3,4-dihydro-2H-isoquinoline-1-one and 2,3-dihydro-isoindol-1-one compounds

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.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, A, m, n and p are as described herein, compositions including the compounds and methods of using the compounds.

Claims

1. A Compound of formula (I) ##STR00090## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from H, alkyl and cycloalkyl; R.sup.5, R.sup.7 and R.sup.9 are independently selected from H or alkyl; R.sup.8 (i) is hydrogen and both R.sup.6 and R.sup.9 together are CH.sub.2, and, R.sup.10 and R.sup.11 together are CH.sub.2; or, (ii) and R.sup.6, R.sup.9 and R.sup.11 are independently H or alkyl, and R.sup.10 is H; or, (iii) and both R.sup.6 and R.sup.9 are independently H or alkyl and R.sup.10 and R.sup.11 together are CH.sub.2; or, (iv) and R.sup.11 together are CH.sub.2CH.sub.2; and R.sup.6 and R.sup.10 are independently H or alkyl; A is C(O) or S(O).sub.2; B is C or N; R.sup.12 is cycloalkyl or substituted heteroaryl, wherein substituted heteroaryl is substituted with one to three substituent independently selected from H, alkyl, cycloalkyl, hydroxy, alkoxy, cyano and halogen; R.sup.13 is halogen, cyano, alkoxy or haloalkoxy; R.sup.14 is H, alkyl or cycloalkyl; R.sup.15 is H, alkyl, cycloalkyl or halogen; m, n and p are independently selected from zero and 1; w is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein A is S(O).sub.2.

3. The compound according to claim 1, wherein A is C(O).

4. The compound according to claim 1, wherein R.sup.12 is cycloalkyl or substituted pyridinyl, wherein substituted pyridinyl is substituted with one to three substituent independently selected from H, alkyl and halogen.

5. The compound according to claim 1, wherein R.sup.12 is cycloalkyl or substituted pyridinyl, wherein substituted pyridinyl is substituted with one to three substituent independently selected from alkyl and halogen.

6. The compound according to claim 1 wherein R.sup.12 is cycloalkyl.

7. The compound according to claim 1, R.sup.12 is substituted heteroaryl, wherein substituted heteroaryl is substituted with one to three substituent independently selected from alkyl and halogen.

8. The compound according to claim 1, wherein R.sup.12 is substituted pyridinyl, wherein substituted pididinyl is substituted with one to three substituent independently selected from alkyl and halogen.

9. The compound according to claim 1 wherein R.sup.1 and R.sup.2 are independently selected from H and alkyl.

10. The compound according to claim 1 wherein R.sup.1 and R.sup.2 are alkyl.

11. The compound according to claim 1 wherein R.sup.1 and R.sup.2 are methyl.

12. The compound according to claim 1 wherein m, n and p are zero.

13. The compound according to claim 1 wherein w is 1 or 2.

14. The compound according to claim 1 wherein R.sup.3 and R.sup.4 are H.

15. The compound according to claim 1, wherein R.sup.5, R.sup.7 and R.sup.9 are H.

16. The compound according to claim 1 wherein R.sup.9 is H and R.sup.10 and R.sup.11 together form (CH.sub.2).sub.w.

17. The compound according to claim 1 wherein R.sup.14 is H.

18. The compound according to claim 1 wherein R.sup.13 is chloro.

19. The compound according to claim 1, wherein R.sup.15 is H.

20. The compound according to claim 1 selected from 5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one; 5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one; 5-Chloro-2-[5-[[(3R or 3 S)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one; 5-Chloro-2-[5-[[(3 S or 3R)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one; 5-Chloro-2-[5-[(1-cyclopropylsulfonylpiperidin-4-yl)-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one; 5-Chloro-2-[5-[[(3R or 3 S)-1-cyclopropylsulfonylpiperidin-3-yl]amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one; 5-Chloro-2-[5-[[(3 S or 3R)-1-cyclopropylsulfonylpiperidin-3-yl]amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one; 5-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one; 5-Chloro-3,3-dimethyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindol-1-one; 5-Chloro-3,3-dimethyl-2-[5-[[1-(5-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindol-1-one; 5-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3-methyl-3H-isoindol-1-one; 5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3H-isoindol-1-one; 5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3-methyl-3H-isoindol-1-one; 6-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one; 6-Chloro-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one; 6-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one; 6-Chloro-2-[5-[[1-(5-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one; 5-Chloro-3,3-dimethyl-2-[5-[[2-(4-methylpyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl]amino]pyridin-3-yl]isoindol-1-one; 5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one; 6-Chloro-2-[5-[[1-(3,5-dimethylisoxazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinolin-1-one; 6-Chloro-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinolin-1-one; 6-Chloro-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinolin-1-one; 5-Chloro-2-[5-[[1-(3,5-dimethylisoxazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,3-dimethyl-isoindolin-1-one; 5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one; (3R or 3 S)-5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one; (3S or 3R)-5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one; (3R or 3 S)-5-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3-methyl-isoindolin-1-one; (3 S or 3R)-5-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3-methyl-isoindolin-1-one; (3R or 3 S)-5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3-methyl-isoindolin-1-one; (3 S or 3R)-5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3-methyl-isoindolin-1-one; 2-[5-[(1-Cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile; 3,3-Dimethyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile; 3,3-Dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile; 3,3-Dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile; 2-[5-[(1-Cyclopropylsulfonyl-4-piperidyl)amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile; 2-[5-[[1-(3-Chloropyridine-2-carbonyl)-4-piperidyl]amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile; 3,3-Dimethyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile; 2-[5-[[1-(3-Chloropyridine-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile; 3,3-Dimethyl-2-[5-[[1-(3-methylimidazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile; 3,3-Dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile; 3,3-Dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile; 3,3-Dimethyl-2-[5-[[1-(3-methylimidazole-4-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile; or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 1 selected from 5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one; 5-Chloro-2-[5-[[(3 S or 3R)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one; 5-Chloro-3,3-dimethyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindol-1-one; 5-Chloro-3,3-dimethyl-2-[5-[[1-(5-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindol-1-one; 5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one; 6-Chloro-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one; 6-Chloro-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinolin-1-one; 5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one; (3R or 3 S)-5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one; 2-[5-[(1-Cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile; 3,3-Dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile; or a pharmaceutically acceptable salt thereof.

22. A process to prepare a compound according to claim 1 comprising a) the reaction of a compound of formula (II) in the presence of a compound of formula (III); ##STR00091## or b) the reaction of a compound of formula (IV) in the presence of a compound of formula (V); ##STR00092## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, A, m, n and p are as defined in claim 1 and X in step a) is halogen or triflate and in step b) is halogen.

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

Description

EXAMPLES

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

Intermediate A-1

6-Chloro-3,4-dihydro-2H-isoquinolin-1-one

(2) ##STR00012##

[A] [2-(3-Chloro-phenyl)-ethyl]-carbamic acid methyl ester

(3) ##STR00013##

(4) At 0 C., methyl chloroformate (4.6 g, 48 mmol) was added dropwise to a solution of 2-(3-chloro-phenyl)-ethylamine (5.0 g, 32 mmol) and Et.sub.3N (6.4 g, 64 mmol) in DCM (100 mL). After the addition, the mixture was stirred at room temperature for 0.5 hours. The organic layer was washed with water (330 mL), 1N HCl (20 mL) and brine (30 mL), dried over anhy. Na.sub.2SO.sub.4, filtered and concentrated in vacuo. After vacuum drying, the title compound was obtained (6.49 g, 95%) as a white solid. MS: 214.1 (M+H.sup.+).

[B] 6-Chloro-3,4-dihydro-2H-isoquinolin-1-one

(5) ##STR00014##

(6) Under N.sub.2 protection, a mixture of [2-(3-chloro-phenyl)-ethyl]-carbamic acid methyl ester (5.0 g, 23.4 mmol) and PPA (polyphosphoric acid) (20 g) in a 250 mL round-bottom flask was vigorously stirred at 120 C. for 2 hours. After cooling to room temperature, the reaction mixture was treated with ice-water and aqueous ammonia solution to adjust the pH to 8. Then, the mixture was extracted with EtOAc, and the organic layer was washed with brine, dried over anhy. Na.sub.2SO.sub.4 and filtered. After removal of solvent under reduced pressure, the crude product obtained was further washed with ethyl ether to give the title compound (1.66 g, 39%) as a white solid. MS: 182.0 (M+H.sup.+).

Intermediate A-2

5-Chloro-3-methyl-2,3-dihydro-isoindol-1-one

(7) ##STR00015##

[A] 1-(2-Bromo-5-chloro-phenyl)-ethylamine

(8) ##STR00016##

(9) To a stirred solution of 2-bromo-5-chlorobenzonitrile (80 g, 370 mmol) in THF (1000 mL) at 0 C. was added EtMgBr (370 mL, 1110 mmol) dropwise. The reaction mixture was stirred at 0-5 C. for 5 hours before MeOH (500 mL) was added dropwise. After the solution was stirred for another 15 min, NaBH.sub.4 (28 g, 740 mmol) was added carefully and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was then poured into water and exacted with EtOAc (3200 mL). The combined organic layers were dried over anhy. Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a crude product, which was purified by column chromatography (petroleum ether:EtOAc=3:1) to afford the title compound (30 g, 34.6%) as yellowish oil. MS: 235.5 [M+H.sup.+].

[B] 5-Chloro-3-methyl-2,3-dihydro-isoindol-1-one

(10) ##STR00017##

(11) A mixture of 1-(2-bromo-5-chlorophenyl)-ethylamine (30 g, 127.9 mmol), Pd(dppf)Cl.sub.2 (3.2 g, 12.79 mmol), and DIPEA (49.5 g, 383.7 mmol) in DMF (1.2 L) was stirred in an autoclave under 2 MPa of CO at 130 C. for 24 hours. After the reaction was cooled to room temperature, the reaction mixture was diluted with EtOAc (500 mL). The organic layer was washed with brine, filtered, and concentrated in vacuo to give a crude product, which was purified by chromatography (PE:EtOAc=3:1) to give the title compound (5.2 g, 22.5%) as a brown solid. MS: 181.7 [M+H.sup.+].

Intermediate A-3

5-Chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one

(12) ##STR00018##

[A] 1-(2-Bromo-5-chloro-phenyl)-1-methyl-ethylamine

(13) ##STR00019##

(14) To a stirred solution of 2-bromo-5-chloro-benzonitrile (10 g, 46 mmol) in THF (200 mL) at 0 C., was added MeMgBr (77 mL, 230 mmol) dropwise. The reaction mixture was allowed to warm up to room temperature and stirred for 2 hours. Ti(Oi-Pr).sub.4 (13 g, 46 mmol) was added and the solution was stirred for another 16 hours before it was quenched with aq. HCl solution and washed with EtOAc. The aqueous phase was adjusted to pH 10 with aq. NaOH solution, and exacted with EtOAc (3100 mL). The combined organic layers were concentrated to give a crude title product (3.8 g, yield 33%) as oil, which was used directly in the next step without further purification. MS: 249.30 (M+H.sup.+)

[B] 5-Chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one

(15) ##STR00020##

(16) A mixture of 1-(2-bromo-5-chloro-phenyl)-1-methyl-ethylamine (3.8 g, 15.3 mmol), Pd(dppf)Cl.sub.2 (0.4 g, 0.55 mmol) and DIPEA (6 g, 45.9 mmol) in DMF (20 mL) was stirred in an autoclave under 2 MPa of CO at 130 C. for 16 hours. Then, it was cooled to room temperature and the reaction mixture was diluted with EtOAc (300 mL). The organic layer was washed with brine (280 mL), filtered, and concentrated in vacuo to give a crude product, which was purified by chromatography to give the title compound (1.13 g, 38%) as a brown solid. MS: 195.70 (M+H.sup.+)

Intermediate A-4

3,3-Dimethyl-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile

(17) ##STR00021##

[A] 4-Bromo-2-methyl-benzoic acid methyl ester

(18) ##STR00022##

(19) To a solution of 4-bromo-2-methyl-benzoic acid (30.0 g, 0.14 mol) in 115 mL of methanol was added thionyl chloride (20.25 mL, 0.28 mol) slowly and the reaction mixture was stirred at 70 C. for 2 hours before it was concentrated to afford a crude product which was then purified by column chromatography to give the title compound (30.03 g, 93.6%) as a solid.

[B] 4-Cyano-2-methyl-benzoic acid methyl ester

(20) ##STR00023##

(21) A mixture of 4-bromo-2-methyl-benzoic acid methyl ester (26.0 g, 113.5 mmol) and CuCN (12.48 g, 140.7 mmol) was heated at 180 C. for 5 hours before it was poured into ice-water. The solid precipitate was collected by vacuum filtration to give a crude product which was then purified by column chromatography to afford the title compound (12.53 g, 63%) as a solid.

[C] 2-Bromomethyl-4-cyano-benzoic acid methyl ester

(22) ##STR00024##

(23) A mixture of 4-cyano-2-methyl-benzoic acid methyl ester (12.5 g, 71.35 mmol), NBS (12.7 g, 71.35 mmol) and di-benzoyl peroxide (BPO) (0.8 g, 3.28 mmol) in CCl.sub.4 (200 mL) was heated to reflux temperature for 3 hours. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give a crude product (18.2 g) which was used in the next step reaction without further purification.

[D] 2-(4-Methoxy-benzyl)-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile

(24) ##STR00025##

(25) To a solution of 2-bromomethyl-4-cyano-benzoic acid methyl ester (18.1 g, 71.24 mmol) in THF (300 mL) was added PMBNH.sub.2 (23.4 g, 178.1 mmol) at 0 C. and the reaction mixture was stirred at room temperature for 16 hours. After vacuum filtration, the filtrate was concentrated in vacuo. The residue obtained was re-dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhy. Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give a crude product which was purified by column chromatography to give the title compound as a solid (11.69 g, 56.0%).

[E] 2-(4-Methoxy-benzyl)-3,3-dimethyl-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile

(26) ##STR00026##

(27) To a solution of 2-(4-methoxy-benzyl)-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile (11.6 g, 41.7 mmol) in THF (300 mL) was added NaH (8.34 g, 208.4 mmol, 60% in mineral oil) and the reaction mixture was stirred at room temperature for 1 hour before iodomethane (35.5 g, 250.1 mmol) was added. After the addition, the reaction mixture was stirred at 70 C. for 2 hours until all the starting material was consumed. After cooling to room temperature, satd. aq. NH.sub.4Cl solution was added and the mixture was extracted with EtOAc (200 mL3). The combined organic layers were dried over anhy. MgSO.sub.4, filtered, and concentrated under reduced pressure to give a crude product which was purified by column chromatography to afford the title compound (7.22 g, 56.5%) as a solid.

[F] 3,3-Dimethyl-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile

(28) ##STR00027##

(29) To a solution of 2-(4-methoxy-benzyl)-3,3-dimethyl-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile (3.5 g, 11.42 mmol) in MeCN (70 mL) was added CAN (18.79 g, 34.27 mmol) in 30 mL of water at 0 C. The resulting reaction mixture was stirred at 0 C. for 1 hour until all the starting material was consumed. The reaction mixture was extracted between water and EtOAc and the combined organic layers were dried over anhy. MgSO.sub.4, filtered, and concentrated under reduced pressure to give a crude product which was purified by column chromatography to afford the title compound (1.06 g, 49.8%) as a solid.

Intermediate A-5

3,5-Diiodo-pyridine

(30) ##STR00028##

(31) A mixture of 3,5-dibromopyridine (20 g, 84 mmol), CuI (4.76 g, 25 mmol), KI (83.7 g, 504 mmol) and N.sup.1,N.sup.2-dimethylethane-1,2-diamine (4.4 g, 50.4 mmol) in dioxane (400 mL) was stirred at 110 C. for 16 hours. During this time, the reaction progress was monitored by LC/MS. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford a solid, which was then washed with EtOAc (100 mL) and DCM (100 mL) to give the crude title compound as a gray solid (13 g, 47%). MS: 331.50 (M+H.sup.+). It was used in the next step without further purification.

Intermediate A-6

3-[5-(6-Chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylamino]-azetidine-1-carboxylic acid tert-butyl ester

(32) ##STR00029##

[A] 5-Chloro-2-(5-iodo-pyridin-3-yl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one

(33) ##STR00030##

(34) In a 75-mL sealed tube, 3,5-diiodo-pyridine (intermediate A-5, 6.6 g, 20 mmol), 5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one (intermediate A-3, 1.95 g, 10 mmol), CuI (571 mg, 3 mmol), K.sub.3PO.sub.4 (4.24 g, 20 mmol) and (+)-(S,S)-1,2-diaminocyclohexane (0.7 mL, 6 mmol) were dissolved in 20 mL of dioxane. The resulting reaction mixture was heated at 120 C. for 3 hours before it was poured into water (50 mL) and extracted with EtOAc (2125 mL). The combined organic layers were washed with brine, dried over anhy. Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography (0-30% EtOAc-hexane gradient) to yield the title compound (1.8 g, 45%) as a light yellow solid. MS: 399.2 (M+H.sup.+).

[B] 3-[5-(6-Chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylamino]-azetidine-1-carboxylic acid tert-butyl ester

(35) ##STR00031##

(36) A mixture of 5-chloro-2-(5-iodo-pyridin-3-yl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one (2.16 g, 5.4 mmol), 3-amino-azetidine-1-carboxylic acid tert-butyl ester (1.8 g, 10.8 mmol), CuI (103 mg, 0.54 mmol), Cs.sub.2CO.sub.3 (3.5 g, 10.8 mmol) and 2-isobutyryl-cyclohexanone (0.36 mL, 2.16 mmol) in DMF (12 mL) were stirred at 100 C. for 12 hours. After cooling to room temperature, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (2100 mL). The combined organic layers were washed with brine, dried over anhy. Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography (30-100% EtOAc-hexane gradient) to yield the title compound (1.1 g, 48%) as a light yellow foam. MS: 443.2 (M+H.sup.+).

(37) The following intermediates listed in Table 1 were prepared in analogy to the procedures described for the preparation of intermediate A-6, using appropriate reaction partners.

(38) TABLE-US-00002 TABLE 1 MS Intermediate Name Reactants (M + H.sup.+) A-7 3-[5-(5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)- pyridin-3-ylamino]-azetidine-1-carboxylic acid tert-butyl ester 5-Chloro-3-methyl-2,3- dihydro-isoindol-1-one (Intermediate A-2), 3,5- diiodo-pyridine (Intermediate A-5), and 3-amino-azetidine- 1-carboxylic acid tert- butyl ester 429.1 A-8 3-[5-(6-Chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3- ylamino]-azetidine-1-carboxylic acid tert-butyl ester 6-Chloro-3,4-dihydro-2H- isoquinolin-1-one (Intermediate A-1), 3,5- diiodo-pyridine (Intermediate A-5), and 3-amino-azetidine-1- carboxylic acid tert-butyl ester 429.1 A-9 3-[5-(6-Chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)- pyridin-3-ylamino]-piperidine-1-carboxylic acid tert-butyl ester 5-Chloro-3,3-dimethyl- 2,3-dihydro-isoindol-1-one (Intermediate A-3), 3,5- diiodo-pyridine (Intermediate A-5), and 3- amino-piperidine-1- carboxylic acid tert-butyl ester 471.1 A-10 6-[5-(6-Chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)- pyridin-3-ylamino]-2-aza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester 5-Chloro-3,3-dimethyl- 2,3-dihydro-isoindol-1-one (Intermediate A-3), 3,5- diiodo-pyridine (Intermediate A-5), and 6- amino-2-aza- spiro[3.3]heptane-2- carboxylic acid tert-butyl ester 483.1 A-11 tert-Butyl 3-[[5-(6-cyano-1,1-dimethyl-3-oxo-isoindolin-2-yl)-3- pyridyl]amino]azetidine-1-carboxylate 3,3-Dimethyl-1-oxo-2,3- dihydro-1H-isoindole-5- carbonitrile (Intermediate A-4), 3,5-diiodo-pyridine (Intermediate A-5), and 3- amino-azetidine-1- carboxylic acid tert-butyl ester 434.1 A-12 tert-Butyl 4-[[5-(6-cyano-[1,1-dimethyl-3-oxo-isoindolin-2-yl)-3- pyridyl]amino]piperidine-1-carboxylate 3,3-Dimethyl-1-oxo-2,3- dihydro-1H-isoindole-5- carbonitrile (Intermediate A-4), 3,5-diiodo-pyridine (Intermediate A-5), and 4- amino-piperidine-1- carboxylic acid tert-butyl ester 462.1

Example 1

5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one

(39) ##STR00038##

[A] 2-[5-(Azetidin-3-ylamino)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one

(40) ##STR00039##

(41) A mixture of 3-[5-(6-chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (Intermediate A-6, 360 mg, 0.812 mmol), acetyl chloride (0.56 mL) in methanol (12 mL) was stirred at room temperature for 2 hours. After concentration under reduced pressure, it gives a crude product as light yellow foam, which was used in the next step without further purification. MS: 343.2 (M+H.sup.+).

[B] 5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one

(42) ##STR00040##

(43) To a stirred solution of 2-[5-(azetidin-3-ylamino)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one (56 mg, 0.163 mmol) and Et.sub.3N (0.5 mL) in DCM (5 mL) was added cyclopropanesulfonyl chloride (30 mg, 0.21 mmol) at 0 C. and stirring at 0 C. was continued for 1 hour. The resulting reaction mixture was extracted with EtOAc (2100 mL) and the combined organic layers were washed with brine, dried over anhy. Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a crude product, which was purified by Prep-HPLC to afford title compound (22 mg, 30%) as a white foam. MS: 447.1 (M+H.sup.+).

Example 2

5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one

(44) ##STR00041##

(45) To a stirred solution of 2-[5-(azetidin-3-ylamino)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one (Example 1 [A], 56 mg, 0.163 mmol) and Et.sub.3N (0.5 mL) in DCM (5 mL) was added HATU (124 mg, 0.326 mmol) and 1-methylimidazole-2-carboxylic acid (27 mg, 0.212 mmol) at room temperature and stirring was continued at room temperature for 1 hour. The resulting reaction mixture was extracted with EtOAc (250 mL) and the combined organics were washed with brine, dried over anhy. Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a crude product, which was purified by Prep-HPLC to afford title compound (15.4 mg, 21%) as a white foam. MS: 451.1 (M+H.sup.+).

Example 3

5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one

(46) ##STR00042##

[A] 3-{[5-(6-Chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-yl]-methyl-amino}-azetidine-1-carboxylic acid tert-butyl ester

(47) ##STR00043##

(48) A mixture of 5-chloro-2-(5-iodo-pyridin-3-yl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one (398 mg, 1 mmol, intermediate A-6 [A]), 3-methylamino-azetidine-1-carboxylic acid tert-butyl ester (250 mg, 1.3 mmol), Pd(OAc).sub.2 (35 mg, 10% of weight), Xanphos (70 mg, 20% of weight) and t-BuONa (192 mg, 2 mmol) in dioxane (6 mL) was stirred at 115 C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (2100 mL). The combined organic layers were washed with brine, dried over anhy. Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography (40-100% EtOAc-hexane gradient) to yield the title compound (196 mg, 43%) as a light yellow foam. MS: 457.1 (M+H.sup.+).

[B] 2-[5-(Azetidin-3-yl-methyl-amino)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one

(49) ##STR00044##

(50) A mixture of 3-{[5-(6-chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-yl]-methyl-amino}-azetidine-1-carboxylic acid tert-butyl ester (196 mg, 0.43 mmol), acetyl chloride (0.56 mL) in methanol (12 mL) was stirred at room temperature for 2 hours. It was then concentrated in vacuo to give a crude product as a light yellow foam. It was used in the next step of reaction without further purification. MS: 357.2 (M+H.sup.+).

[C] 5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one

(51) ##STR00045##

(52) To a stirred solution of 2-[5-(azetidin-3-yl-methyl-amino)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one (60 mg, 0.17 mmol) and Et.sub.3N (0.50 mL) in DCM (5 mL) was added cyclopropanesulfonyl chloride (31 mg, 0.22 mmol) at 0 C. and stirring at 0 C. was continued for 1 hour. The resulting mixture was extracted with EtOAc (2100 mL) and combined organics were washed with brine, dried over anhy. Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford a crude product, which was purified by Prep-HPLC to afforded title compound (19 mg, 24%) as white foam. MS: 461.1 (M+H.sup.+).

Example 4 and Example 5

(+)-5-Chloro-2-[5-[[(3R or 3S)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one and ()-5-chloro-2-[5-[[(3S or 3R)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one

(53) ##STR00046##
Example 4, (+)-(R or S)

(54) ##STR00047##
Example 5, ()-(S or R)

[A] 3-{[5-(6-Chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-yl]-methyl-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester

(55) ##STR00048##

(56) In analogy to the procedure described for the preparation of Example 3 [A], 3-methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester was used to give the title compound as a light yellow foam (47%). MS: 471.1 (M+H.sup.+).

[B] 5-Chloro-3,3-dimethyl-2-[5-(methyl-pyrrolidin-3-yl-amino)-pyridin-3-yl]-2,3-dihydro-isoindol-1-one

(57) ##STR00049##

(58) In analogy to the procedure described for the preparation of Example 3 [B], the title compound was obtained as a crude product of light yellow foam. It was used in the next step without further purification. MS: 371.2 (M+H.sup.+).

[C] (rac)-5-Chloro-2-{5-[(1-cyclopropylsulfonyl-pyrrolidin-3-yl)-methyl-amino]-pyridin-3-yl}-3,3-dimethyl-2,3-dihydro-isoindol-1-one

(59) ##STR00050##

(60) In analogy to the procedure described for the preparation of Example 3 [C], cyclopropanesulfonyl chloride was used to yield the title compound (105 mg, 40%) as a racemic mixture of white foam. MS: 475.1 (M+H.sup.+).

[D] (+)-5-Chloro-2-[5-[[(3R or 3S)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one (Example 4) and ()-5-chloro-2-[5-[[(3S or 3R)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one (Example 5)

(61) ##STR00051##
Example 4, (+)-(R or S)

(62) ##STR00052##
Example 5, ()-(S or R)

(63) The title compounds were prepared by chiral separation of (rac)-5-chloro-2-{5-[(1-cyclopropylsulfonyl-pyrrolidin-3-yl)-methyl-amino]-pyridin-3-yl}-3,3-dimethyl-2,3-dihydro-isoindol-1-one on a Chiralpak IA column (10% ACN in ethanol) to give (+)-5-chloro-2-[5-[[(3R or 3S)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one (10 mg, 20%, example 4), MS: 475.1 (M+H.sup.+) and ()-5-chloro-2-[5-[[(3S or 3R)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one (12.5 mg, 25%, example 5) as off-white foam. MS: 475.1 (M+H.sup.+).

(64) The following examples listed in Table 2 were prepared in analogy to the procedures described for the preparation of examples 1, 2, 3, 4 (or 5) by using appropriate starting materials:

(65) TABLE-US-00003 TABLE 2 Ex Name/Structure/MS (M + H.sup.+) Reactant Reference 6 5-Chloro-2-[5-(1-cyclopropylsulfonylpiperidin-4-yl)-methylamino]pyridin- 3-yl]-3,3-dimethylisoindol-1-one 489.1 5-Chloro-3,3- dimethyl-2-[5- (methyl- piperidin-4-yl- amino)- pyridin-3-yl]- 2,3-dihydro- isoindol-1-one and cyclopropane sulfonyl chloride Expl. 3 7 (+)-5-Chloro-2-[5-[[(3R or 3S)-1-cyclopropylsulfonylpiperidin-3- yl]amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one. 475.1 3-[5-(6- Chloro-1,1- dimethyl-3- oxo-1,3- dihydro- isoindol-2-yl)- pyridin-3- ylamino]- piperidine-1- carboxylic acid tert-butyl ester (Intermediate A-9) and cyclopropyl sulfonyl chloride Expl. 4 and chiral separation 8 ()-5-Chloro-2-[5-[[3S or 3R)-1-cyclopropylsulfonylpiperidin-3- yl]amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one 475.1 3-[5-(6- Chloro-1,1- dimethyl-3- oxo-1,3- dihydro- isoindol-2-yl)- pyridin-3- ylamino]- piperidine-1- carboxylic acid tert-butyl ester (Intermediate A-9) and cyclopropyl sulfonyl chloride Expl. 4 and chiral separation 9 5-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3- yl]amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one 482.1 2-[5-(azetidin- 3-ylamino)- pyridin-3-yl]- 5-chloro-3,3- dimethyl-2,3- dihydro- isoindol-1-one (Example 1[A]) and 3- chloropyridine- 2-carboxylic acid Expl. 2 10 5-Chloro-3,3-dimethyl-2-[5-[[1-(4-methylpyridin-3-carbonyl)azetidin-3- yl]amino]pyridin-3-yl]isoindol-1-one 462.1 2-[5-(azetidin- 3-ylamino)- pyridin-3-yl]- 5-chloro-3,3- dimethyl-2,3- dihydro- isoindol-1-one (Example 1[A]) and 4- methylpyridine- 3-carboxylic acid Expl. 2 11 5-Chloro-3,3-dimethyl-2-[5-[[1-(5-methylpyridine-3-carbonyl)azetidin-3- yl]amino]pyridin-3-yl]isoindol-1-one 462.1 2-[5-(azetidin- 3-ylamino)- pyridin-3-yl]- 5-chloro-3,3- dimethyl-2,3- dihydro- isoindol-1-one (Example 1[A]) and 5- methylpyridine- 3-carboxylic acid Expl. 2 12 5-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3- yl]amino]pyridin-3-yl]-3-methyl-3H-isoindol-1-one 468.1 3-[5-(5- Chloro-3- methyl-1-oxo- 1,3-dihydro- isoindol-2-yl)- pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester (Intermediate 7) and 3- chloropyridine- 2-carboxylic acid Expl. 2 13 5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3- yl]amino]pyridin-3-yl]-3H-isoindol-1-one 0 448.1 3-[5-(5- Chloro-3- methyl-1-oxo- 1,3-dihydro- isoindol-2-yl)- pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester (Intermediate 7) and 4- methylpyridine- 3-carboxylic acid Expl. 2 14 5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3- yl]-3-methyl-3H-isoindol-1-one 433.1 3-[5-(5- Chloro-3- methyl-1-oxo- 1,3-dihydro- isoindol-2-yl)- pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester (Intermediate A-7) and cyclopropane- sulfonyl chloride Expl. 1 15 6-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,4- dihydroisoquinolin-1-one 433.1 3-[5-(6- Chloro-1-oxo- 3,4-dihydro- 1H- isoquinolin-2- yl)-pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester (Intermediate A-8) and cyclopropane- sulfonyl chloride Expl. 1 16 6-Chloro-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3- yl]amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one 448.1 3-[5-(6- Chloro-1-oxo- 3,4-dihydro- 1H- isoquinolin-2- yl)-pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester (Intermediate A-8) and 4- methylpyridine- 3-carboxylic acid Expl. 2 17 6-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3- yl]amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one 468.1 3-[5-(6- Chloro-1-oxo- 3,4-dihydro- 1H- isoquinolin-2- yl)-pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester (Intermediate A-8) and 3- chloropyridine- 2-carboxylic acid Expl. 2 18 6-Chloro-2-[5-[[1-(5-methylpyridine-3-carbonyl)azetidin-3- yl]amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one 448.1 3-[5-(6- Chloro-1-oxo- 3,4-dihydro- 1H- isoquinolin-2- yl)-pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester (Intermediate A-8) and 4- methylpyridine- 3-carboxylic acid Expl. 2 19 5-Chloro-3,3-dimethyl-2-[5-[[2-(4-methylpyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl]amino]pyridin-3-yl]isoindol-1-one 502.1 6-[5-(6- Chloro-1,1- dimethyl-3- oxo-1,3- dihydro- isoindol-2-yl)- pyridin-3- ylamino]-2-aza- spiro[3.3]heptane- 2-carboxylic acid tert-butyl ester (Intermediate 10) and 4- methylpyridine- 3-carboxylic acid Expl. 2 20 6-Chloro-2-[5-[[1-(3,5-dimethylisoxazole-4-carbonyl)azetidin-3- yl]amino]-3-pyridyl]-3,4-dihydroisoquinolin-1-one 452.1 3-[5-(6- Chloro-1-oxo- 3,4-dihydro-1H- isoquinolin-2- yl)-pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester (Intermediate A-8) and 3,5- dimethylisoxazole- 4-carboxylic acid Expl. 2 21 6-Chloro-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3- yl]amino]-3-pyridyl]-3,4-dihydroisoquinolin-1-one 437.1 3-[5-(6- Chloro-1-oxo- 3,4-dihydro- 1H- isoquinolin-2- yl)-pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester (Intermediate A-8) and 1- methylpyrazole- 4-carboxylic acid Expl. 2 22 6-Chloro-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3- yl]amino]-3-pyridyl]-3,4-dihydroisoquinolin-1-one 437.1 3-[5-(6- Chloro-1-oxo- 3,4-dihydro-1H- isoquinolin-2- yl)-pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester (Intermediate A-8) and 1- methylimidazole- 2-carboxylic acid Expl. 2 23 5-Chloro-2-[5-[[1-(3,5-dimethylisoxazole-4-carbonyl)azetidin-3- yl]amino]-3-pyridyl]-3,3-dimethyl-isoindolin-1-one 0 466.1 2-[5-(Azetidin- 3-ylamino)- pyridin-3-yl]- 5-chloro-3,3- dimethyl-2,3- dihydro- isoindol-1-one (Example 1[A]) and 3,5- dimethylisoxazole- 4-carboxylic acid Expl. 2 24 5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylpyrazole-4- carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one 451.1 2-[5-(Azetidin- 3-ylamino)- pyridin-3-yl]- 5-chloro-3,3- dimethyl-2,3- dihydro- isoindol-1-one (Example 1[A]) and 1- methylpyrazole- 4-carboxylic acid Expl. 2 25 (3R or 3S)-5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridine-3- carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one 448.1 Chloro-3- methyl-1-oxo- 1,3-dihydro- isoindol-2-yl)- pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester (Intermediate A-7) and 4- methylpyridine-3- carboxylic acid Expl. 2 and chiral separation 26 (3S or 3R)-5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridine-3- carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one 448.1 Chloro-3- methyl-1-oxo- 1,3-dihydro- isoindol-2-yl)- pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester (Intermediate A-7) and 4- methylpyridine- 3-carboxylic acid Expl. 2 and chiral separation 27 (3R or 3S)-5-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3- yl]amino]-3-pyridyl]-3-methyl-isoindolin-1-one 468.1 Chloro-3- methyl-1-oxo- 1,3-dihydro- isoindol-2-yl)- pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester (Intermediate A-7) and 3- chloropyridine- 2-carboxylic acid Expl. 2 and chiral separation 28 (3S or 3R)-5-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin- 3-yl]amino]-3-pyridyl]-3-methyl-isoindolin-1-one 468.1 Chloro-3- methyl-1-oxo- 1,3-dihydro- isoindol-2-yl)- pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester (Intermediate A-7) and 3- chloropyridine- 2-carboxylic acid Expl. 2 and chiral separation 29 (3R or 3S)-5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3- yl)amino]-3-pyridyl]-3-methyl-isoindolin-1-one 433.1 Chloro-3- methyl-1-oxo- 1,3-dihydro- isoindol-2-yl)- pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester (Intermediate A-7) and cyclopropane- sulfonyl chloride Expl. 1 and chiral separation 30 (3S or 3R)-5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin- 3-yl)amino]-3-pyridyl]-3-methyl-isoindolin-1-one 433.1 Chloro-3- methyl-1-oxo- 1,3-dihydro- isoindol-2-yl)- pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester (Intermediate A-7) and cyclopropane- sulfonyl chloride Expl. 1 and chiral separation 31 2-[5-[(1-Cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3,3- dimethyl-1-oxo-isoindoline-5-carbonitrile 438.1 tert-Butyl 3- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2- yl)-3- pyridyl]amino] azetidine-1- carboxylate (Intermediate 11) and cyclopropane- sulfonyl chloride Expl. 1 32 3,3-Dimethyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3- yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile 453.1 tert-Butyl 3- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2- yl)-3- pyridyl]amino] azetidine-1- carboxylate (Intermediate 11) and 4- methylpyridine- 3-carboxylic acid Expl. 2 33 3,3-Dimethyl-2-[5-[[1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]- 3-pyridyl]-1-oxo-isoindoline-5-carbonitrile 0 442.1 tert-Butyl 3- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2- yl)-3- pyridyl]amino] azetidine-1- carboxylate (Intermediate 11) and 1- methylpyrazole- 4-carboxylic acid Expl. 2 34 3,3-Dimethyl-2[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3- yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile 442.1 tert-Butyl 3- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2- yl)-3- pyridyl]amino] azetidine-1- carboxylate (Intermediate 11) and 1- methylimidazole- 2-carboxylic acid Expl. 2 35 2-[5-[(1-Cyclopropylsulfonyl-4-piperidyl)amino]-3-pyridyl]- 3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile 466.1 tert-Butyl 4- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2- yl)-3- pyridyl]amino] piperidine-1- carboxylate (Intermediate 12) and cyclopropane- sulfonyl chloride Expl. 1 36 2-[5-[[1-(3-Chloropyridine-2-carbonyl)-4-piperidyl]amino]-3-pyridyl]- 3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile 501.1 tert-Butyl 4- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2- yl)-3- pyridyl]amino] piperidine-1- carboxylate (Intermediate 12) and 3- chloropyridine- 2-carboxylic acid Expl. 2 37 3,3-Dimethyl-2[5-[[1-(4-methylpyridine-3-carbonyl)-4-piperidyl]amino]- 3-pyridyl]-1-oxo-isoindoline-5-carbonitrile 481.1 tert-Butyl 4- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2- yl)-3- pyridyl]amino] piperidine-1- carboxylate (Intermediate 12) and 4- methylpyridine- 3-carboxylic acid Expl. 2 38 2-[5-[[1-(3-Chloropyridine-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]- 3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile 473.1 tert-Butyl 3- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2- yl)-3- pyridyl]amino] azetidine-1- carboxylate (Intermediate 11) and 3- chloropyridine- 2-carboxylic acid Expl. 2 39 3,3-Dimethyl-2-[5-[[1-(3-methylimidazole-4-carbonyl)azetidin-3- yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile 442.1 tert-Butyl 3- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2- yl)-3- pyridyl]amino] azetidine-1- carboxylate (Intermediate 11) and 3- methylimidazole- 4-carboxylic acid Expl. 2 40 3,3-Dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)-4-piperidyl]amino]-3- pyridyl]-1-oxo-isoindoline-5-carbonitrile 470.1 tert-Butyl 4- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2- yl)-3- pyridyl]amino] piperidine-1- carboxylate (Intermediate 12) and 1- methylpyrazole- 4-carboxylic acid Expl. 2 41 3,3-Dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)-4-piperidyl]amino]- 3-pyridyl]-1-oxo-isoindoline-5-carbonitrile 470.1 tert-Butyl 4- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2- yl)-3- pyridyl]amino] piperidine-1- carboxylate (Intermediate 12) and 1- methylimidazole- 2-carboxylic acid Exp1. 2 42 3,3-Dimethyl-2-[5-[[1-(3-methylimidazole-4-carbonyl)-4-piperidyl]amino]- 3-pyridyl]-1-oxo-isoindoline-5-carbonitrile 470.1 tert-Butyl 4- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2- yl)-3- pyridyl]amino] piperidine-1- carboxylate (Intermediate 12) and 3- methylimidazole- 4-carboxylic acid Expl. 2

Example A

(66) 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:

(67) TABLE-US-00004 Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

Example B

(68) 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:

(69) TABLE-US-00005 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