-[5-(3-Fluoro-2-oxo-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one; 1-Methyl-6-[5-(6-methyl-2-oxo-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one; 1-Methyl-6-[5-(4-methyl-2-oxo-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one; 6-[5-(5-Chloro-2-oxo-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one; 1-Methyl-6-[5-(2-oxo-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one; 1-Methyl-6-[5-(2-oxo-3-trifluoromethyl-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one; 1-Methyl-6-[5-(2-methyl-6-oxo-6H-pyrimidin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one; 1-Methyl-6-[5-(2-oxo-2H-pyrimidin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one; 1-[5-(1-Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-ylmethyl]-2-oxo-1,2-dihydro-pyridine-4-carbonitrile; 1-Methyl-6-[5-(2-oxo-5-trifluoromethyl-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one; 1-[5-(1-Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-ylmethyl]-6-oxo-1,6-dihydro-pyridine-3-carbonitrile; 6-[5-(6-Chloro-2-oxo-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one; 6-[5-(6-Fluoro-2-oxo-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one; 7-Fluoro-6-[5-(3-fluoro-2-oxo-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one; 7-Fluoro-1-methyl-6-[5-(4-methyl-2-oxo-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one; 6-[5-(5-Chloro-2-oxo-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one; 6-[5-(6-Chloro-2-oxo-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one; 7-Fluoro-1-methyl-6-[5-(6-methyl-2-oxo-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one; 7-Fluoro-1-methyl-6-[4-methyl-5-(6-methyl-2-oxo-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one; 6-[5-(6-Chloro-2-oxo-2H-pyridin-1-ylmethyl)-4-methyl-pyridin-3-yl]-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one; 7-Fluoro-6-[5-(3-fluoro-2-oxo-2H-pyridin-1-ylmethyl)-4-methyl-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one; 7-Fluoro-6-[5-(6-fluoro-2-oxo-2H-pyridin-1-ylmethyl)-4-methyl-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one; and pharmaceutically acceptable salts thereof.

19. The compound according to claim 1, selected from 1-Methyl-6-[5-(2-oxo-benzothiazol-3-ylmethyl)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one; 6-[5-(3-Fluoro-2-oxo-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one; 7-Fluoro-1-methyl-6-[5-(6-methyl-2-oxo-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one; 7-Fluoro-1-methyl-6-[4-methyl-5-(6-methyl-2-oxo-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one; 6-[5-(6-Chloro-2-oxo-2H-pyridin-1-ylmethyl)-4-methyl-pyridin-3-yl]-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one; and pharmaceutically acceptable salts thereof.

20. A process to prepare a compound of formula (I) according to claim 1 comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III); ##STR00064## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.9, R.sup.10, R.sup.11 and A are as defined above, R.sup.101 and R.sup.102 are independently selected from alkyl and cycloalkyl, or R.sup.101 and R.sup.102 together with the boron atom to which they are attached form a borolane and X is halogen or triflate.

21. A pharmaceutical composition comprising a compound according to claim 1 and a therapeutically inert carrier.

22. The compound of claim 1, when manufactured according to a process of claim 20.

Description

EXAMPLES

(1) All examples and intermediates were prepared under argon atmosphere if not specified otherwise.

Intermediate A-1

1-Methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one

(2) ##STR00014##

[A] 6-Bromo-1-methyl-3,4-dihydro-1H-quinolin-2-one

(3) ##STR00015##

(4) To a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (5 g, 22.1 mmol) in DMF (100 mL) cooled to 0 C. was added potassium tert-butoxide (4.96 g, 44.2 mmol) portionwise and the reaction mixture was stirred at 0 C. for 15 min. Then, methyl iodide (4.08 g, 28.8 mmol) was added and the reaction mixture allowed to warm up to room temperature and stirring was continued over night. More MeI (1.25 g, 8.86 mmol) was added and the reaction mixture was heated to 40 C. until completion of the reaction. The mixture was diluted with EtOAc, poured into 100 mL of 1M HCl and the aqueous phase was extracted with EtOAc (2200 mL). Combined organics were washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 30% EtOAc-heptane gradient to give the title compound (4.23 g, 80%) as an off white solid. MS: 240.0, 242.1 (M+H.sup.+).

[B] 1-Methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one

(5) ##STR00016##

(6) A flask was charged with 6-bromo-1-methyl-3,4-dihydro-1H-quinolin-2-one (3 g, 12.5 mmol), 4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (3.81 g, 15.0 mmol), potassium acetate (3.68 g, 37.5 mmol) and dioxane (48 mL). The mixture was purged with Ar, then dichloro[1,1-bis(diphenylphosphino)-ferrocene]palladium(II) dichloromethane complex (1:1) [PdCl.sub.2(DPPF)-CH.sub.2Cl.sub.2 adduct] (457 mg, 0.625 mmol) was added and the resulting mixture was heated to 80 C. over night. The reaction mixture was diluted with EtOAc, filtered through Dicalite and washed with EtOAc (2150 mL). The resulting filtrate was washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 40% EtOAc-heptane gradient to give the title compound (2.63 g, 73%) as an off white solid. MS: 288.0 (M+H.sup.+).

Intermediate A-2

1-(5-Bromo-pyridin-3-ylmethyl)-6-chloro-1H-pyridin-2-one

(7) ##STR00017##

[A] 3-Bromo-5-chloromethyl-pyridine

(8) ##STR00018##

(9) To a solution of (5-bromopyridin-3-yl)methanol (1 g, 5.32 mmol) in DCM (5 mL) was added thionyl chloride (2.53 g, 21.3 mmol) dropwise and the reaction mixture was stirred at room temperature over night. The mixture was diluted with DCM, poured into a 20% aq. NaOH solution (20 mL) and the resulting solution was extracted with DCM (225 mL). Combined organics were washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness to give to the title compound (1.02 g, 93%) as a light brown solid. MS: 208.3 (M+H.sup.+).

[B] 2-((5-Bromopyridin-3-yl)methoxy)-6-chloropyridine and 1-(5-bromo-pyridin-3-ylmethyl)-6-chloro-1H-pyridin-2-one

(10) ##STR00019##

(11) To a solution of 3-bromo-5-chloromethyl-pyridine (0.05 g, 0.242 mmol) in DMF (1 mL) were added 6-chloro-1H-pyridin-2-one (0.031 g, 0.242 mmol) and K.sub.2CO.sub.3 (0.067 g, 0.484 mmol) and the reaction mixture was stirred at room temperature for 6 h. The mixture was diluted with EtOAc, poured into H.sub.2O (3 mL) and the aqueous layer was extracted with EtOAc (210 mL). Combined organics were dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by silica gel flash chromatography eluting with a 0 to 100% EtOAc-heptane gradient to give 2-((5-bromopyridin-3-yl)methoxy)-6-chloropyridine (0.05 g, 69%) as a colorless liquid, MS: 301.3 (M+H.sup.+); and 1-(5-bromo-pyridin-3-ylmethyl)-6-chloro-1H-pyridin-2-one (0.011 g, 15%) as a yellow solid. MS: 301.3 (M+H.sup.+).

Intermediate A-3

6-(5-Chloromethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one

(12) ##STR00020##

[A] 6-(5-Hydroxymethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one

(13) ##STR00021##

(14) A sealed tube was charged with (5-bromo-pyridin-3-yl)-methanol (1 g, 5.32 mmol), 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) (1.6 g, 5.58 mmol) and DMF (15 mL). After purging the reaction mixture with argon, bis(triphenylphosphine)palladium(II)chloride (0.373 g, 0.532 mmol) and 1 M aq. Na.sub.2CO.sub.3 solution (13.3 mL, 13.3 mmol) were added and the reaction was heated to 120 C. for 1.5 h. The mixture was filtered over Dicalite, washed with EtOAc and the resulting filtrate was evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 3 to 10% MeOH-DCM gradient to give the title compound (1.392 g, 97.5%) as a brown solid. MS: 269.5 (M+H.sup.+).

[B] 6-(5-Chloromethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one

(15) ##STR00022##

(16) To a solution of 6-(5-hydroxymethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one (1.39 g, 5.19 mmol) in DCM (10 mL) was slowly added thionyl chloride (2.47 g, 20.8 mmol) dropwise and the reaction mixture was stirred at room temperature for 3.5 h. The mixture was diluted with DCM, poured into a 20% aq. NaOH solution (20 mL) cooled to 0 C. with an ice bath and the resulting solution was extracted with DCM (250 mL). Combined organics were dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated to dryness. The residue was triturated with Et.sub.2O, the solid precipitate was filtered off and further dried to give title compound (1.37 g, 90%) as a yellow solid. MS: 287.4 (M+H.sup.+).

(17) The following intermediates listed in Table 1 were prepared from 3-bromo-5-chloromethyl-pyridine (intermediate A-2 [A]), in analogy to the procedure described for the preparation of intermediates A-2 [B], using appropriate reaction partners:

(18) TABLE-US-00002 TABLE 1 Inter- MS mediate Name/Structure Reactant Aspect (M + H.sup.+) A-4 3H- Benzothiazol-2- one Colorless solid 323.3 A-5 3H-Thiazol-2- one Colorless solid 271.2 A-6 3-Chloro-1H- pyridin-2-one Light brown solid 299.5, 301.3 A-7 3-Fluoro-5- trifluoromethyl- 1H-pyridin-2- one Light brown solid 351.3, 353.3 A-8 3-Fluoro-1H- pyridin-2-one Off-white solid 281.2, 283.3

Intermediate A-9

7-Fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one

(19) ##STR00028##

[A] 3-Chloro-N-(3-fluoro-phenyl)-propionamide

(20) ##STR00029##

(21) To a solution of 3-fluoroaniline (10 mL, 104.02 mmol) in DCM (100 mL) was added pyridine (21 mL, 260.2 mmol) and 3-chloropropionyl chloride (12 mL, 124.4 mmol). The reaction mixture was stirred for 3 hr at room temperature until the starting material had disappeared as shown by LC-MS analysis. The reaction mixture was then diluted with H.sub.2O and extracted with EtOAc. The organic layer was dried over anhy. Na.sub.2SO.sub.4 and concentrated in vacuo to afford the title compound as a solid. It was used in the next step without further purification.

[B] 7-Fluoro-3,4-dihydro-1H-quinolin-2-one

(22) ##STR00030##

(23) A flame-dried 50-mL flask equipped with a magnetic stirring bar was charged with 3-chloro-N-(3-fluoro-phenyl)-propionamide (10 g, 49.6 mmol) and AlCl.sub.3 (23.1 g, 173.6 mmol). On a pre-heated oil bath, the flask was heated at 120125 C. for 2 hr until a LC-MS analysis indicated the reaction was complete. After cooling to room temperature, the mixture was treated with ice-water slowly. After extraction with EtOAc, the combined organic layers were washed with water and brine in sequence. The organic layer was dried over anhy. Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to afford a white solid (7.63 g) as a crude mixture of two regioisomeric products (7-fluoro-3,4-dihydro-1H-quinolin-2-one and 5-fluoro-3,4-dihydro-1H-quinolin-2-one) in a ratio of 5.3:1. This mixture was then refluxed in EtOAc (70 mL) for 30 min before it was cooled to room temperature and concentrated to 35 mL. The precipitated solid (5.83 g) was collected by vacuum filtration affording the desired 7-fluoro-3,4-dihydro-1H-quinolin-2-one enriched to 95.8%. After repeating three more times the above recrystallization procedure, 4.12 g of the title compound was obtained as a white solid in >99.5% purity.

[C] 7-Fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one

(24) ##STR00031##

(25) To an ice cold solution of 7-fluoro-3,4-dihydro-1H-quinolin-2-one (16.5 g, 0.1 mol) in DMF (200 mL) was added potassium tert-butoxide (22.4 g, 0.2 mol) in 2 portions. The reaction mixture was stirred at 0 C. for 30 min before MeI (25.4 g, 0.18 mol) was added. After the addition, the reaction mixture was allowed to warm up to room temperature slowly and stirred at room temperature over night. The reaction mixture was diluted with EtOAc (500 mL), then poured into 200 mL of 1 N aq. HCl. After extraction with EtOAc (200 mL, 3), the combined organic layers were washed with brine, dried over anhy. Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the crude title compound as oil (16.0 g, 89% yield). It was used in the next step without further purification.

[D] 6-Bromo-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one

(26) ##STR00032##

(27) To an ice cold solution of 7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one (16.0 g, 89.4 mmol) in DMF (200 mL) was added NBS (16.0 g, 89.4 mmol). After the addition, the reaction mixture was warmed up to room temperature and stirred for 3 hr. After LC-MS analysis indicated the completion of reaction, the mixture was diluted with EtOAc (500 mL) and poured into water (500 mL). The aqueous layer was then extracted with EtOAc (200 mL, 3) and the combined organic layers were washed with brine, dried over anhy. Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the crude title compound as oil (18.0 g, 78% yield). It was used in the next step without further purification.

[E] 7-Fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one

(28) ##STR00033##

(29) To a mixture of 6-bromo-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one (18.0 g, 69.8 mmol) in dry dioxane (400 mL) was added 4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (20.0 g, 83.8 mmol), potassium acetate (20.5 g, 209.4 mmol) and dichloro[1,1-bis(diphenylphosphino)-ferrocene]palladium(II) dichloromethane complex (1:1) [PdCl.sub.2(DPPF)-CH.sub.2Cl.sub.2 adduct] (2.55 g, 3.49 mmol). Under argon protection, the reaction mixture was heated at 85 C. over night. After dilution with EtOAc, the mixture was filtered through a Celite pad and the filter cake was washed with additional EtOAc several times. The combined filtrate was then washed with brine, dried over anhy. Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Silica gel column chromatography separation (0 to 30% EtOAc in hexane) afforded the crude title compound as white sticky material. Trituration with hexane several times gave the crude product as a light brown solid (10.0 g, 47% yield). MS: 306.1 (M+H.sup.+).

Intermediate A-10

6-(5-Chloromethyl-pyridin-3-yl)-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one

(30) ##STR00034##

(31) In analogy to the procedure described for the preparation of intermediates A-3, (5-bromo-pyridin-3-yl)-methanol has been reacted with 7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-9) to give 7-fluoro-6-(5-hydroxymethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one; further treatment with thionyl chloride then gave the title compound as yellow solid. MS: 305.5 (M+H.sup.+).

Intermediate A-11

6-(5-Chloromethyl-4-methyl-pyridin-3-yl)-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one

(32) ##STR00035##

(33) In analogy to the procedure described for the preparation of intermediates A-3, (5-bromo-4-methyl-pyridin-3-yl)-methanol has been reacted with 7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-9) to give 7-fluoro-6-(5-hydroxymethyl-4-methyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one; further treatment with thionyl chloride then gave the title compound as light brown solid. MS: 319.4 (M+H.sup.+).

Example 1

1-Methyl-6-[5-(2-oxo-benzothiazol-3-ylmethyl)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one

(34) ##STR00036##

(35) A sealed tube was charged with 3-(5-bromo-pyridin-3-ylmethyl)-3H-benzothiazol-2-one (intermediate A-4) (0.04 g, 0.125 mmol), 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) (0.039 g, 0.137 mmol) and DMF (1 mL). After purging the reaction mixture with argon, bis(triphenylphosphine)palladium(II)chloride (0.009 g, 0.012 mmol) and 1 M aq. Na.sub.2CO.sub.3 solution (0.31 mL, 0.31 mmol) were added and the reaction was heated to 100 C. for 1 h. The reaction mixture was diluted with EtOAc, poured into H.sub.2O (5 mL) and washed with EtOAc (210 mL). The resulting filtrate was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography, eluting with a 0 to 100% EtOAc-heptane gradient to give the title compound (0.026 g, 52%) as a light red solid. MS: 402.5 (M+H.sup.+).

Example 2

6-[5-(5-Fluoro-2-oxo-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one

(36) ##STR00037##

(37) To a solution of 6-(5-chloromethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one (intermediate A-3 [B]) (0.05 g, 0.147 mmol) in DMF (1 mL) was added 5-fluoro-1H-pyridin-2-one (0.019 g, 0.174 mmol) and K.sub.2CO.sub.3 (0.048 g, 0.349 mmol) and the reaction mixture was stirred at room temperature over night. The mixture was evaporated to dryness and the residue purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give 6-[5-(5-fluoro-pyridin-2-yloxymethyl)-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one (0.016 g, 25%), as colorless solid, MS: 364.5 (M+H.sup.+); and 6-[5-(5-fluoro-2-oxo-2H-pyridin-1-ylmethyl)-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one (0.045 g, 71%) as colorless solid. MS: 364.5 (M+H.sup.+).

(38) The following examples listed in Table 2 were prepared in analogy to the procedures described for the preparation of example 1 or example 2 using appropriate starting materials:

(39) TABLE-US-00003 TABLE 2 Aspect/ MS Ex Name/Structure Reactant Reference (M + H.sup.+) 3 3-(5-Bromo- pyridin-3- ylmethyl)- 3H-thiazol-2- one (intermediate A-5) Light yellow solid Expl. 1 352.4 4 1-(5-Bromo- pyridin-3- ylmethyl)-3- chloro-1H- pyridin-2- one (intermediate A-6) Off-white amorphous solid Expl. 1 380.5 5 0 1-(5-Bromo- pyridin-3- ylmethyl)-3- fluoro-5- trifluorometh- yl-1H- pyridin-2- one (intermediate A-7) Colorless solid Expl. 1 432.5 6 1-(5-Bromo- pyridin-3- ylmethyl)-3- fluoro-1H- pyridin-2- one (intermediate A-8) Off-white solid Expl. 1 364.5 7 6-Methyl- 1H-pyridin- 2-one Off-white morphous solid Expl. 2 360.5 8 4-Methyl- 1H-pyridin- 2-one Colorless solid Expl. 2 360.5 9 5-chloro- 1H-pyridin- 2-one Colorless solid Expl. 2 380.5 10 1H-Pyridin- 2-one Colorless solid Expl. 2 346.5 11 3- Trifluorometh- yl-1H- pyridin-2- one Colorless solid Expl. 2 414.5 12 2-Methyl- 3H- pyrimidin-4- one Colorless amporphous solid Expl. 2 361.5 13 1H- Pyrimidin-2- one Light yellow solid Expl. 2 347.6 14 2-Oxo-1,2- dihydro- pyridine-4- carbonitrile Colorless solid Expl. 2 371.6 15 0 5- Trifluorometh- yl-1H- pyridin-2- one Colorless solid Expl. 2 414.6 16 6-Oxo-1,6- dihydro- pyridine-3- carbonitrile Colorless solid Expl. 2 371.6 17 6-Chloro- 1H-pyridin- 2-one Colorless amorphous solid Expl. 2 380.5 18 6-Fluoro-1H- pyridin-2- one Colorless amorphous solid Expl. 2 364.6

(40) The following examples listed in Table 3 were prepared in analogy to the procedure described for the preparation of examples 2, by reacting 6-(5-chloromethyl-pyridin-3-yl)-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one (intermediate A-10) with the reaction partners listed below:

(41) TABLE-US-00004 TABLE 3 MS Ex Name Reactant Aspect (M + H.sup.+) 19 3-Fluoro-1H- pyridin-2-one Colorless solid 382.6 20 4-Methyl-1H- pyridin-2-one Colorless solid 378.5 21 5-Chloro-1H- pyridin-2-one Colorless solid 398.5 22 6-Chloro-1H- pyridin-2-one Colorless solid 398.5 23 6-Methyl-1H- pyridin-2-one Colorless amorphous solid 378.5

(42) The following examples listed in Table 4 were prepared in analogy to the procedure described for the preparation of examples 2, by reacting 6-(5-chloromethyl-4-methyl-pyridin-3-yl)-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one (intermediate A-11) with the reaction partners listed below:

(43) TABLE-US-00005 TABLE 4 MS Ex Name Reactant Aspect (M + H.sup.+) 24 6-Methyl-1H- pyridin-2-one Light brown amorphous solid 392.5 25 0 6-Chloro-1H- pyridin-2-one Light brown amorphous solid 412.5 26 3-Fluoro-1H- pyridin-2-one Colorless amorphous solid 396.5 27 6-Fluoro-1H- pyridin-2-one Light brown amorphous solid 396.5

Example A

(44) A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:

(45) TABLE-US-00006 Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

Example B

(46) A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:

(47) TABLE-US-00007 Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg