Inhibitors of indoleamine 2,3-dioxygenase

Abstract

A compound of Formula I: ##STR00001##
or pharmaceutically acceptable enantiomers, or salts thereof. The present invention also relates to the use of compounds of Formula (I) as selective inhibitors of indoleamine 2,3-dioxygenase. The invention also relates to the use of the compounds of Formula (I) for the treatment or prevention of diseases cancer, infections, central nervous system disease or disorder, and immune-related disorders, either as a single agent or in combination with other therapies.

Claims

1. A compound of Formula I: ##STR00017## or a pharmaceutically acceptable salt thereof wherein, R.sup.1 is selected from the group consisting of: ##STR00018## R.sup.11 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy, all alkyl and alkoxy groups optionally being substituted with one or more halogen; R.sup.12 is halogen, (1-2C)alkyl (2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, (3-8C)cycloalkyl, or cyano, all alkyl, alkoxy and cycloalkyl groups optionally being substituted with one or more halogen; R.sup.13 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy, all alkyl and alkoxy groups optionally being substituted with one or more halogen; R.sup.14 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy, all alkyl and alkoxy groups optionally being substituted with one or more halogen; R.sup.15 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy, all alkyl and alkoxy groups optionally being substituted with one or more halogen; R.sup.2 is selected from the group consisting of: a) hydrogen, b) (1-6C)alkyl, wherein (1-6C)alkyl optionally can be substituted, R.sup.3 is selected from the group consisting of: a) (6-10C)aryl, b) (1-9C)heteroaryl, c) (3-8C)cycloalkyl, d) (2-7C)heterocycloalkyl, e) (1-6C)alkyl, f) (1-6)alkylamino, g) (3-6C)cycloalkylamino h) (6-10C)arylamino, i) (1-9C)heteroarylamino, j) (2-7C)heterocycloalkylamino, wherein all groups optionally can be substituted, R.sup.4 is selected from the group consisting of: a) hydrogen, b) (1-6C)alkyl, wherein (1-6C)alkyl optionally can be substituted, R.sup.5 is selected from the group consisting of: a) hydrogen, b) (1-6C)alkyl, wherein (1-6C)alkyl optionally can be substituted, A is selected from CH(R.sup.a), C(O), S(O) or SO.sub.2, R.sup.a is selected from the group consisting of: a) hydrogen, b) (1-6C)alkyl, wherein (1-6C)alkyl optionally can be substituted with fluorine or hydroxyl.

2. The compound according to claim 1 wherein R.sup.2 is hydrogen, and A is C(O) or CH(R.sup.a).

3. The compound according to claim 1 wherein R.sup.4 and R.sup.5 are selected from the group of hydrogen, methyl, and ethyl, whereby if one of R.sup.4 and R.sup.5 is not hydrogen, the other one must be hydrogen.

4. The compound according to claim 1 wherein R.sup.1 is ##STR00019## R.sup.11 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy, all alkyl and alkoxy groups optionally being substituted with one or more halogen; R.sup.12 is halogen, (1-2C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, (3-8C)cycloalkyl, or cyano, all alkyl, alkoxy and cycloalkyl groups optionally being substituted with one or more halogen; R.sup.13 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy, all alkyl and alkoxy groups optionally being substituted with one or more halogen; R.sup.14 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy, all alkyl and alkoxy groups optionally being substituted with one or more halogen; R.sup.15 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy, all alkyl and alkoxy groups optionally being substituted with one or more halogen.

5. The compound according to claim 1 wherein R.sup.1 is ##STR00020## R.sup.11, R.sup.15, R.sup.14 is H or fluorine, R.sup.12 is halogen, (1-2C)alkyl, (2-3C)alkenyl or (2-3C)alkynyl, all alkyl groups optionally being substituted with one or more halogen, R.sup.13 is H or halogen.

6. The compound according to claim 1 wherein R.sup.3 is selected from the group consisting of (6-10C)aryl, (1-9C)heteroaryl, (3-8C)cycloalkyl, (2-7C)heterocycloalkyl, and (1-6C)alkyl, preferably (6-10C)aryl, (1-9C)heteroaryl and (3-8C)cycloalkyl, wherein all groups optionally can be substituted.

7. The compound according to claim 1 wherein R.sup.3 is ##STR00021## R.sup.31 and R.sup.35 are independently selected from the group consisting of: hydrogen, halogen, cyano, (1-2C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl and (1-2C)alkoxy, all alkyl and alkoxy groups optionally being substituted with one or more halogen; R.sup.32 and R.sup.34 are independently selected from the group consisting of: hydrogen, halogen, cyano, (1-6C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, (1-3C)alkoxy(1-6C)alkylaminocarbonyl, amino, nitro, (1-6C)alkylcarbonylamino or (1-6C)alkylsulfonylamino, all alkyl and alkoxy groups optionally being substituted with one or more halogen; R.sup.33 is selected from the group consisting of: hydrogen, halogen, cyano, (1-6C)alkyl, (2-3C)alkenyl, (2-6C)alkynyl, (1-3C)alkoxy, (6-10C)aryl, (1-5C)heteroaryl, (2-7C)heterocycloalkyl, (3-8C)cycloalkyl, (6-10C)aryloxy, (1-6C)alkylsulfonylamino(1-6C)alkyl, aminosulfonylamino(1-6C)alkyl, (3-8C)cycloalkyl(1-6C)alkyl, (1-6C)alkylcarbonylamino(2-6C)alkynyl, amino(2-6C)alkynyl, aminosulfonylamino(2-6C)alkynyl, (3-8C)cycloalkyl(2-3C)alkynyl, (1-6C)alkylsulfonylamino(2-6C)alkynyl, (1-3C)alkoxy(1-6C)alkylaminocarbonyl, (6-10C)aryl(1-6C)alkyl, (1-3C)alkylsulfonyl(6-10C)aryl, di[(1-6C)alkyl]amino, all alkyl and alkoxy groups optionally being substituted with one or more halogen or hydroxy, all (1-5C)heteroaryl groups optionally being substituted with one or more halogen or one or more (1-6C)alkyl.

8. The compound according to claim 1 wherein R.sup.3 is ##STR00022## R.sup.31 and R.sup.35 are independently selected from the group consisting of: hydrogen, fluoro and chloro; R.sup.32 and R.sup.34 are hydrogen; R.sup.33 hydrogen, halogen, (1-6C)alkyl, (2-3C)alkenyl, (2-6C)alkynyl, (1-3C)alkoxy, (6-10C)aryl, (1-5C)heteroaryl, (3-8C)cycloalkyl, (1-6C)alkylsulfonylamino(1-6C)alkyl, aminosulfonylamino(1-6C)alkyl, (3-8C)cycloalkyl(1-6C)alkyl, amino(2-6C)alkynyl, aminosulfonylamino(2-6C)alkynyl, (3-8C)cycloalkyl(2-3C)alkynyl, (1-6C)alkylsulfonylamino(2-6C)alkynyl, (1-3C)alkoxy(1-6C)alkylaminocarbonyl, di[(1-6C)alkyl]amino, all alkyl and alkoxy groups optionally being substituted with one or more halogen or hydroxy, all (1-5C)heteroaryl groups optionally being substituted with one or more halogen or one or more (1-6C)alkyl.

9. A method for inhibiting an indoleamine 2,3-dioxygenase (IDO1), comprising contacting the IDO1 with the compound or the pharmaceutically acceptable salt thereof according to claim 1.

10. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof according to claim 1, and one or more pharmaceutically acceptable excipients.

11. The pharmaceutical composition according to claim 10, which further comprises at least one additional therapeutically active agent.

12. A method of treating an increase in indoleamine 2,3-dioxygenase (IDO1) activity associated with diseases, disorders or conditions, comprising administering the compound or the pharmaceutically acceptable salt thereof according to claim 1 to a patient in need of the treating.

13. The method according to claim 12, wherein the diseases, disorders or conditions are selected from cancer, viral or parasitic infections, central nervous system diseases, neuropsychiatric and neurodegenerative diseases, cerebrovascular disease, and immune-related disorders.

14. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or the pharmaceutically acceptable salt thereof has an inhibitory potency on indoleamine 2,3-dioxygenase (IDO1) with an IC.sub.50 of 25 M or less.

15. The method according to claim 12, wherein the diseases, disorders or conditions is selected from the group of infection with influenza virus or Leishmania major, depression, Huntington's disease, Parkinson's disease, AIDS dementia complex, infections of the central nervous system, malaria, ischemia, hypoxia at birth, traumatic brain injury, epilepsy, anxiety, schizophrenia, inflammatory bowel disease (IBD), colitis Crohn's disease, obesity, and diabetes.

Description

EXAMPLES

(1) The following examples are illustrative embodiments of the invention, not limiting the scope of the invention in any way. Reagents are either commercially available or are prepared according to procedures known in the literature.

(2) Method LCMS (A)

(3) TABLE-US-00001 Method name NTRC_C18_Short.M Column Waters XTerra C18-MS, 50 4.6 mm ID, 2.5 m Flow 0.5 ml/min. Temperature 40 C. Detector DAD 210, 254, 280 nm Detector MSD API-ES MSD signal 1 2 Mode Scan Scan Polarity Positive Negative Mass Range 100-1000 m/z 100-1000 m/z Fragmentor 70 70 Cycle Time 50% 50% Sample N/A preparation Concentration 1 mg/ml in MeOH or ACN Injection volume 1.0 l Eluent A B % 0.05% Formic Acid in Time [min] % 0.1% Formic Acid Acetonitrile 0 90 10 0.3 90 10 7.0 10 90 7.1 90 10 10.0 90 10 Post time 0.2 min Stop time 10 min
Method LCMS (B)

(4) TABLE-US-00002 Method LCMS NTRC_C18.M (B) Method name Column Waters XTerra C18-MS, 50 4.6 mm ID, 2.5 m Flow 0.5 ml/min. Temperature 40 C. Detector DAD 210, 254, 280 nm Detector MSD API-ES MSD signal 1 2 Mode Scan Scan Polarity Positive Negative Mass Range 100-1000 m/z 100-1000 m/z Fragmentor 70 70 Cycle Time 50% 50% Sample N/A preparation Concentration 1 mg/ml in MeOH or ACN Injection volume 1.0 l Eluent A B % 0.05% Formic Acid in Time [min] % 0.1% Formic Acid Acetonitrile 0 90 10 1 90 10 22.0 10 90 22.1 90 10 30.0 90 10 Post time 0.2 min Stop time 30 min
Method Preparative HPLC

(5) TABLE-US-00003 LC System Waters Prep System Column Phenomenex Luna, C18(2) 100 A, 150 mm 21.2 mm, 5 m Column Temp 20 C. Sample(s) 10-50 mg Autosamp. Temp 20 C. Injection volume 500-950 L Flow 15 ml/min Eluent A = MilliQ + MeCN (9/1) B = Acetonitrile time (min) % A % B % C Gradient 0 97 0 3 20 37 60 3 25 37 60 3 25.1 97 0 3 30 97 0 3 UV detection Photo Diode Array

(6) The following abbreviations are used throughout the application with respect to chemical terminology: HATU O-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate DCM Dichloromethane EDCI.HCl N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride NEM 4-Ethylmorpholine DiPEA N,N-Diisopropylethylamine Pd(OH).sub.2/C Palladium hydroxide on carbon (Pearlman's catalyst) HPLC High Performance Liquid Chromatography LCMS Liquid Chromatography with Mass Spectrometry detection HCl Hydrogen chloride NaHCO.sub.3 Sodium bicarbonate Boc tert-Butyloxycarbonyl Cbz Benzyloxycarbonyl DMSO Dimethyl sulfoxide DMEM Dulbecco's Modified Eagle's Medium TFA Trifluoroacetic acid EtOAc Ethyl acetate LiOH Lithium hydroxide Na.sub.2SO.sub.4 Sodium sulfate PdCl.sub.2(dppf) [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh.sub.3).sub.4 Tetrakis(triphenylphosphine)palladium(0) BF.sub.3.OEt Boron trifluoride diethyl etherate DMF N,N-Dimethylformamide NaH Sodium hydride THF Tetrahydrofuran MeOH Methanol

(7) The names of the final products in the examples are generated using Accelrys Draw (version 4.1).

Intermediate 1

2-Aminoethanehydroxamic Acid

(a) Benzyl N-[2-(benzyloxyamino)-2-oxo-ethyl]carbamate

(8) To a cold solution (0 C.) of Cbz-Gly-OH (2.75 g, 13.2 mmol) and O-benzylhydroxylamine hydrochloride (2.1 g, 13.2 mmol) in ethyl acetate/DMF=5/1 v/v % (132 mL) was added DiPEA (6.53 mL, 39.5 mmol) and EDCI.HCl (2.57 g, 13.4 mmol), after which the reaction mixture was allowed to warm to room temperature and stirred for 3 days. After TLC indicated a complete conversion of starting material the mixture was added dropwise to a stirred solution of water/brine=1/1 v/v % (250 mL). After separation of the organic and the water layers, the water layer was extracted with ethyl acetate (2150 mL). The combined organic layers were subsequently washed with a solution of 1N HCl (100 mL), water (100 mL), 5% sodium bicarbonate (100 mL), water and brine. The organic layer was subsequently dried over sodium sulfate and concentrated in vacuo to give 2.93 g of N-[2-(benzyloxyamino)-2-oxo-ethyl]carbamate (yield: 71%).

(b) 2-Aminoethanehydroxamic Acid

(9) 10% Palladium on charcoal (700 mg) was added to a suspension of benzyl N-[2-(benzyloxyamino)-2-oxo-ethyl]carbamate (7 g, 22.3 mmol) in methanol/ethyl acetate=3/1 v/v % (400 mL). The mixture was hydrogenated at atmospheric pressure at room temperature for 2 h. The palladium catalyst was removed by filtration and the solvent was removed by evaporation at reduced pressure. The residue was dissolved in water and lyophilized yielding 2-aminoethanehydroxamic acid (4.3 g, 77%) as a white powder.

Intermediate 2

3-Hydroxy-2-[3-(trifluoromethyl)phenyl]imidazolidin-4-one

(10) 2-Aminoethanehydroxamic acid (Intermediate 1, 130 mg, 1.43 mmol) and 3-(trifluoromethyl)benzaldehyde (273 mg, 1.57 mmol) were suspended in absolute ethanol (2.5 mL). The mixture was heated to reflux for 1 h to give a clear orange/yellow solution. The reaction mixture was cooled to room temperature and stirred overnight. The resulting turbid solution was subsequently concentrated in vacuo. The residue was dissolved in dichloromethane (2 mL) and heptane (4 mL) was added under vigorous stirring. The resulting precipitate was collected by decantation to give 198 mg of 3-hydroxy-2-[3-(trifluoromethyl)phenyl]imidazolidin-4-one as a light brown solid (yield: 56%).

Intermediate 3

3-(1-Hydroxy-5-oxo-imidazolidin-2-yl)benzonitrile

(11) This compound was prepared in an analogous manner as described for Intermediate 2, starting from Intermediate 1 and 3-cyanobenzaldehyde to afford the title compound (173 mg, 59%).

Intermediate 4

2-[4-Chloro-3-(trifluoromethyl)phenyl]-3-hydroxy-imidazolidin-4-one

(12) This compound was prepared in an analogous manner as described for Intermediate 2, starting from Intermediate 1 and 4-chloro-3-(trifluoromethyl)benzaldehyde to afford the title compound (202 mg, 50%).

Intermediate 5

2-(3-Fluorophenyl)-3-hydroxy-imidazolidin-4-one

(13) This compound was prepared in an analogous manner as described for Intermediate 2, starting from Intermediate 1 and 3-fluorobenzaldehyde to afford the title compound (115 mg, 41%).

Intermediate 6

2-(3-Chlorophenyl)-3-hydroxy-imidazolidin-4-one

(14) This compound was prepared in an analogous manner as described for Intermediate 2, starting from Intermediate 1 and 3-chlorobenzaldehyde to afford the title compound (245 mg, 80%).

Intermediate 7

2-(3-Bromophenyl)-3-hydroxy-imidazolidin-4-one

(15) This compound was prepared in an analogous manner as described for Intermediate 2, starting from Intermediate 1 and 3-bromobenzaldehyde to afford the title compound (150 mg, 23%).

Intermediate 8

2-(3-Bromo-4-fluoro-phenyl)-3-hydroxy-imidazolidin-4-one

(16) This compound was prepared in an analogous manner as described for Intermediate 2, starting from Intermediate 1 and 3-bromo-4-fluorobenzaldehyde to afford the title compound (333 mg, 47%).

Intermediate 9

2-(3-Chloro-4-fluoro-phenyl)-3-hydroxy-imidazolidin-4-one

(17) This compound was prepared in an analogous manner as described for Intermediate 2, starting from Intermediate 1 and 3-chloro-4-fluorobenzaldehyde to afford the title compound (168 mg, 29%).

Intermediate 10

4-Ethynyl-2,6-difluoro-benzoic Acid

(a) Methyl 4-bromo-2,6-difluoro-benzoate

(18) Thionylchloride (6.12 mL, 84.4 mmol) was added dropwise to dry methanol (100 mL) at 20 C. 4-Bromo-2,6-difluorobenzoic acid (10 g, 42.2 mmol)) was added and the reaction mixture was heated under reflux o/n. The mixture was concentrated in vacuo and traces of hydrochloric acid were co-evaporated with methanol (3 times). The residue crystallized upon standing giving 11.8 g of the title compound.

(b) Methyl 2,6-difluoro-4-(2-trimethylsilylethynyl)benzoate

(19) 4-Bromo-2,6-difluoro-benzoic acid methyl ester (250 mg, 1 mmol) was dissolved in triethylamine (5 mL) and to this solution dichloropalladium(bis)triphenylphosphine (36 mg, 0.05 mmol) was added followed by copper iodide (10 mg, 0.05 mmol) and trimethylsilylacetylene (170 L, 1.2 mmol). The reaction mixture was heated for 1 hour at 100 C. under microwave radiation. The mixture was cooled to room temperature and filtered through Decalite and concentrated under reduced pressure. The crude residue was purified by column chromatography (heptane to ethyl acetate=9/1 v/v %) to afford 293.6 mg of the title compound (quantitative yield).

(20) Methyl 2,6-difluoro-4-(2-trimethylsilylethynyl)benzoate (293.6 mg, 1.09 mmol) was dissolved in methanol (5 mL) and 5 mL of a 2M LiOH-solution in water. The mixture was refluxed overnight, after which methanol was removed by concentration in vacuo and the resulting solution was extracted with EtOAc, acidified, and again extracted with EtOAc. The organic layers were washed with brine, dried (Na.sub.2SO.sub.4), filtered and concentrated under vacuum to give the title compound (154.7 mg, 77.9%).

Intermediate 11

4-(2-Cyclopropylethynyl)-2,6-difluoro-benzoic Acid

(a) Methyl 4-(2-cyclopropylethynyl)-2,6-difluoro-benzoate

(21) 4-Bromo-2,6-difluoro-benzoic acid methyl ester (250 mg, 1 mmol) was dissolved in triethylamine (5 mL) and dichloropalladium(bis)triphenylphosphine (36 mg, 0.05 mmol) was added followed by copper iodide (10 mg, 0.05 mmol) and cyclopropylacetylene (85 L, 1.2 mmol). The reaction mixture was heated for 1 hour at 100 C. under microwave radiation. The mixture was cooled to room temperature and filtered through Decalite and concentrated under reduced pressure. The crude residue was purified by column chromatography (heptane to ethyl acetate=9/1 v/v %) to afford 214 mg of the title compound (yield: 90.6%).

(b) 4-(2-Cyclopropylethynyl)-2,6-difluoro-benzoic Acid (Intermediate 11)

(22) Methyl 4-(2-cyclopropylethynyl)-2,6-difluoro-benzoate (214 mg, 0.91 mmol) was dissolved in methanol (5 mL) and 5 mL of a 2M LiOH-solution in water and the mixture was refluxed overnight. Methanol was removed by concentration in vacuo and the resulting solution was extracted with EtOAc, acidified, and again extracted with EtOAc. The organic layers were washed with brine, dried (Na.sub.2SO.sub.4), filtered and concentrated under vacuum to give the title compound (193.5 mg, 96.0%).

Intermediate 12

2,6-Difluoro-4-(3-methylbut-1-ynyl)benzoic Acid

(a) Methyl 2,6-difluoro-4-(3-methylbut-1-ynyl)benzoate

(23) 4-Bromo-2,6-difluoro-benzoic acid methyl ester (502 mg, 2 mmol) was dissolved in triethylamine (10 mL) and dichloropalladium(bis)triphenylphosphine (70.2 mg, 0.1 mmol) was added followed by copper iodide (19 mg, 0.1 mmol) and 3-methyl-1-butyne (307 L, 1.5 mmol). The reaction mixture was heated for 1 hour at 100 C. under microwave radiation. The mixture was cooled to room temperature and filtered through Celite and concentrated in vacuo. The crude residue was purified by column chromatography (heptane to ethyl acetate=100/0 to 9/1 v/v %) to afford 440 mg of the title compound (yield: 92.4%).

(b) 2,6-Difluoro-4-(3-methylbut-1-ynyl)benzoic Acid (Intermediate 12)

(24) Methyl 2,6-difluoro-4-(3-methylbut-1-ynyl)benzoate (440 mg, 1.85 mmol) was dissolved in 5 mL of methanol and 5 mL of a 2M LiOH-solution in water. The mixture was stirred at room temperature for 2 h, after which the reaction mixture was acidified, and extracted with dichloromethane. The organic layer was washed with brine, dried (Na.sub.2SO.sub.4), filtered over an PE-filter and concentrated in vacuo to give the title compound (367.8 mg, 88.7%).

Intermediate 13

4-(2-Cyclohexylethynyl)-2,6-difluoro-benzoic Acid

(a) Methyl 4-(2-cyclohexylethynyl)-2,6-difluoro-benzoate

(25) Methyl 4-bromo-2,6-difluoro-benzoate (502 mg, 2 mmol) was dissolved in N,N-dimethylformamide (5 mL) and triethylamine (1.59 mL, 10 mmol). The solution was purged with nitrogen for 5 min and copper(I)iodide (19 mg, 0.1 mmol) and bis(triphenylphosphine)palladium(II)chloride (70.2 mg, 0.1 mmol) were added. The mixture was stirred for 5 min after which cyclohexylacetylene (1.29 mL, 10 mmol) was added and the reaction mixture was stirred at 80 C. for 2 h. The reaction mixture was added to a stirred mixture of water/brine/ethyl acetate=1/1/1 v/v % (45 mL). The organic layer was separated, washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (heptane/ethyl acetate=95/5 v/v %) to afford 360 mg of the title compound (yield: 64.7%).

(b) 4-(2-Cyclohexylethynyl)-2,6-difluoro-benzoic Acid (Intermediate 13)

(26) Methyl 4-(2-cyclohexylethynyl)-2,6-difluoro-benzoate (360 mg, 1.29 mmol) was dissolved in methanol (5 mL) and 5 mL of a 2M LiOH-solution in water. The reaction mixture was stirred at room temperature for 2 h, after which the reaction mixture was acidified and extracted with dichloromethane The organic layer was separated and washed with brine, dried (Na.sub.2SO.sub.4), filtered over an PE-filter and concentrated under reduced pressure to give the title compound (311.1 mg, 91.2%).

Intermediate 14

4-[3-(tert-Butoxycarbonylamino)prop-1-ynyl]-2,6-difluoro-benzoic Acid

(27) This compound was prepared in an analogous manner as described for Intermediate 13, starting from methyl 4-bromo-2,6-difluoro-benzoate (Intermediate 10a) and tert-butyl N-prop-2-ynylcarbamate to afford the title compound (185.3 mg, 97.6%).

Intermediate 15

2,6-Difluoro-4-[3-(methanesulfonamido)prop-1-ynyl]benzoic Acid

(a) N-prop-2-ynylmethanesulfonamide

(28) To a cold (4 C.) solution of propargylamine (0.86 g, 15.6 mmol) and triethylamine (2.39 mL, 17.2 mmol) in dichloromethane (10 mL) was added dropwise a solution of methanesulfonyl chloride (1.52 mL, 15.6 mmol) in dichloromethane (5 mL). The reaction mixture was allowed to warm to room temperature, stirred for 1 h. and concentrated in vacuo. The crude residue was purified by column chromatography (heptane to ethyl acetate=8/2 to 1/1 v/v %) to afford 465 mg of the title compound (yield: 22.4%).

(b) 2,6-Difluoro-4-[3-(methanesulfonamido)prop-1-ynyl]benzoic Acid (Intermediate 15)

(29) This compound was prepared in an analogous manner as described for Intermediate 13, starting from methyl 4-bromo-2,6-difluoro-benzoate (Intermediate 10a) and N-prop-2-ynylmethanesulfonamide to afford the title compound (187.7 mg, 57.9%).

Intermediate 16

4-[3-(tert-Butoxycarbonylsulfamoylamino)prop-1-ynyl]-2,6-difluoro-benzoic Acid

(a) tert-Butyl N-(prop-2-ynylsulfamoyl)carbamate

(30) To a cold (4 C.) solution of chlorosulfonyl isocyanate (1.63 mL, 18.7 mmol) in dichloromethane (10 mL) was added dropwise a solution of tert-butanol 2.24 mL, 23.4 mmol) in dichloromethane (5 mL). The reaction mixture was stirred for 15 min at 5 C. Triethylamine (4.78 mL, 34.4 mmol) and propargylamine (1 mL, 15.6 mmol) were added subsequently to the reaction mixture and the mixture was allowed to warm to room temperature and stirred for 1 h. and subsequently concentrated in vacuo. The crude residue was purified by column chromatography (heptane to ethyl acetate=8/2 to 1/1 v/v %) to afford 2.79 g of the title compound (yield: 76.3%).

(b) 4-[3-(tert-butoxycarbonylsulfamoylamino)prop-1-ynyl]-2,6-difluoro-benzoic Acid (Intermediate 16)

(31) This compound was prepared in an analogous manner as described for Intermediate 13, starting from methyl 4-bromo-2,6-difluoro-benzoate (Intermediate 10a) and tert-butyl N-(prop-2-ynylsulfamoyl)carbamate to afford the title compound (219.6 mg, 59.8%).

Intermediate 17

4-[3-(tert-Butoxycarbonylamino)-3-methyl-but-1-ynyl]-2,6-difluoro-benzoic Acid

(a) tert-Butyl N-(1,1-dimethylprop-2-ynyl)carbamate

(32) A mixture of 2-methyl-3-butyn-2-amine (1 mL) and di-tert-butyl dicarbonate (2.07 g) without solvent was warmed up to 50 C. for 30 min. The resulting solution was diluted with n-hexane (5 mL) and the crystals formed were, subsequently, collected by filtration, washed with hexane and dried under vacuum to give 620 mg of the title compound (yield: 35.6%).

(b) 4-[3-(tert-Butoxycarbonylamino)-3-methyl-but-1-ynyl]-2,6-difluoro-benzoic Acid (Intermediate 17)

(33) This compound was prepared in an analogous manner as described for Intermediate 13, starting from methyl 4-bromo-2,6-difluoro-benzoate (Intermediate 10a) and tert-butyl N-(1,1-dimethylprop-2-ynyl)carbamate to afford the title compound (608.4 mg, 93.4%).

Intermediate 18

4-Cyclopropyl-2,6-difluoro-benzoic Acid

(a) Methyl 4-cyclopropyl-2,6-difluoro-benzoate

(34) Methyl 4-bromo-2,6-difluoro-benzoate (502 mg, 2 mmol), tricyclohexylphosphine (168 mg, 0.6 mmol), cesium carbonate (3.9 g, 12 mmol) and cyclopropylboronic acid methyliminodiacetic acid anhydride (552 mg, 2.8 mmol) were dissolved in toluene/water=5/1 v/v % (24 mL) and the solution was degassed with nitrogen for 5 minutes. Palladium(II)acetate (67.3 mg, 0.3 mmol) was added under nitrogen atmosphere and the reaction mixture was refluxed at 100 C. for 3 hours. The crude reaction mixture was filtered over Decalite. The filtrate was diluted with ethyl acetate and washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (heptane/ethyl acetate=95/5 v/v %) to afford the title compound (240 mg, yield: 56.6%).

(b) 4-Cyclopropyl-2,6-difluoro-benzoic Acid (Intermediate 18)

(35) Methyl 4-cyclopropyl-2,6-difluoro-benzoate (240 mg, 1.13 mmol) was dissolved in methanol (5 mL) and 2M LiOH-solution in water (5 mL) and the mixture was stirred at room temperature for 2 h, after which the reaction mixture was acidified, and extracted with dichloromethane. The organic layer was washed with brine, dried (Na.sub.2SO.sub.4), filtered over an PE-filter and concentrated under vacuum to give the title compound (200 mg, 89.3%).

Intermediate 19

2,6-Difluoro-4-vinyl-benzoic Acid

(a) Methyl 2,6-difluoro-4-vinyl-benzoate

(36) Methyl 4-bromo-2,6-difluoro-benzoate (251 mg, 1.0 mmol) was dissolved in dioxane (5 mL) and potassium carbonate (207 mg, 1.5 mmol) was added. The solution was purged with nitrogen for 5 min and vinylboronic anhydride pyridine complex (240.7 mg, 1.0 mmol) and PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (40.8 mg, 0.05 mmol) were added. The reaction mixture was stirred for 2 h. at 100 C. The reaction mixture was added to a stirred mixture of 5% citric acid solution/brine/ethyl acetate=1/1/1 v/v % (150 mL). The organic layer was separated, washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure The crude residue was purified by column chromatography (dichloromethane/methanol=98/2 v/v %) to afford two batches of the title compound (174 mg, yield: 87.7%).

(b) 2,6-Difluoro-4-vinyl-benzoic Acid (Intermediate 19)

(37) This compound was prepared in an analogous manner as described for Intermediate 18b, starting from methyl 2,6-difluoro-4-vinyl-benzoate to afford the title compound (140.4 mg, 86.7%).

Intermediate 20

2,6-Difluoro-4-methyl-benzoic Acid

(38) This compound was prepared in an analogous manner as described for Intermediate 19, starting from methyl 4-bromo-2,6-difluoro-benzoate (Intermediate 10a) and trimethylboroxine to afford the title compound (468 mg, 84.2%).

Intermediate 21

2,6-Difluoro-4-phenyl-benzoic Acid

(39) Methyl 4-bromo-2,6-difluoro-benzoate (300 mg, 1.2 mmol) was dissolved in dioxane/water=4/1 v/v % (10 mL) and sodium carbonate (382 mg, 3.6 mmol) was added. The solution was purged with nitrogen for 5 min and phenylboronic acid (161 mg, 1.3 mmol) and Pd(PPh.sub.3).sub.4 (69 mg, 0.06 mmol) were added. The reaction mixture was stirred for 1 h at 100 C. under microwave radiation. The reaction mixture was cooled and a 2M NaOH-solution in water was added (4 mmol). The mixture was stirred for 1 h at 50 C. Ethyl acetate (10 mL) was added and the aqueous layer was separated. The organic layer was extracted twice with 2N NaOH-solution in water. The pH of the water layers was adjusted to pH<2 and the acidic water layer was extracted with ethyl acetate. The ethyl acetate layers were collected and washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was triturated with heptane/ethyl acetate=7/3 v/v %. White solids formed were collected by filtration, washed with heptane and dried under vacuum to give 108 mg of the title compound (yield: 38%).

Intermediate 22

2,6-Difluoro-4-(4-pyridyl)benzoic Acid

(40) This compound was prepared in an analogous manner as described for Intermediate 21, starting from methyl 4-bromo-2,6-difluoro-benzoate (Intermediate 10a) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford 165 mg of the title compound.

Intermediate 23

2,6-Difluoro-4-(1-methylpyrazol-4-yl)benzoic Acid

(41) This compound was prepared in an analogous manner as described for Intermediate 21, starting from methyl 4-bromo-2,6-difluoro-benzoate (Intermediate 10a) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford 86 mg of the title compound (yield: 60%).

Intermediate 24

2,6-Difluoro-4-(2-thienyl)benzoic Acid

(42) This compound was prepared in an analogous manner as described for Intermediate 21, starting from methyl 4-bromo-2,6-difluoro-benzoate (Intermediate 10a) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene to afford 74 mg of the title compound (yield: 51%).

Intermediate 25

2,6-Difluoro-4-(5-fluoro-2-thienyl)benzoic Acid

(43) This compound was prepared in an analogous manner as described for Intermediate 21, starting from methyl 4-bromo-2,6-difluoro-benzoate (Intermediate 10a) and 2-(5-fluoro-2-thienyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to afford 69 mg of the title compound (yield: 55%).

Intermediate 26

2,6-Difluoro-4-(1,3,5-trimethylpyrazol-4-yl)benzoic Acid

(44) This compound was prepared in an analogous manner as described for Intermediate 21, starting from methyl 4-bromo-2,6-difluoro-benzoate (Intermediate 10a) and 1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester to afford 87 mg of the title compound (yield: 54%).

Intermediate 27

2,6-Difluoro-4-(3-pyridyl)benzoic Acid

(45) This compound was prepared in an analogous manner as described for Intermediate 21, starting from methyl 4-bromo-2,6-difluoro-benzoate (Intermediate 10a) and pyridine-3-boronic acid 1,3-propanediol cyclic ester to afford 65 mg of the title compound (yield: 34%).

Intermediate 28

4-[3-(tert-Butoxycarbonylsulfamoylamino)-3-methyl-but-1-ynyl]-2,6-difluoro-benzoic Acid

(46) This compound was prepared in an analogous manner as described for Intermediate 13 and Intermediate 16, starting from methyl 4-bromo-2,6-difluoro-benzoate (Intermediate 10a) and tert-butyl N-(1,1-dimethylprop-2-ynylsulfamoyl)carbamate to afford the title compound (221 mg, 76.7%).

Intermediate 29

3-Hydroxy-2-(3-vinylphenyl)imidazolidin-4-one

(a) 3-Vinylbenzaldehyde

(47) 3-Bromobenzaldehyde (185 mg, 1.0 mmol) was suspended in dioxane (2 mL) and potassium carbonate (207 mg, 1.5 mmol) was added. The solution was purged with nitrogen for 5 min and vinylboronic anhydride pyridine complex (240.7 mg, 1.0 mmol) and PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (40.8 mg, 0.05 mmol) were added. The reaction mixture was stirred for 2 h. at 100 C. The reaction mixture was added to a stirred mixture of 5% citric acid solution/brine/ethyl acetate=1/1/1 v/v % (30 mL). The organic layer was separated, washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure The crude residue was purified by column chromatography (heptane to ethyl acetate=10/0 to 1/1 v/v %) to afford the title compound (91 mg, yield: 69%).

(b) 3-Hydroxy-2-(3-vinylphenyl)imidazolidin-4-one

(48) This compound was prepared in an analogous manner as described for Intermediate 2, starting from Intermediate 1 and 3-vinylbenzaldehyde to afford the title compound (90 mg, 64%).

Intermediate 30

2,6-Difluoro-4-(methanesulfonamidomethyl)benzoic Acid

(a) tert-Butyl 4-bromo-2,6-difluoro-benzoate

(49) 4-Bromo-2,6-difluorobenzoic acid (1.5 g, 6.33 mmol) was suspended in dichloromethane (10 mL). A solution of tert-butyl 2,2,2-trichloroacetamidate (1.38 g, 6.33 mmol) in cyclohexane (30 mL) and BF.sub.3.Et.sub.2O (47.5 L, 0.38 mmol) were added subsequently to the suspension. After stirring at room temperature for 16 h, the reaction was cooled on an ice bath and solid NaHCO.sub.3 (0.5 g) was added in one portion. This mixture was stirred for 10 min and filtered over a silica plug. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (heptane/ethyl acetate=7/3 v/v %) to provide the title compound as a colourless oil (1.43 g, 77.1%).

(b) tert-Butyl 4-cyano-2,6-difluoro-benzoate

(50) To a solution of tert-butyl 4-bromo-2,6-difluoro-benzoate (1.4 g, 4.78 mmol) in DMF (10 mL) were added zinc cyanide (561 mg, 4.78 mmol), and Pd(PPh.sub.3).sub.4 (552 mg, 0.48 mmol). The reaction mixture was refluxed at 80 C. under nitrogen atmosphere o/n. The reaction mixture was added to a stirred mixture of 5% NaHCO.sub.3-solution/brine/ethyl acetate=1/1/1 v/v % (150 ml). The organic layer was separated, washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (heptane/ethyl acetate=100/0 to 95/5 v/v %) to afford 810 mg of the title compound (yield: 70.8%).

(51) 10% Palladium on charcoal (20 mg) and 420 L of a 2N hydrochloride solution were added to a solution of tert-butyl 4-cyano-2,6-difluoro-benzoate (200 mg, 0.84 mmol) in ethanol (20 mL). The mixture was hydrogenated at atmospheric pressure at room temperature for 3 h. The palladium catalyst was removed by filtration and the solvent was removed by evaporation at reduced pressure yielding tert-butyl 4-(aminomethyl)-2,6-difluoro-benzoate hydrochloride quantitatively.

(d) tert-Butyl 2,6-difluoro-4-(methanesulfonamidomethyl)benzoate

(52) To a suspension of tert-butyl 4-(aminomethyl)-2,6-difluoro-benzoate hydrochloride (200 mg, 0.84 mmol) in DCM (10 mL) was added triethylamine (240 L, 1.68 mmol) and methanesulfonyl chloride (65 L, 0.84 mmol). The mixture was stirred at room temperature o/n. Mixture was concentrated under reduced pressure and the crude residue was purified by column chromatography (dichloromethane/methanol=98/2 to 96/4 v/v %) to afford 113.7 mg of the title compound (yield: 42.1%).

(e) 2,6-Difluoro-4-(methanesulfonamidomethyl)benzoic Acid (Intermediate 30)

(53) To a solution of 2,6-difluoro-4-(methanesulfonamidomethyl)benzoic acid (113.7 mg, 0.35 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo and co-evaporated with dichloromethane (3) to give the title compound in quantitative crude yield.

Intermediate 31

4-(2-Cyclohexylethyl)-2,6-difluoro-benzoic Acid

(54) 10% Palladium on charcoal (20 mg) was added to a solution of 4-(2-cyclohexylethynyl)-2,6-difluoro-benzoic acid (125 mg, 0.47 mmol) in methanol (10 mL). The mixture was hydrogenated at atmospheric pressure at room temperature for 5 h. The palladium catalyst was removed by filtration and the solvent was removed by evaporation at reduced pressure yielding 4-(2-cyclohexylethyl)-2,6-difluoro-benzoic acid quantitatively.

Intermediate 32

4-[3-(tert-Butoxycarbonylsulfamoylamino)propyl]-2,6-difluoro-benzoic Acid

(a) Methyl 4-[3-(tert-butoxycarbonylsulfamoylamino)propyl]-2,6-difluoro-benzoate

(55) 10% Palladium on charcoal (30 mg) was added to a solution of methyl 4-[3-(tert-butoxycarbonylsulfamoylamino)prop-1-ynyl]-2,6-difluoro-benzoate (Intermediate 16b, 300 mg, 0.74 mmol) in methanol (10 mL). The mixture was hydrogenated at atmospheric pressure at room temperature for 5 h. The palladium catalyst was removed by filtration and the solvent was removed by evaporation at reduced pressure to give 273.1 mg of methyl 4-[3-(tert-butoxycarbonylsulfamoylamino)propyl]-2,6-difluoro-benzoate (yield: 90.4%).

(b) 4-[3-(tert-Butoxycarbonylsulfamoylamino)propyl]-2,6-difluoro-benzoic Acid (Intermediate 32)

(56) Methyl 4-[3-(tert-butoxycarbonylsulfamoylamino)propyl]-2,6-difluoro-benzoate (273.1 mg, 0.69 mmol) was dissolved in methanol (5 mL) and 2M LiOH-solution (3.3 ml) and the mixture was stirred at room temperature for 2 h. The basic layer acidified, and extracted with dichloromethane. The organic layer was washed with brine, dried (Na.sub.2SO.sub.4), filtered over an PE-filter and concentrated in vacuo to give the title compound (223.2 mg, 82.1%).

Intermediate 33

2,6-Difluoro-4-morpholino-benzoic Acid

(a) Methyl 2,6-difluoro-4-morpholino-benzoate

(57) To a solution of methyl 2,4,6-trifluorobenzoate (272 L, 2 mmol) and morpholine (176 L, 2 mmol) in DMSO (6 mL) was added potassium carbonate (331 mg, 2.4 mmol) and the reaction mixture was stirred at 55 C. for 1 h. Ethyl acetate was added to the mixture and the mixture was washed with water, brine, dried over sodium sulfate, filtered and the solvent was removed by evaporation at reduced pressure. The crude residue was purified by column chromatography (heptane/ethyl acetate=10/0 to 1/1 v/v %) to afford 191 mg of the title compound (yield: 22%).

(b) 2,6-Difluoro-4-morpholino-benzoic Acid (Intermediate 33)

(58) This compound was prepared in an analogous manner as described for Intermediate 32b, starting with methyl 2,6-difluoro-4-morpholino-benzoate to afford the title compound (173 mg, 96%).

Intermediate 34

4-(Azetidin-1-yl)-2,6-difluoro-benzoic Acid

(59) This compound was prepared in an analogous manner as described for Intermediate 33, starting with methyl 2,4,6-trifluorobenzoate and azetidine to afford the title compound (188 mg, 84%).

Intermediate 35

4-[2-Benzyloxyethyl(methyl)amino]-2,6-difluoro-benzoic Acid

(a) Methyl 2,6-difluoro-4-[2-hydroxyethyl(methyl)amino]benzoate

(60) This compound was prepared in an analogous manner as described for Intermediate 33, starting with methyl 2,4,6-trifluorobenzoate and 2-(methylamino)ethanol to afford the title compound (160 mg, 33%).

(b) Methyl 4-[2-benzyloxyethyl(methyl)amino]-2,6-difluoro-benzoate

(61) To a cold (0 C.) solution of methyl 2,6-difluoro-4-[2-hydroxyethyl(methyl)amino]-benzoate (160 mg, 0.65 mmol) in DMF (3 mL) was added NaH (60% dispersion in mineral oil, 26 mg, 0.65 mmol) and the reaction mixture was stirred for 10 min at 0 C. Then a solution of benzylbromide (77 L, 0.65 mmol) in DMF (0.5 ml) was added and the mixture was stirred for 1 h allowing the temperature to come to room temperature. The reaction mixture was added to a stirred mixture of water/brine/ethyl acetate=1/1/1 v/v % (30 ml). The organic layer was separated, washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (heptane/ethyl acetate=10/0 to 0/10 v/v %) to afford 126 mg of the title compound (yield: 58%).

(62) This compound was prepared in an analogous manner as described for Intermediate 32b, starting with methyl 4-[2-benzyloxyethyl(methyl)amino]-2,6-difluoro-benzoate to afford the title compound (118 mg, 97%).

Intermediate 36

2,6-Difluoro-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]benzoic Acid

(63) This compound was prepared in an analogous manner as described for Intermediate 33, starting with methyl 2,4,6-trifluorobenzoate and L-prolinol to afford the title compound (50 mg, 29%).

Intermediate 37

2,6-Difluoro-4-(2-methoxyethylcarbamoyl)benzoic Acid

(a) 4-tert-Butoxycarbonyl-3,5-difluoro-benzoic Acid

(64) To a cold (78 C.) solution of tert-butyl 4-bromo-2,6-difluoro-benzoate (Intermediate 30a, 820 mg, 2.80 mmol) in THF (24 mL) was added drop-wise n-butyllithium (1.6M solution in hexane, 1.92 mL, 3.1 mmol). The reaction mixture turned into a red solution and after stirring for an additional 5 minutes at 78 C. solid crushed CO.sub.2 (large excess) was added. The mixture was warmed to room temperature. The mixture was quenched by adding water (30 mL). The biphasic system was stirred thoroughly for 15 minutes at room temperature. The layers were separated and the organic layer was extracted with water (10 mL). The combined water layers were washed with ethyl acetate (20 mL) and acidified by addition of 2N HCl-solution (4 mL). The water layer was extracted with ethyl acetate (220 mL). The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4), filtered and concentrated to give 450 mg of 4-tert-butoxycarbonyl-3,5-difluoro-benzoic acid.

(b) tert-Butyl 2,6-difluoro-4-(2-methoxyethylcarbamoyl)benzoate

(65) HATU (491 mg, 1.29 mmol) was added to a cold (0 C.) solution of 4-tert-butoxycarbonyl-3,5-difluoro-benzoic acid (303 mg, 1.17 mmol) and DiPEA (579 L, 3.51 mmol) in DMF (11.7 mL). After stirring for 10 minutes at 0 C., 2-methoxyethylamine (153 L, 1.76 mmol) was added and the reaction mixture was stirred for 3 h allowing the mixture to come to room temperature. The reaction mixture was added to a stirred mixture of water/brine/ethyl acetate=1/1/1 v/v % (300 ml). The organic layer was separated, washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (heptane/ethyl acetate=10/0 to 1/1 v/v %) to afford 268 mg of the title compound (yield: 73%).

(66) This compound was prepared in an analogous manner as described for Intermediate 30e starting with tert-butyl 2,6-difluoro-4-(2-methoxyethylcarbamoyl)benzoate to afford the title compound in quantitative crude yield.

Intermediate 38

2-[[(1S)-1-phenylethyl]amino]ethanehydroxamic Acid hydrochloride

(a) Methyl 2-[[(1S)-1-phenylethyl]amino]acetate

(67) To a solution of (1S)-1-phenylethylamine (500 mg, 3.9 mmol) in acetonitrile (20 mL) was added methyl bromoacetate (371 L, 3.9 mmol) and potassium carbonate (1.08 g, 7.8 mmol). The reaction mixture was stirred o/w at room temperature. The mixture was filtered and the filtrate was concentrated under vacuum to give the crude tile compound (703 mg, 93%).

(b) Methyl 2-[tert-butoxycarbonyl-[(1S)-1-phenylethyl]amino]acetate

(68) To a solution of methyl 2-[[(1S)-1-phenylethyl]amino]acetate (703 mg, 3.64 mmol) in water (15 mL) was added a solution of di-tert-butyl dicarbonate (1.19 g, 5.46 mmol) in dioxane (3 mL) and the mixture was stirred at room temperature for 3 h. The mixture was extracted with ethyl acetate. The organic layer was separated and washed with water, brine, dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure to give methyl 2-[tert-butoxycarbonyl-[(1S)-1-phenylethyl]amino]acetate in quantitative yield.

(69) To a solution of methyl 2-[tert-butoxycarbonyl-[(1S)-1-phenylethyl]amino]acetate (1.3 g, 3.87 mmol) in THF/MeOH=3/1 v/v % (40 mL) was added 1N LiOH-solution (10 mL) and the reaction mixture was stirred at room temperature o/n. Cold water was added to the mixture and 5% citric acid solution was added until pH<3. Ethyl acetate was added and after stirring, the organic phase was separated, washed with water, brine, dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure to give the 947 mg of the title compound (Yield: 88%).

(d) tert-Butyl N-[2-oxo-2-(tetrahydropyran-2-yloxyamino)ethyl]-N-[(1S)-1-phenylethyl]carbamate

(70) This compound was prepared in an analogous manner as described for Intermediate 37b starting with 2-[tert-butoxycarbonyl-[(1S)-1-phenylethyl]amino]acetic acid and 0-tetrahydropyran-2-ylhydroxylamine to give 1.68 g of the title compound (quantitative crude yield).

(e) tert-Butyl N-[2-(hydroxyamino)-2-oxo-ethyl]-N-[(1S)-1-phenylethyl]carbamate

(71) To a solution of tert-butyl N-[2-oxo-2-(tetrahydropyran-2-yloxyamino)ethyl]-N-[(1S)-1-phenylethyl]carbamate (1.64 g, 3.24 mmol) in methanol (25 mL) was added p-toluenesulfonic acid monohydrate (1.23 g, 6.48 mmol) and the reaction mixture was stirred for 1 h at room temperature. Dichloromethane (225 mL) was added and the mixture was washed with 5% NaHCO.sub.3-solution, water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (heptane to ethyl acetate=10/0 to 1/3 v/v %) to afford 775 mg of the title compound (yield: 81%).

(f) 2-[[(1S)-1-phenylethyl]amino]ethanehydroxamic Acid hydrochloride (Intermediate 38)

(72) To a solution of tert-butyl N-[2-(hydroxyamino)-2-oxo-ethyl]-N-[(1S)-1-phenylethyl]carbamate (775 mg, 2.63 mmol) in dioxane (1.5 mL) was added 4N HCl in dioxane (5 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and traces of hydrochloric acid were removed by co-evaporated with dichloromethane (3) to give 681 mg of the title compound (quantitative yield).

Intermediate 39

2-[1-(2,6-Difluorophenyl)ethylamino]ethanehydroxamic Acid hydrochloride

(73) This compound was prepared in an analogous manner as described for Intermediate 38, starting with 1-(2,6-difluorophenyl)ethanamine to afford 100 mg of the title compound.

Intermediate A

3-Benzyloxy-2-(3-bromophenyl)imidazolidin-4-one

(a) tert-Butyl N-[2-(benzyloxyamino)-2-oxo-ethyl]carbamate

(74) Boc-Gly-OH (2.5 g, 14.3 mmol) and O-benzylhydroxylamine hydrochloride (2.07 g, 13.0 mmol) were suspended in DCM (25 mL). HATU (4.93 g, 13.0 mmol) and NEM (3.3 mL, 25.9 mmol) were added subsequently to the reaction mixture and the mixture stirred at room temperature o/n. The reaction mixture was concentrated to small volume and subsequently diluted with ethyl acetate. The organic layer was washed with a 5% NaHCO.sub.3-solution, 0.2M HCl-solution, water and brine, then dried over sodium sulfate, filtered and concentrated in vacuo to give 3.3 g of the crude product as an oil (yield 90.6%). This crude product was used in the next step without further purification.

(b) 2-Amino-N-benzyloxy-acetamide 2,2,2-trifluoroacetic Acid

(75) tert-Butyl N-[2-(benzyloxyamino)-2-oxo-ethyl]carbamate (3.3 g, 11.8 mmol) was dissolved in dichloromethane (20 mL). Water (300 L) and trifluoroacetic acid (20 mL) were added and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated to a small volume and added dropwise to 300 mL of diethyl ether under vigorous stirring. After stirring for an additional hour at room temperature, the diethyl ether layer was decanted. Diethyl ether was added to the remaining precipitate and stirred again for 1 hour. The precipitate was filtered, washed with diethyl ether and dried under vacuum to give 2.87 g of 2-amino-N-benzyloxy-acetamide 2,2,2-trifluoroacetic acid as a white powder (yield: 82.7%).

(76) Part of the product was dissolved in methanol and then filtered over a SCX-2 column. After rinsing the column with methanol, the desired product was eluted with an 0.7N ammonia/methanol solution to give 2-amino-N-benzyloxy-acetamide (500 mg).

(77) To a suspension of 2-amino-N-benzyloxy-acetamide (500 mg, 2.77 mmol) in ethanol (5 mL) was added 3-bromobenzaldehyde (356 L, 3.05 mmol). The reaction mixture was refluxed for 1 h and after TLC indicated a complete conversion of the starting material the mixture was concentrated in vacuo and the crude residue was purified by column chromatography (heptane to ethyl acetate=8/2 to 1/1 v/v %) to afford the title compound: 620 mg (64.5% yield).

Intermediate B

(5S)-3-benzyloxy-2-(3-bromophenyl)-5-methyl-imidazolidin-4-one

(78) This compound was prepared in an analogous manner as described for Intermediate A, starting from Boc-L-Ala-OH and O-benzylhydroxylamine hydrochloride to afford the title compound (250 mg, 67%).

Intermediate C

(5R)-3-benzyloxy-2-(3-bromophenyl)-5-methyl-imidazolidin-4-one

(79) This compound was prepared in an analogous manner as described for Intermediate A, starting from Boc-D-Ala-OH and O-benzylhydroxylamine hydrochloride to afford the title compound (145 mg, 80%).

Intermediate D

3-Benzyloxy-2-(3-chlorophenyl)imidazolidin-4-one

(80) This compound was prepared in an analogous manner as described for Intermediate A, starting from Boc-Gly-OH, O-benzylhydroxylamine hydrochloride and 3-chlorobenzaldehyde to afford the title compound (260 mg, 34%).

Example 1

1-Benzoyl-3-hydroxy-2-[3-(trifluoromethyl)phenyl]imidazolidin-4-one

(81) Chlorotrimethylsilane (29.5 L, 0.23 mmol) was added to a solution of DiPEA (57.8 L, 0.35 mmol) in dichloromethane (1 mL). The resulting mixture was added dropwise to a stirred suspension 3-hydroxy-2-[3-(trifluoromethyl)phenyl]imidazolidin-4-one (Intermediate 2, 29.5 mg, 0.12 mmol) in dichloromethane (1 mL). After stirring for 15 minutes at room temperature, the reaction mixture was cooled to 0 C. and DiPEA (37.9 L, 0.23 mmol) was added followed by a solution of benzoyl chloride (13.9 L, 0.12 mmol) in dichloromethane (0.5 mL). The resulting solution was stirred for 15 minutes at 0 C. After TLC analysis indicated a complete conversion of starting material, the reaction was quenched with 5% citric acid solution (4 m L). The water layer was extracted with dichloromethane. The combined organic layers were washed with a solution of 5% NaHCO.sub.3 (4 mL), filtered over a PE filter and concentrated in vacuo to give an oil. Purification was performed using preparative HPLC to afford the title compound (10.2 mg, 24%). Data: LCMS (B) R.sub.t: 9.800 min; m/z 351.1 (M+H).sup.+.

Example 2

1-(2-Chlorobenzoyl)-3-hydroxy-2-[3-(trifluoromethyl)phenyl]imidazolidin-4-one

(82) This compound was prepared from Intermediate 2 and 2-chlorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (11.8 mg, 37%). Data: LCMS (B) R.sub.t: 10.271 min; m/z 385.1/387.0 (M+H).sup.+ (chloride-pattern).

Example 3

1-(2-Chloro-6-fluoro-benzoyl)-3-hydroxy-2-[3-(trifluoromethyl)phenyl]imidazolidin-4-one

(83) This compound was prepared from Intermediate 2 and 2-chloro-6-fluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (9.1 mg, 19%). Data: LCMS (B) R.sub.t: 10.403 min; m/z 403.0/405.0 (M+H).sup. (chloride-pattern).

Example 4

1-(2,6-Difluorobenzoyl)-3-hydroxy-2-[3-(trifluoromethyl)phenyl]imidazolidin-4-one

(84) This compound was prepared from Intermediate 2 and 2,6-difluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (20 mg, 43%). Data: LCMS (B) R.sub.t: 10.113 min; m/z 387.0 (M+H).sup.+.

Example 5

3-[1-(2-Fluorobenzoyl)-3-hydroxy-4-oxo-imidazolidin-2-yl]benzonitrile

(85) This compound was prepared from Intermediate 3 and 2-fluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (16.8 mg, 43%). Data: LCMS (B) R.sub.t: 7.223 min; m/z 326.1 (M+H).sup.+.

Example 6

3-[1-(2-Chloro-6-fluoro-benzoyl)-3-hydroxy-4-oxo-imidazolidin-2-yl]benzonitrile

(86) This compound was prepared from Intermediate 3 and 2-chloro-6-fluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (14.3 mg, 33%). Data: LCMS (B) R.sub.t: 7.861 min; m/z 360.0 (M+H).sup.+.

Example 7

1-(2-Chloro-6-fluoro-benzoyl)-2-[4-chloro-3-(trifluoromethyl)phenyl]-3-hydroxy-imidazolidin-4-one

(87) This compound was prepared from Intermediate 4 and 2-chloro-6-fluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (26 mg, 50%). Data: LCMS (B) R.sub.t: 11.615 min; m/z 437.0/439.0 (M+H).sup.+ (dichloride-pattern).

Example 8

2-[4-Chloro-3-(trifluoromethyl)phenyl]-1-(2-fluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(88) This compound was prepared from Intermediate 4 and 2-fluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (29 mg, 60%). Data: LCMS (B) R.sub.t: 11.144 min; m/z 403.0/405.1 (M+H).sup.+ (chloride-pattern).

Example 9

2-[4-Chloro-3-(trifluoromethyl)phenyl]-1-(2,6-difluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(89) This compound was prepared from Intermediate 4 and 2,6-difluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (32 mg, 63%). Data: LCMS (B) R.sub.t: 11.295 min; m/z 421.0/423.0 (M+H).sup.+ (chloride-pattern).

Example 10

1-(2-Fluorobenzoyl)-3-hydroxy-2-[3-(trifluoromethyl)phenyl]imidazolidin-4-one

(90) This compound was prepared from Intermediate 2 and 2-fluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (7.6 mg, 17%). Data: LCMS (B) R.sub.t: 9.889 min; m/z 369.1 (M+H).sup.+.

Example 11

1-(2,6-Difluorobenzoyl)-2-(3-fluorophenyl)-3-hydroxy-imidazolidin-4-one

(91) This compound was prepared from Intermediate 5 and 2,6-difluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (20 mg, 50%). Data: LCMS (B) R.sub.t: 8.146 min; m/z 337.1 (M+H).sup.+.

Example 12

1-(2-Fluorobenzoyl)-2-(3-fluorophenyl)-3-hydroxy-imidazolidin-4-one

(92) This compound was prepared from Intermediate 5 and 2-fluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (17 mg, 44%). Data: LCMS (B) R.sub.t: 8.017 min; m/z 319.1 (M+H).sup.+.

Example 13

2-(3-Chlorophenyl)-1-(2-fluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(93) This compound was prepared from Intermediate 6 and 2-fluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (27 mg, 67%). Data: LCMS (B) R.sub.t: 8.992 min; m/z 335.1/337.0 (M+H).sup.+ (chloride pattern).

Example 14

1-(2-Chloro-6-fluoro-benzoyl)-2-(3-chlorophenyl)-3-hydroxy-imidazolidin-4-one

(94) This compound was prepared from Intermediate 6 and 2-chloro-6-fluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (27 mg, 61%). Data: LCMS (B) R.sub.t: 9.564 min; m/z 369.0/371.0 (M+H).sup.+ (dichloride pattern).

Example 15

2-(3-Chlorophenyl)-1-(2,6-difluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(95) This compound was prepared from Intermediate 6 and 2,6-difluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (26 mg, 61%). Data: LCMS (B) R.sub.t: 9.136 min; m/z 353.0/355.0 (M+H).sup.+ (chloride pattern).

Example 16

2-(3-Bromophenyl)-1-(2,4-dichlorobenzoyl)-3-hydroxy-imidazolidin-4-one

(96) This compound was prepared from Intermediate 7 and 2,4-dichlorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (32 mg, 62%). Data: LCMS (B) R.sub.t: 11.483 min; m/z 430.9 (M+H).sup.+ (chloride/bromide pattern).

Example 17

1-Benzoyl-2-(3-bromophenyl)-3-hydroxy-imidazolidin-4-one

(97) This compound was prepared from Intermediate 7 and benzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (106 mg, 28%). Data: LCMS (B) R.sub.t: 9.253 min; m/z 361.0/363.0 (M+H).sup.+ (bromide pattern).

Example 18

2-(3-Bromophenyl)-3-hydroxy-1-(4-methoxybenzoyl)imidazolidin-4-one

(98) This compound was prepared from Intermediate 7 and p-anisoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (8.5 mg, 24%). Data: LCMS (B) R.sub.t: 9.456 min; m/z 391.0/393.0 (M+H).sup.+ (bromide pattern).

Example 19

2-(3-Bromophenyl)-1-(cyclohexanecarbonyl)-3-hydroxy-imidazolidin-4-one

(99) This compound was prepared from Intermediate 7 and cyclohexanecarbonyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (19 mg, 43%). Data: LCMS (B) R.sub.t: 10.698 min; m/z 367.1/369.1 (M+H).sup.+ (bromide pattern).

Example 20

2-(3-Bromophenyl)-3-hydroxy-1-(2-methylbenzoyl)imidazolidin-4-one

(100) This compound was prepared from Intermediate 7 and o-toluoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (21 mg, 47%). Data: LCMS (B) R.sub.t: 9.932 min; m/z 375.0/377.0 (M+H).sup.+ (bromide pattern).

Example 21

2-(3-bromophenyl)-1-(2,6-dichlorobenzoyl)-3-hydroxy-imidazolidin-4-one

(101) This compound was prepared from Intermediate 7 and 2,6-dichlorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (13 mg, 25%). Data: LCMS (B) R.sub.t: 10.292 min; m/z 428.9/430.9 (M+H).sup.+ (chloride/bromide pattern).

Example 22

2-(3-Bromophenyl)-1-(furan-2-carbonyl)-3-hydroxy-imidazolidin-4-one

(102) This compound was prepared from Intermediate 7 and 2-furoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (21 mg, 50%). Data: LCMS (B) R.sub.t: 8.144 min; m/z 351.0/353.0 (M+H).sup.+ (bromide pattern).

Example 23

2-(3-Bromo-4-fluoro-phenyl)-1-(cyclobutanecarbonyl)-3-hydroxy-imidazolidin-4-one

(103) This compound was prepared from Intermediate 8 and cyclobutanecarbonyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (14 mg, 33%). Data: LCMS (B) R.sub.t: 9.218 min; m/z 357.0/359.0 (M+H).sup.+ (bromide pattern).

Example 24

1-(2-Bromobenzoyl)-2-(3-bromophenyl)-3-hydroxy-imidazolidin-4-one

(104) This compound was prepared from Intermediate 7 and 2-bromobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (36 mg, 68%). Data: LCMS (B) R.sub.t: 10.003 min; m/z 440.9/442.9 (M+H).sup.+ (bromide pattern).

Example 25

4-[2-(3-Bromophenyl)-3-hydroxy-4-oxo-imidazolidine-1-carbonyl]-3-chloro-5-fluoro-benzonitrile

(105) This compound was prepared from Intermediate 7 and 2-chloro-6-fluoro-4-cyanobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (19 mg, 36%). Data: LCMS (B) R.sub.t: 10.025 min; m/z 481.9/483.9 (M+H).sup.+ (bromide/chloride pattern).

Example 26

2-(3-Bromophenyl)-1-(2,5-difluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(106) This compound was prepared from Intermediate 7 and 2,5-difluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (27 mg, 57%). Data: LCMS (B) R.sub.t: 9.745 min; m/z 397.0/399.0 (M+H).sup.+ (bromide pattern).

Example 27

2-(3-Bromophenyl)-1-(2,6-difluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(107) This compound was prepared from Intermediate 7 and 2,6-difluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (23.2 mg, 49%). Data: LCMS (B) R.sub.t: 9.374 min; m/z 397.0/399.0 (M+H).sup.+ (bromide pattern).

Example 28

2-(3-Bromophenyl)-3-hydroxy-1-[2-(trifluoromethyl)benzoyl]imidazolidin-4-one

(108) This compound was prepared from Intermediate 7 and 2-(trifluoromethyl)benzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (36 mg, 70%). Data: LCMS (B) R.sub.t: 10.654 min; m/z 429.0/431.0 (M+H).sup.+ (bromide pattern).

Example 29

2-(3-Bromophenyl)-1-(4-fluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(109) This compound was prepared from Intermediate 7 and 4-fluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (10 mg, 21%). Data: LCMS (B) R.sub.t: 9.775 min; m/z 379.0/381.0 (M+H).sup.+ (bromide pattern).

Example 30

2-(3-Bromophenyl)-1-(2-chloro-4-fluoro-benzoyl)-3-hydroxy-imidazolidin-4-one

(110) This compound was prepared from Intermediate 7 and 2-chloro-4-fluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (24.8 mg, 50%). Data: LCMS (B) R.sub.t: 10.231 min; m/z 412.9/414.9 (M+H).sup.+ (chloride/bromide pattern).

Example 31

2-(3-Bromophenyl)-1-(2-chloro-5-fluoro-benzoyl)-3-hydroxy-imidazolidin-4-one

(111) This compound was prepared from Intermediate 7 and 2-chloro-5-fluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (28.6 mg, 58%). Data: LCMS (B) R.sub.t: 10.103 min; m/z 412.9/414.9 (M+H).sup.+ (chloride/bromide pattern).

Example 32

2-(3-Bromophenyl)-1-(2-chloro-6-fluoro-benzoyl)-3-hydroxy-imidazolidin-4-one

(112) This compound was prepared from Intermediate 7 and 2-chloro-6-fluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (31 mg, 62%). Data: LCMS (B) R.sub.t: 9.902 min; m/z 412.9/414.9 (M+H).sup.+ (chloride/bromide pattern).

Example 33

2-(3-Bromophenyl)-1-(2-fluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(113) This compound was prepared from Intermediate 7 and 2-fluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (28 mg, 62%). Data: LCMS (B) R.sub.t: 9.395 min; m/z 379.0/381.0 (M+H).sup.+ (bromide pattern).

Example 34

2-(3-Bromophenyl)-1-(2-chlorobenzoyl)-3-hydroxy-imidazolidin-4-one

(114) This compound was prepared from Intermediate 7 and 2-chlorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (28 mg, 59%). Data: LCMS (B) R.sub.t: 9.338 min; m/z 394.9/379.0 (M+H).sup.+ (chloride/bromide pattern).

Example 35

2-(3-Bromophenyl)-1-(2,3-dichlorobenzoyl)-3-hydroxy-imidazolidin-4-one

(115) This compound was prepared from Intermediate 7 and 2,3-dichlorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (8.97 mg, 17%). Data: LCMS (B) R.sub.t: 10.889 min; m/z 428.9/430.9 (M+H).sup.+ (chloride/bromide pattern).

Example 36

2-(3-Bromophenyl)-1-(3-fluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(116) This compound was prepared from Intermediate 7 and 3-fluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (25.1 mg, 55%). Data: LCMS (B) R.sub.t: 9.790 min; m/z 378.9/380.9 (M+H).sup.+ (bromide pattern).

Example 37

2-(3-Bromophenyl)-1-[2-fluoro-6-(trifluoromethyl)benzoyl]-3-hydroxy-imidazolidin-4-one

(117) This compound was prepared from Intermediate 7 and 2-fluoro-6-(trifluoromethyl)benzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (13.9 mg, 26%). Data: LCMS (B) R.sub.t: 10.579 min; m/z 447.0/449.0 (M+H).sup.+ (bromide pattern).

Example 38

2-(3-Bromophenyl)-1-[2-fluoro-4-(trifluoromethyl)benzoyl]-3-hydroxy-imidazolidin-4-one

(118) This compound was prepared from Intermediate 7 and 2-fluoro-4-(trifluoromethyl)benzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (37.1 mg, 69%). Data: LCMS (B) R.sub.t: 11.744 min; m/z 447.0/449.0 (M+H).sup.+ (bromide pattern).

Example 39

1-Benzoyl-2-(3-bromo-4-fluoro-phenyl)-3-hydroxy-imidazolidin-4-one

(119) This compound was prepared from Intermediate 8 and benzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (14 mg, 31%). Data: LCMS (B) R.sub.t: 9.578 min; m/z 379.0/381.0 (M+H).sup.+ (bromide pattern).

Example 40

2-(3-Bromo-4-fluoro-phenyl)-1-(4-fluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(120) This compound was prepared from Intermediate 8 and 4-fluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (5 mg, 10%). Data: LCMS (B) R.sub.t: 10.083 min; m/z 397.0/399.0 (M+H).sup.+ (bromide pattern).

Example 41

1-(Benzenesulfonyl)-2-(3-bromo-4-fluoro-phenyl)-3-hydroxy-imidazolidin-4-one

(121) This compound was prepared from Intermediate 8 and phenyl sulphonyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (2.1 mg, 4.2%). Data: LCMS (B) R.sub.t: 10.960 min; m/z 414.9/416.9 (M+H).sup.+ (bromide pattern).

Example 42

2-(3-Bromo-4-fluoro-phenyl)-1-(cyclopropanecarbonyl)-3-hydroxy-imidazolidin-4-one

(122) This compound was prepared from Intermediate 8 and cyclopropanecarbonyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (10 mg, 24%). Data: LCMS (B) R.sub.t: 8.048 min; m/z 343.0/345.0 (M+H).sup.+ (bromide pattern).

Example 43

2-(3-Bromo-4-fluoro-phenyl)-1-(3-fluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(123) This compound was prepared from Intermediate 8 and 3-fluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (26 mg, 55%). Data: LCMS (B) R.sub.t: 10.135 min; m/z 397.0/399.0 (M+H).sup.+ (bromide pattern).

Example 44

2-(3-Bromo-4-fluoro-phenyl)-1-(2,6-difluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(124) This compound was prepared from Intermediate 8 and 2,6-difluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (30 mg, 60%). Data: LCMS (B) R.sub.t: 9.745 min; m/z 415.0/417.0 (M+H).sup.+ (bromide pattern).

Example 45

2-(3-Bromo-4-fluoro-phenyl)-1-(2-chloro-6-fluoro-benzoyl)-3-hydroxy-imidazolidin-4-one

(125) This compound was prepared from Intermediate 8 and 2-chloro-6-fluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (25 mg, 48%). Data: LCMS (B) R.sub.t: 10.249 min; m/z 430.9/432.9 (M+H).sup.+ (chloride/bromide pattern).

Example 46

2-(3-Bromo-4-fluoro-phenyl)-1-(2-fluoro-benzoyl)-3-hydroxy-imidazolidin-4-one

(126) This compound was prepared from Intermediate 8 and 2-fluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (12 mg, 25%). Data: LCMS (B) R.sub.t: 9.780 min; m/z 397.0/399.0 (M+H).sup.+ (bromide pattern).

Example 47

2-(3-Bromo-4-fluoro-phenyl)-3-hydroxy-1-(4-methoxybenzoyl)imidazolidin-4-one

(127) This compound was prepared from Intermediate 8 and p-anisoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (32 mg, 65%). Data: LCMS (B) R.sub.t: 9.763 min; m/z 408.9/411.0 (M+H).sup.+ (bromide pattern).

Example 48

2-(3-Bromo-4-fluoro-phenyl)-1-(2,6-dichlorobenzoyl)-3-hydroxy-imidazolidin-4-one

(128) This compound was prepared from Intermediate 8 and 2,6-dichlorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (11 mg, 20%). Data: LCMS (B) R.sub.t: 10.547 min; m/z 446.9/448.9 (M+H).sup.+ (chloride/bromide pattern).

Example 49

2-(3-Chloro-4-fluoro-phenyl)-1-(2,6-dichlorobenzoyl)-3-hydroxy-imidazolidin-4-one

(129) This compound was prepared from Intermediate 9 and 2,6-dichlorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (9 mg, 19%). Data: LCMS (B) R.sub.t: 10.429 min; m/z 402.9/404.9 (M+H).sup.+ (chloride pattern).

Example 50

1-Benzoyl-2-(3-chloro-4-fluoro-phenyl)-3-hydroxy-imidazolidin-4-one

(130) This compound was prepared from Intermediate 9 and benzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (23 mg, 57%). Data: LCMS (B) R.sub.t: 9.457 min; m/z 335.1/337.1 (M+H).sup.+ (chloride pattern).

Example 51

2-(3-Chloro-4-fluoro-phenyl)-1-(2-fluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(131) This compound was prepared from Intermediate 9 and 2-fluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (20 mg, 47%). Data: LCMS (B) R.sub.t: 9.572 min; m/z 353.0/355.1 (M+H).sup.+ (chloride pattern).

Example 52

2-(3-Chloro-4-fluoro-phenyl)-1-(2,6-difluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(132) This compound was prepared from Intermediate 9 and 2,6-difluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (21.2 mg, 47%). Data: LCMS (B) R.sub.t: 9.604 min; m/z 371.0/372.0 (M+H).sup.+ (chloride pattern).

Example 53

1-(2-Chloro-6-fluoro-benzoyl)-2-(3-chloro-4-fluoro-phenyl)-3-hydroxy-imidazolidin-4-one

(133) This compound was prepared from Intermediate 9 and 2-chloro-6-fluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (18 mg, 47%). Data: LCMS (B) R.sub.t: 10.087 min; m/z 387.0/389.0 (M+H).sup.+ (chloride pattern).

Example 54

2-(3-Bromophenyl)-1-(2,4-difluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(a) 3-Benzyloxy-2-(3-bromophenyl)-1-(2,4-difluorobenzoyl)imidazolidin-4-one

(134) To a cold (4 C.) solution of 3-benzyloxy-2-(3-bromophenyl)imidazolidin-4-one (Intermediate A, 40 mg, 0.12 mmol) in dichloromethane (5 mL) and N,N-diisopropylethylamine (38.1 L, 0.23 mmol) was added dropwise a solution of 2,4-difluorobenzoyl chloride (14.2 L, 0.12 mmol) in dichloromethane (1 mL). The reaction mixture was stirred for 2 h allowing to come to room temperature. The reaction mixture was concentrated in vacuo and the crude residue was purified by column chromatography (heptane to ethyl acetate=9/1 to 1/1 v/v %) to afford the title compound: 49.2 mg (84.1% yield).

(b) 2-(3-Bromophenyl)-1-(2,4-difluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(135) A solution of 3-benzyloxy-2-(3-bromophenyl)-1-(2,4-difluorobenzoyl)imidazolidin-4-one (49.2 mg, 0.1 mmol) in ethyl acetate (10 mL) was hydrogenated using an H-Cube continuous-flow reactor, 20% Pd(OH).sub.2/C, at room temperature, 1 bar, full H.sub.2 modus, 1 mL/min. The pooled eluate was concentrated in vacuo and the crude product was purified using preparative HPLC to afford the title compound (18 mg, 45.3%). Data: LCMS (B) R.sub.t: 9.748 min; m/z 397.0/399.0 (M+H).sup.+ (bromide pattern)

Example 55

(5S)-2-(3-Bromophenyl)-1-(2-fluorobenzoyl)-3-hydroxy-5-methyl-imidazolidin-4-one (Stereoisomer 4)

(136) This compound was prepared from Intermediate B and 2-fluorobenzoyl chloride according to procedures described in Example 54. Purification was performed using preparative HPLC to afford the two separated diastereomers of title compound (7.53 mg, 16%) (Stereoisomer 4 is the last eluted isomer). Data: LCMS (B) R.sub.t: 10.035 min; m/z 393.0/395.0 (M+H).sup.+ (bromide pattern).

Example 56

(5R)-2-(3-Bromophenyl)-1-(2-chloro-6-fluoro-benzoyl)-3-hydroxy-5-methyl-imidazolidin-4-one (Stereoisomer 1)

(137) This compound was prepared from Intermediate C and 2-chloro-6-fluorobenzoyl chloride according to procedures described in Example 54. Purification was performed using preparative HPLC to afford the pure diastereomeric title compound (8.34 mg, 24%) (Stereoisomer 1 is the first eluted isomer). Data: LCMS (B) R.sub.t: 10.222 min; m/z 427.0/428.9 (M+H).sup.+ (chloride/bromide pattern).

Example 57

(5R)-2-(3-Bromophenyl)-1-(2-fluorobenzoyl)-3-hydroxy-5-methyl-imidazolidin-4-one (Stereoisomer 1)

(138) This compound was prepared from Intermediate C and 2-fluorobenzoyl chloride according to procedures described in Example 54. Purification was performed using preparative HPLC to afford the pure diastereomeric title compound (2.3 mg, 10%) (Stereoisomer 1 is the first eluted isomer). Data: LCMS (B) R.sub.t: 9.660 min; m/z 393.0/395.0 (M+H).sup.+ (bromide pattern).

Example 58

2-(3-Bromophenyl)-3-hydroxy-1-(pyrazine-2-carbonyl)imidazolidin-4-one

(a) 3-Benzyloxy-2-(3-bromophenyl)-1-(pyrazine-2-carbonyl)imidazolidin-4-one

(139) This compound was prepared from Intermediate A and 2-pyrazinecarbonyl chloride according to procedures described in Example 54a.

(b) 2-(3-Bromophenyl)-3-hydroxy-1-(pyrazine-2-carbonyl)imidazolidin-4-one

(140) To a cold (0 C.) solution of 3-benzyloxy-2-(3-bromophenyl)-1-(pyrazine-2-carbonyl) imidazolidin-4-one (30 mg, 0.066 mmol) in dichloromethane (2 mL) was added dropwise a solution of BBr.sub.3 (1M in DCM, 130 L). The reaction mixture was stirred for 1 h at 0 C. and then allowed to come to room temperature. Methanol (200 L) was added to the reaction mixture followed by 1 mL 5% NaHCO.sub.3, 1 mL water, 1 mL NaOH and 2 mL DCM. The water layer was extracted with DCM. The water layer was carefully acidified with 2 mL HCl to pH 5-6. The water layer was extracted with 2 times with dichloromethane/methanol 9/1 v/v % (2 mL). The organic fractions were filtered over a PE filter and concentrated. Purification was performed using preparative HPLC to afford the title compound (4.85 mg, 20%). Data: LCMS (B) R.sub.t: 6.847 m in; m/z 363.0/365.0 (M+H).sup.+ (bromide pattern).

Example 59

2-(3-Chlorophenyl)-1-(2,4-difluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(141) This compound was prepared from Intermediate D and 2,4-difluorobenzoyl chloride according to procedures described in Example 54a and Example 58b. Purification was performed using preparative HPLC to afford the title compound (13.9 mg, 59%). Data: LCMS (B) R.sub.t: 9.193 min; m/z 353.1/355.1 (M+H).sup.+ (chloride pattern).

Example 60

1-Benzoyl-2-(3-chlorophenyl)-3-hydroxy-imidazolidin-4-one

(142) This compound was prepared from Intermediate D and benzoyl chloride according to procedures described in Example 54a and Example 58b. Purification was performed using preparative HPLC to afford the title compound (11.1 mg, 53%). Data: LCMS (B) R.sub.t: 8.451 min; m/z 317.1/319.1 (M+H).sup.+ (chloride pattern).

Example 61

2-(3-Bromophenyl)-1-(2-chloropyridine-3-carbonyl)-3-hydroxy-imidazolidin-4-one

(143) This compound was prepared from Intermediate A and 2-chloropyridine-3-carbonyl chloride according to procedures described in Example 54a and Example 58b. Purification was performed using preparative HPLC to afford the title compound (3.3 mg, 12%). Data: LCMS (B) R.sub.t: 7.203 min; m/z 396.0/398.0 (M+H).sup.+ (bromide/chloride pattern).

Example 62

2-(3-Bromophenyl)-3-hydroxy-1-(2,3,4,5,6-pentafluorobenzoyl)imidazolidin-4-one

(144) This compound was prepared from Intermediate A and pentafluorobenzoyl chloride according to procedures described in Example 54a and Example 58b. Purification was performed using preparative HPLC to afford the title compound (3.3 mg, 9.7%). Data: LCMS (B) R.sub.t: 10.697 min; m/z 450.8/452.8 (M+H).sup.+ (bromide pattern). Separation of enantiomers of Example 17

Example 63

1-Benzoyl-2-(3-bromophenyl)-3-hydroxy-imidazolidin-4-one (Isomer 1 and Isomer 2)

(145) To a cold (0 C.) solution of 1-benzoyl-2-(3-bromophenyl)-3-hydroxy-imidazolidin-4-one (Example 17, 40 mg, 0.11 mmol) in dichloromethane (1.5 mL) was added subsequently N,N-diisopropylethylamine (37 L, 0.22 mmol) and a solution of (2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-propanoyl chloride (22 L, 0.12 mmol) in dichloromethane (1.5 mL). The reaction mixture was stirred for 30 min allowing the temperature to come to room temperature. The mixture was diluted with ethyl acetate and washed with water, brine, dried over sodium sulfate, filtered and the solvent was removed by evaporation at reduced pressure to give 69 mg of the crude product. The mixture of the two diastereomers was separated by column chromatography (hexane/diethyl ether=3/1 v/v % isocratic) to afford the two separate diastereomers (diastereomer 1, first eluting from the column, obtained in 20 mg and diastereomer 2, last eluting, in 39 mg). .sup.1H-NMR showed for diastereomer 1 an 80% de and for diastereomer 2 20% de.

(146) Both diastereomers were reacted separately with 5 eq. of morpholine in ethyl acetate at room temperature o/n. After reaction, ethyl acetate was added and the mixture was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. Enantiomeric enriched compounds were obtained after purification using preparative HPLC to afford Example 63a, 1-benzoyl-2-(3-bromophenyl)-3-hydroxy-imidazolidin-4-one (isomer 1, 2.8 mg, 22%) and Example 63b, 1-benzoyl-2-(3-bromophenyl)-3-hydroxy-imidazolidin-4-one (isomer 2, 9 mg, 36%). Data: Example 63a LCMS (B) R.sub.t: 9.021 min; m/z 361.0/363.0 (M+H).sup.+ (bromide pattern). Example 63b LCMS (B) R.sub.t: 9.024 min; m/z 361.0/363.0 (M+H).sup.+ (bromide pattern).

Separation of Enantiomers of Example 17

Example 64

1-Benzoyl-2-(3-bromophenyl)-3-hydroxy-imidazolidin-4-one (Isomer 1 and Isomer 2)

(147) These diastereomers were prepared in an analogous manner as described for Example 63a and 63b starting from Example 17 and (2S)-2-methoxy-2-phenyl-acetyl chloride. The mixture of the two diastereomers was separated by column chromatography (heptane/ethyl acetate=1/1 to 0/10 v/v %) to afford the two separate diastereomers (diastereomer 1, first eluting from the column, obtained in 74 mg and diastereomer 2, last eluting, in 75 mg). .sup.1H-NMR showed for diastereomer 1>50% de and for diastereomer 2<50% de.

(148) Diastereomer 1 were reacted with morpholine according to the procedure as described in Example 63. Enantiomeric enriched compound was obtained after purification using preparative HPLC to afford 1-benzoyl-2-(3-bromophenyl)-3-hydroxy-imidazolidin-4-one (Example 64, isomer 1, 35.5 mg, 66%). Data: LCMS (B) R.sub.t: 9.022 min; m/z 361.0/363.0 (M+H).sup.+ (bromide pattern).

Example 65

2-(2-Bromo-4-pyridyl)-1-(2,6-difluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(a) 3-Benzyloxy-2-(2-bromo-4-pyridyl)-1-(2,6-difluorobenzoyl)imidazolidin-4-one

(149) To a suspension of 2-amino-N-benzyloxy-acetamide 2,2,2-trifluoroacetic acid (Intermediate Ab, 59 mg, 0.2 mmol) and 2-bromopyridine-4-carboxaldehyde (37 mg, 0.2 mmol) in acetonitrile (1 mL) was added N,N-diisopropylethylamine (33.0 L, 0.2 mmol). The white suspension was heated for 2 h at 50 C. The mixture was cooled on an ice-water bath to <5 C. and N,N-diisopropylethylamine (33.0 L, 0.2 mmol) was added. Subsequently a solution of 2,6-difluorobenzoyl chloride (30 L, 0.24 mmol) in acetonitrile (0.1 mL) was added dropwise keeping the temperature below 5 C. The temperature of the reaction mixture was allowed to come to room temperature. The mixture was partially diluted with ethyl acetate (5 mL) and water (3 mL) was added slowly. The resulting phases were separated and the water layer was extracted with ethyl acetate (3 mL). The combined organic layers were washed with water (5 mL), 5% NaHCO.sub.3-solution (5 mL), water (5 mL) and brine (5 mL), filtered over an PE filter filled with Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude residue was purified by column chromatography (heptane to ethyl acetate=100/0 to 0/100 v/v %) to afford the title compound (63 mg, 64%) as a white solid.

(b) 2-(2-Bromo-4-pyridyl)-1-(2,6-difluorobenzoyl)-3-hydroxy-imidazolidin-4-one (Example 65)

(150) This compound was prepared in an analogous manner as described for Example 58b starting from 3-benzyloxy-2-(2-bromo-4-pyridyl)-1-(2,6-difluorobenzoyl)imidazolidin-4-one. Purification was performed using preparative HPLC to afford the title compound (5.0 mg, 10%). Data: LCMS (B) R.sub.t: 7.553 min; m/z 397.9/400.0 (M+H).sup.+ (bromide pattern).

Example 66

2-(3-Bromophenyl)-1-(2,6-difluoro-4-methoxy-benzoyl)-3-hydroxy-imidazolidin-4-one

(151) This compound was prepared from Intermediate A and 2,6-difluoro-4-methoxy-benzoyl chloride according to procedure described in Example 54. Purification was performed using preparative HPLC to afford the title compound (3.0 mg, 5%). Data: LCMS (B) R.sub.t: 10.319 min; m/z 426.9/428.9 (M+H).sup.+ (bromide pattern).

Example 67

1-(2,6-Difluorobenzoyl)-3-hydroxy-2-(3-nitrophenyl)imidazolidin-4-one

(152) This compound was prepared in an analogous manner as described for Example 65 starting from Intermediate Ab, 3-nitrobenzaldehyde and 2,6-difluorobenzoyl chloride. Subsequent benzyl-deprotection was performed according to the procedure described in Example 58b. Purification was performed using preparative HPLC to afford the title compound (27.1 mg, 53%). Data: LCMS (B) R.sub.t: 8.492 min; m/z 362.0 (MH).sup..

Example 68

2-(6-Bromo-2-pyridyl)-1-(2,6-difluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(153) This compound was prepared in an analogous manner as described for Example 65 starting from Intermediate Ab, 6-bromo-2-pyridinecarboxaldehyde and 2,6-difluorobenzoyl chloride. Subsequent benzyl-deprotection was performed using boron trifluoride methyl sulfide complex according to the procedure described in Example 69b. Purification was performed using preparative HPLC to afford the title compound (49 mg, 72%). Data: LCMS (B) R.sub.t: 8.281 min; m/z 397.9/399.9 (M+H).sup.+ (bromide pattern).

Example 69

1-(2,6-Difluorobenzoyl)-3-hydroxy-2-(m-tolyl)imidazolidin-4-one

(a) 3-Benzyloxy-1-(2,6-difluorobenzoyl)-2-(m-tolyl)imidazolidin-4-one

(154) This compound was prepared in an analogous manner as described for Example 65 starting from Intermediate Ab, 3-tolylbenzaldehyde and 2,6-difluorobenzoyl chloride to give 42 mg of the title compound (yield 50%).

(b) 1-(2,6-Difluorobenzoyl)-3-hydroxy-2-(m-tolyl)imidazolidin-4-one (Example 69)

(155) To a cold (0 C.) solution of 3-benzyloxy-1-(2,6-difluorobenzoyl)-2-(m-tolyl)imidazolidin-4-one (42 mg, 0.10 mmol) in dichloromethane (4 mL) was added boron trifluoride methyl sulfide complex (23 L, 0.22 mmol) to give a yellow/white suspension, which slowly turned into a clear solution. The reaction mixture was stirred for 3 h allowing the temperature to reach room temperature. The mixture was quenched with methanol (0.5 mL) and stirred 30 minutes at room temperature. 5% NaHCO.sub.3-solution in water (2 mL) and dichloromethane were added. The layers were separated. The water layer was extracted with dichloromethane (3 mL). The combined organic layers were washed with water (5 mL) and filtered over a PE filter and concentrated in vacuo to give 35 mg of the crude title compound. Purification was performed using preparative HPLC to afford the title compound (18.3 mg, 55%). Data: LCMS (B) R.sub.t: 8.970 min; m/z 333.1 (M+H).sup.+.

Example 70

2-(3-Bromo-2-fluoro-phenyl)-1-(2,6-difluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(156) This compound was prepared in an analogous manner as described for Example 65 starting from Intermediate Ab, 3-bromo-2-fluorobenzaldehyde and 2,6-difluorobenzoyl chloride. Subsequent benzyl-deprotection was performed using boron trifluoride methyl sulfide complex according to the procedure described in Example 69b. Purification was performed using preparative HPLC to afford the title compound (54 mg, 81%). Data: LCMS (B) R.sub.t: 9.843 min; m/z 414.9/416.8 (M+H).sup.+ (bromide pattern).

Example 71

1-(2,6-Difluorobenzoyl)-3-hydroxy-2-(3-iodophenyl)imidazolidin-4-one

(157) This compound was prepared in an analogous manner as described for Example 65 starting from Intermediate Ab, 3-iodobenzaldehyde and 2,6-difluorobenzoyl chloride. Subsequent benzyl-deprotection was performed using boron trifluoride methyl sulfide complex according to the procedure described in Example 69b. Purification was performed using preparative HPLC to afford the title compound (44.5 mg, 77%). Data: LCMS (B) R.sub.t: 10.091 min; m/z 444.8 (M+H).sup.+, 488.9 (M+HCOOHH).sup..

Example 72

1-(2-chloro-6-fluoro-benzoyl)-3-hydroxy-2-(3-iodophenyl)imidazolidin-4-one

(158) This compound was prepared in an analogous manner as described for Example 65 starting from Intermediate Ab, 3-iodobenzaldehyde and 2-chloro-6-fluorobenzoyl chloride. Subsequent benzyl-deprotection was performed using boron trifluoride methyl sulfide complex according to the procedure described in Example 69b. Purification was performed using preparative HPLC to afford the title compound (46.6 mg, 79%). Data: LCMS (B) R.sub.t: 10.505 min; m/z 460.8 (M+H).sup.+ , 504.9 (M+HCOOHH).sup. (chloride pattern).

Example 73

1-(2-Fluorobenzoyl)-3-hydroxy-2-(3-iodophenyl)imidazolidin-4-one

(159) This compound was prepared in an analogous manner as described for Example 65 starting from Intermediate Ab, 3-iodobenzaldehyde and 2-fluorobenzoyl chloride. Subsequent benzyl-deprotection was performed using boron trifluoride methyl sulfide complex according to the procedure described in Example 69b. Purification was performed using preparative HPLC to afford the title compound (42.9 mg, 77%). Data: LCMS (B) R.sub.t: 9.941 min; m/z 426.9 (M+H).sup.+, 470.9 (M+HCOOHH).sup..

Example 74

1-(4-Benzylbenzoyl)-2-(3-bromophenyl)-3-hydroxy-imidazolidin-4-one

(160) This compound was prepared in an analogous manner as described for Example 65 starting from Intermediate Ab, 3-bromobenzaldehyde and 4-benzylbenzoyl chloride. Subsequent benzyl-deprotection was performed using boron trifluoride methyl sulfide complex according to the procedure described in Example 69b. Purification was performed using preparative HPLC to afford the title compound (45 mg, 55%). Data: LCMS (B) R.sub.t: 13.428 min; m/z 451.0/453.0 (M+H).sup.+ (bromide pattern).

Example 75

2-(3-Bromophenyl)-1-(2,6-difluoro-3-nitro-benzoyl)-3-hydroxy-imidazolidin-4-one

(a) 2,6-Difluoro-3-nitro-benzoyl chloride

(161) 2,6-Difluoro-3-nitro-benzoic acid (180 mg, 0.89 mmol) was dissolved in thionyl chloride (3 mL) and one drop of DMF was added. The reaction mixture was stirred at 75 C. for 1 h. After the mixture was cooled to room temperature, the solvent was evaporated under reduced pressure. Traces of thionyl chloride and hydrochloric acid were removed by co-evaporation with dichloromethane (2) to give the title compound in a quantitative yield.

(b) [2-(3-Bromophenyl)-3-(2,6-difluoro-3-nitro-benzoyl)-5-oxo-imidazolidin-1-yl] 2,6-difluoro-3-nitro-benzoate

(162) To a cold (0 C.) suspension of 2-(3-bromophenyl)-3-hydroxy-imidazolidin-4-one (Intermediate 7, 100 mg, 0.39 mmol) in acetonitrile (5 mL) was added subsequently DiPEA (257 L, 1.56 mmol) and a solution of 2,6-difluoro-3-nitro-benzoyl chloride (0.89 mmol) in acetonitrile (1 mL). After stirring for 5 min at 0 C., the ice-bath was removed and the mixture was stirred for 30 min allowing the temperature to reach room temperature. The mixture was diluted with ethyl acetate and washed with water. The organic layer was separated and washed with 1M HCl-solution in water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (heptane to ethyl acetate=100/0 to 1/1 v/v %) to afford the title compound (205 mg, 84%).

(163) To a solution of [2-(3-bromophenyl)-3-(2,6-difluoro-3-nitro-benzoyl)-5-oxo-imidazolidin-1-yl] 2,6-difluoro-3-nitro-benzoate (205 mg, 0.33 mmol) in ethyl acetate (9 mL) was added a solution of 1-methylpiperazine (55 L, 0.49 mmol) in ethyl acetate (1 mL). The reaction mixture was stirred at room temperature for 30 min. Ethyl acetate was added and the mixture was washed with 0.1M HCl-solution in water and brine. The organic layer was subsequently dried over sodium sulfate, filtered and concentrated by evaporation under reduced pressure to give 166 mg of crude 2-(3-bromophenyl)-1-(2,6-difluoro-3-nitro-benzoyl)-3-hydroxy-imidazolidin-4-one. Purification was performed on part of the product (18.5 mg) using preparative HPLC to afford the title compound (6 mg, 32.4%). Data: LCMS (B) R.sub.t: 10.194 min; m/z 485.9/487.9 (M+HCOOHH).sup. (bromide pattern).

Example 76

1-(3-Amino-2,6-difluoro-benzoyl)-2-(3-bromophenyl)-3-hydroxy-imidazolidin-4-one

(164) To a cold (0 C.) solution of 2-(3-bromophenyl)-1-(2,6-difluoro-3-nitro-benzoyl)-3-hydroxy-imidazolidin-4-one (Example 75, 40 mg, 0.09 mmol) and acetic acid (77 L, 1.35 mmol) in THF (5 mL) was added portion wise zinc (118 mg, 1.8 mmol). The mixture was stirred at room temperature for 1 h. and subsequently filtered over Decalite. The filtrate was concentrated in vacuo. Purification was performed using preparative HPLC to afford the title compound (2.3 mg, 6%). Data: LCMS (B) R.sub.t: 8.067 min; m/z 411.9/413.9 (M+H).sup.+ (bromide pattern).

Example 77

N-[3-[2-(3-bromophenyl)-3-hydroxy-4-oxo-imidazolidine-1-carbonyl]-2,4-difluoro-phenyl]acetamide

(a) 3-Benzyloxy-2-(3-bromophenyl)-1-(2,6-difluoro-3-nitro-benzoyl)imidazolidin-4-one

(165) This compound was prepared from Intermediate A and 2,6-difluoro-3-nitro-benzoyl chloride according to procedures described in Example 54a (1.02 g, 84%).

(b) 1-(3-Amino-2,6-difluoro-benzoyl)-3-benzyloxy-2-(3-bromophenyl)imidazolidin-4-one

(166) This compound was prepared from 3-benzyloxy-2-(3-bromophenyl)-1-(2,6-difluoro-3-nitro-benzoyl)imidazolidin-4-one using zinc/acetic acid according to procedures described in Example 76 to give 945 mg of the title compound (yield: 98%).

(167) To a solution of 1-(3-amino-2,6-difluoro-benzoyl)-3-benzyloxy-2-(3-bromophenyl)-imidazolidin-4-one (18 mg, 0.036 mmol) was added triethylamine (7.5 L, 0.054 mmol) and acetyl chloride (3.8 L, 0.054 mmol). The reaction mixture was stirred at room temperature o/n. To complete the reaction, additional triethylamine (7.5 L) and acetyl chloride (3.8 L) were added. Ethyl acetate was added and the mixture was washed with water, brine, dried over sodium sulfate, filtered and the solvent was removed by evaporation under reduced pressure to give 20 mg of crude N-[3-[3-benzyloxy-2-(3-bromophenyl)-4-oxo-imidazolidine-1-carbonyl]-2,4-difluoro-phenyl]acetamide which was used directly in the next step.

(d) N-[3-[2-(3-bromophenyl)-3-hydroxy-4-oxo-imidazolidine-1-carbonyl]-2,4-difluoro-phenyl]acetamide (Example 77)

(168) This compound was prepared according to the procedure described in Example 69b. Purification was performed using preparative HPLC to afford the title compound (4 mg, 24%). Data: LCMS (B) R.sub.t: 7.951 min; m/z 453.9/456.0 (M+H).sup.+ (bromide pattern).

Example 78

N-[3-[2-(3-bromophenyl)-3-hydroxy-4-oxo-imidazolidine-1-carbonyl]-2,4-difluoro-phenyl]methanesulfonamide

(169) This compound was prepared in an analogous manner as described for Example 77 starting from Example 77c and methanesulfonyl chloride. Subsequent benzyl-deprotection was performed using boron trifluoride methyl sulfide complex according to the procedure described in Example 69b. Purification was performed using preparative HPLC to afford the title compound (14.6 mg, 83%). Data: LCMS (B) R.sub.t: 10.058 min; m/z 487.9/489.9 (MH).sup. (bromide pattern).

Example 79

2-(5-Bromo-3-pyridyl)-1-(2,6-difluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(170) This compound was prepared in an analogous manner as described for Example 65 starting from Intermediate Ab, 5-bromonicotinaldehyde and 2,6-difluorobenzoyl chloride. Subsequent benzyl-deprotection was performed using boron trifluoride methyl sulfide complex according to the procedure described in Example 69b. Purification was performed using preparative HPLC to afford the title compound (5 mg, 10%). Data: LCMS (B) R.sub.t: 7.565 min; m/z 397.9/400.0 (M+H).sup.+ (bromide pattern).

Example 80

1-(2,6-Difluorobenzoyl)-3-hydroxy-2-(3-methoxyphenyl)imidazolidin-4-one

(171) This compound was prepared in an analogous manner as described for Example 65 starting from Intermediate Ab, 3-methoxybenzaldehyde and 2,6-difluorobenzoyl chloride. Subsequent benzyl-deprotection was performed using boron trifluoride methyl sulfide complex according to the procedure described in Example 69b. Purification was performed using preparative HPLC to afford the title compound (28.1 mg, 50%). Data: LCMS (B) R.sub.t: 8.123 min; m/z 393.1 (M+HCOOHH).sup..

Example 81

2-(5-Bromo-2-fluoro-phenyl)-1-(2,6-difluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(172) This compound was prepared in an analogous manner as described for Example 65 starting from Intermediate Ab, 5-bromo-2-fluorobenzaldehyde and 2,6-difluorobenzoyl chloride. Subsequent benzyl-deprotection was performed using boron trifluoride methyl sulfide complex according to the procedure described in Example 69b. Purification was performed using preparative HPLC to afford the title compound (41 mg, 70%). Data: LCMS (B) R.sub.t: 9.797 min; m/z 414.8/416.8 (M+H).sup.+ (bromide pattern).

Example 82

2-(3-Bromophenyl)-3-hydroxy-1-(2,4,6-trifluorobenzoyl)imidazolidin-4-one

(173) This compound was prepared from Intermediate 7 and 2,4,6-trifluorobenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (24.6 mg, 59%). Data: LCMS (B) R.sub.t: 10.381 min; m/z 458.9/461.0 (M+HCOOHH).sup. (bromide pattern).

Example 83

2-(3-Bromophenyl)-3-hydroxy-1-(thiophene-3-carbonyl)imidazolidin-4-one

(174) This compound was prepared from Intermediate 7 and thiophene-3-carbonyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (17 mg, 46%). Data: LCMS (B) R.sub.t: 8.971 min; m/z 367.0/368.9 (M+H).sup.+ (bromide pattern).

Example 84

2-(3-Bromophenyl)-1-(2-fluoro-2-methyl-propanoyl)-3-hydroxy-imidazolidin-4-one

(175) This compound was prepared in an analogous manner as described for Example 65 starting from Intermediate Ab, 3-bromobenzaldehyde and 2-fluoro-2-methyl-propanoyl chloride. Subsequent benzyl-deprotection was performed using boron trifluoride methyl sulfide complex according to the procedure described in Example 69b. Purification was performed using preparative HPLC to afford the title compound (31 mg, 45%). Data: LCMS (B) R.sub.t: 9.254 min; m/z 345.0/347.0 (M+.sup.H(bromide pattern).

Example 85

1-(4-Bromo-2,6-difluoro-benzoyl)-2-(3-bromophenyl)-3-hydroxy-imidazolidin-4-one

(176) This compound was prepared from Intermediate 7 and 4-bromo-2,6-difluoro-benzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (17 mg, 24%). Data: LCMS (B) R.sub.t: 11.665 min; m/z 518.8/520.8/522.8 (M+HCOOHH).sup. (dibromide pattern).

Example 86

2-(3-Bromophenyl)-1-(3-fluoropyridine-4-carbonyl)-3-hydroxy-imidazolidin-4-one

(177) This compound was prepared in an analogues manner as described for Example 65 starting from Intermediate Ab, 3-bromobenzaldehyde and 3-fluoropyridine-4-carbonyl chloride. Subsequent benzyl-deprotection was performed using boron trifluoride methyl sulfide complex according to the procedure described in Example 69b. Purification was performed using preparative HPLC to afford the title compound (8 mg, 12%). Data: LCMS (B) R.sub.t: 7.601 min; m/z 380.0/382.0 (M+H).sup.+ (bromide pattern).

Example 87

2-(3-Bromophenyl)-1-(2-fluoropyridine-3-carbonyl)-3-hydroxy-imidazolidin-4-one

(178) This compound was prepared in an analogous manner as described for Example 65 starting from Intermediate Ab, 3-bromobenzaldehyde and 2-fluoropyridine-3-carbonyl chloride. Subsequent benzyl-deprotection was performed using boron trifluoride methyl sulfide complex according to the procedure described in Example 69b. Purification was performed using preparative HPLC to afford the title compound (7 mg, 9%). Data: LCMS (B) R.sub.t: 7.837 min; m/z 423.9/425.9 (M+HCOOHH).sup. (bromide pattern).

Example 88

2-(3-Bromophenyl)-1-(2-fluoro-6-methyl-benzoyl)-3-hydroxy-imidazolidin-4-one

(179) This compound was prepared in an analogous manner as described for Example 65 starting from Intermediate Ab, 3-bromobenzaldehyde and 2-fluoro-6-methylbenzoyl chloride. Subsequent benzyl-deprotection was performed using boron trifluoride methyl sulfide complex according to the procedure described in Example 69b. Purification was performed using preparative HPLC to afford the title compound (25 mg, 31%). Data: LCMS (B) R.sub.t: 10.210 min; m/z 393.0/395.0 (M+H).sup.+ (bromide pattern).

Example 89

2-(3-Bromophenyl)-1-(3-fluoropyridine-2-carbonyl)-3-hydroxy-imidazolidin-4-one

(180) This compound was prepared in an analogous manner as described for Example 65 starting from Intermediate Ab, 3-bromobenzaldehyde and 3-fluoropyridine-2-carbonyl chloride. Subsequent benzyl-deprotection was performed using boron trifluoride methyl sulfide complex according to the procedure described in Example 69b. Purification was performed using preparative HPLC to afford the title compound (19 mg, 11%). Data: LCMS (B) R.sub.t: 17.875 min; m/z 379.9/381.9 (M+H).sup.+ (bromide pattern).

Example 90

2-(3-Bromophenyl)-3-hydroxy-1-(thiophene-2-carbonyl)imidazolidin-4-one

(181) This compound was prepared from Intermediate 7 and thiophene-2-carbonyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (23 mg, 42%). Data: LCMS (B) R.sub.t: 9.304 min; m/z 366.9/368.9 (M+H).sup.+ (bromide pattern).

Example 91

2-(3-Bromophenyl)-3-hydroxy-1-(4-phenoxybenzoyl)imidazolidin-4-one

(182) This compound was prepared from Intermediate 7 and 4-phenoxybenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (17 mg, 25%). Data: LCMS (B) R.sub.t: 13.014 min; m/z 453.0/454.9 (M+H).sup.+ (bromide pattern).

Example 92

2-(3-Bromophenyl)-1-(furan-2-carbonyl)-3-hydroxy-imidazolidin-4-one

(183) This compound was prepared from Intermediate 7 and furan-3-carbonyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (9 mg, 17%). Data: LCMS (B) R.sub.t: 8.300 min; m/z 350.9/352.9 (M+H).sup.+ (bromide pattern).

Example 93

2-(3-Bromophenyl)-3-hydroxy-1-(5-methylthiophene-2-carbonyl)imidazolidin-4-one

(184) This compound was prepared from Intermediate 7 and 5-methylthiophene-2-carbonyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (1 mg, 2%). Data: LCMS (B) R.sub.t: 10.425 min; m/z 381.9/383.0 (M+H).sup.+ (bromide pattern).

Example 94

2-(3-Bromophenyl)-1-(4-ethylthiophene-2-carbonyl)-3-hydroxy-imidazolidin-4-one

(185) This compound was prepared from Intermediate 7 and 4-ethylthiophene-2-carbonyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (3 mg, 5%). Data: LCMS (B) R.sub.t: 11.705 min; m/z 395.0/397.0 (M+H).sup.+ (bromide pattern).

Example 95

2-(3-Bromophenyl)-3-hydroxy-1-(4-phenylbenzoyl)imidazolidin-4-one

(186) This compound was prepared from Intermediate 7 and 4-phenylbenzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (31 mg, 47%). Data: LCMS (B) R.sub.t: 12.888 min; m/z 437.0/439.0 (M+H).sup.+ (bromide pattern).

Example 96

2-(3-Bromophenyl)-3-hydroxy-1-(5-isopropylisoxazole-3-carbonyl)imidazolidin-4-one

(187) This compound was prepared from Intermediate 7 and 5-isopropylisoxazole-3-carbonyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (17 mg, 29%). Data: LCMS (B) R.sub.t: 11.727 min; m/z 394.0/396.0 (M+H).sup.+ (bromide pattern).

Example 97

2-(3-Bromophenyl)-3-hydroxy-1-[4-(4-methylsulfonylphenyl)benzoyl]imidazolidin-4-one

(188) This compound was prepared from Intermediate 7 and 4-(4-methylsulfonylphenyl)benzoyl chloride according to the procedure described in Example 1. Purification was performed using preparative HPLC to afford the title compound (37 mg, 48%). Data: LCMS (B) R.sub.t: 10.045 min; m/z 559.0/561.0 (M+HCOOHH).sup. (bromide pattern).

Example 98

1-(2,6-Difluorobenzoyl)-2-(3-ethynylphenyl)-3-hydroxy-imidazolidin-4-one

(a) 3-Benzyloxy-2-(3-bromophenyl)-1-(2,6-difluorobenzoyl)imidazolidin-4-one

(189) To a suspension of 2-amino-N-benzyloxy-acetamide 2,2,2-trifluoroacetic acid (Intermediate Ab, 10 g, 34 mmol) in acetonitril (50 mL) was added subsequently DiPEA (5.62 mL, 34 mmol) and 3-bromobenzaldehyde (4 mL, 34.3 mmol). The reaction mixture was refluxed for 2 h. The mixture was cooled to room temperature and then placed on an ice-water bath. Additional DiPEA (6.2 mL, 37.4 mmol) was added and a solution of 2,6-difluorobenzoyl chloride (4.5 mL, 35.7 mmol) in acetonitril (5 mL) was added dropwise at 4 C. The reaction mixture was stirred for 15 min allowing to come to room temperature. Ethyl acetate (100 mL) was added to the precipitate formed and the mixture was stirred until a clear solution was obtained. The mixture was washed with water (2100 mL). The water layer was separated and extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with 0.2N HCl-solution in water (100 mL), water (100 mL), 0.2N NaOH-solution (100 mL) in water, water (50 mL) and brine (50 mL). The organic phase was dried over sodium sulfate, filtered and partially concentrated under reduced pressure until the first solids appears. Ethyl acetate (50 mL) was added, a slurry formed, and next heptane (100 mL) was added dropwise under thorough stirring. The resulting slurry was stirred at room temperature o/n. The suspension was filtered and the residue was washed with heptane/ethyl acetate=2/1 v/v % (100 mL) and further dried on the filter, collected and dried under high vacuum at 40 C. to give 13.7 g of 3-benzyloxy-2-(3-bromophenyl)-1-(2,6-difluorobenzoyl)-imidazolidin-4-one (yield: 82.7%).

(b) 3-Benzyloxy-1-(2,6-difluorobenzoyl)-2-[3-(2-trimethylsilylethynyl)phenyl]imidazolidin-4-one

(190) 3-Benzyloxy-2-(3-bromophenyl)-1-(2,6-difluorobenzoyl)imidazolidin-4-one (200 mg, 0.41 mmol) was dissolved in N,N-dimethylformamide (1.0 L). Under nitrogen atmosphere, trimethylsilylacetylene (289 L, 2.05 mmol), triethylamine (342 L, 6.0 mmol) and palladium(II) bis(triphenylphosphine) dichloride (14 mg, 0.05 mmol) were added. The resulting bright yellow suspension was stirred at 70 C. for 1 h. The reaction mixture was added to a stirred mixture of water/brine/ethyl acetate=1/1/1 v/v % (45 mL). The mixture was filtered over Decalite and the organic layer was separated, washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (heptane to ethyl acetate=100/0 to 1/1 v/v %) to afford 194 mg of the title compound (yield: 94%).

(191) This compound was prepared according to the procedure described in Example 69b starting from 3-benzyloxy-1-(2,6-difluorobenzoyl)-2-[3-(2-trimethylsilylethynyl)phenyl]imidazolidin-4-one. Purification was performed using preparative HPLC to afford the title compound (8 mg, 6%). Data: LCMS (B) R.sub.t: 8.964 min; m/z 343.0 (M+H).sup.+.

Example 99

2-(3-Cyclopropylphenyl)-1-(2,6-difluorobenzoyl)-3-hydroxy-imidazolidin-4-one

(a) 3-Benzyloxy-2-(3-cyclopropylphenyl)-1-(2,6-difluorobenzoyl)imidazolidin-4-one

(192) To a suspension of 3-benzyloxy-2-(3-bromophenyl)-1-(2,6-difluorobenzoyl)imidazolidin-4-one (100 mg, 0.21 mmol) in toluene/water=5/1 v/v % (2.4 mL) was added cyclopropylboronic acid methyliminodiacetic acid anhydride (113 mg, 0.57 mmol) and cesium carbonate (390 mg, 1.2 mmol). The suspension was purged with nitrogen for 3 min. Next, tricyclohexylphosphine (16.8 mg, 0.06 mmol) and palladium(II) acetate (6.7 mg, 0.03 mmol) were added and the reaction mixture was stirred at 100 C. for 3 h. The reaction mixture was added to a stirred mixture of water/brine/ethyl acetate=1/1/1 v/v % (30 mL). The mixture was filtered over Decalite and the organic layer was separated, washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (heptane to ethyl acetate=1/1 to 0/100 v/v %) to afford 62 mg of the title compound (yield: 62%).

(b) 2-(3-Cyclopropylphenyl)-1-(2,6-difluorobenzoyl)-3-hydroxy-imidazolidin-4-one (Example 99)

(193) This compound was prepared according to the procedure described in Example 69b starting from 3-benzyloxy-2-(3-cyclopropylphenyl)-1-(2,6-difluorobenzoyl)imidazolidin-4-one. Purification was performed using preparative HPLC to afford the title compound (34 mg, 73%). Data: LCMS (B) R.sub.t: 10.150 min; m/z 359.1 (M+H).sup.+.

Example 100

2-(3-Bromophenyl)-3-hydroxy-1-(1-methylsulfonylpiperidine-4-carbonyl)imidazolidin-4-one

(a) (tert-Butyl 4-chlorocarbonylpiperidine-1-carboxylate

(194) 1-tert-Butoxycarbonylpiperidine-4-carboxylic acid (750 mg, 3.27 mmol) was dissolved in dichloromethane (11 mL), 5 drops of DMF were added and the mixture was stirred at 4 C. under nitrogen atmosphere. Thionyl chloride (261 L, 3.59 mmol) was added and the reaction mixture was stirred for 45 min at 4 C. This mixture was used in the next step without work-up.

(b) tert-Butyl 4-[3-benzyloxy-2-(3-bromophenyl)-4-oxo-imidazolidine-1-carbonyl]piperidine-1-carboxylate

(195) This compound was prepared from Intermediate A and tert-butyl 4-chlorocarbonylpiperidine-1-carboxylate according to procedures described in Example 54a. The crude residue was purified by column chromatography (heptane to ethyl acetate=10/0 to 1/9 v/v %) to afford 1.11 g of the title compound (yield: 64%).

(196) To a cold (4 C.) solution of tert-butyl 4-[3-benzyloxy-2-(3-bromophenyl)-4-oxo-imidazolidine-1-carbonyl]piperidine-1-carboxylate (950 mg, 1.7 mmol) in dichloromethane (4 mL) was added TFA (1 mL) and the resulting mixture was stirred for 1.5 h allowing the temperature to come to room temperature. The pH was adjusted by careful addition of aq. sat. NaHCO.sub.3-solution until pH7. Water was added to the mixture followed by DCM/methanol=9/1 v/v %. The organic phase was filtered over a PE filter and concentrated to obtain 895 mg of the title compound as a white foam.

(d) 3-Benzyloxy-2-(3-bromophenyl)-1-(1-methylsulfonylpiperidine-4-carbonyl)imidazolidin-4-one

(197) To a cold (4 C.) solution of 3-benzyloxy-2-(3-bromophenyl)-1-(piperidine-4-carbonyl)-imidazolidin-4-one (100 mg, 0.22 mmol) in dichloromethane (1 mL) were added subsequently DiPEA (73.2 L, 0.42 mmol) and a solution of methanesulfonyl chloride (24.7 L, 0.33 mmol) in dichloromethane (0.2 mL). The reaction mixture was stirred for 15 min at 4 C. and subsequently 1 h at room temperature. The reaction was quenched by addition of 50% aq. NH.sub.4Cl-solution. The mixture was diluted with dichloromethane and the layers were separated. The organic layer was washed with aq. 0.1N HCl-solution, 5% NaHCO.sub.3-solution, brine, filtered over a PE filter and concentrated in vacuo to give 89 mg of the title compound (yield: 75%).

(e) 2-(3-Bromophenyl)-3-hydroxy-1-(1-methylsulfonylpiperidine-4-carbonyl)imidazolidin-4-one Example 100

(198) This compound was prepared according to the procedure described in Example 69b starting from 3-benzyloxy-2-(3-bromophenyl)-1-(1-methylsulfonylpiperidine-4-carbonyl)imidazolidin-4-one. Purification was performed using preparative HPLC to afford the title compound (7 mg, 9%). Data: LCMS (B) R.sub.t: 7.572 min; m/z 446.0/448.0 (M+H).sup.+ (bromide pattern).

Example 101

4-[2-(3-Bromophenyl)-3-hydroxy-4-oxo-imidazolidine-1-carbonyl]piperidine-1-sulfonamide

(199) This compound was prepared from Intermediate A and tert-butyl N-chlorosulfonyl-carbamate according to procedures described in Example 54a and Example 69b. Purification was performed using preparative HPLC to afford the title compound (25 mg, 21%). Data: LCMS (B) R.sub.t: 6.569 min; m/z 446.9/449.0 (M+H).sup.+ (bromide pattern).

Example 102

(Trans)-ethyl N-[[4-[2-(3-bromophenyl)-3-hydroxy-4-oxo-imidazolidine-1-carbonyl]cyclohexyl]-methyl]carbamate

(200) This compound was prepared from Intermediate A, trans-4-[(tert-butoxycarbonylamino)methyl]cyclohexanecarboxylic acid and ethyl chloroformate according to procedures described in Example 100. Purification was performed using preparative HPLC to afford the title compound (24 mg, 51%). Data: LCMS (B) R.sub.t: 9.672 min; m/z 468.0/470.0 (M+H).sup.+ (bromide pattern).

Example 103

2-(3-Bromophenyl)-3-hydroxy-1-(1H-indazole-6-carbonyl)imidazolidin-4-one

(201) This compound was prepared in an analogous manner as described for Example 65 starting from Intermediate Ab, 3-bromobenzaldehyde and 1-tetrahydropyran-2-ylindazole-6-carbonyl chloride. Subsequent benzyl- and tetrahydropyranyl-deprotection was performed using boron trifluoride methyl sulfide complex according to the procedure described in Example 69b. Purification was performed using preparative HPLC to afford the title compound (7 mg, 9%). Data: LCMS (B) R.sub.t: 7.875 min; m/z 401.0/403.0 (M+H).sup.+ (bromide pattern).

Example 104

(Trans)-2-(3-bromophenyl)-3-hydroxy-1-(4-phenylcyclohexanecarbonyl)imidazolidin-4-one

(202) This compound was prepared from Intermediate A and trans-4-phenylcyclohexanecarbonyl chloride according to procedures described in Example 54a and Example 69b. Purification was performed using preparative HPLC to afford the title compound (24 mg, 33%). Data: LCMS (B) R.sub.t: 13.604 min; m/z 443.0/445.0 (M+H).sup.+ (bromide pattern).

Example 105

2-(3-Bromophenyl)-1-(4-ethynyl-2,6-difluoro-benzoyl)-3-hydroxy-imidazolidin-4-one

(203) This compound was prepared from Intermediate A and 4-ethynyl-2,6-difluoro-benzoic acid (Intermediate 10) according to procedures described in Example 100. Purification was performed using preparative HPLC to afford the title compound (40 mg, 63%). Data: LCMS (B) R.sub.t: 9.672 min; m/z 468.0/470.0 (M+H).sup.+ (bromide pattern).

Example 106

2-(3-Bromophenyl)-1-[4-(2-cyclopropylethynyl)-2,6-difluoro-benzoyl]-3-hydroxy-imidazolidin-4-one

(204) This compound was prepared from Intermediate 7 and 4-(2-cyclopropylethynyl)-2,6-difluoro-benzoic acid (Intermediate 11) according to procedures described in Example 1 and Example 100a. Purification was performed using preparative HPLC to afford the title compound (47 mg, 50%). Data: LCMS (B) R.sub.t: 13.497 min; m/z 461.0/463.0 (M+H).sup.+ (bromide pattern).

Example 107

2-(3-Bromophenyl)-1-[2,6-difluoro-4-(3-methylbut-1-ynyl)benzoyl]-3-hydroxy-imidazolidin-4-one

(205) This compound was prepared from Intermediate 7 and 2,6-difluoro-4-(3-methylbut-1-ynyl)benzoic acid (Intermediate 12) according to procedures described in Example 1 and Example 100a. Purification was performed using preparative HPLC to afford the title compound (34 mg, 49%). Data: LCMS (B) R.sub.t: 14.494 min; m/z 463.0/465.0 (M+H).sup.+ (bromide pattern).

Example 108

2-(3-Bromophenyl)-1-[4-(2-cyclohexylethynyl)-2,6-difluoro-benzoyl]-3-hydroxy-imidazolidin-4-one

(206) This compound was prepared from Intermediate 7 and 4-(2-cyclohexylethynyl)-2,6-difluoro-benzoic acid (Intermediate 13) according to procedures described in Example 1 and Example 100a. Purification was performed using preparative HPLC to afford the title compound (25 mg, 33%). Data: LCMS (B) R.sub.t: 16.941 min; m/z 503.0/505.0 (M+H).sup.+ (bromide pattern).

Example 109

1-[4-(3-Aminoprop-1-ynyl)-2,6-difluoro-benzoyl]-2-(3-bromophenyl)-3-hydroxy-imidazolidin-4-one

(207) This compound was prepared from Intermediate 7 and 4-[3-(tert-butoxycarbonylamino)prop-1-ynyl]-2,6-difluoro-benzoic acid (Intermediate 14) according to procedures described in Example 1 and Example 100a. Purification was performed, after Boc-deprotection, using preparative HPLC to afford the title compound (7 mg, 19%). Data: LCMS (B) R.sub.t: 6.265 min; m/z 449.9/451.9 (M+H).sup.+ (bromide pattern).

Example 110

N-[3-[4-[2-(3-bromophenyl)-3-hydroxy-4-oxo-imidazolidine-1-carbonyl]-3,5-difluoro-phenyl]prop-2-ynyl]methanesulfonamide

(208) This compound was prepared from Intermediate 7 and 2,6-difluoro-4-[3-(methanesulfonamido)prop-1-ynyl]benzoic acid (Intermediate 15) according to procedures described in Example 1 and Example 100a. Purification was performed using preparative HPLC to afford the title compound (47 mg, 59%). Data: LCMS (B) R.sub.t: 9.554 min; m/z 527.9/529.9 (M+H).sup.+ (bromide pattern).

Example 111

2-(3-Bromophenyl)-1-[2,6-difluoro-4-[3-(sulfamoylamino)prop-1-ynyl]benzoyl]-3-hydroxy-4-oxo-imidazolidine

(209) This compound was prepared from Intermediate 7 and 4-[3-(tert-butoxycarbonylsulfamoylamino)prop-1-ynyl]-2,6-difluoro-benzoic acid (Intermediate 16) according to procedures described in Example 1 and Example 100a. Purification was performed, after Boc-deprotection, using preparative HPLC to afford the title compound (12 mg, 25%). Data: LCMS (B) R.sub.t: 8.710 min; m/z 572.9/574.9 (M+HCOOHH).sup. (bromide pattern).

Example 112

1-[4-(3-Amino-3-methyl-but-1-ynyl)-2,6-difluoro-benzoyl]-2-(3-bromophenyl)-3-hydroxy-imidazolidin-4-one

(210) This compound was prepared from Intermediate 7 and 4-[3-(tert-butoxycarbonylamino)-3-methyl-but-1-ynyl]-2,6-difluoro-benzoic acid (Intermediate 17) according to procedures described in Example 1 and Example 100a. Purification was performed, after Boc-deprotection, using preparative HPLC to afford the title compound (5 mg, 7%). Data: LCMS (B) R.sub.t: 7.235 min; m/z 522.0/524.0 (M+HCOOHH).sup. (bromide pattern).

Example 113

N-[3-[4-[2-(3-bromophenyl)-3-hydroxy-4-oxo-imidazolidine-1-carbonyl]-3,5-difluoro-phenyl]-1,1-dimethyl-prop-2-ynyl]acetamide

(211) To a cold (4 C.) solution of 1-[4-(3-amino-3-methyl-but-1-ynyl)-2,6-difluoro-benzoyl]-2-(3-bromophenyl)-3-hydroxy-imidazolidin-4-one (Example 112, 40 mg, 0.08 mmol) in DCM (2 mL) were added subsequently DiPEA (69.8 L, 0.40 mmol) and a solution of acetyl chloride (17.1 L, 0.24 mmol) in DCM (0.2 mL). The reaction mixture was stirred for 1 h at 4 C. 1-Methylpiperazine (88 L, 0.4 mmol) was added and the reaction mixture was stirred for 15 min at 4 C. DCM was added to the mixture and the pH was adjusted to pH<2 by addition of a 2N HCl-solution. The layers were separated and the organic layer was washed with 2N HCl-solution and brine, then filtered over a PE filter and concentrated in vacuo. Purification was performed using preparative HPLC to afford the title compound (11 mg, 26%). Data: LCMS (B) R.sub.t: 10.058 min; m/z 520.0/522.0 (M+H).sup.+ (bromide pattern).

Example 114

2-(3-Bromophenyl)-1-(4-cyclopropyl-2,6-difluoro-benzoyl)-3-hydroxy-imidazolidin-4-one

(212) This compound was prepared from Intermediate 7 and 4-cyclopropyl-2,6-difluoro-benzoic acid (Intermediate 18) according to procedures described in Example 1 and Example 100a. Purification was performed using preparative HPLC to afford the title compound (18 mg, 27%). Data: LCMS (B) R.sub.t: 12.013 min; m/z 437.0/439.0 (M+H).sup.+ (bromide pattern).

Example 115

2-(3-Bromophenyl)-1-(2,6-difluoro-4-vinyl-benzoyl)-3-hydroxy-imidazolidin-4-one

(213) This compound was prepared from Intermediate 7 and 2,6-difluoro-4-vinyl-benzoic acid (Intermediate 19) according to procedures described in Example 1 and Example 100a. Purification was performed using preparative HPLC to afford the title compound (22 mg, 35%). Data: LCMS (B) R.sub.t: 11.466 min; m/z 422.9/424.9 (M+H).sup.+ (bromide pattern).

Example 116

2-(3-Bromophenyl)-1-(2,6-difluoro-4-methyl-benzoyl)-3-hydroxy-imidazolidin-4-one

(214) This compound was prepared from Intermediate 7 and 2,6-difluoro-4-methyl-benzoic acid (Intermediate 20) according to procedures described in Example 1 and Example 100a. Purification was performed using preparative HPLC to afford the title compound (21 mg, 34%). Data: LCMS (B) R.sub.t: 10.826 min; m/z 410.9/412.9 (M+H).sup.+ (bromide pattern).

Example 117

2-(3-Bromophenyl)-1-(2,6-difluoro-4-phenyl-benzoyl)-3-hydroxy-imidazolidin-4-one

(215) This compound was prepared from Intermediate A and 2,6-difluoro-4-phenyl-benzoic acid (Intermediate 21) according to procedures described in Example 54 and Example 69b. Purification was performed using preparative HPLC to afford the title compound (63 mg, 67%). Data: LCMS (B) R.sub.t: 13.344 min; m/z 472.9/474.9 (M+H).sup.+ (bromide pattern).

Example 118

2-(3-Bromophenyl)-1-[2,6-difluoro-4-(4-pyridyl)benzoyl]-3-hydroxy-imidazolidin-4-one

(216) This compound was prepared from Intermediate 7 and 2,6-difluoro-4-(4-pyridyl)benzoic acid (Intermediate 22) according to procedures described in Example 1 and Example 100a. Purification was performed using preparative HPLC to afford the title compound (20 mg, 28%). Data: LCMS (B) R.sub.t: 7.015 min; m/z 474.0/476.0 (M+H).sup.+ (bromide pattern).

Example 119

2-(3-Bromophenyl)-1-[2,6-difluoro-4-(1-methylpyrazol-4-yl)benzoyl]-3-hydroxy-imidazolidin-4-one

(217) This compound was prepared from Intermediate 7 and 2,6-difluoro-4-(1-methylpyrazol-4-yl)benzoic acid (Intermediate 23) according to procedures described in Example 1 and Example 100a. Purification was performed using preparative HPLC to afford the title compound (1 mg, 1%). Data: LCMS (B) R.sub.t: 9.358 min; m/z 477.0/478.9 (M+H).sup.+ (bromide pattern).

Example 120

2-(3-Bromophenyl)-1-[2,6-difluoro-4-(2-thienyl)benzoyl]-3-hydroxy-imidazolidin-4-one

(218) This compound was prepared from Intermediate 7 and 2,6-difluoro-4-(2-thienyl)benzoic acid (Intermediate 24) according to procedures described in Example 1 and Example 100a. Purification was performed using preparative HPLC to afford the title compound (12 mg, 17%). Data: LCMS (B) R.sub.t: 12.863 min; m/z 478.9/480.9 (M+H).sup.+ (bromide pattern).

Example 121

2-(3-Bromophenyl)-1-[2,6-difluoro-4-(5-fluoro-2-thienyl)benzoyl]-3-hydroxy-imidazolidin-4-one

(219) This compound was prepared from Intermediate 7 and 2,6-difluoro-4-(5-fluoro-2-thienyl)benzoic acid (Intermediate 25) according to procedures described in Example 1 and Example 100a. Purification was performed using preparative HPLC to afford the title compound (10 mg, 13%). Data: LCMS (B) R.sub.t: 13.726 min; m/z 496.9/498.9 (M+H).sup.+ (bromide pattern).

Example 122

2-(3-Bromophenyl)-1-[2,6-difluoro-4-(1,3,5-trimethylpyrazol-4-yl)benzoyl]-3-hydroxy-imidazolidin-4-one

(220) This compound was prepared from Intermediate 7 and 2,6-difluoro-4-(1,3,5-trim ethylpyrazol-4-yl)benzoic acid (Intermediate 26) according to procedures described in Example 1 and Example 100a. Purification was performed using preparative HPLC to afford the title compound (4 mg, 5%). Data: LCMS (B) R.sub.t: 9.900 min; m/z 505.0/507.0 (M+H).sup.+ (bromide pattern).

Example 123

2-(3-Bromophenyl)-1-[2,6-difluoro-4-(3-pyridyl)benzoyl]-3-hydroxy-imidazolidin-4-one

(221) This compound was prepared from Intermediate 7 and 2,6-difluoro-4-(3-pyridyl)benzoic acid (Intermediate 27) according to procedures described in Example 1 and Example 100a. Purification was performed using preparative HPLC to afford the title compound (18 mg, 25%). Data: LCMS (B) R.sub.t: 8.169 min; m/z 474.0/476.0 (M+H).sup.+ (bromide pattern).

Example 124

1-[(2-Fluorophenyl)methyl]-3-hydroxy-2-(3-iodophenyl)imidazolidin-4-one

(a) 2-[(2-Fluorophenyl)methylamino]ethanehydroxamic Acid

(222) A solution of 2-fluorobenzaldehyde (351 L, 3.33 mmol) in methanol (7 mL) was added to a solution of 2-aminoethanehydroxamic acid (300 mg, 3.33 mmol) in water (1.33 mL) and a 2N NaOH-solution in water (1.66 mL, 3.33 mmol). The reaction mixture was stirred for 5 min at room temperature after which precipitation occurred. NaBH.sub.4 (126 mg, 3.33 mmol) was added and the reaction mixture was stirred for 30 min at room temperature. Methanol was removed by evaporation under reduced pressure and the resulting solution was diluted by addition of water. After addition of 2M HCl-solution till pH7, dichloromethane/methanol=9/1 v/v % was added to the solution. The organic layer was then separated over a PE filter and concentrated in vacuo. The crude residue was purified by column chromatography (dichloromethane to methanol=9/1 to 8/2 v/v %) to afford 128 mg of the title compound (yield: 19%).

(b) 1-[(2-Fluorophenyl)methyl]-3-hydroxy-2-(3-iodophenyl)imidazolidin-4-one (Example 124)

(223) To a solution 2-[(2-fluorophenyl)methylamino]ethanehydroxamic acid (25 mg, 0.126 mmol) in ethanol (2 mL) was added 3-iodobenzaldehyde (29 mg, 0.126 mmol) and the reaction mixture was stirred at reflux temperature for 1 h. The solvent was evaporated under reduced pressure. The crude residue was purified by column chromatography (heptane to ethyl acetate=10/0 to 2/8 v/v). Purification was performed using preparative HPLC to afford the title compound (25 mg, 48%). Data: LCMS (B) R.sub.t: 12.953 min; m/z 413.0 (M+H).sup.+.

Example 125

2-(3-Bromophenyl)-1-[(2-fluorophenyl)methyl]-3-hydroxy-imidazolidin-4-one

(224) This compound was prepared according to procedures described in Example 124 starting from 2-[(2-fluorophenyl)methylamino]ethanehydroxamic acid and 3-bromobenzaldehyde. Purification was performed using preparative HPLC to afford the title compound (53 mg, 54%). Data: LCMS (A) R.sub.t: 4.536 min; m/z 365.0/367.0 (M+H).sup.+ (bromide pattern).

Example 126

2-(3-Bromo-4-fluoro-phenyl)-1-[(2-fluorophenyl)methyl]-3-hydroxy-imidazolidin-4-one

(225) This compound was prepared according to procedures described in Example 124 starting from 2-[(2-fluorophenyl)methylamino]ethanehydroxamic acid and 3-bromo-4-fluorobenzaldehyde. Purification was performed using preparative HPLC to afford the title compound (11.5 mg, 24%). Data: LCMS (B) R.sub.t: 12.791 min; m/z 383.0/385.0 (M+H).sup.+ (bromide pattern).

Example 127

2-(3-Bromophenyl)-1-[(2,6-difluorophenyl)methyl]-3-hydroxy-imidazolidin-4-one

(226) This compound was prepared according to procedures described in Example 124 starting from 2-[(2,6-difluorophenyl)methylamino]ethanehydroxamic acid and 3-bromobenzaldehyde. Purification was performed using preparative HPLC to afford the title compound (29 mg, 45%). Data: LCMS (B) R.sub.t: 12.422 min; m/z 383.0/385.0 (M+H).sup.+ (bromide pattern).

Example 128

2-(3-Bromophenyl)-1-[2,6-difluoro-4-[3-methyl-3-(sulfamoylamino)but-1-ynyl]benzoyl]-3-hydroxy-4-oxo-imidazolidine

(227) This compound was prepared from Intermediate 7 and 4-[3-(tert-butoxycarbonylsulfamoylamino)-3-methyl-but-1-ynyl]-2,6-difluoro-benzoic acid (Intermediate 28) according to procedures described in Example 1 and Example 100a. Purification was performed, after Boc-deprotection, using preparative HPLC to afford the title compound (10 mg, 15%). Data: LCMS (B) R.sub.t: 9.972 min; m/z 555.0/557.0 (M+HCOOHH).sup. (bromide pattern).

Example 129

1-(2,6-Difluorobenzoyl)-3-hydroxy-2-(3-vinylphenyl)imidazolidin-4-one

(228) This compound was prepared from Intermediate 29 and 2,6-difluorobenzoyl chloride according to procedures described in Example 1. Purification was performed using preparative HPLC to afford the title compound (24 mg, 31.7%). Data: LCMS (B) R.sub.t: 9.526 min; m/z 345.1 (M+H).sup.+.

Example 130

N-[[4-[2-(3-bromophenyl)-3-hydroxy-4-oxo-imidazolidine-1-carbonyl]-3,5-difluoro-phenyl]methyl]methanesulfonamide

(229) This compound was prepared from Intermediate 7 and 2,6-difluoro-4-(methanesulfonamidomethyl)benzoic acid (Intermediate 30) according to procedures described in Example 1 and Example 100a. Purification was performed using preparative HPLC to afford the title compound (27 mg, 36%). Data: LCMS (B) R.sub.t: 8.247 min; m/z 503.9/505.9 (M+H).sup.+ (bromide pattern).

Example 131

2-(3-Bromophenyl)-1-[4-(2-cyclohexylethyl)-2,6-difluoro-benzoyl]-3-hydroxy-imidazolidin-4-one

(230) This compound was prepared from Intermediate 7 and 4-(2-cyclohexylethyl)-2,6-difluoro-benzoic acid (Intermediate 31) according to procedures described in Example 1 and Example 100a. Purification was performed using preparative HPLC to afford the title compound (34 mg, 45%). Data: LCMS (B) R.sub.t: 17.712 min; m/z 507.0/509.0 (M+H).sup.+ (bromide pattern).

Example 132

2-(3-Bromophenyl)-1-[2,6-difluoro-4-[3-(sulfamoylamino)propyl]benzoyl]-3-hydroxy-4-oxo-imidazolidine

(231) This compound was prepared from Intermediate 7 and 4-[3-(tert-butoxycarbonylsulfamoylamino)propyl]-2,6-difluoro-benzoic acid (Intermediate 32) according to procedures described in Example 1 and Example 100a. Purification was performed, after Boc-deprotection, using preparative HPLC to afford the title compound (5 mg, 19%). Data: LCMS (B) R.sub.t: 8.470 min; m/z 533.0/535.0 (M+H).sup.+ (bromide pattern).

Example 133

2-(3-Bromophenyl)-1-(2,6-difluoro-4-morpholino-benzoyl)-3-hydroxy-imidazolidin-4-one

(232) This compound was prepared from Intermediate 7 and 2,6-difluoro-4-morpholino-benzoic acid (Intermediate 33) according to procedures described in Example 1 and Example 100a. Purification was performed using preparative HPLC to afford the title compound (29 mg, 60%). Data: LCMS (B) R.sub.t: 9.848 min; m/z 482.0/484.0 (M+H).sup.+ (bromide pattern).

Example 134

1-[4-(Azetidin-1-yl)-2,6-difluoro-benzoyl]-2-(3-bromophenyl)-3-hydroxy-imidazolidin-4-one

(233) This compound was prepared from Intermediate 7 and 4-(azetidin-1-yl)-2,6-difluoro-benzoic acid (Intermediate 34) according to procedures described in Example 1 and Example 100a. Purification was performed using preparative HPLC to afford the title compound (3.8 mg, 2.9%). Data: LCMS (B) R.sub.t: 11.410 min; m/z 452.0/454.0 (M+H).sup.+ (bromide pattern).

Example 135

2-(3-Bromophenyl)-1-[2,6-difluoro-4-[2-hydroxyethyl(methyl)amino]benzoyl]-3-hydroxy-imidazolidin-4-one

(234) This compound was prepared from Intermediate A and 4-[2-benzyloxyethyl(methyl)amino]-2,6-difluoro-benzoic acid (Intermediate 35) according to procedures described in Example 100a, Example 54a and Example 58b. Purification was performed using preparative HPLC to afford the title compound (13 mg, 8%). Data: LCMS (B) R.sub.t: 8.599 min; m/z 470.0/472.0 (M+H).sup.+ (bromide pattern).

Example 136

2-(3-Bromophenyl)-1-[2,6-difluoro-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]benzoyl]-3-hydroxy-imidazolidin-4-one

(235) This compound was prepared from Intermediate A and 2,6-difluoro-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]benzoic acid (Intermediate 36) according to procedures described in Example 100a and Example 54a. Purification was performed, after benzyl-deprotection with hydrogenation using platinumoxide according to the procedure described in Example 54b, using preparative HPLC to afford the title compound (5.9 mg, 40%). Data: LCMS (B) R.sub.t: 9.794 min; m/z 496.0/498.0 (M+H).sup.+ (bromide pattern).

Example 137

4-[2-(3-Bromophenyl)-3-hydroxy-4-oxo-imidazolidine-1-carbonyl]-3,5-difluoro-N-(2-methoxyethyl)benzamide

(236) This compound was prepared from Intermediate 7 and 2,6-difluoro-4-(2-methoxyethylcarbamoyl)benzoic acid (Intermediate 37) according to procedures described in Example 1 and Example 100a. Purification was performed using preparative HPLC to afford the title compound (10 mg, 4.4%). Data: LCMS (B) R.sub.t: 8.205 min; m/z 498.0/500.0 (M+H).sup.+ (bromide pattern).

Example 138

6-Bromo-3-[2-(3-bromophenyl)-3-hydroxy-4-oxo-imidazolidine-1-carbonyl]-2,4-difluoro-N-(2-m ethoxyethyl)benzamide

(237) This compound was isolated during prep HPLC purification of Example 137 (26 mg, 10%). Data: LCMS (B) R.sub.t: 9.335 min; m/z 577.9 (M+H).sup.+ (dibromide pattern).

Example 139a and Example 139b

2-(3-Bromophenyl)-3-hydroxy-1-[(1S)-1-phenylethyl]imidazolidin-4-one (Isomer 1 and Isomer 2)

(238) This compound was prepared in an analogous manner as described for Intermediate 2, starting from Intermediate 38 and 3-bromobenzaldehyde to afford the title compound as a mixture of two diastereomers.

(239) The mixture of the two diastereomers was separated by preparative HPLC to afford the two separate diastereomers (diastereomer 1, first eluting from the column, less active isomer, and diastereomer 2, last eluting, most active isomer). LCMS showed for both diastereomers >95% de. Example 139a, isomer 1, 2.7 mg, 7.5%). Data: LCMS (B) R.sub.t: 12.866 min; m/z 361.0/363.0 (M+H).sup.+ (bromide pattern). Example 139b, isomer 2, 3 mg, 8.3%). Data: LCMS (B) R.sub.t: 13.375 min; m/z 361.0/363.0 (M+H).sup.+ (bromide pattern).

Example 140a and Example 140b

3-Hydroxy-2-(3-iodophenyl)-1-[(1S)-1-phenylethyl]imidazolidin-4-one (Isomer 1 and Isomer 2)

(240) This compound was prepared in an analogous manner as described for Intermediate 2, starting from Intermediate 38 and 3-iodobenzaldehyde to afford the title compound as a mixture of two diastereomers.

(241) The mixture of the two diastereomers was separated by preparative HPLC to afford the two separate diastereomers (diastereomer 1, first eluting from the column, less active isomer, and diastereomer 2, last eluting, most active isomer). LCMS showed for both diastereomers >95% de. Example 140a, isomer 1, 12.2 mg, 6%). Data: LCMS (B) R.sub.t: 13.273 min; m/z 409.0 (M+H).sup.+. Example 140b, isomer 2, 48 mg, 23%). Data: LCMS (B) R.sub.t: 13.782 min; m/z 409.0 (M+H).sup.+.

Example 141a and Example 141b

2-(3-Bromophenyl)-1-[1-(2,6-difluorophenyl)ethyl]-3-hydroxy-imidazolidin-4-one (Diastereomeric Pair 1 and Diastereomeric Pair 2)

(242) This compound was prepared in an analogous manner as described for Intermediate 2, starting from Intermediate 39 and 3-bromobenzaldehyde to afford the title compound as a mixture of four diastereomers.

(243) The mixture of the four diastereomers was separated by preparative HPLC to afford the two separate diastereomers as pairs of enantiomers (enantiomeric pair 1, first eluting from the column, less active isomer, and enantiomeric pair 2, last eluting, most active isomer). Example 141a, diastereomeric pair 1, 4.6 mg, 3%). Data: LCMS (B) R.sub.t: 12.618 min; m/z 397.0/399.0 (M+H).sup.+ (bromide pattern). Example 142b, diastereomeric pair 2, 14 mg, 11%). Data: LCMS (B) R.sub.t: 13.610 min; m/z 397.0/399.0 (M+H).sup.+ (bromide pattern).

Separation of Enantiomers of Example 27

Example 142a and Example 142b

2-(3-Bromophenyl)-1-(2,6-difluorobenzoyl)-3-hydroxy-imidazolidin-4-one (Isomer 1 and Isomer 2)

(244) These diastereomers were prepared in an analogous manner as described for Example 63a and 63b starting from Example 17 and (2S)-2-methoxy-2-phenyl-acetyl chloride.

(245) The mixture of the two diastereomers was separated by column chromatography (toluene/diethyl ether=4/1 v/v % isocratic) to afford the two separate diastereomers (diastereomer 1, first eluting from the column obtained in 87 mg and diastereomer 2, last eluting in 23 mg). .sup.1H-NMR showed for diastereomer 1>90% de and for diastereomer 2>80% de.

(246) Both diastereomers were reacted separately with morpholine according to the procedure as described in Example 63. Enantiomeric enriched compounds were obtained after purification using preparative HPLC to afford Example 142a, 2-(3-bromophenyl)-1-(2,6-difluorobenzoyl)-3-hydroxy-imidazolidin-4-one (isomer 1, less active isomer, 44 mg, 69%) and Example 142b, 2-(3-bromophenyl)-1-(2,6-difluorobenzoyl)-3-hydroxy-imidazolidin-4-one (isomer 2, most active isomer, 14 mg, 84%). Data: Example 142a LCMS (B) R.sub.t: 8.899 min; m/z 397.0/399.0 (M+H).sup.+ (bromide pattern). Example 142b LCMS (B) R.sub.t: 8.963 min; m/z 397.0/399.0 (M+H).sup.+ (bromide pattern).

Separation of Enantiomers of Example 45

Example 143a and Example 143b

2-(3-Bromo-4-fluoro-phenyl)-1-(2-chloro-6-fluoro-benzoyl)-3-hydroxy-imidazolidin-4-one (Isomer 1 and Isomer 2)

(247) These diastereomers were prepared in an analogous manner as described for Example 63a and 63b starting from Example 45 and (2S)-2-phenylbutanoic acid.

(248) The mixture of the two diastereomers was separated by column chromatography (toluene/ethyl acetate=97/3 v/v % isocratic) to afford the two separate diastereomers (diastereomer 1, first eluting from the column obtained in 12 mg (yield: 43%) and diastereomer 2, last eluting in 10 mg (yield: 36%)). .sup.1H-NMR showed for diastereomer 1>80% de and for diastereomer 2>80% de.

(249) Both diastereomers were reacted separately with 1-methylpiperazine according to the procedure as described in Example 63. Enantiomeric enriched compounds were obtained after purification using preparative HPLC to afford Example 143a, 2-(3-bromo-4-fluoro-phenyl)-1-(2-chloro-6-fluoro-benzoyl)-3-hydroxy-imidazolidin-4-one (isomer 1, less active isomer, 8.3 mg, 69%) and Example 143b, 2-(3-bromo-4-fluoro-phenyl)-1-(2-chloro-6-fluoro-benzoyl)-3-hydroxy-imidazolidin-4-one (isomer 2, most active isomer, 6 mg, 77%). Data: Example 142a LCMS (B) R.sub.t: 10.451 min; m/z 474.9/476.9 (M+HCOOHH).sup. (bromide/chloride pattern). Example 142b LCMS (B) R.sub.t: 10.456 min; m/z 474.9/476.9 (M+HCOOHH).sup. (bromide/chloride pattern).

Separation of Enantiomers of Example 106

Example 144a and Example 144b

2-(3-Bromophenyl)-1-[4-(2-cyclopropylethynyl)-2,6-difluoro-benzoyl]-3-hydroxy-imidazolidin-4-one (Isomer 1 and Isomer 2)

(250) These diastereomers were prepared in an analogous manner as described for Example 63a and 63b starting from Example 106 and (2S)-2-phenylbutanoic acid.

(251) The mixture of the two diastereomers was separated by column chromatography (toluene/ethyl acetate=97/3 v/v % isocratic) to afford the two separate diastereomers (diastereomer 1, first eluting from the column obtained in 12 mg (yield: 22%) and diastereomer 2, last eluting in 8 mg (yield: 15%)). .sup.1H-NMR showed for diastereomer 1>80% de and for diastereomer 2>80% de.

(252) Both diastereomers were reacted separately with 1-methylpiperazine according to the procedure as described in Example 63. Enantiomeric enriched compounds were obtained after purification using preparative HPLC to afford Example 144a, 2-(3-bromophenyl)-1-[4-(2-cyclopropylethynyl)-2,6-difluoro-benzoyl]-3-hydroxy-imidazolidin-4-one (isomer 1, less active isomer, 8.3 mg, 69%) and Example 144b, 2-(3-bromophenyl)-1-[4-(2-cyclopropylethynyl)-2,6-difluoro-benzoyl]-3-hydroxy-imidazolidin-4-one (isomer 2, most active isomer, 4.9 mg, 66%). Data: Example 144a LCMS (B) R.sub.t: 13.425 min; m/z 461.0/463.0 (M+H).sup.+ (bromide pattern). Example 144b LCMS (B) R.sub.t: 13.413 min; m/z 461.0/463.0 (M+H).sup.+ (bromide pattern).

Separation of Enantiomers of Example 127

Example 145a and Example 145b

2-(3-Bromophenyl)-1-[(2,6-difluorophenyl)methyl]-3-hydroxy-imidazolidin-4-one (Isomer 1 and Isomer 2)

(253) These diastereomers were prepared in an analogous manner as described for Example 63a and 63b starting from Example 127 and (2S)-2-phenylbutanoic acid.

(254) The mixture of the two diastereomers was separated by column chromatography (toluene/ethyl acetate=97/3 v/v % isocratic) to afford the two separate diastereomers (diastereomer 1, first eluting from the column obtained in 7 mg (yield: 22%) and diastereomer 2, last eluting in 7 mg (yield: 22%)). .sup.1H-NMR showed for diastereomer 1>80% de and for diastereomer 2>80% de.

(255) Both diastereomers were reacted separately with 1-methylpiperazine according to the procedure as described in Example 63. Enantiomeric enriched compounds were obtained after purification using preparative HPLC to afford Example 145a, 2-(3-bromophenyl)-1-[(2,6-difluorophenyl)methyl]-3-hydroxy-imidazolidin-4-one (isomer 1, less active isomer, 4.3 mg, 86%) and Example 145b, 2-(3-bromophenyl)-1-[(2,6-difluorophenyl)methyl]-3-hydroxy-imidazolidin-4-one (isomer 2, most active isomer, 3.7 mg, 74%). Data: Example 145a LCMS (B) R.sub.t: 12.382 min; m/z 383.0/385.0 (M+H).sup.+ (bromide pattern). Example 145b LCMS (B) R.sub.t: 12.374 min; m/z 383.0/385.0 (M+H).sup.+ (bromide pattern).

Separation of Enantiomers of Example 124

Example 146a and Example 146b

1-[(2-fluorophenyl)methyl]-3-hydroxy-2-(3-iodophenyl)imidazolidin-4-one (Isomer 1 and Isomer 2)

(256) These diastereomers were prepared in an analogous manner as described for Example 63a and 63b starting from Example 124 and (2S)-2-phenylbutanoic acid.

(257) The mixture of the two diastereomers was separated by column chromatography (toluene/ethyl acetate=97/3 v/v % isocratic) to afford the two separate diastereomers (diastereomer 1, first eluting from the column obtained in 26 mg (yield: 19%) and diastereomer 2, last eluting in 27 mg (yield: 20%)). .sup.1H-NMR showed for diastereomer 1>80% de and for diastereomer 2>80% de.

(258) Both diastereomers were reacted separately with 1-methylpiperazine according to the procedure as described in Example 63. Enantiomeric enriched compounds were obtained after purification using preparative HPLC to afford Example 146a, 1-[(2-fluorophenyl)methyl]-3-hydroxy-2-(3-iodophenyl)imidazolidin-4-one (isomer 1, less active isomer, 32.5 mg, 69%) and Example 146b, 1-[(2-fluorophenyl)methyl]-3-hydroxy-2-(3-iodophenyl)imidazolidin-4-one (isomer 2, most active isomer, 19 mg, 56%). Data: Example 146a LCMS (B) R.sub.t: 12.921 min; m/z 413.0 (M+H).sup.+. Example 146b LCMS (B) R.sub.t: 12.920 min; m/z 413.0 (M+H).sup.+ (bromide pattern).

Separation of Enantiomers of Example 111

Example 147a and Example 147b

2-(3-Bromophenyl)-1-[2,6-difluoro-4-[3-(sulfamoylamino)prop-1-ynyl]benzoyl]-3-hydroxy-4-oxo-imidazolidine (Isomer 1 and Isomer 2)

(259) These diastereomers were prepared in an analogous manner as described for Example 63a and 63b starting from Example 111 and (2S)-2-phenylbutanoic acid.

(260) The mixture of the two diastereomers was separated by column chromatography (toluene/ethyl acetate=85/15 v/v % isocratic) to afford the two separate diastereomers (diastereomer 1, first eluting from the column obtained in 41.4 mg (yield: 30%) and diastereomer 2, last eluting in 32 mg (yield: 23.2%)). .sup.1H-NMR showed for diastereomer 1>80% de and for diastereomer 2>80% de.

(261) Diastereomer 2 was reacted with 1-methylpiperazine according to the procedure as described in Example 63. Enantiomeric enriched compound was obtained, after Boc-deprotection and after purification using preparative HPLC to afford Example 147b, 2-(3-bromophenyl)-1-[2,6-difluoro-4-[3-(sulfamoylamino)prop-1-ynyl]benzoyl]-3-hydroxy-4-oxo-imidazolidine (isomer 2, most active isomer, 15.3 mg, 60%). Data: Example 147b LCMS (A) R.sub.t: 4.691 min; m/z 572.9/574.9 (M+HCOOHH).sup. (bromide pattern).

Example 148

Biochemical IDO1 Assay

(262) To determine the inhibitory activity of compounds on IDO1, the NFK GreenScreen assay was used, which makes use of a chemical probe to detect NFK (Seegers, N., et al., J. Biol. Screen. 19: 1266; 2014). Compounds were serially diluted in dimethylsulfoxide (DMSO) and finally in IDO1 reaction buffer, consisting of 50 mM NaH.sub.2PO.sub.4, pH7.0, supplemented with 0.05% Tween-20 (cat. No. P7949; Sigma Aldrich) and 1% glycerol. Recombinant full-length IDO1 (Seegers, N., et al.) and all other assay components were diluted in IDO1 reaction buffer. 10 l of compound solution, 20 l of enzyme solution supplemented with 20 mM ascorbic acid, 20 g/ml catalase, and 20 M methylene blue were combined in the well of a black 384-well plate (cat. no. 3573; Corning, Corning, N.Y., USA) and incubated for 30 min at room temperature. Subsequently, 10 l of 0.4 mM of the substrate L-tryptophan was added, i.e., the final concentration of L-tryptophan was 100 M. The DMSO concentration in the assay was 0.3%. The concentration of IDO1 was 25 nM. Incubation was continued for 60 min at room temperature. Then, 10 l of NFK Green (NTRC, Oss, The Netherlands) was added, the plate was sealed, and the reaction was developed for 3 hours at 37 C. To determine the production of N-formyl kynurenine (NFK), the seal was removed and fluorescence was read on an EnVision multimode reader (Perkin Elmer, Waltham, Mass., USA). IC.sub.50 were calculated using XLfit software (ID Business Solutions, Ltd., Surrey, U.K.). The IC.sub.50 of 1-MT in this assay is >100 M. The IC.sub.50 values of all exemplified compounds were found to be smaller than 25 M. Compounds of examples 1, 2, 7, 8, 10, 14, 16, 17, 18, 20, 23, 24, 25, 28, 29, 30, 31, 38, 39, 40, 43, 47, 48, 50, 57, 60, 61, 63b, 64, 65, 69, 70, 74, 78, 88, 89, 90, 91, 96, 97, 99, 100, 101, 102, 103, 112, 113, 121, 123, 131, 134, 135, 140a, 142a and 143a showed an IC.sub.50 value >1 M and <5 M and compounds of examples 3, 4, 9, 13, 15, 26, 27, 32, 33, 34, 35, 36, 37, 44, 45, 46, 51, 52, 53, 54, 59, 62, 63a, 66, 67, 71, 72, 73, 75, 76, 77, 82, 85, 86, 87, 98, 105, 106, 107, 108, 109, 110, 111, 114, 115, 116, 117, 118, 119, 120, 124, 125, 126, 127, 128, 129, 130, 132, 137, 138, 139b, 140b, 141b, 142b, 143b, 144a, 144b, 145a, 145b, 146a, 146b and 147b showed an IC.sub.50 of <1 M.

Example 149

Cell-Based Assay for IDO1

(263) A-375 melanoma cells were purchased from LGC Standards GmbH (Wesel, Germany) and cultured in DMEM tissue culture medium (Life Technologies, Bleiswijk, The Netherlands), supplemented with 10% (v/v) bovine calf serum. Compounds were dissolved in DMSO and diluted in DMEM. Final DMSO concentration in the assay was 0.4% (v/v). Eight thousand cells per well in 35 l were seeded in a black 384-well tissue plate (cat. No. 781086; Greiner Bio-One GmbH, Frickenhausen, Germany) and allowed to adhere by incubation at 37 C., 95% humidity, and 5% CO.sub.2 overnight. Then, 5 l of compound solution was added to the cells 1 hour prior to stimulation with 5 l of 500 ng/ml interferon- (R&D Systems, Minneapolis, Minn., USA) diluted in DMEM medium. At the same time, 5 l of L-tryptophan in 20 mM Hepes buffer pH 7.4 was added. Incubation was continued for 48 hours. To determine NFK levels, 12 l NFK Green (NTRC, Oss, The Netherlands) was added to each well, and the plate was sealed and incubated for 4 hours at 37 C. Fluorescence was measured on an EnVision multimode reader (Perkin Elmer, Waltham, Mass., USA). IC.sub.50 were calculated using XLfit software (ID Business Solutions, Ltd., Surrey, U.K.). Compounds of examples 2, 3, 4, 7, 9, 10, 13, 15, 17, 25, 26, 27, 32, 33, 34, 35, 39, 43, 44, 45, 46, 51, 52, 53, 54, 59, 62, 66, 67, 71, 72, 73, 76, 82, 85, 86, 87, 98, 99, 105, 106, 107, 108, 114, 115, 116, 118, 119, 120, 124, 125, 127, 129, 137, 138, 139b, 140a, 140b, 141b, 142a and 142b showed an IC.sub.50 value of <5 M

Example 150

Biochemical Assay for TDO

(264) The NFK GreenScreen assay was also used to determine the inhibitory activity of compounds on TDO (Seegers, N., et al., J. Biol. Screen. 19: 1266; 2014). Compounds were serially diluted in DMSO and finally in TDO reaction buffer, consisting of 100 mM NaH.sub.2PO.sub.4, pH 7.0, supplemented with 0.01% Tween-20 (cat. No. P7949; Sigma Aldrich). Recombinant TDO (Seegers, N., et al.) and all other assay components were diluted in TDO reaction buffer. 10 l of compound solution and 20 l of enzyme solution supplemented with 200 M ascorbic acid were combined in the well of a black 384-well plate (cat. no. 3573; Corning, Corning, N.Y., USA), and incubated for 60 min at room temperature. Subsequently, 10 l of 0.8 mM of the substrate L-tryptophan was added, i.e., the final concentration of L-tryptophan was 200 M. The DMSO concentration in the assay was 0.3%. The concentration of IDO1 was 50 nM. Incubation was continued for 15 min at room temperature. Then, 10 l of NFK Green (NTRC, Oss, The Netherlands) was added and the reaction was developed as described in Example 58 for the IDO1 assay. Fluorescence was read and IC.sub.50 were calculated also as described above for IDO1. The IC.sub.50 values of all exemplified compounds were found to be higher than 25 M.

Example 151

Cytochrome P450 Assays

(265) To determine the inhibitory potency of compounds on CYP3A4 enzyme, the P450-Glo CYP3A4 luciferin isopropylacetal (Luc-IP) assay was used (Promega, Madison, Wis., USA, Cat. No. V9920). The assay makes use of a luminogenic isopropylacetal (IPA) substrate that is a derivative from beetle luciferin, a substrate of luciferase enzymes. The IPA substrate is converted by CYP3A4 to luciferin, which in turn reacts with luciferase to produce an amount of light that is directly proportional to the activity of CYP3A4. Compounds were serially diluted in DMSO and finally in 400 mM K.sub.2HPO.sub.4, pH 7.4. 5 l of compound solution and 5 l of CYP3A4/substrate solution were combined in the well of a white 384-well Optiplate (Perkin Elmer). The DMSO concentration in the assay was 0.1%. After incubation for 10 minutes at room temperature in the dark, 10 l of NADPH regeneration system was added and incubation was continued for 10 min. Then, 20 l of Luciferin Detection Reagent was added to stop the reaction, and incubation was continued for another 20 min. Luminescence was measured on an Envision multimode reader and IC.sub.50 values were calculated using XLfit. Concentrations of enzyme, substrate and other reagents were set according to the instructions of the manufacturer (Promega document TB325, revision 3/15). Instead of in a 96-well plate, the assay was performed in 384-well white Perkin Elmer Optiplate (cat. no. 6007290).

(266) A similar assay was used to determine the inhibitory potency of compounds on CYP2D6. The P450-Glo CYP2D6 Luc-IP assay (Promega; Cat. No. V9890) makes use of a luminogenic substrate (ME EGE) that is converted to luciferin by CYP2D6. This assay was performed according to the instruction of the manufacturer (Promega document TB325, revision 3/15), with the difference that it was performed in a 384-well white Perkin Elmer Optiplates (cat. no. 6007290), instead of a 96-well plate. All volumes mentioned in the manufacturer's instruction were divided by a factor 2.5. The DMSO concentration during the incubation phase of the assay was 0.1%. The IC.sub.50 values of all exemplified compounds were found to be higher than 10 M in both assays.

Inhibitors of indoleamine 2,3-dioxygenase

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Abstract

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