AHR AGONISTS

Abstract

The present invention relates to certain substituted AHR agonist compounds, to pharmaceutical compositions comprising the compounds and to methods of using the compounds to treat immune-mediated diseases.

Claims

1. A compound of the formula: ##STR00103## R.sup.1 is selected from phenyl optionally substituted with 1-2 R, 5- to 6-membered heteroaryl optionally substituted with R.sup.k and C.sub.3-C.sub.6 cycloalkyl optionally substituted with R.sup.j; R.sup.i is independently selected from halogen, C.sub.1-C.sub.4 alkyl, CF.sub.3, OH, O(C.sub.1-C.sub.4 alkyl), O(C.sub.1-C.sub.3)OCH.sub.3 and NH(C.sub.1-C.sub.3 alkyl)N(CH.sub.3).sub.2; R.sup.k is selected from halogen, C.sub.1-C.sub.4 alkyl, nitrile, CF.sub.3 and O(C.sub.1-C.sub.4 alkyl); R.sup.j is O(C.sub.1-C.sub.4 alkyl); X is selected from N and —C(R.sup.4)—; R.sup.2 is C.sub.1-C.sub.3 alkyl, or together with R.sup.4 it forms a 5- to 6-membered heterocyclic fused ring; R.sup.4 is hydrogen, halogen, NH(C.sub.1-C.sub.3 alkyl)N(CH.sub.3).sub.2, or together with R.sup.2 it forms a 5- to 6-membered heterocyclic fused ring, R.sup.3 is selected from hydrogen, halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl, NH(C.sub.1-C.sub.3 alkyl), N(C.sub.1-C.sub.3 alkyl).sub.2, NH(C.sub.1-C.sub.3 alkyl)OH, NH(C.sub.1-C.sub.3 alkyl)N(C.sub.1-C.sub.3 alkyl).sub.2 and O(C.sub.1-C.sub.3 alkyl)OH; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R.sup.1 is 5- to 6-membered heteroaryl optionally substituted with R.sup.k, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein R.sup.1 is 5- to 6-membered heteroaryl, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, wherein X is CH, or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, wherein R.sup.2 is C.sub.1-C.sub.3 alkyl, or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, wherein R.sup.2 is CH.sub.3, or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, wherein R.sup.3 is selected from hydrogen, CH.sub.3, NH(CH.sub.3), N(CH.sub.3).sub.2, N(CH.sub.2CH.sub.2)OH, N(CH.sub.2CH.sub.2)N(CH.sub.3).sub.2 and O(CH.sub.2CH.sub.2)OH.

8. The compound according to claim 1, wherein R.sup.3 is selected from hydrogen and N(CH.sub.2CH.sub.2)N(CH.sub.3).sub.2.

9. The compound according to claim 1, which is selected from: ##STR00104## or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, which is selected from: ##STR00105##

11. A pharmaceutical composition, comprising a compound or a pharmaceutically acceptable salt thereof according to claim 1 with one or more pharmaceutically acceptable carriers, diluents, or excipients.

12. A method of treating an immune-mediated disease in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to claim 1.

13. A method of treating a disease or disorder selected from psoriasis, ulcerative colitis, Crohn's disease, graft-versus-host disease and multiple sclerosis in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to claim 1.

14. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, for use in therapy.

15. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from psoriasis, ulcerative colitis, Crohn's disease, graft-versus-host disease and multiple sclerosis.

Description

PREPARATIONS AND EXAMPLES

[0044] The following Preparations and Examples further illustrate the invention.

Intermediate 1

1-Methyl-2-Oxo-1,8-Naphthyridine-3-Carboxylic Acid

[0045] ##STR00005##

[0046] Step A: A mixture of 2-amino-3-pyridinecarboxaldehyde (500 mg, 3.972 mmol), diethyl malonate (6 mL, 39.48 mmol) and piperidine (1.6 mL, 16 mmol) is stirred in EtOH (7 mL, 120 mmol) for 1 hr. at ambient temperature. The mixture is refluxed for 2 hrs., and the precipitate collected by filtration. The solids are washed with cold EtOH and dried under vacuum to give ethyl 2-oxo-1H-1,8-naphthyridine-3-carboxylate (710 mg, 3.254 mmol, 81.93%) ES/MS (m/z): 219.0 (M+H). .sup.1H NMR (400 MHz, d6-DMSO): 12.40 (s, 1H), 8.61 (dd, J=1.8, 4.7 Hz, 1H), 8.50 (s, 1H), 8.28 (dd, J=1.8, 7.8 Hz, 1H), 7.30 (dd, J=4.7, 7.8 Hz, 1H), 4.29 (q, J=7.1 Hz, 2H), 3.33 (s, 1H), 1.31 (t, J=7.1 Hz, 4H).

[0047] Step B: Iodomethane (0.61 mL, 9.8 mmol) and potassium carbonate (372 mg, 2.69167 mmol) are added to a suspension of ethyl 2-oxo-1H-1,8-naphthyridine-3-carboxylate (710 mg, 3.254 mmol) in EtOH (8 mL, 198 mmol) and N,N-dimethylformamide (8 mL, 103 mmol). The mixture is stirred overnight at ambient temperature, then diluted with ethyl acetate. The quenched reaction is washed sequentially with saturated aqueous sodium bicarbonate, and brine, dried with anhydrous sodium sulfate and filtered off. The filtrate is concentrated in vacuo. The residue is purified by silica gel chromatography to give ethyl 1-methyl-2-oxo-1,8-naphthyridine-3-carboxylate (648 mg, 2.7344 mmol, 84.039% Yield). ES/MS (m/z): 233.0 (M+H). .sup.1H NMR (400 MHz, d6-DMSO): 8.75 (dd, J=1.9, 4.8 Hz, 1H), 8.51 (s, 1H), 8.35 (dd, J=1.9, 7.7 Hz, 1H), 7.39 (dd, J=4.7, 7.8 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.70 (s, 3H), 1.32 (t, J=7.1 Hz, 3H).

[0048] Step C: Intermediate 1: Ethyl 1-methyl-2-oxo-1,8-naphthyridine-3-carboxylate (648 mg, 2.734 mmol) is dissolved in a mixture of THF (0.2M, 168 mmol) and methanol (10.94 mmol). 1M aqueous solution of lithium hydroxide (10.94 mmol) is added, and the reaction stirred overnight at ambient temperature. The reaction is concentrated to dryness then dissolved in water and pH adjusted to 1 with 1M aqueous solution of HCl. The white solid is filtered off and dried under house vacuum overnight to give the title product (532 mg, 2.606 mmol, 95.287%). .sup.1H NMR (400 MHz, d6-DMSO): 8.94 (s, 1H), 8.88 (dd, J=1.9, 4.7 Hz, 1H), 8.54 (dd, J=1.9, 7.8 Hz, 1H), 7.54 (dd, J=4.7, 7.8 Hz, 1H), 3.83 (s, 3H).

Intermediate 2

Ethyl 7-Bromo-1-Methyl-2-Oxo-Quinoline-3-Carboxylate

[0049] ##STR00006##

[0050] Step A: A mixture of 2-amino-4-bromobenzaldehyde (3.0 g, 15 mmol), diethyl malonate (22 mL, 144.8 mmol) and piperidine (5.8 mL, 59 mmol) is refluxed in EtOH (40 mL, 687 mmol) for 3 hrs. The reaction is cooled to ambient temperature, filtered, rinsing the solids with cold EtOH followed by Et.sub.2O to give the ethyl 7-bromo-2-oxo-1H-quinoline-3-carboxylate (Step A; 2.71 g, 9.14 mmol, 62%). ES/MS (m/z) (.sup.79Br/.sup.81Br): 297.0/298.0 (M+H). .sup.1H NMR (400 MHz, d6-DMSO): 12.07 (bs, 1H), 8.49 (s, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.50 (d, J=1.9 Hz, 1H), 7.40 (dd, J=1.9, 8.4 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H).

[0051] Step B; Intermediate 2: Ethyl 7-bromo-2-oxo-1H-quinoline-3-carboxylate (2.707 g, 9.142 mmol) is dissolved in N,N-dimethylformamide (30 mL, 388 mmol, 28.4 g). Potassium carbonate (2.78 g, 20.1 mmol) is added followed by iodomethane (1.25 mL, 20.1 mmol, 2.85 g), and stirred at ambient temperature overnight. The reaction is poured into saturated aqueous sodium bicarbonate, and the resulting mixture extracted with ethyl acetate (3×). The organic layers are combined and washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting material is purified by silica gel chromatography eluting with 0-100% ethyl acetate/hexanes gradient to give the title product (2.58 g, 8.32 mmol, 91.0%). ES/MS (m/z) (.sup.79Br/.sup.81Br): 310.0/311.0 (M+H). .sup.1H NMR (399.80 MHz, DMSO): 8.46 (s, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.79 (d, J=1.7 Hz, 1H), 7.51 (dd, J=1.8, 8.4 Hz, 1H), 4.28 (q, J=7.1 Hz, 2H), 3.62 (s, 3H), 1.30 (t, J=7.1 Hz, 3H).

Intermediate 3

5-Bromo-1-Methyl-2-Oxo-Quinoline-3-Carboxylic Acid

[0052] ##STR00007##

[0053] Step A: Diethyl malonate (696 mg, 4.345 mmol) and potassium carbonate (910 mg, 6.519 mmol) are added to a solution of 2-bromo-6-nitro-benzaldehyde (1 g, 4.347 mmol) in acetic anhydride (10 mL). The mixture is stirred at 806185 for 1 hr. The reaction is cooled to ambient temperature and diluted with water (20 mL) and extracted with dichloromethane (20 mL×3). The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the diethyl 2-[(2-bromo-6-nitro-phenyl)methylene]propanedioate (1.6 g, 4.3 mmol, 99%). ES/MS (m/z) (.sup.79Br/.sup.81Br): 370.0/372.0 (M+H).

[0054] Step B: Iron (2.4 g, 37 mmol) is added to a solution of diethyl 2-[(2-bromo-6-nitro-phenyl) methylene] propanedioate (1.6 g, 4.3 mmol) in glacial acetic acid (10 mL). The reaction mixture is stirred at 80° C. for 12 hrs., then filtered through a pad of celite. The pH is adjusted to pH=8 with saturated aqueous sodium bicarbonate. The reaction is extracted with dichloromethane (50 mL×3). The combined organic layers with are washed with brine (30 mL×2), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product is triturated with methanol at ambient temperature for 20 min, then filtered to give the ethyl 5-bromo-2-oxo-1H-quinoline-3-carboxylate (200 mg, 0.540 mmol, 50.28%). ES/MS (m/z) (.sup.79Br/.sup.81Br): 295.0/298.0 (M+H).

[0055] Step C: Cesium carbonate (573 mg, 1.76 mmol) and iodomethane (0.3 mL, 5 mmol) are added to a solution of ethyl 5-bromo-2-oxo-1H-quinoline-3-carboxylate (400 mg, 0.946 mmol) in dimethylformamide (10 mL). The resulting mixture is stirred at 50° C. for 12 hrs. The reaction mixture is quenched with water (10 mL) and extracted with dichloromethane (15 mL×3). The organic layers are combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue is purified with silica gel chromatography eluting with 0˜40% ethyl acetate/petroleum ether gradient to give ethyl 5-bromo-1-methyl-2-oxo-quinoline-3-carboxylate (150 mg, 0.339 mmol, 100%). ES/MS (m/z) (.sup.79Br/.sup.81Br): 310.0/312.0 (M+H).

[0056] Step D: Intermediate 3: Lithium hydroxide (40 mg, 0.934 mmol) in water (2 mL) is added to a solution of ethyl 5-bromo-1-methyl-2-oxo-quinoline-3-carboxylate (100 mg, 0.323 mmol) in THE (2 mL). The resulting mixture is stirred at 40° C. for 1 hr. The mixture is cooled to ambient temperature and pH adjusted to pH 4 with 1 N aqueous HCl. The mixture is diluted with water (5 mL) and extracted with dichloromethane (10 mL×3). The combined organic layers are washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product (70 mg, 0.248 mmol, 77%). .sup.1H NMR (400.13 MHz, d6-DMSO): 14.91-14.86 (m, 1H), 8.94 (s, 1H), 7.84-7.76 (m, 3H), 3.80 (s, 3H).

Example 1

N-(4-Methoxyphenyl)-1-Methyl-2-Oxo-Quinoline-3-Carboxamide

[0057] ##STR00008##

[0058] 1-Methyl-2-oxo-quinoline-3-carboxylic acid (418 mg, 2.057 mmol), 4-methoxyaniline (304 mg, 2.469 mmol), N,N-dimethylformamide (7 mL, 90.5 mmol), HATU (880 mg, 2.268 mmol) and N,N-diisopropylethylamine (1.8 mL, 10 mmol, 100) are added together. The reaction is stirred overnight at ambient temperature, and concentrated. The resulting material is purified by silica gel chromatography eluting with 0-5% dichloromethane/methanol gradient. The resulting solids are triturated with Et.sub.2O to give the title product (548 mg, 1.777 mmol, 86.40% ). ES/MS (m/z): 309.0 (M+H). .sup.1H NMR (400.13 MHz, d6-DMSO): 11.99 (s, 1H), 8.98 (s, 1H), 8.09 (dd, J=1.3, 7.9 Hz, 1H), 7.86-7.81 (m, 1H), 7.74-7.67 (m, 3H), 7.46-7.42 (m, 1H), 6.98-6.95 (m, 2H), 3.81 (s, 3H), 3.77 (s, 3H).

[0059] The following examples in Table 1 are synthesized essentially as described for N-(4-methoxyphenyl)-1-methyl-2-oxo-quinoline-3-carboxamide (Example 1) using the appropriate starting material and reagents.

TABLE-US-00001 TABLE 1 Examples 2-39 ES/MS (m/z) Ex. Chemical Name Structure (M + H)  2 N-(2-Hydroxyphenyl)-1- methyl-2-oxo-quinoline-3- carboxamide [00009] 295.0  3 N-(3,4-Dimethoxyphenyl)-1- methyl-2-oxo-quinoline-3- carboxamide [00010] 339.0  4 N-(4-Fluorophenyl)-1-methyl- 2-oxo-quinoline-3- carboxamide [00011] 297.2  5 1-Methyl-2-oxo-N-(p-tolyl) quinoline-3-carboxamide [00012] 293.0  6 N-(4-Methoxy-2-methyl- phenyl)-1-methyl-2-oxo- quinoline-3-carboxamide [00013] 323.0  7 1-Methyl-N-(4-methyl-2- pyridyl)-2-oxo-quinoline-3- carboxamide [00014] 294.0  8 N-(3-Methoxyphenyl)-1- methyl-2-oxo-quinoline-3- carboxamide [00015] 309.0  9 1-Methyl-2-oxo-N-(2- pyridyl)quinoline-3- carboxamide [00016] 280.0 10 N-(4-Ethoxyphenyl)-1-methyl- 2-oxo-quinoline-3- carboxamide [00017] 323.2 11 1-Methyl-N-(o-tolyl)-2-oxo- quinoline-3-carboxamide [00018] 293.0 12 1-Methyl-2-oxo-N-(4- pyridyl)quinoline-3- carboxamide [00019] 280.0 13 1-Methyl-2-oxo-N-(3- pyridyl)quinoline-3- carboxamide [00020] 280.0 14 N-(5-Fluoropyrimidin-2-yl)-1- methyl-2-oxo-quinoline-3- carboxamide [00021] 299.0 15 N-(5-Methoxypyrimidin-2-yl)- 1-methyl-2-oxo-quinoline-3- carboxamide [00022] 311.0 16 N-(5-Methoxypyrazin-2-yl)-1- methyl-2-oxo-quinoline-3- carboxamide [00023] 311.0 17 1-Methyl-N-(5- methylpyrimidin-2-yl)-2-oxo- quinoline-3-carboxamide [00024] 295.0 18 N-(4-Fluorophenyl)-1-methyl- 2-oxo-1,8-naphthyridine-3- carboxamide [00025] 298.0 19 1-Methyl-N-(6-methyl-2- pyridyl)-2-oxo-quinoline-3- carboxamide [00026] 294.0 20 1-Methyl-N-(5-methyl-2- pyridyl)-2-oxo-quinoline-3- carboxamide [00027] 294.0 21 N-(6-Methoxy-2-pyridyl)-1- methyl-2-oxo-quinoline-3- carboxamide [00028] 310.0 22 N-(5-Fluoro-2-pyridyl)-1- methyl-2-oxo-quinoline-3- carboxamide [00029] 298.0 23 N-(3-Fluorophenyl)-1-methyl- 2-oxo-quinoline-3- carboxamide [00030] 297.0 24 N-(6-Cyano-3-pyridyl)-1- methyl-2-oxo-quinoline-3- carboxamide [00031] 305.1 25 N-(4-Methoxyphenyl)-2-oxo-1- azatricyclo[7.3.1.05,13]trideca- 3,5,7,9(13)-tetraene-3- carboxamide [00032] 335.0 26 N-(4-Methoxyphenyl)-11-oxo-1- azatricyclo[6.3.1.04,12]dodeca- 4(12),5,7,9-tetraene-10- carboxamide [00033] 321.0 27 1-Methyl-N-(1-methylpyrazol- 4-yl)-2-oxo-4a,8a- dihydroquinoline-3- carboxamide; hydrochloride [00034] 283.0 28 N-(3-Fluoro-2-pyridyl)-1- methyl-2-oxo-quinoline-3- carboxamide [00035] 298.0 29 11-Oxo-N-(p-tolyl)-1- azatricyclo[6.3.1.04,12]dodeca- 4(12),5,7,9-tetraene-10- carboxamide [00036] 305.0 30 N-(4-Fluorophenyl)-11-oxo-1- azatricyclo[6.3.1.04,12]dodeca- 4(12),5,7,9-tetraene-10- carboxamide [00037] 309.0 31 11-Oxo-N-[rel-(1S,3R)-3- methoxycyclopentyl]-1- azatricyclo[6.3.1.04,12]dodeca- 4(12),5,7,9-tetraene-10- carboxamide [00038] 313.0 32 N-(3-Bicyclo[1.1.1]pentanyl)- 1-methyl-2-oxo-quinoline-3- carboxamide [00039] 269.0 33 11-Oxo-N-[4- (trifluoromethyl)phenyl]-1- azatricyclo[6.3.1.04,12]dodeca- 4(12),5,7,9-tetraene-10- carboxamide [00040] 359.0 34 2-Oxo-N-phenyl-1H-quinoline- 3-carboxamide [00041] 265.0 35 N-(4-Methoxyphenyl)-1- methyl-2-oxo-1,8- naphthyridine-3-carboxamide [00042] 310.0 36 7-Bromo-N-(4- methoxyphenyl)-1-methyl-2- oxo-quinoline-3-carboxamide [00043] 387.0/389.0 37 N-(5-Fluoro-2-pyridyl)-11- oxo-1- azatricyclo[6.3.1.04,12]dodeca- 4(12),5,7,9-tetraene-10- carboxamide [00044] 310.0 38 11-Oxo-N-pyrimidin-2-yl-1- azatricyclo[6.3.1.04,12]dodeca- 4(12),5,7,9-tetraene-10- carboxamide [00045] 293.0 39 1-Methyl-2-oxo-N-pyrimidin- 2-yl-quinoline-3-carboxamide [00046] 281.0

[0060] Intermediate 4

[0061] Tert-Butyl 4-[4-[(11-Oxo-1-Azatricyclo[6.3.1.04,12]Dodeca-4(12),5,7,9-Tetraene-10-Carbonyl)Amino]Phenyl]Piperidine-1-Carboxylate

##STR00047##

[0062] The title intermediate was synthesized essentially as described for N-(4-methoxyphenyl)-1-methyl-2-oxo-quinoline-3-carboxamide (Example 1) using the appropriate starting material and reagents. ES/MS (m/z) (M+H) 375.2.

Example 40

7-Bromo-1-Methyl-2-Oxo-N-Phenyl-Quinoline-3-Carboxamide

[0063] ##STR00048##

[0064] Trimethylaluminum (2 M) in hexanes (0.5 ml, 1.0 mmol) is slowly added to a 0° C. solution of aniline (0.10 mL, 1.1 mmol) in toluene (2.1 mL, 20 mmol). The reaction is allowed to warm to ambient temperature and stirred for 10 min. Ethyl 7-bromo-1-methyl-2-oxo-quinoline-3-carboxylate (0.208 g, 0.671 mmol) is added as a solid. The reaction is sealed and heated via microwave irradiation to 100° C. for 3 hrs. The reaction is poured into a separatory funnel containing Rochelle's salt and extracted with ethyl acetate (×3).

[0065] The combined organics are washed with 1 N aqueous HCl followed by brine and concentrated in vacuo. The resulting material is purified by silica gel chromatography eluting with 0-100% ethyl acetate/hexanes gradient to give the title product (0.140 g, 0.392 mmol, 58.4% Yield). ES/MS (m/z) (.sup.79Br/.sup.81Br): (M+H) 357.0/359.0. .sup.1H NMR (399.80 MHz, CDCl.sub.3): 11.96 (s, 1H), 8.97 (s, 1H), 7.80-7.77 (m, 2H), 7.69-7.65 (m, 2H), 7.50 (dd, J=1.7, 8.3 Hz, 1H), 7.42-7.37 (m, 2H), 7.18-7.14 (m, 1H), 3.83 (s, 3H).

Example 41

N-(5-Methyl-2-Pyridyl)-11-Oxo-1-Azatricyclo[6.3.1.04,12]Dodeca-4(12),5,7,9-Tetraene-10-Carboxamide

[0066] ##STR00049##

[0067] DIEA (0.12 mL, 0.66 mmol) is added to a solution of 4-oxo-1,2-dihydro-4h-pyrrolo[3,2,1-IJ]quinoline-5-carboxylic acid (0.075 g, 0.33 mmol), 2-amino-5-methylpyridine (0.041 g, 0.36 mmol), and 1-propanephosphonic anhydride (50% mass) in ethyl acetate (0.39 mL, 0.66 mmol, 1.67 mol/L) and dichloromethane (2 mL). The resulting mixture is stirred for 1 hr. at 80° C. The reaction is cooled to ambient temperature and washed with aqueous saturated ammonium chloride. The organics are dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography, eluted with 0-100% ethyl acetate in hexanes to give the title product (3.9 mg, 0.013 mmol, 3.9%). ES/MS (m/z): 306.0 (M+H). .sup.1H NMR (399.80 MHz, d6-DMSO): 12.54 (s, 1H), 9.05 (s, 1H), 8.24-8.22 (m, 2H), 7.82 (dd, J=0.7, 8.0 Hz, 1H), 7.72-7.68 (m, 1H), 7.63-7.61 (m, 1H), 7.33 (dd, J=7.3, 8.0 Hz, 1H), 4.51-4.47 (m, 2H), 3.49 (t, J=7.9 Hz, 2H), 2.29 (s, 3H).

[0068] The following examples in Table 2 are synthesized essentially as described for N-(5-methyl-2-pyridyl)-11-oxo-1-azatricyclo[6.3.1.04,12]dodeca-4(12),5,7,9-tetraene-10-carboxamide (Example 41) using the appropriate starting material and reagents.

TABLE-US-00002 TABLE 2 Examples 42 and 43 ES/MS (m/z) Ex. Chemical Name Structure (M + H) 42 11-Oxo-N-(2-pyridyl)-1- azatricyclo[6.3.1.04,12]dodeca- 4(12),5,7,9-tetraene-10- carboxamide [00050] 291.24592.0 43 N-(1-Methyl-2-oxo-1,8- naphthyridin-3-yl)benzamide [00051] 280.3

[0069] The following intermediates in Table 3 are synthesized essentially as described for N-(5-methyl-2-pyridyl)-11-oxo-1l-azatricyclo[6.3.1.04,12] dodeca-4(12), 5,7,9-tetraene-10-carboxamide (Example 41) using the appropriate starting material and reagents.

TABLE-US-00003 TABLE 3 Intermediates 5-9 Int. Chemical Name Structure Analytical Data 5 8-Bromo-1-methyl-2- oxo-N-phenyl- quinoline-3- carboxamide [00052] ES/MS (m/z) (.sup.79Br/.sup.81Br): 357.0/359.0 6 5-Bromo-1-methyl-2- oxo-N-phenyl- quinoline-3- carboxamide [00053] ES/MS (m/z) (.sup.79Br/.sup.81Br): 357.0/359.0 7 6-Bromo-1-methyl-2- oxo-N-phenyl- quinoline-3- carboxamide [00054] ES/MS (m/z) (.sup.79Br/.sup.81Br): 357.0/359.0 8 5-Bromo-N-(5- fluoro-2-pyridyl)-1- methyl-2-oxo- quinoline-3- carboxamide [00055] 1H NMR (400.14 MHz, CDCl.sub.3): 12.46-12.39 (m, 1H), 9.34 (s, 1H), 8.36 (dd, J = 4.1, 9.1 Hz, 1H), 8.17 (d, J = 3.0 Hz, 1H), 7.95 (s, 1H), 7.56-7.54 (m, 1H), 7.50-7.41 (m, 3H), 3.78 (s, 3H). 9 5-Bromo-N-(5- fluoropyrimidin-2- yl)-1-methyl-2-oxo- quinoline-3- carboxamide [00056] ES/MS (m/z) (.sup.79Br/.sup.81Br): 377.0/379.0

[0070] Intermediate 10

5-Bromo-1-Methyl-2-Oxo-N-(2-Pyridyl)Quinoline-3-Carboxamide

[0071] ##STR00057##

[0072] Pyridine (255 mg, 3.224 mmol) and POCl.sub.3 (200 mg, 1.3044 mmol) are added to a solution of 5-bromo-1-methyl-2-oxo-quinoline-3-carboxylic acid (500 mg, 1.7725 mmol) and pyridin-2-amine (205 mg, 2.178 mmol) in dichloromethane (5 mL). The resulting mixture is stirred at 20° C. for 2 hrs. The mixture is concentrated under reduced pressure. The resulting residue is triturated with methanol at ambient temperature for 10 min, then filtered to give 5-bromo-1-methyl-2-oxo-N-(2-pyridyl)quinoline-3-carboxamide (600 mg, 1.675 mmol, 94.50% Yield) ES/MS (m/z) (.sup.79Br/.sup.81Br): 357.9/359.9 (M+H).

[0073] The following intermediates in Table 4 are synthesized essentially as described for 5-bromo-1-methyl-2-oxo-N-(2-pyridyl)quinoline-3-carboxamide (Intermediate 10) using the appropriate starting material and reagents.

TABLE-US-00004 TABLE 4 Intermediates 11-17 Int. Chemical Name Structure Analytical Data 11 6-Bromo-1-methyl-2-oxo- N-(2-pyridyl)quinoline-3- carboxamide [00058] ES/MS (m/z) (.sup.79Br/.sup.81Br): 357.9/359.9 12 6-Bromo-N-(5-fluoro-2- pyridyl)-1-methyl-2-oxo- quinoline-3-carboxamide [00059] ES/MS (m/z) (.sup.79Br/.sup.81Br): 373.0/376.0 13 5-Bromo-1-methyl-2-oxo- N-[5- (trifluoromethyl)pyrimidin- 2-yl]quinoline-3- carboxamide [00060] ES/MS (m/z) (.sup.79Br/.sup.81Br): 425.8/428.8 14 6-Bromo-1-methyl-2-oxo- N-[5- (trifluoromethyl)pyrimidin- 2-yl]quinoline-3- carboxamide [00061] ES/MS (m/z) (.sup.79Br/.sup.81Br): 426.0/429.0 15 6-Bromo-N-(5- fluoropyrimidin-2-yl)-1- methyl-2-oxo-quinoline-3- carboxamide [00062] ES/MS (m/z) (.sup.79Br/.sup.81Br): 374.1/377.1 16 7-Bromo-N-(5- fluoropyrimidin-2-yl)-1- methyl-2-oxo-quinoline-3- carboxamide [00063] 1H NMR (400.13 MHz, CDCl.sub.3): 12.75-12.71 (m, 1H), 8.92 (s, 1H), 8.74 (d, J = 5.1 Hz, 1H), 8.50 (s, 2H), 7.91 (dd, J = 6.7, 7.3 Hz, 1H), 7.64-7.58 (m, 2H), 7.43 (dd, J = 1.6, 8.4 Hz, 1H), 3.77-3.76 (m, 3H). 17 5-Bromo-N-(5- fluorothiazol-2-yl)-1- methyl-2-oxo-quinoline-3- carboxamide [00064] 383.9

Example 44

N-(4-Methoxyphenyl)-1,7-Dimethyl-2-Oxo-Quinoline-3-Carboxamide

[0074] ##STR00065##

[0075] 7-Bromo-N-(4-methoxyphenyl)-1-methyl-2-oxo-quinoline-3-carboxamide (0.100 g, 0.258 mmol) is dissolved in 1,4-dioxane (1.5 mL, 18 mmol). Methyl boronic acid (0.038 g, 0.62 mmol) and cesium carbonate (0.165 g, 0.506 mmol) are added. Nitrogen is bubbled through the reaction mixture for 5 min. 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.036 g, 0.043 mmol) is added then sealed and heated via microwave to 100° C. for 2 hrs. The crude reaction is purified by silica gel chromatography, eluted with 0-50% ethyl acetate/hexanes to give the title product (0.015 g, 0.047 mmol, 18% Yield). ES/MS (m/z) (M+H): 323.0. .sup.1H NMR (399.80 MHz, CDCl.sub.3): 12.02-11.96 (m, 1H), 8.99 (s, 1H), 7.74-7.71 (m, 3H), 7.27 (m, 1H), 7.21 (d, J=7.7 Hz, 1H), 6.94 (d, J=8.8 Hz, 2H), 2.59 (s, 3H), 1.59 (s, 3H).

Example 45

7-Cyclopropyl-N-(4-Methoxyphenyl)-1-Methyl-2-Oxo-Quinoline-3-Carboxamide

[0076] ##STR00066##

[0077] The title compound is synthesized essentially as described for N-(4-methoxyphenyl)-1,7-dimethyl-2-oxo-quinoline-3-carboxamide (Example 44) using the appropriate starting material and reagents. ES/MS (m/z) (.sup.79Br/.sup.81Br): (M+H) 349.0.

Example 46

N-(4-Methoxyphenyl)-1-Methyl-7-(Methylamino)-2-Oxo-Quinoline-3-Carboxamide

[0078] ##STR00067##

[0079] 7-Bromo-N-(4-methoxyphenyl)-1-methyl-2-oxo-quinoline-3-carboxamide (0.154 g, 0.398 mmol) is dissolved in toluene (2 mL). Sodium tert-butoxide (0.100 g, 1.01 mmol) is added. Nitrogen is bubbled through the reaction for 10 min. Methylamine (2.0 mol/L) in tetrahydrofuran (0.600 mL, 1.2 mmol) is added followed by (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.035 g, 0.055 mmol) then tris(dibenzylideneacetone)dipalladium(0) (0.040 g, 0.042 mmol). The reaction is sealed and heated via microwave to 80° C. for 2 hrs. The crude reaction is purified via silica gel chromatography eluting with 0-10% (7 N NH.sub.3 in methanol)/dichloromethane to give the crude product. The crude product is purified with SCX ion exchange column rinsed with 1:1 methanol/dichloromethane followed by methanol then 7 N ammonia in methanol (×2). The ammonia containing rinse is concentrated in vacuo to give the title product (33 mg, 0.0978 mmol, 24.60%). ES/MS (m/z) (M+H) 338.0. .sup.1HNMR (399.80 MHz, CDCl.sub.3): 11.99 (s, 1H), 8.82 (s, 1H), 7.73-7.70 (m, 2H), 7.54 (d, J=8.7 Hz, 1H), 6.93-6.91 (m, 2H), 6.62 (dd, J=2.0, 8.6 Hz, 1H), 6.34 (d, J=1.9 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 3H).

[0080] The following Examples in Table 5 are synthesized essentially as described for N-(4-Methoxyphenyl)-1-methyl-7-(methylamino)-2-oxo-quinoline-3-carboxamide (Example 46) using the appropriate starting material and reagents.

TABLE-US-00005 TABLE 5 Examples 47-56 ES/MS (m/z) Ex. Chemical Name Structure (M + H) 47 7-(Dimethylamino)-N-(4- methoxyphenyl)-1-methyl-2- oxo-quinoline-3-carboxamide [00068] 352.0 48 5-[2- (Dimethylamino)ethylamino]- 1-methyl-2-oxo-N-phenyl- quinoline-3-carboxamide [00069] 365.4 49 6-[2- (Dimethylamino)ethylamino]- 1-methyl-2-oxo-N-phenyl- quinoline-3-carboxamide [00070] 365.4 50 8-[2- (Dimethylamino)ethylamino]- 1-methyl-2-oxo-N-phenyl- quinoline-3-carboxamide [00071] 365.4 51 5-[2- (Dimethylamino)ethylamino]- N-(5-fluoro-2-pyridyl)-1- methyl-2-oxo-quinoline-3- carboxamide [00072] 384.4 52 6-[2- (Dimethylamino)ethylamino]- N-(5-fluoro-2-pyridyl)-1- methyl-2-oxo-quinoline-3- carboxamide [00073] 383.9 53 5-[2- (Dimethylamino)ethylamino]- 1-methyl-2-oxo-N-(2- pyridyl)quinoline-3- carboxamide [00074] 366.4 54 5-[2- (Dimethylamino)ethylamino]- 1-methyl-2-oxo-N-[5- (trifluoromethyl)pyrimidin-2- yl]quinoline-3-carboxamide [00075] 465.4 55 6-[2- (Dimethylamino)ethylamino]- 1-methyl-2-oxo-N-(2- pyridyl)quinoline-3- carboxamide [00076] 366.4 56 7-[2- (Dimethylamino)ethylamino]- N-(4-methoxyphenyl)-1- methyl-2-oxo-quinoline-3- carboxamide [00077] 395.2

[0081] The following Intermediates in Table 6 are synthesized essentially as described for N-(4-Methoxyphenyl)-1-methyl-7-(methylamino)-2-oxo-quinoline-3-carboxamide (Example 46) using the appropriate starting material and reagents.

TABLE-US-00006 TABLE 6 Intermediates 18-25 ES/MS (m/z) Int. Chemical Name Structure (M + H) 18 6-[2-[tert- Butyl(dimethyl)silyl]oxyethylamino]- 1-methyl-2-oxo-N-phenyl-quinoline- 3-carboxamide [00078] 452.3 19 5-[2-[tert- Butyl(dimethyl)silyl]oxyethylamino]- 1-methyl-2-oxo-N-phenyl-quinoline- 3-carboxamide [00079] 452.3 20 5-[2-[tert- Butyl(dimethyl)silyl]oxyethylamino]- N-(5-fluorothiazol-2-yl)-1-methyl-2- oxo-quinoline-3-carboxamide [00080] 477.3 21 5-[2-[tert- Butyl(dimethyl)silyl]oxyethylamino]- 1-methyl-2-oxo-N-(2- pyridyl)quinoline-3-carboxamide [00081] 453.3 22 5-[2-[tert- Butyl(dimethyl)silyl]oxyethylamino]- N-(5-fluoro-2-pyridyl)-1-methyl-2- oxo-quinoline-3-carboxamide [00082] 471.3 23 5-[2-[tert- Butyl(dimethyl)silyl]oxyethylamino]- N-(5-fluoropyrimidin-2-yl)-1-methyl- 2-oxo-quinoline-3-carboxamide [00083] 472.2 24 5-[2-[tert- Butyl(dimethyl)silyl]oxyethylamino]- 1-methyl-2-oxo-N-[5- (trifluoromethyl)pyrimidin-2- yl]quinoline-3-carboxamide [00084] 522.2 25 7-[2-[tert- Butyl(dimethyl)silyl]oxyethylamino]- 1-methyl-2-oxo-N-phenyl-quinoline- 3-carboxamide [00085] 452.7

Example 57

5-[2-(Dimethylamino)Ethylamino]-N-(5-Fluoropyrimidin-2-Yl)-1-Methyl-2-Oxo-Quinoline-3-Carboxamide

[0082] ##STR00086##

[0083] BrettPhos Pd G3 (75 mg, 0.0786 mmol), Pd.sub.2(dba).sub.3 (73 mg, 0.0797 mmol) are added to a solution of 5-bromo-N-(5-fluoropyrimidin-2-yl)-1-methyl-2-oxo-quinoline-3-carboxamide (100 mg, 0.2651 mmol), 2-(4,4-difluoro-1-piperidyl)ethanamine (150 mg, 0.3977 mmol) and t-BuONa (117 mg, 1.1930 mmol) in N,N-dimethylethylenediamine (185 mg, 1.994 mmol). The reaction mixture is stirred at 130° C. for 12 hrs., then concentrated in vacuo to give a residue. The residue is purified by silica gel chromatography eluting with 0-5% methanol/dichloromethane to give the crude product. The crude product is triturated with MeOH at 20° C. for 5 min. The mixture is filtered to give the title product (17.74 mg, 0.0357 mmol, 8.973%). ES/MS (m/z) (M+H) 385.2. .sup.1H NMR (400.14 MHz, d6-DMSO): 12.93 (s, 1H), 9.28 (s, 1H), 8.82 (s, 2H), 7.64-7.59 (m, 1H), 7.20-7.13 (m, 1H), 6.87 (d, J=8.5 Hz, 1H), 6.66-6.62 (m, 1H), 3.73 (s, 3H), 3.66-3.63 (m, 2H), 3.47-3.45 (m, −2H), 2.84 (s, 6H).

Alternative Synthesis for Example 57

5-[2-(Dimethylamino)Ethylamino]-N-(5-Fluoropyrimidin-2-Yl)-1-Methyl-2-Oxo-Quinoline-3-Carboxamide

[0084] ##STR00087##

[0085] BrettPhos Pd G3 (75 mg, 0.0786 mmol), Pd.sub.2(dba).sub.3 (73 mg, 0.0797 mmol) are added to a solution of 5-bromo-N-(5-fluoropyrimidin-2-yl)-1-methyl-2-oxo-quinoline-3-carboxamide (100 mg, 0.2651 mmol), N,N-dimethylethylenediamine (185 mg, 1.994 mmol) and t-BuONa (117 mg, 1.1930 mmol) in DMF (4 mL). The reaction mixture is stirred at 130° C. for 12 hrs., then concentrated in vacuo to give a residue. The residue is purified by silica gel chromatography eluting with 0-5% methanol/dichloromethane to give the crude product. The crude product is triturated with MeOH at 20° C. for 5 min. The mixture is filtered to give the title product (17.74 mg, 0.0357 mmol, 8.973%).

[0086] ES/MS (m/z) (M+H) 385.2. .sup.1H NMR (400.14 MHz, d6-DMSO): 12.93 (s, 1H), 9.28 (s, 1H), 8.82 (s, 2H), 7.64-7.59 (m, 1H), 7.20-7.13 (m, 1H), 6.87 (d, J=8.5 Hz, 1H), 6.66-6.62 (m, 1H), 3.73 (s, 3H), 3.66-3.63 (m, 2H), 3.47-3.45 (m, −2H), 2.84 (s, 6H).

Intermediate 26

6-[2-[Tert-Butyl(Dimethyl)Silyl]Oxoethylamino]-N-(5-Fluoro-2-Pyridyl)-1-Methyl-2-Oxo-Quinoline-3-Carboxamide

[0087] ##STR00088##

[0088] BrettPhos Pd G3 (32 mg, 0.033 mmol) is added to a solution of 6-bromo-N-(5-fluoro-2-pyridyl)-1-methyl-2-oxo-quinoline-3-carboxamide (250 mg, 0.6313 mmol), 2-(4,4-difluoro-1-piperidyl)ethanamine (150 mg, 0.3977 mmol) and t-BuONa (75 mg, 0.765 mmol) in THE (5 mL). The reaction mixture is stirred at 100° C. for 16 hrs. then concentrated in vacuo to give a residue. The residue is purified by silica gel chromatography eluting with 0-70% petroleum ether/ethyl acetate to give the title product (200 mg, 0.2975 mmol, 47.12%). ES/MS (m/z) (M+H) 471.2. .sup.1H NMR (400.14 MHz, d6-DMSO): 12.83 (s, 1H), 8.81 (s, 1H), 8.36-8.31 (m, 3H), 7.83-7.75 (m, 1H), 7.46 (d, J=9.3 Hz, 1H), 7.21 (dd, J=2.6, 9.1 Hz, 1H), 7.06 (d, J=2.6 Hz, 1H), 5.82 (t, J=5.9 Hz, 1H), 3.74-3.70 (m, 6H), 3.20 (q, J=5.9 Hz, 2H), 0.83 (s, 10H), −0.00 (s, 6H).

Alternative Synthesis for Intermediate 26

6-[2-[Tert-Butyl(Dimethyl)Silyl]Oxoethylamino]-N-(5-Fluoro-2-Pyridyl)-1-Methyl-2-Oxo-Quinoline-3-Carboxamide

[0089] ##STR00089##

[0090] BrettPhos Pd G3 (32 mg, 0.033 mmol) is added to a solution of 6-bromo-N-(5-fluoro-2-pyridyl)-1-methyl-2-oxo-quinoline-3-carboxamide (250 mg, 0.6313 mmol), 2-[tert-butyl(dimethyl)silyl]oxoethanamine (335 mg, 1.91 mmol) and t-BuONa (75 mg, 0.765 mmol) in THE (5 mL). The reaction mixture is stirred at 100° C. for 16 hrs. then concentrated in vacuo to give a residue. The residue is purified by silica gel chromatography eluting with 0-300% ethyl acetate/petroleum etherto give the title product (200 mg, 0.2975 mmol, 47.12%). ES/MS (m/z) (M+H) 471.2. .sup.1H NMR (400.14 MHz, d6-DMSO): 12.83 (s, 1H), 8.81 (s, 1H), 8.36-8.31 (m, 3H), 7.83-7.75 (m, 1H), 7.46 (d, J=9.3 Hz, 1H), 7.21 (dd, J=2.6, 9.1 Hz, 1H), 7.06 (d, J=2.6 Hz, 1H), 5.82 (t, J=5.9 Hz, 1H), 3.74-3.70 (m, 6H), 3.20 (q, J=5.9 Hz, 2H), 0.83 (s, 10H), −0.00 (s, 6H).

Example 58

6-(2-Hydroxyethoxy)-1-Methyl-2-Oxo-N-Phenyl-Quinoline-3-Carboxamide

[0091] ##STR00090##

[0092] Step A: 6-Bromo-1-methyl-2-oxo-N-phenyl-quinoline-3-carboxamide (2.005 g, 5.052 mmol) and 1,4-dioxane (10 mL) are added together. Trisdibenzilidenedipalladium (0) (465 mg, 0.508 mmol), tBuXphos (443 mg, 1.012 mmol), and potassium hydroxide (876 mg, 15.15 mmol) in water (10 mL, 555.1 mmol) are then added. The mixture is stirred at 100° C. for 15 hrs., then cooled to ambient temperature. Water (100 mL) is added to the cooled reaction. The resulting mixture is extracted with ethyl acetate (50 mL×3). The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue is purified by silica gel chromatography, eluting with 0-50% ethyl acetate/petroleum ether to give 6-hydroxy-1-methyl-2-oxo-N-phenyl-quinoline-3-carboxamide (1 g, 3.058 mmol, 60.54%). ES/MS (m/z) (M+H) 370.2. .sup.1H NMR (400.15 MHz, d6-DMSO): 12.38 (s, 1H), 8.79 (s, 1H), 7.74 (d, J=7.6 Hz, 2H), 7.52 (d, J=9.3 Hz, 1H), 7.39 (t, J=7.9 Hz, 2H), 7.30-7.25 (m, 1H), 7.23 (d, J=2.6 Hz, 1H), 7.15-7.11 (m, 1H), 3.76 (s, 3H).

[0093] Step B: 6-Hydroxy-1-methyl-2-oxo-N-phenyl-quinoline-3-carboxamide (101 mg, 0.309 mmol) is dissolved in dimethylformamide (2 mL). 2-(2-bromoethoxy)tetrahydropyran (101 mg, 0.483 mmol) and cesium carbonate (403 mg, 1.237 mmol). The mixture is stirred at 80° C. for 12 hrs., then cooled to ambient temperature. Water (50 mL) is added to the cooled reaction. The mixture is extracted with ethyl acetate (20 mL×3). The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue is purified by silica gel chromatography eluting with 0-100% ethyl acetate/petroleum ether to give 1-methyl-2-oxo-N-phenyl-6-(2-tetrahydropyran-2-yloxyethoxy)quinoline-3-carboxamide (60 mg, 0.128 mmol, 41.38%) ES/MS (m/z) (M+H) 423.2. .sup.1H NMR (400.14 MHz, CDCl.sub.3): 12.24-12.20 (m, 1H), 8.97 (s, 1H), 7.82 (d, J=7.8 Hz, 2H), 7.42-7.38 (m, 3H), 7.18-7.14 (m, 1H), 4.75 (dd, J=3.2, 3.8 Hz, 1H), 4.31-4.27 (m, 2H), 4.17-4.12 (m, 2H), 3.86 (s, 6H), 3.62-3.57 (m, 1H), 1.93-1.91 (m, 2H), 1.73-1.71 (m, 4H), 1.30-1.27 (m, 1H).

[0094] Step C; Example 58: 1-Methyl-2-oxo-N-phenyl-6-(2-tetrahydropyran-2-yloxyethoxy)quinoline-3-carboxamide (60 mg, 0.1278 mmol) is dissolve in 1M hydrochloric acid in ethyl acetate (2 mL). The mixture is stirred at ambient temperature for 2 hrs. The reaction mixture is concentrated in vacuo to give a residue. The residue is triturated with methanol (10 mL) at ambient temperature for 10 min. The resulting mixture is filtered to give the title product (Example 81; 14 mg, 0.0398 mmol, 31.14%).

[0095] ES/MS (m/z) (M+H) 339.3. .sup.1H NMR (400.15 MHz, d6-DMSO): 12.27 (s, 1H), 8.96 (s, 1H), 7.75 (d, J=7.6 Hz, 2H), 7.69-7.65 (m, 2H), 7.47 (dd, J=2.9, 9.3 Hz, 1H), 7.40 (t, J=7.9 Hz, 2H), 7.14 (t, J=7.4 Hz, 1H), 4.10 (t, J=4.9 Hz, 2H), 3.80-3.76 (m, 5H).

[0096] The following Examples in Table 7 are synthesized essentially as described for 6-(2-hydroxyethoxy)-1-methyl-2-oxo-N-phenyl-quinoline-3-carboxamide (Example 58) using the appropriate starting material and reagents.

TABLE-US-00007 TABLE 7 Examples 59-61 ES/MS (m/z) Ex. Chemical Name Structure (M + H) 59 6-(2-Hydroxyethoxy)-1-methyl-2- oxo-N-(2-pyridyl)quinoline-3- carboxamide [00091] 340.3 60 5-(2-Hydroxyethoxy)-1-methyl-2- oxo-N-phenyl-quinoline-3- carboxamide [00092] 339.3 61 7-(2-Hydroxyethoxy)-1-methyl-2- oxo-N-phenyl-quinoline-3- carboxamide [00093] 339.3

Example 62

6-(2-Hydroxyethylamino)-1-Methy-2-Oxo-N-Phenyl-Quinoline-3-Carboxamide

[0097] ##STR00094##

[0098] 6-[2-[tert-Butyl(dimethyl)silyl]oxoethylamino]-1-methyl-2-oxo-N-phenyl-quinoline-3-carboxamide (140 mg, 0.275 mmol) is dissolved in THE (1.5 mL). 1M tetrabutylammonium fluoride in THE (0.38 mL) at 0° C. is added slowly. The reaction is warmed to ambient temperature and stirred for 2 hrs. The reaction is poured into saturated aqueous ammonium chloride (30 mL) and stirred at ambient temperature for 10 min. The resulting mixture is extracted with ethyl acetate (30 mL×3). The organic layers are combined, washed with saturated aqueous ammonium chloride (30 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue is purified to give the title product (10 mg, 0.0288 mmol, 10.45%) ES/MS (m/z) (M+H) 338.1. .sup.1H NMR (400.14 MHz, CDCl.sub.3): 12.33-12.29 (m, 1H), 8.92 (s, 1H), 7.84-7.81 (m, 2H), 7.41-7.31 (m, 3H), 7.18-7.12 (m, 2H), 6.97-6.95 (m, 1H), 4.28-4.26 (m, 1H), 4.01-3.93 (m, 2H), 3.84 (s, 3H), 3.43-3.37 (m, 2H), 1.76-1.74 (m, 1H).

[0099] The following Examples in Table 8 are synthesized essentially as described for 6-(2-hydroxyethylamino)-1-methyl-2-oxo-N-phenyl-quinoline-3-carboxamide (Example 62) using the appropriate starting material and reagents.

TABLE-US-00008 TABLE 8 Examples 63-70 ES/MS (m/z) Ex. Chemical Name Structure (M + H) 63 5-(2-Hydroxyethylamino)- 1-methyl-2-oxo-N-phenyl- quinoline-3-carboxamide [00095] 338.1 64 N-(5-Fluorothiazol-2-yl)-5- (2-hydroxyethylamino)-1- methyl-2-oxo-quinoline-3- carboxamide [00096] 363.3 65 5-(2-Hydroxyethylamino)- 1-methyl-2-oxo-N-(2- pyridyl)quinoline-3- carboxamide [00097] 339.3 66 N-(5-Fluoro-2-pyridyl)-6- (2-hydroxyethylamino)-1- methyl-2-oxo-quinoline-3- carboxamide [00098] 357.3 67 N-(5-Fluoro-2-pyridyl)-5- (2-hydroxyethylamino)-1- methyl-2-oxo-quinoline-3- carboxamide [00099] 357.3 68 N-(5-Fluoropyrimidin-2- yl)-5-(2- hydroxyethylamino)-1- methyl-2-oxo-quinoline-3- carboxamide [00100] 358.1 69 5-(2-Hydroxyethylamino)- 1-methyl-2-oxo-N-[5- (trifluoromethyl)pyrimidin- 2-yl]quinoline-3- carboxamide [00101] 408.3 70 7-(2-Hydroxyethylamino)- 1-methyl-2-oxo-N-phenyl- quinoline-3-carboxamide [00102] 338.4

hAHR Nuclear Translocation Assay PGP135,TRE,M

[0100] Stable cell lines were established using Jump-In™ T-REx™ HEK293 Retargeting Kit (Life Technologies). Human AhR cDNA was cloned into the pJTI R4 CMV-TO EGFP vector. The EGFP was cloned to the C-terminal of AHR to form AhR-EGFP chimera. The pJTI R4 CMV-TO AhR-EGFP vector was transfected using FuGENE® HD into Jump-In™ T-REx™ HEK293 cells. Transfected cells were selected using 2.5 mg/ml G418 for 10 to 14 days, then expanded, harvested, and suspended in freeze media (FBS with 8% DMSO) at 2×10.sup.7 cells/ml, and aliquots were stored in liquid nitrogen. One day before the assay date, cells were thawed and resuspended in DMEM with 5% FBS in the presence of 1 ug/ml Doxycycline and plated into ploy-L-Lysine coated CELLCARRIER-384 ULTRA Microplates (Perkin Elmer) at 12,000 to 15,000 cells per well and incubated at 37° C. and 5% CO.sub.2 overnight. On the assay date, compound was serially diluted (1:2) into 384-well nunc plates with DMSO using acoustic dispensing (ECHO). The dose response was a 20-point curve. Compound was resuspended in 40 μl of DMEM plus 0.1% BSA. The culture media was damped and 25 μl of DMEM plus 0.1% BSA was added, then 25 μl of compound in DMEM plus 0.1% BSA was added into cell plates. Cells were incubated compounds at 37° C. and 5% CO.sub.2 for 45 minutes. The final DMSO concentration was 0.2%. The media was damped after 45 minutes incubation. The cells were fixed with 40 μl of cold methanol (−20° C.) for 20 minutes. The methanol was damped and 50 μl of DPBS containing 1 μg/ml Hochst was added into the cell plates. The intensity of EGFP was quantitated by using OPERA PHENIX® or Operetta™ high content image system (Perkin Elmer) with 20× Water Objective and five field per well. The ratio of EGFP fluorescent intensity in nuclear over cytosol was analyzed using a 4-parameter nonlinear logistic equation to determine the potency of AhR agonists.

[0101] Table 9 shows the hATHR nuclear translocation assay EC.sub.50 values for the exemplified compounds.

TABLE-US-00009 TABLE 9 hAHR Nuclear Translocation Assay EC.sub.50 Values Example EC.sub.50 (nM) 1 0.304 2 2.41 3 0.837 4 0.214 5 0.0971 6 5.17 7 6.13 8 1.12 9 0.613 10 0.669 11 3.50 12 6.89 13 3.72 14 0.993 15 14.2 16 1.09 17 2.37 18 0.468 19 25.8 20 0.675 21 10.8 22 0.389 23 0.601 24 7.36 25 2.57 26 0.701 27 10.6 28 1.91 29 0.570 30 0.511 31 53.2 32 16.4 33 1.33 34 9.04 35 2.29 36 0.832 37 0.807 38 6.34 39 3.52 40 0.831 41 6.24 42 3.96 43 11.5 44 0.595 45 2.14 46 2.21 47 18.0 48 21.3 49 9.00 50 26.8 51 16.4 52 20.3 53 16.2 54 18.3 55 40.6 56 79.2 57 62.8 58 7.45 59 19.2 60 1.40 61 16.1 62 6.00 63 1.91 64 52.9 65 6.69 66 53.9 67 1.92 68 81.2 69 6.66 70 15.1

[0102] The results of this assay demonstrate that the exemplified compounds are AhR agonists.