DIHYDROQUINOLINONES FOR MEDICAL TREATMENT

Abstract

The present invention provides dihydroquinolinone compounds which bind to the ubiquitously expressed E3 ligase protein cereblon (CRBN) and alter the substrate specificity of the CRBN E3 ubiquitin ligase complex, resulting in breakdown of intrinsic downstream proteins. The disclosed compounds are useful for the treatment of cancer.

Claims

1. A method for the treatment of cancer comprising administering an effective amount of a compound of formula: ##STR00081## or a pharmaceutically acceptable salt thereof to a patient in need thereof; wherein X.sup.1 is CH or N; X.sup.2 is CH or N; X.sup.3 is CH or N, and if one of X.sup.1, X.sup.2 or X.sup.3 is N, then the other two are CH; R.sup.1 is selected from the group consisting of i) —C(═O)—R.sup.6; ii) heterocyclyl; iii) heterocyclyl, substituted by 1 or 2 substituents individually selected from R.sup.10; iv) aryl; and v) aryl, substituted by 1 or 2 substituents individually selected from R.sup.9; R.sup.2 is H, or R.sup.1 and R.sup.2 together with the nitrogen they are attached to form a heteroaryl, which is optionally substituted by 1 or 2 substituents individually selected from R.sup.3; R.sup.3 is selected from the group consisting of: i) —(CH.sub.2).sub.0-1-aryl substituted by 1 or 2 substituents selected from R.sup.4; ii) —(CH.sub.2).sub.0-2—N(R.sup.3c)C(═O)—C.sub.3-7cycloalkyl; iii) amino-C.sub.1-6alkyl; iv) —C(═O)N(R.sup.3a, R.sup.3b); v) C(═O)O—C.sub.1-6alkyl; vi) C.sub.1-6alkyl; and vii) —C.sub.3-7cycloalkyl; R.sup.3a is selected from the group consisting of hydrogen and C.sub.1-6alkyl; R.sup.3b is selected from the group consisting of hydrogen and C.sub.1-6alkyl; or R.sup.3a and R.sup.3b form together with the nitrogen to which they are attached form a heterocycloalkyl; R.sup.3c is hydrogen; R.sup.4 is selected from the group consisting of amino, —C(═O)N(R.sup.3a, R.sup.3b), C.sub.1-6alkoxy, C.sub.1-6alkyl, halo-C.sub.1-6alkyl, and hydroxy-C.sub.1-6alkyl; R.sup.6 is selected from the group consisting of i) unsubstituted aryl; ii) unsubstituted heteroaryl; and iii) heteroaryl substituted by 1 or 2 substituents selected from R.sup.7; R.sup.7 is selected from the group consisting of i) unsubstituted heteroaryl; and ii) heteroaryl substituted by 1 or 2 substituents selected from R.sup.1; R.sup.8 is C.sub.1-6alkyl; Y is CH.sub.2 or NH; R.sup.9 is selected from the group consisting of i) C.sub.1-6alkyl; and ii) —C(═O)O—C.sub.1-6alkyl; R.sup.10 is selected from the group consisting of i) C.sub.1-6alkyl; and ii) —C(═O)O—C.sub.1-6alkyl.

2. The method of claim 1, wherein X.sup.1 is N.

3. The method of claim 1, wherein X.sup.2 is N.

4. The method of claim 1, wherein X.sup.3 is N.

5. The method of claim 1, wherein R.sup.3 is aryl substituted by 1 or 2 substituents selected from R.sup.4, wherein R.sup.4 is selected from —C(═O)N(R.sup.3a, R.sup.3b), C.sub.1-6alkyl, and C.sub.1-6alkoxy.

6. The method of claim 1, wherein R.sup.3 is —C(═O)N(R.sup.3a, R.sup.3b).

7. The method of claim 6, wherein R.sup.3a is hydrogen and R.sup.3b is C.sub.1-6alkyl.

8. The method of claim 7, wherein R.sup.3b is methyl.

9. The method of claim 1, wherein R.sup.1 is —C(═O)—R.sup.6.

10. The method of claim 1, wherein R.sup.1 is heterocyclyl.

11. The method of claim 1, wherein R.sup.1 is heterocyclyl, substituted by 1 or 2 substituents individually selected from R.sup.10.

12. The method of claim 1, wherein R.sup.1 is aryl.

13. The method of claim 1, wherein R.sup.1 is aryl, substituted by 1 or 2 substituents individually selected from R.sup.9.

14. A compound of Formula: ##STR00082## ##STR00083## ##STR00084## or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of claim 14, optionally in a pharmaceutically acceptable carrier.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0585] FIG. 1. Data from the dual fluorescent FACS assay show that compounds reduce BRD4-eGFP levels. Values given in the curve plot (left panel) and in the table (right panel) are the Medians of GFP vs. RFP fluorescence, the dotted line represents the mean GFP vs. RFP values in the DMSO conditions.

[0586] FIG. 2. Immunoassay data showing degradation of endogenous BRD4 upon compound treatment. Values shown are signal peak areas which were normalized to a loading control (vinculin) and expressed as % of DMSO.

PHARMACOLOGICAL TESTS

[0587] The compounds of formula I or formula P-L-C and their pharmaceutically acceptable salts possess valuable pharmacological properties. The compounds were investigated in accordance with the test given hereinafter.

[0588] Dual Fluorescent Reporter Assay

[0589] In order to measure BRD4 protein abundance in a mammalian cell system at medium throughput, a dual fluorescent reporter system was developed based on a principle described in.sup.1. Transient expression vectors were designed that contain the BRD4 coding sequence (NM_058243.2) fused to a fluorescent tag. Vectors were synthesized at ATUM (Newark, Calif., USA) using the pD2610 CMV backbone and were built up as follows: c-terminal version BRD4_eGFP—IRES—FresnoRFP_NLS, n-terminal version eGFP_BRD4—IRES—FresnoRFP_NLS, empty vector control eGFP—IRES—FresnoRFP_NLS. The c-terminal version was used for the reporter assays, as it presented with the best assay window. HEK293A cells (Invitrogen, Cat. No. R705-07) were cultured in Dulbecco's Modified Eagle Medium (DMEM), 10% fetal calf serum, 2 mM L-Glutamine, 1% Penicillin/Streptomycin.

[0590] Transfections of the plasmids were performed with Lipofectamine 2000 according to the manufacturer's protocol (Invitrogen, Carlsbad, Calif., USA). 40 hours after transfection, cells were seeded at a density of 40′000/100 ul/96 well flat-bottom and 8 hours later treated with compounds (stocks 10 mM in DMSO) at a 10-point dilution ranging from 0-25 μM. After 16 hours of treatment, cells were washed with PBS, resuspended in Accumax solution (Sigma-Aldrich Cat. No. A7089) and analyzed by flow-cytometry (CytoFlex S, BeckmanCoulter). Single cells were gated based on their forward and side-scatter profiles and pulse-width was used to exclude doublets. A minimum of 20′000 cells was acquired per sample. Analysis was performed with the program Flow Jo V10.1 on BRD4-eGFP low/medium cells (<10.sup.6 FL1-A Mean Fluorescence Intensity (MFI)). A factor was derived to normalize BRD4-eGFP values to the RFP protein abundance control (20×FL1A-GFP/FL11A-RFP), then Median and Mode values were calculated and used for comparisons between treatment conditions.

[0591] Capillary-Based Immunoassays to Measure Endogenous BRD4 Levels

[0592] The biological activity of selected compounds (cut-off >20% reduction in BRD4-eGFP levels) was confirmed in an additional assay which allowed the quantification of endogenous BRD4 levels. To this end, HEK293A cells (origin and culture conditions see above) were seeded at 400′000/300 ul/48 well and were treated 6 hours later with compound concentrations as indicated for. 16 hours after the treatment, the cells were washed with PBS and lysed in 50 ul of UREA lysis buffer (10 mM Tris-HCl pH 8, 2% CHAPS, 7M UREA, 0.4% DTT), supplemented with 1×protease inhibitor cocktail (Complete Mini, Roche) and 1×phosphatase inhibitor cocktail (PhosSTOP, Sigma-Aldrich). Samples were then analyzed by Peggy Sue or WES capillary-based immunoassay systems according to the manufacturer's protocol (Protein Simple/Bio-Techne, San Jose, Calif., 95134 USA). Antibodies used were anti-BRD4 (Cell signaling, CST 13440 1:50) and anti-Vinculin (Sigma, V9131, 1:4000). To quantify BRD4 protein levels, the peak signal areas were normalized to the vinculin loading control and to the DMSO condition.

[0593] Further, please see Yen, H.-C. S., Xu, Q., Chou, D. M., Zhao, Z. & Elledge, S. J. Global Protein Stability Profiling in Mammalian Cells. Science 2008, 322, 918-923, doi:10.1126/science.1160489.

[0594] Fluorescence Direct Binding Protocol

[0595] Principle

[0596] Determination of the affinities of compounds to protein containing one or more tryptophan is measurable by monitoring the fluorescence emission in direct mode. The measurements depending on the protein available amounts are performed either manually in a cuvette on ISS-PC1 photon counting spectrofluorometer or automatically in well plates on a fluorescence plate reader device. Fluorescence titrations are performed at 20° C. in the chosen binding assay buffer by using a defined constant protein concentration against ligand concentration variations. Small aliquots of known ligand concentration solubilized in DMSO were added and the fluorescence, excited at 280 nm, was recorded at 340 nm. The fluorescence intensity was corrected for protein dilution and for the filter effect (Birdsall, B., King, R. W., Wheeler, M. R., Lewis, C. A. Jr, Goode, S. R., Dunlap, R. B. & Roberts, G. C. Anal. Biochem. 1983, 132, 353-361). The corrected fluorescence intensity was plotted against the ligand concentration and fitted using a four-parameter sigmoidal function, from which the equilibrium dissociation constant Kd was computed using the law of mass action assuming a 1:1 protein-ligand complex (Eftink, Methods Enzymol. 1997, 278, 221-57).

[0597] Process

[0598] 1) Optimization of measurement parameters to minimize protein consumption and to minimize the dilution effect and the DMSO content

[0599] 2) Titration measurements of the protein against ligand by at least 12 titration steps to obtain a good s-curve fit

[0600] 3) Repeat the same titration measurements with the ligand alone to enable correction

[0601] 4) Check the stability of the protein once by titration against DMSO alone

[0602] 5) Determination of the molar extinction coefficients of the ligand at 280 and 340 nm with help of a UV-spectrophotometer

[0603] 6) Use Excel template for the correction of the measured raw data

[0604] 7) Use GraphPad Prism software for the quadratic binding fit and the K.sub.d evaluation.

[0605] Experimental Details

TABLE-US-00001 TABLE 1 Protein-buffers, Reference compound: thalidomide, Contergan, Softenon Protein Batch # Cereblon_17_13 Construct name hCereblon(M1-L442)_hDDB1(M1-H1140) Concentration 2.54 mg/ml MW 180180 Da Molar extinction ε.sub.280 = 165045 M.sup.−1 .Math. cm.sup.−1 coefficient Storage buffer 20 mM MES pH 6.5 200 mM NaCl 1 mM TCEP Assay buffer 50 mM Hepes 7.4 200 mM NaCl

TABLE-US-00002 TABLE 2 Settings Device ISS-PC1 Excitation wavelength [nm] 280 Emission wavelength [nm] 340 Cuvette Hellma 115F-QS Volume [μL] 500
Protein preparation:

TABLE-US-00003 TABLE 3 Protein preparation Volume Volume Protein Protein [μL] buffer [μL] concentration [M] 1.8 @ 2.54 mg/ml 498.2 5.0E−8

TABLE-US-00004 TABLE 4 Titration steps C Lig C Aliquot V Aliquot C Prot Dilution [M] [M] [μL] [M] factor     1E−10 1.0E−07 0.5 4.995E−08 1.001   1.1E−09 1.0E−06 0.5 4.990E−08 1.002   3.1E−09 1.0E−06 1 4.980E−08 1.004   5.1E−09 1.0E−06 1 4.970E−08 1.006   1.51E−08 1.0E−05 0.5 4.965E−08 1.007   2.51E−08 1.0E−05 0.5 4.960E−08 1.008   4.51E−08 1.0E−05 1 4.950E−08 1.01   6.51E−08 1.0E−05 1 4.941E−08 1.012  1.651E−07 1.0E−04 0.5 4.936E−08 1.013  3.651E−07 1.0E−04 1 4.926E−08 1.015  5.651E−07 1.0E−04 1 4.916E−08 1.017  7.651E−07 1.0E−04 1 4.907E−08 1.019  9.651E−07 1.0E−04 1 4.897E−08 1.021  1.9651E−06 1.0E−03 0.5 4.892E−08 1.022  2.9651E−06 1.0E−03 0.5 4.888E−08 1.023 1.29651E−05 1.0E−02 0.5 4.883E−08 1.024 2.29651E−05 1.0E−02 0.5 4.878E−08 1.025 4.29651E−05 1.0E−02 1 4.869E−08 1.027 6.29651E−05 1.0E−02 1 4.859E−08 1.029 8.29651E−05 1.0E−02 1 4.850E−08 1.031

TABLE-US-00005 TABLE 5 affinities of examples to CRBN protein Fluorescence h-Cereblon_DDB1 Mean Example Name K.sub.d_EQ (μM) 1 6-Imidazol-1-yl-3,4-dihydro-1H-quinolin-2-one 0.416 2 N-Methyl-2-[2-(3-methylimidazol-4-yl)-4-quinolyl]-1-(2- 0.040 oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5- carboxamide 3 2-Ethyl-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6- 0.190 yl)benzimidazole-5-carboxamide 4 N-Methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2- 0.049 (quinolin-4-yl)-1H-benzo[d]imidazole-5-carboxamide 5 3-(1-Methyl-1H-imidazol-5-yl)-N-(2-oxo-1,2,3,4- 0.677 tetrahydroquinolin-6-yl)-1-naphthamide 6 2-Benzyl-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin- 0.702 6-yl)-1H-benzo[d]imidazole-5-carboxamide 7 2-Cyclopropyl-N-methyl-1-(2-oxo-1,2,3,4- 0.456 tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5- carboxamide 8 2-((Benzyloxy)methyl)-N-methyl-1-(2-oxo-1,2,3,4- 0.788 tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5- carboxamide 9 6-(1H-Imidazol-1-yl)-3,4-dihydro-1,8-naphthyridin- 0.016 2(1H)-one 10 2-(2-Methoxybenzyl)-N-methyl-1-(2-oxo-1,2,3,4- 0.010 tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5- carboxamide 11 N-Methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2- 0.616 (1-phenylcyclopropyl)-1H-benzo[d]imidazole-5- carboxamide 12 N-Methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2- 0.250 (1H-pyrazo]-4-y])-1H-benzo[d]imidazole-5-carboxamide 13 2-(2-Methoxypyridin-4-yl)-N-methyl-1-(2-oxo-1,2,3,4 0.031 tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5- carboxamide 14 6-(5-Phenyl-1H-imidazol-1-yl)-3,4-dihydroquinolin- 0.009 2(1H)-one 15 2-(Hydroxymethyl)-N-methyl-1-(2-oxo-1,2,3,4- 0.011 tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5- carboxamide 16 2-(2-(Cyclopropanecarboxamido)ethyl)-N-methyl-1-(2- 0.027 oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H- benzo[d]imidazole-5-carboxamide 17 Ethyl 5-(methylcarbamoyl)-1-(2-oxo-1,2,3,4- 0.010 tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-2- carboxylate 18 2-(2-aminoethyl)-N-methyl-1-(2-oxo-1,2,3,4- 0.004 tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5- carboxamide 19 Methyl 4-((2-oxo-1,2,3,4-tetrahydroquinolin-6- 0.030 yl)amino)benzoate 20 N-Methyl-2-(morpholine-4-carbonyl)-1-(2-oxo-1,2,3,4- 0.010 tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5- carboxamide 21 (RS)-N-(7-Oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)- 0.004 1,2,3,4-tetrahydronaphthalene-1-carboxamide 22 Methyl 2-(2-methoxypyridin-4-yl)-1-(2-oxo-1,2,3,4 0.004 tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5- carboxylate 23 2-(6-Methoxypyridin-2-yl)-N-methyl-1-(2-oxo-1,2,3,4- 0.015 tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5- carboxamide 24 2-(6-Methoxypyridin-3-yl)-N-methyl-1-(2-oxo-1,2,3,4- 0.012 tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5- carboxamide 25 2-(4-Methoxypyridin-2-yl)-N-methyl-1-(2-oxo-1,2,3,4- 0.003 tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5- carboxamide 26 2-(2-Methoxypyridin-3-yl)-N-methyl-1-(2-oxo-1,2,3,4- 0.015 tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5- carboxamide 27 6-(5-(4-Methoxyphenyl)-1H-imidazol-1-yl)-3,4- 0.022 dihydroquinolin-2(1H)-one 28 2-Isopropyl-N-methyl-1-(7-oxo-6,8-dihydro-5H-1,8- 0.008 naphthyridin-3-yl)benzimidazole-5-carboxamide 29 2-(2-Methoxy-4-pyridyl)-N-methyl-1-(7-oxo-6,8- 0.035 dihydro-5H-1,8-naphthyridin-3-yl)benzimidazole-5- carboxamide 30 2-(2-Acetylphenyl)-N-methyl-1-(2-oxo-3,4-dihydro-1H- 0.579 quinolin-6-yl)benzimidazole-5-carboxamide 31 N-Methyl-2-[2-(methylcarbamoyl)phenyl]-1-(2-oxo-3,4- 0.004 dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide 32 2-(3-Methoxyphenyl)-N-methyl-1-(2-oxo-3,4-dihydro- 0.017 1H-quinolin-6-yl)benzimidazole-5-carboxamide 33 2-(5-Methoxy-2-methyl-phenyl)-N-methyl-1-(2-oxo-3,4- 0.045 dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide 34 2-[4-(Acetamidomethyl)phenyl]-N-methyl-1-(2-oxo-3,4- 0.431 dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide 35 2-(2-Fluoro-5-methoxy-phenyl)-N-methyl-1-(2-oxo-3,4- 0.014 dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide 36 2-[2-(Hydroxymethyl)phenyl]-N-methyl-1-(2-oxo-3,4- 0.039 dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide 37 2-(2-Acetamidophenyl)-N-methyl-1-(2-oxo-3,4-dihydro- 0.439 1H-quinolin-6-yl)benzimidazole-5-carboxamide 38 2-(2-Aminophenyl)-N-methyl-1-(2-oxo-3,4-dihydro-1H- 0.006 quinolin-6-yl)benzimidazole-5-carboxamide 39 2-(4-Methoxy-6-methyl-2-pyridyl)-N-methyl-1-(2-oxo- 0.006 3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5- carboxamide 40 Methyl 2-[5-(methylcarbamoyl)-1-(2-oxo-3,4-dihydro- 0.069 1H-quinolin-6-yl)benzimidazol-2-yl]pyridine-3- carboxylate 41 Methyl 2-[[5-(methylcarbamoyl)-1-(2-oxo-3,4-dihydro- 0.068 1H-quinolin-6-yl)benzimidazol-2-yl]methyl]benzoate 42 2-(3-Acetamido-2-pyridyl)-N-methyl-1-(2-oxo-3,4- 0.004 dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide 43 2-(3-Amino-2-pyridyl)-N-methyl-1-(2-oxo-3,4-dihydro- 0.031 1H-quinolin-6-yl)benzimidazole-5-carboxamide 44 2-(5-Fluoro-2-methoxy-4-pyridyl)-N-methyl-1-(2-oxo- 0.010 3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5- carboxamide 45 N-Methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-2-[3- 0.027 (trifluoromethyl)-4-pyridyl]benzimidazole-5- carboxamide 46 2-[2-(Hydroxymethyl)-4-pyridyl]-N-methyl-1-(2-oxo- 0.014 3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5- carboxamide 47 2-[[2-Methoxy-4-(trifluoromethyl)phenyl]methyl]-N- 0.017 methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6- yl)benzimidazole-5-carboxamide 48 2-(2-Acetyl-3-pyridyl)-N-methyl-1-(2-oxo-3,4-dihydro- 0.004 1H-quinolin-6-yl)benzimidazole-5-carboxamide 49 N-Methyl-2-[3-(methylcarbamoyl)-2-pyridyl]-1-(2-oxo- 0.002 3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5- carboxamide 50 Methyl 2-isopropyl-1-(6-oxo-7,8-dihydro-5H-1,5- 0.020 naphthyridin-2-yl)benzimidazole-5-carboxylate 51 2-Isopropyl-N-methyl-1-(6-oxo-7,8-dihydro-5H-1,5- 0.011 naphthyridin-2-yl)benzimidazole-5-carboxamide 52 2-Isopropyl-N,N-dimethyl-1-(6-oxo-7,8-dihydro-5H-1,5- 0.022 naphthyridin-2-yl)benzimidazole-5-carboxamide 53 7-(1H-Imidazol-1-yl)-3,4-dihydroquinolin-(1H)-one 0.016 54 6-(Indoline-1-carbonyl)-3,4-dihydro-1H-quinolin-2-one 0.232 55 6-(2,3-Dihydropyrrolo[2,3-b]pyridine-1-carbonyl)-3,4- 0.023 dihydro-1H-quinolin-2-one 56 6-(3,4-Dihydro-2H-quinoline-1-carbonyl)-3,4-dihydro- 0.005 1H-quinolin-2-one 57 N-(1-Acetyl-4-piperidyl)-2-oxo-3,4-dihydro-1H- 0.041 quinoline-6-carboxamide 58 6-(Indoline-1-carbonyl)-3,4-dihydro-1H-1,8- 0.062 naphthyridin-2-one 59 6-(2,3-Dihydropyrrolo[2,3-b]pyridine-1-carbonyl)-3,4- 0.003 dihydro-1H-1,8-naphthyridin-2-one 60 6-(3,4-Dihydro-2H-quinoline-1-carbonyl)-3,4-dihydro- 0.001 1H-1,8-naphthyridin-2-one 61 6-(2-Isopropyl-1H-benzo[d]imidazol-1-yl)-3,4- 0.171 dihydroquinazolin-2(1H)-one 62 2-Isopropyl-N-methyl-1-(2-oxo-1,2,3,4- 0.12 tetrahydroquinazolin-6-yl)-1H-benzo[d]imidazole-5- carboxamide A N-(10-(2-((6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H- 0.338 thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6- yl)acetamido)decyl)-2-(2-(1-methyl-1H-imidazol-5- yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6- yl)-1H-benzo[d]imidazole-5-carboxamide B N-(5-(2-((6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H- 0.258 thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6- yl)acetamido)pentyl)-2-(2-(1-methyl-1H-imidazol-5- yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6- yl)-1H-benzo[d]imidazole-5-carboxamide C N-(2-(2-(2-(2-((6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl- 0.524 6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6- yl)acetamido)ethoxy)ethoxy)ethyl)-2-(2-(1-methyl-1H- imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4- tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5- carboxamide

Pharmaceutical Compositions

[0606] The compounds of formula I or formula P-L-C and the pharmaceutically acceptable salts can be used as therapeutically active substances, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

[0607] The compounds of formula I or formula P-L-C and the pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

[0608] The pharmaceutical preparations can, moreover, contain pharmaceutically acceptable auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

[0609] Medicaments containing a compound of formula I or formula P-L-C or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also provided by the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.

[0610] The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.

[0611] The following examples illustrate the present invention without limiting it, but serve merely as representative thereof. The pharmaceutical preparations conveniently contain about 1-500 mg, particularly 1-100 mg, of a compound of formula I or formula P-L-C. Examples of compositions according to the invention are:

Example A

[0612] Tablets of the following composition are manufactured in the usual manner:

TABLE-US-00006 TABLE 6 possible tablet composition mg/tablet ingredient 5 25 100 500 Compound of formula 5 25 100 500 A, I or formula P-L-C Lactose Anhydrous DTG 125 105 30 150 Sta-Rx 1500 6 6 6 60 Microcrystalline Cellulose 30 30 30 450 Magnesium Stearate 1 1 1 1 Total 167 167 167 831

Manufacturing Procedure

[0613] 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.
2. Dry the granules at 50° C.
3. Pass the granules through suitable milling equipment.
4. Add ingredient 5 and mix for three minutes; compress on a suitable press.

Example B-1

[0614] Capsules of the following composition are manufactured: P

TABLE-US-00007 TABLE 7 possible capsule ingredient composition mg/capsule ingredient 5 25 100 500 Compound of formula 5 25 100 500 A, I or formula P-L-C Hydrous Lactose 159 123 148 — Corn Starch 25 35 40 70 Talk 10 15 10 25 Magnesium Stearate 1 2 2 5 Total 200 200 300 600

Manufacturing Procedure

[0615] 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.
2. Add ingredients 4 and 5 and mix for 3 minutes.
3. Fill into a suitable capsule.

[0616] The compound of formula A, I or formula P-L-C, lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine. The mixture is returned to the mixer; the talc is added thereto and mixed thoroughly. The mixture is filled by machine into suitable capsules, e.g. hard gelatin capsules.

Example B-2

[0617] Soft Gelatin Capsules of the following composition are manufactured:

TABLE-US-00008 TABLE 8 possible soft gelatin capsule ingredient composition ingredient mg/capsule Compound of formula 5 A, I or formula P-L-C Yellow wax 8 Hydrogenated Soya bean oil 8 Partially hydrogenated plant oils 34 Soya bean oil 110 Total 165

TABLE-US-00009 TABLE 9 possible soft gelatin capsule composition ingredient mg/capsule Gelatin 75 Glycerol 85% 32 Karion 83 8 (dry matter) Titan dioxide 0.4 Iron oxide yellow 1.1 Total 116.5

Manufacturing Procedure

[0618] The compound of formula A, I or formula P-L-C is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are treated according to the usual procedures.

Example C

[0619] Suppositories of the following composition are manufactured:

TABLE-US-00010 TABLE 10 possible suppository composition ingredient mg/supp. Compound of formula 15 A, I or formula P-L-C Suppository mass 1285 Total 1300

Manufacturing Procedure

[0620] The suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 45° C. Thereupon, the finely powdered compound of formula A, I or formula P-L-C is added thereto and stirred until it has dispersed completely. The mixture is poured into suppository moulds of suitable size, left to cool; the suppositories are then removed from the moulds and packed individually in wax paper or metal foil.

Example D

[0621] Injection solutions of the following composition are manufactured:

TABLE-US-00011 TABLE 11 possible injection solution composition ingredient mg/injection solution. Compound of formula 3 A, I or formula P-L-C Polyethylene Glycol 400 150 acetic acid q.s. ad pH 5.0 water for injection solutions ad 1.0 ml

Manufacturing Procedure

[0622] The compound of formula A, I or formula P-L-C is dissolved in a mixture of Polyethylene Glycol 400 and water for injection (part). The pH is adjusted to 5.0 by addition of acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

Example E

[0623] Sachets of the following composition are manufactured:

TABLE-US-00012 TABLE 12 possible sachet composition ingredient mg/sachet Compound of formula I or formula P-L-C 50 Lactose, fine powder 1015 Microcrystalline cellulose (AVICEL PH 102) 1400 Sodium carboxymethyl cellulose 14 Polyvinylpyrrolidon K 30 10 Magnesium stearate 10 Flavoring additives 1 Total 2500

Manufacturing Procedure

[0624] The compound of formula A, I or formula P-L-C is mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granulate is mixed with magnesium stearate and the flavoring additives and filled into sachets.

Experimental Part

[0625] The following examples are provided for illustration of the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof.

Example 1

6-Imidazol-1-yl-3,4-dihydro-1H-quinolin-2-one

[0626] ##STR00016##

[0627] The title compound can be purchased.

Example 2

N-Methyl-2-[2-(3-methylimidazol-4-yl)-4-quinolyl]-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0628] ##STR00017##

a) Methyl 3-nitro-4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzoate

[0629] To a stirred solution of methyl 4-fluoro-3-nitrobenzoate.sup.Error! Bookmark not defined. (300 mg) and 6-amino-3,4-dihydro-1H-quinolin-2-one.sup.Error! Bookmark not defined. (244 mg) in N-methyl-2-pyrrolidinone (3 ml) was added dropwise N,N-diisopropylethylamine (395 μl). The reaction mixture was heated at 60° C. overnight. TLC analysis showed the reaction was complete. The reaction mixture was then cooled to room temperature and diluted with ethyl acetate and with water. The resulting mixture was filtered through sintered glass to afford methyl 3-nitro-4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzoate as a red solid (365 mg, 71%). The filtrate was washed three times with water and then the organic layer was dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford methyl 3-nitro-4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzoate (441 mg, 86%) as a red solid. MS (ISP): 342.1 ([M+H].sup.+).

b) Methyl 3-amino-4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzoate

[0630] To a stirred suspension of methyl 3-nitro-4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzoate (440 mg) in methanol (120 ml) and THE (40 ml) was added 10% palladium on charcoal (69 mg). The reaction mixture was stirred at room temperature under an atmosphere of hydrogen for 2 h. The reaction mixture was filtered through celite, washing with methanol. The filtrate was then concentrated in vacuo to afford methyl 3-amino-4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzoate (351 mg, 88%) as a grey solid. MS (ISP): 312.1 ([M+H].sup.+).

c) Methyl 2-[2-(3-methylimidazol-4-yl)-4-quinolyl]-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxylate

[0631] To a stirred solution of methyl 3-amino-4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzoate (106 mg) and 2-(1-methyl-1H-imidazol-5-yl)quinoline-4-carbaldehyde (CAS 432517-57-2) (88.9 mg) in N,N-dimethylformamide (4 ml) was added sodium metabisulfite (129 mg) at room temperature. The reaction mixture was then heated at 80° C. for 2 h. TLC and LC-MS analysis showed the reaction was incomplete. A further portion of sodium metabisulfite (129 mg) was added and the reaction mixture was then heated at 120° C. for 5 h. TLC and LC-MS analysis showed the reaction was complete. The reaction mixture was then cooled to room temperature and poured into EtOAc/THF (1:1 mixture). The resulting mixture was washed sequentially with water and with saturated brine. The organic phase was then separated, dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to afford methyl 2-[2-(3-methylimidazol-4-yl)-4-quinolyl]-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxylate (204 mg, 99%, 88% purity) as a yellow amorphous solid which was used in the next step without further purification. MS (ISP): 529.2 ([M+H].sup.+).

d) 2-[2-(3-Methylimidazol-4-yl)-4-quinolyl]-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxylic acid

[0632] To a stirred solution of methyl 2-[2-(3-methylimidazol-4-yl)-4-quinolyl]-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxylate (203 mg) in THE (2 ml) and MeOH (1 ml) was added dropwise 1 M aq. LiGH solution (1.01 ml). The reaction mixture was stirred at room temperature overnight. Subsequent LC-MS showed the reaction was complete. Water was added and then a few drops of 1 N aq. NaOH solution were added until the pH was basic. The mixture was extracted twice with EtOAc. 5 N aq. HCl was then added to the aqueous layer until pH 1 was reached. The aqueous layer was extracted twice with THF/EtOAc (3:1). LC-MS analysis showed no product remained in the organic layer. The aqueous layer was concentrated in vacuo and the residue was lyophilised to afford 2-[2-(3-methylimidazol-4-yl)-4-quinolyl]-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxylic acid as a yellow solid (311 mg, 100%, 56% purity) which was used in the next step without further purification. MS (ISP): 515.2 ([M+H]).

e) N-Methyl-2-[2-(3-methylimidazol-4-yl)-4-quinolyl]-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0633] To a suspension of 2-[2-(3-methylimidazol-4-yl)-4-quinolyl]-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxylic acid (310 mg), N,N-diisopropylethylamine (236 μl) and methylamine (337 μl, 2 M solution in THF) in DMF (2 ml) was added HATU (308 mg). The reaction mixture was stirred at room temperature overnight. The resulting yellow suspension was filtered through sintered glass. The filtrate was concentrated in vacuo and the residue was purified by reversed phase HPLC to afford N-methyl-2-[2-(3-methylimidazol-4-yl)-4-quinolyl]-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide as an off-white solid (50 mg, 28%). MS (ISP): 528.8 ([M+H].sup.+).

Example 3

2-Ethyl-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0634] ##STR00018##

[0635] The title compound was obtained in analogy to example 2 using propionaldehyde (CAS 123-38-6) in place of 2-(1-methyl-1H-imidazol-5-yl)quinoline-4-carbaldehyde in step c. White solid. MS (ISP): 349.1 ([M+H].sup.+).

Example 4

N-Methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-(quinolin-4-yl)-1H-benzo[d]imidazole-5-carboxamide

[0636] ##STR00019##

[0637] The title compound was obtained in analogy to example 2 using quinoline-4-carboxaldehyde (CAS 4363-93-3) in place of 2-(1-methyl-1H-imidazol-5-yl)quinoline-4-carbaldehyde in step c. White solid. MS (ISP): 448.3 ([M+H].sup.+).

Example 5

3-(1-Methyl-1H-imidazol-5-yl)-N-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1-naphthamide

[0638] ##STR00020##

[0639] To a mixture of 6-amino-3,4-dihydroquinolin-2(1H)-one.sup.Error!Bookmark not defined. (35.4 mg) and 2-(1-methyl-1H-imidazol-5-yl)quinoline-4-carboxylic acid (CAS 432516-70-6) (50.24 mg) were added a solution of 0.27 M HATU in DMF (811 μl) and N,N-diisopropylethylamine (69.3 μl). The reaction mixture was stirred at room temperature for 2.5 hours. LC-MS analysis indicated that the reaction was complete. The reaction mixture was directly purified by reversed phase HPLC. The collected fractions were concentrated in vacuo and the residue was resuspended in ethyl acetate and water. The organic phase was then separated, dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to afford 3-(1-methyl-1H-imidazol-5-yl)-N-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1-naphthamide (39 mg, 50%) as as an off-white. MS (ISP): 398.6 ([M+H].sup.+).

Example 6

2-Benzyl-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0640] ##STR00021##

a) N-Methyl-3-nitro-4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzamide

[0641] To a stirred solution of 4-fluoro-N-methyl-3-nitrobenzamide.sup.Error! Bookmark not defined. (500 mg) in N-methyl-2-pyrrolidinone (5 ml) were added 6-amino-3,4-dihydroquinolin-2(1H)-one.sup.Error!Bookmark not defined. (450 mg) and N,N-diisopropylethylamine (489 mg). The reaction mixture was heated at 80° C. for 3 days. LC-MS analysis indicated that the reaction was incomplete. The reaction mixture was heated at 120° C. for 1 day. The reaction mixture was cooled to room temperature and ethyl acetate (10 ml) and water (3 ml) were added. An orange precipitate formed. The precipitate was collected by filtration, washed with ethyl acetate, and dried in vacuo to give N-methyl-3-nitro-4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzamide as an orange solid (825 mg, 96%). MS (ISP): 341.0 ([M+H].sup.+).

b) 3-Amino-N-methyl-4-[(2-oxo-3,4-dihydro-1H-quinolin-6-yl)amino]benzamide

[0642] To a stirred suspension of N-methyl-3-nitro-4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzamide (825 mg) in methanol (20 ml) and THE (40 ml) was added 10% palladium on charcoal (258 mg). The reaction mixture was stirred at room temperature under an atmosphere of hydrogen for 15 h. The reaction mixture was filtered through celite, washing with methanol. The filtrate was then concentrated in vacuo to afford 3-amino-N-methyl-4-[(2-oxo-3,4-dihydro-1H-quinolin-6-yl)amino]benzamide (73 mg, 10%) as an off-white solid. MS (ISP): 311.0 ([M+H].sup.+).

c) 2-Benzyl-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0643] To a stirred solution of 3-amino-N-methyl-4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzamide (85 mg) and 2-phenylacetaldehyde (CAS 122-78-1) (36.2 mg) in N,N-dimethylformamide (1 ml) was added sodium metabisulfite (104 mg) at room temperature. The reaction mixture was then heated at 120° C. for 16 h. TLC and LC-MS analysis showed the reaction was complete. The reaction mixture was then cooled to room temperature and diluted with EtOAc. The resulting mixture was washed with water. The organic phase was then separated, dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 10 g, 0% to 10% methanol in dichloromethane) to afford 2-benzyl-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide as a light brown solid (24 mg, 21%). MS (ISP): 411.6 ([M+H].sup.+).

Example 7

2-Cyclopropyl-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0644] ##STR00022##

[0645] The title compound was obtained in analogy to example 6 using cyclopropanecarbaldehyde (CAS 7051-34-5) in place of 2-phenylacetaldehyde in step c. Grey solid. MS (ISP): 361 ([M+H].sup.+).

Example 8

2-((Benzyloxy)methyl)-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0646] ##STR00023##

[0647] The title compound was obtained in analogy to example 6 using 2-(benzyloxy)acetaldehyde (CAS 60656-87-3) in place of 2-phenylacetaldehyde in step c. Yellow solid. MS (ISP): 441.3 ([M+H].sup.+).

Example 9

6-(1H-Imidazol-1-yl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

[0648] ##STR00024##

[0649] To a solution of 6-bromo-3,4-dihydro-1,8-naphthyridin-2(1H)-one.sup.Error! Bookmark not defined. (100 mg) in DMF (2 ml) were added 1H-imidazole (CAS 288-32-4) (33 mg), CuI (8.39 mg), hexamethylenetetramine (6.17 mg) and potassium carbonate (123 mg). The reaction mixture was heated at 130° C. for 22 hours. The reaction mixture was diluted with water (40 ml) and ethyl acetate (20 ml). The two layers were separated and the aqueous layer was back-extracted twice with ethyl acetate (2×20 ml). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel; 12 g; eluent: heptane/ethyl acetate=100/0 to 0/100 and then to 10% MeOH) to afford 6-(1H-imidazol-1-yl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one as a light yellow solid (21.9 mg, 23%). %). MS (ISP): 215.4 ([M+H].sup.+).

Example 10

2-(2-Methoxybenzyl)-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0650] ##STR00025##

[0651] The title compound was obtained in analogy to example 6 using 2-(2-methoxyphenyl)acetaldehyde (CAS 33567-59-8) in place of 2-phenylacetaldehyde in step c. Light yellow solid. MS (ISP): 441.3 ([M+H].sup.+).

Example 11

N-Methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-(1-phenylcyclopropyl)-1H-benzo[d]imidazole-5-carboxamide

[0652] ##STR00026##

[0653] The title compound was obtained in analogy to example 6 using 1-phenylcyclopropane-carbaldehyde (CAS 21744-88-7) in place of 2-phenylacetaldehyde in step c. Light yellow solid. MS (ISP): 437.5 ([M+H].sup.+).

Example 12

N-Methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-(1H-pyrazol-4-yl)-1H-benzo[d]imidazole-5-carboxamide

[0654] ##STR00027##

[0655] To a stirred solution of methyl 3-amino-N-methyl-4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzamide (80 mg) in N,N-dimethylformamide (1 ml) was added 1H-pyrazole-4-carboxaldehyde (CAS 35344-95-7) (41.5 mg). After stirring for 2 hours at 80° C., sodium metabisulfite (98 mg) was added and the reaction mixture was heated at 120° C. for 48 h. TLC and LC-MS analysis showed the reaction was complete. The reaction mixture was then cooled to room temperature and diluted with EtOAc. The resulting mixture was washed with water. The organic phase was then separated, dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was stirred in dichloromethane, filtered, washed with dichloromethane to afford N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-(1H-pyrazol-4-yl)-1H-benzo[d]imidazole-5-carboxamide as a light brown solid (47.8 mg, 48%). MS (ISP): 387.2 ([M+H].sup.+).

Example 13

2-(2-Methoxypyridin-4-yl)-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0656] ##STR00028##

[0657] The title compound was obtained in analogy to example 6 using 2-methoxyisonicotinaldehyde (CAS 72716-87-1) in place of 2-phenylacetaldehyde in step c. Light yellow solid. MS (ISP): 428.3 ([M+H].sup.+).

Example 14

6-(5-Phenyl-1H-imidazol-1-yl)-3,4-dihydroquinolin-2(1H)-one

[0658] ##STR00029##

a) Ethyl 3-(5-fluoro-2-nitrophenyl)propanoate

[0659] To a flask containing THE (200 ml) was added with stirring LiHMDS (20.5 ml, 1 M solution in THF). The solution was cooled to −78° C. and ethyl acetate (2 ml) was added slowly. After stirring for 30 min, a solution of 2-(bromomethyl)-4-fluoro-1-nitrobenzene (CAS 82420-35-7) (4 g) dissolved in THE (100 ml) was added dropwise over 30 min. The reaction mixture was then allowed to warm to room temperature and stirring continued for a further 2 hours. The reaction was quenched with water and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed sequentially with water and with sat. brine, dried over MgSO.sub.4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, eluent: 0 to 10% of ethyl acetate in hexane) to afford ethyl 3-(5-fluoro-2-nitrophenyl)propanoate (2.20 g, 53% yield) as a yellow oil. MS (ISP): 242.1 ([M+H].sup.+).

b) Ethyl 3-(2-nitro-5-(5-phenyl-1H-imidazol-1-yl)phenyl)propanoate

[0660] To a stirred solution of 5-phenyl-1H-imidazole (CAS 670-95-1) (100 mg) in N,N-dimethylformamide (2 ml) were added sequentially ethyl 3-(5-fluoro-2-nitrophenyl)propanoate (184 mg) and potassium carbonate (201 mg). The reaction mixture was irradiated in a microwave synthesizer apparatus for 15 min at 130° C. LC/MS analysis indicated that the reaction was finished. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO.sub.4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, eluent: 0 to 10% of methanol in dichloromethane) to afford ethyl 3-(2-nitro-5-(5-phenyl-1H-imidazol-1-yl)phenyl)propanoate (98 mg, 39% yield) as a white solid. MS (ISP): 366.2 ([M+H].sup.+).

c) Ethyl 3-(2-amino-5-(5-phenyl-1H-imidazol-1-yl)phenyl)propanoate

[0661] To a stirred suspension of ethyl 3-(2-nitro-5-(5-phenyl-1H-imidazol-1-yl)phenyl)propanoate (98 mg) in methanol (20 ml) and THE (40 ml) was added 10% palladium on charcoal (10 mg). The reaction mixture was stirred under an atmosphere of hydrogen at room temperature for 3 h. The reaction mixture was filtered through celite, washing with methanol. The filtrate was then concentrated in vacuo to afford ethyl 3-(2-amino-5-(5-phenyl-1H-imidazol-1-yl)phenyl)propanoate (90 mg, 100%) as an off-white foam. MS (ISP): 336.96 ([M+H].sup.+).

d) 6-(5-Phenyl-1H-imidazol-1-yl)-3,4-dihydroquinolin-2(1H)-one

[0662] A solution of ethyl 3-(2-amino-5-(5-phenyl-1H-imidazol-1-yl)phenyl)propanoate (90 mg) was stirred in ethanol (1 ml) at reflux for 48 hours. TLC analysis indicated that the reaction was incomplete. After cooling to room temperature, sodium methanolate (50 mg) was added and the mixture was then heated at reflux for 6 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between CH.sub.2Cl.sub.2/MeOH (90:10) and water. The organic layer was separated, dried over MgSO.sub.4, filtered, and concentrated in vacuo. The residue was suspended in CH.sub.2C.sub.2 and the mixture was stirred at room temperature for 30 min. The resulting solid was collected by filtration to afford 6-(5-phenyl-1H-imidazol-1-yl)-3,4-dihydroquinolin-2(1H)-one_as a white solid (30 mg, 39%). MS (ISP): 290.2 ([M+H].sup.+).

Example 15

2-(Hydroxymethyl)-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0663] ##STR00030##

[0664] To a stirred suspension of 2-(benzyloxymethyl)-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide (63 mg, example 8) in methanol (3 ml) was added 10% palladium on charcoal (20 mg). The reaction mixture was hydrogenated at 70° C. and 5 bar for 18 hours. The reaction mixture was cooled to room temperature and then filtered through celite, washing with methanol. The filtrate was then concentrated in vacuo to afford 2-(hydroxymethyl)-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide (25.3 mg, 51%) as a white crystalline solid. MS (ISP): 351.1 ([M+H].sup.+).

Example 16

2-(2-(Cyclopropanecarboxamido)ethyl)-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0665] ##STR00031##

a) Benzyl (2-(5-(methylcarbamoyl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazol-2-yl)ethyl)carbamate

[0666] The title compound was obtained in analogy to example 6 using benzyl (3-oxopropyl)carbamate (CAS 65564-05-8) in place of 2-phenylacetaldehyde in step c. Light yellow solid. MS (ISP): 498.1 ([M+H].sup.+).

b) 2-(2-Aminoethyl)-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0667] To a stirred suspension of benzyl (2-(5-(methylcarbamoyl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazol-2-yl)ethyl)carbamate (194 mg) in methanol (4 ml) was added 10% palladium on charcoal (20 mg). The reaction mixture was hydrogenated at 70° C. and 5 bar for 18 hours. The reaction mixture was filtered through celite, washing with methanol. The filtrate was then concentrated in vacuo to afford 2-(2-aminoethyl)-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide (59 mg, 42%) as a colorless oil. MS (ISP): 364.3 ([M+H].sup.+).

c) 2-(2-(Cyclopropanecarboxamido)ethyl)-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0668] To a stirred solution of 2-(2-aminoethyl)-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide (59 mg) in dichloromethane (2 ml) were added sequentially cyclopropanecarbonyl chloride (CAS 4023-34-1) (16.2 μl) and triethylamine (45.3 μl). The reaction mixture was stirred at room temperature for 48 hours. LC-MS analysis indicated that the reaction was complete. The reaction mixture was partitioned between dichloromethane and water. The organic layer was dried over MgSO.sub.4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, eluent: 0 to 10% of methanol in dichloromethane) to afford 2-(2-(cyclopropanecarboxamido)ethyl)-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide (6 mg, 7%, 90% purity) as a white solid. MS (ISP): 432.1 ([M+H].sup.+).

Example 17

Ethyl 5-(methylcarbamoyl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-2-carboxylate

[0669] ##STR00032##

[0670] To a stirred solution of methyl 3-amino-N-methyl-4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzamide (80 mg) in N,N-dimethylformamide (1 ml) was added ethyl 2-oxoacetate (CAS 924-44-7) (26.2 μl). After stirring for 2 hours at 80° C., sodium metabisulfite (98 mg) was added and the reaction mixture was heated at 120° C. for 16 h. LC-MS analysis indicated that the reaction was incomplete. A further aliquot of ethyl 2-oxoacetate.sup.Error! Bookmark not defined. (26.2 μl) was added and the reaction mixture was stirred at 120° C. for 4 hours. The reaction mixture was then cooled to room temperature and diluted with EtOAc. The resulting mixture was washed with water. The organic phase was then separated, dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, eluent: 0 to 5% of methanol in dichloromethane) to afford ethyl 5-(methylcarbamoyl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-2-carboxylate (26 mg, 26%) as an off-white solid. MS (ISP): 393.1 ([M+H].sup.+).

Example 18

2-(2-Aminoethyl)-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0671] ##STR00033##

[0672] a) Benzyl (2-(5-(methylcarbamoyl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazol-2-yl)ethyl)carbamate The title compound was obtained in analogy to example 2 using benzyl (3-oxopropyl)carbamate.sup.Error! Bookmark not defined. in place of 2-(1-methyl-1H-imidazol-5-yl)quinoline-4-carbaldehyde in step c and stirring at 120° C. overnight instead of for 5 hours. Yellow solid. MS (ISP): 496.1 ([M+H].sup.+).

b) 2-(2-Aminoethyl)-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0673] To a stirred solution of benzyl (2-(5-(methylcarbamoyl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazol-2-yl)ethyl)carbamate (106.0 mg) in methanol (2 ml) was added 10% palladium on charcoal (22.7 mg). The reaction mixture was stirred at room temperature under an atmosphere of hydrogen for 16 hours. The reaction mixture was filtered, washing with methanol. The filtrate was then concentrated in vacuo. The residue was suspended in ethyl acetate and stirred for 2 hours. The suspension was filtered and the solid was dried under vacuo to afford 2-(2-aminoethyl)-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide (40 mg, 87%) as a light brown solid. MS (ISP): 364.0 ([M+H].sup.+).

Example 19

Methyl 4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzoate

[0674] ##STR00034##

[0675] To a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (CAS 3279-90-1) (50 mg) and methyl 4-aminobenzoate (CAS 619-45-4) (43.5 mg) in toluene (1 ml) were added sequentially under argon tris(dibenzylidineacetone)dipalladium (3.04 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (5.27 mg) and sodium tert-butoxide (31.9 mg). The reaction mixture was stirred at 100° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, eluent: 0 to 10% of methanol in dichloromethane) to afford methyl 4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzoate (25.8 mg, 39.4%) as a light yellow solid. MS (ISP): 297.2 ([M+H].sup.+).

Example 20

N-Methyl-2-(morpholine-4-carbonyl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0676] ##STR00035##

[0677] To a stirred solution of ethyl 5-(methylcarbamoyl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-2-carboxylate (22 mg) in dioxane (572 μl) at room temperature under argon was added a solution of 2 M triethylaluminium in toluene (112 μl). After stirring at room temperature for 10 minutes, morpholine (19.5 mg) was added and the reaction mixture was then stirred at 95° C. for 1 hour. According to LC-MS, the reaction was finished. The reaction mixture was carefully quenched with water (0.5 ml), and the solvent was then concentrated in vacuo. The residue was purified by chromatography (silica gel, eluent: 0 to 10% of methanol in dichloromethane) to afford N-methyl-2-(morpholine-4-carbonyl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide (19 mg, 78.2%) as a light yellow solid. MS (ISP): 434.2 ([M+H].sup.+).

Example 21

(RS)—N-(7-Oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

[0678] ##STR00036##

[0679] The title compound was obtained in analogy to example 5 using 6-amino-3,4-dihydro-1,8-naphthyridin-2(1H)-one (CAS 1378866-33-1) in place of 6-amino-3,4-dihydroquinolin-2(1H)-one and 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (CAS 1914-65-4) in place of 2-(1-methyl-1H-imidazol-5-yl)quinoline-4-carboxylic acid. White solid. MS (ISP): 322.2 ([M+H].sup.+).

Example 22

Methyl 2-(2-methoxypyridin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxylate

[0680] ##STR00037##

[0681] The title compound was obtained in analogy to example 2 steps a-c using 2-methoxyisonicotinaldehyde.sup.Error! Bookmark not defined. in place of 2-(1-methyl-1H-imidazol-5-yl)quinoline-4-carbaldehyde in step c. Light brown solid. MS (ISP): 429.2 ([M+H].sup.+).

Example 23

2-(6-Methoxypyridin-2-yl)-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0682] ##STR00038##

[0683] The title compound was obtained in analogy to example 6 using 6-methoxypicolinaldehyde (CAS 269058-49-3) in place of 2-phenylacetaldehyde in step c. Light yellow solid. MS (ISP): 428.4 ([M+H].sup.+).

Example 24

2-(6-Methoxypyridin-3-yl)-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0684] ##STR00039##

[0685] The title compound was obtained in analogy to example 6 using 6-methoxynicotinaldehyde (CAS 65873-72-5) in place of 2-phenylacetaldehyde in step c. Light yellow solid. MS (ISP): 428.3 ([M+H].sup.+).

Example 25

2-(4-Methoxypyridin-2-yl)-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0686] ##STR00040##

[0687] The title compound was obtained in analogy to example 6 using 4-methoxypicolinaldehyde (CAS 16744-81-3) in place of 2-phenylacetaldehyde in step c. Light yellow solid. MS (ISP): 428.3 ([M+H].sup.+).

Example 26

2-(2-Methoxypyridin-3-yl)-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0688] ##STR00041##

[0689] The title compound was obtained in analogy to example 6 using 2-methoxynicotinaldehyde (CAS 71255-09-9) in place of 2-phenylacetaldehyde in step c. Light yellow solid. MS (ISP): 428.3 ([M+H].sup.+).

Example 27

6-(5-(4-Methoxyphenyl)-1H-imidazol-1-yl)-3,4-dihydroquinolin-2(1H)-one

[0690] ##STR00042##

[0691] The title compound was obtained in analogy to example 14 using 5-(4-methoxyphenyl)-1H-imidazole (CAS 35512-31-3) in place of 5-phenyl-1H-imidazole in step c. Light brown solid. MS (ISP): 434.2 ([M+H].sup.+).

Example 28

2-Isopropyl-N-methyl-1-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)benzimidazole-5-carboxamide

[0692] ##STR00043##

a) Methyl 3-nitro-4-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)amino]benzoate

[0693] To a solution of 6-amino-3,4-dihydro-1H-1,8-naphthyridin-2-one.sup.Error! Bookmark not defined. (1.1 g) in N-methyl-2-pyrrolidinone (15 ml) were added methyl 4-fluoro-3-nitro-benzoate.sup.Error!Bookmark not defined. (0.68 g) and N,N-diisopropylethylamine (1.2 ml). The mixture was stirred at 120° C. for 12 hours. The reaction mixture was cooled to 20° C., and was then poured into water. The solid obtained was filtered, and the filter cake was washed with ethyl acetate and dried in vacuo to afford methyl 3-nitro-4-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)amino]benzoate (320 mg, 24.5%) as a brown solid. MS (ISP): 343.1 ([M+H].sup.+).

b) Methyl 3-amino-4-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)amino]benzoate

[0694] To a stirred solution of methyl 3-nitro-4-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)amino]benzoate (360 mg) in methanol (10 ml) was added 10% palladium on charcoal (100 mg). The reaction mixture was stirred at room temperature under an atmosphere of hydrogen for 12 hours. The reaction mixture was filtered, washing with N,N-dimethylformamide. The filtrate was then concentrated in vacuo to afford methyl 3-amino-4-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)amino]benzoate (280 mg, 89%) as a brown solid. MS (ISP): 343.1 ([M+H].sup.+).

c) Methyl 2-isopropyl-1-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)benzimidazole-5-carboxylate

[0695] To a solution of methyl 3-amino-4-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)amino]benzoate (130 mg) and isobutyraldehyde (CAS 78-84-2) (28.21 mg) in DMF (6 ml) was added sodium metabisulfite (81.8 mg). The reaction mixture was stirred at 110° C. for 1 hour. The mixture was poured into water and extracted with ethyl acetate (3×10 ml). The combined organic layer was concentrated in vacuo to afford methyl 2-isopropyl-1-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)benzimidazole-5-carboxylate (140 mg, 87.8%) as a yellow oil. MS (ISP): 365.1 ([M+H].sup.+).

d) 2-Isopropyl-1-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)benzimidazole-5-carboxylic acid

[0696] Methyl 2-isopropyl-1-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)benzimidazole-5-carboxylate (120 mg) was dissolved in a 1:1 mixture of THF/1 M aqueous lithium hydroxide solution (8.0 ml). After stirring at 15° C. for 3 hours, the reaction mixture was extracted three times with ethyl acetate. The aqueous layer was adjusted to pH 2 by addition of 1 N aq. HCl and was then concentrated in vacuo before purification with preparative HPLC to afford 2-isopropyl-1-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)benzimidazole-5-carboxylic acid (17.8 mg, 17%) as a yellow solid. MS (ISP): 351.2 ([M+H].sup.+).

e) 2-Isopropyl-N-methyl-1-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)benzimidazole-5-carboxamide

[0697] To a mixture of -isopropyl-1-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)benzimidazole-5-carboxylic acid (100 mg) and HATU (67.72 mg) in DMF (5 ml) were added N,N-diisopropylethylamine (0.08 ml) and methylamine (CAS 74-89-5) (0.15 ml). The reaction mixture was stirred at 15° C. for 12 hours. The mixture was poured into water and extracted with ethyl acetate (3×10 ml). The combined organic layers were concentrated and purified by preparative HPLC to afford 2-isopropyl-N-methyl-1-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)benzimidazole-5-carboxamide (16.8 mg, 31.1%) as a yellow solid. MS (ISP): 364.4 ([M+H].sup.+).

Example 29

2-(2-Methoxy-4-pyridyl)-N-methyl-1-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)benzimidazole-5-carboxamide

[0698] ##STR00044##

a) N-Methyl-3-nitro-4-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)amino]benzamide

[0699] To a solution of 6-amino-3,4-dihydro-1H-1,8-naphthyridin-2-one.sup.Error! Bookmark not defined. (1.0 g) in N-methyl-2-pyrrolidinone (5 ml) were added 4-fluoro-N-methyl-3-nitro-benzamide.sup.Error!Bookmark not defined. (0.78 g) and N,N-diisopropylethylamine (1.4 ml). The mixture was stirred at 120° C. for 12 hours. The reaction mixture was then cooled to 20° C. and poured into water. The resulting solid was collected by filtration, and the filter cake was washed with ethyl acetate and dried in vacuo to afford N-methyl-3-nitro-4-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)amino]benzamide (290 mg, 19.7%) as a brown solid. MS (ISP): 342.1 ([M+H].sup.+).

b) 3-Amino-N-methyl-4-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)amino]benzamide

[0700] To a stirred solution of N-methyl-3-nitro-4-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)amino]benzamide (290 mg) in methanol (6 ml) was added 10% palladium on charcoal (100 mg). The reaction mixture was stirred at room temperature under an atmosphere of hydrogen for 12 hours. The reaction mixture was filtered, washing with N,N-dimethylformamide. The filtrate was then concentrated in vacuo to afford 3-amino-N-methyl-4-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)amino]benzamide (180 mg, 63.7%) as a brown solid. MS (ISP): 312.3 ([M+H].sup.+).

c) 2-(2-Methoxy-4-pyridyl)-N-methyl-1-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)benzimidazole-5-carboxamide

[0701] To a solution of 3-amino-N-methyl-4-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)amino]benzamide (120 mg) and 2-methoxypyridine-4-carboxaldehyde.sup.Error! Bookmark not defined. (28.2 mg) in DMF (6 ml) was added sodium metabisulfite (109 mg). The reaction mixture was stirred at 110° C. for 1 hour. The mixture was then poured into water and extracted with ethyl acetate (3×10 ml). The combined organic layers were concentrated in vacuo and purified by preparative HPLC to afford methyl 2-(2-methoxy-4-pyridyl)-N-methyl-1-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)benzimidazole-5-carboxamide (63.8 mg, 38.6%) as a brown solid. MS (ISP): 429.3 ([M+H].sup.+).

Example 30

2-(2-Acetylphenyl)-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0702] ##STR00045##

[0703] To a 4 M solution of HCl in dioxane were added 3-amino-N-methyl-4-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)amino]benzamide (200.0 mg) and 2-acetylbenzoic acid (CAS 577-56-0) (126.95 mg). The reaction mixture was stirred at 110° C. for 12 hours and was then concentrated in vacuo and purified by preparative HPLC to afford 2-(2-acetylphenyl)-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide (4.4 mg, 2.6%) as a white solid. MS (ISP): 439.3 ([M+H].sup.+).

Example 31

N-Methyl-2-[2-(methylcarbamoyl)phenyl]-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0704] ##STR00046##

a) 2-[5-(Methylcarbamoyl)-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazol-2-yl]benzoic acid

[0705] The title compound was obtained in analogy to example 6 using 2-formylbenzoic acid (CAS 119-67-5) in place of 2-phenylacetaldehyde in step c. Yellow oil. MS (ISP): 441.1 ([M+H].sup.+).

b) N-Methyl-2-[2-(methylcarbamoyl)phenyl]-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0706] The title compound was obtained in analogy to example 2 step e using 2-[5-(methylcarbamoyl)-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazol-2-yl]benzoic acid in place 2-[2-(3-methylimidazol-4-yl)-4-quinolyl]-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxylic acid. White solid. MS (ISP): 454.3 ([M+H].sup.+).

Example 32

2-(3-Methoxyphenyl)-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0707] ##STR00047##

[0708] The title compound was obtained in analogy to example 6 using 3-methoxybenzaldehyde (CAS 591-31-1) in place of 2-phenylacetaldehyde in step c. White solid. MS (ISP): 427.3 ([M+H].sup.+).

Example 33

2-(5-Methoxy-2-methyl-phenyl)-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0709] ##STR00048##

[0710] The title compound was obtained in analogy to example 6 using 5-methoxy-2-methyl-benzaldehyde (CAS 56724-09-5) in place of 2-phenylacetaldehyde in step c. White solid. MS (ISP): 441.3 ([M+H].sup.+).

Example 34

2-[4-(Acetamidomethyl)phenyl]-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0711] ##STR00049##

[0712] The title compound was obtained in analogy to example 6 using N-[(4-formylphenyl)methyl]acetamide (CAS 156866-50-1) in place of 2-phenylacetaldehyde in step c. White solid. MS (ISP): 468.3 ([M+H].sup.+).

Example 35

2-(2-Fluoro-5-methoxy-phenyl)-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0713] ##STR00050##

[0714] The title compound was obtained in analogy to example 6 using 2-fluoro-5-methoxybenzaldehyde (CAS 105728-90-3) in place of 2-phenylacetaldehyde in step c. White solid. MS (ISP): 445.2 ([M+H].sup.+).

Example 36

2-[2-(Hydroxymethyl)phenyl]-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0715] ##STR00051##

a) Methyl 2-[5-(methylcarbamoyl)-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazol-2-yl]benzoate

[0716] The title compound was obtained in analogy to example 6 using methyl 2-formylbenzoate (CAS 4122-56-9) in place of 2-phenylacetaldehyde in step c. White solid. MS (ISP): 455.1 ([M+H].sup.+).

b) 2-[2-(Hydroxymethyl)phenyl]-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0717] To a cooled solution of methyl 2-[5-(methylcarbamoyl)-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazol-2-yl]benzoate (120 mg) in THE (10 ml) at 0° C. was added dropwise DIBAL-H (0.24 ml). The reaction mixture was stirred at 15° C. for 24 hours then a solution of saturated aq. potassium sodium tartrate was added to quench the reaction and the mixture was then stirred at 15° C. for 1 hour. The suspension was filtered, and the filtrate was concentrated and purified by preparative HPLC to afford 2-[2-(hydroxymethyl)phenyl]-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide (8 mg, 11.8%) as a yellow solid. MS (ISP): 427.3 ([M+H].sup.+).

Example 37

2-(2-Acetamidophenyl)-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0718] ##STR00052##

[0719] The title compound was obtained in analogy to example 6 using N-(2-formylphenyl)acetamide (CAS 13493-47-5) in place of 2-phenylacetaldehyde in step c. Yellow solid. MS (ISP): 454.0 ([M+H].sup.+).

Example 38

2-(2-Aminophenyl)-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0720] ##STR00053##

[0721] To a mixture of 2-(2-acetamidophenyl)-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide (570 mg) in methanol (10 ml) was added cesium carbonate (148 mg). The reaction mixture was stirred at 80° C. for 36 hours and was then concentrated in vacuo and purified by preparative HPLC to afford 2-(2-aminophenyl)-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide (15.7 mg) as a yellow solid. MS (ISP): 412.3 ([M+H].sup.+).

Example 39

2-(4-Methoxy-6-methyl-2-pyridyl)-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0722] ##STR00054##

[0723] The title compound was obtained in analogy to example 6 using 4-methoxy-6-methyl-pyridine-2-carbaldehyde (CAS 75358-79-1) in place of 2-phenylacetaldehyde in step c. Yellow solid. MS (ISP): 442.3 ([M+H].sup.+).

Example 40

Methyl 2-[5-(methylcarbamoyl)-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazol-2-yl]pyridine-3-carboxylate

[0724] ##STR00055##

[0725] The title compound was obtained in analogy to example 6 using methyl 2-formylpyridine-3-carboxylate (CAS 25230-59-5) in place of 2-phenylacetaldehyde in step c. Yellow solid. MS (ISP): 456.3 ([M+H].sup.+).

Example 41

Methyl 2-[[5-(methylcarbamoyl)-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazol-2-yl]methyl]benzoate

[0726] ##STR00056##

[0727] The title compound was obtained in analogy to example 6 using methyl 2-(2-oxoethyl)benzoate (CAS 62723-81-3) in place of 2-phenylacetaldehyde in step c. Yellow solid. MS (ISP): 469.2 ([M+H].sup.+).

Example 42

2-(3-Acetamido-2-pyridyl)-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0728] ##STR00057##

[0729] The title compound was obtained in analogy to example 6 using N-(2-formyl-3-pyridyl)acetamide (CAS 1207715-24-9) in place of 2-phenylacetaldehyde in step c. Yellow solid. MS (ISP): 455.3 ([M+H].sup.+).

Example 43

2-(3-Amino-2-pyridyl)-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0730] ##STR00058##

[0731] The title compound was obtained in analogy to example 6 using 3-aminopyridine-2-carbaldehyde (CAS 55234-58-7) in place of 2-phenylacetaldehyde in step c. Yellow solid. MS (ISP): 413.3 ([M+H].sup.+).

Example 44

2-(5-Fluoro-2-methoxy-4-pyridyl)-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0732] ##STR00059##

[0733] The title compound was obtained in analogy to example 6 using 5-fluoro-2-methoxy-pyridine-4-carbaldehyde (CAS 884495-12-9) in place of 2-phenylacetaldehyde in step c. White solid. MS (ISP): 446.3 ([M+H].sup.+).

Example 45

N-Methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-2-[3-(trifluoromethyl)-4-pyridyl]benzimidazole-5-carboxamide

[0734] ##STR00060##

[0735] The title compound was obtained in analogy to example 6 using 3-(trifluoromethyl)pyridine-4-carbaldehyde (CAS 1060801-92-4) in place of 2-phenylacetaldehyde in step c. Yellow solid. MS (ISP): 466.2 ([M+H].sup.+).

Example 46

2-[2-(Hydroxymethyl)-4-pyridyl]-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0736] ##STR00061##

a) (4-Bromo-2-pyridyl)methoxy-triisopropyl-silane

[0737] To a solution of (4-bromo-2-pyridyl)methanol (CAS 131747-45-0) (1 g) and triisopropylsilyl chloride (2.05 g) in N,N-dimethylformamide (20 ml) was added imidazole.sup.Error! Bookmark not defined. (905 mg). The reaction mixture was stirred at 15° C. for 12 hours and was then quenched by addition of water. Ethyl acetate was then added. The layers were separated and the organic layer was concentrated in vacuo and purified by column chromatography (SiO.sub.2, petrol ether/ethyl acetate=50:1) to afford (4-bromo-2-pyridyl)methoxy-triisopropyl-silane (2.6 g, 71%) as a colourless oil.

[0738] .sup.1H NMR (400 MHz, CDCl3): δ=8.31 (d, J=5.3 Hz, 1H), 7.77 (d, J=1.0 Hz, 1H), 7.33 (dd, J=1.8, 5.3 Hz, 1H), 4.91 (s, 2H), 1.24-1.16 (m, 3H), 1.06 (s, 18H).

b) 2-(Triisopropylsilyloxymethyl)pyridine-4-carbaldehyde

[0739] To a solution of (4-bromo-2-pyridyl)methoxy-triisopropyl-silane (2.4 g) in dry THE (30 ml) was added n-BuLi solution (2.93 ml) at −70° C. under a nitrogen atmosphere. After stirring at −70° C. for 1 hour, dry N,N-dimethylformamide (0.76 ml) was added dropwise to the reaction mixture and stirring was continued at 10° C. for 2 hours. The reaction was quenched by addition of a solution of saturated aq. ammonium chloride and then the layers were separated. The organic layer was concentrated in vacuo and purified by column chromatography (SiO.sub.2, petrol ether to petrol ether/ethyl acetate=10:1) to give 2-triisopropylsilyloxymethyl)pyridine-4-carbaldehyde (460 mg, 32.1%) as a yellow oil.

c) N-Methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-2-[2-(triisopropylsilyloxymethyl)-4-pyridyl]benzimidazole-5-carboxamide

[0740] The title compound was obtained in analogy to example 6 using 2-(triisopropylsilyloxymethyl)pyridine-4-carbaldehyde in place of 2-phenylacetaldehyde in step c. Yellow oil. MS (ISP): 584.3 ([M+H].sup.+).

d) 2-[2-(Hydroxymethyl)-4-pyridyl]-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0741] A solution of N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-2-[2-(triisopropylsilyloxymethyl)-4-pyridyl]benzimidazole-5-carboxamide (130.0 mg) in pyridine hydrofluoride (2.0 ml) and THE (8 ml) was stirred at 15° C. for 1 hour. The mixture was adjusted to pH 8 by addition of aq. ammonium hydroxide and the layers were then separated. The organic layer was dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuo and purified by preparative HPLC to afford 2-[2-(hydroxymethyl)-4-pyridyl]-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide (17.2 mg, 32.9% yield) as a yellow solid. MS (ISP): 428.3 ([M+H].sup.+).

Example 47

2-[[2-Methoxy-4-(trifluoromethyl)phenyl]methyl]-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0742] ##STR00062##

[0743] The title compound was obtained in analogy to example 6 using 2-[2-methoxy-4-(trifluoromethyl)phenyl]acetaldehyde (CAS 1823320-58-6) in place of 2-phenylacetaldehyde in step c. White solid. MS (ISP): 509.4 ([M+H].sup.+).

Example 48

2-(2-Acetyl-3-pyridyl)-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0744] ##STR00063##

a) 2-[2-(1-Ethoxyvinyl)-3-pyridyl]-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0745] The title compound was obtained in analogy to example 6 using 2-(1-ethoxyvinyl)pyridine-3-carbaldehyde (CAS 2138266-81-4) in place of 2-phenylacetaldehyde in step c. Yellow oil. MS (ISP): 468.2 ([M+H].sup.+).

b) 2-(2-Acetyl-3-pyridyl)-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0746] A solution of 2-[2-(1-ethoxyvinyl)-3-pyridyl]-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide (300 mg) in a 1:2 mixture of 2 M aq. HCl/acetonitrile (12 ml) was stirred at 110° C. for 1 hour. The reaction mixture was neutralized by addition of a saturated aq. solution of NaHCO.sub.3 and extracted with ethyl acetate (3×15 ml). The combined organic phases were dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuo and purified by preparative HPLC to give 2-(2-acetyl-3-pyridyl)-N-methyl-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide (20.4 mg, 26.3%) as a yellow solid. MS (ISP): 440.3 ([M+H].sup.+).

Example 49

N-Methyl-2-[3-(methylcarbamoyl)-2-pyridyl]-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0747] ##STR00064##

a) Methyl 2-[5-(methylcarbamoyl)-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazol-2-yl]pyridine-3-carboxylate

[0748] The title compound was obtained in analogy to example 6 using methyl 2-formylpyridine-3-carboxylate.sup.Error! Bookmark not defined. in place of 2-phenylacetaldehyde in step c. Yellow oil. MS (ISP): 456.3 ([M+H].sup.+).

b) 2-[5-(Methylcarbamoyl)-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazol-2-yl]pyridine-3-carboxylic acid

[0749] The title compound was obtained in analogy to example 2 step d using methyl 2-[5-(methylcarbamoyl)-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazol-2-yl]pyridine-3-carboxylate in place of methyl 2-[2-(3-methylimidazol-4-yl)-4-quinolyl]-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxylate in step d. Yellow oil. MS (ISP): 442.1 ([M+H].sup.+).

c) N-Methyl-2-[3-(methylcarbamoyl)-2-pyridyl]-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxamide

[0750] The title compound was obtained in analogy to example 2 step e using 2-[5-(methylcarbamoyl)-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazol-2-yl]pyridine-3-carboxylic acid in place of 2-[2-(3-methylimidazol-4-yl)-4-quinolyl]-1-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzimidazole-5-carboxylic acid. White solid. MS (ISP): 455.3 ([M+H].sup.+).

Example 50

Methyl 2-isopropyl-1-(6-oxo-7,8-dihydro-5H-1,5-naphthyridin-2-yl)benzimidazole-5-carboxylate

[0751] ##STR00065##

a) Methyl 3-nitro-4-[(6-oxo-7,8-dihydro-5H-1,5-naphthyridin-2-yl)amino]benzoate

[0752] To a solution of 6-chloro-3,4-dihydro-1H-1,5-naphthyridin-2-one.sup.Error! Bookmark not defined. (1.3 g) in 1,4-dioxane (40 ml) were added methyl 4-amino-3-nitro-benzoate.sup.Error! Bookmark not defined. (1.536 g), cesium carbonate (4.639 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (165 mg) and tris(dibenzylideneacetone)dipalladium (0) (130 mg). The reaction mixture was stirred at 120° C. for 12 hours under a nitrogen atmosphere and then water was added. The resulting precipitate was then collected by filtration and dried in vacuo to afford methyl 3-nitro-4-[(6-oxo-7,8-dihydro-5H-1,5-naphthyridin-2-yl)amino]benzoate (800 mg, 31.2%) as a brown solid. MS (ISP): 343.1 ([M+H].sup.+).

b) 2-Isopropyl-1-(6-oxo-7,8-dihydro-5H-1,5-naphthyridin-2-yl)benzimidazole-5-carboxylic acid

[0753] The title compound was obtained in analogy to example 28 steps b-d using methyl 3-nitro-4-[(6-oxo-7,8-dihydro-5H-1,5-naphthyridin-2-yl)amino]benzoate in place of methyl 3-nitro-4-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)amino]benzoate in step b. Brown oil. MS (ISP): 313.1 ([M+H].sup.+).

c) Methyl 2-isopropyl-1-(6-oxo-7,8-dihydro-5H-1,5-naphthyridin-2-yl)benzimidazole-5-carboxylate

[0754] The title compound was obtained in analogy to example 28 using 2-isopropyl-1-(6-oxo-7,8-dihydro-5H-1,5-naphthyridin-2-yl)benzimidazole-5-carboxylic acid in place of 2-isopropyl-1-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)benzimidazole-5-carboxylic acid in step e. White solid. MS (ISP): 365.4 ([M+H].sup.+).

Example 51

2-Isopropyl-N-methyl-1-(6-oxo-7,8-dihydro-5H-1,5-naphthyridin-2-yl)benzimidazole-5-carboxamide

[0755] ##STR00066##

a) 2-Isopropyl-1-(6-oxo-7,8-dihydro-5H-1,5-naphthyridin-2-yl)benzimidazole-5-carboxylic acid

[0756] The title compound was obtained in analogy to example 28 step d using methyl 2-isopropyl-1-(6-oxo-7,8-dihydro-5H-1,5-naphthyridin-2-yl)benzimidazole-5-carboxylate in place of methyl 2-isopropyl-1-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)benzimidazole-5-carboxylate. Yellow solid. MS (ISP): 351.1 ([M+H].sup.+).

b) 2-Isopropyl-N-methyl-1-(6-oxo-7,8-dihydro-5H-1,5-naphthyridin-2-yl)benzimidazole-5-carboxamide

[0757] To a solution of 2-isopropyl-1-(6-oxo-7,8-dihydro-5H-1,5-naphthyridin-2-yl)benzimidazole-5-carboxylic acid (100 mg) in DMF (5 ml) were added 1-propanephosphonic anhydride (264 mg, 0.42 mmol, triethylamine (0.12 ml) and methylamine.sup.Error! Bookmark not defined. (17.2 mg). The mixture was stirred at 20° C. for 12 hours then the reaction mixture was concentrated in vacuo and purified by preparative HPLC to give 2-isopropyl-N-methyl-1-(6-oxo-7,8-dihydro-5H-1,5-naphthyridin-2-yl)benzimidazole-5-carboxamide (22 mg, 21.9%) as a white solid. MS (ISP): 364.4 ([M+H].sup.+).

Example 52

2-Isopropyl-N,N-dimethyl-1-(6-oxo-7,8-dihydro-5H-1,5-naphthyridin-2-yl)benzimidazole-5-carboxamide

[0758] ##STR00067##

[0759] The title compound was obtained in analogy to example 51 step b using dimethylamine (CAS 124-40-3) in place of methylamine. Yellow solid. MS (ISP): 378.4 ([M+H].sup.+).

Example 53

7-(1H-Imidazol-1-yl)-3,4-dihydroquinolin-2(1H)-one

[0760] ##STR00068##

[0761] To a solution of 7-amino-3,4-dihydroquinolin-2(1H)-one (CAS 22246-07-7) (200 mg) in methanol (2 ml) were added ammonium acetate (190 mg), oxalaldehyde (40% solution in water, 283 μl) and formaldehyde (36% in water, 472 μl). The yellow solution was stirred at 95° C. for 4 hours. The reaction mixture was then cooled to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate and a saturated aq. solution of sodium hydrogen carbonate and then the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, eluent: 0 to 10% of methanol in dichloromethane) to afford 7-(1H-imidazol-1-yl)-3,4-dihydroquinolin-2(1H)-one (118 mg, 44.9%) as a light yellow solid. MS (ISP): 214.2 ([M+H].sup.+).

Example 54

6-(Indoline-1-carbonyl)-3,4-dihydro-1H-quinolin-2-one

[0762] ##STR00069##

[0763] To a stirred solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (902 mg) and 1-hydroxybenzotriazole (636 mg) in N,N-dimethylformamide (3 ml) were added 2-oxo-3,4-dihydro-1H-quinoline-6-carboxylic acid (CAS 88371-24-8) (300 mg) and indoline.sup.Error! Bookmark not defined. (0.23 ml) and then the reaction mixture was stirred at 25° C. for 16 hours. The reaction was diluted into water (10 ml) and extracted with ethyl acetate (2×5 ml). The combined organic phases were concentrated in vacuo and the residue was purified by preparative HPLC to give 6-(indoline-1-carbonyl)-3,4-dihydro-1H-quinolin-2-one (14.4 mg, 3%) as a yellow solid. MS (ISP): 307.2 ([M+H].sup.+).

Example 55

6-(2,3-Dihydropyrrolo[2,3-b]pyridine-1-carbonyl)-3,4-dihydro-1H-quinolin-2-one

[0764] ##STR00070##

[0765] The title compound was obtained in analogy to example 54 using 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (CAS 1221503-20-3) in place of indoline. White solid. MS (ISP): 294.1 ([M+H].sup.+).

Example 56

6-(3,4-Dihydro-2H-quinoline-1-carbonyl)-3,4-dihydro-1H-quinolin-2-one

[0766] ##STR00071##

[0767] To a stirred solution of 2-oxo-3,4-dihydro-1H-quinoline-6-carboxylic acid (300 mg) and 1,2,3,4-tetrahydroquinoline (CAS 635-46-1) (0.3 ml) in acetonitrile (5 ml) at 0° C. were added sequentially 3-methylpyridine (731 mg) and methanesulfonyl chloride (360 mg). The reaction mixture was warmed to 25° C. and stirred at 25° C. for 16 hours. The solution was diluted with water (5 ml) and was extracted with ethyl acetate (3×5 ml). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC to afford 6-(3,4-dihydro-2H-quinoline-1-carbonyl)-3,4-dihydro-1H-quinolin-2-one as a yellow solid. MS (ISP): 293.1 ([M+H].sup.+).

Example 57

N-(1-Acetyl-4-piperidyl)-2-oxo-3,4-dihydro-1H-quinoline-6-carboxamide

[0768] ##STR00072##

[0769] The title compound was obtained in analogy to example 54 using 1-acetyl-4-amino-piperidine (CAS 160357-94-8) in place of indoline. White solid. MS (ISP): 316.2 ([M+H].sup.+).

Example 58

6-(Indoline-1-carbonyl)-3,4-dihydro-1H-1,8-naphthyridin-2-one

[0770] ##STR00073##

a) 7-Oxo-6,8-dihydro-5H-1,8-naphthyridine-3-carboxylic acid

[0771] Methyl 7-oxo-6,8-dihydro-5H-1,8-naphthyridine-3-carboxylate (CAS 1822623-53-9) (800 mg) and lithium hydroxide (185 mg) were dissolved in a 1:1 mixture of THF/water (16.0 ml). After stirring at 15° C. for 3 hours, the reaction mixture was extracted twice with ethyl acetate. The aqueous layer was adjusted to pH 2 by addition of 1 N aq. HCl and then extracted with ethyl acetate. The organic layer was separated, dried over Na.sub.2SO.sub.4, and concentrated in vacuo to afford 7-oxo-6,8-dihydro-5H-1,8-naphthyridine-3-carboxylic acid (200 mg, 24.8%) as a yellow oil. MS (ISP): 193.1 ([M+H].sup.+).

b) 6-(Indoline-1-carbonyl)-3,4-dihydro-1H-1,8-naphthyridin-2-one

[0772] The title compound was obtained in analogy to example 54 using 7-oxo-6,8-dihydro-5H-1,8-naphthyridine-3-carboxylic acid in place of added 2-oxo-3,4-dihydro-1H-quinoline-6-carboxylic acid. Yellow solid. MS (ISP): 294.2 ([M+H].sup.+).

Example 59

6-(2,3-Dihydropyrrolo[2,3-b]pyridine-1-carbonyl)-3,4-dihydro-1H-1,8-naphthyridin-2-one

[0773] ##STR00074##

[0774] The title compound was obtained in analogy to example 54 using 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine.sup.Error! Bookmark not defined. in place of indoline and 7-oxo-6,8-dihydro-5H-1,8-naphthyridine-3-carboxylic acid in place of 2-oxo-3,4-dihydro-1H-quinoline-6-carboxylic acid. White solid. MS (ISP): 295.2 ([M+H].sup.+).

Example 60

6-(3,4-Dihydro-2H-quinoline-1-carbonyl)-3,4-dihydro-1H-1,8-naphthyridin-2-one

[0775] ##STR00075##

[0776] The title compound was obtained in analogy to example 56 using 7-oxo-6,8-dihydro-5H-1,8-naphthyridine-3-carboxylic acid in place of 2-oxo-3,4-dihydro-1H-quinoline-6-carboxylic acid. Yellow solid. MS (ISP): 308.2 ([M+H].sup.+).

Example 61

6-(2-Isopropyl-1H-benzo[d]imidazol-1-yl)-3,4-dihydroquinazolin-2(1H)-one

[0777] ##STR00076##

[0778] The title compound was obtained in analogy to example 6 using 1-fluoro-2-nitrobenzene.sup.Error!Bookmark not defined. in place of 4-fluoro-N-methyl-3-nitrobenzamide and 6-amino-3,4-dihydroquinazolin-2(1H)-one (CAS 1260835-29-7) in place of 6-amino-3,4-dihydroquinolin-2(1H)-one in step a, and isobutyraldehyde.sup.Error! Bookmark not defined. in place of 2-phenylacetaldehyde in step c. White solid. MS (ISP): 307.2 ([M+H].sup.+).

Example 62

2-Isopropyl-N-methyl-1-(2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0779] ##STR00077##

[0780] The title compound was obtained in analogy to example 6 using 6-amino-3,4-dihydroquinazolin-2(1H)-one.sup.Error! Bookmark not defined. in place of 6-amino-3,4-dihydroquinolin-2(1H)-one in step a, and isobutyraldehyde.sup.Error! Bookmark not defined, in place of 2-phenylacetaldehyde in step c. Light yellow solid. MS (ISP): 364.2 ([M+H].sup.+).

Example A

N-(10-(2-((6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)decyl)-2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0781] ##STR00078##

a) tert-Butyl (10-(2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamido)decyl)carbamate

[0782] To 2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxylic acid (70 mg) were added sequentially HATU (556 μl, 0.27 M solution in DMF), tert-butyl (5-aminopentyl)carbamate (CAS 51644-96-3) (35.8 mg) and N,N-diisopropylethylamine (95 μl). The brown solution was stirred at room temperature for 19 h. The reaction mixture was purified by reversed phase HPLC. The fractions were collected and lyophilised to afford tert-butyl (10-(2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamido)decyl)carbamate as a white foam (27 mg, 28%). MS (ISP): 769.9 ([M+H].sup.+).

b) N-(10-Aminodecyl)-2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide hydrochloride

[0783] To a stirred solution of tert-butyl (10-(2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamido)decyl)carbamate (40 mg, 52 μmol, Eq: 1) in EtOAc (500 μl) was added a solution of 4 M HCl in dioxane (780 μl). The reaction mixture was stirred at room temperature for 3 hours. LC/MS analysis indicated that the reaction was finished. The solvent was evaporated to afford N-(10-aminodecyl)-2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide hydrochloride as a light yellow foam (34.8 mg, 95%) which was used in the next step without further purification. MS (ISP): 670 ([M+H].sup.+).

c) N-(10-(2-((6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)decyl)-2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0784] To a mixture of N-(10-aminodecyl)-2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide hydrochloride (34.8 mg) and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (23.7 mg) were added HATU (202 μl, 0.27 M solution in DMF) and N,N-diisopropylethylamine (34.5 μl). The reaction mixture was shaken at room temperature for 2 hours. LC/MS analysis indicated that the reaction was finished. The reaction mixture was purified by reversed phase HPLC. The fractions were collected and lyophilised. The resulting foam was stirred in diethyl ether, and the ensuing crystals were collected by filtration and dried in vacuo to afford N-(10-(2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)decyl)-2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide as a white solid (17 mg, 31%). MS (ISP): 1051.4 ([M+H].sup.+).

Example B

N-(5-(2-((6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)pentyl)-2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0785] ##STR00079##

a) tert-Butyl (5-(2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamido)pentyl)carbamate

[0786] The title compound was obtained in analogy to example A using tert-butyl (10-aminodecyl)carbamate (CAS 216961-61-4) in place of tert-butyl (5-aminopentyl)carbamate in step a. Off-white foam. MS (ISP): 699.5 ([M+H].sup.+).

b) N-(5-Aminopentvl)-2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide hydrochloride

[0787] The title compound was obtained in analogy to example A using tert-butyl (5-(2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamido)pentyl)carbamate in place of tert-butyl (10-(2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamido)decyl)carbamate in step b. Off-white foam. MS (ISP): 599.4 ([M+H].sup.+).

c) N-(5-(2-((6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)pentyl)-2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0788] To a mixture of N-(5-aminopentyl)-2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide hydrochloride (34 mg) and 2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (27.3 mg) were added HATU (202 μl, 0.27 M solution in DMF) and N,N-diisopropylethylamine (34.5 μl). The reaction mixture was shaken at room temperature for 2 hours. LC/MS analysis indicated that the reaction was finished. The reaction mixture was then transferred to a separating funnel. Ethyl acetate/TBME (1:1) and water were added to give a sticky solid. After removal of the aqueous and organic layers, the sticky solid was recovered by dissolving in CH.sub.2C.sub.2. The organic phase was dried over MgSO.sub.4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, eluent: 0 to 10% of methanol in dichloromethane) to afford N-(5-(2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)pentyl)-2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide as an off-white solid (27 mg, 51%). MS (ISP): 981.4 ([M+H].sup.+).

Example C

N-(2-(2-(2-(2-((6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)ethyl)-2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0789] ##STR00080##

a) (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-2-hydroxy-2-phenylethyl)pyrrolidine-2-carboxamide

[0790] The title compound was obtained in analogy to example A using tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (CAS 153086-78-3) in place of tert-butyl (5-aminopentyl)carbamate in step a. White foam. MS (ISP): 745.45 ([M+H].sup.+).

b) N-(2-(2-(2-Aminoethoxy)ethoxy)ethyl)-2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide hydrochloride

[0791] The title compound was obtained in analogy to example A using tert-butyl (2-(2-(2-(2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamido)ethoxy)ethoxy)ethyl)carbamate in place of tert-butyl (10-(2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamido)decyl)carbamate in step b. Off-white foam. MS (ISP): 645.48 ([M+H].sup.+).

c) N-(2-(2-(2-(2-((6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)ethyl)-2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide

[0792] To a mixture of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide hydrochloride (44 mg) and 2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (32 mg) were added HATU (264 μl, 0.27 M solution in DMF) and N,N-diisopropylethylamine (44.1 μl). The reaction mixture was shaken at room temperature for 2 hours. LC/MS analysis indicated that the reaction was finished. The reaction mixture was partioned between dichloromethane and water. The organic phase was separated, dried over MgSO.sub.4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, eluent: 0 to 10% of methanol in dichloromethane) to afford N-(2-(2-(2-(2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)ethyl)-2-(2-(1-methyl-1H-imidazol-5-yl)quinolin-4-yl)-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-benzo[d]imidazole-5-carboxamide as an off-white solid (11.7 mg, 18%). MS (ISP): 1027.4 ([M+H].sup.+).

[0793] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be readily apparent to one of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the invention as defined in the appended claims.