BICYCLIC QUINAZOLINONE 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.8, R.sup.9, R.sup.10, R.sup.12, R.sup.13, R.sup.14, A.sup.1, A.sup.2, A.sup.3, n and m are as described herein.

Claims

1-42. (canceled)

43. A compound, wherein the compound is: (3R)-3-[[2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-N-benzyl-3-[4-(trifluoromethyl)phenyl]propanamide; 2-[6-(4-acetylpiperazin-1-yl)-2,4-dioxo-1H-quinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]acetamide; 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[2-(3,4-dichlorophenyl)ethyl]acetamide; 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[[3-(4-chlorophenyl)-1,2-oxazol-5-yl]methyl]acetamide; or 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]methyl]acetamide; or a pharmaceutically acceptable salt thereof.

44. The compound of claim 43, wherein the compound is (3R)-3-[[2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-N-benzyl-3-[4-(trifluoromethyl)phenyl]propanamide, or a pharmaceutically acceptable salt thereof.

45. The compound of claim 43, wherein the compound is 2-[6-(4-acetylpiperazin-1-yl)-2,4-dioxo-1H-quinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]acetamide, or a pharmaceutically acceptable salt thereof.

46. The compound of claim 43, wherein the compound is 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[2-(3,4-dichlorophenyl)ethyl]acetamide, or a pharmaceutically acceptable salt thereof.

47. The compound of claim 43, wherein the compound is 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[[3-(4-chlorophenyl)-1,2-oxazol-5-yl]methyl]acetamide, or a pharmaceutically acceptable salt thereof.

48. The compound of claim 43, wherein the compound is 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]methyl]acetamide, or a pharmaceutically acceptable salt thereof.

49. A pharmaceutical composition, comprising a compound according to claim 43, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

50. A method for the treatment of a condition, comprising administering a compound according to claim 43, or a pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus, and acute and chronic organ transplant rejection.

51. The method of claim 45, wherein the condition is an ocular condition.

52. The method of claim 46, wherein the ocular condition is proliferative retinopathy, non-proliferative diabetic retinopathy, dry age-related macular degeneration, wet age-related macular degeneration, macular edema, central arterial occlusion, central venous occlusion, traumatic injury, or glaucoma.

53. The method of claim 47, wherein the condition is glaucoma.

Description

EXAMPLES

[0376] All examples and intermediates were prepared under nitrogen atmosphere if not specified otherwise.

[0377] CDI=N,N-carbonyldiimidazole [CAS RN 530-62-1], DCC=N,N-dicyclohexylcarbodiimide [CAS RN 538-75-0], DCM=dichloromethane, DIPEA=diisopopylethylamine=iPr.sub.2NEt=N-ethyl diisopropylamine=Huenig's base, DMF=N,N-dimethylformamide, dppf=1,1-bis(diphenylphosphino)ferrocen [CAS RN 12150-46-8], EtOAc=ethyl acetate, h=hour, HATU=1-[bis(dimethylamino) methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate [CAS RN 148893-10-1], HOBT=1-hydroxy-1,2,3-benzotriazole [CAS RN 123333-53-9], HPLC=high performance liquid chromatography, MPLC=medium pressure liquid chromatography, MS=mass spectrometry, NaBH.sub.3CN=sodium cyanoborohydride, NaBH(OAc).sub.3=sodium triacetoxyborohydride, NH.sub.4OAc=ammonium acetate, OAc=acetate, PFA=perfluoroalkoxy polymer, Ph=phenyl, PYBOP=(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate [CAS RN 128625-52-5], rt=room temperature, TBTU=O-benzotriazol-1-yl-N,N,N,N-tetramethyluronium tetrafluoroborate [CAS RN 125700-67-6], THF=tetrahydrofuran.

Intermediate A-1

2-[6-[4-(9H-Fluoren-9-ylmethoxycarbonyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]acetic acid

[0378] ##STR00012##

[A] 2-Nitro-5-piperazin-1-ylbenzoic acid

[0379] ##STR00013##

[0380] A mixture of 5-chloro-2-nitrobenzoic acid (5.0 g, 24.87 mmol; [CAS RN 2516-95-2]) and piperazin (5.34 g, 62.19 mmol; [CAS RN 110-85-0]) in DMF (10 mL) was heated at 110 C. for 6 h. The reaction mixture was cooled to rt followed by the addition of ice water (50 mL) into the reaction mixture and stirred for 15 min at rt. The precipitated solid was collected by filtration, washed with water (350 mL) and dried under vacuum. The title compound was obtained as yellow solid and used directly in the consecutive reaction step without further purification (4.3 g, 69%). MS: m/e=252.1 [M+H].sup.+.

[B] 5-[4-(9H-Fluoren-9-ylmethoxycarbonyl)piperazin-1-yl]-2-nitrobenzoic acid

[0381] ##STR00014##

[0382] To a suspension of 2-nitro-5-piperazin-1-ylbenzoic acid (4.0 g, 15.94 mmol) in dioxane (40 mL) and aq. 10% NaHCO.sub.3 solution (30 mL) was added dropwise 9-fluorenylmethyl chloroformate (4.4 g, 16.73 mmol; [CAS RN 28920-43-6]) in dioxane (40 mL) at 0 C. for 15 min. The resulting mixture was stirred at rt for 20 h. The crude reaction mixture was concentrated under reduce pressure and partitioned between water (50 mL) and EtOAc (50 mL). The organic phase was separated and the aqueous phase extracted with EtOAc (250 mL). After that the aqueous phase was neutralized by addition of 35% conc. HCl (2.0 mL) to get a solid precipitate. The obtained solid was collected by filtration, followed by washing with water (225 mL) and dried under vacuum. The title compound was obtained as yellow solid and used directly in the consecutive reaction step without further purification (4.8 g, 62%). MS: m/e=474.2 [M+H].sup.+.

[C] 9H-Fluoren-9-ylmethyl 4-[3-[[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]carbamoyl]-4-nitrophenyl]piperazine-1-carboxylate

[0383] ##STR00015##

[0384] To a solution of 5-[4-(9H-fluoren-9-ylmethoxycarbonyl)piperazin-1-yl]-2-nitrobenzoic acid (4.5 g, 9.53 mmol) in DMF (50 mL) were added TBTU (5.4 g, 14.30 mmol; [CAS RN 125700-67-6]) and DIPEA (4.0 mL, 28.60 mmol) under an atmosphere of nitrogen. Then, tert-butyl 2-aminoacetate (1.87 g, 14.30 mmol; [CAS RN 6456-74-2]) was added and the reaction mixture stirred at rt for 18 h. Ice water (50 mL) was added into the reaction mass and stirred for 30 min at rt. The solid precipitated out, was collected by filtration followed by washing with water (350 mL) and dried under vacuum. The title compound was obtained as light yellow solid and used directly in the consecutive reaction step without further purification (3.0 g, 54%). MS: m/e=587.0 [M+H].sup.+.

[D] 9H-Fluoren-9-ylmethyl 4-[4-amino-3-[[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]carbamoyl]phenyl]piperazine-1-carboxylate

[0385] ##STR00016##

[0386] To a stirred solution of 9H-fluoren-9-ylmethyl 4-[3-[[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]carbamoyl]-4-nitrophenyl]piperazine-1-carboxylate (2.75 g, 4.69 mmol) in acetic acid (25 mL) was added zinc powder (1.5 g, 23.46 mmol; [CAS RN: 7440-66-6]) portion wise over a period of 10 min and then vigorously stirred at rt for 6 h. The reaction mixture was filtered through Celite followed by washing with acetic acid (210 mL). The filtrate was concentrated under reduce pressure to afford a viscous liquid, which was partitioned between water (25 mL) and EtOAc (25 mL). The aqueous phase was extracted with EtOAc (225 mL), the combined organic phases dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude reaction product was purified by column chromatography (100-200 mesh size silica gel) using 40% EtOAchexane as eluent affording the title compound as off-white solid (1.3 g, 50%). MS: m/e=557.2 [M+H].sup.+.

[E] 9H-Fluoren-9-ylmethyl 4-[3-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazine-1-carboxylate

[0387] ##STR00017##

[0388] A mixture of 9H-fluoren-9-ylmethyl 4-[4-amino-3-[[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]carbamoyl]phenyl]piperazine-1-carboxylate (1.2 g, 2.16 mmol) and triethyl orthoformate (5 mL, 30.1 mmol; [CAS RN 122-51-0]) in EtOH (5 mL) was heated in an oil bath to 80 C. for 12 h under an atmosphere of nitrogen. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude reaction product was partitioned between water (25 mL) and EtOAc (25 mL) and the aqueous phase extracted with EtOAc (225 mL). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude reaction product was purified by column chromatography (100-200 mesh size silica gel) using 50% EtOAchexane as eluent affording the title compound as grey solid (0.75 g, 61%). MS: m/e=567.2 [M+H].sup.+.

[F] 2-[6-[4-(9H-Fluoren-9-ylmethoxycarbonyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]acetic acid (Intermediate A-i: [CAS RN 269078-82-2])

[0389] ##STR00018##

[0390] To a stirred solution of 9H-fluoren-9-ylmethyl 4-[3-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazine-1-carboxylate (0.6 g, 1.06 mmol) in dioxane (2.5 mL) was added 4 M HCl in dioxane (10 mL) and the reaction mixture stirred at rt for 8 h. The solvent was removed under reduced pressure, an aq. solution of 10% NaHCO.sub.3 solution (25 mL) was added and the reaction extracted with EtOAc (325 mL). After that the aqueous phase was neutralized by addition of 35% conc. HCl (0.5 mL) and extracted with 5% methanol in DCM (325 mL). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure affording the title compound as off-white solid (0.36 g, 66%). MS: m/e 25=511.2 [M+H].sup.+.

Intermediate A-2

2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]aceticacid

[0391] ##STR00019##

[0392] To a suspension of 2-(4-oxo-6-piperazin-1-ylquinazolin-3-yl)acetic acid (5.0 g, 17.34 mmol; [CAS RN 889958-08-1]) in DCM (100 mL) was added triethylamine (6.02 mL, 43.40 mmol) at 0 C. under an atmosphere of nitrogen. The reaction mixture was stirred at 0 C. for 15 min, then acetic anhydride (1.97 mL, 20.83 mmol) was added slowly at 0 C. and the reaction mixture was stirred at rt for 4 h. After completion of the reaction, the solvent was concentrated under reduced pressure to a minimum volume (30 mL) and the obtained solid filtered and washed with hexane. The title compound was isolated as an off-white solid (5.44 g, 95%). MS: m/e=331.2 [M+H].sup.+.

Intermediate A-3

(3R)-3-[[2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-3-(4-chloro-phenyl)propanoic acid

[0393] ##STR00020##

[A] Benzyl (3R)-3-(4-chlorophenyl)-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate

[0394] ##STR00021##

[0395] To a solution of (R)-3-(4-chlorophenyl)-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (1.0 g, 3.34 mmol; [CAS RN 479064-93-2]) in DCM (20 mL) were added EDC HCl (1.08 g, 5.65 mmol) and HOBt (0.76 g, 5.65 mmol) at rt under an atmosphere of nitrogen. Then, DIPEA (1.97 mL, 11.30 mmol) was added and the reaction mixture was stirred at rt for 30 min, followed by the addition of benzyl alcohol (0.49 mL, 4.71 mmol). After stirring for 16 h, water was added (100 mL) and the reaction mixture extracted with DCM (2100 mL). The combined organic phase was washed with water (50 mL), a sat. aq. solution of sodium chloride (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude reaction product was purified by column chromatography (100-200 mesh size silica gel) using 10% EtOAchexane as eluent affording the title compound as white solid (0.7 g, 54%). MS: m/e=390.4 [M+H].sup.+.

[B] Benzyl (3R)-3-amino-3-(4-chlorophenyl)propanoate hydrochloride

[0396] ##STR00022##

[0397] To benzyl (R)-3-(4-chlorophenyl)-3-[(2-methylpropan-2-yl)oxycarbonylamino]-propanoate (0.7 g, 1.80 mmol) was added HCl (15 mL, 4.0 M solution in dioxane) at 0 C. under an atmosphere of Ar. The reaction mixture was stirred at rt for 4 h and then concentrated under reduced pressure. The obtained solid was filtered and washed with dry diethyl ether. The title compound was isolated as white solid (0.51 g, 87%) and used in the consecutive reaction step without further purification. MS: m/e=290.1 [M+H].sup.+.

[C] Benzyl (3R)-3-[[2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-3-(4-chlorophenyl)propanoate

[0398] ##STR00023##

[0399] To a solution of 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetic acid (intermediate A-2) (0.63 g, 1.91 mmol) in dry DMF (10 mL) were added EDC HCl (0.50 g, 2.61 mmol) and HOBt (0.35 g, 2.61 mmol) at rt under an atmosphere of nitrogen. Then, DIPEA (0.91 mL, 5.22 mmol) was added and the reaction mixture was stirred at rt for 30 min, followed by the addition of benzyl (R)-3-amino-3-(4-chlorophenyl)propanoate hydrochloride (0.50 g, 1.73 mmol). After stirring for 16 h, the reaction mixture was quenched by addition to ice and the precipitate was washed with ice cold water (330 mL), diethyl ether (330 mL), and hexane (230 mL). The title compound was obtained as off-white solid (0.75 g, 65%). MS: m/e=602.2 [M+H].sup.+.

[D] (3R)-3-[[2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-3-(4-chlorophenyl)propanoic acid (Intermediate A-3)

[0400] ##STR00024##

[0401] To a degassed solution of benzyl (R)-3-[[2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-3-(4-chlorophenyl)propanoate (0.50 g, 0.83 mmol) in EtOAc (40 mL) was added 10% Pd/C (0.040 g, 0.038 mmol) and the reaction mixture stirred under hydrogen (atmospheric pressure) at rt for 4 h. The reaction mixture was filtered through Celite using ethanol, the organic phase concentrated in vacuo and the solid material purified by washing with diethyl ether (320 mL) and DCM (130 mL). The title compound was obtained as off-white solid (0.23 g, 54%) and used in the consecutive reaction step without further purification. MS: m/e=512.3 [M+H].sup.+.

Intermediate A-4

(3R)-3-[[2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-3-[4-(trifluoromethyl)phenyl]propanoic acid

[0402] ##STR00025##

[A] Benzyl (3R)-3-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[4-(trifluoromethyl)phenyl]-propanoate

[0403] ##STR00026##

[0404] The title compound was prepared in analogy to the procedure described for the preparation of benzyl (R)-3-(4-chlorophenyl)-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate (intermediate A-3, step A), replacing (R)-3-(4-chlorophenyl)-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid with (R)-3-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[4-(trifluoromethyl)phenyl]propanoic acid (1.0 g, 3.00 mmol; [CAS RN 501015-19-6]). Purification by column chromatography (100-200 mesh size silica gel) using 10% EtOAc-hexane as eluent afforded the title compound as white solid (1.11 g, 87%). MS: m/e=424.2 [M+H].sup.+.

[B] Benzyl (3R)-3-amino-3-[4-(trifluoromethyl)phenyl]propanoate hydrochloride

[0405] ##STR00027##

[0406] The title compound was prepared in analogy to the procedure described for the preparation of benzyl (R)-3-amino-3-(4-chlorophenyl)propanoate hydrochloride (intermediate A-3, step B), replacing benzyl (R)-3-(4-chlorophenyl)-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate with benzyl (R)-3-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[4-(trifluoromethyl)phenyl]propanoate (1.11 g, 2.62 mmol). The title compound was isolated as white solid and used in the consecutive reaction step without further purification (0.84 g, 89%). MS: m/e=324.2 [M+H].sup.+.

[C] Benzyl (3R)-3-[[2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-3-[4-(trifluoromethyl)phenyl]propanoate

[0407] ##STR00028##

[0408] The title compound was prepared in analogy to the procedure described for the preparation of benzyl (3R)-3-[[2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-3-(4-chlorophenyl)propanoate (intermediate A-3, step C), replacing benzyl (3R)-3-amino-3-(4-chlorophenyl)propanoate hydrochloride with benzyl (3R)-3-amino-3-[4-(trifluoromethyl)phenyl]propanoate hydrochloride (0.84 g, 2.60 mmol). The title compound was obtained as off-white solid (1.40 g, 77%). MS: m/e=636.2 [M+H].sup.+.

[D] (3R)-3-[[2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-3-[4-(trifluoromethyl)phenyl]propanoic acid (Intermediate A-4)

[0409] ##STR00029##

[0410] The title compound was prepared in analogy to the procedure described for the preparation of (3R)-3-[[2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-3-(4-chlorophenyl)propanoic acid (intermediate A-3, step D), replacing benzyl (3R)-3-[[2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-3-(4-chlorophenyl)propanoate with benzyl (3R)-3-[[2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-3-[4-(trifluoromethyl)phenyl]propanoate (0.70 g, 1.10 mmol). After concentration of the organic phase in vacuo the solid material was purified by washing with DCM (330 mL) and hexane (220 mL). The title compound was obtained as yellow solid (0.30 g, 50%) and used in the consecutive reaction step without further purification. MS: m/e=546.2 [M+H].sup.+.

Intermediate A-5

9H-Fluoren-9-ylmethyl 4-[3-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazine-1-carboxylate

[0411] ##STR00030##

[0412] To a solution of 2-[6-[4-(9H-fluoren-9-ylmethoxycarbonyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]acetic acid (intermediate A-1; [CAS RN 269078-82-2]) (3.0 g, 5.88 mmol) in dry DMF (30 mL) were added PYBOP (3.1 g, 5.88 mmol; [CAS RN 128625-52-5]) and DIPEA (1.23 mL, 7.05 mmol) under an atmosphere of nitrogen. Then, (3,4-dichlorophenyl)methanamine (1.24 g, 7.05 mmol; [CAS RN 102-49-8]) was added and the reaction mixture stirred at rt for 2 h. Heptane (100 mL) was added, the white precipate filtered off, the solid material washed with heptane (50 mL) and dried under high vacuum. The title compound was obtained as white solid and used directly in the consecutive reaction step without further purification (2.20 g, 56%). MS: m/e=670.6 [M+H].sup.+.

Intermediate A-6

9H-Fluoren-9-ylmethyl 4-[3-[2-[(3,4-dichlorophenyl)methyl-methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazine-1-carboxylate

[0413] ##STR00031##

[0414] To a solution of 2-[6-[4-(9H-fluoren-9-ylmethoxycarbonyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]acetic acid (intermediate A-1; [CAS RN 269078-82-2]) (0.75 g, 1.47 mmol) in DCM (20 mL) were added TBTU (0.71 g, 2.21 mmol; [CAS RN 125700-67-6]) and DIPEA (0.77 mL, 4.41 mmol) under an atmosphere of nitrogen. Then, 1-(3,4-dichlorophenyl)-N-methylmethanamine (0.31 g, 1.62 mmol; [CAS RN 5635-67-6]) was added and the reaction mixture stirred at rt for 2 h. Heptane (100 mL) was added, the white precipate filtered off, the solid material washed with heptane (50 mL) and dried under high vacuum. The title compound was obtained as white solid and used directly in the consecutive reaction step without further purification (0.85 g, 85%). MS: m/e=683.3 [M+H].sup.+.

Intermediate A-7

Methyl 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetate

[0415] ##STR00032##

[A] 5-(4-Acetylpiperazin-1-yl)-2-nitrobenzoic acid

[0416] ##STR00033##

[0417] A mixture of 5-chloro-2-nitrobenzoic acid (2.0 g, 9.95 mmol; [CAS RN 2516-95-2] and 1-piperazin-1-ylethanone (6.1 g, 47.7 mmol; [CAS RN 13889-98-0]) was heated at 110 C. for 18 h. Then, the reaction mixture was cooled to rt and the residue basified to pH 10-12 by addition of an aq. solution of 50% NaOH (6.0 mL) keeping the temperature at 10 C. To the clear solution was added an aq. solution of 35% HCl (1.3 mL), the formed precipitate separated by filtration, the solid material washed with EtOAc (220 mL) and dried under high vacuum. The title compound was obtained as light yellow solid and used directly in the consecutive reaction step without further purification (1.5 g, 51%). MS: m/e=294.1 [M+H].sup.+.

[B] Methyl 2-[[5-(4-acetylpiperazin-1-yl)-2-nitrobenzoyl]amino]acetate

[0418] ##STR00034##

[0419] To a stirred solution of 5-(4-acetylpiperazin-1-yl)-2-nitrobenzoic acid (0.7 g, 2.39 mmol) in dry DMF (10 mL) was added HATU (1.36 g, 3.58 mmol; [CAS RN 148893-10-1]) and DIPEA (1.7 mL, 9.5 mmol) at rt under an atmosphere of nitrogen. After stirring for 30 min, glycine methyl ester hydrochloride (0.4 g, 3.58 mmol; [CAS RN 5680-79-5]) was added. After stirring for 18 h, the reaction mixture was concentrated under reduced pressure followed by the addition of ice water (40 mL). The obtained solid was filtered and dried under vacuum. The title compound was obtained as light yellow solid and used directly in the consecutive reaction step without further purification (0.45 g, 52%). MS: m/e=364.9 [M+H].sup.+. [C] Methyl 2-[[5-(4-acetylpiperazin-1-yl)-2-aminobenzoyl]amino]acetate

##STR00035##

[0420] To a degassed solution of methyl 2-[[5-(4-acetylpiperazin-1-yl)-2-nitrobenzoyl]amino]acetate (3.25 g, 11.09 mmol) in methanol (50 mL) was added 10% Pd/C (0.15 g, 0.14 mmol) and the reaction mixture stirred under hydrogen (atmospheric pressure) at rt for 6 h. The reaction mixture was filtered through Celite using methanol, the organic phase concentrated under reduced pressure and the solid material purified by washing with diethyl ether (320 mL). The title compound was obtained as light brown solid and used directly in the consecutive reaction step without further purification (2.75 g, 74%). MS: m/e=335.2 [M+H].sup.+.

[D] Methyl 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetate (Intermediate A-7)

[0421] ##STR00036##

[0422] A solution of methyl 2-[[5-(4-acetylpiperazin-1-yl)-2-aminobenzoyl]amino]acetate (2.75 g, 8.23 mmol) in triethyl orthoformate (20 mL, 0.12 mol; [CAS RN 122-51-0]) was heated in an oil bath to 140 C. for 36 h under an atmosphere of nitrogen. The reaction mixture was cooled to rt, concentrated under reduced pressure and the crude product purified by column chromatography (100-200 mesh size silica gel) using 10% methanolDCM as eluent. The title compound was obtained as white solid (2.0 g, 71%). MS: m/e=345.4 [M+H].sup.+.

Intermediate A-8

2-[6-[1-(9H-Fluoren-9-ylmethoxycarbonyl)-4-piperidyl]-4-oxoquinazolin-3-yl]acetic acid

[0423] ##STR00037##

[A] Methyl 2-[(5-bromo-2-nitrobenzoyl)amino]acetate

[0424] ##STR00038##

[0425] To a stirred solution of 5-bromo-2-nitrobenzoic acid (10.0 g, 40.6 mmol; [CAS RN 6950-43-2] in DMF (50 mL) were added HATU (23 g, 60 mmol) and DIPEA (35 ml, 203.2 mmol) under an atmosphere of nitrogen. Then, glycine methyl ester hydrochloride (6.0 g, 48.7 mmol; [CAS RN 5680-79-5]) was added and the reaction mixture was stirred at rt for 18 h. After completion of the reaction, the solvent was evaporated under reduced pressure providing a yellow solid. Water (25 ml) was added and the resulting yellow solid filtered off, the precipitate washed with water (425 mL) and dried under reduced pressure. The title compound was obtained as light yellow solid and used directly in the consecutive reaction step without further purification (7.0 g, 63%). MS: m/e=318.1 [M+H].sup.+.

[B] tert-Butyl 4-[3-[(2-methoxy-2-oxoethyl)carbamoyl]-4-nitrophenyl]-3,6-dihydro-2H-pyridine-1-carboxylate

[0426] ##STR00039##

[0427] To a solution of methyl 2-[(5-bromo-2-nitrobenzoyl)amino]acetate (4.0 g, 12.61 mmol) in dioxane (80 mL) were added tert-butyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (4.28 g, 13.88 mmol; [CAS RN 286961-14-6]) and carefully dried K.sub.2CO.sub.3 (3.91 g, 28.39 mmol). The reaction mixture was degassed for 5 min by bubbling through nitrogen and then [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(II) dichloromethane complex (0.922 g, 1.26 mmol; [CAS RN 95464-05-4]) was added. The resultant reaction mixture was further degassed for 5 min and then stirred at 90 C. for 3 h. The reaction mixture was cooled to rt, EtOAc (250 mL) was added and the organic phase washed with water (100 mL) and a sat. solution of NaCl (100 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude reaction product was purified by column chromatography (100-200 mesh size silica gel) using 25% EtOAchexane as eluent affording the title compound as yellow solid (3.5 g, 62%). MS: m/e=418.2 [MH].sup..

[C] tert-Butyl 4-[4-amino-3-[(2-methoxy-2-oxoethyl)carbamoyl]phenyl]piperidine-1-carboxylate

[0428] ##STR00040##

[0429] To a solution of tert-butyl 4-[3-[(2-methoxy-2-oxoethyl)carbamoyl]-4-nitrophenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (2.3 g, 5.48 mmol) in methanol (50 mL) was added 10% Pd/C (0.23 g, 0.22 mmol) and the reaction mixture stirred under hydrogen (atmospheric pressure) at rt for 3 h. The reaction mixture was filtered through Celite using methanol and the organic phase concentrated in vacuo. The crude material was obtained as off-white solid and used in the consecutive reaction step without further purification (2.0 g, crude). MS: m/e=392.0 [M+H].sup.+.

[D] tert-Butyl 4-[3-(2-methoxy-2-oxoethyl)-4-oxoquinazolin-6-yl]piperidine-1-carboxylate

[0430] ##STR00041##

[0431] To a solution of tert-butyl 4-[4-amino-3-[(2-methoxy-2-oxoethyl)carbamoyl]phenyl]piperidine-1-carboxylate (0.5 g, 1.27 mmol) in methanol (20 mL) was added triethyl orthoformate (2 mL, 12.0 mmol; [CAS RN 122-51-0]) and the reaction mixture heated in an oil bath to 80 C. for 24 h under an atmosphere of nitrogen. The reaction mixture was cooled to rt, concentrated under reduced pressure and the crude reaction product purified by column chromatography (100-200 mesh size silica gel) using 60% EtOAchexane as eluent. The title compound was obtained as a sticky solid (0.30 g, 78% over 2 steps). MS: m/e=401.7 [M+H].sup.+.

[E] 2-[6-(1-tert-Butoxycarbonyl-4-piperidyl)-4-oxoquinazolin-3-yl]acetic acid

[0432] ##STR00042##

[0433] To a solution of tert-butyl 4-[3-(2-methoxy-2-oxoethyl)-4-oxoquinazolin-6-yl]piperidine-1-carboxylate (5.0 g, 12.46 mmol) in THF (25 mL) was added an aq. solution of LiOH H.sub.2O (0.79 g, 18.70 mmol; [CAS RN 1310-66-3]) in water (2.5 ml). After stirring of the reaction mixture at rt for 2 h, the solvent was evaporated under reduced pressure. To the crude reaction product was added water (20 mL), the aqueous part acidified by addition of 1 N HCl (pH ca. 4) and the aqueous phase extracted with 5% MeOH in DCM (325 mL). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The title compound was obtained as off-white solid (4.0 g, 83%). MS: m/e=387.7 [M+H].sup.+.

[F] 2-[6-[1-(9H-Fluoren-9-ylmethoxycarbonyl)-4-piperidyl]-4-oxoquinazolin-3-yl]acetic acid (Intermediate A-8)

[0434] ##STR00043##

[0435] To a solution of 2-[6-(1-tert-butoxycarbonyl-4-piperidyl)-4-oxoquinazolin-3-yl]acetic acid (1.5 g, 3.87 mmol) in dioxan (15 mL) was added 4 M HCl in dioxane (15 mL) and the reaction mixture stirred at rt for 12 h. The solvent was evaporated under reduced pressure and the intermediate redissolved in dioxane (30 mL) and aq. 10% NaHCO.sub.3 solution (30 mL). 9-Fluorenylmethyl chloroformate (1.69 g, 6.53 mmol; [CAS RN 28920-43-6]) was added and the reaction mixture stirred ar rt for 2 h. The crude reaction mixture was concentrated under reduce pressure and partitioned between water (50 mL) and EtOAc (50 mL). The organic phase was separated and the aqueous phase extracted with EtOAc (250 mL). After that the aqueous phase was acidified by addition of 25% HCl (pH ca. 3) and extracted with DCM (350 mL). The combined organic phases were dried over anhydrous MgSO.sub.4 and concentrated under reduced pressure. The title compound was obtained as off-white solid (0.61 g, 31%). MS: m/e=510.2 [M+H].sup.+.

Intermediate A-9

N-[(3-Chloro-4-cyanophenyl)methyl]-N-methyl-2-(4-oxo-6-piperidin-4-ylquinazolin-3-yl)acetamide

[0436] ##STR00044##

[0437] To a solution of 2-[6-[1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidyl]-4-oxoquinazolin-3-yl]acetic acid (intermediate A-8) (0.40 g, 0.79 mmol) in DCM (8 mL) were added TBTU (0.38 g, 1.18 mmol; [CAS RN 125700-67-6]) and DIPEA (0.41 mL, 2.36 mmol) under an atmosphere of nitrogen. Then, 2-chloro-4-(methylaminomethyl)benzonitrile hydrochloride (example 56, step A) (0.17 g, 0.79 mmol) was added and the reaction mixture stirred at rt for 18 h. A solution of methanamine (4.5 mL, 3.40 g, 36.1 mmol; 33 wt. % solution in EtOH; [CAS RN 74-89-5]) was added and stirring at rt continued overnight. The crude reaction mixture was concentrated under reduced pressure, redissolved in dioxane (5 mL) and treated with 4 M HCl in dioxane (20 mL). The white precipate was filtered off, washed with TBME (40 mL) and dried under high vacuum. The title compound was obtained as white solid and used directly in the consecutive reaction step without further purification (0.38 g, 98%). MS: m/e=450.2 [M+H].sup.+.

Example 1

(3R)-3-[[2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-3-(4-chlorophenyl)-N-methylpropanamide

[0438] ##STR00045##

[0439] The synthesis was conducted in flow. Reagent solution A contained (3R)-3-[[2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-3-(4-chlorophenyl)propanoic acid (intermediate A-3) (10.2 mg, 0.020 mmol), TBTU (12.8 mg, 0.040 mmol; [CAS RN 125700-67-6]) and DIPEA (7.0 l, 0.040 mmol) in DMF (280 l) and reagent solution B contained methanamine (100 l, 0.80 mmol; 8.0 M solution in ethanol; [CAS RN 74-89-5]) in DMF (300 l). The two reagent solutions were injected (300 L of each solution) by means of Gilson LH 215 auto-sampler into the reactor sample loops (300 L each, Gilson 819). Then, both reagent streams were combined at a T-piece connector and the reagent mixture heated at 100 C. for 10 min in a 10 ml PFA tube reactor coil. The crude product stream was purified in-line by preparative HPLC (C18 reverse phase, acetonitrile/water (0.05% triethylamine)=2:98 to 98:2) to yield the title compound as light yellow solid (3.1 mg, 30%). MS: m/e=525.3 [M+H].sup.+.

Examples 2 to 8

[0440] According to the procedure described for the synthesis of example 1 further examples were prepared from (3R)-3-[[2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-3-(4-chlorophenyl)propanoic acid (intermediate A-3) and (3R)-3-[[2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-3-[4-(trifluoromethyl)phenyl]propanoic acid (intermediate A-4) and the respective amine intermediates as indicated in Table 1. The results are compiled in Table 1 and comprise examples 2 to 8.

TABLE-US-00002 TABLE 1 No Compound Name & Structure Starting Materials MS 2 [00046] (3R)-3-[[2-[6-(4- Acetylpiperazin-1- yl)-4-oxoquinazolin- 3-yl]acetyl]amino]-3- (4- chlorophenyl)propanoic acid (intermediate A-3) and N- methylmethanamine ([CAS RN 124-40-3]) [M + H].sup.+ 539.4 3 [00047] (3R)-3-[[2-[6-(4- Acetylpiperazin-1- yl)-4-oxoquinazolin- 3-yl]acetyl]amino]-3- (4- chlorophenyl)propanoic acid (intermediate A-3) and benzenamine ([CAS RN 62-53-3]) [M + H].sup.+ 587.4 4 [00048] (3R)-3-[[2-[6-(4- Acetylpiperazin-1- yl)-4-oxoquinazolin- 3-yl]acetyl]amino]-3- [4- (trifluoromethyl)phenyl] propanoic acid (intermediate A-4) and methanamine ([CAS RN 74-89-5]) [M + H].sup.+ 559.4 5 [00049] (3R)-3-[[2-[6-(4- Acetylpiperazin-1- yl)-4-oxoquinazolin- 3-yl]acetyl]amino]-3- [4- (trifluoromethyl)phenyl] propanoic acid (intermediate A-4) and N- methylmethanamine ([CAS RN 124-40-3]) [M + H].sup.+ 573.4 6 [00050] (3R)-3-[[2-[6-(4- Acetylpiperazin-1- yl)-4-oxoquinazolin- 3-yl]acetyl]amino]-3- [4- (trifluoromethyl)phenyl] propanoic acid (intermediate A-4) and 2-methylpropan- 1-amine ([CAS RN 78-81-9]) [M + H].sup.+ 601.5 7 [00051] (3R)-3-[[2-[6-(4- Acetylpiperazin-1- yl)-4-oxoquinazolin- 3-yl]acetyl]amino]-3- [4- (trifluoromethyl)phenyl] propanoic acid (intermediate A-4) and benzenamine ([CAS RN 62-53-3]) [M + H].sup.+ 621.5 8 [00052] (3R)-3-[[2-[6-(4- Acetylpiperazin-1- yl)-4-oxoquinazolin- 3-yl]acetyl]amino]-3- [4- (trifluoromethyl)phenyl] propanoic acid (intermediate A-4) and phenylmethanamine ([CAS RN 100-46-9]) [M + H].sup.+ 635.5

Example 9

(3R)-3-[[2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-N-methyl-3-(4-nitrophenyl)propanamide

[0441] ##STR00053##

[A] (3R)-tert-Butyl N-[3-(methylamino)-1-(4-nitrophenyl)-3-oxopropyl]carbamate

[0442] ##STR00054##

[0443] To a solution of 3-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(4-nitrophenyl)propanoic acid (0.25 g, 0.80 mmol; [CAS RN 500770-85-4]) in dry DCM (20 mL) were added EDC HCl (0.23 g, 1.20 mmol) and HOBt (0.16 g, 1.20 mmol) at rt under an atmosphere of nitrogen. Then, triethylamine (0.33 mL, 2.40 mmol) was added and the reaction mixture was stirred at rt for 30 min, followed by the addition of methanamine (0.5 mL, 1.00 mmol; 2.0 M solution in THF; [CAS RN 74-89-5]). After stirring for 16 h, the reaction mixture was quenched by addition of water (20 mL) and the aq. phase extracted with DCM (350 mL). The combined organic phases were dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. Purification by column chromatography (100-200 mesh size silica gel) using 2% methanolDCM as eluent afforded the title compound as white solid (0.20 g, 77%). MS: m/e=324.3 [M+H].sup.+.

[B] (3R)-3-Amino-N-methyl-3-(4-nitrophenyl)propanamide hydrochloride

[0444] ##STR00055##

[0445] To (3R)-tert-butyl N-[3-(methylamino)-1-(4-nitrophenyl)-3-oxopropyl]carbamate (0.20 g, 0.62 mmol) was added HCl (5 mL, 4.0 M solution in dioxane) at 0 C. under an atmosphere of Ar. The reaction mixture was stirred at rt for 4 h and then concentrated under reduced pressure. The obtained solid was filtered and washed with dry diethyl ether. The title compound was isolated as moisture sensitive yellow gummy liquid (0.14 g, 87%) and used in the consecutive reaction step without further purification. MS: m/e=224.2 [M+H].sup.+.

[C] (3R)-3-[[2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl] acetyl]amino]-N-methyl-3-(4-nitrophenyl)propanamide

[0446] ##STR00056##

[0447] To a solution of 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetic acid (intermediate A-2) (0.20 g, 0.60 mmol) in dry DMF (5 mL) were added EDC HCl (0.17 g, 0.90 mmol) and HOBt (0.12 g, 0.90 mmol) at rt under an atmosphere of nitrogen. Then, DIPEA (0.31 mL, 1.81 mmol) was added and the reaction mixture was stirred at rt for 30 min, followed by the addition of (3R)-3-amino-N-methyl-3-(4-nitrophenyl)propanamide hydrochloride (0.14 g, 0.60 mmol). After stirring for 16 h, the reaction mixture was quenched by addition to ice and the aq. phase extracted with DCM (230 mL). The combined organic phase was washed with water (210 mL), a sat. aq. solution of sodium chloride (10 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude reaction product was triturated with 20% DCM-n-pentane to get a precipitate which was further washed with DCM. The title compound was obtained as off-white solid (0.095 g, 30%). MS: m/e=536.2 [M+H].sup.+.

Example 10

2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(4-chlorophenyl)methyl]acetamide

[0448] ##STR00057##

[0449] To a solution of 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetic acid (intermediate A-2) (11.9 mg, 0.036 mmol) in dry DMF (1 mL) were added TBTU (17.3 mg, 0.054 mmol; [CAS RN 125700-67-6]) and DIPEA (50 L, 0.29 mmol) under an atmosphere of nitrogen. Then, (4-chlorophenyl)methanamine (6.1 mg, 0.043 mmol; [CAS RN 104-86-9]) was added and the reaction mixture heated by mirowave irradiation to 100 C. for 15 min. Water was added (1 mL) and the crude reaction product purified by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater. The title compound was obtained as white solid (1.8 mg, 11%). MS: m/e=454.2 [M+H].sup.+.

Examples 11 to 27

[0450] According to the procedure described for the synthesis of example 10 further examples were prepared from 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetic acid (intermediate A-2) and the respective amine intermediate as indicated in Table 2. Alternatively, the amide formation reaction can be conducted in flow as described in Example 1 ((3R)-3-[[2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-3-(4-chlorophenyl)-N-methylpropanamide). The results are compiled in Table 2 and comprise examples 11 to 27.

TABLE-US-00003 TABLE 2 Starting No Compound Name & Structure Materials MS 11 [00058] 2-[6-(4- Acetylpiperazin-1- yl)-4- oxoquinazolin-3- yl]acetic acid (intermediate A-2) and (6- chloropyridin-3- yl)methanamine ([CAS RN 97004- 04-1]) [M + H].sup.+ 455.2 12 [00059] 2-[6-(4- Acetylpiperazin-1- yl)-4- oxoquinazolin-3- yl]acetic acid (intermediate A-2) and (5- chloropyridin-2- yl)methanamine ([CAS RN 67938- 76-5]) [M + H].sup.+ 455.2 13 [00060] 2-[6-(4- Acetylpiperazin-1- yl)-4- oxoquinazolin-3- yl]acetic acid (intermediate A-2) and 1-(4- chlorophenyl) ethanamine ([CAS RN 6299-02-1]) [M + H].sup.+ 468.3 14 [00061] 2-[6-(4- Acetylpiperazin-1- yl)-4- oxoquinazolin-3- yl]acetic acid (intermediate A-2) and (4- fluorophenyl) methanamine ([CAS RN 140-75-0]) [M + H].sup.+ 438.3 15 [00062] 2-[6-(4- Acetylpiperazin-1- yl)-4- oxoquinazolin-3- yl]acetic acid (intermediate A-2) and 1,3- benzodioxol-5- ylmethanamine ([CAS RN 2620- 50-0]) [M + H].sup.+ 464.3 16 [00063] 2-[6-(4- Acetylpiperazin-1- yl)-4- oxoquinazolin-3- yl]acetic acid (intermediate A-2) and [6- (trifluoromethyl) pyridin-3- yl]methanamine ([CAS RN 387350-39-2]) [M + H].sup.+ 489.3 17 [00064] 2-[6-(4- Acetylpiperazin-1- yl)-4- oxoquinazolin-3- yl]acetic acid (intermediate A-2) and [4- (trifluoromethyl) phenyl]methanamine ([CAS RN 3300- 51-4]) [M + H].sup.+ 488.3 18 [00065] 2-[6-(4- Acetylpiperazin-1- yl)-4- oxoquinazolin-3- yl]acetic acid (intermediate A-2) and 5- (aminomethyl) pyridine-2-carbonitrile ([CAS RN 181130-14-3]) [M + H].sup.+ 446.3 19 [00066] 2-[6-(4- Acetylpiperazin-1- yl)-4- oxoquinazolin-3- yl]acetic acid (intermediate A-2) and 4- (aminomethyl) benzonitrile ([CAS RN 10406-25-4]) [M + H].sup.+ 445.3 20 [00067] 2-[6-(4- Acetylpiperazin-1- yl)-4- oxoquinazolin-3- yl]acetic acid (intermediate A-2) and [4- (trifluoromethoxy) phenyl]methanamine ([CAS RN 93919-56-3]) [M + H].sup.+ 504.3 21 [00068] 2-[6-(4- Acetylpiperazin-1- yl)-4- oxoquinazolin-3- yl]acetic acid (intermediate A-2) and (4- nitrophenyl)meth- anamine ([CAS RN 7409-30-5]) [M + H].sup.+ 465.3 22 [00069] 2-[6-(4- Acetylpiperazin-1- yl)-4- oxoquinazolin-3- yl]acetic acid (intermediate A-2) and (3,4- dichlorophenyl) methanamine ([CAS RN 102-49-8]) [M + H].sup.+ 488.3 23 [00070] 2-[6-(4- Acetylpiperazin-1- yl)-4- oxoquinazolin-3- yl]acetic acid (intermediate A-2) and (2,4- dichlorophenyl) methanamine ([CAS RN 95-00-1]) [M + H].sup.+ 488.2 24 [00071] 2-[6-(4- Acetylpiperazin-1- yl)-4- oxoquinazolin-3- yl]acetic acid (intermediate A-2) and (4-chloro-3- fluorophenyl)meth- anamine ([CAS RN 72235-58-6]) [M + H].sup.+ 472.2 25 [00072] 2-[6-(4- Acetylpiperazin-1- yl)-4- oxoquinazolin-3- yl]acetic acid (intermediate A-2) and 4- (aminomethyl)-2- chlorobenzonitrile ([CAS RN 202522-15-4]) [M + H].sup.+ 479.3 26 [00073] 2-[6-(4- Acetylpiperazin-1- oxoquinazolin-3- yl]acetic acid (intermediate A-2) and [4-fluoro-3- (trifluoromethoxy) phenyl]methanamine ([CAS RN 886501-20-8]) [M + H].sup.+ 522.3 27 [00074] 2-[6-(4- Acetylpiperazin-1- yl)-4- oxoquinazolin-3- yl]acetic acid (intermediate A-2) and (3R)-3-amino- 3-(4- chlorophenyl) propanamide ([CAS RN 1307443-59- 9]) [M + H].sup.+ 511.3

Example 28

2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(4-cyano-3-fluorophenyl)methyl]acetamide

[0451] ##STR00075##

[0452] To a solution of 2-[6-[4-(9H-fluoren-9-ylmethoxycarbonyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]acetic acid (intermediate A-1; [CAS RN 269078-82-2]) (50 mg, 0.098 mmol) in dry DCM (2 mL) were added TBTU (47.2 mg, 0.15 mmol; [CAS RN 125700-67-6]) and DIPEA (50 L, 0.29 mmol) under an atmosphere of nitrogen. Then, 4-(aminomethyl)-2-fluorobenzonitrile (20.1 mg, 0.11 mmol; [CAS RN 368426-73-7]) was added and the reaction mixture stirred at rt for 90 min. A solution of methanamine (2 mL, 16.0 mmol; 8.0 M solution in ethanol; [CAS RN 74-89-5]) was added and stirring at rt continued overnight. The crude reaction mixture was concentrated under reduced pressure and redissolved in dry DMF (2 mL). DIPEA (50 L, 0.29 mmol) and acetyl chloride (7.0 L, 0.098 mmol; [CAS RN 368426-73-7]) were added and the reaction mixture stirred at rt for 2 h under an atmosphere of nitrogen. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as white solid (19 mg, 42%). MS: m/e=463.3 [M+H].sup.+.

Examples 29 to 51

[0453] According to the procedure described for the synthesis of example 28 further examples were prepared from 2-[6-[4-(9H-fluoren-9-ylmethoxycarbonyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]acetic acid (intermediate A-1) and the respective amine intermediate as indicated in Table 3. The results are compiled in Table 3 and comprise examples 29 to 51.

TABLE-US-00004 TABLE 3 No Compound Name & Structure Starting Materials MS 29 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(2-chloro-4- cyanophenyl)methyl]acetamide [00076] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin- 3-yl]acetic acid (intermediate A-1) and 4-(aminomethyl)-3- chlorobenzonitrile ([CAS RN 202521-97-9]) [M + H].sup.+ 479.3 30 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(4-cyano-2- fluorophenyl)methyl]acetamide [00077] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin-3- yl]acetic acid (intermediate A-1) and 4-(aminomethyl)-3- fluorobenzonitrile ([CAS RN 701264-00-8]) [M + H].sup.+ 463.3 31 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(4-cyano-2,6- difluorophenyl)methyl]acetamide [00078] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin-3- yl]acetic acid (intermediate A-1) and 4-(aminomethyl)- 3,5-difluorobenzonitrile ([CAS RN 633336-81-9]) [M + H].sup.+ 481.3 32 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(4-cyano-2- methoxyphenyl)methyl]acetamide [00079] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin- 3-yl]acetic acid (intermediate A-1) and 4-(aminomethyl)-3- methoxybenzonitrile ([CAS RN 182159-14-4]) [M + H].sup.+ 475.3 33 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[[4-cyano-2-(2,2,2- trifluoroethoxy)phenyl]methyl]acetamide [00080] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin- 3-yl]acetic acid (intermediate A-1) and 4-(aminomethyl)-3- (2,2,2-trifluoroethoxy)- benzonitrile ([CAS RN 1055904-78-3]) [M + H].sup.+ 543.3 34 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[[4-chloro-3- (trifluoromethyl)phenyl]methyl]acetamide [00081] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin-3- yl]acetic acid (intermediate A-1) and [4-chloro-3-(trifluoro- methyl)phenyl]methanamine ([CAS RN 62039-92-3]) [M + H].sup.+ 522.3 35 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3-cyano-2- methylphenyl)methyl]acetamide [00082] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin- 3-yl]acetic acid (intermediate A-1) and 3-(aminomethyl)-2- methylbenzonitrile ([CAS RN 780693-78-9]) [M + H].sup.+ 459.4 36 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(2-chloropyridin-4- yl)methyl]acetamide [00083] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin-3- yl]acetic acid (intermediate A-1) and (2-chloropyridin-4- yl)methanamine ([CAS RN 144900-57-2]) [M + H].sup.+ 455.3 37 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3- nitrophenyl)methyl]acetamide [00084] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin-3- yl]acetic acid (intermediate A-1) and (3- nitrophenyl)methanamine ([CAS RN 26177-43-5]) [M + H].sup.+ 465.3 38 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[[4-chloro-3- (trifluoromethoxy)phenyl]methyl]acetamide [00085] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin-3- yl]acetic acid (intermediate A-1) and [4-chloro-3- (trifluoromethoxy) phenyl]methanamine ([CAS RN 916210-69-0]) [M + H].sup.+ 538.3 39 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[[4-(pentafluoro-.sup.6- sulfanyl)phenyl]methyl]acetamide [00086] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin-3- yl]acetic acid (intermediate A-1) and [4-(pentafluoro-.sup.6- sulfanyl)phenyl]methanamine ([CAS RN 771573-35-4]) [M + H].sup.+ 546.3 40 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3-methyl-4- methylsulfonylphenyl)methyl]acetamide [00087] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin-3- yl]acetic acid (intermediate A-1) and (3-methyl-4-methyl- sulfonylphenyl)methanamine ([CAS RN 694481-22-6]) [M + H].sup.+ 512.3 41 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(4,5-dichloropyridin-2- yl)methyl]acetamide [00088] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin-3- yl]acetic acid (intermediate A-1) and (4,5-dichloropyridin-2- yl)methanamine ([CAS RN 1196157-20-6]) [M + H].sup.+ 489.2 42 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3-chloro-4- methylphenyl)methyl]acetamide [00089] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin-3- yl]acetic acid (intermediate A-1) and (3-chloro-4- methylphenyl)methanamine ([CAS RN 67952-93-6]) [M + H].sup.+ 468.3 43 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(4-chlorophenyl)methyl]-N- methylacetamide [00090] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin-3- yl]acetic acid (intermediate A-1) and 1-(4-chlorophenyl)-N- methylmethanamine ([CAS RN 104-11-0]) [M + H].sup.+ 468.3 44 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]- N-methylacetamide [00091] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin-3- yl]acetic acid (intermediate A-1) and 1-(3,4-dichlorophenyl)- N-methylmethanamine ([CAS RN 5635-67-6]) [M + H].sup.+ 502.2 45 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(4-cyano-3- fluorophenyl)methyl]-N-methylacetamide [00092] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin-3- yl]acetic acid (intermediate A-1) and 2-fluoro-4-(methyl- aminomethyl)benzonitrile ([CAS RN 1565551-88-3]) [M + H].sup.+ 477.3 46 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(2,6-dichloropyridin-4- yl)methyl]-N-methylacetamide [00093] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin-3- yl]acetic acid (intermediate A-1) and 1-(2,6-dichloropyridin-4- yl)-N-methylmethanamine ([CAS RN 873928-49-5]) [M + H].sup.+ 503.2 47 6-(4-Acetylpiperazin-1-yl)-3-[2-[2-(4-chlorophenyl)pyrrolidin-1-yl]-2- oxoethyl]quinazolin-4-one [00094] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin-3- yl]acetic acid (intermediate A-1) and 2-(4- chlorophenyl)pyrrolidine ([CAS RN 38944-14-8]) [M + H].sup.+ 494.3 48 6-(4-Acetylpiperazin-1-yl)-3-[2-[(2R)-2-(4-methylphenyl)pyrrolidin-1- yl]-2-oxoethyl]quinazolin-4-one [00095] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin-3- yl]acetic acid (intermediate A-1) and (2R)-2-(4- methylphenyl)pyrrolidine ([CAS RN 1227908-77-1]) [M + H].sup.+ 474.4 49 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[2-(3,4- dichlorophenyl)ethyl]acetamide [00096] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin-3- yl]acetic acid (intermediate A-1) and 2-(3,4- dichlorophenyl)ethanamine ([CAS RN 21581-45-3]) [M + H].sup.+ 502.2 50 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[[3-(4-chlorophenyl)-1,2-oxazol- 5-yl]methyl]acetamide [00097] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin-3- yl]acetic acid (intermediate A-1) and [3-(4-chlorophenyl)-1,2- oxazol-5-yl]methanamine ([CAS RN 66046-42-2]) [M + H].sup.+ 521.3 51 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[[5-(4-chlorophenyl)-1,2,4-oxadiazol-3- yl]methyl]acetamide [00098] 2-[6-[4-(9H-Fluoren-9- ylmethoxycarbonyl)piperazin- 1-yl]-4-oxoquinazolin-3- yl]acetic acid (intermediate A-1) and [5-(4-chlorophenyl)- 1,2,4-oxadiazol-3- yl]methanamine ([CAS RN 919750-83-7]) [M + H].sup.+ 522.3

Example 52

3-[[2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-3-(3,4-dichlorophenyl)-N-methylpropanamide

[0454] ##STR00099##

[0455] To a solution of 2-[6-[4-(9H-fluoren-9-ylmethoxycarbonyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]acetic acid (intermediate A-1; [CAS RN 269078-82-2]) (40 mg, 0.078 mmol) in dry DCM (2 mL) were added TBTU (37.7 mg, 0.12 mmol; [CAS RN 125700-67-6]) and DIPEA (41 L, 0.24 mmol) under an atmosphere of nitrogen. Then, ethyl 3-amino-3-(3,4-dichlorophenyl)propanoate (24.6 mg, 0.094 mmol; [CAS RN 380842-80-8]) was added and the reaction mixture stirred at rt for 90 min. A solution of methanamine (2 mL, 16.0 mmol; 8.0 M solution in ethanol; [CAS RN 74-89-5]) was added and stirring at rt continued overnight. The crude reaction mixture was concentrated under reduced pressure and redissolved in DMF (2 mL). DIPEA (41 L, 0.24 mmol) and acetyl chloride (5.6 L, 0.078 mmol; [CAS RN 368426-73-7]) were added and the reaction mixture stirred at rt for 2 h under an atmosphere of nitrogen. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as white solid (8.4 mg, 19%). MS: m/e=559.3 [M+H].sup.+.

Example 53

Methyl 3-[[2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]-[(3,4-dichlorophenyl)methyl]amino]propanoate

[0456] ##STR00100##

[0457] To a solution of 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetic acid (intermediate A-2) (41.6 mg, 0.13 mmol) in dry DCM (1.5 mL) were added HATU (71.8 mg, 0.19 mmol) and DIPEA (66 L, 0.38 mmol) under an atmosphere of nitrogen. Then, methyl 3-[(3,4-dichlorophenyl)methylamino]propanoate (33 mg, 0.13 mmol; [CAS RN 4020-24-0]) was added and the reaction mixture stirred at rt for 2 h. The reaction mixture was quenched by addition of a sat. aq. solution of sodium hydrogen carbonate (10 mL) and the aq. phase extracted with DCM (310 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure. Purification by MPLC (20 g SiO.sub.2, Telos-cartridge) eluting with a gradient of 0 to 3% methanolDCM provided the title compound (35 mg, 48%) as white solid. MS: 574.4 (M+H).sup.+.

Example 54

3-[[2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]-[(3,4-dichlorophenyl)methyl]amino]propanoic acid

[0458] ##STR00101##

[0459] To a solution of methyl 3-[[2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]-[(3,4-dichlorophenyl)methyl]amino]propanoate (example 53) (26 mg, 0.045 mmol) in THF-water (0.5 mL: 1 mL) was added LiOH H.sub.2O (47.2 mg, 0.15 mmol) and the reaction mixture stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure, 1 M HCl added (5 mL) and the aq. phase extracted with DCM (310 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as white solid (9.5 mg, 38%). MS: m/e=558.4 [MH].sup..

Example 55

3-[[2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]-[(3,4-dichlorophenyl)methyl]amino]-N-methylpropanamide

[0460] ##STR00102##

[0461] In analogy to the procedure described for the preparation of 3-[[2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-3-(3,4-dichlorophenyl)-N-methylpropanamide (example 52), replacing ethyl 3-amino-3-(3,4-dichlorophenyl)propanoate with methyl 3-[(3,4-dichlorophenyl)methylamino]propanoate ([CAS RN 4020-24-0]). After completion of the reaction, the reaction mixture was quenched by addition of a sat. aq. solution of sodium hydrogen carbonate (10 mL) and the aq. phase extracted with DCM (310 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure. Purification by MPLC (20 g SiO.sub.2, Telos-cartridge) eluting with a gradient of 0 to 3% methanolDCM provided the title compound (47 mg, 84%) as light orange solid. MS: 573.2 (M+H).sup.+.

Example 56

2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3-chloro-4-cyanophenyl)methyl]-N-methylacetamide

[0462] ##STR00103##

[A] 2-Chloro-4-(methylaminomethyl)benzonitrile hydrochloride

[0463] ##STR00104##

[0464] To 4-(bromomethyl)-2-chlorobenzonitrile (3.04 g, 13.2 mmol; [CAS RN 83311-25-5]) was added dropwise a solution of methanamine (20 mL, 40.0 mmol; 2.0 M solution in THF; [CAS RN 74-89-5]) at 0 C. within 30 min. The crude reaction mixture was warmed up to rt and stirring continued for 10 min. The precipitate was filtered off, washed with THF (50 mL) and the filtrate concentrated under reduced pressure. A solution of 1 M NaOH was added (50 mL) and the aq. phase extracted with DCM (350 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure. The crude reaction product was dissolved in dioxane (50 mL) and treated with 4 M HCl in dioxane (20 mL). The white precipate was filtered off, washed with TBME (40 mL) and dried under high vacuum. The title compound was obtained as white solid (1.33 g, 46%). MS: m/e=181.1 [M+H].sup.+.

[B] 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3-chloro-4-cyanophenyl)methyl]-N-methylacetamide

[0465] ##STR00105##

[0466] In analogy to the procedure described for the preparation of 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(4-cyano-3-fluorophenyl)methyl]acetamide (example 28), replacing 4-(aminomethyl)-2-fluorobenzonitrile with 2-chloro-4-(methylaminomethyl)benzonitrile hydrochloride. After completion of the reaction, the reaction mixture was quenched by addition of a sat. aq. solution of sodium hydrogen carbonate (10 mL) and the aq. phase extracted with DCM (310 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure. Purification by MPLC (20 g SiO.sub.2, Telos-cartridge) eluting with a gradient of 0 to 5% methanolDCM provided the title compound (36 mg, 75%) as colorless oil. MS: 492.2 (M+H).sup.+.

Example 57

2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(4-chloro-3-cyanophenyl)methyl]-N-methylacetamide

[0467] ##STR00106##

[A] 2-Chloro-5-(methylaminomethyl)benzonitrile hydrochloride

[0468] ##STR00107##

[0469] To a solution of 2-chloro-5-methylbenzonitrile (1.0 g, 6.6 mmol; [CAS RN 4387-32-0]) in carbon tetrachloride (40 mL) was added N-bromosuccinimide (1.17 g, 6.6 mmol) and benzoyl peroxide (8.0 mg, 0.033 mmol). The reaction mixture was heated to reflux and irradiated using a fluorescent lamp (A=365 nm) for 4 h. The precipitate was filtered off and the filtrate concentrated under reduced pressure. To the crude reaction product was added dropwise a solution of methanamine (20 mL, 40.0 mmol; 2.0 M solution in THF; [CAS RN 74-89-5]) at 0 C. within 30 min. The crude reaction mixture was warmed up to rt and stirring continued for 10 min. The precipitate was filtered off, washed with THF (50 mL) and the filtrate concentrated under reduced pressure. A solution of 1 M NaOH was added (40 mL) and the aq. phase extracted with DCM (340 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure. The crude reaction product was dissolved in dioxane (30 mL) and treated with 4 M HCl in dioxane (10 mL). The white precipate was filtered off, washed with TBME (30 mL) and dried under high vacuum. The title compound was obtained as white solid (0.75 g, 52%). MS: m/e=181.9 [M+H].sup.+.

[B] 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(4-chloro-3-cyanophenyl)methyl]-N-methylacetamide

[0470] ##STR00108##

[0471] In analogy to the procedure described for the preparation of 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(4-cyano-3-fluorophenyl)methyl]acetamide (example 28), replacing 4-(aminomethyl)-2-fluorobenzonitrile with 2-chloro-5-(methylaminomethyl)benzonitrile hydrochloride. After completion of the reaction, the reaction mixture was quenched by addition of a sat. aq. solution of sodium hydrogen carbonate (10 mL) and the aq. phase extracted with DCM (310 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure. Purification by MPLC (20 g SiO.sub.2, Telos-cartridge) eluting with a gradient of 0 to 5% methanolDCM provided the title compound (22 mg, 46%) as white solid. MS: 492.2 (M+H).sup.+.

Example 58

2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(4-cyano-3,5-difluorophenyl)methyl]-N-methylacetamide

[0472] ##STR00109##

[A] 2,6-Difluoro-4-(methylaminomethyl)benzonitrile

[0473] ##STR00110##

[0474] To a solution of 2,6-difluoro-4-formylbenzonitrile (0.10 g, 0.60 mmol; [CAS RN 433939-88-9]) in methanol (2 mL) was added methanamine hydrochloride (40 mg, 0.60 mmol; [CAS RN 593-51-1]) and acetic acid (3.5 L, 0.060 mmol). After stirring of the reaction mixture at rt for min, sodium cyanoborohydride (57 mg, 0.90 mmol; [CAS RN 25895-60-7]) was added in portions over 10 min. Stirring of the reaction mixture was continued for 40 min and then the reaction mixture concentrated under reduced pressure. A solution of 1 M NaOH was added (50 mL) and the aq. phase extracted with DCM (340 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure. The crude reaction product was obtained as colorless oil and used directly in the consecutive reaction step without further purification (7 mg, 6%). MS: m/e=183.1 [M+H].sup.+.

[B] 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(4-cyano-3,5-difluorophenyl)methyl]-N-methylacetamide

[0475] ##STR00111##

[0476] To a solution of 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetic acid (intermediate A-2) (11.9 mg, 0.036 mmol) in dry DCM (1.5 mL) were added HATU (20.5 mg, 0.054 mmol) and DIPEA (19 L, 0.11 mmol) under an atmosphere of nitrogen. Then, 2,6-difluoro-4-(methylaminomethyl)benzonitrile (7 mg, 0.038 mmol) was added and the reaction mixture stirred at rt for 12 h. DCM (2 mL) and a sat. aq. solution of sodium hydrogen carbonate (5 mL) were added and the aq. phase extracted with DCM (310 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure. Purification by prep. TLC (Merck silica TLC glass plates, 2020 cm) eluting with a mixture of tolueneacetone-methanol (5:5:1) provided the title compound as slightly yellow solid (7 mg, 37%). MS: m/e=495.3 [M+H].sup.+.

Example 59

N-[(3,4-Dichlorophenyl)methyl]-2-[6-[4-(3-methylbutanoyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]acetamide

[0477] ##STR00112##

[0478] To a solution of 9H-fluoren-9-ylmethyl 4-[3-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazine-1-carboxylate (intermediate A-5) (15 mg, 0.022 mmol) in dry DMF (1 mL) was added a solution of methanamine (2 mL, 16.0 mmol; 8.0 M solution in ethanol; [CAS RN 74-89-5]) and stirring at rt continued overnight. The crude reaction mixture was concentrated under reduced pressure and redissolved in DMF (1 mL). Triethylamine (30 L, 0.22 mmol) and 3-methylbutanoyl chloride (5.2 mg, 0.043 mmol; [CAS RN 108-12-3]) were added and the reaction mixture stirred at rt overnight under an atmosphere of nitrogen. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as white solid (3.6 mg, 32%). MS: m/e=530.3 [M+H].sup.+.

Examples 60 to 69

[0479] According to the procedure described for the synthesis of example 59 further examples were prepared from 9H-fluoren-9-ylmethyl 4-[3-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazine-1-carboxylate (intermediate A-5) and 9H-fluoren-9-ylmethyl 4-[3-[2-[(3,4-dichlorophenyl)methyl-methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazine-1-carboxylate (intermediate A-6) and the respective carboxylic acid chloride as indicated in Table 4. The results are compiled in Table 4 and comprise examples 60 to 69.

TABLE-US-00005 TABLE 4 No Compound Name & Structure Starting Materials MS 60 N-[(3,4-Dichlorophenyl)methyl]-2-[4-oxo-6-(4-pentanoylpiperazin-1-yl)quinazolin-3-yl]acetamide [00113] 9H-Fluoren-9-ylmethyl 4-[3-[2- [(3,4- dichlorophenyl)methylamino]- 2-oxoethyl]-4-oxoquinazolin-6- yl]piperazine-1-carboxylate (intermediate A-5) and pentanoyl chloride ([CAS RN 638-29-9]) [M + H].sup.+ 530.3 61 N-[(3,4-Dichlorophenyl)methyl]-2-[6-[4-(2-methoxyacetyl)piperazin-1-yl]-4-oxoquinazolin-3- yl]acetamide [00114] 9H-Fluoren-9-ylmethyl 4-[3-[2- [(3,4- dichlorophenyl)methylamino]- 2-oxoethyl]-4-oxoquinazolin-6- yl]piperazine-1-carboxylate (intermediate A-5) and 2-methoxyacetyl chloride ([CAS RN 38870-89-2]) [M + H].sup.+ 518.2 62 N-[(3,4-Dichlorophenyl)methyl]-2-[4-oxo-6-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]quinazolin- 3-yl]acetamide [00115] 9H-Fluoren-9-ylmethyl 4-[3-[2- [(3,4- dichlorophenyl)methylamino]- 2-oxoethyl]-4-oxoquinazolin-6- yl]piperazine-1-carboxylate (intermediate A-5) and 2,2,2-trifluoroacetyl chloride ([CAS RN 354-32-5]) [M + H].sup.+ 542.2 63 2-[6-[4-(Cyclobutanecarbonyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]-N-[(3,4- dichlorophenyl)methyl]acetamide [00116] 9H-Fluoren-9-ylmethyl 4-[3-[2- [(3,4- dichlorophenyl)methylamino]- 2-oxoethyl]-4-oxoquinazolin-6- yl]piperazine-1-carboxylate (intermediate A-5) and cyclobutanecarbonyl chloride ([CAS RN 5006-22-6]) [M + H].sup.+ 528.3 64 2-[6-[4-(Cyclopentanecarbonyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]-N-[(3,4- dichlorophenyl)methyl]acetamide [00117] 9H-Fluoren-9-ylmethyl 4-[3-[2- [(3,4- dichlorophenyl)methylamino]- 2-oxoethyl]-4-oxoquinazolin-6- yl]piperazine-1-carboxylate (intermediate A-5) and cyclopentanecarbonyl chloride ([CAS RN 4524-93-0]) [M + H].sup.+ 542.3 65 2-[6-[4-(Cyclohexanecarbonyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]-N-[(3,4- dichlorophenyl)methyl]acetamide [00118] 9H-Fluoren-9-ylmethyl 4-[3-[2- [(3,4- dichlorophenyl)methylamino]- 2-oxoethyl]-4-oxoquinazolin-6- yl]piperazine-1-carboxylate (intermediate A-5) and cyclohexanecarbonyl chloride ([CAS RN 2719-27-9]) [M + H].sup.+ 556.3 66 2-N-[(3,4-Dichlorophenyl)methyl]-2-[6-[4-(oxane-4-carbonyl)piperazin-1-yl]-4-oxoquinazolin- 3-yl]acetamide [00119] 9H-Fluoren-9-ylmethyl 4-[3- [2-[(3,4- dichlorophenyl)methylamino]- 2-oxoethyl]-4- oxoquinazolin-6-yl]piperazine- 1-carboxylate (intermediate A-5) and oxane-4-carbonyl chloride ([CAS RN 40191-32-0]) [M + H].sup.+ 558.3 67 N-[(3,4-Dichlorophenyl)methyl]-2-[6-[4-(1,2-oxazole-5-carbonyl)piperazin-1-yl]-4- oxoquinazolin-3-yl]acetamide [00120] 9H-Fluoren-9-ylmethyl 4-[3- [2-[(3,4- dichlorophenyl)methylamino]- 2-oxoethyl]-4-oxoquinazolin- 6-yl]piperazine-1-carboxylate (intermediate A-5) and 1,2-oxazole-5-carbonyl chloride ([CAS RN 62348-13-4]) [M + H].sup.+ 541.2 68 N-[(3,4-Dichlorophenyl)methyl]-N-methyl-2-[4-oxo-6-(4-propanoylpiperazin-1-yl)quinazolin- 3-yl]acetamide [00121] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl)methyl- methylamino]-2-oxoethyl]-4- oxoquinazolin-6-yl]piperazine- 1-carboxylate (intermediate A-6) and propanoyl chloride ([CAS RN 79-03-8]) [M + H].sup.+ 516.4 69 N-[(3,4-Dichlorophenyl)methyl]-N-methyl-2-[6-[4-(2-methylpropanoyl)piperazin-1-yl]-4- oxoquinazolin-3-yl]acetamide [00122] 9H-Fluoren-9-ylmethyl 4-[3-[2-[(3,4- dichlorophenyl)methyl- methylamino]-2-oxoethyl]-4- oxoquinazolin-6-yl]piperazine- 1-carboxylate (intermediate A-6) and 2-methylpropanoyl chloride ([CAS RN 79-30-1]) [M + H].sup.+ 530.2

Example 70

2-[6-[4-(3-Aminooxetane-3-carbonyl)piperazin-1-yl]-4-oxoquinazolin-3-yl-N-(3,4-dichlorophenyl)methyl]acetamide

[0480] ##STR00123##

[0481] To a solution of 9H-fluoren-9-ylmethyl 4-[3-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazine-1-carboxylate (intermediate A-5) (30 mg, 0.044 mmol) in dry DMF (1 mL) was added a solution of methanamine (2 mL, 16.0 mmol; 8.0 M solution in ethanol; [CAS RN 74-89-5]) and stirring at rt continued overnight. The crude reaction mixture was concentrated under reduced pressure and redissolved in THF(2 mL). To this solution were added PYBOP (28.6 mg, 0.055 mmol; [CAS RN 128625-52-5]) and DIPFA (12 L, 0.066 mmol) under an atmosphere of nitrogen. Then, 3-aminooxetane-3-carboxylic acid (6.4 mg, 0.055 mmol; [CAS RN 138650-24-5]) was added and the reaction mixture stirred at rt overnight. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as colorles soil (2.6 mg, 11). MS: m/e=545.3 [M+H].sup.+.

Examples 71 to 81

[0482] According to the procedure described for the synthesis of example 70 further examples were prepared from 9H-fluoren-9-ylmethyl 4-[3-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazine-1-carboxylate (intermediate A-5) and 9H-fluoren-9-ymethyl 4-[3-[2-[(3,4-dichlorophenyl)methyl-methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazine-1-carboxylate (intermediate A-6) and the respective carboxylic acid as indicated in Table 5. The results are compiled in Table 5 and comprise examples 71 to 81.

TABLE-US-00006 TABLE 5 No Compound Name & Structure Starting Materials MS 71 N-[(3,4-Dichlorophenyl)methyl]-2-[4-oxo-6-[4-(2-sulfamoylacetyl)piperazin-1-yl]quinazolin-3- yl]acetamide [00124] 9H-Fluoren-9-ylmethyl 4-[3-[2-[(3,4-dichloro- phenyl)methylamino]- 2-oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-5) and 2-sulfamoylacetic acid ([CAS RN 17551-00-7]) [M + H].sup.+ 567.2 72 N-[(3,4-Dichlorophenyl)methyl]-2-[4-oxo-6-[4-(4-sulfamoylbutanoyl)piperazin-1-yl]quinazolin-3- yl]acetamide [00125] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4-dichloro- phenyl)methylamino]- 2-oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-5) and 4-sulfamoylbutanoic acid ([CAS RN 175476-52-5]) [M + H].sup.+ 567.2 73 2-[6-[4-(Cyclobutanecarbonyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]-N-[(3,4- dichlorophenyl)methyl]-N-methylacetamide [00126] 9H-Fluoren-9- ylmethyl 4-[3-[2-[(3,4- dichlorophenyl)methyl- methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-6) and cyclobutane- carboxylic acid ([CAS RN 3721-95-7]) [M + H].sup.+ 542.3 74 N-[(3,4-Dichlorophenyl)methyl]-2-[6-[4-(3-fluorocyclobutanecarbonyl)piperazin-1-yl]-4- oxoquinazolin-3-yl]-N-methylacetamide [00127] 9H-Fluoren-9- ylmethyl 4-[3-[2-[(3,4- dichlorophenyl)methyl- methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-6) and 3-fluorocyclobutane- 1-carboxylic acid ([CAS RN 122665-96-7]) [M + H].sup.+ 560.3 75 N-[(3,4-Dichlorophenyl)methyl]-2-[6-[4-(3,3-difluorocyclobutanecarbonyl)piperazin-1-yl]-4- oxoquinazolin-3-yl]-N-methylacetamide [00128] 9H-Fluoren-9-ylmethyl 4-[3-[2-[(3,4- dichlorophenyl)methyl- methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-6) and 3,3- difluorocyclobutane-1- carboxylic acid ([CAS RN 107496-54-8]) [M + H].sup.+ 578.3 76 N-[(3,4-Dichlorophenyl)methyl]-N-methyl-2-[4-oxo-6-[4-[1- (trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]quinazolin-3-yl]acetamide [00129] 9H-Fluoren-9-ylmethyl 4-[3-[2-[(3,4- dichlorophenyl)methyl- methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-6) and 1- (trifluoromethyl)cyclo- butane-1-carboxylic acid ([CAS RN 277756-45-3]) [M + H].sup.+ 610.3 77 2-[6-[4-(3-Chlorocyclobutanecarbonyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]-N-[(3,4- dichlorophenyl)methyl]-N-methylacetamide [00130] 9H-Fluoren-9-ylmethyl 4-[3-[2-[(3,4- dichlorophenyl)methyl- methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-6) and 3-chlorocyclobutane- 1-carboxylic acid ([CAS RN 35207- 71-7]) [M + H].sup.+ 578.1 78 N-[(3,4-Dichlorophenyl)methyl]-2-[6-[4-(3-methoxycyclobutanecarbonyl)piperazin-1-yl]-4- oxoquinazolin-3-yl]-N-methylacetamide [00131] 9H-Fluoren-9-ylmethyl 4-[3-[2-[(3,4- dichlorophenyl)methyl- methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-6) and 3-methoxycyclobutane- 1-carboxylic acid ([CAS RN 480450- 03-1]) [M + H].sup.+ 572.3 79 N-[(3,4-Dichlorophenyl)methyl]-N-methyl-2-[6-[4-(oxetane-3-carbonyl)piperazin-1-yl]-4- oxoquinazolin-3-yl]acetamide [00132] 9H-Fluoren-9-ylmethyl 4-[3-[2-[(3,4- dichlorophenyl)methyl- methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-6) and oxetane-3-carboxylic acid ([CAS RN 114012-41-8]) [M + H].sup.+ 544.3 80 N-[(3,4-Dichlorophenyl)methyl]-N-methyl-2-[6-[4-(3-methyloxetane-3-carbonyl)piperazin- 1-yl]-4-oxoquinazolin-3-yl]acetamide [00133] 9H-Fluoren-9-ylmethyl 4-[3-[2-[(3,4- dichlorophenyl)methyl- methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-6) and 3-methyloxetane-3- carboxylic acid ([CAS RN 28562-68-7]) [M + H].sup.+ 558.3 81 2-[6-[4-(1-Acetylazetidine-3-carbonyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]-N-[(3,4- dichlorophenyl)methyl]-N-methylacetamide [00134] 9H-Fluoren-9-ylmethyl 4-[3-[2-[(3,4- dichlorophenyl)methyl- methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-6) and 1-acetylazetidine-3- carboxylic acid ([CAS RN 97628-91-6]) [M + H].sup.+ 585.3

Example 82

4-[3-[2-[(3,4-Dichlorophenyl)methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]-N-propan-2-ylpiperazine-1-carboxamide

[0483] ##STR00135##

[0484] To a solution of 9H-fluoren-9-ylmethyl 4-[3-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazine-1-carboxylate (intermediate A-5) (30 mg, 0.044 mmol) in dry DMF (1 mL) was added a solution of methanamine (2 mL, 16.0 mmol; 8.0 M solution in ethanol; [CAS RN 74-89-5]) and stirring at rt continued overnight. The crude reaction mixture was concentrated under reduced pressure and redissolved in dry THF (2 mL). To this solution was added 2-isocyanatopropane (4.7 mg, 0.055 mmol; [CAS RN 1795-48-8]) under an atmosphere of nitrogen and the reaction mixture stirred at rt overnight. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as white solid (5.7 mg, 25) MS: m/e=531.2 [M+H].sup.+.

Examples 83 to 87

[0485] According to the procedure described for the synthesis of example 82 further examples were prepared from 9H-fluoren-9-ylmethyl 4-[3-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazine-1-carboxylate (intermediate A-5) and the respective isonitrile as indicated in Table 6. The results are compiled in Table 6 and comprise examples 83 to 87.

TABLE-US-00007 TABLE 6 No Compound Name & Structure Starting Materials MS 83 [00136] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-5) and isocyanatocyclo- propane ([CAS RN 4747-72-2]) [M + H].sup.+ 529.2 84 [00137] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-5) and isocyanatocyclo- pentane ([CAS RN 4747-71-1]) [M + H].sup.+ 557.3 85 [00138] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-5) and 1-isocyanato- 2-methoxyethane ([CAS RN 42170- 95-6]) [M + H].sup.+ 547.3 86 [00139] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-5) and 4-isocyanato- 3,5-dimethyl-1,2- oxazole ([CAS RN 131825-41-7]) [M + H].sup.+ 584.3 87 [00140] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-5) and 3-isocyanatopyridine ([CAS RN 15268- 31-2]) [M + H].sup.+ 566.2

Example 88

N-[(3,4-Dichlorophenyl)methyl]-2-[6-(4-methylsulfonylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetamide

[0486] ##STR00141##

[0487] To a solution of 9H-fluoren-9-ylmethyl 4-[3-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazine-1-carboxylate (intermediate A-5) (15 mg, 0.022 mmol) in dry DMF (1 mL) was added a solution of methanamine (2 mL, 16.0 mmol; 8.0 M solution in ethanol; [CAS RN 74-89-5]) and stirring at rt continued overnight. The crude reaction mixture was concentrated under reduced pressure and redissolved in dry DMF (1 mL). Triethylamine (30 L, 0.22 mmol) and methanesulfonyl chloride (4.9 mg, 0.088 mmol; [CAS RN 124-63-0]) were added and the reaction mixture stirred at rt overnight under an atmosphere of nitrogen. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as white solid (5.6 mg, 50%). MS: m/e=524.2 [M+H].sup.+.

Examples 89 to 92

[0488] According to the procedure described for the synthesis of example 88 further examples were prepared from 9H-fluoren-9-ylmethyl 4-[3-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazine-1-carboxylate (intermediate A-5) and 9H-fluoren-9-ylmethyl 4-[3-[2-[(3,4-dichlorophenyl)methyl-methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazine-1-carboxylate (intermediate A-6) and the respective sulfonyl chloride as indicated in Table 7. The results are compiled in Table 7 and comprise examples 89 to 92.

TABLE-US-00008 TABLE 7 No Compound Name & Structure Starting Materials MS 89 [00142] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-5) and cyclopentanesulfonyl chloride ([CAS RN 26394-17-2]) [M + H].sup.+ 578.3 90 [00143] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-5) and cyclohexanesulfonyl chloride ([CAS RN 4837- 38-1]) [M + H].sup.+ 592.3 91 [00144] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methyl- methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-6) and cyclopropanesulfonyl chloride ([CAS RN [M + H].sup.+ 564.2 139631-62-2]) 92 [00145] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methyl- methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-6) and cyclobutylmethane sulfonyl chloride ([CAS RN [M + H].sup.+ 592.2 1220695-06-6])

Example 93 Methyl 2-[4-[3-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazin-1-yl]acetate

[0489] ##STR00146##

[0490] To a solution of 9H-fluoren-9-ylmethyl 4-[3-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazine-1-carboxylate (intermediate A-5) (58 mg, 0.085 mmol) in dry DMF (1 mL) was added a solution of methanamine (2 mL, 16.0 mmol; 8.0 M solution in ethanol; [CAS RN 74-89-5]) and stirring at rt continued overnight. The crude reaction mixture was concentrated under reduced pressure and redissolved in dry THF(4 mL). To this solution was added NaH (6.8 mg, 0.17 mmol; 60% dispersion in mineral oil) and the reaction mixture stirred at rt. After 45 min, methyl 2-bromoacetate (19.5 mg, 0.13 mmol; [CAS RN 96-32-2]) was added and stirring of the reaction mixture continued at rt overnight. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as white solid (4.6 mg, 10%). MS: m/e=518.2 [M+H].sup.+.

Example 94

N-[(3,4-Dichlorophenyl)methyl]-2-[6-[4-(2-hydroxyethyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]acetamide

[0491] ##STR00147##

[0492] To a solution of 9H-fluoren-9-ylmethyl 4-[3-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazine-1-carboxylate (intermediate A-5) (30 mg, 0.044 mmol) in dry DMF (1 mL) was added a solution of methanamine (2 mL, 16.0 mmol; 8.0 M solution in ethanol; [CAS RN 74-89-5]) and stirring at rt continued overnight. The crude reaction mixture was concentrated under reduced pressure and redissolved in dry THF (2 mL). To this solution was added 2-hydroxyacetaldehyde (4.0 mg, 0.066 mmol; [CAS RN 141-46-8]) and acetic acid (4 L, 0.066 mmol) under an atmosphere of nitrogen and the reaction mixture stirred at rt. After 45 min, sodium cyanoborohydride (4.1 mg, 0.066 mmol; [CAS RN 25895-60-7]) was added and stirring of the reaction mixture continued at rt overnight. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as white solid (2.5 mg, 12%). MS: m/e=490.2 [M+H].sup.+.

Examples 95 to 103

[0493] According to the procedure described for the synthesis of example 94 further examples were prepared from 9H-fluoren-9-ylmethyl 4-[3-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazine-1-carboxylate (intermediate A-5) and the respective aldehyde as indicated in Table 8. The results are compiled in Table 8 and comprise examples 95 to 103.

TABLE-US-00009 TABLE 8 No Compound Name & Structure Starting Materials MS 95 [00148] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-5) and 2,3-dihydroxypropanal ([CAS RN 56-82-6]) [M + H].sup.+ 520.2 96 [00149] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-5) and cyclobutanecarbaldehyde ([CAS RN 2987-17-9]) [M + H].sup.+ 514.3 97 [00150] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-5) and oxolane-3- carbaldehyde [M + H].sup.+ 530.3 ([CAS RN 79710- 86-4]) 98 [00151] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-5) and oxane-4- carbaldehyde [M + H].sup.+ 544.3 ([CAS RN 50675- 18-8]) 99 [00152] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-5) and 1-methylpyrrole-2- carbaldehyde ([CAS RN 1192-58-1]) [M + H].sup.+ 539.3 100 [00153] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-5) and 1H-imidazole- 2-carbaldehyde [M + H].sup.+ 526.2 ([CAS RN 10111- 08-7]) 101 [00154] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-5) and 1H-imidazole- 5-carbaldehyde [M + H].sup.+ 526.2 ([CAS RN 3034- 50-2]) 102 [00155] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-5) and 3-formylfuran-2- carboxylic acid ([CAS RN 29182- 07-8]) [M H].sup. 568.3 103 [00156] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-5) and 2,4-dimethyl- 1,3-oxazole-5- [M + H].sup.+ 555.3 carbaldehyde ([CAS RN 69062- 86-8])

Example 104

2-[6-[4-(Cyclopropylmethyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]l-N-methylacetamide

[0494] ##STR00157##

[0495] To a solution 9H-fluoren-9-ylmethyl 4-[3-[2-[(3,4-dichlorophenyl)methyl-methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazine-1-carboxylate (intermediate A-6) (37 mg, 0.054 mmol) in dry DMF (1 mL) was added a solution of methanamine (2 mL, 16.0 mmol; 8.0 M solution in ethanol; [CAS RN 74-89-5]) and stirring at rt continued overnight. The crude reaction mixture was concentrated under reduced pressure and redissolved in acetonitrile (1.5 mL). To this solution were added bromomethylcyclopropane (11.0 mg, 0.081 mmol; [CAS RN 7051-34-5]) and potassium carbonate (30 mg, 0.22 mmol) and the reaction mixture heated under microwave irradiation to 120 C. for 15 min. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as white solid (2.1 mg, 8%). MS: m/e=514.3 [M+H].sup.+.

Examples 105 and 106

[0496] According to the procedure described for the synthesis of example 104 further examples were prepared from 9H-fluoren-9-ylmethyl 4-[3-[2-[(3,4-dichlorophenyl)methyl-methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazine-1-carboxylate (intermediate A-6) and the respective alkyl bromide as indicated in Table 9. The results are compiled in Table 9 and comprise examples 105 and 106.

TABLE-US-00010 TABLE 9 No Compound Name & Structure Starting Materials MS 105 [00158] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methyl- methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-6) and 1-bromo-2- [M + H].sup.+ 518.3 methoxyethane ([CAS RN 6482-24-2]) 106 [00159] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methyl- methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-6) and 3-(bromomethyl) [M + H].sup.+ 530.3 oxetane ([CAS RN 1374014-30-8])

Example 107

N-[(3,4-Di chloro phenyl)methyl]-N-methyl-2-[6-[4-[2-(methylamino)-2-oxoethyl]lpiperazin-1-yl]-4-oxoquinazolin-3-yl] acetamide

[0497] ##STR00160##

[0498] To a solution 9H-fluoren-9-ylmethyl 4-[3-[2-[(3,4-dichlorophenyl)methyl-methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazine-1-carboxylate (intermediate A-6) (37 mg, 0.054 mmol) in dry DMF (1 mL) was added a solution of methanamine (2 mL, 16.0 mmol; 8.0 M solution in ethanol; [CAS RN 74-89-5]) and stirring at rt continued overnight. The crude reaction mixture was concentrated under reduced pressure and redissolved in dry DMF (1.5 mL). To this solution were added DIPFA (38 L, 0.22 mmol) and 2-chloro-N-methylacetamide (11.6 mg, 0.11 mmol; [CAS RN 96-30-0]) and the reaction mixture heated under microwave irradiation to 100 C. for 10 min. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as white solid (16.4 mg, 57). MS: m/e=531.3 [M+H].sup.+.

Examples 108 to 112

[0499] According to the procedure described for the synthesis of example 107 further examples were prepared from 9H-fluoren-9-ylmethyl 4-[3-[2-[(3,4-dichlorophenyl)methyl-methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazine-1-carboxylate (intermediate A-6) and the respective alkyl chloride as indicated in Table 10. The results are compiled in Table 10 and comprise examples 108 to 112.

TABLE-US-00011 TABLE 10 No Compound Name & Structure Starting Materials MS 108 [00161] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methyl- methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-6) and 2-chloro-N,N- dimethylacetamide ([CAS RN 2675-89-0]) [M + H].sup.+ 545.3 109 [00162] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methyl- methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-6) and 2-chloro-N- propan-2- ylacetamide [M + H].sup.+ 559.3 ([CAS RN 2895-21-5]) 110 [00163] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methyl- methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-6) and 2-chloro-N,N- diethylacetamide ([CAS RN 2315- 36-8]) [M + H].sup.+ 573.3 111 [00164] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methyl- methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-6) and 2-chloro-1- morpholin-4- ylethanone ([CAS RN 1440-61-5]) [M + H].sup.+ 587.3 112 [00165] 9H-Fluoren-9- ylmethyl 4-[3-[2- [(3,4- dichlorophenyl) methyl- methylamino]-2- oxoethyl]-4- oxoquinazolin-6- yl]piperazine-1- carboxylate (intermediate A-6) and 2-chloro-N- phenylacetamide [M + H].sup.+ 593.3 ([CAS RN 587-65-5])

Example 113

N-[(2-Chloro-4-cyanophenyl)methyl]-2-[6-[4-(oxetane-3-carbonyl)piperazin-1-yl]-4-oxoquinazolin-3-yl] acetamide

[0500] ##STR00166##

[0501] To a solution of 2-[6-[4-(9H-fluoren-9-ylmethoxycarbonyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]acetic acid (intermediate A-; [CAS RN 269078-82-2]) (50 mg, 0.098 mmol) in dry DCM (2 mL) were added TBTU (47.2 mg, 0.15 mmol; [CAS RN25700-67-6]) and DIPEA (50 L, 0.29 mmol) under an atmosphere of nitrogen. Then, 4-(aminomethyl)-3-chlorobenzonitrile (20.4 mg, 0.12 mmol; [CAS RN 20252i-97-9]) was added and the reaction mixture stirred at rt for 90 min. A solution of methanamine (2 mL, 16.0 mmol; 8.0 M solution in ethanol; [CAS RN 74-89-5]) was added and stirring at rt continued overnight. The crude reaction mixture was concentrated under reduced pressure and redissolved in dry DMF (2 mL). To this solution were added DIPEA (50 L, 0.29 mmol), TBTU (47.2 mg, 0.15 mmol; [CAS RN 125700-67-6]) and oxetane-3-carboxylic acid (7.0 L, 0.098 mmol; [CAS RN 114012-41-8]) and the reaction mixture stirred at rt for 2 h under an atmosphere of nitrogen. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as light brown solid (20 mg, 39%). MS: m/e=521.3 [M+H].sup.+.

Example 114

N-[(3-Chloro-4-cyanophenyl)methyl]-N-methyl-2-[4-oxo-6-[4-(oxolan-3-ylmethyl)piperazin-1-yl]quinazolin-3-yl]acetamide

[0502] ##STR00167##

[0503] To a solution of 2-[6-[4-(9H-fluoren-9-ylmethoxycarbonyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]acetic acid (intermediate A-1; [CAS RN 269078-82-2]) (50 mg, 0.098 mmol) in dry DCM (2 mL) were added TBTU (47.2 mg, 0.15 mmol; [CAS RN 125700-67-6]) and DIPEA (50 L, 0.29 mmol) under an atmosphere of nitrogen. Then, 2-chloro-4-(methylaminomethyl)benzonitrile hydrochloride (26.7 mg, 0.12 mmol; example 56, step A) was added and the reaction mixture stirred at rt for 90 min. A solution of methanamine (2 mL, 16.0 mmol; 8.0 M solution in ethanol; [CAS RN 74-89-5]) was added and stirring at rt continued overnight. The crude reaction mixture was concentrated under reduced pressure and redissolved in methanol (2 mL). To this solution was added oxolane-3-carbaldehyde (27 L, 29.4 mg, 0.15 mmol; 50 wt. % sol. in water; [CAS RN 79710-86-4]) and acetic acid (9 L, 0.15 mmol) under an atmosphere of nitrogen and the reaction mixture stirred at rt. After 45 min, sodium cyanoborohydride (9.2 mg, 0.15 mmol; [CAS RN 25895-60-7]) was added and stirring of the reaction mixture continued at rt overnight. The crude reaction mixture was concentrated under reduced pressure, a sat. aq. solution of sodium hydrogen carbonate (20 mL) was added and the aq. phase extracted with DCM (320 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure. Purification by column chromatography (100-200 mesh size silica gel) eluting with a gradient of 0 to 4% methanolDCM and crystallization from methanol afforded the title compound as white solid (25 mg, 48%). MS: m/e=535.4 [M+H].sup.+.

Example 115

N-[(4-Chloro-3-cyanophenyl)methyl]-N-methyl-2-[4-oxo-6-[4-(oxolan-3-ylmethyl)piperazin-1-yl]quinazolin-3-yl]acetamide

[0504] ##STR00168##

[0505] In analogy to the procedure described for the preparation of N-[(3-chloro-4-cyanophenyl)methyl]-N-methyl-2-[4-oxo-6-[4-(oxolan-3-ylmethyl)piperazin-1-yl]quinazolin-3-yl]acetamide (example 114), replacing 2-chloro-4-(methylaminomethyl)benzonitrile hydrochloride with 2-chloro-5-(methylaminomethyl)benzonitrile hydrochloride (example 57, step A). Purification by column chromatography (100-200 mesh size silica gel) eluting with a gradient of 0 to 4% methanolDCM afforded the title compound as colorless oil (26 mg, 50%). MS: m/e=535.3 [M+H].sup.+.

Example 116

2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]-N-ethylacetamide

[0506] ##STR00169##

[A] N-[(3,4-Dichlorophenyl)methyl]ethanamine hydrochloride

[0507] ##STR00170##

[0508] To a solution of 3,4-dichlorobenzaldehyde (1.0 g, 5.71 mmol; [CAS RN 6287-38-3]) and ethanamine (5.71 mL, 11.4 mmol; 2.0 M solution in THF; [CAS RN 75-04-7]) in isopropanol (12 mL) was added acetic acid (0.34 mL, 5.71 mmol) under an atmosphere of nitrogen and the reaction mixture stirred at rt. After 45 min, sodium cyanoborohydride (0.72 g, 5.71 mmol; [CAS RN 25895-60-7]) was added and stirring of the reaction mixture continued at rt overnight. The crude reaction mixture was concentrated under reduced pressure, EtOAc (50 mL) was added and the organic phase extracted with an aq. solution of 0.1 M HCl (320 mL). The combined aqueous phases were set to pH 14 upon addition of solid NaOH and the aq. phase extracted with EtOAc (3100 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure. The crude reaction product was dissolved in dioxane (50 mL) and treated with 4 M HCl in dioxane (20 mL). The white precipate was filtered off, washed with TBME (30 mL) and dried under high vacuum. The title compound was obtained as white solid (0.95 g, 69%). MS: m/e=204.0 [M+H].sup.+.

[B] 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]-N-ethyl-acetamide

[0509] ##STR00171##

[0510] To a suspension of methyl 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetate (intermediate A-7) (50 mg, 0.15 mmol) and N-[(3,4-dichlorophenyl)methyl]ethanamine hydrochloride (38.1 mg, 0.16 mmol) in dry THF (2 mL) was added bis(trimethylaluminium)-1,4-diazabicyclo[2.2.2]octane adduct (44.7 mg, 0.17 mmol; [CAS RN 137203-34-0]) under an atmosphere of nitrogen and the reaction mixture heated under microwave irradiation to 130 C. for 1 h. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as white solid (7.6 mg, 10%). MS: m/e=516.3 [M+H].sup.+.

Example 117

2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]-N-propan-2-ylacetamide

[0511] ##STR00172##

[A] N-[(3,4-Dichlorophenyl)methyl]propan-2-amine hydrochloride

[0512] ##STR00173##

[0513] In analogy to the procedure described for the preparation of N-[(3,4-dichlorophenyl)methyl]ethanamine hydrochloride (example 116, step A), replacing ethanamine with 2-propanamine ([CAS RN 75-31-0]). The title compound was obtained as white solid (1.10 g, 73%). MS: m/e=218.1 [M+H]t.

[B] 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]-N-isopropyl-acetamide

[0514] ##STR00174##

[0515] In analogy to the procedure described for the preparation of 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]-N-ethyl-acetamide (example 116, step B), replacing N-[(3,4-dichlorophenyl)methyl]ethanamine hydrochloride with N-[(3,4-dichlorophenyl)methyl]propan-2-amine hydrochloride. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as white solid (7.9 mg, 10%). MS: m/e=530.3 [M+H].sup.+.

Example 118

2-[6-(4-Acetyl-1,4-diazepan-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]acetamide

[0516] ##STR00175##

[0517] To a solution of 2-[6-[4-(9H-fluoren-9-ylmethoxycarbonyl)-1,4-diazepan-1-yl]-4-oxoquinazolin-3-yl]acetic acid (prepared as described in US2010/0069307A1, pp. 12; [CAS RN 1217190-17-2]) (50 mg, 0.095 mmol) in dry DMF (0.5 mL) were added TBTU (45.9 mg, 0.14 mmol; [CAS RN 125700-67-6]) and DIPEA (50 L, 0.29 mmol) under an atmosphere of nitrogen. Then, (3,4-dichlorophenyl)methanamine (20.1 mg, 0.11 mmol; [CAS RN 102-49-8]) was added and the reaction mixture stirred at rt for 5 h. A solution of methanamine (60 L, 0.48 mmol; 8.0 M solution in ethanol; [CAS RN 74-89-5]) was added and stirring at rt continued overnight. The crude reaction mixture was concentrated under reduced pressure and redissolved in dry DMF (0.5 mL). DIPEA (50 L, 0.29 mmol) and acetyl chloride (34 L, 0.48 mmol; [CAS RN 368426-73-7]) were added and the reaction mixture stirred at rt for 16 h under an atmosphere of nitrogen. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as light yellow solid (17.7 mg, 37%). MS: m/e=463.3 [M+H].sup.+.

Examples 119 to 127

[0518] According to the procedure described for the synthesis of example 118 further examples were prepared from 2-[6-[4-(9H-fluoren-9-ylmethoxycarbonyl)-1,4-diazepan-1-yl]-4-oxoquinazolin-3-yl]acetic acid (prepared as described in US2010/0069307A1, pp. 12; [CAS RN 1217190-17-2]) and 2-[6-[1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidyl]-4-oxoquinazolin-3-yl]acetic acid (intermediate A-8) and the respective amine intermediate as indicated in Table 11. The results are compiled in Table 11 and comprise examples 119 to 127.

TABLE-US-00012 TABLE 11 No Compound Name & Structure Starting Materials MS 119 [00176] 2-[6-[4-(9H- Fluoren-9- ylmethoxycarbonyl)- 1,4-diazepan-1- yl]-4- oxoquinazolin-3- yl]acetic acid and [4-(trifluoromethyl) phenyl]methanamine ([CAS RN 3300-51-4]) [M + H].sup.+ 502.2 120 [00177] 2-[6-[4-(9H- Fluoren-9- ylmethoxycarbonyl)- 1,4-diazepan-1- yl]-4- oxoquinazolin-3- yl]acetic acid and 2-chloro-4- (methylaminomethyl) benzonitrile hydrochloride (example 56, step A) [M + H].sup.+ 507.3 121 [00178] 2-[6-[4-(9H- Fluoren-9- ylmethoxycarbonyl)- 1,4-diazepan-1- yl]-4- oxoquinazolin-3- yl]acetic acid and 2-chloro-5- (methylaminomethyl) benzonitrile hydrochloride (example 57, step A) [M + H].sup.+ 507.2 122 [00179] 2-[6-[1-(9H- Fluoren-9- ylmethoxycarbonyl)- 4-piperidyl]-4- oxoquinazolin-3- yl]acetic acid (intermediate A-8) and (3,4-dichlorophenyl) methanamine ([CAS RN 102-49-8]) [M + H].sup.+ 487.1 123 [00180] 2-[6-[1-(9H- Fluoren-9- ylmethoxycarbonyl)- 4-piperidyl]-4- oxoquinazolin-3- yl]acetic acid (intermediate A-8) and [4-(trifluoromethyl) phenyl]methanamine ([CAS RN 3300-51-4]) [M + H].sup.+ 487.2 124 [00181] 2-[6-[1-(9H- Fluoren-9- ylmethoxycarbonyl)- 4-piperidyl]-4- oxoquinazolin-3- yl]acetic acid (intermediate A-8) and 1-(3,4- dichlorophenyl)- N- methylmethanamine ([CAS RN 5635-67-6]) [M + H].sup.+ 501.2 125 [00182] 2-[6-[1-(9H- Fluoren-9- ylmethoxycarbonyl)- 4-piperidyl]-4- oxoquinazolin-3- yl]acetic acid (intermediate A-8) and 2-chloro-4- (methylaminomethyl) benzonitrile hydrochloride (example 56, step A) [M + H].sup.+ 492.2 126 [00183] 2-[6-[1-(9H- Fluoren-9- ylmethoxycarbonyl)- 4-piperidyl]-4- oxoquinazolin-3- yl]acetic acid (intermediate A-8) and 2-chloro-5- (methylaminomethyl) benzonitrile hydrochloride (example 57, step A) [M + H].sup.+ 492.2 127 [00184] 2-[6-[1-(9H- Fluoren-9- ylmethoxycarbonyl)- 4-piperidyl]-4- oxoquinazolin-3- yl]acetic acid (intermediate A-8) and 2-fluoro-4- (methylaminomethyl) benzonitrile ([CAS RN 1565551-88-3]) [M + H].sup.+ 476.2

Example 128

2-[6-(1-Acetylpiperidin-4-yl)-4-oxoquinazolin-3-yl]-N-[[4-chloro-3-(trifluoromethoxy)phenyl]methyl]-N-methylacetamide

[0519] ##STR00185##

[A] 1-[4-Chloro-3-(trifluoromethoxy)phenyl]-N-methyl-methanamine

[0520] ##STR00186##

[0521] To a solution of 4-chloro-3-(trifluoromethoxy)benzaldehyde (0.30 g, 1.34 mmol; [CAS RN 886499-59-8]) in methanol (3 mL) was added methanamine (0.22 mL, 0.16 g, 1.74 mmol; 33 wt. % solution in EtOH; [CAS RN 74-89-5]) and acetic acid (0.10 mL, 1.74 mmol). After stirring of the reaction mixture at rt for 30 min, sodium cyanoborohydride (86 mg, 2.61 mmol; [CAS RN 25895-60-7]) was added in portions over 10 min. Stirring of the reaction mixture was continued for 40 min and then the reaction mixture concentrated under reduced pressure. A solution of 1 M NaOH was added (50 mL) and the aq. phase extracted with DCM (350 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure. The crude reaction product was obtained as colorless oil and used directly in the consecutive reaction step without further purification (70 mg, 22%). MS: m/e=240.1 [M+H].sup.+. [B] 2-[6-(1-Acetyl-4-piperidyl)-4-oxoquinazolin-3-yl]-N-[[4-chloro-3-(trifluoromethoxy)phenyl]methyl]-N-methyl-acetamide

##STR00187##

[0522] In analogy to the procedure described for the preparation of 2-[6-(4-acetyl-1,4-diazepan-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]acetamide (example 118), replacing 2-[6-[4-(9H-fluoren-9-ylmethoxycarbonyl)-1,4-diazepan-1-yl]-4-oxoquinazolin-3-yl]acetic acid with 2-[6-[1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidyl]-4-oxoquinazolin-3-yl]acetic acid (intermediate A-8) and (3,4-dichlorophenyl)methanamine with 1-[4-chloro-3-(trifluoromethoxy)phenyl]-N-methyl-methanamine, respectively. Purification by column chromatography (100-200 mesh size silica gel) eluting with a gradient of 0 to 3% methanol-DCM afforded the title compound as white solid (38 mg, 73%). MS: m/e=551.2 [M+H].sup.+.

Example 129

N-[(3-Chloro-4-cyanophenyl)methyl]-N-methyl-2-[4-oxo-6-[4-(oxolan-3-ylmethyl)-1,4-diazepan-1-yl]quinazolin-3-yl]acetamide

[0523] ##STR00188##

[0524] To a solution of 2-[6-[4-(9H-fluoren-9-ylmethoxycarbonyl)-1,4-diazepan-1-yl]-4-oxoquinazolin-3-yl]acetic acid (prepared as described in US2010/0069307A1, pp. 12; [CAS RN 1217190-17-2]) (50 mg, 0.095 mmol) in dry DMF (0.5 mL) were added TBTU (45.9 mg, 0.14 mmol; [CAS RN 125700-67-6]) and DIPEA (50 L, 0.29 mmol) under an atmosphere of nitrogen. Then, 2-chloro-4-(methylaminomethyl)benzonitrile hydrochloride (23.9 mg, 0.11 mmol; example 56, step A) was added and the reaction mixture stirred at rt for 5 h. A solution of methanamine (60 L, 0.48 mmol; 8.0 M solution in ethanol; [CAS RN 74-89-5]) was added and stirring at rt continued overnight. The crude reaction mixture was concentrated under reduced pressure and redissolved in methanol (2 mL). To this solution was added oxolane-3-carbaldehyde (27 L, 29.4 mg, 0.15 mmol; 50 wt. % solution in water; [CAS RN 79710-86-4]) and acetic acid (9 L, 0.15 mmol) under an atmosphere of nitrogen and the reaction mixture stirred at rt. After 45 min, sodium cyanoborohydride (9.2 mg, 0.15 mmol; [CAS RN 25895-60-7]) was added and stirring of the reaction mixture continued at rt overnight. The crude reaction mixture was concentrated under reduced pressure, a sat. aq. solution of sodium hydrogen carbonate (20 mL) was added and the aq. phase extracted with DCM (320 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure. Purification by column chromatography (100-200 mesh size silica gel) eluting with a gradient of 0 to 5% methanolDCM afforded the title compound as colorless oil (19 mg, 36%). MS: m/e=549.3 [M+H].sup.+.

Example 130

N-[(4-Chloro-3-cyanophenyl)methyl]-N-methyl-2-[4-oxo-6-[4-(oxolan-3-ylmethyl)-1,4-diazepan-1-yl]quinazolin-3-yl]acetamide

[0525] ##STR00189##

[0526] In analogy to the procedure described for the preparation of N-[(3-chloro-4-cyanophenyl)methyl]-N-methyl-2-[4-oxo-6-[4-(tetrahydrofuran-3-ylmethyl)-1,4-diazepan-1-yl]quinazolin-3-yl]acetamide (example 129), replacing 2-chloro-4-(methylaminomethyl)benzonitrile hydrochloride with 2-chloro-5-(methylaminomethyl)benzonitrile hydrochloride (example 57, step A). Purification by column chromatography (100-200 mesh size silica gel) eluting with a gradient of 0 to 5% methanol-DCM afforded the title compound as colorless oil (31 mg, 60%). MS: m/e=549.4 [M+H].sup.+.

Example 131

N-[(3-Chloro-4-cyanophenyl)methyl]-2-[6-[1-(2-hydroxyacetyl)piperidin-4-yl]-4-oxoquinazolin-3-yl]-N-methylacetamide

[0527] ##STR00190##

[0528] To a solution of N-[(3-chloro-4-cyanophenyl)methyl]-N-methyl-2-(4-oxo-6-piperidin-4-ylquinazolin-3-yl)acetamide (intermediate A-9) (27 mg, 0.056 mmol) in dry DMF (1.5 mL) were added TBTU (27 mg, 0.083 mmol; [CAS RN 125700-67-6]) and DIPEA (50 L, 0.29 mmol) under an atmosphere of nitrogen. Then, 2-hydroxyacetic acid (5.1 mg, 0.067 mmol; [CAS RN 79-14-1]) was added and the reaction mixture stirred at rt for 18 h. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as white solid (10.7 mg, 38%). MS: m/e=508.3 [M+H].sup.+.

Examples 132 to 142

[0529] According to the procedure described for the synthesis of example 131 further examples were prepared from N-[(3-chloro-4-cyanophenyl)methyl]-N-methyl-2-(4-oxo-6-piperidin-4-ylquinazolin-3-yl)acetamide (intermediate A-9) and the respective carboxylic acid as indicated in Table 12. The results are compiled in Table 12 and comprise examples 132 to 142.

TABLE-US-00013 TABLE 12 Starting No Compound Name & Structure Materials MS 132 N-[(3-Chloro-4-cyanophenyl)methyl]-2-[6-[1-(2- N-[(3-Chloro-4- [M + H].sup.+ methoxyacetyl)piperidin-4-yl]-4-oxoquinazolin-3- cyanophenyl)methyl]- 522.2 yl]-N-methylacetamide N-methyl-2-(4-oxo-6- [00191] piperidin-4- ylquinazolin-3- yl)acetamide (intermediate A- 9) and 2- methoxyacetic acid ([CAS RN 625-45-6]) 133 N-[(3-Chloro-4-cyanophenyl)methyl]-2-[6-[1-(2- N-[(3-Chloro-4- [M + H].sup.+ methoxypropanoyl)piperidin-4-yl]-4- cyanophenyl)methyl]- 536.3 oxoquinazolin-3-yl]-N-methylacetamide N-methyl-2- [00192] (4-oxo-6- piperidin-4- ylquinazolin-3- yl)acetamide (intermediate A- 9) and 2- methoxypropanoic acid ([CAS RN 4324-37-2]) 134 N-[(3-Chloro-4-cyanophenyl)methyl]-2-[6-[1-(3- N-[(3-Chloro-4- [M + H].sup.+ methoxypropanoyl)piperidin-4-yl]-4- cyanophenyl)methyl]- 536.3 oxoquinazolin-3-yl]-N-methylacetamide N-methyl-2- [00193] (4-oxo-6- piperidin-4- ylquinazolin-3- yl)acetamide (intermediate A- 9) and 3- methoxypropanoic acid ([CAS RN 2544-06-1]) 135 N-[(3-Chloro-4-cyanophenyl)methyl]-N-methyl- N-[(3-Chloro-4- [M + H].sup.+ 2-[4-oxo-6-[1-(2-propan-2-yloxyacetyl)piperidin- cyanophenyl)methyl]- 550.3 4-yl]quinazolin-3-yl]acetamide N-methyl-2- [00194] (4-oxo-6-piperidin- 4-ylquinazolin-3- yl)acetamide (intermediate A- 9) and 2- isopropoxyacetic acid ([CAS RN 33445-07-7]) 136 N-[(3-Chloro-4-cyanophenyl)methyl]-2-[6-[1- N-[(3-Chloro-4- [M + H].sup.+ (cyclopropanecarbonyl)piperidin-4-yl]-4- cyanophenyl)methyl]- 518.3 oxoquinazolin-3-yl]-N-methylacetamide N-methyl-2-(4-oxo- [00195] 6-piperidin-4- ylquinazolin-3- yl)acetamide (intermediate A- 9) and cyclopropanecarboxylic acid ([CAS RN 1759-53-1]) 137 N-[(3-Chloro-4-cyanophenyl)methyl]-2-[6-[1- N-[(3-Chloro-4- [M + H].sup.+ (cyclobutanecarbonyl)piperidin-4-yl]-4- cyanophenyl)methyl]- 532.3 oxoquinazolin-3-yl]-N-methylacetamide N-methyl-2-(4-oxo-6- [00196] piperidin-4- ylquinazolin-3-yl) acetamide(intermediate A-9) and cyclobutanecarboxylic acid ([CAS RN 3721-95-7]) 138 N-[(3-Chloro-4-cyanophenyl)methyl]-2-[6-[1-(3- N-[(3-Chloro-4- [M + H].sup.+ fluorocyclobutanecarbonyl)piperidin-4-yl]-4- cyanophenyl)methyl]- 550.3 oxoquinazolin-3-yl]-N-methylacetamide N-methyl-2-(4-oxo-6- [00197] piperidin-4- ylquinazolin-3- yl)acetamide (intermediate A-9) and 3-fluorocyclobutane carboxylic acid ([CAS RN 122665-96-7]) 139 N-[(3-Chloro-4-cyanophenyl)methyl]-2-[6-[1-(3- N-[(3-Chloro-4- [M + H].sup.+ chlorocyclobutanecarbonyl)piperidin-4-yl]-4- cyanophenyl)methyl]- 566.3 oxoquinazolin-3-yl]-N-methylacetamide N-methyl-2-(4-oxo-6- [00198] piperidin-4- ylquinazolin-3- yl)acetamide (intermediate A- 9) and 3- chlorocyclobutane-1- carboxylic acid ([CAS RN 35207-71-7]) 140 N-[(3-Chloro-4-cyanophenyl)methyl]-2-[6-[1- N-[(3-Chloro-4- [M + H].sup.+ (3,3-difluorocyclobutanecarbonyl)piperidin-4-yl]- cyanophenyl)methyl]- 568.6 4-oxoquinazolin-3-yl]-N-methylacetamide N-methyl-2-(4-oxo-6- [00199] piperidin-4- ylquinazolin-3- yl)acetamide (intermediate A- 9) and 3,3- difluorocyclobutane- 1-carboxylic acid ([CAS RN 107496-54-8]) 141 N-[(3-Chloro-4-cyanophenyl)methyl]-N-methyl- N-[(3-Chloro-4- [M + H].sup.+ 2-[6-[1-(oxetane-2-carbonyl)piperidin-4-yl]-4- cyanophenyl)methyl]- 534.3 oxoquinazolin-3-yl]acetamide N-methyl-2-(4-oxo- [00200] 6-piperidin-4- ylquinazolin-3- yl)acetamide (intermediate A- 9) and oxetane-2- carboxylic acid ([CAS RN 864373-47-7]) 142 N-[(3-Chloro-4-cyanophenyl)methyl]-N-methyl- N-[(3-Chloro-4- [M + H].sup.+ 2-[6-[1-(oxetane-3-carbonyl)piperidin-4-yl]-4- cyanophenyl)methyl]- 534.3 oxoquinazolin-3-yl]acetamide N-methyl-2-(4-oxo- [00201] 6-piperidin-4- ylquinazolin-3- yl)acetamide (intermediate A- 9) and oxetane-3- carboxylic acid ([CAS RN 114012-41-8])

Example 143

N-[(3-Chloro-4-cyanophenyl)methyl]-N-methyl-2-[4-oxo-6-[1-(oxolan-3-ylmethyl)piperidin-4-yl]quinazolin-3-yl]acetamide

[0530] ##STR00202##

[0531] In analogy to the procedure described for the preparation of N-[(3-chloro-4-cyanophenyl)methyl]-N-methyl-2-[4-oxo-6-[4-(tetrahydrofuran-3-ylmethyl)-1,4-diazepan-1-yl]quinazolin-3-yl]acetamide (example 129), replacing 2-[6-[4-(9H-fluoren-9-ylmethoxycarbonyl)-1,4-diazepan-1-yl]-4-oxoquinazolin-3-yl]acetic acid with 2-[6-[1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidyl]-4-oxoquinazolin-3-yl]acetic acid (intermediate A-8). Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as colorless oil (14.2 mg, 28%). MS: m/e=536.4 [M+H].sup.+.

Example 144

N-[(4-Chloro-3-cyanophenyl)methyl]-N-methyl-2-[4-oxo-6-[1-(oxolan-3-ylmethyl)piperidin-4-yl]quinazolin-3-yl]acetamide

[0532] ##STR00203##

[0533] In analogy to the procedure described for the preparation of N-[(3-chloro-4-cyanophenyl)methyl]-N-methyl-2-[4-oxo-6-[4-(tetrahydrofuran-3-ylmethyl)-1,4-diazepan-1-yl]quinazolin-3-yl]acetamide (example 129), replacing 2-[6-[4-(9H-fluoren-9-ylmethoxycarbonyl)-1,4-diazepan-1-yl]-4-oxoquinazolin-3-yl]acetic acid with 2-[6-[1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidyl]-4-oxoquinazolin-3-yl]acetic acid (intermediate A-8) and 2-chloro-4-(methylaminomethyl)benzonitrile hydrochloride with 2-chloro-5-(methylaminomethyl)benzonitrile hydrochloride (example 57, step A). Purification by column chromatography (100-200 mesh size silica gel) eluting with a gradient of 0 to 5% methanol-DCM afforded the title compound as colorless oil (21.3 mg, 42%). MS: m/e=534.3 [M+H].sup.+.

Example 145

N-[(3-Chloro-4-cyanophenyl)methyl]-N-methyl-2-[6-(1-methylsulfonylpiperidin-4-yl)-4-oxoquinazolin-3-yl]acetamide

[0534] ##STR00204##

[0535] To a solution of N-[(3-chloro-4-cyanophenyl)methyl]-N-methyl-2-(4-oxo-6-piperidin-4-ylquinazolin-3-yl)acetamide (intermediate A-9) (22 mg, 0.045 mmol) in dry DMF (1.5 mL) was added DIPEA (25 L, 0.15 mmol) and methanesulfonyl chloride (6.2 mg, 0.054 mmol; [CAS RN 124-63-0]) and the reaction mixture stirred at rt overnight under an atmosphere of nitrogen. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as white solid (12.8 mg, 54%). MS: m/e=528.2 [M+H].sup.+.

Example 146

N-Cyclopropyl-N-[(3,4-dichlorophenyl)methyl]-2-[6-[1-(2-methoxyacetyl)piperidin-4-yl]-4-oxoquinazolin-3-yl]acetamide

[0536] ##STR00205##

[A] N-[(3,4-Dichlorophenyl)methyl]cyclopropanamine hydrochloride

[0537] ##STR00206##

[0538] In analogy to the procedure described for the preparation of N-[(3,4-dichlorophenyl)methyl]ethanamine hydrochloride (example 116, step A), replacing ethanamine with cyclopropanamine ([CAS RN 765-30-0]). The title compound was obtained as white solid (0.46 g, 32%). MS: m/e=216.1 [M+H].sup.+.

[B] N-Cyclopropyl-N-[(3,4-dichlorophenyl)methyl]-2-[6-[1-(2-methoxyacetyl)-4-piperidyl]-4-oxoquinazolin-3-yl]acetamide

[0539] ##STR00207##

[0540] In analogy to the procedure described for the preparation of 2-[6-(4-acetyl-1,4-diazepan-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]acetamide (example 118), replacing 2-[6-[4-(9H-fluoren-9-ylmethoxycarbonyl)-1,4-diazepan-1-yl]-4-oxoquinazolin-3-yl]acetic acid with 2-[6-[1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidyl]-4-oxoquinazolin-3-yl]acetic acid (intermediate A-8), (3,4-dichlorophenyl)methanamine with N-[(3,4-dichlorophenyl)methyl]cyclopropanamine hydrochloride and acetyl chloride with 2-methoxyacetyl chloride ([CAS RN 38870-89-2]), respectively. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as white solid (11.1 mg, 21%). MS: m/e=557.6 [M+H].sup.+.

Example 147

2-[6-[2-Acetyl-2-azabicyclo[2.2.1]heptan-5-yl]-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]acetamide

[0541] ##STR00208##

[0542] In analogy to the procedure described for the preparation of 2-[6-(4-acetyl-1,4-diazepan-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]acetamide (example 118), replacing 2-[6-[4-(9H-fluoren-9-ylmethoxycarbonyl)-1,4-diazepan-1-yl]-4-oxoquinazolin-3-yl]acetic acid with 2-[6-[2-(9H-fluoren-9-ylmethoxycarbonyl)-2-azabicyclo[2.2.1]heptan-5-yl]-4-oxoquinazolin-3-yl]acetic acid (prepared as described in US2010/0069307A1, pp. 19; [CAS RN 1217190-42-5]). Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as light yellow solid (17 mg, 36%). MS: m/e=499.1 [M+H].sup.+.

Example 148

2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]propanamide

[0543] ##STR00209##

[A] tert-Butyl N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]carbamate

[0544] ##STR00210##

[0545] To a solution of 2-(tert-butoxycarbonylamino)propanoic acid (1.0 g, 5.3 mmol; [CAS RN 3744-87-4]) in DCM (40 mL) were added HATU (2.4 g, 5.3 mmol; [CAS RN 148893-10-1]) and triethylamine (1.4 mL, 10.6 mmol) under an atmosphere of nitrogen. Then, (3,4-dichlorophenyl)methanamine (0.9 g, 5.3 mmol; [CAS RN 102-49-8]) was added and the reaction mixture stirred at rt overnight. A 1 M solution of citric acid (20 mL) was added and the aq. phase extracted with DCM (320 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure. Purification by column chromatography (100-200 mesh size silica gel) eluting with a gradient of 1:20 to 1:1 EtOAcpetroleum ether afforded the title compound as white solid (1.6 g, 87%). MS: m/e=347.1 [M+H].sup.+.

[B] 2-Amino-N-[(3,4-dichlorophenyl)methyl]propanamide hydrochloride

[0546] ##STR00211##

[0547] A solution of tert-butyl N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]carbamate (1.6 g, 4.6 mmol) in EtOAc (10 mL) was treated with 4 M HCl in dioxane (10 mL) and the reaction mixture stirred at rt for 2 h. The white precipitate was filtered off, washed with TBME (40 mL) and dried under high vacuum. The title compound was obtained as white solid and used crude in the consecutive reaction step (1.2 g, 92%). MS: m/e=247.0 [M+H].sup.+.

[C] 5-(4-Acetylpiperazin-1-yl)-N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]-2-nitrobenzamide

[0548] ##STR00212##

[0549] To a solution of 5-(4-acetylpiperazin-1-yl)-2-nitrobenzoic acid (intermediate A-7, step A) (0.51 g, 2.1 mmol) in DCM (40 mL) were added HATU (0.78 g, 2.1 mmol; [CAS RN 148893-10-1]) and triethylamine (0.5 mL, 3.4 mmol) under an atmosphere of nitrogen. Then, 2-amino-N-[(3,4-dichlorophenyl)methyl]propanamide hydrochloride (0.50 g, 1.7 mmol) was added and the reaction mixture stirred at rt overnight. A 1 M solution of citric acid (40 mL) was added and the aq. phase extracted with DCM (340 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure. Purification by column chromatography (100-200 mesh size silica gel) eluting with a gradient of 1:80 to 1:30 methanol-DCM afforded the title compound as yellow solid (0.44 g, 50%). MS: m/e=522.1 [M+H].sup.+.

[D] 5-(4-Acetylpiperazin-1-yl)-2-amino-N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]benzamide

[0550] ##STR00213##

[0551] To 5-(4-acetylpiperazin-1-yl)-N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]-2-nitrobenzamide (0.44 g, 0.84 mmol) dissolved in ethanol (20 mL) was added dropwise a solution of tin(II) chloride dihydrate (1.1 g, 5.05 mmol) in conc. HCl (2 mL) at rt. After stirring of the reaction mixture for 2 h, an aq. solution of 10% sodium carbonate (50 mL) was added, the reaction filtered and the aq. phase extracted with DCM (340 mL). The combined organic phases were dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. Purification by column chromatography (100-200 mesh size silica gel) eluting with a gradient of 1:50 to 1:20 methanol-DCM afforded the title compound as light brown solid (0.20 g, 48%). MS: m/e=492.1 [M+H].sup.+.

[E] 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]propanamide

[0552] ##STR00214##

[0553] To a solution of 5-(4-acetylpiperazin-1-yl)-2-amino-N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]benzamide (100 mg, 0.20 mmol) in ethanol (5 mL) was added acetic acid (12 g, 0.20 mmol) and trimethyl orthoformate (22 mg, 0.20 mmol; [CAS RN 149-73-5]) and the reaction mixture heated to 60 C. for 12 h. The crude reaction mixture was concentrated under reduced pressure and purified by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater. The title compound was obtained as white solid (47 mg, 46%). MS: m/e=502.1 [M+H].sup.+.

Example 149

2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]-N-methylpropanamide

[0554] ##STR00215##

[A] tert-Butyl N-[1-[(3,4-dichlorophenyl)methyl-methylamino]-1-oxopropan-2-yl]carbamate

[0555] ##STR00216##

[0556] In analogy to the procedure described for the preparation of tert-butyl N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]carbamate (example 148, step A), replacing (3,4-dichlorophenyl)methanamine with 1-(3,4-dichlorophenyl)-N-methyl-methanamine ([CAS RN 5635-67-6]). Purification by column chromatography (100-200 mesh size silica gel) eluting with a gradient of 1:10 to 1:3 EtOAcpetroleum ether afforded the title compound as colorless oil (1.7 g, 90%). MS: m/e=362.3 [M+H].sup.+.

[B] 2-Amino-N-[(3,4-dichlorophenyl)methyl]-N-methylpropanamide hydrochloride

[0557] ##STR00217##

[0558] In analogy to the procedure described for the preparation of 2-amino-N-[(3,4-dichlorophenyl)methyl]propanamide hydrochloride (example 148, step B), replacing tert-butyl N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]carbamate with tert-butyl N-[1-[(3,4-dichlorophenyl)methyl-methylamino]-1-oxopropan-2-yl]carbamate. The title compound was obtained as white solid and used crude in the consecutive reaction step (1.0 g, 71%). MS: m/e=261.1 [M+H].sup.+.

[C] 5-(4-Acetylpiperazin-1-yl)-N-[1-[(3,4-dichlorophenyl)methyl-methylamino]-1-oxopropan-2-yl]-2-nitrobenzamide

[0559] ##STR00218##

[0560] In analogy to the procedure described for the preparation of 5-(4-acetylpiperazin-1-yl)-N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]-2-nitrobenzamide (example 148, step C), replacing 2-amino-N-[(3,4-dichlorophenyl)methyl]propanamide hydrochloride with 2-amino-N-[(3,4-dichlorophenyl)methyl]-N-methylpropanamide hydrochloride. Purification by column chromatography (100-200 mesh size silica gel) eluting with a gradient of 1:80 to 1:30 methanol-DCM afforded the title compound as red solid (2.0 g, 58%; 53% purity). MS: m/e=536.0 [M+H].sup.+.

[D] 5-(4-Acetylpiperazin-1-yl)-2-amino-N-[1-[(3,4-dichlorophenyl)methyl-methylamino]-1-oxopropan-2-yl]benzamide

[0561] ##STR00219##

[0562] In analogy to the procedure described for the preparation of 5-(4-acetylpiperazin-1-yl)-2-amino-N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]benzamide (example 148, step D), replacing 5-(4-acetylpiperazin-1-yl)-N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]-2-nitrobenzamide with 5-(4-acetylpiperazin-1-yl)-N-[1-[(3,4-dichlorophenyl)methyl-methylamino]-1-oxopropan-2-yl]-2-nitrobenzamide. Purification by column chromatography (100-200 mesh size silica gel) eluting with a gradient of 1:30 to 1:10 methanolDCM afforded the title compound as light yellow oil (0.45 g, 31%; 65% purity). MS: m/e=506.0 [M+H].sup.+.

[E] 2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]-N-methylpropanamide

[0563] ##STR00220##

[0564] In analogy to the procedure described for the preparation of 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]propanamide (example 148, step E), replacing 5-(4-acetylpiperazin-1-yl)-2-amino-N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]benzamide with 5-(4-acetylpiperazin-1-yl)-2-amino-N-[1-[(3,4-dichlorophenyl)methyl-methylamino]-1-oxopropan-2-yl]benzamide. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as white solid (25 mg, 13%). MS: m/e=515.2 [M+H].sup.+.

Example 150

1-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]cyclopropane-1-carboxamide

[0565] ##STR00221##

[A] tert-Butyl N-[1-[(3,4-dichlorophenyl)methylcarbamoyl]cyclopropyl]carbamate

[0566] ##STR00222##

[0567] In analogy to the procedure described for the preparation of tert-butyl N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]carbamate (example 148, step A), replacing 2-(tert-butoxycarbonylamino)propanoic acid with 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid ([CAS RN 88950-64-5]). Purification by column chromatography (100-200 mesh size silica gel) eluting with a gradient of 1:20 to 1:1 EtOAc-petroleum ether afforded the title compound as colorless oil (2.0 g, 90%; 66% purity). MS: m/e=381.0 [M+H].sup.+.

[B] 1-Amino-N-[(3,4-dichlorophenyl)methyl]cyclopropanecarboxamide hydrochloride

[0568] ##STR00223##

[0569] In analogy to the procedure described for the preparation of 2-amino-N-[(3,4-dichlorophenyl)methyl]propanamide hydrochloride (example 148, step B), replacing tert-butyl N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]carbamate with tert-butyl N-[1-[(3,4-dichlorophenyl)methylcarbamoyl]cyclopropyl]carbamate. The title compound was obtained as white solid and used crude in the consecutive reaction step (1.0 g, 61%). MS: m/e=259.1 [M+H].sup.+.

[C] 5-(4-Acetylpiperazin-1-yl)-N-[1-[(3,4-dichlorophenyl)methylcarbamoyl]cyclopropyl]-2-nitrobenzamide

[0570] ##STR00224##

[0571] In analogy to the procedure described for the preparation of 5-(4-acetylpiperazin-1-yl)-N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]-2-nitrobenzamide (example 148, step C), replacing 2-amino-N-[(3,4-dichlorophenyl)methyl]propanamide hydrochloride with 1-amino-N-[(3,4-dichlorophenyl)methyl]cyclopropanecarboxamide hydrochloride. Purification by column chromatography (100-200 mesh size silica gel) eluting with a gradient of 1:80 to 1:30 methanol-DCM afforded the title compound as red solid (1.1 g, 60%). MS: m/e=534.1 [M+H].sup.+.

[D] 5-(4-Acetylpiperazin-1-yl)-2-amino-N-[1-[(3,4-dichlorophenyl)methylcarbamoyl]cyclopropyl]benzamide

[0572] ##STR00225##

[0573] In analogy to the procedure described for the preparation of 5-(4-acetylpiperazin-1-yl)-2-amino-N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]benzamide (example 148, step D), replacing 5-(4-acetylpiperazin-1-yl)-N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]-2-nitrobenzamide with 5-(4-acetylpiperazin-1-yl)-N-[1-[(3,4-dichlorophenyl)methylcarbamoyl]cyclopropyl]-2-nitrobenzamide. The title compound was isolated as light yellow solid (0.35 g, 69%). MS: m/e=557.3 [M+H].sup.+.

[E] 1-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]cyclopropane-1-carboxamide

[0574] ##STR00226##

[0575] In analogy to the procedure described for the preparation of 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]propanamide (example 148, step E), replacing 5-(4-acetylpiperazin-1-yl)-2-amino-N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]benzamide with 5-(4-acetylpiperazin-1-yl)-2-amino-N-[1-[(3,4-dichlorophenyl)methylcarbamoyl]cyclopropyl]benzamide. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as white solid (25 mg, 16%). MS: m/e=514.0 [M+H].sup.+.

Example 151

2-[6-(4-Acetylpiperazin-1-yl)-2-methyl-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]acetamide

[0576] ##STR00227##

[A] tert-Butyl N-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]carbamate

[0577] ##STR00228##

[0578] In analogy to the procedure described for the preparation of tert-butyl N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]carbamate (example 148, step A), replacing 2-(tert-butoxycarbonylamino)propanoic acid with 2-(tert-butoxycarbonylamino)acetic acid ([CAS RN 4530-20-5]). Purification by column chromatography (100-200 mesh size silica gel) eluting with a gradient of 1:20 to 1:1 EtOAcpetroleum ether afforded the title compound as white solid (2.5 g, 66%). MS: m/e=276.8 [M+H tert-Bu].sup.+.

[B] 2-Amino-N-[(3,4-dichlorophenyl)methyl]acetamide hydrochloride

[0579] ##STR00229##

[0580] In analogy to the procedure described for the preparation of 2-amino-N-[(3,4-dichlorophenyl)methyl]propanamide hydrochloride (example 148, step B), replacing tert-butyl N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]carbamate with tert-butyl N-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]carbamate. The title compound was obtained as white solid and used crude in the consecutive reaction step (1.3 g, 67%). MS: m/e=233.1 [M+H].sup.+.

[C] 5-(4-Acetylpiperazin-1-yl)-N-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]-2-nitrobenzamide

[0581] ##STR00230##

[0582] In analogy to the procedure described for the preparation of 5-(4-acetylpiperazin-1-yl)-N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]-2-nitrobenzamide (example 148, step C), replacing 2-amino-N-[(3,4-dichlorophenyl)methyl]propanamide hydrochloride with 2-amino-N-[(3,4-dichlorophenyl)methyl]acetamide hydrochloride. Purification by column chromatography (100-200 mesh size silica gel) eluting with a gradient of 1:100 to 1:20 methanol-DCM afforded the title compound as yellow solid (1.6 g, 71%). MS: m/e=508.6 [M+H].sup.+.

[D] 5-(4-Acetylpiperazin-1-yl)-2-amino-N-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]benzamide

[0583] ##STR00231##

[0584] In analogy to the procedure described for the preparation of 5-(4-acetylpiperazin-1-yl)-2-amino-N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]benzamide (example 148, step D), replacing 5-(4-acetylpiperazin-1-yl)-N-[1-[(3,4-dichlorophenyl)methylamino]-1-oxopropan-2-yl]-2-nitrobenzamide with 5-(4-acetylpiperazin-1-yl)-N-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]-2-nitrobenzamide. Purification by column chromatography (100-200 mesh size silica gel) eluting with a gradient of 1:100 to 1:20 methanol-DCM afforded the title compound as light brown solid (0.9 g, 60%). MS: m/e=478.1 [M+H].sup.+.

[E] 2-[6-(4-Acetylpiperazin-1-yl)-2-methyl-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]acetamide

[0585] ##STR00232##

[0586] To a solution of 5-(4-acetylpiperazin-1-yl)-2-amino-N-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]benzamide (200 mg, 0.42 mmol) in ethanol (10 mL) was added acetic acid (24 g, 0.42 mmol) and trimethyl orthoacetate (50 mg, 0.42 mmol; [CAS RN 1445-45-0]) and the reaction mixture heated to reflux overnight. The crude reaction mixture was concentrated under reduced pressure and purified by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater. The title compound was obtained as white solid (120 mg, 57%). MS: m/e=502.1 [M+H].sup.+.

Example 152

2-[6-(4-Acetylpiperazin-1-yl)-2,4-dioxo-1H-quinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]acetamide

[0587] ##STR00233##

[0588] To a solution of 5-(4-acetylpiperazin-1-yl)-2-amino-N-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]benzamide (example 151, step D) (200 mg, 0.42 mmol) in DCM (10 mL) was added N,N-carbonyldiimidazole (102 mg, 0.63 mmol; [CAS RN 530-62-1]) and the reaction mixture heated to 80 C. overnight. The crude reaction mixture was concentrated under reduced pressure and purified by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater. The title compound was obtained as white solid (100 mg, 47%). MS: m/e=504.1 [M+H].sup.+.

Example 153

2-[6-(4-Acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[1-(3,4-dichlorophenyl)-3-methoxypropyl]acetamide

[0589] ##STR00234##

[0590] To a solution of 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetic acid (intermediate A-2) (11.9 mg, 0.036 mmol) in dry DMF (1 mL) were added HATU (20.5 mg, 0.054 mmol; [CAS RN 148893-10-1]) and DIPEA (50 L, 0.29 mmol) under an atmosphere of nitrogen. Then, 1-(3,4-dichlorophenyl)-3-methoxypropan-1-amine hydrochloride (11.6 mg, 0.043 mmol; [CAS RN 1803587-38-3]) was added and the reaction mixture heated by microwave irradiation to 100 C. for 10 min. Water was added (1 mL) and the crude reaction product purified by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water. The title compound was obtained as white solid (1.4 mg, 7%). MS: m/e=546.1 [M+H].sup.+.

Example 154

N-[(3-Chloro-4-cyanophenyl)methyl]-2-[6-[1-(2-cyanoacetyl)piperidin-4-yl]-4-oxoquinazolin-3-yl]-N-methylacetamide

[0591] ##STR00235##

[0592] To a solution of N-[(3-chloro-4-cyanophenyl)methyl]-N-methyl-2-(4-oxo-6-piperidin-4-ylquinazolin-3-yl)acetamide (intermediate A-9) (68 mg, 0.15 mmol) in DCM (2 mL) were added HATU (86.2 mg, 0.23 mmol; [CAS RN 148893-10-1]) and DIPEA (79 L, 0.45 mmol) under an atmosphere of nitrogen. Then, 2-cyanoacetic acid (19.3 mg, 0.23 mmol; [CAS RN 372-09-8]) was added and the reaction mixture heated by microwave irradiation to 100 C. for 10 min. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as light yellow solid (35.1 mg, 45%). MS: m/e=517.2 [M+H].sup.+.

Example 155

N-[(3-Chloro-4-cyanophenyl)methyl]-2-[6-[1-(3-cyanopropanoyl)piperidin-4-yl]-4-oxoquinazolin-3-yl]-N-methylacetamide

[0593] ##STR00236##

[0594] To a solution of N-[(3-chloro-4-cyanophenyl)methyl]-N-methyl-2-(4-oxo-6-piperidin-4-ylquinazolin-3-yl)acetamide (intermediate A-9) (50 mg, 0.11 mmol) in dry DMF (2 mL) were added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (69.4 mg, 0.13 mmol; PyBOP; [CAS RN 128625-52-5]) and DIPEA (97 L, 0.56 mmol) under an atmosphere of nitrogen. Then, 3-cyanopropanoic acid (13.2 mg, 0.13 mmol; [CAS RN 16051-87-9]) was added and the reaction mixture stirred at rt for 1 h. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as white solid (5 mg, 9%). MS: m/e=531.3 [M+H].sup.+.

Examples 156 to 159

[0595] According to the procedure described for the synthesis of example 155 further examples were prepared from N-[(3-chloro-4-cyanophenyl)methyl]-N-methyl-2-(4-oxo-6-piperidin-4-ylquinazolin-3-yl)acetamide (intermediate A-9) and the respective carboxylic acid as indicated in Table 13. The results are compiled in Table 13 and comprise examples 156 to 159.

TABLE-US-00014 TABLE 13 Starting No Compound Name & Structure Materials MS 156 N-[(3-Chloro-4-cyanophenyl)methyl]-2-[6-[1- N-[(3-Chloro-4- [M + H].sup.+ [(2R)-2-hydroxypropanoyl]piperidin-4-yl]-4- cyanophenyl)methyl]- 522.3 oxoquinazolin-3-yl]-N-methylacetamide N-methyl-2- [00237] (4-oxo-6- piperidin-4- ylquinazolin-3- yl)acetamide (intermediate A- 9) and (R)-2- hydroxypropanoic acid ([CAS RN 10326-41-7]) 157 N-[(3-Chloro-4-cyanophenyl)methyl]-2-[6-[1- N-[(3-Chloro-4- [M + H].sup.+ [(2R)-2-hydroxy-3-methylbutanoyl]piperidin-4- cyanophenyl)methyl]- 550.4 yl]-4-oxoquinazolin-3-yl]-N-methylacetamide N-methyl-2- [00238] (4-oxo-6- piperidin-4- ylquinazolin-3- yl)acetamide (intermediate A- 9) and (R)-2- hydroxy-3- methylbutanoic acid ([CAS RN 17407-56-6]) 158 N-[(3-Chloro-4-cyanophenyl)methyl]-2-[6-[1- N-[(3-Chloro-4- [M + H].sup.+ [(2R)-2-methoxypropanoyl]piperidin-4-yl]-4- cyanophenyl)methyl]- 536.3 oxoquinazolin-3-yl]-N-methylacetamide N-methyl-2- [00239] (4-oxo-6- piperidin-4- ylquinazolin-3- yl)acetamide (intermediate A- 9) and (R)-2- methoxypropanoic acid ([CAS RN 23943-96-6]) 159 N-[(3-Chloro-4-cyanophenyl)methyl]-2-[6-[1- N-[(3-Chloro-4- [M + H].sup.+ [(2S)-2-methoxypropanoyl]piperidin-4-yl]-4- cyanophenyl)methyl]- 536.3 oxoquinazolin-3-yl]-N-methylacetamide N-methyl-2- [00240] (4-oxo-6- piperidin-4- ylquinazolin-3- yl)acetamide (intermediate A- 9) and (S)-2- methoxypropanoic acid ([CAS RN 23953-00-6])

Example 160

Methyl 4-[3-[2-[(3-chloro-4-cyanophenyl)methyl-methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperidine-1-carboxylate

[0596] ##STR00241##

[0597] To a solution of N-[(3-chloro-4-cyanophenyl)methyl]-N-methyl-2-(4-oxo-6-piperidin-4-ylquinazolin-3-yl)acetamide (intermediate A-9) (50 mg, 0.11 mmol) in dry DMF (2 mL) were added methyl chloroformate (10 L, 0.13 mmol; [CAS RN 79-22-1]) and DIPEA (97 L, 0.56 mmol) and the reaction mixture stirred at rt for 1 h under an atmosphere of nitrogen. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as white solid (40 mg, 70%). MS: m/e=508.3 [M+H].sup.+.

Example 161

2-[6-(1-Acetylpiperidin-4-yl)-4-oxoquinazolin-3-yl]-N-[[3-chloro-5-(trifluoromethyl)phenyl]methyl]acetamide

[0598] ##STR00242##

[0599] To a solution of 2-[6-(1-tert-butoxycarbonyl-4-piperidyl)-4-oxoquinazolin-3-yl]acetic acid (intermediate A-8, step E) (100 mg, 0.26 mmol) in DCM (2 mL) were added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (161 mg, 0.31 mmol; PyBOP; [CAS RN 128625-52-5]) and DIPEA (225 L, 1.29 mmol) under an atmosphere of nitrogen. Then, (3-chloro-5-(trifluoromethyl)phenyl)methanamine (59.5 mg, 0.28 mmol; [CAS RN 400771-41-7]) was added and the reaction mixture stirred at rt for 1 h. The solvent was evaporated under reduced pressure and 4 M HCl in dioxane (2 mL) was added. After stirring at rt for 15 min, the reaction mixture was concentrated under reduced pressure and the crude reaction mixture redissolved in dry DMF (2 mL). DIPEA (500 L, 2.86 mmol), (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (161 mg, 0.31 mmol; PyBOP; [CAS RN 128625-52-5]) and acetic acid (30 L, 0.52 mmol) were added and the reaction mixture stirred at rt for 1 h under an atmosphere of nitrogen. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as white solid (46 mg, 35%). MS: m/e=521.3 [M+H].sup.+.

Examples 162 to 164

[0600] According to the procedure described for the synthesis of example 161 further examples were prepared from 2-[6-(1-tert-butoxycarbonyl-4-piperidyl)-4-oxoquinazolin-3-yl]acetic acid (intermediate A-8, step E) and the respective benzylamine as indicated in Table 14. The results are compiled in Table 14 and comprise examples 162 to 164.

TABLE-US-00015 TABLE 14 Starting No Compound Name & Structure Materials MS 162 2-[6-(1-Acetylpiperidin-4-yl)-4-oxoquinazolin-3- 2-[6-(1-tert- [M + H].sup.+ yl]-N-[[4-fluoro-3- Butoxycarbonyl- 505.2 (trifluoromethyl)phenyl]methyl]acetamide 4-piperidyl)-4- [00243] oxoquinazolin-3- yl] acetic acid (intermediate A- 8, step E) and (4- fluoro-3- (trifluoromethyl) phenyl)methanamine ([CAS RN 67515-74-6]) 163 2-[6-(1-Acetylpiperidin-4-yl)-4-oxoquinazolin-3- 2-[6-(1-tert- [M + H].sup.+ yl]-N-[[4-chloro-3- Butoxycarbonyl- 521.4 (trifluoromethyl)phenyl]methyl]acetamide 4-piperidyl)-4- [00244] oxoquinazolin-3- yl]acetic acid (intermediate A- 8, step E) and (4- chloro-3- (trifluoromethyl) phenyl)methanamine ([CAS RN 62039-92-3]) 164 2-[6-(1-Acetylpiperidin-4-yl)-4-oxoquinazolin-3- 2-[6-(1-tert- [M + H].sup.+ yl]-N-[(3,5-dichlorophenyl)methyl]acetamide Butoxycarbonyl- 487.3 [00245] 4-piperidyl)-4- oxoquinazolin-3- yl]acetic acid (intermediate A- 8, step E) and (3, 5-dichlorophenyl) methanamine ([CAS RN 39989- 43-0])

Example 165

N-[(3,4-Dichlorophenyl)methyl]-N-methyl-2-[4-oxo-6-[1-(2-sulfamoylacetyl)piperidin-4-yl]quinazolin-3-yl]acetamide

[0601] ##STR00246##

[A] N-[(3,4-Dichlorophenyl)methyl]-N-methyl-2-(4-oxo-6-piperidin-4-ylquinazolin-3-yl)acetamide

[0602] ##STR00247##

[0603] To a solution of 2-[6-(1-tert-butoxycarbonyl-4-piperidyl)-4-oxoquinazolin-3-yl]acetic acid (intermediate A-8, step E) (2.03 g, 5.23 mmol) in DCM (50 mL) were added HATU (2.98 g, 7.84 mmol; [CAS RN 148893-10-1]) and DIPEA (2.74 mL, 15.7 mmol) under an atmosphere of nitrogen. Then, 1-(3,4-dichlorophenyl)-N-methylmethanamine (1.0 g, 5.23 mmol; [CAS RN 5635-67-6]) was added and the reaction mixture stirred at rt for 1 h. To the reaction mixture was added 4 M HCl in dioxane (15 mL) and stirring at rt continued overnight. The reaction mixture was set to pH 14 by addition of a solution of 2 M sodium hydroxide and the aq. phase extracted with DCM (3200 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure. Purification by MPLC (20 g SiO.sub.2, Telos-cartridge) eluting with a gradient of 0 to 5% methanolDCM provided the title compound as light brown solid (0.77 g, 32%). MS: 459.3 (M+H).sup.+.

[B] N-[(3,4-Dichlorophenyl)methyl]-N-methyl-2-[4-oxo-6-[1-(2-sulfamoylacetyl)piperidin-4-yl]quinazolin-3-yl]acetamide

[0604] ##STR00248##

[0605] To a solution of N-[(3,4-dichlorophenyl)methyl]-N-methyl-2-(4-oxo-6-piperidin-4-ylquinazolin-3-yl)acetamide (50 mg, 0.11 mmol) in dry DMF (2 mL) were added HATU (62.1 mg, 0.16 mmol; [CAS RN 148893-10-1]) and DIPEA (150 L, 0.86 mmol) under an atmosphere of nitrogen. Then, 2-sulfamoylacetic acid (23.9 mg, 0.16 mmol; [CAS RN 17551-00-7]) was added and the reaction mixture heated by microwave irradiation to 100 C. for 10 min. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as colorless oil (19 mg, 30%). MS: m/e=580.1 [M+H].sup.+.

Examples 166 to 183

[0606] According to the procedure described for the synthesis of example 165 further examples were prepared from N-[(3,4-dichlorophenyl)methyl]-N-methyl-2-(4-oxo-6-piperidin-4-ylquinazolin-3-yl)acetamide (Example 165, step A) and the respective carboxylic acid as indicated in Table 15. The results are compiled in Table 15 and comprise examples 166 to 183.

TABLE-US-00016 TABLE 15 No Compound Name & Structure Starting Materials MS 166 N-[(3,4-Dichlorophenyl)methyl]-2-[6-[1-[2-(2- N-[(3,4-Dichlorophenyl) [M + H].sup.+ methoxyethoxy)acetyl]piperidin-4-yl]-4- methyl]-N-methyl-2-(4- 575.2 oxoquinazolin-3-yl]-N-methylacetamide oxo-6-piperidin-4- [00249] ylquinazolin-3-yl)acetamide (Example 165, step A) and 2-(2-methoxyethoxy) acetic acid ([CAS RN 16024-56-9]) 167 N-[(3,4-Dichlorophenyl)methyl]-2-[6-[1-[(2R)-2- N-[(3,4-Dichlorophenyl) [M + H].sup.+ methoxypropanoyl]piperidin-4-yl]-4- methyl]-N-methyl-2- 545.2 oxoquinazolin-3-yl]-N-methylacetamide (4-oxo-6-piperidin-4- [00250] ylquinazolin-3-yl)acetamide (Example 165, step A) and (R)-2-methoxypropanoic acid ([CAS RN 23943-96-6]) 168 N-[(3,4-Dichlorophenyl)methyl]-2-[6-[1-[(2S)-2- N-[(3,4-Dichlorophenyl) [M + H].sup.+ methoxypropanoyl]piperidin-4-yl]-4- methyl]-N-methyl-2- 545.2 oxoquinazolin-3-yl]-N-methylacetamide (4-oxo-6-piperidin-4- [00251] ylquinazolin-3- yl)acetamide (Example 165, step A) and (S)-2- methoxypropanoic acid ([CAS RN 23953-00-6]) 169 N-[3,4-Dichlorophenyl)methyl]-2-[6-[1-[(2R)-2- N-[(3,4-Dichlorophenyl) [M + H].sup.+ hydroxy-3-methylbutanoyl]piperidin-4-yl]-4- methyl]-N-methyl-2-(4- 559.2 oxoquinazolin-3-yl]-N-methylacetamide oxo-6-piperidin-4- [00252] ylquinazolin-3-yl)acetamide (Example 165, step A) and (R)-2-hydroxy-3- methylbutanoic acid ([CAS RN 17407-56-6]) 170 N-[3,4-Dichlorophenyl)methyl]-2-[6-[1-[(2S)-2- N-[(3,4-Dichlorophenyl) [M + H].sup.+ hydroxy-3-methylbutanoyl]piperidin-4-yl]-4- methyl]-N-methyl-2-(4- 559.2 oxoquinazolin-3-yl]-N-methylacetamide oxo-6-piperidin-4- [00253] ylquinazolin-3-yl)acetamide (Example 165, step A) and (S)-2-hydroxy-3- methylbutanoic acid ([CAS RN 17407-55-5]) 171 N-[3,4-Dichlorophenyl)methyl]-2-[6-[1-(2- N-[(3,4-Dichlorophenyl) [M + H].sup.+ methoxyacetyl)piperidin-4-yl]-4-oxoquinazolin-3- methyl]-N-methyl-2-(4-oxo- 531.1 yl]-N-methylacetamide 6-piperidin-4-ylquinazolin- [00254] 3-yl)acetamide (Example 165, step A) and 2-methoxyacetyl chloride ([CAS RN 38870-89-2]) 172 N-[(3,4-Dichlorophenyl)methyl]-2-[6-[1-(2- N-[(3,4-Dichlorophenyl) [M + H].sup.+ hydroxy-2-methylpropanoyl)piperidin-4-yl]-4- methyl]-N-methyl-2-(4-oxo- 545.2 oxoquinazolin-3-yl]-N-methylacetamide 6-piperidin-4-ylquinazolin-3- [00255] yl)acetamide (Example 165, step A) and 2-hydroxy-2- methylpropanoic acid ([CAS RN 594-61-6]) 173 N-[(3,4-Dichlorophenyl)methyl]-2-[6-[1-(2- N-[(3,4-Dichlorophenyl) [M + H].sup.+ methoxypropanoyl)piperidin-4-yl]-4- methyl]-N-methyl-2-(4-oxo- 545.1 oxoquinazolin-3-yl]-N-methylacetamide 6-piperidin-4-ylquinazolin- [00256] 3-yl)acetamide (Example 165, step A) and 2- methoxypropanoic acid ([CAS RN 4324-37-2]) 174 N-[(3,4-Dichlorophenyl)methyl]-2-[6-[1-[(2R)-2- N-[(3,4-Dichlorophenyl) [M + H].sup.+ hydroxypropanoyl]piperidin-4-yl]-4- methyl]-N-methyl-2- 531.1 oxoquinazolin-3-yl]-N-methylacetamide (4-oxo-6-piperidin-4- [00257] ylquinazolin-3-yl)acetamide (Example 165, step A) and (R)-2-hydroxypropanoic acid ([CAS RN 10326-41-7]) 175 N-[(3,4-Dichlorophenyl)methyl]-2-[6-[1-[(2S)-2- N-[(3,4-Dichlorophenyl) [M + H].sup.+ hydroxypropanoyl]piperidin-4-yl]-4- methyl]-N-methyl-2-(4- 531.1 oxoquinazolin-3-yl]-N-methylacetamide oxo-6-piperidin-4- [00258] ylquinazolin-3-yl) acetamide (Example 165, step A) and (S)-2- hydroxypropanoic acid ([CAS RN 79-33-4]) 176 N-[3,4-Dichlorophenyl)methyl]-2-[6-[1-(1- N-[(3,4-Dichlorophenyl) [M + H].sup.+ hydroxycyclobutanecarbonyl)piperidin-4-yl]-4- methyl]-N-methyl-2-(4- 557.1 oxoquinazolin-3-yl]-N-methylacetamide oxo-6-piperidin-4- [00259] ylquinazolin-3-yl) acetamide (Example 165, step A) and 1- hydroxycyclobutanecarboxylic acid ([CAS RN 41248-13-9]) 177 N-[3,4-Dichlorophenyl)methyl]-2-[6-[1-(2,3- N-[(3,4-Dichlorophenyl) [M + H].sup.+ dihydroxypropanoyl)piperidin-4-yl]-4- methyl]-N-methyl-2-(4- 547.1 oxoquinazolin-3-yl]-N-methylacetamide oxo-6-piperidin-4- [00260] ylquinazolin-3-yl)acetamide (Example 165, step A) and 2,3-dihydroxypropanoic acid (40% in water) ([CAS RN 600-19-1]) 178 N-[3,4-Dichlorophenyl)methyl]-2-[6-[1-(1,4- N-[(3,4-Dichlorophenyl) [M + H].sup.+ dioxane-2-carbonyl)piperidin-4-yl]-4- methyl]-N-methyl-2-(4- 573.1 oxoquinazolin-3-yl]-N-methylacetamide oxo-6-piperidin-4- [00261] ylquinazolin-3-yl)acetamide (Example 165, step A) and 1,4-dioxane-2- carboxylic acid ([CAS RN 89364-41-0]) 179 N-[3,4-Dichlorophenyl)methyl]-2-[6-[1-(1- N-[(3,4-Dichlorophenyl) [M + H].sup.+ hydroxycyclopropanecarbonyl)piperidin-4-yl]-4- methyl]-N-methyl-2-(4- 543.1 oxoquinazolin-3-yl]-N-methylacetamide oxo-6-piperidin-4- [00262] ylquinazolin-3-yl)acetamide (Example 165, step A) and 1- hydroxycyclopropanecarboxylic acid ([CAS RN 17994-25-1]) 180 N-[3,4-Dichlorophenyl)methyl]-N-methyl-2-[4- N-[(3,4-Dichlorophenyl) [M + H].sup.+ oxo-6-[1-(oxolane-2-carbonyl)piperidin-4- methyl]-N-methyl-2-(4- 557.1 yl]quinazolin-3-yl]acetamide oxo-6-piperidin-4- [00263] ylquinazolin-3-yl)acetamide (Example 165, step A) and tetrahydrofuran-2-carboxylic acid ([CAS RN 16874-33-2]) 181 N-[3,4-Dichlorophenyl)methyl]-N-methyl-2-[6- N-[(3,4-Dichlorophenyl) [M + H].sup.+ [1-(2-methyloxolane-2-carbonyl)piperidin-4-yl]- methyl]-N-methyl-2-(4- 571.2 4-oxoquinazolin-3-yl]acetamide oxo-6-piperidin-4- [00264] ylquinazolin-3-yl)acetamide (Example 165, step A) and 2-methyltetrahydrofuran- 2-carboxylic acid ([CAS RN 61449-65-81) 182 N-[3,4-Dichlorophenyl)methyl]-N-methyl-2-[4- N-[(3,4-Dichlorophenyl) [M + H].sup.+ oxo-6-[1-(oxolane-3-carbonyl)piperidin-4- methyl]-N-methyl-2-(4-oxo- 557.1 yl]quinazolin-3-yl]acetamide 6-piperidin-4-ylquinazolin-3- [00265] yl)acetamide (Example 165, step A) and tetrahydrofuran- 3-carboxylic acid ([CAS RN 89364-31-8]) 183 N-[3,4-Dichlorophenyl)methyl]-N-methyl-2-[6- N-[(3,4-Dichlorophenyl) [M + H].sup.+ [1-(1,3-oxazole-5-carbonyl)piperidin-4-yl]-4- methyl]-N-methyl-2-(4-oxo- 554.2 oxoquinazolin-3-yl]acetamide 6-piperidin-4-ylquinazolin- [00266] 3-yl)acetamide (Example 165, step A) and oxazole-5- carboxylic acid ([CAS RN 118994-90-4])

Example 184

2-[6-(1-Acetyl-4-hydroxypiperidin-4-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]-N-methylacetamide

[0607] ##STR00267##

[A] tert-Butyl 4-hydroxy-4-(4-oxo-3H-quinazolin-6-Yl)piperidine-1-carboxylate

[0608] ##STR00268##

[0609] To a solution of 6-bromo-3,4-dihydroquinazolin-4-one (100 mg, 0.44 mmol; [CAS RN 32084-59-6]) in THF (12.5 mL) at 78 C. was added MeLi (0.2 mL, 0.58 mmol) dropwise over 5 min. After 10 min, 1.6 M n-BuLi in hexane (1.8 mL, 1.33 mmol) was added dropwise over 10 min and stirring continued at 78 C. for 1 h. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (900 mg, 0.44 mmol) in THF (2.5 mL) was added dropwise over 10 min at 78 C. and stirring continued for 2 h. The reaction mixture was quenched by addition of a sat. solution of NH.sub.4Cl(25 mL) and the aq. phase extracted with EtOAc (310 mL). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude reaction product was purified by column chromatography (100-200 mesh size silica gel) using 80% EtOAchexane as eluent affording the title compound as light yellow solid (600 mg, 39%). MS: 346.3 (M+H).sup.+.

[B] tert-Butyl 4-hydroxy-4-[3-(2-methoxy-2-oxoethyl)-4-oxoquinazolin-6-yl]piperidine-1-carboxylate

[0610] ##STR00269##

[0611] A suspension of tert-butyl 4-hydroxy-4-(4-oxo-3H-quinazolin-6-yl)piperidine-1-carboxylate (2.0 g, 5.80 mmol), K.sub.2CO.sub.3 (1.60 g, 11.59 mmol) and methyl bromo acetate (1.15 g, 7.54 mmol) in CH.sub.3CN (25 mL) was stirred at reflux temperature for 6 h. The reaction mixture was cooled to rt and volatiles removed under reduced pressure. The crude reaction product was diluted with EtOAc (100 mL) and washed with H.sub.2O (250 mL) and a sat. solution of NaCl (50 mL). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to provide the title compound as brown solid (1.60 g, 66%), which was used in the consecutive reaction step without further purification. MS: 417.9 (M+H).sup.+.

[C] 2-[6-[4-Hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]-4-oxoquinazolin-3-yl]acetic acid

[0612] ##STR00270##

[0613] To a cooled solution of tert-butyl 4-hydroxy-4-[3-(2-methoxy-2-oxoethyl)-4-oxoquinazolin-6-yl]piperidine-1-carboxylate (1.40 g, 3.36 mmol) in THF (20 mL) at 0 C. was added a solution of LiOH H.sub.2O (420 mg, 10.07 mmol) in H.sub.2O (2.5 mL) dropwise over 5 min, followed by stirring at rt for 3 h. The crude reaction mixture was concentrated under reduced pressure and the obtained residue diluted with H.sub.2O (25 mL) and washed with diethyl ether. The aq. phase was neutralized by addition of a 1 M solution of HCl and then concentrated under reduced pressure to afford the title compound as brown solid (1.20 g, crude). The crude material was used in the consecutive reaction step without further purification. MS: 404.1 (M+H).sup.+.

[D] tert-Butyl 4-[3-[2-[(3,4-dichlorophenyl)methyl-methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]-4-hydroxypiperidine-1-carboxylate

[0614] ##STR00271##

[0615] To a solution of 2-[6-[4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]-4-oxoquinazolin-3-yl]acetic acid (1.20 g, 2.98 mmol) and 1-(3,4-dichlorophenyl)-N-methylmethanamine (622 mg, 3.28 mmol; [CAS RN 5635-67-6]) in DMF (20 mL) was added TBTU (1.19 g, 3.72 mmol; [CAS RN 125700-67-6]) and N-methylmorpholine (0.61 mL, 5.96 mmol) under an atmosphere of nitrogen. After stirring of the reaction mixture at rt for 12 h, the solvent was removed under reduced pressure and the obtained residue diluted with EtOAc (100 mL), followed by washing with H.sub.2O (350 mL) and a sat. solution of NaCl (250 mL). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude reaction product was purified by column chromatography (100-200 mesh size silica gel) using 80% EtOAchexane as eluent affording the title compound as off white solid (800 mg, 42% over two steps). MS: 575.1 (M+H).sup.+.

[E] 2-[6-(1-Acetyl-4-hydroxypiperidin-4-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]-N-methylacetamide

[0616] ##STR00272##

[0617] To a stirred solution of tert-butyl 4-[3-[2-[(3,4-dichlorophenyl)methyl-methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]-4-hydroxypiperidine-1-carboxylate (500 mg, 0.87 mmol) in dioxane (10 mL) was added 4 M HCl in dioxane (5 mL) at 0 C. and the reaction mixture stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure and the crude material purified by trituration with TBME (210 mL). To the precipitate was added DCM (10 mL) and Et.sub.3N (0.35 mL, 0.25 mmol) at 0 C., followed by a solution of acetyl chloride (0.09 mL, 1.27 mmol) in DCM (5 mL) dropwise over 5 min. After stirring of the reaction mixture at rt for 6 h, DCM (10 mL) was added and the organic phase washed with H.sub.2O (10 mL) and a sat. solution of NaCl (10 mL). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude reaction product was purified by column chromatography (100-200 mesh size silica gel) eluting with a gradient of 1:50 to 1:40 methanol-EtOAc affording the title compound as off white solid (150 mg, 33% over two steps). MS: 517.2 (M+H).sup.+.

Example 185

2-[6-(1-Acetyl-4-hydroxypiperidin-4-yl)-4-oxoquinazolin-3-yl]-N-[(3-chloro-4-cyanophenyl)methyl]-N-methylacetamide

[0618] ##STR00273##

[0619] The title compound was prepared in analogy to the procedure described for the preparation of 2-[6-(1-acetyl-4-hydroxypiperidin-4-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]-N-methylacetamide (example 184), replacing in step D 1-(3,4-dichlorophenyl)-N-methylmethanamine [CAS RN 5635-67-6] with 2-chloro-4-(methylaminomethyl)benzonitrile hydrochloride (example 56, step A). Purification by column chromatography (100-200 mesh size silica gel) eluting with a gradient of 1:50 to 1:40 methanol-EtOAc affording the title compound as off white solid (80 mg, 34% over last two steps). MS: 508.2 (M+H).sup.+.

Example 186

[2-[4-[3-[2-[(3-Chloro-4-cyanophenyl)methyl-methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperidin-1-yl]-2-oxoethyl] nitrate

[0620] ##STR00274##

[A] 2-[6-[1-(2-Bromoacetyl)piperidin-4-yl]-4-oxoquinazolin-3-yl]-N-[(3-chloro-4-cyanophenyl)methyl]-N-methylacetamide

[0621] ##STR00275##

[0622] To a solution of N-[(3-chloro-4-cyanophenyl)methyl]-N-methyl-2-(4-oxo-6-piperidin-4-ylquinazolin-3-yl)acetamide (intermediate A-9) (25 mg, 0.056 mmol) in DCM (2.5 mL) were added Et.sub.3N (23 L, 0.17 mmol) under an atmosphere of nitrogen. Then, a solution of bromo acetyl chloride (6 L, 0.084 mmol) in DCM (0.5 mL) at 0 C. was added and the reaction mixture stirred for 1 h. The solvent was removed under reduced pressure and the obtained residue diluted with H.sub.2O (5 mL) and extracted with DCM (210 mL). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. Purification by prep. TLC (Merck silica TLC glass plates, 2020 cm) eluting with a mixture of heptaneEtOAc (10:1) provided the title compound as off white solid (15 mg, 44%). MS: m/e=571.0 [M+H].sup.+.

[B] [2-[4-[3-[2-[(3-Chloro-4-cyanophenyl)methyl-methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperidin-1-yl]-2-oxoethyl]nitrate

[0623] ##STR00276##

[0624] To a solution of 2-[6-[1-(2-bromoacetyl)piperidin-4-yl]-4-oxoquinazolin-3-yl]-N-[(3-chloro-4-cyanophenyl)methyl]-N-methylacetamide (0.18 g, 0.30 mmol) in acetonitrile (10 mL) was added silver nitrate (0.20 g, 0.11 mmol) and the reaction mixture was stirred at 70 C. for 24 h under an atmosphere of nitrogen. Evaporation of the solvent and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as off white solid (30 mg, 18%). MS: m/e=552.6 [M+H].sup.+.

Example 187

2-[6-(1-Acetylpiperidin-4-yl)-8-fluoro-4-oxoquinazolin-3-yl]-N-[(3-chloro-4-cyanophenyl)methyl]-N-methylacetamide

[0625] ##STR00277##

[A] 6-Bromo-8-fluoro-3H-quinazolin-4-one

[0626] ##STR00278##

[0627] A suspension of 2-amino-5-bromo-3-fluorobenzoic acid (1.0 g, 4.27 mmol; [CAS RN 874784-14-2]) and formamidine acetate (0.89 g, 8.55 mmol; [CAS RN 3473-63-0]) in 2-methoxyethanol (12 mL) was heated under microwave irradiation to 150 C. for 45 min. The formed precipitate was filtered off, the crystals washed with a small amount of EtOH and dried under reduced pressure. The title compound was isolated as white powder (0.80 g, 77%). MS: m/e=245.0 [M+H].sup.+.

[B] Methyl 2-(6-bromo-8-fluoro-4-oxoquinazolin-3-yl)acetate

[0628] ##STR00279##

[0629] A suspension of 6-bromo-8-fluoro-3H-quinazolin-4-one (0.8 g, 3.29 mmol), methyl 2-bromoacetate (1.01 g, 0.61 mL, 6.58 mmol; [CAS RN 96-32-2]) and potassium carbonate (1.36 g, 9.88 mmol) in DMF (12 mL) was heated under microwave irradiation to 80 C. for 30 min. The crude reaction product was purified by column chromatography (100-200 mesh size silica gel) eluting with a gradient of 0:1 to 1:0 EtOAchexane affording the title compound as light yellow solid (0.67 g, 64%). MS: 317.0 (M+H).sup.+.

[C] 2-(6-Bromo-8-fluoro-4-oxoquinazolin-3-yl)-N-[(3-chloro-4-cyanophenyl)methyl]-N-methylacetamide

[0630] ##STR00280##

[0631] To a solution of methyl 2-(6-bromo-8-fluoro-4-oxoquinazolin-3-yl)acetate (0.65 g, 2.06 mmol) and 2-chloro-4-(methylaminomethyl)benzonitrile hydrochloride example 56, step A) (0.47 g, 2.17 mmol) in THF (10 mL) was added bis(trimethylaluminium)-1,4-diazabicyclo[2.2.2]octane adduct (0.64 g, 2.48 mmol; [CAS RN 137203-34-0]) and the reaction mixture heated under microwave irradiation to 130 C. for 30 min under an atmosphere of Ar. The crude reaction product was purified by column chromatography (100-200 mesh size silica gel) eluting with a gradient of 0:1 to 1:0 EtOAchexane affording the title compound as light yellow solid (0.54 g, 47%). MS: 465.1 (M+H).sup.+.

[D] tert-Butyl 4-[3-[2-[(3-chloro-4-cyanophenyl)methyl-methylamino]-2-oxoethyl-8-fluoro-4-oxoquinazolin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate

[0632] ##STR00281##

[0633] A solution of 2-(6-bromo-8-fluoro-4-oxoquinazolin-3-yl)-N-[(3-chloro-4-cyanophenyl)methyl]-N-methylacetamide (0.54 g, 0.97 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.30 g, 0.97 mmol; [CAS RN 286961-14-6]), triphenylphosphine (51 mg, 0.19 mmol; CAS RN 603-35-0]) and tripotassium phosphate (0.21 g, 0.97 mmol; [CAS RN 7778-53-2]) in a mixture of water (2.5 mL) and 1,2-diethoxyethan (10 mL) was degassed by Ar by sonication for 10 min. Finally, Pd(OAc).sub.2 (22 mg, 0.097 mmol; [CAS RN 3375-31-3]) was added and the reaction mixture heated to 90 C. for 90 min under an atmosphere of Ar. The reaction mixture was evaporated under reduced pressure and then purified by column chromatography (100-200 mesh size silica gel) eluting with a gradient of 0:1 to 1:0 EtOAchexane affording the title compound as light yellow solid (0.40 g, 62%). MS: 568.4 (M+H).sup.+.

[E] N-[(3-Chloro-4-cyanophenyl)methyl]-2-(8-fluoro-4-oxo-6-piperidin-4-ylquinazolin-3-yl)-N-methylacetamide

[0634] ##STR00282##

[0635] To a degassed solution of tert-butyl 4-[3-[2-[(3-chloro-4-cyanophenyl)methyl-methylamino]-2-oxoethyl]-8-fluoro-4-oxoquinazolin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (0.40 g, 0.60 mmol) in MeOH (10 mL) was added 20% Pd(OH).sub.2/C (0.042 g, 0.060 mmol; [CAS RN 12135-22-7]) and the reaction mixture stirred under hydrogen (atmospheric pressure) at rt for 2 h. The reaction mixture was filtered through Celite and the organic phase concentrated in vacuo. The residue was redissolved in dioxane (5 mL), 4 M HCl in dioxane (5 mL) was added and the reaction mixture stirred at rt for 2 h. The reaction mixture was set to pH 14 by addition of a solution of 2 M sodium hydroxide and the aq. phase extracted with DCM (3 10200 mL). The combined organic phases were dried over MgSO.sub.4 and concentrated under reduced pressure providing the title compound as light brown solid (0.22 g, 37%; 48% purity according to LC-MS). MS: 468.3 (M+H).sup.+.

[F] 2-[6-(1-Acetylpiperidin-4-yl)-8-fluoro-4-oxoquinazolin-3-yl]-N-[(3-chloro-4-cyanophenyl)methyl]-N-methylacetamide

[0636] ##STR00283##

[0637] To a solution of N-[(3-chloro-4-cyanophenyl)methyl]-2-(8-fluoro-4-oxo-6-piperidin-4-ylquinazolin-3-yl)-N-methylacetamide (108 mg, 0.11 mmol; 48% purity) in dry DMF (2 mL) were added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (69.4 mg, 0.13 mmol; PyBOP; [CAS RN 128625-52-5]) and DIPEA (97 L, 0.56 mmol) under an atmosphere of nitrogen. Then, acetic acid (8.0 mg, 0.13 mmol) was added and the reaction mixture stirred at rt overnight. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as off-white solid (4.4 mg, 8%). MS: m/e=510.4 [M+H].sup.+.

Example 188

N-[(3-Chloro-4-cyanophenyl)methyl]-2-[8-fluoro-6-[1-(3-methoxypropanoyl)piperidin-4-yl]-4-oxoquinazolin-3-yl]-N-methylacetamide

[0638] ##STR00284##

[0639] The title compound was prepared in analogy to the procedure described for the preparation of 2-[6-(1-acetylpiperidin-4-yl)-8-fluoro-4-oxoquinazolin-3-yl]-N-[(3-chloro-4-cyanophenyl)methyl]-N-methylacetamide (example 187), replacing in step F acetic acid with 3-methoxypropanoic acid ([CAS RN 2544-06-1]). Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as off-white solid (6.6 mg, 11%). MS: m/e=554.4 [M+H].sup.+.

Example 189

2-[6-(1-Acetylpiperidin-4-yl)-4-oxopyrido[3,4-d]pyrimidin-3-yl]-N-[(3-chloro-4-cyanophenyl)methyl]-N-methylacetamide

[0640] ##STR00285##

[0641] The title compound was prepared in analogy to the procedure described for the preparation of 2-[6-(1-acetylpiperidin-4-yl)-8-fluoro-4-oxoquinazolin-3-yl]-N-[(3-chloro-4-cyanophenyl)methyl]-N-methylacetamide (example 187), replacing in step A 2-amino-5-bromo-3-fluorobenzoic acid with 5-amino-2-bromopyridine-4-carboxylic acid ([CAS RN 1242336-80-6]). Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile-water provided the title compound as white solid (8.1 mg, 15%). MS: m/e=493.4 [M+H].sup.+.

Example 190

N-[(3-Chloro-4-cyanophenyl)methyl]-2-[6-[1-(3-methoxypropanoyl)piperidin-4-yl]-4-oxopyrido[3,4-d]pyrimidin-3-yl]-N-methylacetamide

[0642] ##STR00286##

[0643] The title compound was prepared in analogy to the procedure described for the preparation of 2-[6-(1-acetylpiperidin-4-yl)-4-oxopyrido[3,4-d]pyrimidin-3-yl]-N-[(3-chloro-4-cyanophenyl)methyl]-N-methylacetamide (example 189), replacing in step F acetic acid with 3-methoxypropanoic acid ([CAS RN 2544-06-1]). Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrilewater provided the title compound as white solid (10 mg, 17%). MS: m/e=537.4 [M+H].sup.+.

Example A

[0644] 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:

TABLE-US-00017 Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Com starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

Example B

[0645] 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:

TABLE-US-00018 Per capsule Active ingredient 100.0 mg Com starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg