Furanone derivative
RE046815 ยท 2018-05-01
Assignee
Inventors
- Takayuki Irie (Kobe, JP)
- Ayako Sawa (Osaka, JP)
- Masaaki Sawa (Ibaraki, JP)
- Tokiko Asami (Kobe, JP)
- Yoko Funakoshi (Tokyo, JP)
- Chika Tanaka (Tokyo, JP)
Cpc classification
A61K31/4375
HUMAN NECESSITIES
A61K31/4545
HUMAN NECESSITIES
A61K31/4709
HUMAN NECESSITIES
A61K31/444
HUMAN NECESSITIES
A61K31/496
HUMAN NECESSITIES
A61K31/506
HUMAN NECESSITIES
A61K31/437
HUMAN NECESSITIES
A61K31/5355
HUMAN NECESSITIES
C07D519/00
CHEMISTRY; METALLURGY
A61K31/541
HUMAN NECESSITIES
A61P35/00
HUMAN NECESSITIES
International classification
C07D471/02
CHEMISTRY; METALLURGY
C07D519/00
CHEMISTRY; METALLURGY
C07D515/02
CHEMISTRY; METALLURGY
C07D491/02
CHEMISTRY; METALLURGY
C07D498/02
CHEMISTRY; METALLURGY
A61K31/444
HUMAN NECESSITIES
A61K31/496
HUMAN NECESSITIES
A61K31/437
HUMAN NECESSITIES
A61K31/541
HUMAN NECESSITIES
A61K31/5355
HUMAN NECESSITIES
A61K31/506
HUMAN NECESSITIES
A61K31/4709
HUMAN NECESSITIES
A61K31/4545
HUMAN NECESSITIES
C07D513/02
CHEMISTRY; METALLURGY
Abstract
To provide a novel furanone derivative, and a medicine including the same. The furanone derivative is represented by the formula (I): ##STR00001##
wherein A represents COOR1 or a hydrogen atom; R1 represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocycle; R2 and R3 are the same or different and each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted phenyl group, an optionally substituted heterocycle, an optionally substituted heterocyclic fused ring, or an optionally substituted amino group; or alternatively, R2 and R3, taken together with the nitrogen atom to which they are attached, may form an optionally substituted heterocycle or an optionally substituted heterocyclic fused ring; and R4 represents a hydrogen atom or a halogen atom; with the proviso that when A represents COOR1, R2 and R3 are not optionally substituted amino groups at the same time, and when A represents a hydrogen atom, R3 represents a hydrogen atom.
Claims
1. A furanone derivative or a pharmaceutically acceptable salt thereof, represented by .[.the formula (I): [Chemical Formula 1] ##STR00370## .]. .Iadd.the formula (I-Z) or the formula (I-E): ##STR00371## .Iaddend. wherein A represents COOR1 or a hydrogen atom; R1 represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocycle; R2 and R3 are the same or different and each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted phenyl group, an optionally substituted heterocycle, an optionally substituted heterocyclic fused ring, or an optionally substituted amino group; or alternatively, R2 and R3, taken together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle or an optionally substituted heterocyclic fused ring; and R4 represents a hydrogen atom or a halogen atom; with the proviso that when A represents COOR1, R2 and R3 are not optionally substituted amino groups at the same time, and when A represents a hydrogen atom, R3 represents a hydrogen atom.
2. The furanone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is COOR1.
3. The furanone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is a hydrogen atom.
.Iadd.4. The furanone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the furanone derivative or a pharmaceutically acceptable salt thereof is represented by the formula (II-Z) or formula (II-E): ##STR00372## ##STR00373## wherein A represents COOR1 or a hydrogen atom; R1 is selected from the group consisting of a hydrogen atom, an optionally substituted 1 to 6 carbon hydrocarbon group, and an optionally substituted 3 to 8 membered heterocycle; R2 and R3, taken together with the nitrogen atom to which they are attached, form an optionally substituted 3 to 8 membered heterocycle or an optionally substituted 3 to 8 membered heterocyclic fused ring; R4 represents a hydrogen atom or a halogen atom; wherein any and all heterocyclic groups contain up to four heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen; with the proviso that when A represents COOR1, R2 and R3 are not optionally substituted amino groups at the same time, and when A represents a hydrogen atom, R3 represents a hydrogen atom. .Iaddend.
.Iadd.5. The furanone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein any and all heterocyclic groups are optionally substituted 3 to 8 membered heterocycle groups that contain up to two heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen. .Iaddend.
.Iadd.6. The furanone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein any and all hydrocarbon groups are 1 to 6 carbon hydrocarbon groups; and wherein any and all heterocyclic groups are optionally substituted 3 to 8 membered heterocycle groups that contain up to two heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen. .Iaddend.
.Iadd.7. The furanone derivative or a pharmaceutically acceptable salt thereof according to claim 4, wherein A and R4 are both a hydrogen atom and R2 and R3 form a 3 to 8 membered heterocycle. .Iaddend.
.Iadd.8. The furanone derivative or a pharmaceutically acceptable salt thereof according to claim 4, wherein A is COOR1 where R1 is an optionally substituted 1 to 6 carbon hydrocarbon group, R4 is a hydrogen atom and R2 and R3 form a 3 to 8 membered heterocycle containing up to two heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen. .Iaddend.
.Iadd.9. The furanone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is COOR1 where R1 is an optionally substituted 1 to 6 carbon hydrocarbon group, R4 is a hydrogen atom and one of either of R2 and R3 is a hydrogen atom. .Iaddend.
.Iadd.10. The furanone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is COOR1 where R1 is an optionally substituted 1 to 6 carbon hydrocarbon group, R4 is a fluorine atom and one of either of R2 and R3 is a hydrogen atom. .Iaddend.
.Iadd.11. The furanone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein A and R4 are both a hydrogen atom, and one of either of R2 and R3 is a hydrogen atom. .Iaddend.
.Iadd.12. The furanone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is COOR1 where R1 is an optionally substituted 1 to 6 carbon hydrocarbon group, R4 is a hydrogen atom, one of either of R2 and R3 is a hydrogen atom and one of either of R2 and R3 is an optionally substituted amino group. .Iaddend.
.Iadd.13. The furanone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is COOR1 where R1 is an optionally substituted 1 to 6 carbon hydrocarbon group, R4 is a hydrogen atom, one of either of R2 and R3 is an optionally substituted 1 to 6 carbon hydrocarbon group and one of either of R2 and R3 is a 3 to 8 membered heterocycle containing up to two heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen. .Iaddend.
.Iadd.14. The furanone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is COOR1 where R1 is an optionally substituted 1 to 6 carbon hydrocarbon group, R4 is a hydrogen atom, one of either of R2 and R3 is a hydrogen atom and one of either of R2 and R3 is an optionally substituted 3 to 8 membered heterocyclic fused ring. .Iaddend.
.Iadd.15. The furanone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is COOR1 where R1 is a 3 to 8 membered heterocycle containing up to two heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, R4 is a hydrogen atom and one of either of R2 and R3 is a hydrogen atom. .Iaddend.
.Iadd.16. The furanone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the furanone derivative or pharmaceutically acceptable salt thereof is selected from the group consisting of: ##STR00374## ##STR00375## .Iaddend.
.Iadd.17. The furanone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the furanone derivative or pharmaceutically acceptable salt thereof is selected from the group consisting of: ##STR00376## .Iaddend.
.Iadd.18. The furanone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the furanone derivative or pharmaceutically acceptable salt thereof is selected from the group consisting of: ##STR00377## ##STR00378## .Iaddend.
.Iadd.19. The furanone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is the hydrochloride or p-toluenesulfonate salt. .Iaddend.
.Iadd.20. The furanone derivative or a pharmaceutically acceptable salt thereof according to claim 16, wherein the pharmaceutically acceptable salt is the hydrochloride or p-toluenesulfonate salt. .Iaddend.
Description
EXAMPLES
(1) The present invention will be more specifically described below by way of Examples and Test Examples, which are not intended to limit the present invention.
(2) The identification of compounds was performed with hydrogen nuclear magnetic resonance (.sup.1H-NMR) spectra and mass spectra (MS). .sup.1H-NMR spectra were measured at 400 MHz, unless otherwise specified. In the .sup.1H-NMR spectra, exchangeable hydrogens are sometimes not clearly observed, depending on the compound being measured and on the measurement conditions, and br denotes a broad signal. HPLC preparative chromatography was carried out using a commercial available ODS column, and fractions were collected using a water/methanol system (containing formic acid) as an eluent in a gradient mode, unless otherwise specified.
Example 1
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(phenylamino)-4,5-dihydrofuran-3-carboxylate
(3) ##STR00011##
(4) To a solution of 7-azaindole-3-carboxaldehyde (0.10 g, 0.70 mmol) and ethyl 4-oxo-2-(phenylamino)-4,5-dihydrofuran-3-carboxylate (0.18 g, 0.70 mmol) in ethanol (3.0 mL), piperidine (0.083 mL, 0.84 mmol) was added at ambient temperature. The mixture was refluxed for 12 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with cold ethanol and isopropyl ether then dried to afford the titled compound (0.13 g, y. 48%).
(5) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.30 (br. s, 1H), 10.58 (s, 1H), 8.23 (dd, J=1.25, 4.52 Hz, 1H), 7.98 (d, J=7.28 Hz, 1H), 7.79 (d, J=2.76 Hz, 1H), 7.52-7.64 (m, 4H), 7.43-7.51 (m, 1H), 6.80-6.99 (m, 2H), 4.28 (q, J=7.03 Hz, 2H), 1.30 (t, J=7.03 Hz, 3H); LCMS (m/z): 376.0 [M+H].sup.+.
Example 2
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-methoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(6) ##STR00012##
First Step
(7) Under a nitrogen atmosphere, to a mixed solution of ethyl 4-chloroacetoacetate (0.82 mL, 6.0 mmol) and 4-methoxyphenyl isocyanate 1.1 g, 7.2 mmol) in diethyl ether/ethyl acetate (10 mL/1.0 mL) that cooled with ice bath, triethylamine (0.96 mL, 6.9 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 1.5 h then the precipitate was collected by filtration, washed with diethyl ether, 1M hydrochloric acid solution, water and diethyl ether, and then dried to afford ethyl 2-[(4-methoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (1.3 g, y. 78%).
(8) .sup.1H NMR (CDCl.sub.3) (ppm) 10.11 (br. s, 1H), 7.24-7.33 (m, 2H), 6.90-6.96 (m, 2H), 4.65 (s, 2H), 4.38 (q, J=7.07 Hz, 2H), 3.83 (s, 3H), 1.40 (t, J=7.20 Hz, 3H); LCMS (m/z): 277.9 [M+H].sup.+.
(9) Second Step
(10) To a solution of ethyl 2-[(4-methoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.28 g, 1.0 mmol) and 7-azaindole-3-carboxaldehyde (0.15 g, 1.0 mmol) in ethanol (4.0 mL), piperidine (0.12 mL, 1.2 mmol) was added at ambient temperature. The mixture was refluxed for 12 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.092 g, y. 22%).
(11) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.31 (br. s, 1H), 10.47 (s, 1H), 8.24 (dd, J=1.51, 4.52 Hz, 1H), 7.94 (d, J=7.53 Hz, 1H), 7.77 (d, J=2.76 Hz, 1H), 7.50 (d, J=9.03 Hz, 2H), 7.09 (d, J=8.78 Hz, 2H), 6.81-6.92 (m, 2H), 4.26 (q, J=7.03 Hz, 2H), 3.87 (s, 3H), 1.29 (t, J=7.03 Hz, 3H); LCMS (m/z): 406.0 [M+H].sup.+.
Example 3
Ethyl 5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(phenylamino)-4,5-dihydrofuran-3-carboxylate
(12) ##STR00013##
First Step
(13) To a mixed solution of 2-amino-5-chloropyridine (2.6 g, 0.020 mol) in acetic acid/water (7.8 mL/1.8 mL) that cooled with ice bath, conc.sulfuric acid (0.26 mL, 4.9 mmol) was added dropwise, and then periodic acid (0.95 g, 4.2 mmol) and iodine (2.0 g, 8.0 mmol) were added. The reaction mixture was stirred at 80 C. for 6 h. Cooled to ambient temperature, the reaction mixture was poured into ice water, and neutralized by aqueous 5M sodium hydroxide solution. After removal of the precipitate by filtration, the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated sodium thiosulfate solution, aqueous 1M sodium hydroxide solution and brine then dried over sodium sulfate and concentrated to afford 2-amino-5-chloro-3-iodopyridine as solid (4.4 g, y. 85%).
(14) .sup.1H NMR (CDCl.sub.3) (ppm) 7.96 (s, 1H), 7.82 (s, 1H), 4.93 (s, 2H); LCMS (m/z) 255.2 [M+H].sup.+.
(15) Second Step
(16) Under a nitrogen atmosphere, to a solution of 2-amino-5-chloro-3-iodopyridine (4.2 g, 0.017 mol), copper(I) iodide (0.032 g, 0.17 mmol) and triethylamine (7.0 mL, 0.050 mol) in anhydrous tetrahydrofuran (10 mL), dichlorobis(triphenylphosphine)palladium(II) (0.12 g, 0.17 mmol) and ethynyl trimethylsilane (3.0 mL, 0.021 mol) were added and the mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with diethyl ether and removed the precipitate by filtration with C elite. The filtrate was concentrated to afford 2-amino-5-chloro-3-[(trimethylsilyl)ethynyl]pyridine as solid (4.2 g).
(17) .sup.1H NMR (CDCl.sub.3) (ppm) 7.94 (d, 1H, J=2.28 Hz), 7.49 (d, 1H, J=2.32 Hz), 5.02 (s, 2H), 0.18-0.25 (m, 9H); LCMS (m/z): 225.5 [M+H].sup.+.
(18) Third Step
(19) Under a nitrogen atmosphere, to a solution of potassium tert-butoxide (4.0 g, 0.036 mol) in 1-methyl-2-pyrrolidone (8.0 mL) which stirred with heating at 80 C., a solution of 2-amino-5-chloro-3-[(trimethylsilyl)ethynyl]pyridine (4.0 g, 0.018 mol) in 1-methyl-2-pyrrolidone (22 mL) was added dropwise and the mixture was stirred for 1 h. Cooled to ambient temperature, the reaction mixture was diluted with brine and stirred, then extracted with diethyl ether for 3 times. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford 5-chloro-7-azaindole as solid (2.3 g, y. 85%).
(20) .sup.1H NMR (CDCl.sub.3) (ppm) 9.46 (s, 1H), 8.26 (s, 1H), 7.91 (d, 1H, J=1.12 Hz), 7.35 (s, 1H), 6.46 (s, 1H); LCMS (m/z): 153.2 [M+H].sup.+.
(21) Fourth Step
(22) To a solution of 5-chloro-7-azaindole (0.50 g, 3.3 mmol) in acetic acid (5.0 mL), hexamethylenetetramine (0.69 g, 4.9 mmol) was added at ambient temperature. The mixture was refluxed for 8 h. Cooled to ambient temperature, the reaction mixture was diluted with water, extracted with ethyl acetate for 2 times. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel(hexane/ethyl acetate) to afford 5-chloro-7-azaindole-3-carboxaldehyde as solid (0.13 g, y. 22%).
(23) .sup.1H NMR (CDCl.sub.3) (ppm) 10.01 (s, 1H), 9.77 (br. s, 1H), 8.61 (d, 1H, J=2.04 Hz), 8.37 (d, 1H, J=2.08 Hz), 7.99 (d, 1H, J=2.64 Hz); LCMS (m/z): 181.2 [M+H].sup.+.
(24) Fifth Step
(25) To a solution of 5-chloro-7-azaindole-3-carboxaldehyde (0.019 g, 0.11 mmol) and ethyl 4-oxo-2-(phenylamino)-4,5-dihydrofuran-3-carboxylate (0.025 g, 0.10 mmol) in ethanol (1.0 mL), piperidine (0.012 mL, 0.12 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, solvents were removed under reduced pressure then the residue was purified by preparative HPLC to afford the titled compound (0.0020 g, y. 4.6%).
(26) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.52 (br. s, 1H), 10.58 (s, 1H), 8.42 (d, J=2.26 Hz, 1H), 8.26 (d, J=2.26 Hz, 1H), 7.71 (d, J=2.51 Hz, 1H), 7.55-7.63 (m, 2H), 7.51 (t, J=7.78 Hz, 2H), 7.35-7.44 (m, 1H), 7.00 (s, 1H), 4.28 (q, J=7.03 Hz, 2H), 1.30 (t, J=7.15 Hz, 3H); LCMS (m/z): 410.0 [M+H].sup.+.
Example 4
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-piperidino-4,5-dihydrofuran-3-carboxylate
(27) ##STR00014##
First Step
(28) Diethyl malonate (5.0 mL, 0.033 mol) was added dropwise to a solution of sodium hydride (60% w/w in oil, 2.7 g, 0.066 mol) in anhydrous tetrahydrofuran (50 mL) that cooled with ice bath. The mixture was refluxed for 5 min. The reaction mixture was cooled with ice bath, chloroacetyl chloride (2.8 mL, 0.035 mol) was added dropwise to the reaction mixture and the mixture was stirred for 1 h then stirred at 45 C. for 1 h. The reaction mixture was cooled with ice bath again then piperidine (3.9 mL, 0.040 mol) was added dropwise and stirred at ambient temperature for further 12 h. The reaction mixture was diluted with aqueous saturated sodium bicarbonate solution, and extracted with ethyl acetate for 2 times then extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel(chloroform/methanol) to afford ethyl 4-oxo-2-piperidino-4,5-dihydrofuran-3-carboxylate as solid (3.5 g, y. 45%).
(29) .sup.1H NMR (DMSO-d.sub.6) (ppm) 4.53 (s, 2H), 4.10 (q, J=7.03 Hz, 2H), 3.48-3.60 (m, 4H), 1.56-1.67 (m, 6H), 1.20 (t, J=7.03 Hz, 16H); LCMS (m/z): 240.0 [M+H].sup.+.
(30) Second Step
(31) To a solution of ethyl 4-oxo-2-piperidino-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.42 mmol) and 7-azaindole-3-carboxaldehyde (0.061 g, 0.42 mmol) in ethanol (2.0 mL), piperidine (0.041 mL, 0.42 mmol) was added at ambient temperature. The mixture was refluxed for 24 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.045 g, y. 29%).
(32) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.29 (br. s, 1H), 8.37 (dd, J=1.25, 8.03 Hz, 1H), 8.31 (dd, J=1.51, 4.52 Hz, 1H), 7.96 (d, J=2.76 Hz, 1H), 7.19 (dd, J=4.64, 7.91 Hz, 1H), 6.84 (s, 1H), 4.16 (q, J=7.19 Hz, 2H), 3.70-3.80 (m, 4H), 1.65-1.78 (m, 6H), 1.24 (t, J=7.03 Hz, 3H); LCMS (m/z): 368.0 [M+H].sup.+.
Example 5
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(3-methoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(33) ##STR00015##
(34) To a solution of ethyl 2-[(3-methoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.28 g, 1.0 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.15 g, 1.2 mmol) in ethanol (4.0 mL), piperidine (0.12 mL, 1.2 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.17 g, y. 29%).
(35) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.34 (br. s, 1H), 10.52 (s, 1H), 8.25 (dd, J=1.38, 4.64 Hz, 1H), 8.03 (d, J=7.03 Hz, 1H), 7.84 (d, J=2.76 Hz, 1H), 7.45 (t, J=8.03 Hz, 1H), 7.13-7.26 (m, 2H), 7.04 (dd, J=2.01, 8.28 Hz, 1H), 6.86-6.95 (m, 2H), 4.27 (q, J=7.03 Hz, 2H), 3.77 (s, 3H), 1.30 (t, J=7.15 Hz, 3H); LCMS (m/z): 406.0 [M+H].sup.+.
Example 6
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(2-pyridinylamino)-4,5-dihydrofuran-3-carboxylate
(36) ##STR00016##
(37) To a solution of ethyl 4-oxo-2-(2-pyridinylamino)-4,5-dihydrofuran-3-carboxylate (0.080 g, 0.32 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.047 g, 0.32 mmol) in ethanol (2.0 mL), piperidine (0.038 mL, 0.39 mmol) was added at ambient temperature. The mixture was refluxed for 10 h. Cooled to ambient temperature, the precipitate was removed by filtration and the filtrate was purified by preparative HPLC to afford the titled compound as solid (0.0030 g, y. 2.5%).
(38) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.41 (br. s, 1H), 10.74 (br. s, 1H), 8.60 (d, J=3.26 Hz, 1H), 8.35 (d, J=7.78 Hz, 1H), 8.30 (dd, J=1.38, 4.64 Hz, 1H), 8.24 (br. s, 1H), 7.97 (dt, J=1.88, 7.84 Hz, 1H), 7.61 (d, J=8.03 Hz, 1H), 7.36-7.45 (m, 1H), 7.02-7.14 (m, 2H), 4.27 (q, J=7.03 Hz, 2H), 1.29 (t, J=7.03 Hz, 3H); LCMS (m/z): 377.0 [M+H].sup.+.
Example 7
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-methoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(39) ##STR00017##
(40) To a solution of ethyl 2-[(2-methoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.28 g, 1.0 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.15 g, 1.2 mmol) in ethanol (4.0 mL), piperidine (0.12 mL, 1.2 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.30 g, y. 74%).
(41) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.34 (br. s, 1H), 10.35 (s, 1H), 8.25 (dd, J=1.38, 4.64 Hz, 1H), 8.02 (d, J=7.03 Hz, 1H), 7.85 (d, J=2.76 Hz, 1H), 7.66 (dd, J=1.38, 7.91 Hz, 1H), 7.41-7.51 (m, 1H), 7.28 (d, J=7.53 Hz, 1H), 7.12 (t, J=7.65 Hz, 1H), 6.88-6.99 (m, 2H), 4.28 (q, J=7.03 Hz, 2H), 3.85 (s, 3H), 1.30 (t, J=7.15 Hz, 3H); LCMS (m/z): 406.0 [M+H].sup.+.
Example 8
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-chlorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(42) ##STR00018##
(43) To a solution of ethyl 2-[(4-chlorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.18 g, 0.61 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.088 g, 0.61 mmol) in ethanol (10 mL), piperidine (0.0044 mL, 0.044 mmol) was added at ambient temperature. The mixture was refluxed for 6 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and hexane then dried to afford the titled compound (0.061 g, y. 23%).
(44) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.33 (br. s, 1H), 10.61 (s, 1H), 8.26 (d, J=3.26 Hz, 1H), 7.96 (d, J=7.53 Hz, 1H), 7.82 (d, J=2.76 Hz, 1H), 7.58-7.67 (m, 4H), 6.87-6.95 (m, 2H), 4.27 (q, J=7.03 Hz, 2H), 1.29 (t, J=7.03 Hz, 3H); LCMS (m/z): 409.9 [M+H].sup.+.
Example 9
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(3-chlorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(45) ##STR00019##
(46) To a solution of ethyl 2-[(3-chlorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.36 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.051 g, 0.35 mmol) in ethanol (3.0 mL), piperidine (0.0035 mL, 0.035 mmol) was added at ambient temperature. The mixture was refluxed for 6 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound (0.061 g, y. 23%).
(47) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.36 (br. s, 1H), 10.63 (s, 1H), 8.26 (dd, J=1.38, 4.64 Hz, 1H), 8.01 (d, J=7.28 Hz, 1H), 7.82 (d, J=2.76 Hz, 1H), 7.76 (s, 1H), 7.50-7.61 (m, 3H), 6.89-6.96 (m, 2H), 4.28 (q, J=7.03 Hz, 2H), 1.30 (t, J=7.03 Hz, 3H); LCMS (m/z): 409.9 [M+H].sup.+.
Example 10
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(benzylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate hydrochloride
(48) ##STR00020##
(49) A solution of ethyl 2-(benzylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.026 g, 0.10 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.015 g, 0.10 mmol) in 2M hydrochloric acid in ethanol (1.0 mL) was refluxed for 4 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.024 g, y. 56%).
(50) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.25-12.56 (m, 1H), 9.54 (br. s, 1H), 8.25-8.42 (m, 2H), 7.86 (s, 1H), 7.35-7.48 (m, 4H), 7.24-7.33 (m, 1H), 7.08-7.18 (m, 1H), 6.87 (s, 1H), 4.86 (d, J=6.53 Hz, 2H), 4.23 (q, J=7.19 Hz, 2H), 1.27 (t, J=7.03 Hz, 3H); LCMS (m/z): 390.0 [M+H].sup.+.
Example 11
5-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-piperidino-4,5-dihydrofuran-3-carboxylic acid
(51) ##STR00021##
(52) To a solution of the compound of Example 4 in dioxane (0.5 mL), 2M sodium hydroxide solution (0.50 mL, 1.0 mmol) was added at ambient temperature. The mixture was stirred at 110 C. for 1.5 h. Cooled to ambient temperature, the reaction mixture was neutralized by 2M hydrochloric acid solution then the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to afford the titled compound (0.0044 g, y. 45%).
(53) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.24 (br. s, 1H), 8.39 (d, J=8.03 Hz, 1H), 8.30 (dd, J=1.38, 4.64 Hz, 1H), 7.92 (d, J=2.26 Hz, 1H), 7.19 (dd, J=4.77, 8.03 Hz, 1H), 6.73 (s, 1H), 3.35-3.62 (m, 4H), 1.45-1.69 (m, 6H); LCMS (m/z): 339.9 [M+H].sup.+.
Example 12
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(ethylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate hydrochloride
(54) ##STR00022##
(55) To a solution of ethyl 2-(ethylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.033 g, 0.17 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.024 g, 0.17 mmol) in ethanol (1.5 mL), 2M hydrochloric acid in ethanol (0.17 mL, 0.34 mmol) was added at ambient temperature. The mixture was refluxed for 4 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.026 g, y. 42%).
(56) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.46 (br. s, 1H), 9.03 (t, J=6.02 Hz, 1H), 8.45-8.54 (m, 1H), 8.35 (dd, J=1.25, 4.77 Hz, 1H), 8.01 (d, J=1.25 Hz, 1H), 7.25 (dd, J=4.77, 8.03 Hz, 1H), 6.90 (s, 1H), 4.25-4.50 (m, 1H), 4.21 (q, J=7.19 Hz, 2H), 3.61-3.71 (m, 2H), 1.30 (t, J=7.15 Hz, 3H), 1.26 (t, J=7.03 Hz, 3H); LCMS (m/z): 328.0 [M+H].sup.+.
Example 13
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(phenethylamino)-4,5-dihydrofuran-3-carboxylate hydrochloride
(57) ##STR00023##
(58) To a solution of ethyl 4-oxo-2-(phenethylamino)-4,5-dihydrofuran-3-carboxylate (0.041 g, 0.15 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.022 g, 0.15 mmol) in ethanol (1.0 mL), 2M hydrochloric acid in ethanol (0.16 mL, 0.32 mmol) was added at ambient temperature. The mixture was refluxed for 3 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.023 g, y. 32%).
(59) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.45 (br. s, 1H), 9.02 (t, J=6.15 Hz, 1H), 8.40 (d, J=6.78 Hz, 1H), 8.33 (dd, J=1.38, 4.64 Hz, 1H), 7.94 (d, J=2.26 Hz, 1H), 7.23-7.33 (m, 4H), 7.11-7.22 (m, 2H), 6.84 (s, 1H), 4.21 (q, J=7.19 Hz, 2H), 3.85 (q, J=6.94 Hz, 2H), 3.00 (t, J=7.28 Hz, 2H), 1.25 (t, J=7.03 Hz, 3H); LCMS (m/z): 404.0 [M+H].sup.+.
Example 14
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-pyrrolidinyl-4,5-dihydrofuran-3-carboxylate hydrochloride
(60) ##STR00024##
(61) To a solution of ethyl 4-oxo-2-pyrrolidinyl-4,5-dihydrofuran-3-carboxylate (0.034 g, 0.15 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.022 g, 0.15 mmol) in ethanol (1.0 mL), 2M hydrochloric acid in ethanol (0.16 mL, 0.32 mmol) was added at ambient temperature. The mixture was refluxed for 3 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.038 g, y. 61%).
(62) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.38 (br. s, 1H), 8.46 (d, J=8.03 Hz, 1H), 8.33 (dd, J=1.38, 4.64 Hz, 1H), 7.95 (d, J=2.26 Hz, 1H), 7.23 (dd, J=4.77, 7.78 Hz, 1H), 6.84 (s, 1H), 4.16 (q, J=7.03 Hz, 2H), 3.79-3.98 (m, 3H), 3.63-3.73 (m, 2H), 1.92-2.05 (m, 4H), 1.24 (t, J=7.03 Hz, 3H); LCMS (m/z): 354.0 [M+H].sup.+.
Example 15
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-chlorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(63) ##STR00025##
(64) To a solution of ethyl 2[(2-chlorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.14 g, 0.50 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.073 g, 0.50 mmol) in ethanol (2.0 mL), piperidine (0.054 mL, 0.55 mmol) was added at ambient temperature. The mixture was refluxed for 12 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.099 g, y. 48%).
(65) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.31 (br. s, 1H), 10.65 (s, 1H), 8.22 (dd, J=1.38, 4.64 Hz, 1H), 7.70-7.83 (m, 4H), 7.51-7.64 (m, 2H), 6.92 (s, 1H), 6.81 (dd, J=4.64, 7.91 Hz, 1H), 4.29 (q, J=7.11 Hz, 2H), 1.30 (t, J=7.03 Hz, 3H); LCMS (m/z): 409.8 [M+H].sup.+.
Example 16
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[4-(dimethylamino)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate hydrochloride
(66) ##STR00026##
(67) To a solution of ethyl 2-{[4-(dimethylamino)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.073 g, 0.20 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.029 g, 0.20 mmol) in ethanol (1.5 mL), 2M hydrochloric acid in ethanol (0.33 mL, 0.66 mmol) was added at ambient temperature. The mixture was refluxed for 1 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.034 g, y. 35%).
(68) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.51 (br. s, 1H), 10.47 (br. s, 1H), 8.23-8.33 (m, 1H), 8.10 (d, J=7.78 Hz, 1H), 7.81 (s, 1H), 7.50 (d, J=8.03 Hz, 2H), 7.16 (br. s, 2H), 6.95 (dd, J=4.77, 7.78 Hz, 1H), 6.90 (s, 1H), 4.40-5.20 (m, 1H), 4.27 (q, J=7.03 Hz, 2H), 3.08 (s, 6H), 1.29 (t, J=7.15 Hz, 3H); LCMS (m/z): 419.0 [M+H].sup.+.
Example 17
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(diethylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate hydrochloride
(69) ##STR00027##
(70) To a solution of ethyl 2-(diethylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.034 g, 0.15 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.022 g, 0.15 mmol) in ethanol (1.0 mL), 2M hydrochloric acid in ethanol (0.16 mL, 0.32 mmol) was added at ambient temperature. The mixture was refluxed for 3 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.023 g, y. 38%).
(71) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.36 (br. s, 1H), 8.41 (d, J=7.78 Hz, 1H), 8.33 (dd, J=1.25, 4.77 Hz, 1H), 7.93 (d, J=2.26 Hz, 1H), 7.22 (dd, J=4.77, 7.78 Hz, 1H), 6.84 (s, 1H), 4.18 (q, J=7.11 Hz, 2H), 3.50-3.84 (m, 5H), 1.11-1.38 (m, 9H); LCMS (m/z): 356.0 [M+H].sup.+.
Example 18
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(cyclohexylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate hydrochloride
(72) ##STR00028##
(73) To a solution of ethyl 2-(cyclohexylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.019 g, 0.075 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.011 g, 0.075 mmol) in ethanol (1.0 mL), 2M hydrochloric acid in ethanol (0.079 mL, 0.16 mmol) was added at ambient temperature. The mixture was refluxed for 4 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.0070 g, y. 22%).
(74) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.40 (br. s, 1H), 8.53 (d, J=8.53 Hz, 1H), 8.46 (d, J=7.78 Hz, 1H), 8.34 (dd, J=1.26, 4.52 Hz, 1H), 7.99 (d, J=2.26 Hz, 1H), 7.22 (dd, J=4.64, 7.91 Hz, 1H), 6.90 (s, 1H), 4.21 (q, J=7.03 Hz, 2H), 3.91-4.09 (m, 1H), 1.98 (d, J=9.79 Hz, 2H), 1.79 (d, J=13.05 Hz, 2H), 1.55-1.70 (m, 3H), 1.35-1.49 (m, 2H), 1.16-1.29 (m, 4H); LCMS (m/z): 382.4 [M+H].sup.+.
Example 19
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-bromophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(75) ##STR00029##
(76) To a solution of ethyl 2-[(4-bromophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.15 g, 0.46 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.067 g, 0.46 mmol) in ethanol (5.0 mL), piperidine (0.85 mL, 0.92 mmol) was added at ambient temperature. The mixture was refluxed for 24 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound (0.075 g, y. 36%).
(77) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.34 (br. s, 1H), 10.61 (br. s, 1H), 8.26 (d, J=3.42 Hz, 1H), 7.95 (d, J=7.34 Hz, 1H), 7.84 (br. s, 1H), 7.72 (d, J=8.31 Hz, 2H), 7.57 (d, J=8.31 Hz, 2H), 6.77-7.05 (m, 2H), 4.07-4.42 (m, 2H), 1.29 (t, J=6.85 Hz, 3H); LCMS (m/z): 382.4 [M+H].sup.+.
Example 20
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(p-tolylamino)-4,5-dihydrofuran-3-carboxylate
(78) ##STR00030##
(79) The titled compound was similarly prepared according to the procedure described in the Example 19.
(80) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.30 (br. s, 1H), 10.51 (br. s, 1H), 8.24 (d, J=3.42 Hz, 1H), 7.97 (d, J=7.34 Hz, 1H), 7.80 (br. s, 1H), 7.46 (d, J=7.82 Hz, 2H), 7.34 (d, J=8.31 Hz, 2H), 6.74-7.02 (m, 2H), 4.14-4.37 (m, 2H), 2.44 (s, 3H), 1.29 (t, J=6.85 Hz, 3H); LCMS (m/z): 390.6 [M+H].sup.+.
Example 21
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(81) ##STR00031##
(82) The titled compound (solid) was similarly prepared according to the procedure described in the Example 19.
(83) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.28 (br. s, 1H), 10.57 (br. s, 1H), 8.24 (br. s, 1H), 7.95 (d, J=7.82 Hz, 1H), 7.75 (br. s, 1H), 7.60-7.68 (m, 2H), 7.38 (t, J=8.31 Hz, 2H), 6.85-6.93 (m, 2H), 4.11-4.50 (m, 2H), 1.29 (t, J=6.85 Hz, 3H); LCMS (m/z): 394.2 [M+H].sup.+.
Example 22
5-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(phenylamino)-4,5-dihydrofuran-3-carboxylic acid
(84) ##STR00032##
(85) To a solution of the compound (0.050 g, 0.13 mmol) of Example 1 in ethanol (1.0 mL), 50% potassium hydroxide solution (0.5 mL, 0.13 mmol) was added at ambient temperature. The mixture was refluxed for 1 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol. The crude material was dissolved in water (0.5 mL) and tetrahydrofuran (0.5 mL), then 2M hydrochloric acid (0.023 mL, 0.046 mmol) was added and the mixture was stirred for 30 min. The precipitate was collected by filtration, washed with water and diethyl ether then dried to afford the titled compound (0.012 g, y. 26%).
(86) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.11 (br. s, 2H), 8.21 (dd, J=1.25, 4.52 Hz, 1H), 8.06 (d, J=7.78 Hz, 1H), 7.73 (d, J=2.26 Hz, 1H), 7.38-7.49 (m, 2H), 7.32 (d, J=7.53 Hz, 2H), 7.19-7.27 (m, 1H), 6.91 (dd, J=4.64, 7.91 Hz, 1H), 6.66 (s, 1H); LCMS (m/z): 347.9 [M+H].sup.+.
Example 23
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-hydroxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(87) ##STR00033##
(88) To a solution of ethyl 2-[(2-hydroxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.050 g, 0.19 mmol) which similarly prepared according to the procedure described in the Example 4 and 7-azaindole-3-carboxaldehyde (0.023 g, 0.16 mmol) in ethanol (1.0 mL), piperidine (0.0010 mL, 0.010 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed hexane then dried to afford the titled compound (0.008 g, y. 11%).
(89) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.33 (br. s, 1H), 10.35 (s, 1H), 10.30 (s, 1H), 8.25 (dd, J=1.38, 4.64 Hz, 1H), 8.06 (d, J=7.03 Hz, 1H), 7.87 (d, J=2.76 Hz, 1H), 7.58 (d, J=7.03 Hz, 1H), 7.24-7.33 (m, 1H), 7.07 (dd, J=1.00, 8.28 Hz, 1H), 6.90-7.01 (m, 3H), 4.28 (q, J=7.03 Hz, 2H), 1.30 (t, J=7.15 Hz, 3H); LCMS (m/z): 392.0 [M+H].sup.+.
Example 24
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2,4-dimethoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(90) ##STR00034##
(91) To a solution of ethyl 2-[(2,4-dimethoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.35 g, 1.1 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.12 g, 1.1 mmol) in ethanol (10 mL), piperidine (0.5 mL, 4.6 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound (0.13 g, y. 26%).
(92) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.31 (br. s, 1H), 10.14 (br. s, 1H), 8.24 (br. s, 1H), 7.94 (d, J=7.82 Hz, 1H), 7.80 (br. s, 1H), 7.51 (d, J=8.80 Hz, 1H), 6.78-6.93 (m, 3H), 6.68 (d, J=8.31 Hz, 1H), 4.26 (d, J=6.85 Hz, 2H), 3.89 (s, 3H), 3.81 (s, 3H), 1.29 (t, J=6.60 Hz, 3H); LCMS (m/z): 436.2 [M+H].sup.+.
Example 25
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-carbamoylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(93) ##STR00035##
(94) The titled compound (solid) was similarly prepared according to the procedure described in the Example 24.
(95) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.34 (br. s, 1H), 10.67 (br. s, 1H), 8.24 (br. s, 1H), 7.95-8.13 (m, 4H), 7.84 (br. s, 1H), 7.67 (d, J=7.34 Hz, 2H), 7.49 (br. s, 1H), 6.75-7.08 (m, 2H), 4.28 (d, J=6.85 Hz, 2H), 1.30 (t, J=6.36 Hz, 3H); LCMS (m/z): 419.0 [M+H].sup.+.
Example 26
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2,4-dimethylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(96) ##STR00036##
(97) The titled compound (solid) was similarly prepared according to the procedure described in the Example 24.
(98) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.26 (br. s, 1H), 10.35 (br. s, 1H), 8.21 (d, J=3.91 Hz, 1H), 7.65-7.80 (m, 2H), 7.39 (d, J=8.31 Hz, 1H), 7.27 (s, 1H), 7.20 (d, J=7.82 Hz, 1H), 6.84 (s, 1H), 6.73 (dd, J=4.40, 7.83 Hz, 1H), 4.27 (q, J=7.01 Hz, 2H), 2.44 (s, 3H), 2.23 (s, 3H), 1.30 (t, J=6.85 Hz, 3H); LCMS (m/z): 404.0 [M+H].sup.+.
Example 27
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(3-pyridinylamino)-4,5-dihydrofuran-3-carboxylate
(99) ##STR00037##
(100) The titled compound (solid) was similarly prepared according to the procedure described in the Example 24.
(101) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.33 (br. s, 1H), 10.72 (br. s, 1H), 8.82 (br. s, 1H), 8.65 (br. s., 1H), 8.24 (br. s, 1H), 7.90-8.11 (m, 2H), 7.73 (br. s, 1H), 7.54-7.62 (m, 1H), 6.87-6.97 (m, 2H), 4.28 (d, J=6.85 Hz, 2H), 1.30 (t, J=6.36 Hz, 3H); LCMS (m/z): 377.6 [M+H].sup.+.
Example 28
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(3,4-dimethoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(102) ##STR00038##
(103) The titled compound (solid) was similarly prepared according to the procedure described in the Example 24.
(104) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.33 (br. s, 1H), 10.44 (s, 1H), 8.24 (d, J=3.91 Hz, 1H), 7.96 (d, J=7.82 Hz, 1H), 7.82 (br. s, 1H), 7.24 (s, 1H), 7.06-7.14 (m, 2H), 6.78-6.94 (m, 2H), 4.27 (q, J=7.01 Hz, 2H), 3.87 (s, 3H), 3.71 (s, 3H), 1.29 (t, J=7.09 Hz, 3H); LCMS (m/z): 436.5 [M+H].sup.+.
Example 29
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-(2-hydroxyethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(105) ##STR00039##
First Step
(106) A solution of ethyl 2-[(2-hydroxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.38 mmol) which similarly prepared according to the procedure described in the Example 4, First step, 2-chloroethanol (0.038 mL, 0.57 mmol) and potassium carbonate (0.11 g, 0.80 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 90 C. for 2 days. Cooled to ambient temperature, ethyl acetate was added to the reaction mixture, the organic layer was washed with aqueous 5% citric acid solution, water and brine, dried over magnesium sulfate and concentrated. To the residue, tert-butyl methyl ether was added to precipitate the product. The precipitate was collected by filtration, washed with hexane then dried to afford ethyl 2-{[2-(2-hydroxyethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.041 g, y. 35%).
(107) .sup.1H NMR (DMSO-d.sub.6) (ppm) 10.40 (s, 1H), 7.66 (d, J=7.53 Hz, 1H), 7.16-7.25 (m, 2H), 6.97-7.05 (m, 1H), 4.82 (br. s, 1H), 4.75 (s, 2H), 4.24 (q, J=7.03 Hz, 2H), 4.15 (t, J=5.14 Hz, 2H), 3.72-3.80 (m, 2H), 1.26 (t, J=7.15 Hz, 3H); LCMS (m/z): 308.0 [M+H].sup.+.
(108) Second Step
(109) To a solution of ethyl 2-{[2-(2-hydroxyethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.021 g, 0.068 mmol) and 7-azaindole-3-carboxaldehyde (0.0087 g, 0.060 mmol) in ethanol (0.5 mL), 2M hydrochloric acid in ethanol (0.030 mL, 0.059 mmol) was added at ambient temperature. The mixture was refluxed for 4 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and hexane then dried to afford the titled compound as solid (0.021 g, y. 72%).
(110) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.36 (br. s, 1H), 10.33 (s, 1H), 8.24-8.29 (m, 1H), 8.07 (d, J=6.78 Hz, 1H), 7.85 (s, 1H), 7.65-7.70 (m, 1H), 7.38-7.46 (m, 1H), 7.29 (d, J=7.78 Hz, 1H), 7.11 (t, J=7.65 Hz, 1H), 6.92-6.99 (m, 2H), 4.41 (br. s, 1H), 4.28 (q, J=7.20 Hz, 2H), 4.10 (t, J=5.14 Hz, 2H), 3.65 (t, J=5.02 Hz, 2H), 1.30 (t, J=7.03 Hz, 3H); LCMS (m/z): 436 [M+H].sup.+.
Example 30
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-(2-morpholinoethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(111) ##STR00040##
(112) To a solution of ethyl 2-{[2-(2-morpholinoethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.021 g, 0.054 mmol) which similarly prepared according to the procedure described in the Example 29, First step and 7-azaindole-3-carboxaldehyde (0.0070 g, 0.048 mmol) in ethanol (0.5 mL), 2M hydrochloric acid in ethanol (0.024 mL, 0.048 mmol) was added at ambient temperature. The mixture was refluxed for 4 h. The reaction mixture was cooled with ice bath. Aqueous 2M sodium hydroxide solution (0.024 mL, 0.048 mmol) was added dropwise to neutralize and the mixture was stirred for 1 h. The precipitate was collected by filtration then purified by preparative HPLC to afford the titled compound as solid (0.0054 g, y. 21%).
(113) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.31 (br. s, 1H), 10.35 (br. s, 1H), 8.24 (dd, J=1.25, 4.52 Hz, 1H), 7.94 (d, J=7.78 Hz, 1H), 7.83 (d, J=2.01 Hz, 1H), 7.62 (d, J=7.03 Hz, 1H), 7.42-7.50 (m, 1H), 7.28 (d, J=7.78 Hz, 1H), 7.12 (t, J=7.28 Hz, 1H), 6.92 (s, 1H), 6.88 (dd, J=4.64, 7.91 Hz, 1H), 4.27 (q, J=7.03 Hz, 2H), 4.14 (t, J=5.14 Hz, 2H), 3.36-3.42 (m, 4H), 2.59 (t, J=5.02 Hz, 2H), 2.25-2.35 (m, 4H), 1.30 (t, J=7.03 Hz, 3H); LCMS (m/z): 505.4 [M+H].sup.+.
Example 31
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(114) ##STR00041##
(115) To a solution of ethyl 2-[(2-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.38 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.050 g, 0.34 mmol) in ethanol (2.0 mL), piperidine (0.0034 mL, 0.034 mmol) was added at ambient temperature. The mixture was refluxed for 36 h. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.037 g, y. 27%).
(116) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.31 (br. s, 1H), 10.55 (s, 1H), 8.22 (dd, J=1.38, 4.64 Hz, 1H), 7.84 (d, J=7.78 Hz, 1H), 7.67-7.77 (m, 2H), 7.55-7.63 (m, 1H), 7.45-7.53 (m, 1H), 7.37-7.44 (m, 1H), 6.92 (s, 1H), 6.83 (dd, J=4.64, 7.91 Hz, 1H), 4.28 (q, J=7.03 Hz, 2H), 1.30 (t, J=7.03 Hz, 3H); LCMS (m/z): 393.9 [M+H].sup.+.
Example 32
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(o-tolylamino)-4,5-dihydrofuran-3-carboxylate
(117) ##STR00042##
(118) To a solution of ethyl 4-oxo-2-(o-tolylamino)-4,5-dihydrofuran-3-carboxylate (0.098 g, 0.38 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.050 g, 0.34 mmol) in ethanol (2.0 mL), piperidine (0.0034 mL, 0.034 mmol) was added at ambient temperature. The mixture was refluxed for 32 h. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.019 g, y. 27%).
(119) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.26 (br. s, 1H), 10.43 (s, 1H), 8.18-8.22 (m, 1H), 7.69-7.75 (m, 2H), 7.54 (d, J=7.78 Hz, 1H), 7.45-7.49 (m, 2H), 7.37-7.44 (m, 1H), 6.85 (s, 1H), 6.78 (dd, J=4.64, 7.91 Hz, 1H), 4.28 (q, J=7.19 Hz, 2H), 2.28 (s, 3H), 1.30 (t, J=7.03 Hz, 3H); LCMS (m/z): 390 [M+H].sup.+.
Example 33
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({2-([2-(dimethylamino)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(120) ##STR00043##
(121) To a solution of ethyl 2-({2-[2-(dimethylamino)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.010 g, 0.031 mmol) which similarly prepared according to the procedure described in the Example 29, First step and 7-azaindole-3-carboxaldehyde (0.0042 g, 0.029 mmol) in 2-propanol (0.3 mL), piperidine (0.00028 mL, 0.0028 mmol) was added at ambient temperature. The mixture was refluxed for 24 h. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.0029 g, y. 22%).
(122) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.24 (br. s, 1H), 8.23 (dd, J=1.26, 4.52 Hz, 1H), 7.98 (d, J=7.53 Hz, 1H), 7.79 (s, 1H), 7.58 (d, J=7.28 Hz, 1H), 7.36-7.45 (m, 1H), 7.28 (d, J=7.53 Hz, 1H), 7.13 (t, J=7.53 Hz, 1H), 6.89 (dd, J=4.64, 7.91 Hz, 1H), 6.83 (s, 1H), 4.26 (q, J=7.19 Hz, 2H), 4.15 (t, J=5.52 Hz, 2H), 2.55-2.65 (m, 2H), 2.19 (s, 6H), 1.29 (t, J=7.03 Hz, 3H); LCMS (m/z): 463 [M+H].sup.+.
Example 34
Methyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-piperidino-4,5-dihydrofuran-3-carboxylate
(123) ##STR00044##
(124) To a solution of methyl 4-oxo-2-(phenylamino)-4,5-dihydrofuran-3-carboxylate (0.047 g, 0.20 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and phenyl isocyanate, and 7-azaindole-3-carboxaldehyde (0.029 g, 0.20 mmol) in methanol (1.0 mL), piperidine (0.022 mL, 0.22 mmol) was added at ambient temperature. The mixture was refluxed for 5 days. Cooled to ambient temperature, the precipitate was collected by filtration, then purified by preparative HPLC, collected former fraction to afford the titled compound as solid (0.0075 g, y. 11%).
(125) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.30 (br. s, 1H), 8.35-8.43 (m, 1H), 8.31 (dd, J=1.38, 4.64 Hz, 1H), 7.97 (d, J=2.51 Hz, 1H), 7.19 (dd, J=4.64, 7.91 Hz, 1H), 6.87 (s, 1H), 3.70-3.82 (m, 4H), 3.68 (s, 3H), 1.64-1.80 (m, 6H); LCMS (m/z): 354.0 [M+H].sup.+
Example 35
Methyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(phenylamino)-4,5-dihydrofuran-3-carboxylate
(126) ##STR00045##
(127) To a solution of methyl 4-oxo-2-(phenylamino)-4,5-dihydrofuran-3-carboxylate (0.047 g, 0.20 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and phenyl isocyanate, and 7-azaindole-3-carboxaldehyde (0.029 g, 0.20 mmol) in 2-propanol (1.0 mL), piperidine (0.022 mL, 0.22 mmol) was added at ambient temperature. The mixture was refluxed for 5 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound as solid (0.031 g, y. 43%).
(128) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.29 (br. s, 1H), 10.59 (s, 1H), 8.23 (dd, J=1.38, 4.64 Hz, 1H), 7.98 (d, J=7.53 Hz, 1H), 7.77 (d, J=2.51 Hz, 1H), 7.52-7.64 (m, 4H), 7.44-7.51 (m, 1H), 6.93 (s, 1H), 6.89 (dd, J=4.64, 7.91 Hz, 1H), 3.77 (s, 3H); LCMS (m/z): 361.9 [M+H].sup.+.
Example 36
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(4-methylpiperazinyl)-4-oxo-4,5-dihydrofuran-3-carboxylate hydrochloride
(129) ##STR00046##
(130) To a solution of ethyl 2-(4-methylpiperazinyl)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.038 g, 0.15 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.022 g, 0.15 mmol) in ethanol (1.0 mL), 2M hydrochloric acid in methanol (0.17 mL, 0.34 mmol) was added at ambient temperature. The mixture was refluxed for 40 min. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.0069 g, y. 9%).
(131) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.32-12.49 (m, 1H), 10.69 (br. s, 1H), 8.39 (d, J=8.03 Hz, 1H), 8.29-8.36 (m, 1H), 8.08 (d, J=2.76 Hz, 1H), 7.22 (dd, J=4.64, 7.91 Hz, 1H), 6.95 (s, 1H), 4.19 (q, J=7.19 Hz, 2H), 3.57-3.75 (m, 4H), 3.33-3.40 (m, 4H), 2.87 (br. s., 3H), 1.16-1.34 (m, 3H); LCMS (m/z): 383.0 [M+H].sup.+.
Example 37
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-isopropylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(132) ##STR00047##
(133) To a solution of ethyl 2-[(4-isopropylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.26 g, 0.90 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.13 g, 0.90 mmol) in ethanol (6.0 mL), piperidine (0.045 mL, 0.45 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.13 g, y. 35%).
(134) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.35 (br. s, 1H), 10.50 (br. s, 1H), 8.24 (d, J=3.42 Hz, 1H), 8.04 (d, J=7.82 Hz, 1H), 7.82 (br. s, 1H), 7.33-7.58 (m, 4H), 6.82-6.96 (m, 2H), 4.08-4.44 (m, 2H), 2.86-3.17 (m, 1H), 1.31 (s, 3H), 1.29 (s, 6H); LCMS (m/z): 418.0 [M+H].sup.+.
Example 38
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(5-pyrimidinylamino)-4,5-dihydrofuran-3-carboxylate
(135) ##STR00048##
(136) The titled compound (solid) was similarly prepared according to the procedure described in the Example 37.
(137) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.34 (br. s, 1H), 10.80 (br. s, 1H), 9.19 (s, 1H), 9.02-9.12 (m, 2H), 8.25 (d, J=4.40 Hz, 1H), 8.03 (d, J=7.82 Hz, 1H), 7.71 (br. s, 1H), 6.86-7.00 (m, 2H), 4.28 (q, J=6.85 Hz, 2H), 1.30 (t, J=6.00 Hz, 3H); LCMS (m/z): 378.2 [M+H].sup.+.
Example 39
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(1,1-biphenyl)-4-ylamino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(138) ##STR00049##
(139) The titled compound (solid) was similarly prepared according to the procedure described in the Example 37.
(140) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.34 (br. s, 1H), 10.63 (br. s, 1H), 8.20 (br. s, 1H), 8.09 (d, J=6.85 Hz, 1H), 7.75-7.93 (m, 5H), 7.62-7.74 (m, 2H), 7.50-7.58 (m, 2H), 7.39-7.48 (m, 1H), 6.94 (br. s, 1H), 6.83-6.91 (m, 1H), 4.29 (d, J=6.36 Hz, 2H), 1.31 (br. s, 3H); LCMS (m/z): 452.6 [M+H].sup.+.
Example 40
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-nitrophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(141) ##STR00050##
(142) The titled compound (solid) was similarly prepared according to the procedure described in the Example 37.
(143) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.39 (br. s, 1H), 10.89 (br. s, 1H), 8.35 (d, J=8.80 Hz, 2H), 8.27 (d, J=3.91 Hz, 1H), 8.17 (d, J=7.82 Hz, 1H), 7.88 (d, J=8.80 Hz, 2H), 7.84 (d, J=2.45 Hz, 1H), 7.03 (s, 1H), 6.98 (dd, J=4.65, 8.07 Hz, 1H), 4.28 (q, J=7.17 Hz, 2H), 1.29 (t, J=7.09 Hz, 3H); LCMS (m/z): 421.4 [M+H].sup.+.
Example 41
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-aminophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate hydrochloride
(144) ##STR00051##
First Step
(145) To a solution of ethyl 2-({4-[(tert-butoxycarbonyl)amino]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.32 g, 0.88 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.13 g, 0.88 mmol) in ethanol (5.0 mL), piperidine (0.18 mL, 1.8 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[(tert-butoxycarbonyl)amino]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.095 g, y. 21%).
(146) .sup.1H NMR (DMSO-d.sub.6) 12.30 (br. s, 1H), 10.44 (br. s, 1H), 9.60 (s, 1H), 8.20 (d, J=3.76 Hz, 1H), 7.91 (d, J=7.72 Hz, 1H), 7.82 (s, 1H), 7.60 (d, J=8.40 Hz, 2H), 7.45 (d, J=8.56 Hz, 2H), 6.82-6.92 (m, 2H), 4.26 (q, J=6.86 Hz, 2H), 1.53 (s, 9H), 1.29 (t, J=6.90 Hz, 3H); LCMS (m/z): 491.4 [M+H].sup.+.
(147) Second Step
(148) A solution of ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[4-(tert-butoxycarbonyl)aminophenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.090 g, 0.18 mmol) in 4M hydrochloric acid in dioxane (3.0 mL) was stirred at ambient temperature for 2 h. The solvent was removed under reduced pressure, and diethyl ether was added to precipitate the product. The precipitate was collected by filtration, washed with diethyl ether then dried to afford the titled compound as solid (0.066 g, y. 92%).
(149) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.44 (br. s, 1H), 10.61 (br. s, 1H), 8.26 (d, J=3.91 Hz, 1H), 8.02 (d, J=7.82 Hz, 1H), 7.79 (s, 1H), 7.61 (d, J=8.31 Hz, 2H), 7.40 (d, J=7.34 Hz, 2H), 7.01 (dd, J=4.89, 7.83 Hz, 1H), 6.92 (s, 1H), 4.68 (br. s, 3H), 4.27 (q, J=7.01 Hz, 2H), 1.29 (t, J=6.85 Hz, 3H); LCMS (m/z): 391.2 [M+H].sup.+.
Example 42
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-morpholinophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(150) ##STR00052##
(151) The titled compound (solid) was similarly prepared according to the procedure described in the Example 41, First step.
(152) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.31 (br. s, 1H), 10.39 (br. s, 1H), 8.24 (br. s, 1H), 7.99 (d, J=7.34 Hz, 1H), 7.79 (br. s, 1H), 7.42 (d, J=8.31 Hz, 2H), 7.07 (d, J=8.31 Hz, 2H), 6.81-6.96 (m, 2H), 4.26 (d, J=6.85 Hz, 2H), 3.28-3.40 (m, 4H), 3.15-3.28 (m, 4H), 1.29 (t, J=6.85 Hz, 3H); LCMS (m/z): 461.4 [M+H].sup.+.
Example 43
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(4-pyridinylamino)-4,5-dihydrofuran-3-carboxylate
(153) ##STR00053##
(154) The titled compound (solid) was similarly prepared according to the procedure described in the Example 41, First step.
(155) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.30 (br. s, 1H), 11.18 (br. s, 1H), 8.59 (d, J=3.91 Hz, 2H), 8.28 (d, J=3.91 Hz, 1H), 8.19 (d, J=7.34 Hz, 1H), 7.88 (br. s, 1H), 7.55 (br. s, 2H), 7.02 (dd, J=4.40, 7.83 Hz, 1H), 6.93 (br. s, 1H), 4.23 (d, J=6.85 Hz, 2H), 1.26 (t, J=6.85 Hz, 3H); LCMS (m/z): 377.6 [M+H].sup.+.
Example 44
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(6-quinolinylamino)-4,5-dihydrofuran-3-carboxylate
(156) ##STR00054##
(157) The titled compound (solid) was similarly prepared according to the procedure described in the Example 41, First step.
(158) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.29 (br. s, 1H), 10.82 (s, 1H), 9.01 (d, J=3.42 Hz, 1H), 8.39 (d, J=8.31 Hz, 1H), 8.23 (br. s, 1H), 8.17 (d, J=8.80 Hz, 1H), 8.11 (d, J=3.91 Hz, 1H), 8.00 (d, J=8.80 Hz, 1H), 7.88 (d, J=7.34 Hz, 1H), 7.83 (br. s, 1H), 7.62 (dd, J=4.16, 8.07 Hz, 1H), 6.94 (s, 1H), 6.26-6.51 (m, 1H), 4.30 (q, J=6.85 Hz, 2H), 1.32 (t, J=6.85 Hz, 3H); LCMS (m/z): 427.4 [M+H].sup.+.
Example 45
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorobenzyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(159) ##STR00055##
(160) The titled compound (solid) was similarly prepared according to the procedure described in the Example 41, First step.
(161) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.31 (br. s, 1H), 9.51 (br. s, 1H), 8.22-8.37 (m, 2H), 7.86 (br. s, 1H), 7.47 (t, J=6.30 Hz, 2H), 7.22 (t, J=8.31 Hz, 2H), 7.05-7.15 (m, 1H), 6.87 (s, 1H), 4.84 (d, J=5.87 Hz, 2H), 4.23 (q, J=6.52 Hz, 2H), 1.27 (t, J=6.85 Hz, 3H); LCMS (m/z): 408.2 [M+H].sup.+.
Example 46
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-fluorobenzyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(162) ##STR00056##
(163) The titled compound (solid) was similarly prepared according to the procedure described in the Example 41, First step.
(164) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.35 (br. s, 1H), 9.44 (br. s, 1H), 8.15-8.42 (m, 2H), 7.86 (s, 1H), 7.45 (t, J=7.34 Hz, 1H), 7.33-7.40 (m, 1H), 7.18-7.32 (m, 2H), 7.07 (dd, J=5.14, 7.58 Hz, 1H), 6.87 (s, 1H), 4.91 (s, 2H), 4.23 (q, J=7.17 Hz, 2H), 1.27 (t, J=6.85 Hz, 3H); LCMS (m/z): 408.0 [M+H].sup.+.
Example 47
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)-N-methylamino]-4-oxo-4,5-dihydrofuran-3-carboxylate hydrochloride
(165) ##STR00057##
First Step
(166) A solution of ethyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.38 mmol) which similarly prepared according to the procedure described in the Example 4, First step, potassium carbonate (0.063 g, 0.45 mmol) and methyliodide (0.026 mL, 0.42 mmol) in anhydrous N,N-dimethylformamide (2.0 mL) was stirred at ambient temperature for 12 h. The reaction mixture was diluted with water then extracted with ethyl acetate for 3 times. The organic layer was dried over sodium sulfate and concentrated to afford ethyl 2-[(4-fluorophenyl)-N-methylamino]-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.13 g).
(167) .sup.1H NMR (DMSO-d.sub.6) (ppm) 7.38-7.47 (m, 2H), 7.21-7.32 (m, 2H), 4.65 (s, 2H), 3.60 (q, J=7.03 Hz, 2H), 3.43 (s, 3H), 0.96 (t, J=7.15 Hz, 3H); LCMS (m/z): 279.9 [M+H].sup.+.
(168) Second Step
(169) To a solution of ethyl 2-[(4-fluorophenyl)-N-methylamino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.050 g, 0.18 mmol) and 7-azaindole-3-carboxaldehyde (0.026 g, 0.18 mmol) in ethanol (1.0 mL), 2M hydrochloric acid in ethanol (0.19 mL, 0.38 mmol) was added at ambient temperature. The mixture was refluxed for 2 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound as solid (0.011 g, y. 13%).
(170) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.38 (br. s, 1H), 8.28 (dd, J=1.25, 4.77 Hz, 1H), 8.12 (d, J=7.78 Hz, 1H), 7.81 (d, J=2.01 Hz, 1H), 7.53-7.62 (m, 2H), 7.31-7.38 (m, 2H), 7.05 (dd, J=4.77, 7.78 Hz, 1H), 6.90 (s, 1H), 3.80 (q, J=7.03 Hz, 2H), 3.63 (s, 3H), 1.01-1.10 (m, 3H); LCMS (m/z): 407.9 [M+H].sup.+.
Example 48
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-methoxyethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(171) ##STR00058##
(172) To a solution of ethyl 2-[(2-methoxyethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.50 g, 2.2 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.32 g, 2.2 mmol) in ethanol (3.0 mL), piperidine (5 drops) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid.
(173) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.34 (br. s, 1H), 8.89 (br. s, 1H), 8.43 (d, J=7.34 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 8.03 (s, 1H), 7.19 (dd, J=4.40, 7.83 Hz, 1H), 6.90 (s, 1H), 4.21 (q, J=7.17 Hz, 2H), 3.79 (d, J=4.40 Hz, 2H), 3.62 (t, J=5.14 Hz, 2H), 3.28 (s, 3H), 1.26 (t, J=7.09 Hz, 3H); LCMS (m/z): 358.4 [M+H].sup.+.
Example 49
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-[(2-piperidinoethyl)amino]-4,5-dihydrofuran-3-carboxylate
(174) ##STR00059##
(175) The titled compound (solid) was similarly prepared according to the procedure described in the Example 48.
(176) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.35 (br. s, 1H), 8.83 (br. s, 1H), 8.38-8.47 (m, 1H), 8.31 (br. s, 1H), 8.02 (br. s, 1H), 7.20 (br. s, 1H), 6.88 (br. s, 1H), 4.12-4.28 (m, 2H), 3.67-3.80 (m, 2H), 2.25-2.70 (m, 6H), 1.32-1.53 (m, 6H), 1.18-1.32 (m, 3H); LCMS (m/z): 411.5 [M+H].sup.+.
Example 50
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(benzyl-N-methylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(177) ##STR00060##
(178) The titled compound (solid) was similarly prepared according to the procedure described in the Example 48.
(179) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.28 (br. s, 1H), 8.24-8.39 (m, 2H), 7.88 (br. s, 1H), 7.29-7.47 (m, 5H), 7.10 (br. s, 1H), 6.87 (s, 1H), 5.01 (s, 2H), 4.14 (d, J=6.85 Hz, 2H), 3.25 (br. s, 3H), 1.19 (t, J=6.36 Hz, 3H); LCMS (m/z): 404.6 [M+H].sup.+.
Example 51
Methyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(180) ##STR00061##
(181) To a solution of methyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.25 g, 1.0 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and 4-fluorophenyl isocyanate, and 7-azaindole-3-carboxaldehyde (0.15 g, 1.0 mmol) in 2-propanol (5.0 mL), L-proline (0.023 g, 0.20 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound as solid (0.26 g, y. 68%).
(182) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.28 (br. s, 1H), 10.58 (s, 1H), 8.25 (dd, J=1.38, 4.64 Hz, 1H), 7.96 (d, J=8.03 Hz, 1H), 7.74 (d, J=2.51 Hz, 1H), 7.59-7.69 (m, 2H), 7.36-7.43 (m, 2H), 6.92 (s, 1H), 6.89 (dd, J=4.77, 8.03 Hz, 1H), 3.76 (s, 3H); LCMS (m/z): 379.8 [M+H].sup.+.
Example 52
n-Butyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(183) ##STR00062##
First Step
(184) Under a nitrogen atmosphere, a solution of methyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.13 g, 0.50 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and 4-fluorophenyl isocyanate, and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0062 g, 0.0065 mmol) in 1-butanol (2.0 mL) was stirred at 80 C. for 3 days then stirred at ambient temperature for further 3 days. The precipitate was collected by filtration, washed with 2-propanol and diisopropyl ether then dried to afford n-butyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.078 g, y. 53%).
(185) .sup.1H NMR (DMSO-d.sub.6) (ppm) 10.25 (s, 1H), 7.45-7.55 (m, 2H), 7.21-7.31 (m, 2H), 4.65 (s, 2H), 4.17 (t, J=6.53 Hz, 2H), 1.57-1.67 (m, 2H), 1.33-1.45 (m, 2H), 0.92 (t, J=7.40 Hz, 3H); LCMS (m/z): 293.8 [M+H].sup.+.
(186) Second Step
(187) To a solution of n-butyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.035 g, 0.12 mmol) and 7-azaindole-3-carboxaldehyde (0.018 g, 0.12 mmol) in 2-propanol (1.0 mL), L-proline (0.0028 g, 0.024 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound as solid (0.019 g, y. 36%).
(188) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.28 (br. s, 1H), 10.56 (s, 1H), 8.25 (dd, J=1.38, 4.64 Hz, 1H), 7.95 (d, J=7.78 Hz, 1H), 7.75 (d, J=2.76 Hz, 1H), 7.60-7.68 (m, 2H), 7.35-7.42 (m, 2H), 6.85-6.95 (m, 2H), 4.22 (t, J=6.65 Hz, 2H), 1.60-1.72 (m, 2H), 1.37-1.49 (m, 2H), 0.94 (t, J=7.40 Hz, 3H); LCMS (m/z): 421.9 [M+H].sup.+.
Example 53
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2,4-difluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(189) ##STR00063##
(190) To a solution of ethyl 2-[(2,4-difluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.15 g, 0.54 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.074 g, 0.50 mmol) in 2-propanol (2.5 mL), 2M hydrochloric acid in ethanol (0.25 mL, 0.50 mmol) was added at ambient temperature then refluxed for 24 h. Cooled with ice bath, aqueous 2M sodium hydroxide solution (0.024 mL, 0.048 mmol) was added dropwise to neutralize and the mixture was refluxed for 1 h. The precipitate was collected by filtration, washed with ethanol and hexane then dried to afford the titled compound as solid (0.14 g, y. 69%).
(191) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.27 (br. s, 1H), 10.51 (s, 1H), 8.24 (dd, J=1.38, 4.64 Hz, 1H), 7.84 (d, J=7.78 Hz, 1H), 7.66-7.77 (m, 2H), 7.50-7.59 (m, 1H), 7.29 (t, J=7.78 Hz, 1H), 6.80-6.89 (m, 2H), 4.26 (q, J=7.03 Hz, 2H), 1.29 (t, J=7.03 Hz, 3H); LCMS (m/z): 411.8 [M+H].sup.+.
Example 54
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(3,4-difluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(192) ##STR00064##
(193) To a solution of ethyl 2-[(3,4-difluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.084 g, 0.30 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.041 g, 0.28 mmol) in 2-propanol (2.0 mL), 2M hydrochloric acid in ethanol (0.14 mL, 0.28 mmol) was added at ambient temperature. The mixture was refluxed for 18 h. Cooled with ice bath, aqueous 2M sodium hydroxide solution (0.13 mL, 0.26 mmol) was added dropwise to neutralize, ethanol (5.0 mL) was added and the mixture was refluxed for 1.5 h. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.051 g, y. 44%).
(194) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.07 (br. s, 1H), 10.63 (br. s, 1H), 8.22 (dd, J=1.38, 4.64 Hz, 1H), 8.00 (d, J=7.78 Hz, 1H), 7.65 (s, 1H), 7.33-7.51 (m, 2H), 7.13 (br. s, 1H), 6.88 (dd, J=4.64, 7.91 Hz, 1H), 6.56 (br. s, 1H), 4.16 (q, J=6.86 Hz, 2H), 1.24 (t, J=7.15 Hz, 3H); LCMS (m/z): 411.8 [M+H].sup.+.
Example 55
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-{[4-(1-propoxy)phenyl]amino}-4,5-dihydrofuran-3-carboxylate
(195) ##STR00065##
(196) To a solution of ethyl 4-oxo-2-{[4-(1-propoxy)phenyl]amino}-4,5-dihydrofuran-3-carboxylate (0.15 g, 0.50 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.072 g, 0.50 mmol) in ethanol (6.0 mL), L-proline (0.0060 g, 0.05 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.060 g, y. 28%).
(197) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.30 (br. s, 1H), 10.44 (br. s, 1H), 8.22 (br. s, 1H), 7.85-7.99 (m, 1H), 7.79 (br. s, 1H), 7.48 (d, J=6.85 Hz, 2H), 7.07 (d, J=7.34 Hz, 2H), 6.86 (br. s, 2H), 4.18-4.37 (m, 2H), 3.93-4.11 (m, 2H), 1.70-1.90 (m, 2H), 1.22-1.38 (m, 3H), 0.98-1.12 (m, 3H); LCMS (m/z): 433.9 [M+H].sup.+.
Example 56
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(isopropylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(198) ##STR00066##
(199) To a solution of ethyl 2-(isopropylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.50 g, 2.3 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.34 g, 2.3 mmol) in ethanol (15 mL), L-proline (0.027 g, 0.23 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.45 g, y. 56%).
(200) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.32 (br. s, 1H), 8.56 (br. s, 1H), 8.41 (d, J=7.82 Hz, 1H), 8.32 (d, J=3.91 Hz, 1H), 7.99 (s, 1H), 7.20 (dd, J=4.40, 7.83 Hz, 1H), 6.90 (s, 1H), 4.39 (br. s, 1H), 4.21 (q, J=7.01 Hz, 2H), 1.38 (d, J=6.36 Hz, 6H), 1.26 (t, J=6.85 Hz, 3H); LCMS (m/z): 342.3 [M+H].sup.+.
Example 57
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-(dimethylamino)ethyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(201) ##STR00067##
(202) The titled compound (solid) was similarly prepared according to the procedure described in the Example 56.
(203) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.37 (br. s, 1H), 8.82 (br. s, 1H), 8.42 (d, J=7.82 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 8.03 (s, 1H), 7.20 (dd, J=4.89, 7.83 Hz, 1H), 6.90 (s, 1H), 4.20 (q, J=7.34 Hz, 2H), 3.68-3.80 (m, 2H), 2.38-2.65 (m, 2H), 2.23 (s, 6H), 1.26 (t, J=7.09 Hz, 3H); LCMS (m/z): 371.2 [M+H].sup.+.
Example 58
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(3-fluorobenzyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(204) ##STR00068##
(205) The titled compound (solid) was similarly prepared according to the procedure described in the Example 56.
(206) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.33 (br. s, 1H), 9.54 (br. s, 1H), 8.28 (d, J=5.87 Hz, 2H), 7.88 (s, 1H), 7.44 (q, J=7.34 Hz, 1H), 7.20-7.33 (m, 2H), 7.03-7.18 (m, 2H), 6.87 (s, 1H), 4.87 (br. s, 2H), 4.23 (q, J=6.85 Hz, 2H), 1.27 (t, J=6.85 Hz, 3H); LCMS (m/z): 408.0 [M+H].sup.+.
Example 59
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(cycloheptylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(207) ##STR00069##
(208) The titled compound (solid) was similarly prepared according to the procedure described in the Example 56.
(209) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.37 (br. s, 1H), 8.56 (d, J=8.16 Hz, 1H), 8.42 (d, J=7.82 Hz, 1H), 8.32 (d, J=3.91 Hz, 1H), 7.99 (s, 1H), 7.19 (dd, J=4.89, 7.82 Hz, 1H), 6.90 (s, 1H), 4.21 (q, J=6.85 Hz, 2H), 3.39-3.50 (m, 1H), 1.94-2.08 (m, 2H), 1.77-1.91 (m, 2H), 1.48-1.76 (m, 8H), 1.26 (t, J=7.09 Hz, 3H); LCMS (m/z): 396.0 [M+H].sup.+.
Example 60
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-[(2-thienylmethyl)amino]-4,5-dihydrofuran-3-carboxylate
(210) ##STR00070##
(211) The titled compound (solid) was similarly prepared according to the procedure described in the Example 56.
(212) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.36 (br. s, 1H), 9.55 (br. s, 1H), 8.37 (d, J=7.82 Hz, 1H), 8.30 (d, J=3.91 Hz, 1H), 8.03 (s, 1H), 7.45 (d, J=4.89 Hz, 1H), 7.09-7.22 (m, 2H), 7.00 (t, J=3.96 Hz, 1H), 6.91 (s, 1H), 5.01 (br. s, 2H), 4.22 (q, J=7.01 Hz, 2H), 1.26 (t, J=6.85 Hz, 3H); LCMS (m/z): 395.8 [M+H].sup.+.
Example 61
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(cyclopropylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(213) ##STR00071##
(214) The titled compound (solid) was similarly prepared according to the procedure described in the Example 56.
(215) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.33 (br. s, 1H), 8.86 (br. s, 1H), 8.57 (d, J=7.82 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 8.06 (s, 1H), 7.21 (dd, J=4.89, 7.82 Hz, 1H), 6.92 (s, 1H), 4.19 (q, J=7.01 Hz, 2H), 3.08-3.20 (m, 1H), 1.24 (t, J=6.85 Hz, 3H), 0.84-1.01 (m, 4H); LCMS (m/z): 340.0 [M+H].sup.+.
Example 62
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(3,5-dimethylpiperidino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(216) ##STR00072##
(217) The titled compound (solid) was similarly prepared according to the procedure described in the Example 56.
(218) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.32 (br. s, 1H), 8.38 (d, J=7.82 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 7.96 (s, 1H), 7.11-7.26 (m, 1H), 6.84 (s, 1H), 4.00-4.25 (m, 4H), 2.81 (t, J=11.98 Hz, 2H), 1.74-1.93 (m, 3H), 1.24 (t, J=6.85 Hz, 3H), 0.82-1.02 (m, 7H); LCMS (m/z): 396.0 [M+H].sup.+.
Example 63
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-azepinyl-4-oxo-4,5-dihydrofuran-3-carboxylate
(219) ##STR00073##
(220) The titled compound (solid) was similarly prepared according to the procedure described in the Example 56.
(221) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.29 (br. s, 1H), 8.38 (d, J=7.78 Hz, 1H), 8.31 (dd, J=1.51, 4.77 Hz, 1H), 7.93 (d, J=2.26 Hz, 1H), 7.19 (dd, J=4.64, 7.91 Hz, 1H), 6.84 (s, 1H), 4.17 (q, J=7.19 Hz, 2H), 3.73-3.84 (m, 4H), 1.75-1.93 (m, 4H), 1.51-1.64 (m, 4H), 1.24 (t, J=7.03 Hz, 3H); LCMS (m/z): 382.0 [M+H].sup.+.
Example 64
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(cyclopropylmethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(222) ##STR00074##
(223) The titled compound (solid) was similarly prepared according to the procedure described in the Example 56.
(224) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.33 (br. s, 1H), 9.06 (br. s, 1H), 8.41 (d, J=7.82 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 8.00 (br. s, 1H), 7.19 (dd, J=4.65, 7.58 Hz, 1H), 6.89 (s, 1H), 4.22 (q, J=7.01 Hz, 2H), 3.52 (t, J=6.36 Hz, 2H), 1.15-1.35 (m, 4H), 0.52 (d, J=6.85 Hz, 2H), 0.36 (d, J=4.40 Hz, 2H); LCMS (m/z): 354.2 [M+H].sup.+.
Example 65
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(1-methyl-4-piperidinyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(225) ##STR00075##
(226) The titled compound (solid) was similarly prepared according to the procedure described in the Example 56.
(227) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.36 (br. s, 1H), 8.58 (br. s, 1H), 8.42 (d, J=7.83 Hz, 1H), 8.33 (d, J=3.42 Hz, 1H), 7.98 (s, 1H), 7.19 (dd, J=4.65, 7.58 Hz, 1H), 6.90 (s, 1H), 4.21 (q, J=6.85 Hz, 2H), 3.90-4.07 (m, 1H), 2.79 (d, J=10.27 Hz, 2H), 2.21 (s, 3H), 2.08 (t, J=10.27 Hz, 2H), 1.80-1.99 (m, 4H), 1.26 (t, J=6.85 Hz, 3H); LCMS (m/z): 397.2 [M+H].sup.+.
Example 66
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(4-acetylpiperazinyl)-4-oxo-4,5-dihydrofuran-3-carboxylate
(228) ##STR00076##
(229) The titled compound (solid) was similarly prepared according to the procedure described in the Example 56.
(230) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.37 (br. s, 1H), 8.38 (d, J=7.34 Hz, 1H), 8.32 (d, J=3.42 Hz, 1H), 8.01 (s, 1H), 7.21 (dd, J=4.89, 7.82 Hz, 1H), 6.89 (s, 1H), 4.18 (q, J=7.34 Hz, 2H), 3.77-3.95 (m, 4H), 3.62-3.77 (m, 4H), 2.07 (s, 3H), 1.25 (t, J=6.85 Hz, 3H); LCMS (m/z): 411.4 [M+H].sup.+.
Example 67
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(3-pyrazolyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(231) ##STR00077##
(232) To a solution of ethyl 2-[(3-pyrazolyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.30 g, 1.3 mmol) which similarly prepared according to the procedure described in the Example 4, First step, and 7-azaindole-3-carboxaldehyde (0.19 g, 1.3 mmol) in ethanol (6.0 mL), L-proline (0.015 g, 0.13 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.20 g, y. 35%).
(233) .sup.1H NMR (DMSO-d.sub.6) (ppm) 13.07 (br. s, 1H), 12.34 (br. s, 1H), 10.46 (br. s, 1H), 8.27 (d, J=3.91 Hz, 1H), 8.14 (d, J=7.82 Hz, 1H), 7.91-8.20 (m, 2H), 7.08 (dd, J=4.65, 7.58 Hz, 1H), 6.94 (s, 1H), 6.47 (br. s, 1H), 4.26 (q, J=6.85 Hz, 2H), 1.29 (t, J=7.09 Hz, 3H); LCMS (m/z): 366.0 [M+H].sup.+.
Example 68
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(6-indazolyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(234) ##STR00078##
(235) The titled compound (solid) was similarly prepared according to the procedure described in the Example 67.
(236) .sup.1H NMR (DMSO-d.sub.6) (ppm) 13.22 (br. s, 1H), 12.24 (br. s, 1H), 10.66 (br. s, 1H), 8.22 (br. s, 1H), 8.12 (br. s, 1H), 7.91 (d, J=8.31 Hz, 1H), 7.71-7.86 (m, 3H), 7.33 (d, J=7.83 Hz, 1H), 6.89 (s, 1H), 6.33 (br. s, 1H), 4.29 (d, J=6.85 Hz, 2H), 1.31 (t, J=6.60 Hz, 3H); LCMS (m/z): 416.4 [M+H].sup.+.
Example 69
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[4-(hydroxymethyl)piperidino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(237) ##STR00079##
(238) The titled compound (solid) was similarly prepared according to the procedure described in the Example 67.
(239) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.30 (br. s, 1H), 8.37 (d, J=7.82 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 7.97 (br. s, 1H), 7.19 (dd, J=4.40, 7.82 Hz, 1H), 6.84 (s, 1H), 4.57 (t, J=4.89 Hz, 1H), 4.08-4.32 (m, 4H), 3.22-3.40 (m, 4H), 1.70-1.95 (m, 3H), 1.37 (q, J=11.09 Hz, 2H), 1.24 (t, J=6.85 Hz, 3H); LCMS (m/z): 398.0 [M+H].sup.+.
Example 70
2-Methoxyethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(240) ##STR00080##
First Step
(241) A solution of methyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.063 g, 0.25 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and 4-fluorophenyl isocyanate, 2-methoxyethanol (0.2 mL, 2.5 mmol) and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0048 g, 0.0050 mmol) in anhydrous dioxane (1.0 mL) was stirred with the microwave synthesizer (Biotage Initiator) at 120 C. for 1 h. Cooled to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on silica gel(chloroform/ethyl acetate) to afford 2-methoxyethyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.024 g, y. 33%).
(242) .sup.1H NMR (DMSO-d.sub.6) (ppm) 10.22 (s, 1H), 7.43-7.56 (m, 2H), 7.27 (t, J=8.78 Hz, 2H), 4.66 (s, 2H), 4.22-4.37 (m, 2H), 3.52-3.66 (m, 2H), 3.30 (s, 3H); LCMS (m/z): 295.8 [M+H].sup.+
(243) Second Step
(244) To a solution of 2-methoxyethyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.023 g, 0.078 mmol) and 7-azaindole-3-carboxaldehyde (0.011 g, 0.078 mmol) in 2-propanol (1.0 mL), L-proline (0.0018 g, 0.016 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration. The solid was purified by preparative HPLC to afford the titled compound as solid (0.046 g, y. 14%).
(245) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.22 (br. s, 1H), 10.65 (br. s, 1H), 8.24 (dd, J=1.25, 4.52 Hz, 1H), 7.96 (d, J=7.53 Hz, 1H), 7.72 (d, J=2.26 Hz, 1H), 7.52-7.63 (m, 2H), 7.35 (t, J=8.78 Hz, 2H), 6.89 (dd, J=4.77, 8.03 Hz, 1H), 6.82 (br. s, 1H), 4.32 (t, J=4.77 Hz, 2H), 3.54-3.72 (m, 2H), 3.33 (s, 3H); LCMS (m/z): 423.8 [M+H].sup.+.
Example 71
2-(Dimethylamino)ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate formate
(246) ##STR00081##
(247) Under a nitrogen atmosphere, a solution of methyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.038 g, 0.10 mmol) which afforded in the Example 51, 2-(dimethylamino)ethanol (0.10 mL, 1.0 mmol) and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0019 g, 0.0020 mmol) in N,N-dimethylacetamide (0.9 mL) was stirred with the microwave synthesizer (Biotage Initiator) at 130 C. for 1 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.016 g, y. 36%).
(248) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.15 (br. s, 1H), 8.23 (dd, J=1.38, 4.64 Hz, 1H), 8.14 (s, 1H), 7.97 (d, J=7.53 Hz, 1H), 7.68 (d, J=2.01 Hz, 1H), 7.45 (dd, J=5.14, 8.41 Hz, 2H), 7.27-7.36 (m, 2H), 6.89 (dd, J=4.64, 7.91 Hz, 1H), 6.72 (s, 1H), 4.30 (t, J=5.77 Hz, 2H), 2.80 (t, J=5.77 Hz, 2H), 2.41 (s, 6H); LCMS (m/z): 436.9 [M+H].sup.+.
Example 72
2-Hydroxyethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(249) ##STR00082##
(250) Under a nitrogen atmosphere, a solution of the compound (0.038 g, 0.10 mmol) of Example 51, ethylene glycol (0.50 mL, 9.0 mmol) and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0019 g, 0.0020 mmol) in N,N-dimethylacetamide (0.5 mL) was stirred with the microwave synthesizer (Biotage Initiator) at 150 C. for 1 h. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.0040 g, y. 10%).
(251) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.24 (br. s, 1H), 10.52 (br. s, 1H), 8.21-8.28 (m, 1H), 7.96 (d, J=7.78 Hz, 1H), 7.74 (d, J=2.40 Hz, 1H), 7.58 (br. s, 2H), 7.36 (t, J=8.66 Hz, 2H), 6.80-6.94 (m, 2H), 4.90 (br. s, 1H), 4.22 (t, J=5.27 Hz, 2H), 3.67 (t, J=5.27 Hz, 2H); LCMS (m/z): 409.8 [M+H].sup.+.
Example 73
2-Morpholinoethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate formate
(252) ##STR00083##
(253) Under a nitrogen atmosphere, a solution of the compound (0.038 g, 0.10 mmol) of Example 51, N-(2-hydroxyethyl)morpholine (0.20 mL, 1.6 mmol) and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0019 g, 0.0020 mmol) in N,N-dimethylacetamide (0.8 mL) was stirred with the microwave synthesizer (Biotage Initiator) at 150 C. for 40 min. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.0075 g, y. 15%).
(254) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.25 (br. s, 1H), 8.24 (d, J=4.02 Hz, 1H), 8.15 (s, 1H), 7.95 (d, J=7.78 Hz, 1H), 7.72 (s, 1H), 7.60 (br. s, 2H), 7.33-7.43 (m, 2H), 6.84-6.93 (m, 2H), 4.31 (t, J=5.77 Hz, 2H), 3.47-3.58 (m, 4H), 2.78 (s, 2H), 2.62-2.70 (m, 2H), 2.35-2.42 (m, 2H); LCMS (m/z): 478.9 [M+H].sup.+.
Example 74
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[4-(2-hydroxyethoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(255) ##STR00084##
First Step
(256) A solution of 4-nitro-m-cresol (1.4 g, 9.4 mmol), 2-bromoethanol (1.0 mL, 0.014 mol) and potassium carbonate (3.3 g, 0.024 mol) in N,N-dimethylformamide (10 mL) was stirred with heating at 70 C. for 12 h. Cooled to ambient temperature, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel(hexane/ethyl acetate) to afford 2-(3-methyl-4-nitrophenoxy)ethanol as solid (1.3 g, y. 70%).
(257) .sup.1H NMR (DMSO-d.sub.6) (ppm) 8.04 (d, J=9.08 Hz, 1H), 7.03 (br. s, 1H), 6.98 (dd, J=2.44, 9.04 Hz, 1H), 4.92 (t, J=5.42 Hz, 1H), 4.11 (t, J=4.80 Hz, 2H), 3.73 (q, J=4.99 Hz, 2H), 2.55 (s, 3H); LCMS (m/z): 198.3 [M+H].sup.+.
(258) Second Step
(259) Under a nitrogen atmosphere, 2-(3-methyl-4-nitrophenoxy)ethanol (1.0 g, 5.3 mmol) was dissolved in methanol/tetrahydrofuran (30 mL/30 mL) and 10% palladium on carbon (0.37 g) was added at ambient temperature. The reaction mixture was agitated under a hydrogen atmosphere for 4 h. Palladium on carbon was removed by filtration with Celite and the solvent was removed under reduced pressure to afford 4-(2-hydroxyethoxy)-2-methylaniline as solid (0.80 g, y. 90%).
(260) .sup.1H NMR DMSO-d.sub.6) (ppm) 6.57 (br. s, 1H), 6.52 (br. s, 2H), 4.74 (t, J=5.56 Hz, 1H), 4.34 (br. s, 2H), 3.82 (t, J=5.16 Hz, 2H), 3.63 (q, J=5.30 Hz, 2H), 2.02 (s, 3H); LCMS (m/z): 168.0 [M+H].sup.+.
(261) Third Step
(262) Diethyl malonate (8.0 mL, 0.052 mol) was added dropwise to a solution of sodium hydride (60% w/w in oil, 4.2 g, 0.11 mol) in anhydrous tetrahydrofuran (130 mL) that cooled with ice bath. The mixture was refluxed for 7 min. The reaction mixture was cooled with ice bath, chloroacetyl chloride (4.2 mL, 0.052 mol) was added dropwise to the reaction mixture and stirred for 1 h then stirred at 45 C. for 1 h. Cooled to ambient temperature, the reaction mixture was diluted with water, and extracted with chloroform for 4 times. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (chloroform/methanol) to afford ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (5.0 g, y. 48%).
(263) .sup.1H NMR (CDCl.sub.3) (ppm) 4.58-4.70 (m, 4H), 4.30 (q, J=7.03 Hz, 2H), 1.53 (t, J=7.03 Hz, 3H), 1.33 (t, J=7.15 Hz, 3H)
(264) Fourth Step
(265) A solution of 4-(2-hydroxyethoxy)-2-methylaniline (0.69 g, 4.1 mmol) and ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.83 g, 4.2 mmol) in ethanol (8.3 mL) was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure, and ethanol was added to precipitate the product. The precipitate was collected by filtration then dried to afford ethyl 2-{[4-(2-hydroxyethoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.55 g, y. 42%).
(266) .sup.1H NMR (DMSO-d.sub.6) (ppm) 9.99 (br. s, 1H), 7.24 (d, J=7.84 Hz, 1H), 6.89 (br. s, 1H), 6.80 (d, J=8.40 Hz, 1H), 4.83-4.91 (m, 1H), 4.56 (br. s, 2H), 4.20 (q, J=6.95 Hz, 2H), 3.97 (t, J=4.88 Hz, 2H), 3.65-3.74 (m, 2H), 2.20 (s, 3H), 1.24 (t, J=7.04 Hz, 3H); LCMS (m/z): 322.2 [M+H].sup.+.
(267) Fifth Step
(268) To a solution of 7-azaindole-3-carboxaldehyde (0.16 g, 1.1 mmol) and ethyl 2-{[4-(2-hydroxyethoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.36 g, 1.1 mmol) in ethanol (11 mL), L-proline (0.022 g, 0.19 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with diethyl ether then dried to afford the titled compound as solid (0.24 g, y. 48%).
(269) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.27 (br. s, 1H), 10.29 (br. s, 1H), 8.19 (d, J=3.91 Hz, 1H), 7.75 (br. s, 1H), 7.68 (d, J=7.83 Hz, 1H), 7.41 (d, J=8.31 Hz, 1H), 7.03 (br. s, 1H), 6.94 (d, J=8.31 Hz, 1H), 6.72-6.86 (m, 2H), 4.97 (t, J=5.38 Hz, 1H), 4.26 (q, J=6.85 Hz, 2H), 4.09 (t, J=4.65 Hz, 2H), 3.80 (dd, J=5.14, 9.98 Hz, 2H), 2.23 (s, 3H), 1.29 (t, J=7.09 Hz, 3H); LCMS (m/z): 450.2 [M+H].sup.+.
Example 75
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(benzo[d]thiazol-6-ylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(270) ##STR00085##
(271) To a solution of ethyl 2-(benzo[d]thiazol-6-ylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.070 g, 0.23 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.034 g, 0.23 mmol) in ethanol (6.0 mL), L-proline (0.0030 g, 0.023 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.045 g, y. 45%).
(272) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.25 (br. s, 1H), 10.77 (br. s, 1H), 9.52 (s, 1H), 8.40 (s, 1H), 8.23 (d, J=8.80 Hz, 1H), 8.12 (d, J=3.42 Hz, 1H), 7.69-7.85 (m, 3H), 6.89 (s, 1H), 6.36 (t, J=5.94 Hz, 1H), 4.16-4.47 (m, 2H), 1.31 (t, J=6.85 Hz, 3H); LCMS (m/z): 433.2 [M+H].sup.+.
Example 76
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[4-(2-hydroxyethyl)piperazinyl]-4-oxo-4,5-dihydrofuran-3-carboxylate
(273) ##STR00086##
(274) To a solution of ethyl 2-[4-(2-hydroxyethyl)piperazinyl]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.35 g, 1.2 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.18 g, 1.2 mmol) in ethanol (6.0 mL), piperidine (0.12 mL, 1.4 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.050 g, y. 10%).
(275) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.34 (br. s, 1H), 8.37 (d, J=7.82 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 7.99 (s, 1H), 7.20 (dd, J=4.89, 7.82 Hz, 1H), 6.87 (s, 1H), 4.50 (br. s, 1H), 4.16 (q, J=7.34 Hz, 2H), 3.71-3.88 (m, 4H), 3.55 (t, J=5.87 Hz, 2H), 2.57-2.72 (m, 4H), 2.40-2.58 (m, 2H), 1.24 (t, J=7.09 Hz, 3H); LCMS (m/z): 413.2 [M+H].sup.+.
Example 77
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(4-hydroxypiperidino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(276) ##STR00087##
(277) The titled compound (solid) was similarly prepared according to the procedure described in the Example 76.
(278) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.30 (br. s, 1H), 8.37 (d, J=7.82 Hz, 1H), 8.31 (d, J=3.42 Hz, 1H), 7.98 (s, 1H), 7.19 (dd, J=4.40, 7.83 Hz, 1H), 6.85 (s, 1H), 4.92 (d, J=3.91 Hz, 1H), 4.17 (q, J=6.85 Hz, 2H), 3.92-4.02 (m, 2H), 3.80-3.90 (m, 1H), 3.58 (t, J=9.29 Hz, 2H), 1.94 (d, J=3.42 Hz, 2H), 1.52-1.69 (m, 2H), 1.24 (t, J=6.85 Hz, 3H); LCMS (m/z): 384.2 [M+H].sup.+.
Example 78
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(4-methylpiperidino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(279) ##STR00088##
(280) The titled compound (solid) was similarly prepared according to the procedure described in the Example 76.
(281) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.30 (br. s, 1H), 8.37 (d, J=7.34 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 7.97 (s, 1H), 7.19 (dd, J=4.40, 7.82 Hz, 1H), 6.84 (s, 1H), 4.08-4.29 (m, 4H), 3.22-3.40 (m, 2H), 1.68-1.92 (m, 3H), 1.28-1.42 (m, 2H), 1.24 (t, J=6.85 Hz, 3H), 0.96 (d, J=5.87 Hz, 3H); LCMS (m/z): 382.2 [M+H].sup.+.
Example 79
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-morpholino-4-oxo-4,5-dihydrofuran-3-carboxylate
(282) ##STR00089##
(283) The titled compound (solid) was similarly prepared according to the procedure described in the Example 76.
(284) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.34 (br. s, 1H), 8.37 (d, J=7.82 Hz, 1H), 8.31 (d, J=3.42 Hz, 1H), 8.00 (s, 1H), 7.20 (dd, J=4.40, 7.82 Hz, 1H), 6.89 (s, 1H), 4.16 (q, J=7.17 Hz, 2H), 3.73-3.89 (m, 8H), 1.24 (t, J=7.09 Hz, 3H); LCMS (m/z): 370.4 [M+H].sup.+.
Example 80
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-fluoro-4-(2-methoxyethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(285) ##STR00090##
(286) To a solution of ethyl 2-{[2-fluoro-4-(2-methoxyethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.011 g, 0.032 mmol) which similarly prepared according to the procedure described in the Example 29, First step and 7-azaindole-3-carboxaldehyde (0.0045 g, 0.031 mmol) in ethanol (0.2 mL), 2M hydrochloric acid in ethanol (0.016 mL, 0.032 mmol) was added at ambient temperature. The mixture was refluxed for 4 h. Cooled with ice bath, 2M sodium hydroxide solution (0.015 mL, 0.029 mmol) was added dropwise to neutralize, and ethanol (1.5 mL) was added. The mixture was refluxed for further 30 min. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.0051 g, y. 32%).
(287) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.34 (br. s, 1H), 10.38 (s, 1H), 8.21 (dd, J=1.38, 4.64 Hz, 1H), 7.81 (d, J=7.53 Hz, 1H), 7.75 (d, J=2.51 Hz, 1H), 7.58 (t, J=9.03 Hz, 1H), 7.13 (dd, J=2.51, 12.05 Hz, 1H), 6.98 (dd, J=2.26, 8.78 Hz, 1H), 6.89 (s, 1H), 6.82 (dd, J=4.64, 7.91 Hz, 1H), 4.20-4.31 (m, 4H), 3.71-3.77 (m, 2H), 3.37 (br. s, 3H), 1.29 (t, J=7.03 Hz, 3H); LCMS (m/z): 467.9 [M+H].sup.+.
Example 81
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-fluoro-4-(2-hydroxyethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(288) ##STR00091##
(289) To a solution of ethyl 2-{[2-fluoro-4-(2-hydroxyethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.017 g, 0.052 mmol) which similarly prepared according to the procedure described in the Example 29, First step and 7-azaindole-3-carboxaldehyde (0.0075 g, 0.051 mmol) in ethanol (0.2 mL), 2M hydrochloric acid in ethanol (0.052 mL, 0.10 mmol) was added at ambient temperature. The mixture was refluxed for 8.5 h. Cooled with ice bath, 2M sodium hydroxide solution (0.047 mL, 0.094 mmol) was added dropwise to neutralize, and ethanol (0.5 mL) was added and refluxed for further 16 min. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.014 g, y. 59%).
(290) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.14 (br. s, 1H), 10.38 (s, 1H), 8.21 (dd, J=1.20, 4.80 Hz, 1H), 7.87 (d, J=7.20 Hz, 1H), 7.65 (br. s, 1H), 7.38 (br. s, 1H), 6.95-7.07 (m, 1H), 6.85-6.95 (m, 1H), 6.83 (dd, J=4.80, 8.00 Hz, 1H), 6.64 (br. s, 1H), 4.96 (t, J=5.40 Hz, 1H), 4.15-4.25 (m, 2H), 4.09 (t, J=4.80 Hz, 2H), 3.78 (q, J=5.07 Hz, 2H), 1.26 (t, J=7.00 Hz, 3H); LCMS (m/z): 453.8 [M+H].sup.+.
Example 82
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-(2-methoxyethoxy)-4-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(291) ##STR00092##
(292) To a solution of ethyl 2-{[2-(2-methoxyethoxy)-4-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.015 g, 0.045 mmol) which similarly prepared according to the procedure described in the Example 29, First step and 7-azaindole-3-carboxaldehyde (0.0067 g, 0.046 mmol) in ethanol (0.2 mL), 2M hydrochloric acid in ethanol (0.023 mL, 0.045 mmol) was added at ambient temperature. The mixture was refluxed for 4 h. Cooled to ambient temperature, the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to afford the titled compound as solid (0.0090 g, y. 43%).
(293) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.29 (br. s, 1H), 10.30 (br. s, 1H), 8.25 (dd, J=1.38, 4.64 Hz, 1H), 8.00 (d, J=7.03 Hz, 1H), 7.83 (s, 1H), 7.49 (d, J=7.78 Hz, 1H), 7.10 (s, 1H), 6.84-6.95 (m, 3H), 4.26 (q, J=7.03 Hz, 2H), 4.09-4.17 (m, 2H), 3.53-3.60 (m, 2H), 3.17 (s, 3H), 2.43 (s, 3H), 1.29 (t, J=7.03 Hz, 3H); LCMS (m/z): 463.9 [M+H].sup.+.
Example 83
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({2-[2-(dimethylamino)ethoxy]-4-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(294) ##STR00093##
(295) To a stirred solution of ethyl 2-({2-[2-(dimethylamino)ethoxy]-4-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.011 g, 0.030 mmol) which similarly prepared according to the procedure described in the Example 29, First step and 7-azaindole-3-carboxaldehyde (0.0044 g, 0.030 mmol) in ethanol (0.2 mL), 2M hydrochloric acid in ethanol (0.045 mL, 0.091 mmol) was added at ambient temperature. The mixture was refluxed for 9 h. Cooled with ice bath, 2M sodium hydroxide solution (0.041 mL, 0.082 mmol) was added dropwise to neutralize, and ethanol (0.5 mL) was added. The mixture was refluxed for further 16 min. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.00079 g, y. 5%).
(296) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.27 (br. s, 1H), 8.24 (d, J=4.52 Hz, 1H), 8.16 (s, 1H), 7.96 (d, J=8.03 Hz, 1H), 7.79-7.82 (m, 1H), 7.46 (d, J=7.53 Hz, 1H), 7.09-7.12 (m, 1H), 6.93 (d, J=7.53 Hz, 1H), 6.81-6.89 (m, 2H), 4.25 (q, J=6.94 Hz, 2H), 4.10 (t, J=4.64 Hz, 2H), 2.52-2.58 (m, 2H), 2.43 (s, 3H), 2.13 (s, 6H), 1.29 (t, J=7.03 Hz, 3H); LCMS (m/z): 477.0 [M+H].sup.+.
Example 84
Isopropyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(297) ##STR00094##
(298) Under a nitrogen atmosphere, a solution of the compound (0.039 g, 0.10 mmol) of Example 21, 4-dimethylaniline (0.0024 g, 0.020 mmol) and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0012 g, 0.0013 mmol) in 2-propanol (1.0 mL) and N,N-dimethylacetamide (1.0 mL) was stirred with the microwave synthesizer (Biotage Initiator) at 150 C. for 1.5 h. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.011 g, y. 27%).
(299) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.29 (br. s, 1H), 10.54 (s, 1H), 8.25 (dd, J=1.51, 4.77 Hz, 1H), 7.94 (d, J=7.03 Hz, 1H), 7.76 (d, J=2.76 Hz, 1H), 7.56-7.70 (m, 2H), 7.28-7.44 (m, 2H), 6.80-6.98 (m, 2H), 5.08-5.17 (m, 1H), 1.31 (d, J=6.27 Hz, 6H); LCMS (m/z): 408.0 [M+H].sup.+.
Example 85
Cyclopropylmethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(300) ##STR00095##
(301) Under a nitrogen atmosphere, a solution of the compound (0.038 g, 0.10 mmol) of Example 51, cyclopropyl carbinol (0.10 mL, 1.3 mmol) and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0019 g, 0.0020 mmol) in N,N-dimethylacetamide (0.9 mL) was stirred with the microwave synthesizer (Biotage Initiator) at 150 C. for 30 min. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.0080 g, y. 19%).
(302) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.29 (br. s, 1H), 10.57 (s, 1H), 8.25 (d, J=3.51 Hz, 1H), 7.95 (d, J=7.78 Hz, 1H), 7.75 (d, J=2.51 Hz, 1H), 7.60-7.69 (m, 2H), 7.34-7.43 (m, 2H), 6.85-6.95 (m, 2H), 4.08 (d, J=7.03 Hz, 2H), 1.16-1.31 (m, 1H), 0.55 (dd, J=1.51, 8.03 Hz, 2H), 0.36 (d, J=5.02 Hz, 2H); LCMS (m/z): 419.8 [M+H].sup.+.
Example 86
Methyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2,4-difluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(303) ##STR00096##
(304) To a solution of methyl 2-[(2,4-difluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.27 g, 1.0 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and 2,4-difluorophenyl isocyanate, and 7-azaindole-3-carboxaldehyde (0.15 g, 1.0 mmol) in 2-propanol (5.0 mL), L-proline (0.023 g, 0.20 mmol) was added at ambient temperature. The mixture was refluxed for 12 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound as solid (0.30 g, y. 75%).
(305) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.32 (br. s, 1H), 10.53 (s, 1H), 8.24 (dd, J=1.38, 4.64 Hz, 1H), 7.74-7.87 (m, 2H), 7.70 (d, J=2.51 Hz, 1H), 7.54-7.63 (m, 1H), 7.27-7.37 (m, 1H), 6.94 (s, 1H), 6.84 (dd, J=4.77, 8.03 Hz, 1H), 3.77 (s, 3H); LCMS (m/z): 397.9 [M+H].sup.+.
Example 87
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[bis(2-methoxyethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(306) ##STR00097##
(307) To a solution of ethyl 2-[bis(2-methoxyethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.30 g, 1.0 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.15 g, 1.0 mmol) in ethanol (5.0 mL), L-proline (0.023 g, 0.20 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.048 g, y. 11%).
(308) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.36 (br. s, 1H), 8.38 (d, J=7.82 Hz, 1H), 8.31 (d, J=4.89 Hz, 1H), 7.98 (s, 1H), 7.19 (dd, J=4.65, 8.07 Hz, 1H), 6.85 (s, 1H), 4.16 (q, J=6.85 Hz, 2H), 3.97 (t, J=5.14 Hz, 4H), 3.57-3.67 (m, 4H), 3.25 (s, 6H), 1.24 (t, J=7.09 Hz, 3H); LCMS (m/z): 416.2 [M+H].sup.+.
Example 88
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[4-(hydroxymethyl)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(309) ##STR00098##
(310) The titled compound (solid) was similarly prepared according to the procedure described in the Example 87.
(311) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.27 (br. s, 1H), 10.66 (br. s, 1H), 8.22 (d, J=3.42 Hz, 1H), 7.97 (d, J=7.34 Hz, 1H), 7.79 (br. s, 1H), 7.42-7.55 (m, 4H), 6.86-6.94 (m, 1H), 6.84 (br. s, 1H), 5.34 (br. s, 1H), 4.62 (d, J=4.40 Hz, 2H), 4.26 (d, J=6.85 Hz, 2H), 1.29 (t, J=6.85 Hz, 3H); LCMS (m/z): 406.4 [M+H].sup.+.
Example 89
3-Hydroxypropyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(312) ##STR00099##
(313) A solution of the compound of Example 51 and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0019 g, 0.0020 mmol) in 1,3-propanediol (0.5 mL) and N,N-dimethylacetamide (0.5 mL) was stirred at 120 C. for 2 h then at 100 C. for 12 h. Cooled to ambient temperature, the reaction mixture was diluted with water, and the precipitate was collected by filtration. Ethyl acetate was added to the filtrate, and the precipitate was collected by filtration. Those precipitates were combined then purified by preparative HPLC to afford the titled compound as solid (0.0067 g, y. 16%).
(314) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.22 (br. s, 1H), 10.72 (br. s, 1H), 8.24 (dd, J=1.38, 4.64 Hz, 1H), 7.97 (d, J=7.03 Hz, 1H), 7.72 (d, J=2.51 Hz, 1H), 7.50-7.60 (m, 2H), 7.35 (t, J=8.78 Hz, 2H), 6.89 (dd, J=4.52, 8.03 Hz, 1H), 6.81 (br. s, 1H), 4.77 (br. s, 1H), 4.25 (t, J=6.27 Hz, 2H), 3.59 (t, J=5.77 Hz, 2H), 1.79-1.87 (m, 2H); LCMS (m/z): 423.8 [M+H].sup.+.
Example 90
Isopropyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2,4-difluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(315) ##STR00100##
(316) A solution of the compound (0.040 g, 0.10 mmol) of Example 86 and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0012 g, 0.0013 mmol) in 2-propanol (0.5 mL) was stirred at 95 C. for 4 days. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0061 g, y. 13%).
(317) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.32 (br. s, 1H), 10.47 (s, 1H), 8.24 (dd, J=1.51, 4.52 Hz, 1H), 7.67-7.88 (m, 3H), 7.54-7.63 (m, 1H), 7.26-7.38 (m, 1H), 6.88 (s, 1H), 6.83 (dd, J=4.64, 7.91 Hz, 1H), 5.10-5.18 (m, 1H), 1.31 (d, J=6.27 Hz, 6H); LCMS (m/z): 426.2 [M+H].sup.+.
Example 91
2-(Dimethylamino)ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2,4-difluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(318) ##STR00101##
(319) A solution of the compound (0.040 g, 0.10 mmol) of Example 86, 2-dimethylaminoethanol (0.10 mL, 1.0 mmol) and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0019 g, 0.0020 mmol) in N,N-dimethylacetamide (0.9 mL) was stirred at 100 C. for 24 h. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.010 g, y. 22%).
(320) .sup.1H NMR (DMSO-d.sub.6) (ppm) 11.97 (br. s, 1H), 8.19 (dd, J=1.51, 4.52 Hz, 1H), 8.14 (s, 1H), 7.93 (d, J=7.78 Hz, 1H), 7.52 (br. s, 1H), 7.16-7.36 (m, 2H), 7.03-7.13 (m, 1H), 6.83 (dd, J=4.89, 7.91 Hz, 1H), 6.42 (s, 1H), 4.35 (t, J=5.27 Hz, 2H), 3.22 (t, J=5.27 Hz, 2H), 2.67-2.87 (m, 6H); LCMS (m/z): 455.2 [M+H].sup.+.
Example 92
5-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2,4-difluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylic acid
(321) ##STR00102##
(322) To a solution of the compound (0.20 g, 0.45 mmol) of Example 53 in ethanol (2.0 mL), aqueous 50% w/v potassium hydroxide solution (0.5 mL) was added at ambient temperature. The mixture was stirred at 95 C. for 3 h. Cooled to ambient temperature, diluted with water and conc. hydrochloric acid was added dropwise to neutralize. The precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound as solid (0.19 g, y. 98%).
(323) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.36 (br. s, 1H), 8.25 (dd, J=1.51, 4.52 Hz, 1H), 7.86 (d, J=7.03 Hz, 1H), 7.69-7.82 (m, 2H), 7.57 (ddd, J=2.76, 8.97, 10.35 Hz, 1H), 7.25-7.37 (m, 1H), 7.01 (s, 1H), 6.85 (dd, J=4.77, 8.03 Hz, 1H); LCMS (m/z): 381.9 [MH].sup.
Example 93
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-(2-hydroxyethoxy)-4-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(324) ##STR00103##
(325) To a solution of ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2,4-difluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.017 g, 0.052 mmol) which similarly prepared according to the procedure described in the Example 29, First step and 7-azaindole-3-carboxaldehyde (0.0075 g, 0.051 mmol) in ethanol (0.2 mL), 2M hydrochloric acid in ethanol (0.052 mL, 0.10 mmol) was added at ambient temperature. The mixture was refluxed for 8.5 h. Cooled with ice bath, 2M sodium hydroxide solution (0.047 mL, 0.094 mmol) was added dropwise to neutralize then the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to afford the titled compound as solid (0.0066 g, y. 28%).
(326) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.30 (br. s, 1H), 10.22 (br. s, 1H), 8.25 (d, J=3.51 Hz, 1H), 8.03 (d, J=7.78 Hz, 1H), 7.83 (br. s, 1H), 7.43-7.56 (m, 1H), 7.10 (s, 1H), 6.85-6.95 (m, 3H), 4.79 (br. s, 1H), 4.26 (q, J=7.19 Hz, 2H), 4.06 (t, J=5.14 Hz, 2H), 3.62 (t, J=5.20 Hz, 2H), 2.42 (s, 3H), 1.29 (t, J=7.15 Hz, 3H); LCMS (m/z): 449.5 [M+H].sup.+.
Example 94
Methyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(cyclopropylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(327) ##STR00104##
(328) To a solution of methyl 2-(cyclopropylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.50 g, 2.5 mmol) which similarly prepared according to the procedure described in the Example 4, First step using dimethyl malonate, chloroacetyl chloride and cyclopropylamine, and 7-azaindole-3-carboxaldehyde (0.37 g, 2.5 mmol) in ethanol (6.0 mL), L-proline (0.029 g, 0.25 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.012 g, y. 30%).
(329) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.33 (br. s, 1H), 8.88 (br. s, 1H), 8.57 (d, J=7.82 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 8.06 (s, 1H), 7.20 (dd, J=4.89, 7.82 Hz, 1H), 6.94 (s, 1H), 3.69 (s, 3H), 3.08-3.20 (m, 1H), 0.84-1.00 (m, 4H); LCMS (m/z): 326.0 [M+H].sup.+.
Example 95
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-hydroxy-4-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(330) ##STR00105##
(331) To a solution of ethyl 2-[(2-hydroxy-4-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.36 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.061 g, 0.42 mmol) in ethanol (2.5 mL), 2M hydrochloric acid in ethanol (0.56 mL, 1.1 mmol) was added at ambient temperature. The mixture was refluxed for 19 h. Cooled with ice bath, 2M sodium hydroxide solution (0.49 mL, 0.97 mmol) was added dropwise to neutralize, and ethanol (8.0 mL) was added and the mixture was refluxed for 30 min. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.027 g, y. 18%).
(332) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.32 (br. s, 1H), 10.21 (s, 1H), 10.19 (s, 1H), 8.22-8.30 (m, 1H), 8.04 (d, J=7.53 Hz, 1H), 7.87 (d, J=2.26 Hz, 1H), 7.44 (d, J=8.03 Hz, 1H), 6.84-6.94 (m, 3H), 6.77 (d, J=8.03 Hz, 1H), 4.27 (q, J=7.03 Hz, 2H), 2.35 (s, 3H), 1.30 (t, J=7.03 Hz, 3H); LCMS (m/z): 405.9 [M+H].sup.+.
Example 96
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-hydroxy-2-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(333) ##STR00106##
(334) To a solution of ethyl 2-[(4-hydroxy-2-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.37 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.063 g, 0.43 mmol) in ethanol (2.5 mL), 2M hydrochloric acid in ethanol (0.46 mL, 0.92 mmol) was added at ambient temperature. The mixture was refluxed for 2.5 days. Cooled with ice bath, 2M sodium hydroxide solution (0.46 mL, 0.92 mmol) was added dropwise to neutralize, and ethanol (11 mL) was added and the mixture was refluxed for further 40 min. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.10 g, y. 70%).
(335) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.27 (br. s, 1H), 10.20 (s, 1H), 9.76 (s, 1H), 8.20 (dd, J=1.25, 4.52 Hz, 1H), 7.81 (d, J=2.51 Hz, 1H), 7.64 (d, J=7.53 Hz, 1H), 7.28 (d, J=8.28 Hz, 1H), 6.72-6.87 (m, 4H), 4.26 (q, J=7.03 Hz, 2H), 2.16 (s, 3H), 1.29 (t, J=7.03 Hz, 3H); LCMS (m/z): 405.8 [M+H].sup.+.
Example 97
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluoro-2-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(336) ##STR00107##
(337) To a solution of ethyl 2-[(4-fluoro-2-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.30 g, 1.1 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.16 g, 1.1 mmol) in ethanol (7.0 mL), L-proline (0.013 g, 0.10 mmol) was added at ambient temperature. The mixture was refluxed for 3 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.25 g, y. 58%).
(338) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.28 (br. s, 1H), 10.40 (s, 1H), 8.22 (d, J=3.91 Hz, 1H), 7.66-7.76 (m, 2H), 7.59 (dd, J=5.62, 8.56 Hz, 1H), 7.36 (dd, J=2.45, 9.78 Hz, 1H), 7.18-7.28 (m, 1H), 6.85 (s, 1H), 6.78 (dd, J=4.89, 7.83 Hz, 1H), 4.27 (q, J=7.01 Hz, 2H), 2.27 (s, 3H), 1.30 (t, J=7.09 Hz, 3H); LCMS (m/z): 408.4 [M+H].sup.+.
Example 98
Methyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-methoxyethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(339) ##STR00108##
(340) The titled compound (solid) was similarly prepared according to the procedure described in the Example 97.
(341) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.36 (br. s, 1H), 8.94 (br. s, 1H), 8.44 (d, J=7.83 Hz, 1H), 8.31 (d, J=4.40 Hz, 1H), 8.03 (s, 1H), 7.19 (dd, J=4.40, 7.82 Hz, 1H), 6.92 (s, 1H), 3.76-3.84 (m, 2H), 3.71 (s, 3H), 3.62 (t, J=5.14 Hz, 2H), 3.31 (br. s, 3H); LCMS (m/z): 344.2 [M+H].sup.+.
Example 99
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[4-(2-methoxyethoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(342) ##STR00109##
First Step
(343) To a solution of ethyl 2-[(4-hydroxy-2-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.36 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step, 2-methoxyethanol (0.051 mL, 0.65 mmol) and triphenylphosphine (0.19 g, 0.72 mmol) in dichloromethane (2.0 mL) that cooled with ice bath, 2.2M diethyl azodicarboxylate (40% in toluene, 0.33 mL, 0.73 mmol) was added dropwise then the mixture was stirred at ambient temperature for 24 h. The reaction mixture was diluted with water, and extracted with chloroform. The organic layer was washed with 1M sodium hydroxide solution and brine, dried over magnesium sulfate and concentrated to afford ethyl 2-{[4-(2-methoxyethoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate as oil (0.30 g, crude material).
(344) Second Step
(345) To a solution of ethyl 2-{[4-(2-methoxyethoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.12 g, 0.36 mmol, crude material) which afforded in the previous step and 7-azaindole-3-carboxaldehyde (0.043 g, 0.30 mmol) in ethanol (4.0 mL), 2M hydrochloric acid in ethanol (0.30 mL, 0.60 mmol) was added at ambient temperature. The mixture was refluxed for 24 h. Cooled with ice bath, 2M sodium hydroxide solution (0.30 mL, 0.60 mmol) was added dropwise to neutralize, and the solvent was removed under reduced pressure. The residue was suspended in chloroform, then the precipitate was collected by filtration, washed with water, ethanol and hexane then dried to afford the titled compound as solid (0.028 g, y. 12%).
(346) .sup.1H NMR (DMSO-d.sub.6) (ppm) 11.78 (br. s, 1H), 8.13 (d, J=3.51 Hz, 1H), 7.89 (d, J=7.53 Hz, 1H), 7.47 (s, 1H), 6.77-6.90 (m, 3H), 6.72 (d, J=8.28 Hz, 1H), 6.12 (s, 1H), 4.05-4.14 (m, 2H), 3.66-3.74 (m, 2H), 3.36 (s, 3H), 3.28-3.35 (m, 2H), 2.08 (s, 3H), 1.22 (t, J=7.03 Hz, 3H); LCMS (m/z): 464.0 [M+H].sup.+.
Example 100
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-methyl-4-(2-morpholinoethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(347) ##STR00110##
(348) To a stirred solution of ethyl 2-({2-methyl-4-[2-(N-morpholino)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.14 g, 0.36 mmol) which similarly prepared according to the procedure described in the Example 99, First step and 7-azaindole-3-carboxaldehyde (0.038 g, 0.26 mmol) in ethanol (4.0 mL), 2M hydrochloric acid in ethanol (0.60 mL, 1.2 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled with ice bath, 2M sodium hydroxide solution (0.57 mL, 1.1 mmol) was added dropwise to neutralize and refluxed for further 10 min. Then the solvent was removed under reduced pressure. The precipitate was collected by filtration, washed with water and ethyl acetate then dried to afford the titled compound as solid (0.010 g, y. 5%).
(349) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.28 (br. s, 1H), 10.29 (s, 1H), 8.19 (dd, J=1.26, 4.52 Hz, 1H), 7.77 (s, 1H), 7.67 (d, J=7.78 Hz, 1H), 7.42 (d, J=8.53 Hz, 1H), 7.05 (br. s, 1H), 6.95 (d, J=8.28 Hz, 1H), 6.83 (s, 1H), 6.74 (dd, J=4.77, 7.78 Hz, 1H), 4.27 (q, J=7.03 Hz, 2H), 4.15-4.23 (m, 2H), 3.58-3.68 (m, 4H), 2.74-2.82 (m, 2H), 2.50-2.60 (m, 4H), 2.23 (s, 3H), 1.30 (t, J=7.03 Hz, 3H); LCMS (m/z): 519.0 [M+H].sup.+.
Example 101
Methyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-fluorobenzyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(350) ##STR00111##
(351) To a solution of methyl 2-[(2-fluorobenzyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.35 g, 1.5 mmol) which similarly prepared according to the procedure described in the Example 4, First step using dimethyl malonate, chloroacetyl chloride and 2-fluorobenzylamine, and 7-azaindole-3-carboxaldehyde (0.22 g, 1.5 mmol) in ethanol (10 mL), L-proline (0.018 g, 0.15 mmol) was added at ambient temperature. The mixture was refluxed for 3 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.13 g, y. 24%).
(352) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.36 (br. s, 1H), 9.49 (br. s, 1H), 8.28 (br. s, 2H), 7.86 (br. s, 1H), 7.16-7.53 (m, 4H), 7.07 (br. s, 1H), 6.90 (br. s, 1H), 4.91 (br. s, 2H), 3.73 (br. s, 3H); LCMS (m/z): 394.4 [M+H].sup.+.
Example 102
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(3,4-dihydroisoquinolin-2(1H)-yl)-4-oxo-4,5-dihydrofuran-3-carboxylate
(353) ##STR00112##
(354) To a solution of ethyl 2-(3,4-dihydroisoquinolin-2(1H-)yl)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.15 g, 0.60 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.091 g, 0.60 mmol) in ethanol (5.0 mL), L-proline (0.0070 g, 0.060 mmol) was added at ambient temperature. The mixture was refluxed for 3 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.037 g, y. 14%).
(355) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.36 (br. s, 1H), 8.42 (d, J=7.82 Hz, 1H), 8.33 (d, J=3.91 Hz, 1H), 8.07 (s, 1H), 7.17-7.37 (m, 5H), 6.90 (s, 1H), 4.98 (br. s, 2H), 4.21 (q, J=6.85 Hz, 2H), 3.97 (br. s, 2H), 3.09 (t, J=5.62 Hz, 2H), 1.27 (t, J=7.09 Hz, 3H); LCMS (m/z): 416.2 [M+H].sup.+.
Example 103
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(cyclopentylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(356) ##STR00113##
(357) The titled compound (solid) was similarly prepared according to the procedure described in the Example 102.
(358) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.32 (br. s, 1H), 8.53 (br. s, 1H), 8.42 (d, J=7.82 Hz, 1H), 8.32 (d, J=4.40 Hz, 1H), 8.01 (s, 1H), 7.20 (dd, J=4.40, 7.83 Hz, 1H), 6.90 (s, 1H), 4.50 (br. s, 1H), 4.21 (q, J=6.85 Hz, 2H), 2.02-2.15 (m, 2H), 1.57-1.71 (m, 6H), 1.26 (t, J=7.09 Hz, 3H); LCMS (m/z): 368.0 [M+H].sup.+.
Example 104
Methyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(cyclopropylmethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(359) ##STR00114##
(360) To a solution of methyl 2-[(cyclopropylmethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.30 g, 1.4 mmol) which similarly prepared according to the procedure described in the Example 4, First step using dimethyl malonate, chloroacetyl chloride and cyclopropylmethylamine, and 7-azaindole-3-carboxaldehyde (0.21 g, 1.4 mmol) in ethanol (10 mL), L-proline (0.016 g, 0.14 mmol) was added at ambient temperature. The mixture was refluxed for 3 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.065 g, y. 14%).
(361) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.33 (br. s, 1H), 9.08 (br. s, 1H), 8.42 (d, J=7.82 Hz, 1H), 8.31 (d, J=3.42 Hz, 1H), 8.00 (s, 1H), 7.19 (dd, J=4.40, 7.34 Hz, 1H), 6.92 (s, 1H), 3.72 (s, 3H), 3.52 (d, J=6.36 Hz, 2H), 1.23 (br. s, 1H), 0.52 (d, J=7.34 Hz, 2H), 0.37 (d, J=3.91 Hz, 2H); LCMS (m/z): 340.4 [M+H].sup.+.
Example 105
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-isoindolinyl-4-oxo-4,5-dihydrofuran-3-carboxylate
(362) ##STR00115##
(363) To a solution of ethyl 2-isoindolinyl-4-oxo-4,5-dihydrofuran-3-carboxylate (0.20 g, 0.70 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.11 g, 0.70 mmol) in ethanol (10 mL), L-proline (0.0080 g, 0.070 mmol) was added at ambient temperature. The mixture was refluxed for 3 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.080 g, y. 27%).
(364) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.39 (br. s, 1H), 8.44 (d, J=7.34 Hz, 1H), 8.33 (d, J=3.91 Hz, 1H), 8.08 (s, 1H), 7.43-7.53 (m, 2H), 7.33-7.43 (m, 2H), 7.23 (dd, J=4.89, 7.82 Hz, 1H), 6.91 (s, 1H), 5.37 (br. s, 2H), 5.17 (br. s, 2H), 4.23 (q, J=7.34 Hz, 2H), 1.29 (t, J=7.09 Hz, 3H); LCMS (m/z): 402.0 [M+H].sup.+.
Example 106
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-[(1-phenylethyl)amino]-4,5-dihydrofuran-3-carboxylate
(365) ##STR00116##
(366) To a solution of ethyl 4-oxo-2-[(1-phenylethyl)amino]-4,5-dihydrofuran-3-carboxylate (0.40 g, 1.5 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.21 g, 1.5 mmol) in ethanol (20 mL), L-proline (0.017 g, 0.15 mmol) was added at ambient temperature. The mixture was refluxed for 3 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.20 g, y. 34%).
(367) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.35 (br. s, 1H), 8.97 (br. s, 1H), 8.25-8.34 (m, 2H), 7.82 (br. s, 1H), 7.49-7.57 (m, 2H), 7.38-7.45 (m, 2H), 7.24-7.33 (m, 1H), 7.12-7.19 (m, 1H), 6.86 (s, 1H), 5.41 (br. s, 1H), 4.24 (q, J=6.68 Hz, 2H), 1.70 (d, J=6.36 Hz, 3H), 1.27 (t, J=6.85 Hz, 3H); LCMS (m/z): 403.8 [M+H].sup.+.
Example 107
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[3-(2,6-dimethylpyridinyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(368) ##STR00117##
(369) The titled compound (solid) was similarly prepared according to the procedure described in the Example 106.
(370) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.27 (br. s, 1H), 10.47 (s, 1H), 8.21 (d, J=3.91 Hz, 1H), 7.81 (d, J=7.82 Hz, 1H), 7.64-7.76 (m, 2H), 7.27 (d, J=7.83 Hz, 1H), 6.84 (s, 1H), 6.74 (dd, J=4.65, 7.58 Hz, 1H), 4.26 (q, J=7.17 Hz, 2H), 2.57 (s, 3H), 2.41 (s, 3H), 1.29 (t, J=7.09 Hz, 3H); LCMS (m/z): 405.0 [M+H].sup.+.
Example 108
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[N-methyl-N-(2-thienylmethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(371) ##STR00118##
(372) The titled compound (solid) was similarly prepared according to the procedure described in the Example 106.
(373) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.33 (br. s, 1H), 8.37 (d, J=7.82 Hz, 1H), 8.30 (d, J=3.91 Hz, 1H), 8.03 (s, 1H), 7.53 (d, J=4.89 Hz, 1H), 7.14-7.23 (m, 2H), 7.01-7.07 (m, 1H), 6.91 (s, 1H), 5.20 (s, 2H), 4.18 (q, J=7.34 Hz, 2H), 3.26 (br. s, 3H), 1.23 (t, J=7.09 Hz, 3H); LCMS (m/z): 409.8 [M+H].sup.+.
Example 109
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-thiomorpholino-4,5-dihydrofuran-3-carboxylate
(374) ##STR00119##
(375) The titled compound (solid) was similarly prepared according to the procedure described in the Example 106.
(376) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.33 (br. s, 1H), 8.27-8.45 (m, 2H), 7.94-8.04 (m, 1H), 7.20 (dd, J=4.65, 7.58 Hz, 1H), 6.88 (s, 1H), 4.17 (q, J=6.85 Hz, 2H), 4.02 (br. s, 4H), 2.89 (br. s, 4H), 1.25 (t, J=7.09 Hz, 3H); LCMS (m/z): 386.2 [M+H].sup.+.
Example 110
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(3-hydroxypiperidino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(377) ##STR00120##
(378) The titled compound (solid) was similarly prepared according to the procedure described in the Example 106.
(379) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.32 (br. s, 1H), 8.39 (d, J=7.82 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 7.93-8.00 (m, 1H), 7.20 (dd, J=4.40, 7.83 Hz, 1H), 6.85 (s, 1H), 5.11 (br. s, 1H), 4.17 (q, J=6.85 Hz, 2H), 3.85-3.94 (m, 1H), 3.72-3.84 (m, 2H), 3.54-3.65 (m, 1H), 3.41-3.53 (m, 1H), 1.83-2.02 (m, 2H), 1.51-1.69 (m, 2H), 1.25 (t, J=7.09 Hz, 3H); LCMS (m/z): 384.0 [M+H].sup.+.
Example 111
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[2-(dimethylamino)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate formate
(380) ##STR00121##
(381) To a solution of ethyl 2-({4-[2-(dimethylamino)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.070 g, 0.20 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.029 g, 0.20 mmol) in ethanol (2.0 mL), piperidine (0.020 mL, 0.20 mmol) was added at ambient temperature. The mixture was refluxed for 5 days. Cooled to ambient temperature, the precipitate was collected by filtration then purified by preparative HPLC to afford the titled compound as solid (0.016 g, y. 16%).
(382) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.28 (br. s, 1H), 10.53 (br. s, 1H), 8.18 (dd, J=1.63, 4.64 Hz, 1H), 8.16 (s, 1H), 7.76 (s, 1H), 7.67 (d, J=7.28 Hz, 1H), 7.41 (d, J=8.78 Hz, 1H), 7.04 (d, J=3.01 Hz, 1H), 6.94 (dd, J=2.89, 8.66 Hz, 1H), 6.82 (s, 1H), 6.75 (dd, J=4.77, 8.03 Hz, 1H), 4.26 (q, J=7.03 Hz, 2H), 4.16 (t, J=5.77 Hz, 2H), 2.74 (t, J=5.65 Hz, 2H), 2.30 (s, 6H), 2.28 (s, 3H), 1.29 (t, J=7.03 Hz, 3H); LCMS (m/z): 477.1 [M+H].sup.+.
Example 112
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-[(2-phenyl-2-propinyl)amino]-4,5-dihydrofuran-3-carboxylate
(383) ##STR00122##
(384) To a solution of ethyl 4-oxo-2-[(2-phenyl-2-propinyl)amino]-4,5-dihydrofuran-3-carboxylate (0.40 g, 1.4 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.20 g, 1.4 mmol) in ethanol (10 mL), L-proline (0.016 g, 0.14 mmol) was added at ambient temperature. The mixture was refluxed for 3 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.15 g, y. 26%).
(385) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.22 (br. s, 1H), 8.92 (br. s, 1H), 8.25 (d, J=3.42 Hz, 1H), 8.10 (d, J=7.82 Hz, 1H), 7.58 (d, J=7.34 Hz, 2H), 7.44-7.53 (m, 2H), 7.23-7.33 (m, 1H), 7.06 (dd, J=4.65, 7.09 Hz, 1H), 6.90 (br. s, 1H), 6.78 (br. s, 1H), 4.27 (q, J=6.52 Hz, 2H), 1.85 (br. s, 6H), 1.29 (t, J=6.85 Hz, 3H); LCMS (m/z): 418.0 [M+H].sup.+.
Example 113
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(2-adamantylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(386) ##STR00123##
(387) The titled compound (solid) was similarly prepared according to the procedure described in the Example 112.
(388) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.37 (br. s, 1H), 8.71 (d, J=6.85 Hz, 1H), 8.42 (d, J=7.82 Hz, 1H), 8.32 (d, J=3.91 Hz, 1H), 7.99 (s, 1H), 7.20 (dd, J=4.89, 7.83 Hz, 1H), 6.92 (s, 1H), 4.30-4.40 (m, 1H), 4.24 (q, J=7.01 Hz, 2H), 2.10-2.19 (m, 2H), 1.81-1.99 (m, 8H), 1.67-1.80 (m, 4H), 1.27 (t, J=7.09 Hz, 3H); LCMS (m/z): 433.8 [M+H].sup.+.
Example 114
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[3-(6-methylpyridinyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(389) ##STR00124##
(390) The titled compound (solid) was similarly prepared according to the procedure described in the Example 112.
(391) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.23 (br. s, 1H), 8.41-8.61 (m, 2H), 8.25 (d, J=4.40 Hz, 1H), 8.02 (br. s, 1H), 7.79 (d, J=1.96 Hz, 1H), 7.50 (br. s, 1H), 6.89-7.00 (m, 1H), 6.78-6.89 (m, 1H), 4.08-4.28 (m, 2H), 2.27 (s, 3H), 1.18-1.30 (m, 3H); LCMS (m/z): 391.4 [M+H].sup.+.
Example 115
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[4-(3-methylpyridinyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(392) ##STR00125##
(393) The titled compound (solid) was similarly prepared according to the procedure described in the Example 112.
(394) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.23 (br. s, 1H), 8.41-8.61 (m, 2H), 8.25 (d, J=4.40 Hz, 1H), 8.02 (br. s, 1H), 7.79 (d, J=1.96 Hz, 1H), 7.50 (br. s, 1H), 6.89-7.00 (m, 1H), 6.83 (br. s, 1H), 4.19 (br. s, 2H), 2.27 (s, 3H), 1.24 (br. s, 3H); LCMS (m/z): 391.4 [M+H].sup.+.
Example 116
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(trans-4-hydroxycyclohexyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(395) ##STR00126##
(396) To a solution of ethyl 2-[(trans-4-hydroxycyclohexyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.30 g, 1.1 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.16 g, 1.1 mmol) in ethanol (20 mL), L-proline (0.013 g, 0.11 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.14 g, y. 40%).
(397) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.36 (br. s, 1H), 8.39-8.54 (m, 2H), 8.33 (d, J=4.40 Hz, 1H), 7.99 (s, 1H), 7.20 (dd, J=4.89, 7.83 Hz, 1H), 6.89 (s, 1H), 4.69 (d, J=3.91 Hz, 1H), 4.20 (q, J=7.34 Hz, 2H), 3.97 (br. s, 1H), 3.41-3.53 (m, 1H), 1.86-2.03 (m, 4H), 1.61-1.76 (m, 2H), 1.29-1.42 (m, 2H), 1.25 (t, J=7.09 Hz, 3H); LCMS (m/z): 398.1 [M+H].sup.+.
Example 117
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[4-(2-fluoropyridinyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(398) ##STR00127##
(399) The titled compound (solid) was similarly prepared according to the procedure described in the Example 116.
(400) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.44 (br. s, 1H), 10.86 (br. s, 1H), 8.30 (d, J=5.38 Hz, 2H), 8.21 (d, J=7.82 Hz, 1H), 7.94 (d, J=1.96 Hz, 1H), 7.63 (d, J=5.38 Hz, 1H), 7.44 (s, 1H), 7.00-7.09 (m, 2H), 4.29 (q, J=7.01 Hz, 2H), 1.30 (t, J=7.09 Hz, 3H); LCMS (m/z): 395.0 [M+H].sup.+.
Example 118
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(5-indazolyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(401) ##STR00128##
(402) The titled compound (solid) was similarly prepared according to the procedure described in the Example 116.
(403) .sup.1H NMR (DMSO-d.sub.6) (ppm) 13.36 (s, 1H), 12.25 (br. s, 1H), 10.62 (br. s, 1H), 8.17 (s, 1H), 8.09 (d, J=3.91 Hz, 1H), 7.99 (s, 1H), 7.78 (d, J=1.96 Hz, 1H), 7.63-7.72 (m, 2H), 7.52 (d, J=7.82 Hz, 1H), 6.85 (s, 1H), 6.12-6.27 (m, 1H), 4.28 (q, J=7.01 Hz, 2H), 1.30 (t, J=6.85 Hz, 3H); LCMS (m/z): 416.2 [M+H].sup.+.
Example 119
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(5-benzimidazolyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(404) ##STR00129##
(405) To a solution of ethyl 2-[(5-benzimidazolyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.30 g, 1.0 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.15 g, 1.0 mmol) in ethanol (5.0 mL), piperidine (0.20 mL, 3.1 mmol) was added at ambient temperature. The mixture was refluxed for 24 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.015 g, y. 4%).
(406) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.28 (br. s, 1H), 10.82 (s, 1H), 9.55 (s, 1H), 8.16 (d, J=3.91 Hz, 1H), 8.08 (s, 1H), 7.98 (d, J=8.80 Hz, 1H), 7.87 (d, J=7.34 Hz, 1H), 7.59-7.89 (m, 1H), 7.74 (s, 1H), 6.93 (s, 1H), 6.53 (dd, J=4.89, 7.34 Hz, 1H), 4.30 (q, J=7.34 Hz, 2H), 1.31 (t, J=7.09 Hz, 3H); LCMS (m/z): 416.2 [M+H].sup.+.
Example 120
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-indolinyl-4-oxo-4,5-dihydrofuran-3-carboxylate
(407) ##STR00130##
First Step
(408) To a solution of potassium tert-butoxide (0.56 g, 5.0 mmol) in tetrahydrofuran (5.0 mL) that cooled with ice bath, a solution of indoline (0.36 g, 3.0 mmol) in tetrahydrofuran (5.0 mL) was added dropwise. The mixture was stirred at ambient temperature for 30 min. Then the reaction mixture was cooled with ice bath, a solution of ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.50 g, 2.5 mmol) which afforded in the Example 74, Third step dissolved in tetrahydrofuran (5.0 mL) was added dropwise. The mixture was stirred at ambient temperature for further 16 h. The reaction mixture was poured into ice water, extracted with ethyl acetate for 3 times. The combined organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel. Eluted with hexane/ethyl acetate to afford 2-indolinyl-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.095 g, y. 8%).
(409) .sup.1H NMR (DMSO-d.sub.6) (ppm) 7.49 (d, J=8.00 Hz, 1H), 7.35 (d, J=7.60 Hz, 1H), 7.24 (t, J=7.46 Hz, 1H), 7.13 (t, J=7.46 Hz, 1H), 4.73 (s, 2H), 4.05-4.20 (m, 4H), 3.20 (t, J=8.12 Hz, 2H), 1.21 (t, J=7.08 Hz, 3H); LCMS (m/z): 274.0 [M+H].sup.+.
(410) Second Step
(411) To a solution of 2-indolinyl-4-oxo-4,5-dihydrofuran-3-carboxylate (0.090 g, 0.32 mmol) and 7-azaindole-3-carboxaldehyde (0.048 g, 0.32 mmol) in ethanol (5.0 mL), L-proline (0.0040 g, 0.030 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.076 g, y. 58%).
(412) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.40 (br. s, 1H), 8.36 (d, J=6.85 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 8.01 (s, 1H), 7.56-7.63 (m, 1H), 7.44 (d, J=7.34 Hz, 1H), 7.33 (t, J=7.58 Hz, 1H), 7.21-7.27 (m, 1H), 7.12 (dd, J=4.89, 7.83 Hz, 1H), 7.00 (s, 1H), 4.26 (t, J=7.82 Hz, 2H), 4.19 (q, J=7.17 Hz, 2H), 3.24-3.28 (m, 2H), 1.22 (t, J=7.09 Hz, 3H); LCMS (m/z): 402.0 [M+H].sup.+.
Example 121
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(1,1-dioxidothiomorpholino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(413) ##STR00131##
(414) To a solution of ethyl 2-(1,1-dioxidothiomorpholino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.027 g, 0.092 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.014 g, 0.092 mmol) in ethanol (0.5 mL), piperidine (0.00092 mL, 0.0093 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.037 g, y. 47%).
(415) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.40 (br. s, 1H), 8.38 (d, J=8.03 Hz, 1H), 8.32 (dd, J=1.51, 4.77 Hz, 1H), 8.03 (d, J=2.51 Hz, 1H), 7.22 (dd, J=4.64, 7.91 Hz, 1H), 6.94 (s, 1H), 4.12-4.25 (m, 6H), 3.47-3.55 (m, 4H), 1.25 (t, J=7.03 Hz, 3H); LCMS (m/z): 418.0 [M+H].sup.+.
Example 122
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[3-(hydroxymethyl)piperidino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(416) ##STR00132##
(417) To a solution of ethyl 2-[(3-hydroxymethyl)piperidino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.30 g, 1.0 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.16 g, 1.0 mmol) in ethanol (5.0 mL), L-proline (0.0040 g, 0.030 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.045 g, y. 10%).
(418) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.33 (br. s, 1H), 8.38 (d, J=7.82 Hz, 1H), 8.31 (d, J=4.40 Hz, 1H), 7.98 (s, 1H), 7.19 (dd, J=4.89, 7.82 Hz, 1H), 6.84 (s, 1H), 4.72 (br. s, 1H), 4.12-4.24 (m, 2H), 3.24-3.50 (m, 4H), 3.17 (t, J=11.74 Hz, 2H), 1.74-1.91 (m, 2H), 1.60-1.72 (m, 2H), 1.29-1.41 (m, 1H), 1.24 (t, J=6.85 Hz, 3H); LCMS (m/z): 398.2 [M+H].sup.+.
Example 123
2-(Dimethylamino)ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-azepinyl-4-oxo-4,5-dihydrofuran-3-carboxylate formate
(419) ##STR00133##
(420) A solution of the compound (0.052 g, 0.14 mmol) of Example 63, 2-dimethylaminoethanol (0.14 mL, 1.4 mmol), zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0019 g, 0.0020 mmol) and 4-dimethylaminopyridine (0.0049 g, 0.040 mmol) in N,N-dimethylacetamide (1.0 mL) was stirred with the microwave synthesizer (Biotage Initiator) at 150 C. for 1 h. The reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.018 g, y. 24%).
(421) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.31 (br. s, 1H), 8.39 (dd, J=1.25, 7.78 Hz, 1H), 8.31 (dd, J=1.38, 4.64 Hz, 1H), 8.16 (s, 1H), 7.94 (d, J=1.76 Hz, 1H), 7.20 (dd, J=4.77, 7.78 Hz, 1H), 6.86 (s, 1H), 4.22 (t, J=5.77 Hz, 2H), 3.72-3.92 (m, 4H), 2.54-2.60 (m, 2H), 2.24 (s, 6H), 1.78-1.90 (m, 4H), 1.52-1.63 (m, 4H); LCMS (m/z): 425.1 [M+H].sup.+.
Example 124
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-(3-methylthienyl)methyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(422) ##STR00134##
(423) To a solution of ethyl 2-{[2-(3-methylthienyl)methyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.38 g, 1.4 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.20 g, 1.4 mmol) in ethanol (4.0 mL), piperidine (0.014 mL, 0.14 mmol) was added at ambient temperature. The mixture was refluxed for 5 days. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.12 g, y. 21%).
(424) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.38 (br. s, 1H), 9.47 (t, J=6.27 Hz, 1H), 8.35 (d, J=8.03 Hz, 1H), 8.30 (dd, J=1.38, 4.64 Hz, 1H), 7.97 (d, J=2.26 Hz, 1H), 7.32 (d, J=5.02 Hz, 1H), 7.15 (dd, J=4.64, 7.91 Hz, 1H), 6.92 (s, 1H), 6.88 (d, J=5.02 Hz, 1H), 4.95 (d, J=6.27 Hz, 2H), 4.22 (q, J=7.03 Hz, 2H), 2.28 (s, 3H), 1.26 (t, J=7.03 Hz, 3H); LCMS (m/z): 410.0 [M+H].sup.+.
Example 125
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[(2-hydroxyethyl)-N-methylamino]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(425) ##STR00135##
First Step
(426) A solution of 5-fluoro-2-nitrotoluene (1.5 g, 9.6 mmol), N-methylethanolamine (0.90 mL, 0.012 mol) and triethylamine (1.6 mL, 0.012 mol) in N-methyl-2-pyrrolidone (15 mL) was stirred at 60 C. for 12 h. Cooled to ambient temperature, the reaction mixture was poured into ice water, extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to afford 2-[(3-methyl-4-nitrophenyl)-N-methylamino]ethanol as solid (2.0 g, y. 98%).
(427) .sup.1H NMR (DMSO-d.sub.6) (ppm) 7.99 (d, J=9.32 Hz, 1H), 6.58-6.71 (m, 2H), 4.78 (t, J=5.22 Hz, 1H), 3.46-3.63 (m, 4H), 3.06 (s, 3H), 2.56 (s, 3H); LCMS (m/z): 211.2 [M+H].sup.+.
(428) Second Step
(429) 2-[(3-Methyl-4-nitrophenyl)-N-methylamino]ethanol (0.70 g, 3.3 mmol) was dissolved in ethanol (10 mL) and 10% palladium on carbon (0.050 g) was added at ambient temperature. The reaction mixture was agitated under a hydrogen atmosphere at ambient temperature for 4 h. Palladium on carbon was removed by filtration with Celite and the solvent was removed under reduced pressure to afford 2-[(4-amino-3-methylphenyl)-N-methylamino]ethanol as solid (0.58 g, y. 97%).
(430) .sup.1H NMR (DMSO-d.sub.6) (ppm) 6.49 (d, J=8.44 Hz, 1H), 6.43 (d, J=2.60 Hz, 1H), 6.38 (q, J=6.13 Hz, 1H), 4.50 (t, J=5.38 Hz, 1H), 4.12 (br. s, 2H), 3.48 (dd, J=6.38, 12.00 Hz, 2H), 3.16 (t, J=6.58 Hz, 2H), 2.73 (s, 3H), 2.02 (s, 3H); LCMS (m/z): 181.1 [M+H].sup.+.
(431) Third Step
(432) A solution of ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.70 g, 3.5 mmol) which afforded in the Example 74, Third step and 2-[(4-amino-3-methylphenyl)-N-methylamino]ethanol (0.60 g, 3.5 mmol) in ethanol (8.3 mL) was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure, and ethanol was added to precipitate the product. The precipitate was collected by filtration, washed with ethanol then dried to afford 2-({4-[(2-hydroxyethyl)-N-methylamino]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.60 g, y. 60%).
(433) .sup.1H NMR (DMSO-d.sub.6) (ppm) 9.86 (br. s, 1H), 7.12 (d, J=8.76 Hz, 1H), 6.60 (d, J=2.60 Hz, 1H), 5.54 (dd, J=2.74, 8.80 Hz, 1H), 4.65 (br. s, 1H), 4.57 (s, 2H), 4.20 (q, J=7.06 Hz, 2H), 3.53 (t, J=6.14 Hz, 2H), 3.38 (t, J=6.22 Hz, 2H), 2.92 (s, 3H), 2.17 (s, 3H); LCMS (m/z): 335.0 [M+H].sup.+.
(434) Fourth Step
(435) To a solution of 2-({4-[(2-hydroxyethyl)-N-methylamino]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.20 g, 0.60 mmol) and 7-azaindole-3-carboxaldehyde (0.097 g, 0.60 mmol) in ethanol (11 mL), piperidine (0.10 mL, 1.0 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with diethyl ether then dried to afford the titled compound as solid (0.055 g, y. 19%).
(436) .sup.1H NMR DMSO-d.sub.6) (ppm) 12.22 (br. s, 1H), 10.12 (br. s, 1H), 8.15 (d, J=4.40 Hz, 1H), 7.77 (br. s, 1H), 7.68 (d, J=7.82 Hz, 1H), 7.22 (d, J=8.80 Hz, 1H), 6.77 (s, 1H), 6.67-6.73 (m, 2H), 6.63 (d, J=8.31 Hz, 1H), 4.69 (t, J=5.14 Hz, 1H), 4.23 (q, J=6.85 Hz, 2H), 3.55-3.63 (m, 2H), 3.43-3.50 (m, 2H), 3.01 (s, 3H), 2.15 (s, 3H), 1.26 (t, J=6.85 Hz, 3H); LCMS (m/z): 463.2 [M+H].sup.+.
Example 126
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[(2-hydroxyethyl)amino]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(437) ##STR00136##
(438) The titled compound (solid) was similarly prepared according to the procedure described in the Example 125.
(439) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.25 (br. s, 1H), 10.11 (s 1H), 8.18 (d, J=4.40 Hz, 1H), 7.81-7.87 (m, 1H), 7.70 (d, J=7.83 Hz, 1H), 7.16 (d, J=8.31 Hz, 1H), 6.75-6.87 (m, 2H), 6.53-6.67 (m, 2H), 5.85 (t, J=5.38 Hz, 1H), 4.75 (t, J=5.38 Hz, 1H), 4.26 (q, J=6.85 Hz, 2H), 3.63 (q, J=5.87 Hz, 2H), 3.20 (q, J=5.71 Hz, 2H), 2.13 (s, 3H), 1.29 (t, J=7.09 Hz, 3H); LCMS (m/z): 449.2 [M+H].sup.+.
Example 127
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[4-(2,3-dihydroxypropoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(440) ##STR00137##
(441) To a stirred solution of ethyl 2-{[4-(2,3-dihydroxypropoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.17 g, 0.50 mmol) which similarly prepared according to the procedure described in the Example 74, First step to Fourth step and 7-azaindole-3-carboxaldehyde (0.070 g, 0.50 mmol) in ethanol (5.0 mL), piperidine (0.10 mL, 1.0 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with diethyl ether then dried to afford the titled compound as solid (0.054 g, y. 23%).
(442) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.28 (br. s, 1H), 10.30 (br. s, 1H), 8.18 (d, J=2.93 Hz, 1H), 7.78 (br. s, 1H), 7.64 (d, J=7.34 Hz, 1H), 7.41 (d, J=8.31 Hz, 1H), 7.03 (br. s, 1H), 6.94 (d, J=7.34 Hz, 1H), 6.82 (s, 1H), 6.70-6.79 (m, 1H), 5.06 (d, J=4.40 Hz, 1H), 4.76 (t, J=5.04 Hz, 1H), 4.20-4.32 (m, 2H), 4.05-4.15 (m, 1H), 3.93-4.02 (m, 1H), 3.83-3.92 (m, 1H), 3.47-3.57 (m, 2H), 2.22 (br. s, 3H), 1.29 (t, J=6.60 Hz, 3H); LCMS (m/z): 480.2 [M+H].sup.+.
Example 128
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({2-methyl-4-[2-(methylthio)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(443) ##STR00138##
(444) The titled compound (solid) was similarly prepared according to the procedure described in the Example 127.
(445) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.28 (br. s, 1H), 10.30 (br. s, 1H), 8.19 (d, J=4.40 Hz, 1H), 7.77 (s, 1H), 7.65 (d, J=7.82 Hz, 1H), 7.42 (d, J=8.80 Hz, 1H), 7.05 (br. s, 1H), 6.95 (dd, J=2.69, 8.56 Hz, 1H), 6.82 (br. s, 1H), 6.76 (dd, J=4.40, 7.83 Hz, 1H), 4.21-4.32 (m, 4H), 2.94 (t, J=6.36 Hz, 2H), 2.23 (s, 3H), 2.22 (s, 3H), 1.29 (t, J=7.09 Hz, 3H); LCMS (m/z): 480.2 [M+H].sup.+.
Example 129
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[(dimethylamino)methyl]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(446) ##STR00139##
First Step
(447) A solution of 3-methyl-4-nitrobenzyl bromide (1.0 g, 4.3 mmol), anhydrous dimethylamine (0.34 mL, 5.1 mmol) and potassium carbonate (1.5 g, 0.011 mol) in N,N-dimethylformamide (4.5 mL) was stirred at 70 C. for 12 h. Cooled to ambient temperature, the reaction mixture was poured into ice water, extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to afford N,N-dimethyl-1-(3-methyl-4-nitrophenyl)methanamine as oil (0.80 g, y. 95%).
(448) .sup.1H NMR (DMSO-d.sub.6) (ppm) 7.65 (d, J=8.32 Hz, 1H), 7.41 (s, 1H), 7.36 (d, J=8.36 Hz, 1H), 3.44 (s, 2H), 2.52 (s, 3H), 2.15 (s, 6H); LCMS (m/z): 195.4 [M+H].sup.+.
(449) Second Step
(450) N,N-Dimethyl-1-(3-methyl-4-nitrophenyl)methanamine (0.80 g, 4.1 mmol) was dissolved in ethanol (5.0 mL) and 10% palladium on carbon (0.18 g) was added at ambient temperature. The reaction mixture was agitated under a hydrogen atmosphere at ambient temperature for 4 h. Palladium on carbon was removed by filtration with Celite and the solvent was removed under reduced pressure to afford 4-[(dimethylamino)methyl]-2-methylaniline (0.65 g, y. 96%).
(451) .sup.1H NMR (DMSO-d.sub.6) (ppm) 6.81 (s, 1H), 6.77 (d, J=7.92 Hz, 1H), 6.52 (d, J=7.96 Hz, 1H), 4.68 (s, 2H), 3.16 (s, 2H), 2.07 (s, 6H), 2.02 (s, 3H).
(452) Third Step
(453) A solution of ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.47 g, 2.3 mmol) which afforded in the Example 74, Third step and 4-[(dimethylamino)methyl]-2-methylaniline (0.35 g, 2.1 mmol) in ethanol (10 mL) was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure, and ethanol was added to precipitate the product. The precipitate was collected by filtration to afford ethyl 2-({4-[(dimethylamino)methyl]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.26 g, crude material) as solid.
(454) .sup.1H NMR (DMSO-d.sub.6) (ppm) 10.18 (br. s, 1H), 7.48 (d, J=6.96 Hz, 1H), 7.25-7.40 (m, 2H), 4.65 (s, 2H), 4.23 (q, J=7.04 Hz, 2H), 2.40-2.60 (m, 9H), 1.26 (t, J=7.04 Hz, 3H); LCMS (m/z): 319.2 [M+H].sup.+.
(455) Fourth Step
(456) To a solution of ethyl 2-({4-[(dimethylamino)methyl]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.26 g, 0.82 mmol) and 7-azaindole-3-carboxaldehyde (0.12 g, 0.82 mmol) in ethanol (5.0 mL), piperidine (0.16 mL, 1.6 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with diethyl ether then dried to afford the titled compound as solid (0.015 g, y. 4%).
(457) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.26 (br. s, 1H), 8.20 (d, J=3.91 Hz, 1H), 8.15 (s, 1H), 7.82 (d, J=7.34 Hz, 1H), 7.72 (s, 1H), 7.47 (d, J=7.83 Hz, 1H), 7.37 (s, 1H), 7.30 (d, J=8.31 Hz, 1H), 6.83 (s, 1H), 6.79 (dd, J=4.89, 7.82 Hz, 1H), 4.26 (q, J=7.17 Hz, 2H), 3.54 (s, 2H), 2.22-2.29 (m, 9H), 1.29 (t, J=6.85 Hz, 3H); LCMS (m/z): 447.4 [M+H].sup.+
Example 130
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-{[(1R,2S)-2-phenylcyclopropyl]amino}-4,5-dihydrofuran-3-carboxylate
(458) ##STR00140##
(459) To a solution of ethyl 4-oxo-2-{[(1R,2S)-2-phenylcyclopropyl]amino}-4,5-dihydrofuran-3-carboxylate (0.090 g, 0.31 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.045 g, 0.30 mmol) in ethanol (5.0 mL), L-proline (0.0035 g, 0.031 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the solvent was removed under reduced pressure then the residue was purified by preparative HPLC to afford the titled compound as solid (0.018 g, y. 14%).
(460) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.11 (br. s, 1H), 9.10 (br. s, 1H), 8.41 (d, J=7.34 Hz, 1H), 8.26 (d, J=3.91 Hz, 1H), 7.81 (s, 1H), 7.28-7.36 (m, 2H), 7.19-7.27 (m, 3H), 7.03 (dd, J=4.40, 7.82 Hz, 1H), 6.88 (s, 1H), 4.21 (q, J=6.85 Hz, 2H), 3.40-3.48 (m, 1H), 2.88-3.10 (m, 1H), 1.63-1.72 (m, 1H), 1.35-1.43 (m, 1H), 1.26 (t, J=7.08 Hz, 3H); LCMS (m/z): 415.8 [M+H].sup.+.
Example 131
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[2-(2-hydroxyethoxy)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(461) ##STR00141##
(462) To a solution of ethyl 2-({4-[2-(2-hydroxyethoxy)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.15 g, 0.50 mmol) which similarly prepared according to the procedure described in the Example 74, First step to Fourth step and 7-azaindole-3-carboxaldehyde (0.070 g, 0.50 mmol) in ethanol (10 mL), L-proline (0.010 g, 0.087 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with diethyl ether then dried to afford the titled compound (0.031 g, y. 15%) as solid.
(463) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.28 (br. s, 1H), 10.29 (br. s, 1H), 8.20 (d, J=3.91 Hz, 1H), 7.75 (br. s, 1H), 7.68 (d, J=7.82 Hz, 1H), 7.42 (d, J=8.80 Hz, 1H), 7.05 (br. s, 1H), 6.95 (dd, J=2.40, 8.60 Hz, 1H), 6.83 (s, 1H), 6.77 (dd, J=4.40, 7.83 Hz, 1H), 4.64-4.70 (m, 1H), 4.26 (q, J=6.85 Hz, 2H), 4.17-4.23 (m, 2H), 3.79-3.87 (m, 2H), 3.52-3.62 (m, 4H), 2.23 (s, 3H), 1.29 (t, J=6.85 Hz, 3H); LCMS (m/z): 494.0 [M+H].sup.+.
Example 132
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[4-(3-hydroxypropoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(464) ##STR00142##
(465) The titled compound (solid) was similarly prepared according to the procedure described in the Example 131.
(466) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.25 (br. s, 1H), 8.19 (d, J=4.40 Hz, 1H), 7.74 (s, 1H), 7.67 (d, J=7.82 Hz, 1H), 7.36 (d, J=8.80 Hz, 1H), 7.00 (d, J=2.4 Hz, 1H), 6.91 (d, J=8.31 Hz, 1H), 6.71-6.79 (m, 2H), 4.59-4.65 (m, 1H), 4.25 (q, J=6.85 Hz, 2H), 4.14 (t, J=6.11 Hz, 2H), 3.60-3.67 (m, J=5.38 Hz, 2H), 2.21 (s, 3H), 1.94 (t, J=6.11 Hz, 2H), 1.28 (t, J=7.06 Hz, 3H); LCMS (m/z): 464.2 [M+H].sup.+.
Example 133
Ethyl 2-({4-[2-(1H-pyrrol-1-yl)ethoxy]-2-methylphenyl}amino)-5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-4,5-dihydrofuran-3-carboxylate
(467) ##STR00143##
(468) The titled compound (solid) was similarly prepared according to the procedure described in the Example 131.
(469) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.04 (br. s, 1H), 8.08 (d, J=3.91 Hz, 1H), 7.60-7.76 (m, 2H), 7.16 (br. s, 1H), 6.88-6.94 (m, 3H), 6.84 (d, J=7.82 Hz, 1H), 6.60-6.68 (m, 1H), 6.48-6.57 (m, 1H), 6.02-6.07 (m, 2H), 4.22-4.37 (m, 4H), 4.13-4.22 (m, 2H), 2.14 (s, 3H), 1.25 (t, J=6.85 Hz, 3H); LCMS (m/z): 499.2 [M+H].sup.+.
Example 134
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-methyl-4-(1-pyrrolidinylmethyl)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(470) ##STR00144##
(471) To a solution of 2-{[2-methyl-4-(1-pyrrolidinylmethyl)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.25 g, 0.70 mmol) which similarly prepared according to the procedure described in the Example 129, First step to Third step and 7-azaindole-3-carboxaldehyde (0.10 g, 0.70 mmol) in ethanol (10 mL), piperidine (0.014 mL, 0.14 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature then the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.035 g, y. 10%).
(472) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.27 (br. s, 1H), 8.20 (d, J=3.91 Hz, 1H), 8.14 (s, 1H), 7.72-7.82 (m, 2H), 7.48 (d, J=7.83 Hz, 1H), 7.41 (s, 1H), 7.34 (d, J=7.34 Hz, 1H), 6.76-6.86 (m, 2H), 4.26 (q, J=6.85 Hz, 2H), 3.81 (br. s, 2H), 2.57-2.69 (m, 4H), 2.27 (s, 3H), 1.70-1.85 (m, 4H), 1.29 (t, J=6.85 Hz, 3H); LCMS (m/z): 473.2 [M+H].sup.+.
Example 135
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({2-methyl-4-[(4-methylpiperazinyl)methyl]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(473) ##STR00145##
(474) The titled compound (solid) was similarly prepared according to the procedure described in the Example 134.
(475) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.43 (br. s, 1H), 8.18 (br. s, 1H), 8.01 (br. s, 1H), 7.41 (br. s, 1H), 6.99-7.17 (m, 3H), 6.87 (br. s, 2H), 6.40 (d, J=12.72 Hz, 1H), 4.26 (br. s, 2H), 3.57 (br. s, 2H), 2.42 (br. s, 8H), 2.28 (br. s, 3H), 2.08 (br. s, 3H), 1.12-1.39 (m, 3H); LCMS (m/z): 502.4 [M+H].sup.+.
Example 136
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-methyl-4-(morpholinomethyl)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(476) ##STR00146##
(477) The titled compound (solid) was similarly prepared according to the procedure described in the Example 134.
(478) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.29 (br. s, 1H), 10.38 (br. s, 1H), 8.21 (d, J=4.40 Hz, 1H), 7.72-7.83 (m, 2H), 7.46-7.54 (m, 1H), 7.28-7.44 (m, 2H), 6.86 (s, 1H), 6.75-6.81 (m, 1H), 4.27 (q, J=7.17 Hz, 2H), 3.51-3.74 (m, 6H), 2.35-2.59 (m, 4H), 2.27 (s, 3H), 1.30 (t, J=7.09 Hz, 3H); LCMS (m/z): 489.2 [M+H].sup.+.
Example 137
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-{[2-(dimethylamino)ethyl]amino}-2-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate formate
(479) ##STR00147##
(480) To a solution of ethyl 2-[(4-{[2-(dimethylamino)ethyl]amino}-2-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.27 g, 0.70 mmol) which similarly prepared according to the procedure described in the Example 125, First step to Third step and 7-azaindole-3-carboxaldehyde (0.11 g, 0.70 mmol) in ethanol (5.0 mL), piperidine (0.10 mL, 1.0 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the solvent was removed under reduced pressure then the residue was purified by preparative HPLC to afford the titled compound as solid (0.015 g, y. 8%).
(481) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.29 (br. s, 1H), 10.12 (br. s, 1H), 8.11-8.23 (m, 2H), 7.86 (s, 1H), 7.67 (d, J=7.82 Hz, 1H), 7.17 (d, J=8.31 Hz, 1H), 6.75-6.83 (m, 2H), 6.51-6.69 (m, 2H), 5.79 (br. s, 1H), 4.25 (q, J=6.85 Hz, 2H), 3.16-3.28 (m, 2H), 2.58 (t, J=6.11 Hz, 2H), 2.29 (s, 6H), 2.13 (s, 3H), 1.29 (t, J=6.85 Hz, 3H); LCMS (m/z): 476.0 [M+H].sup.+.
Example 138
2-Methoxyethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-azepinyl-4-oxo-4,5-dihydrofuran-3-carboxylate
(482) ##STR00148##
First Step
(483) A solution of ethyl malonyl chloride (0.10 mL, 0.78 mmol) and 2-methoxyethanol (0.061 mL, 0.78 mmol) in dichloromethane (1.5 mL) was cooled with ice bath. To this solution, triethylamine (0.13 mL, 0.94 mmol) was added and stirred at ambient temperature for 1.5 h. The reaction mixture was diluted with water, extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel(hexane/ethyl acetate) to afford ethyl 2-methoxyethyl malonate (0.10 g, y. 69%) as oil.
(484) .sup.1H NMR (CDCl.sub.3) (ppm) 4.28-4.34 (m, 2H), 4.21 (q, J=7.11 Hz, 2H), 3.59-3.64 (m, 2H), 3.42 (s, 2H), 3.39 (s, 3H), 1.29 (t, J=7.15 Hz, 3H)
(485) Second Step
(486) A solution of ethyl 2-methoxyethyl malonate (0.10 g, 0.53 mmol) in anhydrous tetrahydrofuran (1.5 mL) was added dropwise to a solution of sodium hydride (60% w/w in oil, 0.043 g, 1.1 mmol) in anhydrous tetrahydrofuran (2.0 mL) that cooled with ice bath. The mixture was refluxed for 5 min. The reaction mixture was cooled with ice bath, chloroacetyl chloride (0.042 mL, 0.53 mmol) was added dropwise to the reaction mixture and the mixture was stirred for 1 h then stirred with heating at 45 C. for 1 h. The reaction mixture was cooled to ambient temperature then hexamethyleneimine (0.071 mL, 0.63 mmol) was added dropwise and the mixture was stirred at ambient temperature for further 1 h. The reaction mixture was diluted with water, and extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluted with chloroform/methanol to afford 2-methoxyethyl 2-azepinyl-4-oxo-4,5-dihydrofuran-3-carboxylate as oil (0.065 g, y. 43%).
(487) .sup.1H NMR (CDCl.sub.3) (ppm) 4.51 (s, 2H), 4.35-4.39 (m, 2H), 3.56-3.75 (m, 6H), 3.40 (s, 3H), 1.80 (br. s, 4H), 1.61 (br. s, 4H); LCMS (m/z): 284.1 [M+H].sup.+.
(488) Third Step
(489) To a solution of 2-methoxyethyl 2-azepinyl-4-oxo-4,5-dihydrofuran-3-carboxylate (0.065 g, 0.23 mmol) and 7-azaindole-3-carboxaldehyde (0.033 g, 0.23 mmol) in ethanol (0.5 mL), hexamethyleneimine (0.026 mL, 0.023 mmol) was added at ambient temperature. The mixture was refluxed for 3 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and hexane then dried to afford the titled compound as solid (0.019 g, y. 20%).
(490) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.31 (br. s, 1H), 8.39 (dd, J=1.38, 7.91 Hz, 1H), 8.31 (dd, J=1.38, 4.64 Hz, 1H), 7.94 (s, 1H), 7.20 (dd, J=4.64, 7.91 Hz, 1H), 6.85 (s, 1H), 4.21-4.28 (m, 2H), 3.70-3.90 (m, 4H), 3.54-3.62 (m, 2H), 3.29 (s, 3H), 1.78-1.91 (m, 4H), 1.51-1.63 (m, 4H); LCMS (m/z): 412.1 [M+H].sup.+.
Example 139
Isopropyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-azepinyl-4-oxo-4,5-dihydrofuran-3-carboxylate
(491) ##STR00149##
(492) To a stirred solution of isopropyl 2-azepinyl-4-oxo-4,5-dihydrofuran-3-carboxylate (0.033 g, 0.12 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.019 g, 0.13 mmol) in 2-propanol (1.0 mL), hexamethyleneimine (0.0014 mL, 0.012 mmol) was added at ambient temperature. The mixture was refluxed for 12 days. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.024 g, y. 49%).
(493) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.30 (br. s, 1H), 8.37 (dd, J=1.38, 7.91 Hz, 1H), 8.31 (dd, J=1.38, 4.64 Hz, 1H), 7.93 (s, 1H), 7.20 (dd, J=4.77, 7.78 Hz, 1H), 6.81 (s, 1H), 4.94-5.05 (m, 1H), 3.70-3.90 (m, 4H), 1.75-1.91 (m, 4H), 1.52-1.62 (m, 4H), 1.25 (d, J=6.27 Hz, 6H); LCMS (m/z): 396.1 [M+H].sup.+.
Example 140
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-methyl-4-(2-pyridinylmethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(494) ##STR00150##
(495) The titled compound was similarly prepared as solid according to the procedure described in the Example 1, using ethyl 2-{[2-methyl-4-(2-pyridinylmethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate which similarly prepared according to the procedure described in the Example 74, First step to Fourth step and 7-azaindole-3-carboxaldehyde as starting materials.
(496) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.29 (br. s, 1H), 10.30 (br. s, 1H), 8.63 (d, J=3.91 Hz, 1H), 8.17 (d, J=3.91 Hz, 1H), 7.89 (t, J=7.09 Hz, 1H), 7.67-7.79 (m, 2H), 7.62 (d, J=7.34 Hz, 1H), 7.34-7.49 (m, 2H), 7.16 (br. s, 1H), 7.04 (d, J=8.31 Hz, 1H), 6.83 (s, 1H), 6.70-6.77 (m, 1H), 5.29 (s, 2H), 4.26 (q, J=6.85 Hz, 2H), 2.23 (s, 3H), 1.29 (t, J=7.09 Hz, 3H); LCMS (m/z): 497.0 [M+H].sup.+.
Example 141
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-methyl-4-(3-pyridinylmethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(497) ##STR00151##
(498) To a solution of ethyl 2-{[2-methyl-4-(3-pyridinylmethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.080 g, 0.20 mmol) which similarly prepared according to the procedure described in the Example 74, First step to Fourth step and 7-azaindole-3-carboxaldehyde (0.032 g, 0.20 mmol) in ethanol (5.0 mL), L-proline (0.0050 g, 0.043 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.010 g, y. 9%).
(499) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.25 (br. s, 1H), 10.25 (br. s, 1H), 8.76 (s, 1H), 8.59 (d, J=3.42 Hz, 1H), 8.18 (d, J=4.40 Hz, 1H), 7.96 (d, J=7.83 Hz, 1H), 7.69-7.79 (m, 2H), 7.45-7.53 (m, 1H), 7.41 (d, J=8.80 Hz, 1H), 7.14 (br. s, 1H), 7.04 (d, J=8.31 Hz, 1H), 6.79 (br. s, 1H), 6.68-6.76 (m, 1H), 5.27 (s, 2H), 4.20-4.30 (m, 2H), 2.23 (s, 3H), 1.29 (t, J=7.09 Hz, 3H); LCMS (m/z): 497.4 [M+H].sup.+.
Example 142
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(morpholinoamino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(500) ##STR00152##
(501) A solution of ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.50 mmol) which afforded in the Example 74, Third step and 4-aminomorpholine (0.046 mL, 0.48 mmol) in ethanol (2.0 mL) was stirred at ambient temperature for 15 h. To this reaction mixture, 7-azaindole-3-carboxaldehyde (0.061 g, 0.42 mmol) and piperidine (0.0048 mL, 0.048 mmol) were added. The mixture was refluxed for 3 days. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound (0.045 g, y. 24%) as solid.
(502) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.34 (br. s, 1H), 10.07 (s, 1H), 8.93 (d, J=7.78 Hz, 1H), 8.33 (d, J=3.51 Hz, 1H), 8.12 (br. s, 1H), 7.20-7.26 (m, 1H), 6.88 (s, 1H), 4.21 (q, J=6.78 Hz, 2H), 3.74-3.88 (m, 4H), 3.02-3.14 (br. s, 4H), 1.26 (t, J=6.90 Hz, 3H); LCMS (m/z): 385.1 [M+H].sup.+.
Example 143
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-methyl-4-(4-pyridinylmethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(503) ##STR00153##
(504) The titled compound (solid) was similarly prepared according to the procedure described in the Example 141.
(505) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.28 (br. s, 1H), 10.30 (br. s, 1H), 8.62 (d, J=4.40 Hz, 2H), 8.17 (d, J=4.40 Hz, 1H), 7.67-7.79 (m, 2H), 7.52 (d, J=4.89 Hz, 2H), 7.45 (d, J=8.31 Hz, 1H), 7.15 (br. s, 1H), 7.03 (d, J=8.31 Hz, 1H), 6.83 (s, 1H), 6.68-6.75 (m, 1H), 5.31 (s, 2H), 4.26 (q, J=7.17 Hz, 2H), 2.23 (s, 3H), 1.29 (t, J=6.85 Hz, 3H); LCMS (m/z): 496.8 [M+H].sup.+.
Example 144
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[2-(diethylamino)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate Acetate
(506) ##STR00154##
(507) The crude material, which similarly prepared according to the procedure described in the Example 141, was purified by preparative HPLC (aqueous ammonium acetate/acetonitrile) to afford the titled compound (solid).
(508) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.17 (br. s, 1H), 8.16 (d, J=3.91 Hz, 1H), 7.75 (s, 1H), 7.68 (d, J=7.34 Hz, 1H), 7.34 (d, J=8.31 Hz, 1H), 7.00 (br. s, 1H), 6.91 (d, J=8.80 Hz, 1H), 6.70-6.79 (m, 2H), 4.19-4.30 (m, 2H), 4.10 (t, J=5.87 Hz, 2H), 2.86 (t, J=5.87 Hz, 2H), 2.61 (q, J=6.85 Hz, 4H), 2.20 (s, 3H), 1.90 (s, 3H), 1.28 (t, J=6.85 Hz, 3H), 1.02 (t, J=7.09 Hz, 6H); LCMS (m/z): 505.6 [M+H].sup.+.
Example 145
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({2-methyl-4-[2-(4-methylpiperazinyl)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate acetate
(509) ##STR00155##
First Step
(510) A solution of 4-nitro-m-cresol (2.0 g, 0.013 mol), 1-bromo-2-chloroethane (1.7 mL, 0.020 mol) and potassium carbonate (4.7 g, 0.034 mol) in N,N-dimethylformamide (21 mL) was stirred at 70 C. for 18 h. Cooled to ambient temperature, the reaction mixture was poured into ice water, extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel(hexane/ethyl acetate) to afford 4-(2-chloroethoxy)-2-methyl-1-nitrobenzene as solid (2.1 g, y. 73%).
(511) .sup.1H NMR (DMSO-d.sub.6) (ppm) 8.05 (d, J=9.12 Hz, 1H), 7.08 (d, J=2.48 Hz, 1H), 7.01 (dd, J=2.72, 9.08 Hz, 1H), 4.38 (t, J=5.04 Hz, 2H), 3.98 (t, J=5.08 Hz, 2H), 2.55 (s, 3H); LCMS (m/z): 216.2 [M+H].sup.+.
(512) Second Step
(513) A solution of 4-(2-chloroethoxy)-2-methyl-1-nitrobenzene (2.1 g, 9.7 mmol), N-methylpiperazine (1.5 g, 15 mmol) and potassium carbonate (3.4 g, 0.025 mol) in N,N-dimethylformamide (15 mL) was stirred with heating at 70 C. for 18 h. Cooled to ambient temperature, the reaction mixture was poured into ice water, extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel(dichloromethane/methanol) to afford 1-methyl-4-[2-(3-methyl-4-nitrophenoxy)ethyl]piperazine as solid (1.8 g, y. 64%).
(514) .sup.1H NMR (DMSO-d.sub.6) (ppm) 8.03 (d, J=9.12 Hz, 1H), 7.05 (d, J=2.68 Hz, 1H), 6.98 (dd, J=2.76, 9.08 Hz, 1H), 4.18 (t, J=5.78 Hz, 2H), 2.69 (t, J=5.74 Hz, 2H), 2.54 (s, 3H), 2.39-2.52 (m, 4H), 2.22-2.37 (m, 4H), 2.14 (s, 3H); LCMS (m/z): 280.2 [M+H].sup.+.
(515) Third Step
(516) 1-Methyl-4-[2-(3-methyl-4-nitrophenoxy)ethyl]piperazine (0.69 g, 2.5 mmol) was dissolved in ethanol (10 mL) and 10% wt palladium on carbon (0.055 g) was added at ambient temperature. The reaction mixture was agitated under a hydrogen atmosphere at ambient temperature for 4 h. Palladium on carbon was removed by filtration with Celite and the solvent was removed under reduced pressure to afford 2-methyl-4-[2-(4-methylpiperazinyl)ethoxy]aniline as oil (0.60 g, y. 97%).
(517) .sup.1H NMR (DMSO-d.sub.6) (ppm) 6.57 (br. s, 1H), 6.51 (br. s, 2H), 4.35 (br. s, 2H), 3.90 (t, J=5.90 Hz, 2H), 3.17 (br. s, 3H), 2.60 (t, J=5.88 Hz, 2H), 2.38-2.54 (m, 4H), 2.30 (br. s, 4H), 2.14 (s, 3H); LCMS (m/z): 250.4 [M+H].sup.+.
(518) Fourth Step
(519) A solution of ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.32 g, 1.6 mmol) which afforded in the Example 74, Third step and 2-methyl-4-[2-(4-methylpiperazinyl)ethoxy]aniline (0.40 g, 1.6 mmol) in ethanol (5.0 mL) was stirred at 60 C. for 30 min. The solvent was removed under reduced pressure, then the residue was purified by chromatography on silica gel(dichloromethane/methanol) to afford 2-({2-methyl-4-[2-(4-methylpiperazinyl)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.30 g, y. 46%).
(520) .sup.1H NMR (DMSO-d.sub.6) (ppm) 9.99 (br. s, 1H), 7.26 (d, J=8.56 Hz, 1H), 6.91 (d, J=2.28 Hz, 1H), 6.78-6.86 (m, 1H), 4.58 (s, 2H), 4.21 (q, J=7.04 Hz, 2H), 4.03-4.12 (m, 2H), 3.31 (s, 3H), 2.27-2.80 (m, 10H), 2.20 (s, 3H), 1.25 (t, J=7.04 Hz, 3H); LCMS (m/z): 404.2 [M+H].sup.+.
(521) Fifth Step
(522) To a solution of 2-({2-methyl-4-[2-(4-methylpiperazinyl)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.22 g, 0.55 mmol) and 7-azaindole-3-carboxaldehyde (0.080 g, 0.55 mmol) in ethanol (14 mL), L-proline (0.014 g, 0.12 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. The solvent was removed under reduced pressure, and then the residue was purified by preparative HPLC (aqueous ammonium acetate/acetonitrile) to afford the titled compound as solid. (0.032 g, y. 11%).
(523) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.16 (br. s, 1H), 8.17 (d, J=4.40 Hz, 1H), 7.64-7.79 (m, 2H), 7.31 (d, J=8.31 Hz, 1H), 7.00 (br. s, 1H), 6.90 (d, J=8.31 Hz, 1H), 6.65-6.80 (m, 2H), 4.10-4.30 (m, 4H), 2.76 (t, J=5.62 Hz, 2H), 2.25-2.65 (m, 9H), 2.19-2.21 (m, 5H), 1.86 (s, 3H), 1.28 (t, J=6.85 Hz, 3H); LCMS (m/z): 532.3 [M+H].sup.+.
Example 146
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[4-(2-hydroxy-2-methylpropoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(524) ##STR00156##
(525) The titled compound (solid) was similarly prepared according to the procedure described in the Example 141.
(526) .sup.1H (DMSO-d.sub.6) (ppm) 12.28 (br. s, 1H), 10.30 (br. s, 1H), 8.16 (d, J=3.91 Hz, 1H), 7.80 (s, 1H), 7.60 (d, J=7.82 Hz, 1H), 7.40 (d, J=8.31 Hz, 1H), 7.03 (br. s, 1H), 6.94 (d, J=8.31 Hz, 1H), 6.81 (s, 1H), 6.73 (dd, J=4.40, 7.82 Hz, 1H), 4.72 (s, 1H), 4.27 (q, J=7.17 Hz, 2H), 3.81 (s, 2H), 2.22 (s, 3H), 1.25-1.33 (m, 9H); LCMS (m/z): 478.2 [M+H].sup.+.
Example 147
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-methyl-4-{[2-(pyrrolidino)ethyl]amino}phenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate acetate
(527) ##STR00157##
(528) To a solution of 2-[(2-methyl-4-{[2-(pyrrolidino)ethyl]amino}phenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.32 g, 0.85 mmol) which similarly prepared according to the procedure described in the Example 125, First step to Third step and 7-azaindole-3-carboxaldehyde (0.13 g, 0.85 mmol) in ethanol (5.0 mL), piperidine (0.10 mL, 1.0 mmol) was added at ambient temperature. The mixture was refluxed for 24 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC (aqueous ammonium acetate/acetonitrile) to afford the titled compound as solid (0.010 g, y. 3%).
(529) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.05 (br. s, 1H), 8.11-8.20 (m, 1H), 7.71-7.84 (m, 2H), 7.01-7.10 (m, 1H), 6.77-6.85 (m, 1H), 6.49-6.68 (m, 3H), 5.57 (br. s, 1H), 4.15-4.25 (m, 2H), 3.21 (br. s, 2H), 2.63-2.73 (m, 2H), 2.52-2.61 (m, 4H), 2.10 (s, 3H), 1.85 (s, 3H), 1.65-1.78 (m, 4H), 1.27 (t, J=6.85 Hz, 3H); LCMS (m/z): 502.4 [M+H].sup.+.
Example 148
Isopropyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[N-methyl-N-(2-thienylmethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(530) ##STR00158##
(531) A solution of isopropyl 2-isopropoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.44 mmol) which similarly prepared according to the procedure described in the Example 74, Third step using diisopropyl malonate and chloroacetyl chloride, N-methyl-N-(2-thienylmethyl)amine (0.061 mg, 0.048 mmol) and triethylamine (0.18 mL, 1.3 mmol) in 2-propanol (2.0 mL) was stirred for 7 days then refluxed for further 24 h. To this reaction mixture, 7-azaindole-3-carboxaldehyde (0.065 g, 0.44 mmol) was added then the mixture was refluxed for 24 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0038 g, y. 2%).
(532) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.33 (br. s, 1H), 8.35 (d, J=8.03 Hz, 1H), 8.28-8.32 (m, 1H), 8.02 (s, 1H), 7.53 (dd, J=1.13, 5.14 Hz, 1H), 7.14-7.22 (m, 2H), 7.04 (dd, J=3.51, 5.02 Hz, 1H), 6.88 (s, 1H), 5.19 (s, 2H), 4.97-5.05 (m, 1H), 3.26 (s, 3H), 1.24 (d, J=6.27 Hz, 6H); LCMS (m/z): 424.1 [M+H].sup.+.
Example 149
Isopropyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(cyclohexylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(533) ##STR00159##
(534) A solution of isopropyl 2-isopropoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.44 mmol) which similarly prepared according to the procedure described in the Example 74, Third step using diisopropyl malonate and chloroacetyl chloride, and cyclohexylamine (0.055 mL, 0.48 mmol) in 2-propanol (2.0 mL) was stirred at ambient temperature for 14 h. To this reaction mixture, 7-azaindole-3-carboxaldehyde (0.065 g, 0.44 mmol) and piperidine (0.0044 mL, 0.044 mmol) were added then the mixture was refluxed for further 8 days. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0079 g, y. 4%).
(535) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.35 (br. s, 1H), 8.51 (d, J=8.28 Hz, 1H), 8.41 (d, J=7.78 Hz, 1H), 8.32 (dd, J=1.38, 4.64 Hz, 1H), 7.99 (d, J=2.51 Hz, 1H), 7.20 (dd, J=4.64, 7.91 Hz, 1H), 6.86 (s, 1H), 5.00-5.12 (m, 1H), 3.96-4.05 (m, 1H), 1.93-2.04 (m, 2H), 1.72-1.84 (m, 2H), 1.54-1.69 (m, 3H), 1.35-1.49 (m, 2H), 1.18-1.31 (m, 7H); LCMS (m/z): 396.2 [M+H].sup.+.
Example 150
Isopropyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(cyclohexylmethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(536) ##STR00160##
(537) A solution of isopropyl 2-isopropoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.44 mmol) which similarly prepared according to the procedure described in the Example 74, Third step using diisopropyl malonate and chloroacetyl chloride, and aminomethylcyclohexane (0.063 mL, 0.48 mmol) in 2-propanol (2.0 mL) was stirred at ambient temperature for 14 h. To this reaction mixture, 7-azaindole-3-carboxaldehyde (0.065 g, 0.44 mmol) and piperidine (0.0044 mL, 0.044 mmol) were added then the mixture was refluxed for further 8 days. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.036 g, y. 19%).
(538) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.35 (br. s, 1H), 8.90-8.98 (m, 1H), 8.41 (d, J=6.78 Hz, 1H), 8.32 (dd, J=1.38, 4.64 Hz, 1H), 7.99 (s, 1H), 7.19 (dd, J=4.77, 8.03 Hz, 1H), 6.84 (s, 1H), 5.00-5.13 (m, 1H), 3.45-3.53 (m, 2H), 1.56-1.81 (m, 5H), 1.27 (d, J=6.27 Hz, 6H), 1.08-1.24 (m, 4H), 0.94-1.07 (m, 2H); LCMS (m/z): 410.2 [M+H].sup.+.
Example 151
Isopropyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(trans-4-hydroxycyclohexyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(539) ##STR00161##
(540) A solution of isopropyl 2-[(trans-4-hydroxycyclohexyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.44 mmol) which similarly prepared according to the procedure described in the Example 74, Third step using diisopropyl malonate and chloroacetyl chloride, and trans-4-aminomethylcyclohexanol (0.056 mg, 0.49 mmol) in 2-propanol (1.0 mL) was stirred at ambient temperature for 20 h. To this reaction mixture, 7-azaindole-3-carboxaldehyde (0.065 g, 0.44 mmol) and L-proline (0.0050 g, 0.044 mmol) were added then the mixture was refluxed for further 1.5 days. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford isopropyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(trans-4-hydroxycyclohexyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.0076 g, y. 4%).
(541) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.36 (br. s, 1H), 8.46 (d, J=8.28 Hz, 1H), 8.42 (d, J=7.53 Hz, 1H), 8.33 (dd, J=1.38, 4.64 Hz, 1H), 7.99 (d, J=2.51 Hz, 1H), 7.20 (dd, J=4.64, 7.91 Hz, 1H), 6.85 (s, 1H), 5.01-5.09 (m, 1H), 4.69 (d, J=4.27 Hz, 1H), 3.93-3.99 (m, 1H), 3.43-3.51 (m, 1H), 1.86-2.03 (m, 4H), 1.60-1.73 (m, 2H), 1.29-1.42 (m, 2H), 1.26 (d, J=6.27 Hz, 6H); LCMS (m/z): 412.1 [M+H].sup.+.
Example 152
Cyclopropylmethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[2-(dimethylamino)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate formate
(542) ##STR00162##
(543) A solution of ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[2-(dimethylamino)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.033 g, 0.070 mmol) which similarly prepared according to the procedure described in the Example 111, cyclopropyl carbinol (0.10 mL, 1.3 mmol) and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0033 g, 0.0035 mmol) in N,N-dimethylacetamide (0.9 mL) was stirred with the microwave synthesizer (Biotage Initiator) at 150 C. for 30 min. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.0029 g, y. 8%).
(544) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.25 (br. s, 1H), 8.04-8.29 (m, 2H), 7.75 (s, 1H), 7.68 (d, J=7.78 Hz, 1H), 7.38 (d, J=8.28 Hz, 1H), 7.03 (d, J=2.51 Hz, 1H), 6.93 (d, J=8.78 Hz, 1H), 6.70-6.83 (m, 2H), 6.55 (br. s, 1H), 4.15 (t, J=5.65 Hz, 2H), 4.06 (d, J=6.78 Hz, 2H), 2.70 (t, J=5.80 Hz, 2H), 2.28 (s, 6H), 2.22 (s, 3H), 1.15-1.32 (m, 1H), 0.49-0.62 (m, 2H), 0.32-0.39 (m, 2H); LCMS (m/z): 503.2 [M+H].sup.+.
Example 153
Cyclopropylmethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[4-(2-hydroxyethoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(545) ##STR00163##
(546) A solution of the compound (0.032 g, 0.070 mmol) of Example 74, cyclopropyl carbinol (0.10 mL, 1.3 mmol) and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0033 g, 0.0035 mmol) in N,N-dimethylacetamide (0.9 mL) was stirred with the microwave synthesizer (Biotage Initiator) at 150 C. for 30 min. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.0040 g, y. 11%).
(547) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.23 (br. s, 1H), 10.36 (br. s, 1H), 8.19 (d, J=3.51 Hz, 1H), 7.65-7.80 (m, 2H), 7.38 (d, J=8.53 Hz, 1H), 7.01 (d, J=2.26 Hz, 1H), 6.92 (dd, J=2.51, 8.53 Hz, 1H), 6.72-6.84 (m, 2H), 4.95 (t, J=5.40 Hz, 1H), 4.01-4.12 (m, 4H), 3.79 (q, J=5.02 Hz, 2H), 2.22 (s, 3H), 1.14-1.26 (m, 1H), 0.51-0.58 (m, 2H), 0.31-0.39 (m, 2H); LCMS (m/z): 476.1 [M+H].sup.+.
Example 154
Isopropyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[2-(dimethylamino)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate formate
(548) ##STR00164##
(549) A solution of ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[2-(dimethylamino)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.033 g, 0.070 mmol) which similarly prepared according to the procedure described in the Example 111, and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0033 g, 0.0035 mmol) in 2-propanol (0.5 mL) and N,N-dimethylacetamide (0.5 mL) was stirred with the microwave synthesizer (Biotage Initiator) at 150 C. for 30 min. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.0046 g, y. 11%).
(550) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.28 (br. s, 1H), 10.20 (br. s, 1H), 8.18 (dd, J=1.60, 4.40 Hz, 1H), 8.14 (s, 1H), 7.78 (s, 1H), 7.67 (d, J=8.03 Hz, 1H), 7.42 (d, J=8.53 Hz, 1H), 7.04 (d, J=2.51 Hz, 1H), 6.94 (dd, J=2.76, 8.78 Hz, 1H), 6.72-6.81 (m, 2H), 5.10-5.17 (m, 1H), 4.16 (t, J=5.65 Hz, 2H), 2.75 (t, J=5.52 Hz, 2H), 2.31 (s, 6H), 2.23 (s, 3H), 1.31 (d, J=6.27 Hz, 6H); LCMS (m/z): 491.2 [M+H].sup.+.
Example 155
n-Butyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[2-(dimethylamino)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3carboxylate formate
(551) ##STR00165##
(552) A solution of ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[2-(dimethylamino)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.033 g, 0.070 mmol) which similarly prepared according to the procedure described in the Example 111, and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0033 g, 0.0035 mmol) in n-butanol (0.5 mL) and N,N-dimethylacetamide (0.5 mL) was stirred with the microwave synthesizer (Biotage Initiator) at 150 C. for 30 min. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.011 g, y. 31%).
(553) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.28 (br. s, 1H), 10.32 (br. s, 1H), 8.18 (dd, J=1.38, 4.64 Hz, 1H), 8.15 (s, 1H), 7.76 (s, 1H), 7.67 (d, J=7.78 Hz, 1H), 7.41 (d, J=8.78 Hz, 1H), 7.04 (d, J=2.51 Hz, 1H), 6.94 (dd, J=2.76, 8.78 Hz, 1H), 6.81 (s, 1H), 6.75 (dd, J=4.77, 8.03 Hz, 1H), 4.22 (t, J=6.78 Hz, 2H), 4.16 (t, J=5.65 Hz, 2H), 2.74 (t, J=5.65 Hz, 2H), 2.30 (s, 6H), 2.22 (s, 3H), 1.60-1.72 (m, 2H), 1.34-1.51 (m, 2H), 0.94 (t, J=7.40 Hz, 3H); LCMS (m/z): 505.2 [M+H].sup.+.
Example 156
n-Butyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[4-(2-hydroxyethoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(554) ##STR00166##
(555) A solution of the compound (0.032 g, 0.070 mmol) of Example 74, and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0033 g, 0.0035 mmol) in n-butanol (0.5 mL) and N,N-dimethylacetamide (0.5 mL) was stirred with the microwave synthesizer (Biotage Initiator) at 150 C. for 30 min. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.015 g, y. 44%).
(556) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.27 (br. s, 1H), 10.27 (s, 1H), 8.19 (dd, J=1.13, 4.64 Hz, 1H), 7.74 (d, J=2.26 Hz, 1H), 7.69 (d, J=7.78 Hz, 1H), 7.42 (d, J=8.78 Hz, 1H), 7.03 (d, J=2.76 Hz, 1H), 6.94 (dd, J=2.64, 8.66 Hz, 1H), 6.74-6.85 (m, 2H), 4.88-5.05 (m, 1H), 4.22 (t, J=6.65 Hz, 2H), 4.09 (t, J=4.89 Hz, 2H), 3.75-3.85 (m, 2H), 2.23 (s, 3H), 1.59-1.73 (m, 2H), 1.36-1.49 (m, 2H), 0.94 (t, J=7.40 Hz, 3H); LCMS (m/z): 478.2 [M+H].sup.+.
Example 157
Isopropyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[4-(2-hydroxyethoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(557) ##STR00167##
(558) A solution of the compound (0.032 g, 0.070 mmol) of Example 74, and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0033 g, 0.0035 mmol) in 2-propanol (0.5 mL) and N,N-dimethylacetamide (0.5 mL) was stirred with the microwave synthesizer (Biotage Initiator) at 150 C. for 30 min. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.010 g, y. 28%).
(559) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.27 (br. s, 1H), 10.22 (s, 1H), 8.19 (dd, J=1.26, 4.77 Hz, 1H), 7.76 (d, J=2.51 Hz, 1H), 7.69 (d, J=7.78 Hz, 1H), 7.42 (d, J=8.53 Hz, 1H), 7.03 (d, J=2.51 Hz, 1H), 6.94 (dd, J=2.76, 8.78 Hz, 1H), 6.73-6.84 (m, 2H), 5.08-5.18 (m, 1H), 4.95 (t, J=5.40 Hz, 1H), 4.09 (t, J=4.89 Hz, 2H), 3.80 (q, J=5.27 Hz, 2H), 2.23 (s, 3H), 1.31 (d, J=6.27 Hz, 6H); LCMS (m/z): 464.1 [M+H].sup.+.
Example 158
Isopropyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(cyclopropylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(560) ##STR00168##
(561) A solution of isopropyl 2-isopropoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.44 mmol) which similarly prepared according to the procedure described in the Example 74, Third step using diisopropyl malonate and chloroacetyl chloride, and cyclopropylamine (0.034 mL, 0.48 mmol) in 2-propanol (2.0 mL) was stirred at ambient temperature for 14 h. To this reaction mixture, 7-azaindole-3-carboxaldehyde (0.065 g, 0.44 mmol) and piperidine (0.0044 mL, 0.044 mmol) were added then the mixture was refluxed for further 12 days. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0020 g, y. 1%).
(562) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.33 (br. s, 1H), 8.81 (br. s, 1H), 8.56 (d, J=7.28 Hz, 1H), 8.31 (d, J=3.51 Hz, 1H), 8.06 (d, J=2.26 Hz, 1H), 7.21 (dd, J=4.64, 7.91 Hz, 1H), 6.88 (s, 1H), 4.99-5.10 (m, 1H), 3.09-3.18 (m, 1H), 1.26 (d, J=6.27 Hz, 6H), 0.89-0.97 (m, 4H); LCMS (m/z): 354.1 [M+H].sup.+.
Example 159
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(cyclohexylmethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(563) ##STR00169##
(564) A solution of ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.51 mmol) which afforded in the Example 74, Third step and aminomethylcyclohexane (0.072 mL, 0.55 mmol) in ethanol (2.0 mL) was stirred at ambient temperature for 1.5 h. To this reaction mixture, 7-azaindole-3-carboxaldehyde (0.073 g, 0.50 mmol) and L-proline (0.012 mg, 0.10 mmol) were added then the mixture was refluxed for further 5 days. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.024 g, y. 12%).
(565) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.35 (br. s, 1H), 8.98 (t, J=6.27 Hz, 1H), 8.42 (d, J=7.78 Hz, 1H), 8.32 (dd, J=1.38, 4.64 Hz, 1H), 7.99 (d, J=2.51 Hz, 1H), 7.19 (dd, J=4.64, 7.91 Hz, 1H), 6.88 (s, 1H), 4.21 (q, J=7.03 Hz, 2H), 3.48 (t, J=6.40 Hz, 2H), 1.65-1.81 (m, 5H), 1.62 (d, J=9.29 Hz, 1H), 1.09-1.30 (m, 6H), 0.95-1.06 (m, 2H); LCMS (m/z): 396.2 [M+H].sup.+.
Example 160
2-Hydroxyethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[N-methyl-N-(2-thienylmethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(566) ##STR00170##
(567) A solution of the compound (0.050 g, 0.12 mmol) of Example 108, ethylene glycol (0.20 mL, 3.6 mmol), 4-dimethylaminopyridine (0.0030 g, 0.024 mmol) and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0058 g, 0.0061 mmol) in N,N-dimethylacetamide (0.5 mL) was stirred with the microwave synthesizer (Biotage Initiator) at 150 C. for 30 min. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.0061 g, y. 10%).
(568) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.34 (br. s, 1H), 11.7 (br. s, 1H), 8.35-8.44 (m, 1H), 8.30 (dd, J=1.38, 4.64 Hz, 1H), 8.04 (s, 1H), 7.53 (dd, J=1.13, 5.14 Hz, 1H), 7.21 (d, J=3.01 Hz, 1H), 7.17 (dd, J=4.64, 7.91 Hz, 1H), 7.04 (dd, J=3.51, 5.02 Hz, 1H), 6.94 (s, 1H), 5.20 (s, 2H), 4.17 (t, J=5.14 Hz, 2H), 3.62 (q, J=5.52 Hz, 2H), 3.23-3.37 (m, 3H); LCMS (m/z): 426.1 [M+H].sup.+.
Example 161
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-methyl-4-(2-pyrimidinylmethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(569) ##STR00171##
First Step
(570) A solution of 4-nitro-m-cresol (0.25 g, 1.6 mmol), 2-(chloromethyl)pyrimidine hydrochloride (0.40 g, 2.4 mmol) and potassium carbonate (0.50 g, 4.0 mmol) in N,N-dimethylformamide (6.0 mL) was stirred at 70 C. for 18 h. Cooled to ambient temperature, the reaction mixture was poured into ice water, extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to afford 2-[(3-methyl-4-nitrophenoxy)methyl]pyrimidine as crude material (0.32 g, y. 81%) as solid.
(571) .sup.1H NMR (DMSO-d.sub.6) (ppm) 8.84 (d, J=4.92 Hz, 2H), 8.03 (d, J=9.08 Hz, 1H), 7.48 (t, J=4.90 Hz, 1H), 7.10 (d, J=2.68 Hz, 1H), 7.00 (dd, J=2.80, 9.12 Hz, 1H), 5.43 (s, 2H), 2.53 (s, 3H); LCMS (m/z): 246.4 [M+H].sup.+.
(572) Second Step
(573) To a solution of 2-[(3-methyl-4-nitrophenoxy)methyl]pyrimidine (0.18 g, 0.7 mmol) in ethanol (4.0 mL) and water (1.0 mL), iron (0.40 g, 7.2 mmol) and ammonium chloride (0.020 g, 0.37 mmol) were added. The mixture was refluxed for 1.5 h. Cooled to ambient temperature, the reaction mixture was filtered over Celite to remove unneeded materials and the filtrate was concentrated to afford 2-methyl-4-(2-pyrimidinylmethoxy)aniline (0.15 g, crude material) as solid.
(574) .sup.1H NMR (DMSO-d.sub.6) (ppm) 8.82 (d, J=4.88 Hz, 2H), 7.45 (t, J=4.90 Hz, 1H), 6.62 (d, J=2.64 Hz, 1H), 6.55 (dd, J=2.74, 8.60 Hz, 1H), 6.50 (d, J=8.52 Hz, 1H), 5.08 (s, 2H), 4.40 (br. s, 2H), 2.01 (s, 3H); LCMS (m/z): 216.0 [M+H].sup.+.
(575) Third Step
(576) A solution of ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.14 g, 0.60 mmol) which afforded in the Example 74, Third step and 2-methyl-4-(2-pyrimidinylmethoxy)aniline (0.13 g, 0.6 mmol) in ethanol (5.0 mL) was stirred at 60 C. for 30 h. The solvent was removed under reduced pressure, then the residue was purified by chromatography on silica gel(hexane/ethyl acetate) to afford ethyl 2-{[2-methyl-4-(2-pyrimidinylmethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.035 g, y. 15%).
(577) .sup.1H NMR (DMSO-d.sub.6) (ppm) 9.98 (br. s, 1H), 8.84 (d, J=4.88 Hz, 2H), 7.47 (t, J=4.90 Hz, 1H), 7.25 (d, J=8.76 Hz, 1H), 6.96 (d, J=2.72 Hz, 1H), 6.84 (dd, J=2.82, 8.70 Hz, 1H), 5.28 (s, 2H), 4.57 (s, 2H), 4.21 (q, J=7.07 Hz, 2H), 2.19 (s, 3H), 1.24 (t, J=7.04 Hz, 3H); LCMS (m/z): 370.0 [M+H].sup.+.
(578) Fourth Step
(579) To a solution of ethyl 2-{[2-methyl-4-(2-pyrimidinylmethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.035 g, 0.10 mmol) and 7-azaindole-3-carboxaldehyde (0.014 g, 0.10 mmol) in ethanol (5.0 mL), piperidine (0.050 mL, 0.50 mmol) was added at ambient temperature then the mixture was refluxed for 3 days. Cooled to ambient temperature, the solvent was removed under reduced pressure. The residue was suspended in ethanol, then the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (9.0 mg, y. 19%).
(580) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.28 (br. s, 1H), 10.27 (br. s, 1H), 8.88 (d, J=4.40 Hz, 2H), 8.19 (d, J=3.42 Hz, 1H), 7.77 (br. s, 1H), 7.68 (d, J=7.34 Hz, 1H), 7.50 (t, J=4.60 Hz, 1H), 7.42 (d, J=8.80 Hz, 1H), 7.10 (br. s, 1H), 6.98 (d, J=8.31 Hz, 1H), 6.74-6.86 (m, 2H), 5.39 (s, 2H), 4.19-4.32 (m, J=6.80 Hz, 2H), 2.22 (br. s, 3H), 1.18-1.47 (m, 3H); LCMS (m/z): 498.4 [M+H].sup.+.
Example 162
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({2-methyl-4-[2-(1-pyrrolidinyl)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate acetate
(581) ##STR00172##
(582) The mixture, which similarly prepared according to the procedure described in the Example 161, was purified by preparative HPLC (aqueous ammonium acetate/acetonitrile were used as eluents) to afford the titled compound (solid).
(583) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.25 (br. s, 1H), 8.16 (d, J=3.91 Hz, 1H), 7.74 (s, 1H), 7.68 (d, J=7.82 Hz, 1H), 7.35 (d, J=7.82 Hz, 1H), 7.02 (br. s, 1H), 6.86-6.96 (m, 2H), 6.70-6.80 (m, 1H), 4.20-4.35 (m, 2H), 4.16 (t, J=5.62 Hz, 2H), 2.87 (t, J=5.62 Hz, 2H), 2.50-2.72 (m, 4H), 2.21 (s, 3H), 1.90 (s, 3H), 1.68-1.78 (m, 4H), 1.28 (t, J=7.09 Hz, 3H); LCMS (m/z): 503.2 [M+H].sup.+.
Example 163
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({2-methyl-4-[2-(methylsulfonyl)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(584) ##STR00173##
(585) To a mixed solution of the compound (0.070 g, 0.14 mmol) of Example 128 and saturated sodium bicarbonate solution (0.80 mL) in methanol (0.4 mL) and dichloromethane (1.6 mL) that cooled with ice bath, 3-chloroperoxybenzoic acid (0.050 g, 0.28 mmol) was added at 0 C. The mixture was stirred for 1 h. The reaction mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC to afford the titled compound as solid (0.010 g, y. 13%).
(586) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.18 (br. s, 1H), 10.4 (br. s, 1H), 8.19 (d, J=4.40 Hz, 1H), 7.74 (br. s, 1H), 7.64 (d, J=7.34 Hz, 1H), 7.36 (d, J=8.31 Hz, 1H), 7.06 (br. s, 1H), 6.97 (d, J=8.31 Hz, 1H), 6.66-6.80 (m, 2H), 4.44 (t, J=5.38 Hz, 2H), 4.18-4.30 (m, J=6.80 Hz, 2H), 3.66-3.76 (m, 2H), 3.15 (s, 3H), 2.21 (s, 3H), 1.28 (t, J=7.09 Hz, 3H); LCMS (m/z): 512.2 [M+H].sup.+.
Example 164
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-4-oxo-4,5-dihydrofuran-3-carboxylate formate
(587) ##STR00174##
(588) To a solution of 5,6,7,8-tetrahydro-1,6-naphthyridine dihydrochloride (0.049 g, 0.24 mmol) in ethanol (1.0 mL), 4M sodium hydroxide solution (0.13 mL, 0.52 mmol) was added at ambient temperature and the mixture was stirred for 5 min. To this reaction mixture, ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.049 g, 0.24 mmol), which afforded in the Example 74, Third step was added and stirred for 1 h. The solvent was removed under reduced pressure, then chloroform and water were added to the residue and two phases were separated. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. To this residue, 7-azaindole-3-carboxaldehyde (0.027 g, 0.18 mmol), 5,6,7,8-tetrahydro-1,6-naphthyridine (0.0063 g, 0.047 mmol) and ethanol (1.0 mL) were added and the mixture was refluxed for further 14 days. The reaction mixture was filtered and washed with hot ethanol. The solid was purified by preparative HPLC to afford the titled compound as solid (0.0058 g, y. 5%).
(589) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.38 (br. s, 1H), 8.46 (d, J=3.51 Hz, 1H), 8.42 (d, J=7.78 Hz, 1H), 8.33 (dd, J=1.13, 4.64 Hz, 1H), 8.10 (s, 1H), 7.71 (d, J=7.78 Hz, 1H), 7.31 (dd, J=4.77, 7.78 Hz, 1H), 7.22 (dd, J=4.64, 7.91 Hz, 1H), 6.91 (s, 1H), 5.01-5.07 (m, 2H), 4.22 (q, J=7.03 Hz, 2H), 4.07-4.13 (m, 2H), 3.19 (t, J=5.90 Hz, 2H), 1.27 (t, J=7.03 Hz, 3H); LCMS (m/z): 417.1 [M+H].sup.+.
Example 165
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(5,6-dihydro-1,7-naphthyridin-7(8H)-yl)-4-oxo-4,5-dihydrofuran-3-carboxylate formate
(590) ##STR00175##
(591) To a solution of 5,6,7,8-tetrahydro-1,7-naphthyridine dihydrochloride (0.050 g, 0.24 mmol) in ethanol (1.3 mL), 4M sodium hydroxide solution (0.13 mL, 0.52 mmol) was added at ambient temperature and the mixture was stirred for 5 min. To this reaction mixture, ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.049 g, 0.24 mmol), which afforded in the Example 74, Third step was added and stirred for 1 h. The solvent was removed under reduced pressure, then chloroform and water were added to the residue and two phases were separated. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. To this residue, 7-azaindole-3-carboxaldehyde (0.023 g, 0.15 mmol), 5,6,7,8-tetrahydro-1,7-naphthyridine dihydrochloride (0.0056 g, 0.042 mmol) and ethanol (1.0 mL) were added and refluxed for further 14 days. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0033 g, y. 3%).
(592) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.39 (br. s, 1H), 8.39-8.49 (m, 2H), 8.33 (d, J=4.52 Hz, 1H), 8.05 (d, J=2.26 Hz, 1H), 7.70 (d, J=7.03 Hz, 1H), 7.31 (dd, J=4.77, 7.78 Hz, 1H), 7.21 (dd, J=4.77, 7.78 Hz, 1H), 6.92 (s, 1H), 5.00 (br. s, 2H), 4.22 (q, J=7.03 Hz, 2H), 4.02-4.10 (m, 2H), 3.12 (t, J=5.52 Hz, 2H), 1.27 (t, J=7.03 Hz, 3H); LCMS (m/z): 417.1 [M+H].sup.+.
Example 166
2-[(tert-Butoxycarbonyl)oxy]ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-azepinyl-4-oxo-4,5-dihydrofuran-3-carboxylate
(593) ##STR00176##
First Step
(594) To a solution of triethylamine (0.65 mL, 4.7 mmol) in ethylene glycol (1.8 mL, 0.031 mol) that cooled with ice bath, ethyl malonyl chloride (0.40 mL, 3.1 mmol) was added dropwise and the mixture was stirred for 2.5 h. The reaction was terminated by addition of aqueous 10% citric acid solution, the reaction mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel(chloroform/methanol) to afford ethyl (2-hydroxyethyl)malonate as oil (0.37 g, y. 66%).
(595) .sup.1H NMR (CDCl.sub.3) (ppm) 4.28-4.35 (m, 2H), 4.22 (q, J=7.19 Hz, 2H), 3.80-3.88 (m, 2H), 3.43 (s, 2H), 2.18 (br. s, 1H), 1.29 (t, J=7.15 Hz, 3H)
(596) Second Step
(597) To a solution of ethyl 2-hydroxyethyl malonate (0.36 mg, 2.1 mmol) and di-tert-butyl dicarbonate (0.57 mL, 2.5 mmol) in tetrahydrofuran (2.0 mL) that cooled with ice bath, triethylamine (0.43 mL, 3.1 mmol) was added dropwise and 4-dimethylaminopyridine (0.019 mg, 0.16 mmol) was added then the mixture was stirred at ambient temperature for 2 weeks. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel(hexane/ethyl acetate) to afford 2-[(tert-butoxycarbonyl)oxy]ethyl ethyl malonate as oil (0.37 g, y. 43%).
(598) .sup.1H NMR (CDCl.sub.3) (ppm) 4.33-4.39 (m, 2H), 4.26-4.31 (m, 2H), 4.21 (q, J=7.03 Hz, 2H), 3.41 (s, 2H), 1.49 (s, 9H), 1.28 (t, J=7.15 Hz, 3H)
(599) Third Step
(600) A solution of 2-[(tert-butoxycarbonyl)oxy]ethyl ethyl malonate (0.36 g, 1.3 mmol) in anhydrous tetrahydrofuran (1.0 mL) was added dropwise to a solution of sodium hydride (60% w/w in oil, 0.10 g, 2.6 mmol) in anhydrous tetrahydrofuran (4.0 mL) that cooled with ice bath. The mixture was refluxed for 14 min. The reaction mixture was cooled with ice bath, chloroacetyl chloride (0.11 mL, 1.3 mmol) was added dropwise to the reaction mixture and the mixture was stirred for 1 h then stirred at 45 C. for further 1 h. The reaction mixture was diluted with water, extracted with chloroform for 2 times. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel(ethyl acetate/methanol) then concentrated. To this residue (ca. 0.11 g) in ethanol (3.0 mL), hexamethyleneimine (0.046 mL, 0.41 mmol) was added dropwise and the mixture was stirred at ambient temperature for 30 min. Then to the reaction mixture, 7-azaindole-3-carboxaldehyde (0.043 g, 0.30 mmol) was added at ambient temperature then the mixture was refluxed for further 4 days. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.020 g, y. 3%).
(601) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.31 (br. s, 1H), 8.39 (d, J=8.03 Hz, 1H), 8.31 (dd, J=1.38, 4.64 Hz, 1H), 7.95 (d, J=2.51 Hz, 1H), 7.20 (dd, J=4.64, 7.91 Hz, 1H), 6.85 (s, 1H), 4.30-4.36 (m, 2H), 4.21-4.27 (m, 2H), 3.70-3.90 (m, 4H), 1.80-1.90 (m, 4H), 1.53-1.62 (m, 4H), 1.42 (s, 9H); LCMS (m/z): 498.2 [M+H].sup.+.
Example 167
2-Methoxyethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[N-methyl-N-(2-thienylmethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(602) ##STR00177##
(603) A solution of the compound (0.050 g, 0.12 mmol) of Example 108, 2-methoxyethanol (0.20 mL, 2.6 mmol), 4-dimethylaminopyridine (0.0030 g, 0.024 mmol) and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0058 g, 0.0061 mmol) in N,N-dimethylacetamide (0.5 mL) was stirred with the microwave synthesizer (Biotage Initiator) at 150 C. for 3.5 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0029 g, y. 5%).
(604) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.34 (br. s, 1H), 8.38 (d, J=8.03 Hz, 1H), 8.30 (dd, J=1.38, 4.64 Hz, 1H), 8.03 (d, J=2.26 Hz, 1H), 7.53 (dd, J=1.00, 5.02 Hz, 1H), 7.13-7.22 (m, 2H), 7.04 (dd, J=3.51, 5.02 Hz, 1H), 6.93 (s, 1H), 5.20 (s, 2H), 4.23-4.28 (m, 2H), 3.55-3.60 (m, 2H), 3.22-3.32 (m, 6H); LCMS (m/z): 440.1 [M+H].sup.+.
Example 168
n-Butyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[N-methyl-N-(2-thienylmethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(605) ##STR00178##
(606) A solution of the compound (0.050 g, 0.12 mmol) of Example 108, 1-butanol (0.50 mL, 5.5 mmol), 4-dimethylaminopyridine (0.0030 g, 0.024 mmol) and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0058 g, 0.0061 mmol) in N,N-dimethylacetamide (0.5 mL) was stirred with the microwave synthesizer (Biotage Initiator) at 150 C. for 1.5 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0044 g, y. 6%).
(607) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.33 (br. s, 1H), 8.37 (d, J=7.78 Hz, 1H), 8.30 (dd, J=1.25, 4.52 Hz, 1H), 8.01-8.04 (m, 1H), 7.53 (dd, J=1.25, 5.02 Hz, 1H), 7.14-7.22 (m, 2H), 7.04 (dd, J=3.51, 5.02 Hz, 1H), 6.91 (s, 1H), 5.21 (s, 2H), 4.13 (t, J=6.53 Hz, 2H), 3.24-3.31 (m, 3H), 1.55-1.65 (m, 2H), 1.36-1.47 (m, 2H), 0.90 (t, J=7.40 Hz, 3H); LCMS (m/z): 438.1 [M+H].sup.+.
Example 169
2-Hydroxyethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-azepinyl-4-oxo-4,5-dihydrofuran-3-carboxylate hydrochloride
(608) ##STR00179##
(609) To a mixed solution of the compound (0.018 g, 0.037 mmol) of Example 166 in dioxane (0.2 mL) and chloroform (1.0 mL) that cooled with ice bath, 4M hydrochloric acid in dioxane (0.25 mL, 1.0 mmol) was added dropwise. The mixture was stirred at ambient temperature for 24 h. The precipitate was collected by filtration, washed with chloroform and hexane then dried to afford the titled compound as solid (6.3 mg, y. 37%).
(610) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.39 (br. s, 1H), 8.44 (d, J=7.78 Hz, 1H), 8.33 (dd, J=1.38, 4.64 Hz, 1H), 7.96 (s, 1H), 7.23 (dd, J=4.77, 8.03 Hz, 1H), 6.89 (s, 1H), 4.16 (t, J=5.27 Hz, 2H), 3.67-3.95 (m, 6H), 3.62 (t, J=5.14 Hz, 2H), 1.75-1.93 (m, 4H), 1.50-1.65 (m, 4H); LCMS (m/z): 398.1 [M+H].sup.+.
Example 170
2-(Dimethylamino)ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[N-methyl-N-(2-thienylmethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(611) ##STR00180##
(612) A solution of the compound (0.10 g, 0.25 mmol) of Example 108, 2-(dimethylamino)ethanol (0.40 mL, 4.0 mmol), 4-dimethylaminopyridine (0.0060 g, 0.049 mmol) and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.012 g, 0.012 mmol) in N,N-dimethylacetamide (0.5 mL) was stirred with the microwave synthesizer (Biotage Initiator) at 150 C. for 30 min. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0023 g, y. 2%).
(613) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.33 (br. s, 1H), 8.38 (d, J=8.03 Hz, 1H), 8.28-8.32 (m, 1H), 8.03 (s, 1H), 7.53 (dd, J=1.00, 5.02 Hz, 1H), 7.14-7.22 (m, 2H), 7.04 (dd, J=3.51, 5.02 Hz, 1H), 6.92 (s, 1H), 5.20 (s, 2H), 4.21 (t, J=5.90 Hz, 2H), 3.51 (s, 3H), 3.25-3.29 (m, 2H), 2.18 (s, 6H); LCMS (m/z): 453.1 [M+H].sup.+.
Example 171
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({2-methyl-4-[2-(2-pyridinyl)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(614) ##STR00181##
First Step
(615) To a solution of 4-nitro-m-cresol (3.0 g, 0.020 mmol) and triphenylphosphine (7.7 g, 0.029 mmol) in tetrahydrofuran (50 mL) cooled with ice bath, diisopropyl azodicarboxylate (5.8 mL, 0.030 mmol) was added dropwise. The mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled with ice bath, and a solution of 2-pyridineethanol (2.6 mL, 0.024 mmol) in tetrahydrofuran (5.0 mL) was added dropwise to the reaction mixture then the mixture was stirred at ambient temperature for further 16 h. The solvent was removed under reduced pressure, then the residue was purified by chromatography on silica gel(hexane/ethyl acetate) to afford 2-methyl-4-[2-(2-pyridinyl)ethoxy]-1-nitrobenzene as solid (2.0 g, y. 40%).
(616) .sup.1H NMR (DMSO-d.sub.6) (ppm) 8.43-8.59 (m, 1H), 8.03 (d, J=9.08 Hz, 1H), 7.73 (t, J=7.62 Hz, 1H), 7.37 (d, J=7.80 Hz, 1H), 7.25 (t, J=6.12 Hz, 1H), 7.03 (s, 1H), 6.98 (d, J=9.20 Hz, 1H), 4.49 (t, J=6.46 Hz, 2H), 3.22 (t, J=6.54 Hz, 2H), 2.53 (s, 3H); LCMS (m/z): 259.0 [M+H].sup.+.
(617) Second Step
(618) Under a nitrogen atmosphere, 2-methyl-4-[2-(2-pyridinyl)ethoxy]-1-nitrobenzene (2.0 g, 7.7 mmol) was dissolved in tetrahydrofuran (40 mL) and 10% palladium on carbon (0.20 g) was added at ambient temperature. The reaction mixture was agitated under a hydrogen atmosphere at ambient temperature for 4 h. Palladium on carbon was removed by filtration with Celite and the solvent was removed under reduced pressure to afford 2-methyl-4-[2-(2-pyridinyl)ethoxy]aniline as solid (1.4 g, y. 80%).
(619) .sup.1H NMR (DMSO-d.sub.6) (ppm) 8.49 (d, J=4.36 Hz, 1H), 7.71 (t, J=7.64 Hz, 1H), 7.33 (d, J=7.76 Hz, 1H), 7.22 (t, J=6.10 Hz, 1H), 6.45-6.58 (m, 3H), 4.35 (br. s, 2H), 4.18 (t, J=6.66 Hz, 2H), 3.10 (t, J=6.62 Hz, 2H), 2.00 (s, 3H); LCMS (m/z): 229.4 [M+H].sup.+.
(620) Third Step
(621) A solution of ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.35 g, 1.8 mmol) which afforded in the Example 74, Third step and 2-methyl-4-[2-(2-pyridinyl)ethoxy]aniline (0.40 g, 1.8 mmol) in ethanol (5.0 mL) was stirred at ambient temperature for 1.5 days. The solvent was removed under reduced pressure, then the residue was purified by preparative HPLC to afford ethyl 2-({2-methyl-4-[2-(2-pyridinyl)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.15 g, y. 22%).
(622) .sup.1H NMR (DMSO-d.sub.6) (ppm) 9.98 (br. s, 1H), 8.51 (d, J=4.52 Hz, 1H), 7.70-7.78 (m, 1H), 7.37 (d, J=7.92 Hz, 1H), 7.22-7.28 (m, 2H), 6.87-6.92 (m, 1H), 6.77-6.84 (m, 1H), 4.57 (s, 2H), 4.36 (t, J=6.62 Hz, 2H), 4.21 (q, J=7.06 Hz, 2H), 3.13-3.25 (m, 2H), 2.19 (s, 3H), 1.21 (s, 3H); LCMS (m/z): 383.2 [M+H].sup.+.
(623) Fourth Step
(624) To a stirred solution of ethyl 2-({2-methyl-4-[2-(2-pyridinyl)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.15 g, 0.39 mmol) and 7-azaindole-3-carboxaldehyde (0.057 g, 0.39 mmol) in ethanol (5.0 mL), L-proline (5.0 mg, 0.043 mmol) was added at ambient temperature. The mixture was refluxed for 3 days. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to afford the titled compound as solid (0.015 g, y. 8%).
(625) .sup.1H NMR (DMSO-d.sub.6) (ppm) 8.57 (d, J=3.91 Hz, 1H), 8.11 (d, J=3.91 Hz, 1H), 7.78 (t, J=7.58 Hz, 1H), 7.65-7.73 (m, 2H), 7.44 (d, J=7.82 Hz, 1H), 7.24-7.33 (m, 2H), 6.97 (br. s, 1H), 6.88 (d, J=8.31 Hz, 1H), 6.63-6.72 (m, 2H), 4.45 (t, J=6.36 Hz, 2H), 4.21 (d, J=6.85 Hz, 2H), 3.23-3.27 (m, 2H), 2.17 (s, 3H), 1.27 (t, J=6.85 Hz, 3H); LCMS (m/z): 511.2 [M+H].sup.+.
Example 172
2-Hydroxyethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-chlorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(626) ##STR00182##
(627) A solution of the compound (0.10 g, 0.24 mmol) of Example 15, ethylene glycol (0.14 mL, 2.5 mmol) and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.012 g, 0.012 mmol) in N,N-dimethylacetamide (2.0 mL) was stirred with the microwave synthesizer (Biotage Initiator) at 130 C. for 1 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.030 g, y. 29%).
(628) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.11 (br. s, 1H), 8.18 (d, J=4.24 Hz, 1H), 7.82 (d, J=7.34 Hz, 1H), 7.59-7.66 (m, 2H), 7.29-7.55 (m, 3H), 6.79 (dd, J=4.65, 7.58 Hz, 1H), 6.62 (br. s, 1H), 4.12-4.22 (m, 2H), 3.65 (t, J=4.89 Hz, 2H); LCMS (m/z): 426 [M+H].sup.+.
Example 173
2-Methoxyethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-chlorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(629) ##STR00183##
(630) The titled compound (solid) was similarly prepared according to the procedure described in the Example 172.
(631) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.12 (br. s, 1H), 8.18 (d, J=4.04 Hz, 1H), 7.82 (d, J=7.34 Hz, 1H), 7.58-7.67 (m, 2H), 7.32-7.54 (m, 3H), 6.79 (dd, J=4.65, 7.58 Hz, 1H), 6.63 (br. s, 1H), 4.22-4.32 (m, 2H), 3.56-3.66 (m, 2H), 3.30 (s, 3H); LCMS (m/z): 440.2 [M+H].sup.+.
Example 174
3-Hydroxypropyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-chlorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(632) ##STR00184##
(633) The titled compound (solid) was similarly prepared according to the procedure described in the Example 172.
(634) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.23 (br. s, 1H), 10.70 (br. s, 1H), 8.20 (d, J=3.42 Hz, 1H), 7.62-7.85 (m, 4H), 7.43-7.58 (m, 2H), 6.73-6.83 (m, 2H), 4.72 (br. s, 1H), 4.20-4.30 (m, 2H), 3.58 (t, J=5.38 Hz, 2H), 1.75-1.89 (m, 2H); LCMS (m/z): 440.2 [M+H].sup.+.
Example 175
(1R,2S)-2-Hydroxycyclopentyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(635) ##STR00185##
(636) A solution of the compound (0.10 g, 0.25 mmol) of Example 21, (1R,2S)-1,2-cyclopentanediol (0.26 g, 2.5 mmol) and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.012 g, 0.012 mmol) in N,N-dimethylacetamide (1.5 mL) was stirred with the microwave synthesizer (Biotage Initiator) at 130 C. for 2 h. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.025 g, y. 20%).
(637) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.26 (br. s, 1H), 10.60 (br. s, 1H), 8.26 (d, J=4.40 Hz, 1H), 8.05 (d, J=7.82 Hz, 1H), 7.77 (br. s, 1H), 7.52-7.61 (m, 2H), 7.36 (t, J=8.31 Hz, 2H), 6.94 (dd, J=4.65, 7.58 Hz, 1H), 6.87 (br. s, 1H), 5.37 (br. s, 1H), 4.88-4.98 (m, 1H), 4.09-4.18 (m, 1H), 1.94-2.06 (m, 1H), 1.70-1.90 (m, 3H), 1.43-1.69 (m, 2H); LCMS (m/z): 450.2 [M+H].sup.+.
Example 176
4-Hydroxycyclohexyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(638) ##STR00186##
(639) The titled compound (solid) was similarly prepared according to the procedure described in the Example 175.
(640) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.26 (br. s, 1H), 10.65 (br. s, 1H), 8.25 (d, J=2.93 Hz, 1H), 7.95 (d, J=7.34 Hz, 1H), 7.75 (br. s, 1H), 7.55-7.65 (br. s, 2H), 7.36 (t, J=8.07 Hz, 2H), 6.87-6.94 (m, 1H), 6.82 (br. s, 1H), 4.94 (br. s, 1H), 4.53 (br. s, 1H), 3.56-3.68 (m, 1H), 1.79-1.95 (m, 2H), 1.46-1.77 (m, 6H); LCMS (m/z): 463.8 [M+H].sup.+.
Example 177
3-Hydroxy-2,2-dimethylpropyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(641) ##STR00187##
(642) A solution of the compound (0.10 g, 0.25 mmol) of Example 21, 2,2-dimethyl-1,3-propanediol (0.40 g, 3.8 mmol) and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.018 g, 0.019 mmol) in N,N-dimethylacetamide (1.5 mL) was stirred with the microwave synthesizer (Biotage Initiator) at 130 C. for 24 h. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.020 g, y. 17%).
(643) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.27 (br. s, 1H), 10.68 (br. s, 1H), 8.25 (d, J=3.91 Hz, 1H), 7.97 (d, J=7.82 Hz, 1H), 7.74 (br. s, 1H), 7.57-7.65 (m, 2H), 7.37 (t, J=8.31 Hz, 2H), 6.83-6.97 (m, 2H), 4.88 (br. s, 1H), 3.93-4.02 (m, 2H), 3.26-3.36 (m, 2H), 0.93 (s, 6H); LCMS (m/z): 452.4 [M+H].sup.+.
Example 178
2-(1-Pyrrolidinyl)ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate formate
(644) ##STR00188##
(645) The titled compound (solid) was similarly prepared according to the procedure described in the Example 177.
(646) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.11 (br. s, 1H), 8.21 (d, J=4.12 Hz, 1H), 8.17 (s, 1H), 7.96 (d, J=7.83 Hz, 1H), 7.65 (s, 1H), 7.34-7.43 (m, 2H), 7.24-7.33 (m, 2H), 6.87 (dd, J=4.89, 7.34 Hz, 1H), 6.65 (s, 1H), 4.25-4.38 (m, 2H), 3.03-3.12 (m, 2H), 2.87-3.00 (m, 4H), 1.65-1.80 (m, 4H); LCMS (m/z): 463.2 [M+H].sup.+.
Example 179
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-methyl-1-piperazinyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(647) ##STR00189##
(648) To a solution of ethyl 2-[(4-methyl-1-piperazinyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.080 g, 0.30 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.040 g, 0.30 mmol) in ethanol (2.0 mL), L-proline (0.020 g, 0.17 mmol) was added at ambient temperature. The mixture was refluxed for 1.5 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and hexane then dried to afford the titled compound as solid (0.017 g, y. 14%).
(649) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.36 (br. s, 1H), 9.95 (br. s, 1H), 8.96 (d, J=7.34 Hz, 1H), 8.35 (d, J=3.42 Hz, 1H), 8.11 (br. s, 1H), 7.23 (dd, J=4.65, 7.58 Hz, 1H), 6.85 (br. s, 1H), 4.21 (q, J=7.30 Hz, 2H), 3.06 (br. s, 3H), 2.43-2.70 (m, 6H), 2.24-2.35 (m, 2H), 1.26 (t, J=6.85 Hz, 3H); LCMS (m/z): 398.2 [M+H].sup.+.
Example 180
1-Methyl-4-piperidinyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate formate
(650) ##STR00190##
(651) A solution of the compound (0.10 g, 0.25 mmol) (of Example 21, 4-hydroxy-1-methylpiperidine (0.44 g, 3.8 mmol) and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.018 g, 0.019 mmol) in N,N-dimethylacetamide (1.0 mL) was stirred at 180 C. for 16 h then at 130 C. for further 16 h. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.016 g, y. 13%).
(652) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.15 (br. s, 1H), 8.23 (d, J=3.91 Hz, 1H), 8.18 (s, 1H), 7.96 (d, J=7.82 Hz, 1H), 7.69 (s, 1H), 7.42-7.49 (m, 2H), 7.25-7.36 (m, 2H), 6.89 (dd, J=4.89, 7.83 Hz, 1H), 6.68 (s, 1H), 4.83-4.93 (m, 1H), 2.77-2.87 (m, 2H), 2.35-2.45 (m, 2H), 2.30 (s, 3H), 1.85-1.95 (m, 2H), 1.68-1.80 (m, 2H); LCMS (m/z): 463.2 [M+H].sup.+.
Example 181
Isobutyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate formate
(653) ##STR00191##
(654) The titled compound (solid) was similarly prepared according to the procedure described in the Example 180.
(655) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.17 (br. s, 1H), 8.23 (d, J=3.91 Hz, 1H), 8.19 (s, 1H), 7.96 (d, J=7.82 Hz, 1H), 7.70 (s, 1H), 7.43-7.54 (m, 2H), 7.31 (t, J=8.07 Hz, 2H), 6.84-6.96 (m, 1H), 6.72 (br. s, 1H), 3.96 (d, J=5.87 Hz, 2H), 1.90-2.05 (m, 1H), 0.97 (d, J=6.36 Hz, 6H); LCMS (m/z): 422.2 [M+H].sup.+.
Example 182
2-(Dimethylamino)ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-chlorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate acetate
(656) ##STR00192##
(657) A solution of the compound (0.10 g, 0.24 mmol) of Example 15, 2-(dimethylamino)ethanol (0.40 mL, 4.0 mmol), 4-dimethylaminopyridine (0.010 g, 0.082 mmol) and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.018 g, 0.019 mmol) in N,N-dimethylacetamide (2.0 mL) was stirred at 130 C. for 24 h. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC (aqueous ammonium acetate/acetonitrile as eluents) to afford the titled compound as solid (0.012 g, y. 11%).
(658) .sup.1H NMR (DMSO-d.sub.6) (ppm) 11.92 (br. s, 1H), 8.15 (d, J=3.91 Hz, 1H), 7.86 (d, J=7.82 Hz, 1H), 7.48-7.55 (m, 2H), 7.30-7.37 (m, 1H), 7.15-7.23 (m, 2H), 6.73-6.79 (m, 1H), 6.39 (s, 1H), 4.30-4.39 (m, 2H), 3.12-3.22 (m, 2H), 2.73 (br. s, 6H), 1.91 (s, 3H); LCMS (m/z): 453.0 [M+H].sup.+.
Example 183
3-Hydroxycyclohexyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(659) ##STR00193##
(660) A solution of the compound (0.10 g, 0.25 mmol) of Example 21, 1,3-cyclohexanediol (0.44 g, 3.8 mmol) and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.018 g, 0.019 mmol) in N,N-dimethylacetamide (1.0 mL) was stirred at 130 C. for 1.5 days. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.010 g, y. 13%).
(661) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.25 (br. s, 1H), 8.24 (d, J=3.91 Hz, 1H), 7.92-8.00 (m, 1H), 7.74 (br. s, 1H), 7.55-7.65 (m, 2H), 7.31-7.42 (m, 2H), 6.90 (dd, J=4.89, 7.82 Hz, 1H), 6.78-6.86 (m, 1H), 5.19-5.28 (m, 1H), 4.92-5.02 (m, 1H), 4.55 (d, J=3.42 Hz, 1H), 1.15-2.08 (m, 8H); LCMS (m/z): 463.8 [M+H].sup.+.
Example 184
(1-Methyl-2-piperidinyl)methyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate formate
(662) ##STR00194##
(663) The titled compound (solid) was similarly prepared according to the procedure described in the Example 183.
(664) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.11 (br. s, 1H), 8.22 (d, J=4.40 Hz, 1H), 8.16 (s, 1H), 7.98 (d, J=7.82 Hz, 1H), 7.66 (s, 1H), 7.34-7.42 (m, 2H), 7.25-7.33 (m, 2H), 6.88 (dd, J=4.65, 7.58 Hz, 1H), 6.65 (s, 1H), 4.23-4.35 (m, 2H), 2.90-3.00 (m, 1H), 2.62-2.72 (m, 1H), 2.46-2.56 (m, 4H), 1.18-1.83 (m, 6H); LCMS (m/z): 477.4 [M+H].sup.+.
Example 185
2-(4-Methyl-1-piperazinyl)ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate formate
(665) ##STR00195##
(666) The titled compound (solid) was similarly prepared according to the procedure described in the Example 183.
(667) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.14 (br. s, 1H), 8.16-8.25 (m, 2H), 7.95 (d, J=6.85 Hz, 1H), 7.67 (br. s, 1H), 7.38-7.48 (m, 2H), 7.25-7.36 (m, 2H), 6.84-6.91 (m, 1H), 6.68 (br. s, 1H), 4.20-4.34 (m, 2H), 2.22-2.71 (m, 10H), 2.13 (br. s, 3H); LCMS (m/z): 492.4 [M+H].sup.+.
Example 186
2-(N,N-Dimethylamino)-2-methylpropyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate formate
(668) ##STR00196##
(669) The titled compound (solid) was similarly prepared according to the procedure described in the Example 183.
(670) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.01 (br. s, 1H), 8.15-8.29 (m, 2H), 7.98 (d, J=7.34 Hz, 1H), 7.60 (br. s, 1H), 7.05-7.33 (m, 4H), 6.83-6.93 (m, 1H), 6.47 (s, 1H), 4.20 (br. s, 2H), 2.55 (br. s, 6H), 1.22 (br. s, 6H); LCMS (m/z): 465.0 [M+H].sup.+.
Example 187
(1-Methyl-4-piperidinyl)methyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate formate
(671) ##STR00197##
(672) The titled compound (solid) was similarly prepared according to the procedure described in the Example 183.
(673) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.09 (br. s, 1H), 8.18-8.24 (m, 2H), 7.96 (d, J=7.82 Hz, 1H), 7.66 (s, 1H), 7.33-7.43 (m, 2H), 7.22-7.32 (m, 2H), 6.89 (dd, J=4.89, 7.83 Hz, 2H), 6.59 (s, 1H), 4.01 (d, J=6.36 Hz, 2H), 2.88-2.96 (m, 2H), 2.29 (s, 3H), 2.03-2.15 (m, 2H), 1.62-1.82 (m, 3H), 1.26-1.41 (m, 2H); LCMS (m/z): 477.3 [M+H].sup.+.
Example 188
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(4-morpholinopiperidin-1-yl)-4-oxo-4,5-dihydrofuran-3-carboxylate
(674) ##STR00198##
(675) To a stirred solution of ethyl 2-(4-morpholinopiperidin-1-yl)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.31 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.045 g, 0.31 mmol) in ethanol (10 mL), piperidine (0.020 mL, 0.20 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and hexane then dried to afford the titled compound (0.018 g, y. 13%) as solid.
(676) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.31 (br. s, 1H), 8.37 (d, J=7.34 Hz, 1H), 8.31 (d, J=3.42 Hz, 1H), 7.97 (br. s, 1H), 7.16-7.23 (m, 1H), 6.85 (s, 1H), 4.11-4.30 (m, 4H), 3.52-3.64 (m, 4H), 3.23-3.43 (m, 7H), 1.90-2.02 (m, 2H), 1.54-1.76 (m, 2H), 1.24 (t, J=6.60 Hz, 3H); LCMS (m/z): 453.2 [M+H].sup.+.
Example 189
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(3-carbamoylpiperidino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(677) ##STR00199##
(678) To a solution of ethyl 2-(3-carbamoylpiperidino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.15 g, 0.53 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.078 g, 0.53 mmol) in ethanol (10 mL), piperidine (0.020 mL, 0.20 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and hexane then dried to afford the titled compound as solid (0.018 g, y. 9%).
(679) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.34 (br. s, 1H), 8.38 (d, J=7.52 Hz, 1H), 8.31 (d, J=3.72 Hz, 1H), 7.97 (br. s, 1H), 7.44 (br. s, 1H), 7.13-7.23 (m, 1H), 6.99 (br. s, 1H), 6.85 (s, 1H), 4.10-4.22 (m, 4H), 3.25-3.46 (m, 2H), 2.54-2.64 (m, 1H), 1.96-2.06 (m, 1H), 1.82-1.92 (m, 1H), 1.60-1.74 (m, 2H), 1.24 (t, J=6.85 Hz, 3H); LCMS (m/z): 411.4 [M+H].sup.+.
Example 190
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(3-oxopiperazino)-4,5-dihydrofuran-3-carboxylate
(680) ##STR00200##
(681) The titled compound (solid) was similarly prepared according to the procedure described in the Example 189.
(682) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.38 (br. s, 1H), 8.29-8.44 (m, 2H), 8.01 (br. s, 1H), 7.15-7.25 (m, 1H), 6.92 (br. s, 1H), 4.30-4.40 (m, 2H), 4.11-4.23 (m, 2H), 3.92-4.04 (m, 2H), 3.41-3.49 (m, 2H), 1.18-1.31 (m, 3H); LCMS (m/z): 383.0 [M+H].sup.+.
Example 191
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(4-acetyl-1,4-diazepanyl)-4-oxo-4,5-dihydrofuran-3-carboxylate
(683) ##STR00201##
(684) The titled compound (solid) was similarly prepared according to the procedure described in the Example 189.
(685) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.36 (br. s, 1H), 8.41 (d, J=7.68 Hz, 1H), 8.35 (d, J=4.36 Hz, 1H), 7.99 (br. s, 1H), 7.17-7.29 (m, 1H), 6.89 (d, J=3.91 Hz, 1H), 4.15-4.27 (m, 2H), 3.92-4.10 (m, 3H), 3.73-3.90 (m, 3H), 3.51-3.64 (m, 2H), 1.83-2.08 (m, 5H), 1.28 (t, J=6.60 Hz, 3H); LCMS (m/z): 425.3 [M+H].sup.+.
Example 192
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(4-methyl-1,4-diazepanyl)-4-oxo-4,5-dihydrofuran-3-carboxylate acetate
(686) ##STR00202##
(687) The titled compound (solid) was similarly prepared according to the procedure described in the Example 189. Further, preparative HPLC (aqueous ammonium acetate/acetonitrile) was used as purification procedure.
(688) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.48 (br. s, 1H), 8.36 (d, J=7.82 Hz, 1H), 8.30 (d, J=4.40 Hz, 1H), 7.96 (s, 1H), 7.18 (dd, J=4.89, 7.82 Hz, 1H), 6.85 (s, 1H), 4.16 (q, J=7.34 Hz, 2H), 3.70-3.92 (m, 4H), 2.72-2.82 (m, 2H), 2.53-2.63 (m, 2H), 2.28 (s, 3H), 1.92-2.02 (m, 2H), 1.62 (s, 3H), 1.24 (t, J=7.09 Hz, 3H); LCMS (m/z): 397.2 [M+H].sup.+.
Example 193
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(2-methyl-2-phenylhydrazinyl)-4-oxo-4,5-dihydrofuran-3-carboxylate
(689) ##STR00203##
(690) To a solution of ethyl 2-(2-methyl-2-phenylhydrazinyl)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.36 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.053 g, 0.36 mmol) in ethanol (10 mL), L-proline (0.020 g, 0.17 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and hexane then dried to afford the titled compound as solid (0.015 g, y. 10%).
(691) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.28 (br. s, 1H), 10.79 (s, 1H), 8.48 (d, J=8.31 Hz, 1H), 8.22 (d, J=3.91 Hz, 1H), 7.90 (br. s, 1H), 7.32 (t, J=7.82 Hz, 2H), 6.83-7.05 (m, 5H), 4.25 (q, J=6.85 Hz, 2H), 3.34 (s, 3H), 1.29 (t, J=6.85 Hz, 3H); LCMS (m/z): 405.2 [M+H].sup.+.
Example 194
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[4-(diethylamino)piperidino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(692) ##STR00204##
First Step
(693) Under a nitrogen atmosphere, to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.0 g, 0.025 mol) and diethylamine (9.1 mL, 0.090 mol) in methanol (40 mL), 10% palladium on carbon (0.50 g) was added at ambient temperature. The reaction mixture was agitated under a hydrogen atmosphere at ambient temperature for 16 h. Palladium on carbon was removed by filtration with Celite and the solvent was removed under reduced pressure, then the residue was purified by chromatography on silica gel(dichloromethane/methanol) to afford tert-butyl 4-(diethylamino)piperidine-1-carboxylate as solid (6.1 g, y. 95%).
(694) .sup.1H NMR (CDCl.sub.3) (ppm) 4.12 (br. s, 2H), 3.76-3.89 (m, 1H), 2.45-2.72 (m, 6H), 1.30-1.53 (m, 13H), 0.90-1.10 (m, 6H)
(695) Second Step
(696) Cooled with ice bath, 4M hydrochloric acid in dioxane (25 mL) was added to tert-butyl 4-(N,N-diethylamino)piperidine-1-carboxylate (6.1 g, 0.024 mol) and the mixture was stirred at ambient temperature for 2 h. The solvent was removed under reduced pressure, and the residue was suspended in diethyl ether, then the precipitate was collected by filtration, washed with diethyl ether and then dried to afford 4-(diethylamino)piperidine dihydrochloride as solid (3.9 g, y. 99%).
(697) Third Step
(698) To a solution of 4-(diethylamino)piperidine dihydrochloride (3.0 g, 0.019 mmol) in water (20 mL), 2M sodium hydroxide solution (5.0 mL) was added at ambient temperature. The mixture was stirred for 30 min. The solvent was removed under reduced pressure, and methanol (10 mL) was added to the crude material, then the residue was removed by filtration. The filtrate was concentrated and dried to afford 4-(diethylamino)piperidine (1.7 g, y. 77%) as solid.
(699) .sup.1H NMR (DMSO-d.sub.6) (ppm) 3.20-3.29 (m, 2H), 3.09-3.14 (m, 1H), 2.77-2.93 (m, 3H), 2.52-2.62 (m, 4H), 1.64-1.90 (m, 4H), 1.00 (t, J=7.04 Hz, 6H)
(700) Fourth Step
(701) A solution of 4-(diethylamino)piperidine (0.50 g, 3.2 mmol), ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.76 g, 3.8 mmol) which afforded in the Example 74, Third step and triethylamine (0.60 mL, 4.3 mmol) in tetrahydrofuran (10 mL) was stirred at ambient temperature for 24 h. The solvent was removed under reduced pressure, then the crude material was purified by chromatography on silica gel (dichloromethane/methanol) to afford ethyl 2-[4-(diethylamino)piperidino]-4-oxo-4,5-dihydrofuran-3-carboxylate as oil (0.29 g, y. 30%).
(702) .sup.1H NMR (DMSO-d.sub.6) (ppm) 4.53 (s, 2H), 4.03-4.15 (m, 4H), 3.05-3.19 (m, 2H), 2.82 (br. s, 1H), 2.42-2.58 (m, 4H), 1.73-1.86 (m, 2H), 1.40-1.59 (m, 2H), 1.20 (t, J=7.08 Hz, 3H), 0.91-1.02 (m, 6H); LCMS (m/z): 311.0 [M+H].sup.+
(703) Fifth Step
(704) To a solution of ethyl 2-[4-(diethylamino)piperidino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.30 mmol) and 7-azaindole-3-carboxaldehyde (0.047 g, 0.30 mmol) in ethanol (5.0 mL), L-proline (0.0040 mg, 0.035 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and hexane then dried to afford the titled compound as solid (0.035 g, y. 25%).
(705) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.30 (br. s, 1H), 8.37 (d, J=7.82 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 7.97 (s, 1H), 7.19 (dd, J=4.89, 7.82 Hz, 1H), 6.84 (s, 1H), 4.11-4.33 (m, 4H), 3.27-3.37 (m, 2H), 2.82-2.92 (m, 1H), 2.41-2.60 (m, 4H), 1.82-1.92 (m, 2H), 1.56-1.71 (m, 2H), 1.24 (t, J=6.85 Hz, 3H), 0.98 (t, J=7.09 Hz, 6H); LCMS (m/z): 439.4 [M+H].sup.+.
Example 195
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(N-piperidinoamino)-4,5-dihydrofuran-3-carboxylate
(706) ##STR00205##
(707) To a solution of ethyl 4-oxo-2-(N-piperidinoamino)-4,5-dihydrofuran-3-carboxylate (0.25 g, 0.98 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.14 g, 0.98 mmol) in ethanol (10 mL), L-proline (0.011 mg, 0.096 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diethyl ether then dried to afford the titled compound as solid (0.015 g, y. 4%).
(708) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.34 (br. s, 1H), 9.86 (br. s, 1H), 9.00 (d, J=7.82 Hz, 1H), 8.33 (d, J=3.91 Hz, 1H), 8.10 (d, J=2.45 Hz, 1H), 7.18 (dd, J=4.65, 8.07 Hz, 1H), 6.85 (s, 1H), 4.20 (q, J=6.85 Hz, 2H), 2.95-3.05 (m, 4H), 1.69-1.79 (m, 4H), 1.42-1.53 (m, 2H), 1.26 (t, J=6.85 Hz, 3H); LCMS (m/z): 383.2 [M+H].sup.+.
Example 196
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(2,2-dimethylhydrazinyl)-4-oxo-4,5-dihydrofuran-3-carboxylate
(709) ##STR00206##
(710) The titled compound (solid) was similarly prepared according to the procedure described in the Example 195.
(711) .sup.1H NMR (DMSO-d.sub.6) (ppm) 11.85 (br. s, 1H), 8.52 (d, J=7.82 Hz, 1H), 8.23 (d, J=3.91 Hz, 1H), 7.83 (s, 1H), 7.10 (dd, J=4.89, 7.82 Hz, 1H), 6.14 (s, 1H), 4.02 (q, J=6.85 Hz, 2H), 1.70 (s, 6H), 1.18 (t, J=7.09 Hz, 3H); LCMS (m/z): 342.8 [M+H].sup.+.
Example 197
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-(dimethylamino)ethyl]-N-methylamino}-4-oxo-4,5-dihydrofuran-3-carboxylate formate
(712) ##STR00207##
(713) To a solution of ethyl 2-{[2-(dimethylamino)ethyl]-N-methylamino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.20 g, 0.78 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.11 g, 0.78 mmol) in ethanol (6.0 mL), L-proline (0.0093 mg, 0.078 mmol) was added at ambient temperature. The mixture was refluxed for 20 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.035 g, y. 12%).
(714) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.35 (br. s, 1H), 8.38 (d, J=7.83 Hz, 1H), 8.27-8.34 (m, 1H), 8.18 (s, 1H), 7.98 (s, 1H), 7.16-7.22 (m, 1H), 6.85 (s, 1H), 4.17 (q, J=6.85 Hz, 2H), 3.83 (t, J=6.60 Hz, 2H), 3.29 (br. s, 3H), 2.54-2.61 (m, 2H), 2.19 (s, 6H), 1.21-1.28 (m, 3H); LCMS (m/z): 385.0 [M+H].sup.+.
Example 198
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(1,4-oxoazepan-4-yl)-4-oxo-4,5-dihydrofuran-3-carboxylate acetate
(715) ##STR00208##
(716) The titled compound (solid) was similarly prepared according to the procedure described in the Example 197. Further, preparative HPLC (aqueous ammonium acetate/acetonitrile) was used as purification procedure.
(717) .sup.1H NMR (DMSO-d.sub.6) (ppm) 8.35 (d, J=7.82 Hz, 1H), 8.30 (d, J=4.40 Hz, 1H), 7.97 (s, 1H), 7.18 (dd, J=4.89, 7.82 Hz, 1H), 6.87 (s, 1H), 4.17 (q, J=7.17 Hz, 2H), 3.80-4.01 (m, 6H), 3.74 (t, J=5.14 Hz, 2H), 1.95-2.07 (m, 2H), 1.63 (s, 3H), 1.24 (t, J=7.09 Hz, 3H); LCMS (m/z): 383.8 [M+H].sup.+.
Example 199
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(cis-4-hydroxycyclohexyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(718) ##STR00209##
First Step
(719) Cooled with ice bath, to a mixed solution of cyclohexanone oxime (4.0 g, 0.035 mol) in dichloromethane (40 mL) and ethanol (5.0 mL), tert-butyl hypochlorite (4.7 mL, 0.038 mol) was added dropwise and the reaction mixture was cooled to 20 C. then stirred for 30 min. To this reaction mixture, 1,3-cyclohexadiene (5.0 mL, 0.052 mol) was added dropwise and the reaction mixture was allowed to warm to 0 C. then stirred for 4 days. The reaction mixture was concentrated under reduced pressure to half the solvents, and then diethyl ether (80 mL) was added at ambient temperature then the mixture was stirred for further 1 day. To this reaction mixture, ethanol (10 mL) was added and the mixture was stirred for further 4 h, then the precipitate was collected by filtration. The solid was washed with mixed solution of diethyl ether/ethanol (10/1), diethyl ether and hexane then dried to afford 2-oxa-3-azabicyclo[2.2.2]-5-octene hydrochloride as solid (4.2 g, y. 82%).
(720) .sup.1H NMR (CDCl.sub.3) (ppm) 12.43 (br. s, 1H), 11.29 (br. s, 1H), 6.81-6.88 (m, 1H), 6.64-6.71 (m, 1H), 4.87-4.93 (m, 1H), 4.58-4.65 (m, 1H), 2.54-2.66 (m, 1H), 2.31-2.47 (m, 1H), 1.45-1.59 (m, 2H)
(721) Second Step
(722) Under a nitrogen atmosphere, to a mixed solution of 2-oxa-3-azabicyclo[2.2.2]-5-octene hydrochloride (0.20 g, 1.4 mol) in ethanol (2.0 mL) and methanol (1.0 mL), platinum oxide (0.12 g, 0.53 mmol) was added at ambient temperature. The reaction mixture was agitated under a hydrogen atmosphere at ambient temperature for 6.5 h. Platinum oxide was removed by filtration with Celite, cooled this filtrate with ice bath, and 2M hydrochloric acid in ethanol (1.6 mL, 3.2 mmol) was added then the mixture was stirred for 10 min. The solvent was removed under reduced pressure, then 2-propanol (2.0 mL) and ethanol (0.20 mL) were added to the residue then the mixture was refluxed for 40 min and filtered. The filtrate was refluxed for further 10 min, stirred at ambient temperature for 14 h, then cooled with ice bath and stirred for further 30 min. The precipitate was collected by filtration, washed with ice-cold 2-propylalcohol and hexane then dried to afford cis-4-aminocyclohexanol hydrochloride as solid (0.056 g, y. 27%).
(723) .sup.1H NMR (DMSO-d.sub.6) (ppm) 7.92 (br. s, 3H), 4.47 (br. s, 1H), 3.70-3.82 (m, 1H), 2.89-3.04 (m, 1H), 1.57-1.76 (m, 6H), 1.37-1.51 (m, 2H)
(724) Third Step
(725) To a solution of cis-4-aminocyclohexanol hydrochloride (0.051 g, 0.34 mmol) and ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.073 g, 0.37 mmol) which afforded in the Example 74, Third step in ethanol (0.8 mL), triethylamine (0.052 mL, 0.37 mmol) was added. The mixture was stirred at ambient temperature for 1 h. To this reaction mixture, 7-azaindole-3-carboxaldehyde (0.044 g, 0.30 mmol) and piperidine (0.0067 mL, 0.067 mmol) was added at ambient temperature then the mixture was refluxed for 4 days. Ethanol (2.0 mL) was added then the mixture was refluxed for further 1 h, the precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.013 g, y. 11%).
(726) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.33 (br. s, 1H), 8.50 (d, J=8.03 Hz, 1H), 8.42 (d, J=7.78 Hz, 1H), 8.32 (dd, J=1.38, 4.64 Hz, 1H), 8.02 (d, J=2.51 Hz, 1H), 7.20 (dd, J=4.64, 7.91 Hz, 1H), 6.90 (s, 1H), 4.55 (d, J=3.26 Hz, 1H), 4.22 (q, J=7.03 Hz, 2H), 4.03-4.14 (m, 1H), 3.74-3.82 (m, 1H), 1.90-2.02 (m, 2H), 1.72-1.81 (m, 2H), 1.61-1.69 (m, 4H), 1.26 (t, J=7.15 Hz, 3H); LCMS (m/z): 396.1 [M+H].sup.+.
Example 200
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[4-(dimethylamino)piperidino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(727) ##STR00210##
(728) The titled compound (solid) was similarly prepared according to the procedure described in the Example 194.
(729) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.37 (br. s, 1H), 8.39 (d, J=7.00 Hz, 1H), 8.33 (d, J=5.16 Hz, 1H), 8.01 (s, 1H), 7.21 (dd, J=5.12, 7.72 Hz, 1H), 6.89 (s, 1H), 4.35-4.45 (m, 2H), 4.13-4.23 (m, 2H), 3.88-3.98 (m, 1H), 3.61-3.71 (m, 1H), 3.51-3.61 (m, 1H), 2.50 (s, 6H), 2.18-2.28 (m, 1H), 1.95-2.05 (m, 1H), 1.80-1.95 (m, 1H), 1.25 (t, J=6.96 Hz, 3H); LCMS (m/z): 411.2 [M+H].sup.+.
Example 201
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({2-[(2-methoxyethoxy)methoxy]ethyl}-N-methylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(730) ##STR00211##
First Step
(731) To a solution of ethyl 2-[(2-hydroxyethyl)-N-methylamino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.5 g, 2.18 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step in dichloromethane (6.0 mL) that cooled with ice bath, diisopropylethylamine (0.75 mL, 4.36 mmol) then 2-methoxyethoxymethyl chloride (0.5 mL, 4.36 mmol) were added. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 h. The reaction mixture was diluted with water, extracted with ethyl acetate for 3 times. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel(hexane/ethyl acetate) to afford ethyl 2-({2-[(2-methoxyethoxy)methoxy]ethyl}-N-methylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate as oil (0.31 g, y. 46%).
(732) .sup.1H NMR (DMSO-d.sub.6) (ppm) 4.62 (s, 2H), 4.54 (s, 2H), 4.10 (q, J=7.04 Hz, 2H), 3.63-3.80 (m, 4H), 3.52-3.62 (m, 2H), 3.38-3.48 (m, 2H), 3.24 (s, 3H), 3.12 (s, 3H), 1.20 (t, J=7.04 Hz, 3H); LCMS (m/z): 230.0 [M+H].sup.+
(733) Second Step
(734) To a solution of ethyl 2-({2-[(2-methoxyethoxy)methoxy]ethyl}-N-methylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.146 g, 0.46 mmol) and 7-azaindole-3-carboxaldehyde (0.067 g, 0.46 mmol) in ethanol (6.0 mL), L-proline (0.005 g, 0.046 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the reaction mixture was purified by chromatography on silica gel(hexane/ethyl acetate) to afford the titled compound as solid (0.035 g, y. 17%).
(735) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.33 (br. s, 1H), 8.39 (d, J=7.34 Hz, 1H), 8.31 (d, J=4.40 Hz, 1H), 7.98 (s, 1H), 7.19 (dd, J=4.65, 7.58 Hz, 1H), 6.85 (s, 1H), 4.64 (s, 2H), 4.16 (q, J=7.17 Hz, 2H), 3.93-4.00 (m, 2H), 3.75-3.83 (m, 2H), 3.51-3.59 (m, 2H), 3.36-3.42 (m, 2H), 3.25-3.37 (m, 3H), 3.17 (s, 3H), 1.24 (t, J=7.09 Hz, 3H); LCMS (m/z): 446.2 [M+H].sup.+
Example 202
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-hydroxyethyl)-N-methylamino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(736) ##STR00212##
(737) Cooled with ice bath, 4M hydrochloric acid in dioxane (4.0 mL) was added to ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({2-[(2-methoxyethoxy)methoxy]ethyl}-N-methylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.020 mg, 0.046 mmol) which afforded in the Example 201. The mixture was stirred at ambient temperature for 3 h. The solvent was removed under reduced pressure, and the precipitate was suspended in diethyl ether, then collected by filtration. The solid was washed with diethyl ether then dried to afford the titled compound as solid (0.012 g, y. 75%).
(738) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.35 (br. s, 1H), 8.42 (d, J=7.82 Hz, 1H), 8.32 (d, J=3.91 Hz, 1H), 7.99 (s, 1H), 7.21 (dd, J=4.89, 7.82 Hz, 1H), 6.84 (s, 1H), 4.16 (q, J=6.85 Hz, 2H), 3.80-3.86 (m, 2H), 3.65-3.78 (m, 2H), 3.31 (br. s., 3H), 1.24 (t, J=7.09 Hz, 4H); LCMS (m/z): 358.2 [M+H].sup.+
Example 203
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{4-[(2-hydroxyethyl)-N-methylamino]piperidino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(739) ##STR00213##
(740) The titled compound (solid) was similarly prepared according to the procedure described in the Example 194.
(741) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.30 (br. s, 1H), 8.37 (d, J=7.82 Hz, 1H), 8.31 (d, J=4.40 Hz, 1H), 7.97 (s, 1H), 7.20 (dd, J=4.65, 7.58 Hz, 1H), 6.85 (s, 1H), 4.22-4.38 (m, 4H), 4.17 (q, J=6.85 Hz, 2H), 3.45 (q, J=5.87 Hz, 2H), 3.25-3.40 (m, 2H), 2.69-2.81 (m, 1H), 2.23 (s, 3H), 1.85-1.95 (m, 2H), 1.58-1.72 (m, 2H), 1.25 (t, J=6.85 Hz, 3H); LCMS (m/z): 441.2 [M+H].sup.+.
Example 204
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-(phenylamino)furan-3(2H)-one
(742) ##STR00214##
(743) A solution of the compound (0.050 g, 0.13 mmol) of Example 1 in N,N-dimethylformamide (1.0 mL) was refluxed for 6 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.010 g, y. 25%).
(744) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.36 (br. s, 1H), 10.74 (s, 1H), 8.42 (d, J=7.53 Hz, 1H), 8.31 (dd, J=1.25, 4.52 Hz, 1H), 8.10 (d, J=2.26 Hz, 1H), 7.41-7.49 (m, 2H), 7.34 (d, J=7.53 Hz, 2H), 7.13-7.25 (m, 2H), 6.81 (s, 1H), 5.25 (s, 1H); LCMS (m/z): 304.0 [M+H].sup.+.
Example 205
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(4-methoxyphenyl)amino]furan-3(2H)-one
(745) ##STR00215##
(746) To a solution of the compound (0.31 g, 0.76 mmol) of Example 2 in ethanol (6.0 mL), 18M potassium hydroxide solution (0.41 mL, 7.4 mmol) was added at ambient temperature. The mixture was refluxed for 24 h. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.031 g, y. 12%).
(747) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.31 (br. s, 1H), 10.56 (s, 1H), 8.39 (d, J=7.53 Hz, 1H), 8.30 (dd, J=1.51, 4.52 Hz, 1H), 8.05 (s, 1H), 7.25-7.32 (m, 2H), 7.14 (dd, J=4.64, 7.91 Hz, 1H), 6.99-7.04 (m, 2H), 6.76 (s, 1H), 5.05 (s, 1H), 3.79 (s, 3H); LCMS (m/z): 334.0 [M+H].sup.+.
Example 206
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(4-chlorophenyl)amino]furan-3(2H)-one
(748) ##STR00216##
(749) A solution of the compound (0.050 g, 0.12 mmol) of Example 8 in N,N-dimethylformamide (1.0 mL) was refluxed for 6 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0072 g, y. 17%).
(750) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.36 (br. s, 1H), 10.87 (br. s, 1H), 8.41 (d, J=7.28 Hz, 1H), 8.31 (dd, J=1.38, 4.64 Hz, 1H), 8.08 (d, J=2.26 Hz, 1H), 7.48 (d, J=8.78 Hz, 2H), 7.36 (d, J=8.78 Hz, 2H), 7.17 (dd, J=4.64, 7.91 Hz, 1H), 6.82 (s, 1H), 5.27 (s, 1H); LCMS (m/z): 337.9 [M+H].sup.+.
Example 207
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(3-chlorophenyl)amino]furan-3(2H)-one
(751) ##STR00217##
(752) A solution of the compound (0.040 g, 0.098 mmol) of Example 9 in N,N-dimethylformamide (1.0 mL) was refluxed for 6 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0075 g, y. 23%).
(753) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.40 (br. s, 1H), 10.85 (s, 1H), 8.41 (d, J=7.28 Hz, 1H), 8.32 (dd, J=1.38, 4.64 Hz, 1H), 8.09 (d, J=2.76 Hz, 1H), 7.42-7.51 (m, 1H), 7.36-7.41 (m, 1H), 7.32 (d, J=8.03 Hz, 1H), 7.26 (dd, J=1.00, 8.03 Hz, 1H), 7.17 (dd, J=4.64, 7.91 Hz, 1H), 6.85 (s, 1H), 5.31 (s, 1H); LCMS (m/z): 337.9 [M+H].sup.+.
Example 208
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(2-chlorophenyl)amino]furan-3(2H)-one
(754) ##STR00218##
(755) A solution of the compound (0.050 g, 0.12 mmol) of Example 15 in N,N-dimethylformamide (1.0 mL) was stirred at 150 C. for 6 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0050 g, y. 11%).
(756) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.29 (br. s, 1H), 10.63 (br. s, 1H), 8.21-8.32 (m, 2H), 8.01 (br. s, 1H), 7.63 (d, J=8.03 Hz, 1H), 7.57 (d, J=7.28 Hz, 1H), 7.45 (t, J=7.40 Hz, 1H), 7.32-7.39 (m, 1H), 7.06 (dd, J=4.77, 7.53 Hz, 1H), 6.75 (s, 1H), 4.89 (br. s, 1H); LCMS (m/z): 337.9 [M+H].sup.+.
Example 209
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(2,4-dimethoxyphenyl)amino]furan-3(2H)-one
(757) ##STR00219##
(758) A solution of the compound (0.10 g, 0.23 mmol) of Example 24 in N,N-dimethylformamide (3.0 mL) was refluxed for 7 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.015 g, y. 18%).
(759) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.27 (br. s, 1H), 10.11 (br. s, 1H), 8.25-8.36 (br. s, 2H), 8.03 (br. s, 1H), 7.30 (d, J=8.31 Hz, 1H), 7.08 (br. s, 1H), 6.72 (d, J=17.12 Hz, 2H), 6.60 (d, J=8.31 Hz, 1H), 4.74 (br. s, 1H), 3.75-3.92 (m, 6H); LCMS (m/z): 364.2 [M+H].sup.+.
Example 210
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(4-isopropylphenyl)amino]furan-3(2H)-one
(760) ##STR00220##
(761) A solution of the compound (0.12 g, 0.29 mmol) of Example 37 in N,N-dimethylformamide (3.0 mL) was refluxed for 6 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford 2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(4-isopropylphenyl)amino]furan-3(2H)-one as solid (0.0050 g, y. 5%).
(762) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.34 (br. s, 1H), 10.68 (br. s, 1H), 8.41 (d, J=7.82 Hz, 1H), 8.30 (d, J=3.91 Hz, 1H), 8.09 (br. s, 1H), 7.21-7.37 (m, 4H), 7.15 (d, J=4.40 Hz, 1H), 6.77 (s, 1H), 5.18 (br. s, 1H), 2.84-3.00 (m, 1H), 1.22 (d, J=6.85 Hz, 6H); LCMS (m/z): 346.2 [M+H].sup.+.
Example 211
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-(3-pyridinylamino)furan-3(2H)-one
(763) ##STR00221##
(764) The titled compound (solid) was similarly prepared according to the procedure described in the Example 210, using the compound of Example 27.
(765) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.35 (br. s, 1H), 10.95 (br. s, 1H), 8.58 (br. s, 1H), 8.35-8.43 (m, 2H), 8.27-8.33 (m, 1H), 8.06 (br. s, 1H), 7.76 (d, J=6.85 Hz, 1H), 7.38-7.53 (m, 1H), 7.09-7.24 (m, 1H), 6.81 (br. s, 1H), 5.27 (br. s, 1H); LCMS (m/z): 305.2 [M+H].sup.+.
Example 212
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(4-carbamoylphenyl)amino]furan-3(2H)-one
(766) ##STR00222##
(767) The titled compound (solid) was similarly prepared according to the procedure described in the Example 210, using the compound of Example 25.
(768) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.37 (br. s, 1H), 8.42 (d, J=7.34 Hz, 1H), 8.32 (br. s, 1H), 8.12 (br. s, 1H), 7.85-8.04 (m, 4H), 7.28-7.44 (m, 3H), 7.14-7.21 (m, 1H), 6.83 (br. s, 1H), 5.38 (br. s, 1H); LCMS (m/z): 347.2 [M+H].sup.+.
Example 213
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(2,4-dimethylphenyl)amino]furan-3(2H)-one
(769) ##STR00223##
(770) The titled compound (solid) was similarly prepared according to the procedure described in the Example 210, using the compound of Example 26.
(771) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.22 (br. s, 1H), 10.21 (br. s, 1H), 8.11-8.34 (m, 2H), 7.94 (br. s, 1H), 7.25 (d, J=7.92 Hz, 1H), 7.17 (br. s, 1H), 6.99-7.14 (m, 2H), 6.74 (s, 1H), 4.78 (br. s, 1H), 2.31 (s, 3H), 2.22 (s, 3H); LCMS (m/z): 332.2 [M+H].sup.+.
Example 214
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-(p-tolylamino)furan-3(2H)-one
(772) ##STR00224##
(773) The titled compound (solid) was similarly prepared according to the procedure described in the Example 210, using the compound of Example 20.
(774) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.32 (br. s, 1H), 8.40 (d, J=7.34 Hz, 1H), 8.30 (br. s, 1H), 8.06 (br. s, 1H), 7.10-7.36 (m, 5H), 6.74 (br. s, 1H), 5.12 (br. s, 1H), 2.32 (s, 3H); LCMS (m/z): 318.4 [M+H].sup.+.
Example 215
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(4-bromophenyl)amino]furan-3(2H)-one
(775) ##STR00225##
(776) The titled compound (solid) was similarly prepared according to the procedure described in the Example 210, using the compound of Example 19.
(777) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.31 (br. s, 1H), 8.39 (d, J=7.76 Hz, 1H), 8.23-8.35 (m, 1H), 8.05 (s, 1H), 7.58 (d, J=8.31 Hz, 2H), 7.27 (d, J=8.31 Hz, 2H), 7.18 (dd, J=4.65, 7.58 Hz, 1H), 6.80 (s, 1H), 5.20 (br. s, 1H); LCMS (m/z): 382.5 [M+H].sup.+.
Example 216
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(3,4-dimethoxyphenyl)amino]furan-3(2H)-one
(778) ##STR00226##
(779) A solution of the compound (0.043 g, 0.099 mmol) of Example 28 in N,N-dimethylformamide (1.2 mL) was refluxed for 6 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound (0.0050 g, y. 12%).
(780) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.35 (br. s, 1H), 10.56 (br. s, 1H), 8.40 (d, J=7.34 Hz, 1H), 8.30 (d, J=3.91 Hz, 1H), 8.06 (br. s, 1H), 7.08-7.22 (m, 1H), 7.01 (d, J=8.31 Hz, 1H), 6.92 (br. s, 1H), 6.87 (d, J=8.31 Hz, 1H), 6.77 (s, 1H), 5.12 (s, 1H), 3.78 (s, 6H); LCMS (m/z): 364.0 [M+H].sup.+.
Example 217
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(4-fluorophenyl)amino]furan-3(2H)-one
(781) ##STR00227##
(782) The titled compound (solid) was similarly prepared according to the procedure described in the Example 216, using the compound of Example 21.
(783) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.34 (br. s, 1H), 10.72 (br. s, 1H), 8.40 (d, J=7.34 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 8.06 (br. s, 1H), 7.33-7.46 (m, 2H), 7.22-7.33 (m, 2H), 7.16 (dd, J=4.65, 7.58 Hz, 1H), 6.80 (s, 1H), 5.18 (s, 1H); LCMS (m/z): 322.0 [M+H].sup.+.
Example 218
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(1,1-biphenyl)-4-ylamino]furan-3(2H)-one
(784) ##STR00228##
(785) The titled compound (solid) was similarly prepared according to the procedure described in the Example 216, using the compound of Example 39.
(786) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.29 (br. s, 1H), 8.24-8.49 (m, 3H), 8.07 (br. s, 1H), 7.70 (br. s, 3H), 7.48 (br. s, 2H), 7.38 (br. s, 3H), 7.15 (br. s, 1H), 6.72 (br. s, 1H), 5.19 (br. s, 1H); LCMS (m/z): 380.2 [M+H].sup.+.
Example 219
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-{[2-(2-hydroxyethoxy)phenyl]amino}furan-3(2H)-one
(787) ##STR00229##
(788) A solution of the compound (0.015 g, 0.034 mmol) of Example 29 in N,N-dimethylformamide (0.50 mL) was refluxed for 4 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0013 g, y. 11%).
(789) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.24 (br. s, 1H), 8.44 (br. s, 1H), 8.24-8.35 (m, 2H), 8.03 (br. s, 1H), 7.32-7.41 (m, 1H), 6.96-7.25 (m, 4H), 6.67 (br. s, 1H), 4.90 (br. s, 1H), 4.01-4.12 (m, 2H), 3.67-3.80 (m, 2H); LCMS (m/z): 363.9 [M+H].sup.+.
Example 220
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-(6-quinolinylamino)furan-3(2H)-one
(790) ##STR00230##
(791) A solution of the compound (0.075 g, 0.18 mmol) of Example 44 in N,N-dimethylformamide (4.0 mL) was refluxed for 6 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0080 g, y. 13%).
(792) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.41 (br. s, 1H), 11.07 (br. s, 1H), 8.81-8.87 (m, 1H), 8.42 (t, J=8.56 Hz, 2H), 8.31 (d, J=3.91 Hz, 1H), 8.15 (br. s, 1H), 8.07 (d, J=8.80 Hz, 1H), 7.88 (br. s, 1H), 7.73 (d, J=8.80 Hz, 1H), 7.55 (dd, J=3.91, 7.82 Hz, 1H), 7.15 (d, J=4.40 Hz, 1H), 6.85 (br. s, 1H), 5.56 (br. s, 1H); LCMS (m/z): 355.2 [M+H].sup.+.
Example 221
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(2-methoxyphenyl)amino]furan-3(2H)-one
(793) ##STR00231##
(794) A solution of the compound (0.099 g, 0.24 mmol) of Example 7 in N,N-dimethylformamide (2.0 mL) was refluxed for 9 h. Cooled to ambient temperature, the reaction mixture was diluted with 2-butanol and washed with 4M sodium hydroxide solution. The organic layer was concentrated then purified by chromatography on silica gel(chloroform/methanol) to afford the titled compound as solid (0.0097 g, y. 12%).
(795) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.31 (br. s, 1H), 10.29 (s, 1H), 8.33 (d, J=7.78 Hz, 1H), 8.27-8.30 (m, 1H), 8.12 (s, 1H), 7.42 (d, J=7.78 Hz, 1H), 7.26-7.33 (m, 1H), 7.18 (d, J=7.28 Hz, 1H), 7.10 (dd, J=4.77, 8.03 Hz, 1H), 7.04 (t, J=7.65 Hz, 1H), 6.75 (s, 1H), 4.90-4.94 (m, 1H), 3.88 (s, 3H); LCMS (m/z): 333.9 [M+H].sup.+.
Example 222
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(2,4-difluorophenyl)amino]furan-3(2H)-one
(796) ##STR00232##
(797) A solution of the compound (0.099 g, 0.24 mmol) of Example 53 in N,N-dimethylformamide (1.0 mL) was refluxed for 4 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0030 g, y. 4%).
(798) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.31 (br. s, 1H), 10.60 (br. s, 1H), 8.26-8.36 (m, 2H), 8.01 (br. s, 1H), 7.55-7.65 (m, 1H), 7.44-7.54 (m, 1H), 7.16-7.25 (m, 1H), 7.06-7.14 (m, 1H), 6.79 (br. s, 1H), 4.95 (br. s, 1H); LCMS (m/z): 339.8 [M+H].sup.+.
Example 223
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(4-morpholinophenyl)amino]furan-3(2H)-one
(799) ##STR00233##
(800) A solution of the compound (0.080 g, 0.17 mmol) of Example 42 in N,N-dimethylacetamide (3.0 mL) was stirred at 160 C. for 4 h. Cooled to ambient temperature, the reaction mixture was diluted with water and the precipitate was collected by filtration. The solid was washed with water, tetrahydrofuran and diethyl ether then dried to afford the titled compound as solid (0.015 g, y. 22%).
(801) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.32 (br. s, 1H), 10.53 (br. s, 1H), 8.41 (d, J=8.12 Hz, 1H), 8.31 (d, J=4.28 Hz, 1H), 8.05 (br. s, 1H), 7.23 (d, J=8.31 Hz, 2H), 7.12-7.18 (m, 1H), 7.02 (d, J=8.31 Hz, 2H), 6.75 (s, 1H), 5.05 (s, 1H), 3.70-3.83 (m, 4H), 3.05-3.18 (m, 4H); LCMS (m/z): 389.4 [M+H].sup.+.
Example 224
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(4-fluorobenzyl)amino]furan-3(2H)-one
(802) ##STR00234##
(803) A solution of the compound (0.10 g, 0.31 mmol) of Example 45 in N,N-dimethylacetamide (3.0 mL) was refluxed for 7 h. Cooled to ambient temperature, the reaction mixture was diluted with water and the precipitate was collected by filtration. The solid was washed with water and diethyl ether then dried to afford the titled compound as solid (0.0070 g, y. 9%).
(804) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.23 (br. s, 1H), 9.08 (s, 1H), 8.40 (br. s, 1H), 8.21-8.32 (m, 2H), 7.96 (br. s, 1H), 7.34-7.50 (m, 1H), 7.05-7.32 (m, 3H), 6.67 (s, 1H), 4.91 (s, 1H), 4.35-4.60 (m, 2H); LCMS (m/z): 336.0 [M+H].sup.+.
Example 225
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(2-thienylmethyl)amino]furan-3(2H)-one
(805) ##STR00235##
(806) A solution of the compound (0.10 g, 0.26 mmol) of Example 60 in N,N-dimethylformamide (0.80 mL) was refluxed for 16 h. Cooled to ambient temperature, the reaction mixture was diluted with chloroform and the precipitate was collected by filtration. The solid was washed with chloroform/methanol (10/1) and hexane then dried to afford the titled compound as solid (0.019 g, y. 22%).
(807) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.25 (br. s, 1H), 9.20 (t, J=6.02 Hz, 1H), 8.41 (d, J=7.53 Hz, 1H), 8.29 (dd, J=1.26, 4.52 Hz, 1H), 7.99 (d, J=2.01 Hz, 1H), 7.49 (dd, J=1.00, 5.02 Hz, 1H), 7.12-7.20 (m, 2H), 7.02 (dd, J=3.51, 5.02 Hz, 1H), 6.67 (s, 1H), 4.96 (br. s, 1H), 4.69 (br. s, 2H); LCMS (m/z): 324.0 [M+H].sup.+.
Example 226
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-(cycloheptylamino)furan-3(2H)-one
(808) ##STR00236##
(809) A solution of the compound (0.040 g, 0.10 mmol) of Example 59 in N,N-dimethylformamide (2.0 mL) was refluxed for 8 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0040 g, y. 12%).
(810) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.26 (br. s, 1H), 8.64 (d, J=7.82 Hz, 1H), 8.39 (d, J=7.34 Hz, 1H), 8.29 (d, J=3.91 Hz, 1H), 8.00 (br. s, 1H), 7.17 (dd, J=4.89, 7.82 Hz, 1H), 6.61 (s, 1H), 4.78 (br. s, 1H), 2.83-3.11 (m, 1H), 1.85-2.02 (m, 2H), 1.40-1.78 (m, 10H); LCMS (m/z): 324.2 [M+H].sup.+.
Example 227
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-(isopropylamino)furan-3(2H)-one
(811) ##STR00237##
(812) A solution of the compound (0.15 g, 0.43 mmol) of Example 56 in N,N-dimethylacetamide (1.5 mL) was refluxed for 12 h. Cooled to ambient temperature, the reaction mixture was diluted with water and the precipitate was collected by filtration. The solid was washed with diethyl ether then dried to afford the titled compound as solid (0.015 g, y. 12%).
(813) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.24 (br. s, 1H), 8.58 (d, J=7.82 Hz, 1H), 8.38 (d, J=7.83 Hz, 1H), 8.27 (d, J=4.40 Hz, 1H), 7.97 (br. s, 1H), 7.15 (dd, J=4.89, 7.82 Hz, 1H), 6.60 (s, 1H), 4.79 (br. s, 1H), 3.53-3.69 (m, 1H), 1.22 (d, J=6.36 Hz, 6H); LCMS (m/z): 270.2 [M+H].sup.+.
Example 228
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(3-pyrazolyl)amino]furan-3(2H)-one
(814) ##STR00238##
(815) The titled compound (solid) was similarly prepared according to the procedure described in the Example 227, using the compound of Example 67.
(816) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.52 (br. s, 2H), 11.67 (br. s, 1H), 8.45 (d, J=6.85 Hz, 1H), 8.16 (d, J=3.42 Hz, 1H), 7.72 (br. s, 2H), 7.56 (br. s, 1H), 7.13-7.25 (m, 1H), 6.98-7.09 (m, 1H), 4.69 (s, 1H); LCMS (m/z): 294.2 [M+H].sup.+.
Example 229
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(3-fluorobenzyl)amino]furan-3(2H)-one
(817) ##STR00239##
(818) A solution of the compound (0.050 g, 0.12 mmol) of the Example 58 in N,N-dimethyacetamide (1.5 mL) was refluxed for 12 h. Cooled to ambient temperature, the reaction mixture was diluted with water and the precipitate was collected by filtration. The solid was purified by preparative HPLC to afford the titled compound as solid (0.012 g, y. 30%).
(819) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.26 (br. s, 1H), 9.13-9.23 (m, 1H), 8.41 (br. s, 1H), 8.29 (d, J=3.91 Hz, 1H), 7.98 (br. s, 1H), 7.38-7.53 (m, 1H), 7.20-7.32 (m, 2H), 7.16 (d, J=6.36 Hz, 2H), 6.66 (s, 1H), 4.91 (br. s, 1H), 4.41-4.60 (m, 2H); LCMS (m/z): 336.0 [M+H].sup.+.
Example 230
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-(cyclopropylamino)furan-3(2H)-one
(820) ##STR00240##
(821) To a solution of the compound (0.25 g, 0.76 mmol) of Example 94 in ethanol (7.0 mL), 50% potassium hydroxide solution (4.0 mL, 0.071 mol) was added at ambient temperature. The mixture was refluxed for 2 h. Cooled to ambient temperature, the solvent was removed under reduced pressure. The residue was diluted with water, 1M hydrochloric acid was added to adjust pH to acidic, and then the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to afford the titled compound as solid (0.0090 g, y. 4%).
(822) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.26 (br. s, 1H), 8.88 (br. s, 1H), 8.44 (d, J=6.85 Hz, 1H), 8.22-8.34 (m, 1H), 7.97 (br. s, 1H), 7.12-7.20 (m, 1H), 6.66 (br. s, 1H), 4.87 (br. s, 1H), 2.62-2.80 (m, 1H), 0.72-0.88 (m, 2H), 0.55-0.72 (m, 2H); LCMS (m/z): 268.0 [M+H].sup.+.
Example 231
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(2-methoxyethyl)amino]furan-3(2H)-one
(823) ##STR00241##
(824) To a solution of the compound (0.070 g, 0.20 mmol) of Example 98 in ethanol (2.0 mL), 50% potassium hydroxide solution (1.0 mL, 0.018 mol) was added at ambient temperature. The mixture was refluxed for 1 h. Cooled to ambient temperature, 1M hydrochloric acid was added to adjust pH to acidic, and then the solvent was removed under reduced pressure. To this residue, ethanol (2.0 mL) and water (2.0 mL) were added then refluxed for 1 h. Cooled to ambient temperature, the solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to afford the titled compound as solid (0.0060 g, y. 12%).
(825) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.24 (br. s, 1H), 8.65-8.90 (m, 1H), 8.41 (d, J=6.85 Hz, 1H), 8.29 (br. s, 1H), 8.01 (br. s, 1H), 7.08-7.32 (m, 1H), 6.53-6.70 (m, 1H), 4.72-4.97 (m, 1H), 3.30-3.55 (m, 4H), 3.26 (br. s, 3H); LCMS (m/z): 286.2 [M+H].sup.+.
Example 232
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(1-methyl-4-piperidinyl)amino]furan-3(2H)-one
(826) ##STR00242##
(827) The titled compound (solid) was similarly prepared according to the procedure described in the Example 231, using the compound of Example 65.
(828) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.25 (br. s, 1H), 8.61 (d, J=7.34 Hz, 1H), 8.39 (d, J=7.82 Hz, 1H), 8.23-8.34 (m, 1H), 8.17 (br. s, 1H), 7.99 (br. s, 1H), 7.06-7.24 (m, 1H), 6.62 (s, 1H), 4.77-4.99 (m, 1H), 2.73-2.85 (m, 2H), 2.22 (s, 3H), 2.00-2.14 (m, 2H), 1.82-1.97 (m, 2H), 1.49-1.67 (m, 2H); LCMS (m/z): 325.4 [M+H].sup.+.
Example 233
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(4-fluoro-2-methylphenyl)amino]furan-3(2H)-one
(829) ##STR00243##
(830) To a solution of the compound (0.15 g, 0.37 mmol) of Example 97 in ethanol (4.0 mL), 50% potassium hydroxide solution (2.0 mL, 0.036 mol) was added at ambient temperature. The mixture was refluxed for 2 h. Cooled to ambient temperature, the solvent was removed under reduced pressure. Water was added to this residue, the mixture was washed with ethyl acetate then 1M hydrochloric acid was added to adjust pH to acidic. The precipitate was collected by filtration, washed with water, diethyl ether, ethyl acetate and hexane then dried to afford the titled compound as solid (0.12 g, y. 93%).
(831) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.28 (br. s, 1H), 10.24 (s, 1H), 8.19-8.32 (m, 2H), 7.97 (br. s, 1H), 7.43 (dd, J=5.62, 8.56 Hz, 1H), 7.26 (d, J=7.34 Hz, 1H), 7.11-7.19 (m, 1H), 7.04-7.10 (m, 1H), 6.74 (s, 1H), 4.72 (s, 1H), 2.31 (s, 3H); LCMS (m/z): 335.8 [M+H].sup.+.
Example 234
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(2,6-dimethyl-3-pyridinyl)amino]furan-3(2H)-one
(832) ##STR00244##
(833) To a solution of the compound (0.090 g, 0.20 mmol) of Example 107 in ethanol (4.0 mL), 50% potassium hydroxide solution (2.0 mL, 0.036 mol) was added at ambient temperature. The mixture was refluxed for 2 h. Cooled to ambient temperature, the solvent was removed under reduced pressure. Water was added to this residue, the mixture was washed with ethyl acetate then 1M hydrochloric acid was added to adjust pH to acidic. The precipitate was collected by filtration, washed with water and diethyl ether then dried to afford the titled compound (0.037 g, y. 50%) as solid.
(834) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.26 (br. s, 1H), 10.33 (br. s, 1H), 8.28 (d, J=4.40 Hz, 2H), 7.96 (br. s, 1H), 7.64 (d, J=8.31 Hz, 1H), 7.17 (d, J=7.82 Hz, 1H), 7.02-7.12 (m, 1H), 6.70 (br. s, 1H), 4.73 (br. s, 1H), 2.48 (br. s, 3H), 2.44 (br. s, 3H); LCMS (m/z): 333.3 [M+H].sup.+.
Example 235
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(2-fluorobenzyl)amino]furan-3(2H)-one
(835) ##STR00245##
(836) To a solution of the compound (0.10 g, 0.25 mmol) of Example 101 in ethanol (4.0 mL), 50% potassium hydroxide solution (2.0 mL, 0.036 mol) was added at ambient temperature. The mixture was refluxed for 2 h. Cooled to ambient temperature, the solvent was removed under reduced pressure. Water was added to this residue, the mixture was washed with ethyl acetate then 1M hydrochloric acid was added to adjust pH to acidic, and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrate then purified by chromatography on silica gel(dichloromethane/methanol) to afford the titled compound as solid (0.012 g, y. 14%).
(837) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.24 (br. s, 1H), 9.08-9.17 (m, 1H), 8.34-8.46 (m, 1H), 8.22-8.33 (m, 1H), 7.98 (br. s, 1H), 7.45-7.55 (m, 1H), 7.34-7.43 (m, 1H), 7.20-7.31 (m, 2H), 7.10-7.19 (m, 1H), 6.65 (s, 1H), 4.83-4.97 (m, 1H), 4.40-4.64 (m, 2H); LCMS (m/z): 335.8 [M+H].sup.+.
Example 236
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(2-phenyl-2-propanyl)amino]furan-3(2H)-one
(838) ##STR00246##
(839) To a solution of the compound (0.060 g, 0.14 mmol) of Example 112 in ethanol (2.0 mL), 50% potassium hydroxide solution (1.0 mL, 0.018 mol) was added at ambient temperature. The mixture was refluxed for 2 h. Cooled to ambient temperature, the solvent was removed under reduced pressure. Water was added to this residue, the mixture was washed with ethyl acetate then 1M hydrochloric acid was added to adjust pH to acidic. The precipitate was collected by filtration, washed with water and diethyl ether then dried to afford the titled compound as solid (0.010 g, y. 20%).
(840) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.26 (br. s, 1H), 9.05 (br. s, 1H), 8.24-8.38 (m, 2H), 8.0 (br, 1H), 7.36-7.50 (m, 4H), 7.25-7.32 (m, 1H), 7.12-7.18 (m, 1H), 6.57 (s, 1H), 4.06 (br. s, 1H), 1.70 (s, 6H); LCMS (m/z): 346.2 [M+H].sup.+.
Example 237
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-(2-adamantylamino)furan-3(2H)-one
(841) ##STR00247##
(842) The titled compound (solid) was similarly prepared according to the procedure described in the Example 236, using the compound of Example 113.
(843) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.29 (br. s, 1H), 8.55 (br. s, 1H), 8.37 (d, J=7.82 Hz, 1H), 8.30 (d, J=4.40 Hz, 1H), 8.14 (br. s, 1H), 7.17 (dd, J=4.89, 7.83 Hz, 1H), 6.64 (s, 1H), 4.83 (s, 1H), 3.25-3.40 (m, 1H), 1.96-2.11 (m, 4H), 1.80-1.92 (m, 4H), 1.69-1.77 (m, 2H), 1.55-1.63 (m, 2H), 1.09 (t, J=7.00 Hz, 2H); LCMS (m/z): 362.4 [M+H].sup.+.
Example 238
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-(cyclopentylamino)furan-3(2H)-one
(844) ##STR00248##
(845) To a solution of the compound (0.10 g, 0.27 mmol) of Example 103 in ethanol (4.0 mL), 50% potassium hydroxide solution (2.0 mL, 0.036 mol) was added at ambient temperature. The mixture was refluxed for 2 h. Cooled to ambient temperature, the solvent was removed under reduced pressure. Water was added to this residue, the mixture was washed with ethyl acetate then 1M hydrochloric acid was added to adjust pH to acidic, and then the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to afford the titled compound as solid (0.0015 g, y. 5%).
(846) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.25 (br. s, 1H), 8.58-8.70 (m, 1H), 8.39 (d, J=7.83 Hz, 1H), 8.22-8.32 (m, 1H), 7.99 (br. s, 1H), 7.17 (dd, J=4.65, 7.58 Hz, 1H), 6.62 (s, 1H), 6.55 (s, 1H), 4.75-4.96 (m, 1H), 1.90-2.03 (m, 2H), 1.65-1.77 (m, 2H), 1.50-1.65 (m, 4H); LCMS (m/z): 296.2 [M+H].sup.+.
Example 239
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(5-indazolyl)amino]furan-3(2H)-one
(847) ##STR00249##
(848) To a solution of the compound (0.14 g, 0.33 mmol) of Example 118 in ethanol (4.0 mL), 50% potassium hydroxide solution (2.2 mL, 0.039 mol) was added at ambient temperature. The mixture was refluxed for 2 h. Cooled to ambient temperature, 1M hydrochloric acid was added to adjust pH to acidic, and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to afford the titled compound as solid (0.010 g, y. 9%).
(849) .sup.1H NMR (DMSO-d.sub.6) (ppm) 13.16 (br. s, 1H), 12.30 (br. s, 1H), 8.42 (br. s, 1H), 8.37 (d, J=7.76 Hz, 1H), 8.28 (d, J=3.91 Hz, 1H), 8.09 (br. s, 1H), 8.05 (br. s, 1H), 7.71 (s, 1H), 7.61 (d, J=8.80 Hz, 1H), 7.35 (d, J=8.80 Hz, 1H), 7.04-7.11 (m, 1H), 6.73 (s, 1H), 5.10 (s, 1H); LCMS (m/z): 344.2 [M+H].sup.+.
Example 240
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(5-benzimidazolyl)amino]furan-3(2H)-one
(850) ##STR00250##
(851) To a solution of the compound (0.055 g, 0.13 mmol) of Example 119 in ethanol (6.0 mL), 50% potassium hydroxide solution (3.0 mL, 0.053 mol) was added at ambient temperature. The mixture was refluxed for 1.5 h. Cooled to ambient temperature, 1M hydrochloric acid was added to adjust pH to acidic, and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to afford the titled compound (0.0090 g, y. 20%) as solid.
(852) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.28 (br. s, 1H), 12.10 (br. s, 1H), 8.34 (br. s, 1H), 8.22-8.29 (m, 1H), 8.10-8.20 (m, 1H), 7.95 (br. s, 1H), 7.50-7.62 (m, 1H), 7.25-7.38 (m, 1H), 6.98-7.15 (m, 2H), 6.34-6.67 (m, 2H), 4.84 (s, 1H); LCMS (m/z): 344.0 [M+H].sup.+.
Example 241
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(1-phenylethyl)amino]furan-3(2H)-one
(853) ##STR00251##
(854) The titled compound (solid) was similarly prepared according to the procedure described in the Example 240, using the compound of Example 106.
(855) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.29 (br. s, 1H), 9.15 (d, J=7.83 Hz, 1H), 8.23-8.43 (m, 2H), 7.80 (br. s, 1H), 7.11-7.49 (m, 6H), 6.62 (s, 1H), 5.00-5.10 (m, 1H), 4.60-4.80 (m, 1H), 1.36-1.60 (m, 3H); LCMS (m/z): 332.2 [M+H].sup.+.
Example 242
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-{[(3-methyl-2-thienyl)methyl]amino}furan-3(2H)-one
(856) ##STR00252##
(857) A solution of the compound (0.050 g, 0.12 mmol) of Example 124 in N,N-dimethylformamide (1.0 mL) was refluxed for 16 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.012 g, y. 28%).
(858) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.25 (br. s, 1H), 9.09 (t, J=5.77 Hz, 1H), 8.40 (d, J=7.78 Hz, 1H), 8.29 (dd, J=1.38, 4.64 Hz, 1H), 7.99 (d, J=2.26 Hz, 1H), 7.38 (d, J=5.02 Hz, 1H), 7.15 (dd, J=4.77, 8.03 Hz, 1H), 6.90 (d, J=5.02 Hz, 1H), 6.66 (s, 1H), 4.92 (br. s, 1H), 4.59 (br. s, 2H), 2.25 (s, 3H); LCMS (m/z): 338.1 [M+H].sup.+.
Example 243
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(trans-4-hydroxycyclohexyl)amino]furan-3(2H)-one
(859) ##STR00253##
(860) The titled compound (solid) was similarly prepared according to the procedure described in the Example 240, using the compound of Example 116.
(861) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.23 (br. s, 1H), 8.51-8.60 (m, 1H), 8.34-8.43 (m, 1H), 8.24-8.32 (m, 1H), 7.92-8.10 (m., 1H), 7.16 (dd, J=4.64, 7.91 Hz, 1H), 6.61 (s, 1H), 4.85 (br. s, 1H), 4.40-4.72 (m, 2H), 1.69-2.07 (m, 4H), 1.02-1.54 (m, 4H); LCMS (m/z): 326.1 [M+H].sup.+.
Example 244
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxo-4,5-dihydrofuran-3-carboxylate
(862) ##STR00254##
First Step
(863) To a suspension of 7-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.10 g, 10.5 mmol) in tetrahydrofuran, triethylamine (3.48 mL, 25.0 mmol) was added at ambient temperature and the mixture was stirred for 30 min. To this reaction mixture, ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (2.00 g, 10.0 mmol), which afforded in the Example 74, Third step was added and the mixture was stirred for 5 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel(chloroform/methanol) to afford ethyl 2-[7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl]-4-oxo-4,5-dihydrofuran-3-carboxylate as oil (2.85 g, y. 89%).
(864) .sup.1H NMR (CDCl.sub.3) (ppm) 7.09 (d, J=8.4 Hz, 1H), 6.80 (dd, J=8.4, 2.6 Hz, 1H), 6.64 (d, J=2.4 Hz, 1H), 4.78 (s, 2H), 4.54 (s, 2H), 4.33 (q, J=7.1 Hz, 2H), 3.89 (t, J=5.9 Hz, 2H), 3.79 (d, J=2.9 Hz, 3H), 2.86-3.04 (m, 2H), 1.38 (t, J=7.1 Hz, 3H); LCMS (m/z): 318.2 [M+H].sup.+.
(865) Second Step
(866) To a solution of ethyl 2-[7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl]-4-oxo-4,5-dihydrofuran-3-carboxylate (2.58 g, 8.98 mmol) and 7-azaindole-3-carboxaldehyde (1.31 g, 8.98 mmol) in ethanol (12 mL), L-proline was added at ambient temperature. The mixture was refluxed for 24 h. The precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound as solid (1.20 g, y. 30%).
(867) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.37 (s, 1H), 8.41 (dd, J=7.9, 1.5 Hz, 1H), 8.33 (dd, J=4.7, 1.5 Hz, 1H), 8.08 (s, 1H), 7.26-7.13 (m, 2H), 6.90 (s, 2H), 6.85 (dd, J=8.3, 2.6 Hz, 1H), 4.95 (br. s, 2H), 4.21 (q, J=7.1 Hz, 2H), 3.85-4.05 (m, 2H), 3.76 (s, 3H), 3.00 (t, J=5.8 Hz, 2H), 1.26 (t, J=7.1 Hz, 3H); LCMS (m/z): 446.2 [M+H].sup.+.
Example 245
Isopropyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(morpholinoamino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(868) ##STR00255##
First Step
(869) To a solution of isopropyl 2-isopropoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (12.2 g, 53.6 mmol), which similarly prepared according to the procedure described in the Example 74, Third step using diisopropyl malonate and chloroacetyl chloride, in ethanol (45 mL), 4-aminomorpholine (5.7 mL, 59.2 mmol) was added at ambient temperature. The mixture was stirred for 18 h. The solvent was removed under reduced pressure, and the crude product was suspended in methyl tert-butyl ether, then the precipitate was collected by filtration, washed with methyl tert-butyl ether and hexane then dried to afford isopropyl 2-(morpholinoamino)-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (11.2 g, y. 75%).
(870) .sup.1H NMR (DMSO-d.sub.6) (ppm) 9.60 (s, 1H), 4.95-5.05 (m, 1H), 4.57 (s, 2H), 3.60-3.68 (m, 4H), 2.87-2.95 (m, 4H), 1.22 (d, J=6.40 Hz, 6H); LCMS (m/z): 271.0 [M+H].sup.+
(871) Second Step
(872) To a stirred solution of isopropyl 2-(morpholinoamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (5.00 g, 18.5 mmol) and 7-azaindole-3-carboxaldehyde (2.49 g, 17.1 mmol) in ethanol (25 mL), L-proline (0.24 g, 2.04 mmol) was added at ambient temperature. The mixture was refluxed for 3 days. The precipitate was collected by filtration, washed with hot ethanol then hexane, and then dried to afford the titled compound as solid (4.22 g, y. 62%).
(873) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.34 (br. s, 1H), 10.07 (s, 1H), 8.94 (d, J=7.78 Hz, 1H), 8.33 (dd, J=1.38, 4.64 Hz, 1H), 8.12 (d, J=2.76 Hz, 1H), 7.22 (dd, J=4.52, 8.03 Hz, 1H), 6.84 (s, 1H), 4.99-5.12 (m, 1H), 3.75-3.86 (m, 4H), 3.03-3.13 (m, 4H), 1.27 (d, J=6.27 Hz, 6H); LCMS (m/z): 399.1 [M+H].sup.+.
Example 246
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-{[4-(2,2,2-trifluoroethyl)piperazinyl]amino}-4,5-dihydrofuran-3-carboxylate
(874) ##STR00256##
First Step
(875) To a solution of 1-(2,2,2-trifluoroethyl)piperazine (4.88 g, 29.0 mmol) in water (4.9 mL) that cooled with ice bath, a solution of sodium nitrite (4.04 g, 58.6 mmol) in water (20 mL) and acetic acid (5.0 mL, 87.0 mmol) were added dropwise slowly, then the mixture was stirred for 1 h. The reaction mixture was all owed to warm to ambient temperature, stirred for further 2 h. The reaction mixture was adjusted to pH9 using sodium carbonate, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated to afford 1-nitrso-4-(2,2,2-trifluoroethyl)piperazine as oil (5.57 g, y. 97%).
(876) .sup.1H NMR (DMSO-d.sub.6) (ppm) 4.18-4.22 (m, 2H), 3.72-3.76 (m, 2H), 3.32 (q, J=10.13 Hz, 2H), 2.84-2.89 (m, 2H), 2.59-2.64 (m, 2H).
(877) Second Step
(878) To a suspension of lithium aluminum hydride (2.22 g, 58.5 mmol) in tetrahydrofuran (100 mL) that cooled with ice bath, a solution of 1-nitroso-4-(2,2,2-trifluoroethyl)piperazine (5.43 g, 27.5 mmol) in tetrahydrofuran (10 mL) was added dropwise and the reaction mixture was allowed to warm to ambient temperature, then stirred for 5 days. The reaction mixture was cooled with ice bath, ethyl acetate was added until cease bubbling up, and water (2.1 mL) was added then the mixture was stirred for 20 min. To this mixture, 15% w/v sodium hydroxide solution (2.1 mL) and water (6.3 mL) were added, then the suspension mixture was allowed to warm to ambient temperature and then the mixture was stirred vigorously for 1 h. Magnesium sulfate was added to the mixture and stirred for a while, then the suspension was filtered. The filtrate was concentrated to afford 4-(2,2,2-trifluoroethyl)piperazine-1-amine as oil (4.72 g, y. 94%).
(879) .sup.1H NMR (DMSO-d.sub.6) (ppm) 3.12 (br. s, 1H), 2.98 (q, J=9.6 Hz, 2H), 2.60-2.80 (m, 8H).
(880) Third Step
(881) To a solution of 4-(2,2,2-trifluoroethyl)piperazine-1-amine (4.72 g, 25.8 mmol) in ethanol (43 mL), ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (4.70 g, 23.5 mmol) which similarly prepared according to the procedure described in the Example 74, Third step was added at ambient temperature. The mixture was stirred for 2 h. The precipitate was collected by filtration, washed with diethyl ether and hexane then dried to afford ethyl 4-oxo-2-{[4-(2,2,2-trifluoroethyl)piperazinyl]amino}-4,5-dihydrofuran-3-carboxylate as solid (5.64 g, y. 71%).
(882) .sup.1H NMR (DMSO-d.sub.6) (ppm) 8.94 (s, 1H), 4.61 (s, 2H), 4.32 (q, J=7.07 Hz, 2H), 3.03 (q, J=9.47 Hz, 2H), 2.95-2.99 (m, 4H), 2.85-2.90 (m, 4H), 1.37 (t, J=7.20 Hz, 3H); LCMS (m/z): 338.1 [M+H].sup.+.
(883) Fourth Step
(884) To a solution of ethyl 4-oxo-2-{[4-(2,2,2-trifluoroethyl)piperazinyl]amino}-4,5-dihydrofuran-3-carboxylate (3.01 g, 8.93 mmol) and 7-azaindole-3-carboxaldehyde (1.25 g, 8.55 mmol) in ethanol (25 mL), L-proline (99 mg, 0.86 mmol) was added at ambient temperature then the mixture was refluxed for 2 days. The precipitate was collected by filtration, washed with hot ethanol then hexane, and then dried to afford the titled compound a solid (2.64 g, y. 66%).
(885) .sup.1H NMR (DMSO-d.sub.6) (ppm) 12.32 (s, 1H), 10.09 (s, 1H), 8.95 (d, J=7.6 Hz, 1H), 8.33 (d, J=4.1 Hz, 1H), 8.09 (s, 1H), 7.30-7.16 (m, 1H), 6.80 (s, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.31-3.41 (m, 2H), 3.06 (s, 4H), 2.88 (s, 4H), 1.25 (t, J=7.0 Hz, 3H); LCMS (m/z): 466.0 [M+H].sup.+.
(886) Each of the Example compounds shown in the following [Table 1-1] to [Table 1-10] were prepared according to the procedure described in the above Examples or modified procedure well known in the art of organic chemistry if needed, using appropriate starting materials (those materials which are commercially available, or which are derivatized by known methods or their modified methods from commercial compounds). The physicochemical data of each compound were shown in the following [Table 2-1] to [Table 2-6].
(887) TABLE-US-00001 TABLE 1-1 Example Chemical Formula Chemical Name 247
(888) TABLE-US-00002 TABLE 1-2 259
(889) TABLE-US-00003 TABLE 1-3 271
(890) TABLE-US-00004 TABLE1-4 281
(891) TABLE-US-00005 TABLE 1-5 292
(892) TABLE-US-00006 TABLE 1-6 303
(893) TABLE-US-00007 TABLE 1-7 314
(894) TABLE-US-00008 TABLE 1-8 326
(895) TABLE-US-00009 TABLE 1-9 339
(896) TABLE-US-00010 TABLE 1-10 352
(897) TABLE-US-00011 TABLE 2-1 LCMS m/z Example .sup.1H-NMR (ppm) [M + H].sup.+ 247 (DMSO-d6): 12.17-12.43 (m, 1H), 8.18-8.41 (m, 3H), 7.94 (br. s, 1H), 7.12- 383.2 7.23 (m, 1H), 6.85 (br. s, 1H), 4.10-4.23 (m, 2H), 3.65-3.93 (m, 2H), 2.93- 3.13 (m, 2H), 2.77-2.93 (m, 2H), 1.80-1.98 (m, 2H), 1.10-1.35 (m, 5H). 248 (DMSO-d6): 12.37 (s, 1H), 8.40 (d, J = 7.6 Hz, 1H), 8.33 (d, J = 3.7 Hz, 1H), 422.0 8.09 (s, 1H), 7.47 (d, J = 4.9 Hz, 1H), 7.21 (dd, J = 7.7, 4.7 Hz, 1H), 6.87- 6.98 (m, 2H), 5.07 (s, 2H), 4.21 (q, J = 6.9 Hz, 2H), 3.98-4.08 (m, 2H), 2.92- 3.03 (m, 2H), 1.26 (t, J = 7.0 Hz, 3H). 249 (DMSO-d6): 12.37 (s, 1H), 8.28-8.39 (m, 2H), 8.02 (br. s, 1H), 7.10-7.29 430.0 (m, 5H), 6.81 (s, 1H), 5.13 (s, 2H), 4.18-4.30 (m, 2H), 4.00-4.18 (m, 2H), 2.99-3.12 (m, 2H), 1.92-2.07 (m, 2H), 1.28 (t, J = 6.6 Hz, 3H). 250 (DMSO-d6): 12.42 (s, 1H), 8.27-8.38 (m, 2H), 7.97 (s, 1H), 7.30-7.43 (m, 1H), 432.3 7.15-7.27 (m, 2H) 7.03-7.13 (m, 1H), 6.96 (d, J = 7.7 Hz, 1H), 6.85 (s, 1H), 5.18 (s, 2H), 4.40-4.50 (m, 2H), 4.14-4.26 (m, 2H), 4.00-4.14 (m, 2H), 1.26 (t, J = 6.6 Hz, 3H). 251 (DMSO-d6): 12.14 (s, 1H), 10.70-12.05 (m, 1H), 8.23 (d, J = 4.0 Hz, 1H), 8.00 423.2 (d, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.20-7.50 (m, 5H), 6.91 (dd, J = 7.7, 4.7 Hz, 1H), 4.51 (s, 2H). 252 (DMSO-d6): 12.33 (br. s, 1H), 8.57 (d, J = 6.02 Hz, 1H), 8.42 (dd, J = 1.38, 358.0 7.91 Hz, 1H), 8.31 (dd, J = 1.25, 4.52 Hz, 1H), 8.01 (s, 1H), 7.20 (dd, J = 4.77, 8.03 Hz, 1H), 6.90 (s, 1H), 5.20 (t, J = 5.27 Hz, 1H), 4.16-4.34 (m, 3H), 3.52-3.68 (m, 2H), 1.32 (d, J = 6.53 Hz, 3H), 1.26 (t, J = 7.15 Hz, 3H). 253 (DMSO-d6): 12.38 (br. s, 1H), 8.93 (br. s, 1H), 8.43 (dd, J = 1.38, 7.91 Hz, 414.0 1H), 8.31 (dd, J = 1.38, 4.64 Hz, 1H), 8.06 (s, 1H), 7.19 (dd, J = 4.64, 7.91 Hz, 1H), 6.90 (s, 1H), 4.37-4.46 (m, 1H), 4.22 (q, J = 7.03 Hz, 2H), 4.06 (dd, J = 6.53, 8.78 Hz, 1H) 3.68-3.89 (m, 3H), 1.32 (s, 3H), 1.23-1.29 (m, 6H). 254 (DMSO-d6): 12.35 (br. s, 1H), 8.84 (br. s, 1H), 8.46 (dd, J = 1.38, 7.91 Hz, 358.0 1H), 8.31 (dd, J = 1.38, 4.64 Hz, 1H), 8.04 (s, 1H), 7.19 (dd, J = 4.77, 8.03 Hz, 1H), 6.89 (s, 1H), 5.17 (d, J = 4.52 Hz, 1H), 4.21 (q, J = 7.03 Hz, 2H), 3.8 9-4.00 (m, 1H) 3.57-3.67 (m, 1H), 3.45-3.56 (m, 1H), 1.26 (t, J = 7.15 Hz, 3H), 1.16 (d, J = 6.27 Hz, 3H). 255 (DMSO-d6): 12.41 (br. s, 1H), 9.29 (br. s, 1H), 8.49 (d, J = 7.78 Hz, 1H), 8.32 338.0 (dd, J = 1.13, 4.64 Hz, 1H), 8.12 (s, 1H), 7.19 (dd, J = 4.64, 7.91 Hz, 1H), 6.96 (s, 1H), 4.43 (d, J = 1.51 Hz, 2H), 4.22 (q, J = 7.03 Hz, 2H), 3.42 (t, J = 2.26 Hz, 1H), 1.26 (t, J = 7.15 Hz, 3H). 256 (DMSO-d6): 12.35 (s, 1H), 11.34 (s, 1H), 10.67 (s, 1H), 8.33 (d, J = 7.3 Hz, 419.2 1H), 8.10 (d, J = 4.4 Hz, 1H), 7.94-8.05 (m, 3H), 7.68-7.76 (m, 1H), 7.58- 7.68 (m, 2H), 6.93 (s, 1H), 6.29-6.36 (m, 1H), 4.26 (q, J = 7.0 Hz, 2H), 1.29 (t, J = 7.0 Hz, 3H). 257 (DMSO-d6): 12.20-12.50 (m, 1H), 8.26-8.40 (m, 2H), 7.89 (s, 1H), 7.15-7.59 448.2 (m, 5H), 6.84 (s, 1H), 5.03-5.30 (m, 2H), 4.12-4.31 (m, 4H), 3.10-3.50 (m, 2H), 1.22-1 .32 (m, 3H). 258 (DMSO-d6): 12.10-12.60 (m, 1H), 8.25-8.40 (m, 2H), 7.93 (s, 1H), 7.12-7.24 431.2 (m, 2H), 6.96-7.05 (m, 1H), 6.82 (s, 1H), 6.66-6.78 (m, 2H), 5.85 (s, 1H), 5.05 (s, 2H), 4.15-4.30 (m, 2H), 3.75-4.00 (m, 2H), 3.40-3.55 (m, 2H), 1.26 (t, J = 7.0 Hz, 3H). 259 (DMSO-d6): 12.33 (br. s, 1H), 8.40 (d, J = 7.8 Hz, 1H), 8.32 (d, J = 4.3 Hz, 446.2 1H), 8.07 (s, 1H), 7.17-7.29 (m, 2H), 6.80-6.95 (m 3H), 4.96 (s, 2H), 4.21 (q, J = 7.0 Hz, 2H), 3.90-4.07 (m, 2H), 3.81 (s, 3H), 2.88-3.00 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H). 260 (DMSO-d6): 12.32 (s, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.28-8.34 (m, 1H), 8.01 398.2 (s, 1H), 7.19 (dd, J = 8.0, 4.5 Hz, 1H), 6.88 (s, 1H), 4.08-4.24 (m, 4H), 3.73- 3.87 (m, 2H), 2.95-3.06 (m, 2H), 1.24 (t, J = 7.0 Hz, 3H), 1.18 (d, J = 6.0 Hz, 6H). 261 (DMSO-d6): 12.35 (s, 1H), 8.66 (br. s, 1H), 8.41 (d, J = 7.9 Hz, 1H), 8.32 (d, 384.2 J = 3.5 Hz, 1H), 8.01 (s, 1H), 7.21 (dd, J = 7.9, 4.7 Hz, 1H), 6.90 (s, 1H), 4.18-4.30 (m, 3H), 3.89-4.00 (m, 2H), 3.40-3.53 (m, 2H), 1.82-1.96 (m, 4H), 1.25 (q, J = 7.1 Hz, 3H). 262 (DMSO-d6): 12.31 (s, 1H), 9.87 (s, 1H), 8.93 (d, J = 7.8 Hz, 1H), 8.30 (d, J = 369.2 3.6 Hz, 1H), 8.06 (d, J = 2.2 Hz, 1H), 7.14 (dd, J = 8.0, 4.6 Hz, 1H), 6.85 (s, 1H), 4.20 (q, J = 7.0 Hz, 2H), 3.04-3.17 (m, 4H), 1.85-1.98 (m, 4H), 1.26 (t, J = 7.1 Hz, 3H). 263 (DMSO-d6): 12.39 (s, 1H), 10.05 (s, 1H), 8.85 (d, J = 7.8 Hz, 1H), 8.33 (d, J = 397.2 3.8 Hz, 1H), 8.12 (s, 1H), 7.17 (dd, J = 7.8, 4.6 Hz, 1H), 6.87 (s, 1H), 4.20 (q, J = 7.0 Hz, 2H), 3.08-3.20 (m, 4H), 1.63-1.84 (m, 8H), 1.26 (t, J = 7.0 Hz, 3H). 264 (DMSO-d6): 12.26 (s, 1H), 8.16-8.24 (m, 2H), 7.85 (d, J = 7.9 Hz, 1H), 7.62 530.4 (s, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.31 (s, 1H), 7.25 (d, J = 7.6 Hz, 1H), 6.82 (dd, J = 7.8, 4.7 Hz, 1H), 6.75 (s, 1H), 4.20-4.30 (m, 2H), 3.57 (s, 2H), 3.10-3.60 (m, 8H), 2.68-2.77 (m, 1H), 2.24 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 0.99 (d, J = 6.5 Hz, 6H). 265 (DMSO-d6): 8.21 (s, 1H), 8.17 (d, J = 3.4 Hz, 1H), 7.83 (d, J = 7.7 Hz, 1H), 487.2 7.62 (s, 1H), 7.40 (s, 1H), 7.33 (s, 2H), 6.81 (dd, J = 8.0, 4.7 Hz, 1H), 6.63 (s, 1H), 4.15-4.30 (m, 3H), 3.95 (s, 2H), 2.43-2.56 (m, 2H), 2.22 (s, 3H), 1.81-1.94 (m, 2H), 1.63-1.75 (m, 2H), 1.43-1.60 (m, 4H), 1.22-1.33 (m, 3H). 266 (DMSO-d6): 8.16 (d, J = 3.8 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.60 (s, 1H), 461.2 7.18-7.39 (m, 3H), 6.87 (s, 1H), 6.75-6.84 (m, 1H), 6.54 (s, 1H), 4.10-4.25 (m, 2H), 3.93 (s, 2H), 2.95-3.10 (m, 1H), 2.15-2.20 (m, 3H), 1.20-1.30 (m, 3H), 1.10-1.20 (m, 6H).
(898) TABLE-US-00012 TABLE 2-2 267 (DMSO-d6): 12.26 (s, 1H), 10.32 (br. s, 1H), 8.20 (d, J = 3.5 Hz, 1H), 7.71- 503.2 7.82 (m, 2H), 7.46 (d, J = 8.2 Hz, 1H), 7.35 (s, 1H), 7.29 (d, J = 8.5 Hz, 1H), 6.83 (s, 1H), 6.73-6.81 (m, 1H), 4.53-4.61 (m, 1H), 4.20-4.32 (m, 2H), 3.42-3.62 (m, 3H), 2.68-2.80 (m, 2H), 2.26 (s, 3H), 2.03-2.20 (m, 2H), 1.67-1.80 (m, 2H), 1.36-1.51 (m, 2H), 1.29 (t, J = 7.0 Hz, 3H). 268 (DMSO-d6): 12.49 (br. s, 1H), 9.38 (br. s, 1H), 8.44 (d, J = 7.53 Hz, 1H), 8.33 339.0 (dd, J = 1.25, 4.52 Hz, 1H), 8.17 (d, J = 2.51 Hz, 1H), 7.21 (dd, J = 4.77, 8.03 Hz, 1H), 7.02 (s, 1H), 4.79 (s, 2H), 4.23 (q, J = 7.19 Hz, 2H), 1.26 (t, J = 7.03 Hz, 3H). 269 (DMSO-d6): 12.35 (br. s, 1H), 8.60 (d, J = 8.78 Hz, 1H), 8.45 (dd, J = 1.26, 373.9 8.03 Hz, 1H), 8.31 (dd, J = 1.25, 4.52 Hz, 1H), 8.04 (s, 1H), 7.19 (dd, J = 4.77, 8.03 Hz, 1H), 6.90 (s, 1H), 5.18 (t, J = 5.14 Hz, 2H), 4.11-4.27 (m, 3H), 3.67 (t, J = 5.40 Hz, 4H), 1.26 (t, J = 7.15 Hz, 3H). 270 (DMSO-d6): 12.40 (br. s, 1H), 8.84 (t, J = 5.90 Hz, 1H), 8.49 (d, J = 8.03 Hz, 374.0 1H), 8.32 (dd, J = 1.38, 4.64 Hz, 1H), 8.06 (d, J = 2.51 Hz, 1H), 7.21 (dd, J = 4.77, 8.03 Hz, 1H), 6.90 (s, 1H), 4.21 (q, J = 7.03 Hz, 2H), 3.73-3.83 (m, 2H), 3.33-3.66 (m, 5H), 1.26 (t, J = 7.03 Hz, 3H). 271 (DMSO-d6): 12.10-12.20 (m, 1H), 8.20-8.42 (m, 2H), 7.98 (s, 1H), 7.19 (dd, 468.3 J = 7.9, 4.6 Hz, 1H), 6.85 (s, 1H), 4.10-4.40 (m, 4H), 3.85-4.05 (m, 2H), 3.25-3.40 (m, 4H), 2.35-3.45 (m, 3H), 2.65-2.80 (m, 1H), 2.15-2.25 (m, 6H), 1.80-1.95 (m, 2H), 1.53-1.72 (m, 2H), 1.20-1.28 (m, 3H). 272 (DMSO-d6): 12.30 (s, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.31 (d, J = 4.2 Hz, 1H), 486.2 7.98 (s, 1H), 7.19 (dd, J = 7.8, 4.6 Hz, 1H), 6.84 (s, 1H), 4.58-4.73 (m, 3H), 4.16 (q, J = 7.0 Hz, 2H), 3.93-4.01 (m, 2H), 3.68-3.77 (m, 1H), 3.40- 3.56 (m, 3H), 3.31-3.39 (m, 2H), 3.16 (s, 3H), 1.74-1.90 (m, 3H), 1.58- 1.72 (m, 3H), 1.24 (t, J = 7.1 Hz, 3H). 273 (DMSO-d6): 12.35 (s, 1H), 8.41 (d, J = 6.8 Hz, 1H), 8.32 (d, J = 3.4 Hz, 1H), 446.0 8.06 (s, 1H), 7.22 (dd, J = 7.9, 4.6 Hz, 2H), 6.83-6.93 (m, 3H), 4.90 (s, 2H), 4.20 (q, J = 7.0 Hz, 2H), 3.84-4.00 (m, 2H), 3.76 (s, 3H), 3.01-3.09 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H). 274 (DMSO-d6): 12.24 (s, 1H), 8.26-8.48 (m, 2H), 7.95 (s, 1H), 7.10-7.17 (m, 1H), 433.2 6.84-6.94 (m, 3H), 6.59 (d, J = 8.0 Hz, 1H), 4.90 (s, 2H), 4.77 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 3.16 (s, 3H), 2.01 (s, 3H), 1.25-1.19 (m, 3H). 275 (DMSO-d6): 12.31 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.31 (d, J = 3.6 Hz, 1H), 382.2 7.96 (s, 1H), 7.19 (dd, J = 7.9, 4.6 Hz, 1H), 6.84 (s, 1H), 4.00-4.25 (m, 4H), 3.22-3.32 (m, 1H), 3.05-2.95 (m, 1H), 1.75-1.91 (m, 3H), 1.60-1.74 (m, 1H), 1.17-1.33 (m, 4H), 0.95 (d, J = 6.2 Hz, 3H). 276 (DMSO-d6): 12.32 (s, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.31 (d, J = 4.6 Hz, 1H), 398.2 8.01 (s, 1H), 7.19 (dd, J = 7.9, 4.7 Hz, 1H), 6.88 (s, 1H), 4.12-4.22 (m, 4H), 3.76-3.86 (m, 2H), 2.96-3.06 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H), 1.18 (d, J = 6.2 Hz, 6H). 277 (DMSO-d6): 12.37 (s, 1H), 9.96 (s, 1H), 8.99 (d, J = 7.8 Hz, 1H), 8.34 (d, 428.4 J = 3.3 Hz, 1H), 8.11 (d, J = 2.5 Hz, 1H), 7.23 (dd, J = 8.0, 4.7 Hz, 1H), 6.85 (s, 1H), 4.49 (t, J = 5.2 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.56 (q, J = 6.0 Hz, 2H), 2.98-3.12 (m, 4H), 2.57-2.77 (m, 4H), 2.45-2.55 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H). 278 (DMSO-d6): 12.21 (br. s, 1H), 8.28-8.42 (m, 2H), 7.96 (s, 1H), 7.18 (dd, J = 396.2 7.9, 4.7 Hz, 1H), 6.84 (s, 1H), 4.06-4.23 (m, 4H), 2.72-2.88 (m, 2H), 1.75- 1.92 (m, 3H), 1.24 (t, J = 7.0 Hz, 3H), 0.86-1.00 (m, 7H). 279 (DMSO-d6): 12.27 (s, 1H), 9.22 (br. s, 1H), 6.4-8.6 (m, 7H), 4.15-4.25 (m, 367.2 2H), 1.18-1.30 (m, 3H). 280 (DMSO-d6): 12.10-12.65 (m, 1H), 8.25-8.53 (m, 2H), 8.01 (s, 1H), 7.14-7.29 446.0 (m, 2H), 6.80-6.95 (m, 3H), 4.68-4.93 (m, 2H), 4.15-4.27 (m, 2H), 3.93- 4.05 (m, 2H), 3.80-3.92 (m, 3H), 2.98-3.10 (m, 2H), 1.23-1.32 (m, 3H). 281 (DMSO-d6): 12.34 (s, 1H), 9.51 (br. s, 1H), 9.17 (d, J = 7.3 Hz, 1H), 8.33 (d, 411.2 J = 3.3 Hz, 1H), 8.12 (s, 1H), 7.18 (dd, J = 8.0, 4.6 Hz, 1H), 6.82 (s, 1H), 4.22 (q, J = 7.0 Hz, 2H), 2.95-3.10 (m, 2H), 1.70-1.85 (m, 3H), 1.37-1.53 (m, 3H), 1.27 (t, J = 7.1 Hz, 3H), 0.98 (d, J = 6.0 Hz, 6H). 282 (DMSO-d6): 12.25 (br. s, 1H), 8.34-8.39 (m, 1H), 8.32 (d, J = 4.6 Hz, 1H), 7.97 396.2 (s, 1H), 7.19 (dd, J = 7.9, 4.6 Hz, 1H), 6.84 (s, 1H), 4.10-4.27 (m, 2H), 3.73 (dd, J = 13.1, 3.5 Hz, 2H), 3.43-3.59 (m, 2H), 2.06-2.20 (m, 2H), 1.54 (t, J = 5.7 Hz, 2H), 1.25 (t, J = 6.7 Hz, 3H), 0.95 (d, J = 7.3 Hz, 6H). 283 (DMSO-d6): 12.30 (s, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.32 (d, J = 4.7 Hz, 1H), 396.2 7.97 (s, 1H), 7.19 (dd, J = 7.8, 4.7 Hz, 1H), 6.84 (s, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.62-3.71 (m, 2H), 3.54 (s, 2H), 1.71-1.82 (m, 2H), 1.45-1.56 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H), 0.97 (s, 6H). 284 (DMSO-d6): 12.30 (s, 1H), 8.38 (d, J = 8.2 Hz, 1H), 8.31 (d, J = 4.2 Hz, 1H), 398.0 8.00 (s, 1H), 7.19 (dd, J = 8.0, 4.6 Hz, 1H), 6.83 (s, 1H), 4.97-5.10 (m, 1H), 4.42-4.56 (m, 1H), 4.10-4.23 (m, 2H), 3.80-3.95 (m, 2H), 3.57-3.72 (m, 2H), 1.70-1.90 (m, 3H), 1.55-1.70 (m, 3H), 1.24 (t, J = 7.0 Hz, 3H). 285 (DMSO-d6): 12.28 (br. s, 1H), 10.34 (br. s, 1H), 8.20 (dd, J = 1.38, 4.64 Hz, 503.3 1H), 7.73-7.79 (m, 2H), 7.42 (d, J = 7.78 Hz, 1H), 7.31 (s, 1H), 7.25 (d, J = 8.03 Hz, 1H), 6.84 (s, 1H), 6.76 (dd, J = 4.64, 7.91 Hz, 1H), 4.27 (q, J = 7.03 Hz, 2H), 3.61 (t, J = 4.52 Hz, 4H), 3.28-3.34 (m, 4H), 2.82-2.90 (m, 2H), 2.58-2.64 (m, 2H), 2.24 (s, 3H), 1.30 (t, J = 7.03 Hz, 3H). 286 (DMSO-d6): 12.25 (s, 1H), 10.37 (s, 1H), 8.20 (d, J = 3.7 Hz, 1H), 7.78 (d, J = 434.0 7.8 Hz, 1H), 7.72 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H), 7.23 (d, J = 7.7 Hz, 1H), 6.85 (s, 1H), 6.80 (dd, J = 7.8, 4.7 Hz, 1H), 4.77 (t, J = 5.1 Hz, 1H), 4.27 (q, J = 6.9 Hz, 2H), 3.72 (q, J = 6.7 Hz, 2H), 2.85 (t, J = 6.9 Hz, 2H), 2.24 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H).
(899) TABLE-US-00013 TABLE 2-3 287 (DMSO-d6): 12.11 (br. s, 1H), 8.15 (d, J = 3.8 Hz, 1H), 7.68-7.78 (m, 2H), 7.43 497.2 (s, 1H), 7.26-7.38 (m, 2H), 6.80 (dd, J = 7.7, 4.8 Hz, 1H), 6.60 (s, 1H), 4.15- 4.25 (m, 2H), 3.66 (s, 2H), 2.60-2.70 (m, 4H), 2.19 (s, 3H), 1.91 (s, 3H), 1.70- 1.82 (m, 4H), 1.27 (t, J = 7.0 Hz, 3H). 288 (DMSO-d6): 11.80-12.15 (m, 1H), 8.22-8.37 (m, 2H), 8.12-8.18 (m, 1H), 7.74- 513.0 7.83 (m, 1H), 7.54-7.72 (m, 1H), 7.33 (s, 1H), 7.26 (d, J = 8.9 Hz, 1H), 6.9- 7.05 (m, 1H), 6.77-6.84 (m, 1H), 6.27-6.39 (m, 1H), 4.04-4.23 (m, 2H), 3.60- 3.70 (m, 4H), 3.56 (s, 2H), 2.53-2.62 (m, 4H), 2.10 (s, 3H), 1.20-1.30 (m, 3H). 289 (DMSO-d6): 8.05-8.15 (m, 1H), 7.82 (d, J = 7.4 Hz, 1H), 7.52 (s, 1H), 7.27 (s, 1H), 527.0 7.20 (d, J = 7.8 Hz, 1H), 6.91 (d, J = 7.9 Hz, 1H), 6.75-6.84 (m, 1H), 6.18 (s, 1H), 4.02-4.13 (m, 2H), 3.30-3.70 (m, 3H), 2.75-2.85 (m, 2H), 2.36-2.26 (m, 2H), 2.07 (s, 3H), 1.72-1.82 (m, 2H), 1.40-1.50 (m, 2H), 1.15-1.30 (m, 3H). 290 (DMSO-d6): 12.27 (br. s, 1H), 8.20 (dd, J = 1.25, 4.77 Hz, 1H), 7.72-7.80 (m, 2H), 516.3 7.40 (d, J = 8.03 Hz, 1H), 7.30 (s, 1H), 7.23 (d, J = 7.78 Hz, 1H), 6.82 (s, 1H), 6.76 (dd, J = 4.64, 7.91 Hz, 1H), 4.26 (q, J = 7.03 Hz, 2H), 3.25-3.50 (m, 4H), 2.79-2.89 (m, 2H), 2.56-2.66 (m, 2H), 2.31-3.47 (m, 4H), 2.23 (s, 3H), 2.20 (s, 3H), 1.29 (t, J = 7.15 Hz, 3H). 291 (DMSO-d6): 12.31 (s, 1H), 8.39 (d, J = 6.9 Hz, 1H), 8.31 (d, J = 4.6 Hz, 1H), 7.95 342.2 (s, 1H), 7.20 (dd, J = 7.9, 4.7 Hz, 1H), 6.84 (s, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.73 (q, J = 7.0 Hz, 2H), 3.26 (s, 3H), 1.20-1.33 (m, 6H). 292 (DMSO-d6): 8.38 (d, J = 7.9 Hz, 1H), 8.31 (d, J = 3.3 Hz, 1H), 7.95 (s, 1H), 7.19 356.0 (dd, J = 7.9, 4.7 Hz, 1H), 6.84 (s, 1H), 4.50-4.62 (m, 1H), 4.17 (d, J = 7.1 Hz, 2H), 3.09 (s, 3H), 1.36-1.20 (m, 9H). 293 (DMSO-d6): 12.31 (br. s, 1H), 10.01 (br. s, 1H), 8.92 (d, J = 7.8 Hz, 1H), 8.31 399.2 (d, J = 3.7 Hz, 1H), 8.08 (s, 1H), 7.18 (dd, J = 7.9, 4.7 Hz, 1H), 6.83 (s, 1H), 4.97 (br. s, 1H), 4.20 (q, J = 7.0 Hz, 2H), 3.72-3.83 (m, 1H), 3.12-3.20 (m, 1H), 2.97-3.06 (m, 1H), 2.71-2.91 (m, 2H), 1.80-1.93 (m, 2H), 1.56-1.68 (m, 1H), 1.18-1.31 (m, 4H). 294 (DMSO-d6): 12.29 (s, 1H), 8.29-8.38 (m, 2H), 7.96 (s, 1H), 7.19 (dd, J = 7.9, 396.4 4.7 Hz, 1H), 6.82 (s, 1H), 4.95-5.10 (m, 1H), 4.15-4.25 (m, 2H), 3,24-3.34 (m, 2H), 1.68-1.88 (m, 3H), 1.25-1.40 (m, 2H), 1.25 (d, J = 6.2 Hz, 6H), 0.97 (d, J = 6.3 Hz, 3H). 295 (DMSO-d6): 12.35 (s, 1H), 8.40 (d, J = 6.6 Hz, 1H), 8.33 (d, J = 4.6 Hz, 1H), 8.07 430.2 (s, 1H), 7.24-7.32 (m, 4H), 7.22 (dd, J = 7.9, 4.7 Hz, 1H), 6.87 (s, 1H), 5.00- 5.12 (m, 1H), 4.97 (s, 2H), 3.90-4.02 (m, 2H), 3.03-3.13 (m, 2H), 1.27 (t, J = 8.9 Hz, 6H). 296 (DMSO-d6): 12.31 (s, 1H), 9.86 (s, 1H), 8.84 (d, J = 7.8 Hz, 1H), 8.30 (d, J = 3.3 357.2 Hz, 1H), 8.05 (d, J = 2.5 Hz, 1H), 7.20 (dd, J = 8.0, 4.6 Hz, 1H), 6.83 (s, 1H), 4.99-5.10 (m, 1H), 2.77 (s, 6H), 1.27 (d, J = 6.3 Hz, 6H). 297 (DMSO-d6): 12.26 (s, 1H), 10.07 (s, 1H), 8.17 (s, 1H), 7.85 (s, 1H), 7.69 (d, J = 462.8 7.4 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.72-6.88 (m, 2H), 6.52-6.67 (m, 2H), 5.80-5.92 (m, 1H), 5.07-5.18 (m, 1H), 4.71-4.81 (m, 1H), 3.58-3.69 (m, 2H), 3.15-3.25 (m, 2H), 2.13 (s, 3H), 1.30 (d, J = 5.9 Hz, 6H). 298 (MeOD): 8.15-8.24 (m, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.65 (br. s, 1H), 7.40-7.55 526.4 (m, 3H), 6.90-7.03 (m, 2H), 6.61 (s, 1H), 4.34-4.43 (m, 2H), 3.66 (s, 2H), 2.70-2.98 (m, 8H), 2.49 (s, 3H), 2.32 (s, 3H), 1.35-1.42 (m, 3H). 299 (DMSO-d6): 12.31 (s, 1H), 10.42 (br. s, 1H), 8.23 (dd, J = 4.6, 1.4 Hz, 1H), 7.79 487.0 (d, J = 7.3 Hz, H), 7.72 (d, J = 2.7 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.37 (s, 1H), 7.30 (d, J = 7.9 Hz, 1H), 6.87 (s, 1H), 6.78 (dd, J = 7.9, 4.8 Hz, 1H), 4.27 (q, J = 7.1 Hz, H), 3.35-3.70 (m, 4H), 3.03-3.15 (m, 4H), 2.27 (s, 3H), 1.85- 2.10 (s, 4H), 1.30 (t, J = 7.1 Hz, 3H). 300 (DMSO-d6): 12.30 (br. s, 1H), 8.39 (d, J = 7.6 Hz, 1H), 8.31 (d, J = 4.4 Hz, 1H), 396.0 7.93 (s, 1H), 7.19 (dd, J = 7.9, 4.7 Hz, 1H), 6.85 (s, 1H), 4.16 (q, J = 7.1 Hz, 3H), 3.11 (s, 3H), 1.79-1.92 (m, 4H), 1.60-1.75 (m, 3H), 1.28-1.44 (m, 2H), 1.11-1.28 (m, 4H). 301 (DMSO-d6): 12.30 (br. s, 1H), 9.62 (br. s, 1H), 8.91 (d, J = 8.0 Hz, 1H), 8.31 (d, 411.0 J = 3.8 Hz, 1H), 8.07 (s, 1H), 7.16 (dd, J = 8.0, 4.6 Hz, 1H), 6.84 (s, 1H), 4.21 (q, J = 7.0 Hz, 2H), 2.78-2.88 (m, 1H), 2.77 (s, 3H), 1.88-2.00 (m, 2H), 1.68- 1.80 (m, 2H), 1.48-1.59 (m, 1H), 1.16-1.31 (m, 7H), 1.00-1.12 (m, 1H). 302 (DMSO-d6): 12.31 (s, 1H), 10.07 (s, 1H), 8.94 (d, J = 7.5 Hz, 1H), 8.32 (d, J = 426.0 3.4 Hz, 1H), 8.12 (s, 1H), 7.21 (dd, J = 8.0, 4.7 Hz, 1H), 6.88 (s, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.57-3.76 (m, 4H), 2.97-3.12 (m, 4H), 2.08 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H). 303 (DMSO-d6): 12.30 (br. s, 1H), 8.15-8.21 (m, 2H), 7.77 (s, 1H), 7.68 (d, J = 7.8 517.4 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.04 (s, 1H), 6.94 (d, J = 8.7 Hz, 1H), 6.73- 6.81 (m, 2H), 5.08-5.19 (m, 1H), 4.19 (t, J = 5.6 Hz, 2H), 2.94 (t, J = 5.6 Hz, 2H), 2.62-2.71 (m, 4H), 2.23 (s, 3H), 1.70-1.80 (m, 4H), 1.31 (d, J = 6.2 Hz, 6H). 304 (DMSO-d6): 12.25 (br. s, 1H), 9.80 (br. s, 1H), 8.85 (d, J = 7.4 Hz, 1H), 8.29 (d, 357.2 J = 3.6 Hz, 1H), 8.04 (s, 1H), 7.17 (dd, J = 8.0, 4.7 Hz, 1H), 6.78 (br. s, 1H), 4.19 (q, J = 6.9 Hz, 2H), 2.88-3.00 (m, 2H), 2.74 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H). 305 (DMSO-d6): 12.31 (br. s, 1H), 9.49 (br. s, 1H), 8.96 (d, J = 7.8 Hz, 1H), 8.31 (d, 371.2 J = 3.3 Hz, 1H), 8.08 (s, 1H), 7.18 (dd, J = 8.0, 4.6 Hz, 1H), 6.86 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.00 (q, J = 7.0 Hz, 4H), 1.27 (t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.1 Hz, 6H).
(900) TABLE-US-00014 TABLE 2-4 306 (DMSO-d6): 12.09 (br. s, 1H), 8.98 (d, J = 7.6 Hz, 1H), 8.32 (d, J = 3.4 Hz, 1H), 399.2 8.05 (s, 1H), 7.21 (dd, J = 8.0, 4.7 Hz, 1H), 6.73 (s, 1H), 4.80 (s, 1H), 4.17 (q, J = 7.0 Hz, 2H), 3.54-3.69 (m, 1H), 3.04-3.15 (m, 2H), 2.82-2.95 (m, 2H), 1.83-1.94 (m, 2H), 1.63-1.77 (m, 2H), 1.24 (t, J = 7.0 Hz, 3H). 307 (DMSO-d6): 12.29 (s, 1H), 10.23 (s, 1H), 8.18 (d, J = 3.4 Hz, 1H), 7.78 (d, J = 533.4 2.5 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 8.6, 2.7 Hz, 1H), 6.79 (s, 1H), 6.74 (dd, J = 7.9, 4.7 Hz, 1H), 5.09-5.18 (m, 1H), 4.19 (t, J = 5.6 Hz, 2H), 3.58-3.67 (m, 4H), 2.78 (t, J = 5.6 Hz, 2H), 2.49-2.57 (m, 4H), 2.23 (s, 3H), 1.31 (d, J = 6.3 Hz, 6H). 308 (DMSO-d6): 12.20 (br. s, 1H), 10.26 (br. s, 1H), 8.18 (d, J = 3.9 Hz, 1H), 7.66- 546.6 7.77 (m, 2H), 7.26-7.39 (m, 1H), 7.00 (s, 1H), 6.86-6.93 (m, 1H), 6.61-6.78 (s, 2H), 5.06-5.17 (m, 1H), 4.11-4.18 (m, 2H), 2.76 (t, J = 5.5 Hz, 2H), 2.30- 2.50 (m, 8H), 2.20 (s, 3H), 2.17 (s, 3H), 1.29 (d, J = 6.2 Hz, 6H). 309 (DMSO-d6): 12.30 (br. s, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.32 (d, J = 3.3 Hz, 1H), 412.2 7.98 (s, 1H), 7.20 (dd, J = 8.0, 4.7 Hz, 1H), 6.89 (s, 1H), 4.23-4.35 (m, 2H), 3.96-4.07 (m, 1H), 3.54-3.64 (m, 2H), 3.30 (s, 3H), 1.94-2.03 (m, 2H), 1.73- 1.84 (m, 2H), 1.51-1.69 (m, 3H), 1.35-1.49 (m, 2H), 1.15-1.28 (m, 1H). 310 (DMSO-d6): 12.32 (s, 1H), 9.84 (s, 1H), 8.83 (d, J = 8.2 Hz, 1H), 8.30 (d, J = 3.4 373.4 Hz, 1H), 8.05 (s, 1H), 7.20 (dd, J = 8.0, 4.5 Hz, 1H), 6.88 (s, 1H), 4.25-4.32 (m, 2H), 3.57-3.63 (m, 2H), 3.30 (s, 3H), 2.78 (s, 6H). 311 (DMSO-d6): 12.31 (s, 1H), 10.43 (s, 1H), 8.23 (d, J = 3.8 Hz, 1H), 7.73-7.81 (m, 444.4 2H), 7.58 (d, J = 8.1 Hz, 1H), 7.53 (s, 1H), 7.44 (d, J = 7.9 Hz, 1H), 6.88 (s, 1H), 6.83 (dd, J = 7.9, 4.7 Hz, 1H), 5.42 (t, J = 5.9 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 4.27 (q, J = 7.0 Hz, 2H), 2.27 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H). 312 (DMSO-d6): 12.27 (s, 1H), 10.41 (s, 1H), 8.16 (d, J = 3.4 Hz, 1H), 7.79 (d, J = 1.9 471.1 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.48-755 (m, 2H), 7.42 (d, J = 7.9 Hz, 1H), 6.82 (s, 1H), 6.79 (dd, J = 7.9, 4.6 Hz, 1H), 4.24 (q, J = 7.0 Hz, 2H), 3.53 (s, 2H), 2.30 (s, 6H), 2.23 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H). 313 (DMSO-d6): 12.28 (s, 1H), 10.17 (br. s, 1H), 8.21 (d, J = 3.3 Hz, 1H), 7.71-7.80 461.1 (m, 2H), 7.44 (d, J = 8.1 Hz, 1H), 7.32 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 6.84 (s, 1H), 6.75-6.81 (m, 1H), 4.23-4.32 (m, 2H), 2.85-2.95 (m, 2H), 2.75-2.85 (m, 2H), 2.42 (s, 6H), 2.24 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). 314 (DMSO-d6): 12.28 (s, 1H), 10.27 (br. s, 1H), 8.21 (d, J = 4.6 Hz, 1H), 7.72-7.78 517.1 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H), 7.24 (d, J = 8.3 Hz, 1H), 6.84 (s, 1H), 6.76 (dd, J = 7.9, 4.6 Hz, 1H), 4.58-4.72 (m, 1H), 4.22-4.32 (m, 2H), 3.44-3.60 (m, 1H), 2.80-3.00 (m, 4H), 2.40-2.60 (m, 4H), 2.24 (s, 3H), 1.72- 1.85 (m, 2H), 1.38-1.53 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H). 315 (DMSO-d6): 12.26 (br. s, 1H), 9.72 (br. s, 1H), 8.91 (d, J = 7.6 Hz, 1H), 8.30 (d, 371.0 J = 3.7 Hz, 1H), 8.05 (s, 1H), 7.16 (dd, J = 7.8, 4.6 Hz, 1H), 6.77 (br. s, 1H), 4.13-4.24 (m, 2H), 3.08-3.20 (m, 1H), 2.72 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.10 (d, J = 6.3 Hz, 6H). 316 (DMSO-d6): 12.33 (br. s, 1H), 10.25 (br. s, 1H), 8.87-8.99 (m, 1H), 8.30 (d, J = 398.0 3.4 Hz, 1H), 8.01-8.18 (m, 2H), 7.07 (dd, J = 8.0, 4.6 Hz, 1H), 6.85 (br. s, 1H), 4.15-4.26 (m, 2H), 3.60-3.72 (m, 2H), 3.20-3.30 (m, 4H), 1.26 (t, J = 7.0 Hz, 3H). 317 (DMSO-d6): 12.36 (s, 1H), 8.42 (d, J = 7.3 Hz, 1H), 8.33 (d, J = 3.4 Hz, 1H), 8.07 446.1 (s, 1H), 7.24-7.32 (m, 4H), 7.22 (dd, J = 7.9, 4.7 Hz, 1H), 6.91 (s, 1H), 4.98 (br. s, 2H), 4.25-4.33 (m, 2H), 3.89-4.03 (m, 2H), 3.56-3.64 (m, 2H), 3.30 (s, 3H), 3.08 (t, J = 5.7 Hz, 2H). 318 (DMSO-d6): 12.26 (s, 1H), 10.09 (s, 1H), 8.18 (d, J = 3.3 Hz, 1H), 7.83 (s, 1H), 479.1 7.70 (d, J = 7.7 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H), 6.75-6.86 (m, 2H), 6.61 (s, 1H), 6.57 (d, J = 8.5 Hz, 1H), 5.81-5.89 (m, 1H), 4.76 (t, J = 5.4 Hz, 1H), 4.28- 4.36 (m, 2H), 3.58-3.67 (m, 4H), 3.32 (s, 1H), 3.20 (q, J = 5.9 Hz, 2H), 2.13 (s, 3H). 319 (DMSO-d6): 12.24 (br. s, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.31 (d, J = 4.5 Hz, 1H), 451.2 8.00 (s, 1H), 7.20 (dd, J = 7.9, 4.6 Hz, 1H), 6.88 (s, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.76-3.86 (s, 4H), 3.26-3.32 (m, 2H), 2.82-2.90 (m, 4H), 1.25 (q, J = 7.0 Hz, 3H). 320 (DMSO-d6): 12.22 (br. s, 1H), 8.19 (s, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.72 (s, 461.4 1H), 7.21-7.47 (m, 3H), 6.70-6.85 (m, 2H), 5.06-5.18 (m, 1H), 3.49 (s, 2H), 2.25 (s, 3H), 2.22 (s, 6H), 1.91 (s, 3H), 1.30 (d, J = 5.8 Hz, 6H). 321 (DMSO-d6): 8.27-8.35 (m, 2H), 7.95 (s, 1H), 7.24-7.18 (m, 1H), 6.84 (s, 1H), 412.1 4.21-4.27 (m, 2H), 3.54-3.62 (m, 4H), 3.23-3.32 (m, 5H), 1.70-1.85 (m, 3H), 1.23-1.37 (m, 2H), 0.94 (d, J = 6.2 Hz, 3H). 322 (DMSO-d6): 12.27 (s, 1H), 10.24 (s, 1H), 8.16-8.23 (m, 1H), 7.76 (s, 1H), 7.68 548.8 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.05 (s, 1H), 6.95 (d, J = 8.1 Hz, 1H), 6.83 (s, 1H), 6.71-6.79 (m, 1H), 4.30-4.38 (m, 2H), 4.15-4.23 (m, 2H), 3.56-3.69 (m, 6H), 3.33 (s, 3H), 2.74-2.82 (m, 2H), 2.48-2.58 (m, 4H), 2.23 (s, 3H). 323 (DMSO-d6): 11.18 (br. s, 1H), 8.18 (d, J = 3.4 Hz, 1H), 7.66-7.75 (m, 2H), 7.32 562.2 (d, J = 8.6 Hz, 1H), 7.00 (s, 1H), 6.91 (d, J = 8.6 Hz, 1H), 6.70-6.78 (m, 2H), 4.27-4.35 (m, 2H), 4.16 (t, J = 5.7 Hz, 2H), 3.60-3.66 (m, 2H), 3.33 (s, 3H), 2.76 (t, J = 5.6 Hz, 2H), 2.48-2.58 (s, 4H), 2.31-2.42 (m, 4H), 2.20 (s, 3H), 2.17 (s, 3H), 1.90 (s, 3H).
(901) TABLE-US-00015 TABLE 2-5 324 (MeOD): 8.16-8.23 (m, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.30-7.60 (m, 4H), 6.90- 477.0 6.71 (m, 2H), 6.60 (s, 1H), 4.42-4.53 (m, 2H), 3.65-3.80 (m, 4H), 3.41 (s, 3H), 2.41 (s, 6H), 2.35 (s, 3H). 325 (DMSO-d6): 12.39 (s, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.44 (d, J = 7.8 Hz, 1H), 8.34 412.2 (d, J = 4.6 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.22 (dd, J = 7.9, 4.7 Hz, 1H), 6.89 (s, 1H), 4.21 (t, J = 6.3 Hz, 2H), 3.94-4.06 (m, 1H), 3.56 (t, J = 5.9 Hz, 3H), 1.93-2.03 (m, 2H), 1.74-1.84 (m, 4H), 1.53-1.70 (m, 3H), 1.34-1.48 (m, 2H), 1.15-1.28 (m, 1H). 326 (DMSO-d6): 12.35 (s, 1H), 8.50 (br. s, 1H), 8.41 (d, J = 7.0 Hz, 1H), 8.30-8.35 425.2 (m, 1H), 7.98 (s, 1H), 7.20 (dd, J = 7.9, 4.7 Hz, 1H), 6.89 (s, 1H), 4.22 (t, J = 5.8 Hz, 2H), 3.94-4.06 (m, 1H), 2.51-2.58 (m, 2H), 2.23 (s, 6H), 1.96-2.05 (m, 2H), 1.75-1.86 (m, 2H), 1.62-1.72 (m, 1H), 1.34-1.59 (m, 4H), 1.16-1.29 (m, 1H). 327 (DMSO-d6): 12.30 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.31 (d, J = 4.2 Hz, 1H), 7.96 425.2 (s, 1H), 7.19 (dd, J = 7.9, 4.4 Hz, 1H), 6.85 (s, 1H), 4.21 (t, J = 5.7 Hz, 2H), 2.40-2.60 (m, 6H), 2.22 (s, 6H), 1.73-1.87 (m, 2H), 1.15-1.42 (m, 3H), 0.97 (d, J = 6.1 Hz, 3H). 328 (DMSO-d6): 8.37 (d, J = 7.8 Hz, 1H), 8.31 (d, J = 3.6 Hz, 1H), 7.93 (s, 1H), 7.20- 412.2 7.27 (m, 1H), 6.85 (s, 1H), 4.17 (t, J = 6.2 Hz, 2H), 3.70-3.90 (m, 4H), 3.50- 3.56 (m, 2H), 1.70-1.88 (m, 6H), 1.50-1.60 (m, 4H). 329 (DMSO-d6): 12.42 (s, 1H), 8.43 (d, J = 7.9 Hz, 1H), 8.34 (d, J = 4.2 Hz, 1H), 7.98 412.2 (s, 1H), 7.24 (dd, J = 7.9, 4.8 Hz, 1H), 6.88 (s, 1H), 4.35-4.13 (m, 5H), 3.56 (t, J = 6.0 Hz, 2H), 3.25-3.37 (m, 2H), 1.70-1.88 (m, 5H), 1.26-1.40 (m, 2H), 0.96 (d, J = 6.2 Hz, 3H). 330 (DMSO-d6): 8.12-8.17 (m, 1H), 7.72-7.79 (m, 1H), 7.65 (s, 1H), 7.14-7.22 (m, 533.6 1H), 6.94 (s, 1H), 6.82-6.88 (m, 1H), 6.73-6.80 (m, 1H), 6.55 (s, 1H), 4.21- 4.30 (m, 2H), 4.09-4.16 (m, 2H), 3.55-3.66 (m, 2H), 3.32 (s, 3H), 2.85 (t, J = 5.7 Hz, 2H), 2.54-2.61 (m, 4H), 2.16 (s, 3H), 1.90 (s, 3H), 1.68-1.76 (m, 4H). 331 (DMSO-d6): 12.47 (s, 1H), 8.47 (d, J = 7.9 Hz, 1H), 8.36 (br. s, 1H), 8.09 (s, 446.0 1H), 7.16-7.32 (m, 6H), 6.93 (s, 1H), 5.00 (br. s, 2H), 4.22 (t, J = 6.4 Hz, 2H), 3.80-4.10 (m, 2H), 3.57 (t, J = 6.0 Hz, 2H), 3.08 (t, J = 5.6 Hz, 2H), 1.75-1.85 (m, 2H). 332 (DMSO-d6): 12.39 (s, 1H), 10.14 (s, 1H), 8.95 (d, J = 8.0 Hz, 1H), 8.34 (d, J = 415.1 4.5 Hz, 1H), 8.12 (d, J = 2.6 Hz, 1H), 7.24 (dd, J = 8.0, 4.7 Hz, 1H), 6.88 (s, 1H), 4.21 (t, J = 6.3 Hz, 2H), 3.76-3.86 (m, 4H), 3.53-3.61 (m, 3H), 3.02-3.12 (m, 4H), 1.87-1.74 (m, 2H). 333 (DMSO-d6): 12.38 (s, 1H), 9.95 (br. s, 1H), 8.87 (d, J = 7.7 Hz, 1H), 8.32 (d, J = 373.2 3.4 Hz, 1H), 8.03-8.09 (m, 1H), 7.23 (dd, J = 8.0, 4.7 Hz, 1H), 6.88 (s, 1H), 4.21 (t, J = 6.3 Hz, 2H), 3.57 (t, J = 5.8 Hz, 2H), 3.39 (s, 1H), 2.77 (s, 6H), 1.75- 1.85 (m, 2H). 334 (DMSO-d6): 12.31 (br. s, 1H), 8.91 (d, J = 7.53 Hz, 1H), 8.33 (d, J = 3.51 Hz, 415.2 1H), 8.09 (br. s, 1H), 7.22 (dd, J = 4.64, 7.91 Hz, 1H), 6.83 (br. s, 1H), 4.27 (t, J = 4.64 Hz, 2H), 3.77-3.85 (m, 4H), 3.56-3.62 (m, 2H), 3.30 (s, 3H), 3.00- 3.10 (m, 4H). 335 (DMSO-d6): 12.37 (br. s, 1H), 8.40 (dd, J = 1.26, 8.03 Hz, 1H), 8.33 (dd, J = 1.38, 406.2 4.64 Hz, 1H), 8.06 (s, 1H), 7.63 (d, J = 1.51 Hz, 1H), 7.21 (dd, J = 4.64, 7.91 Hz, 1H), 6.92 (s, 1H), 6.47 (d, J = 1.76 Hz, 1H), 4.90 (br. s, 2H), 4.21 (q, J = 7.19 Hz, 2H), 3.95-4.05 (m, 2H), 2.74-2.83 (m, 2H), 1.26 (t, J = 7.03 Hz, 3H). 336 (DMSO-d6): 12.27 (s, 1H), 10.19 (s, 1H), 8.18 (d, J = 3.5 Hz, 1H), 7.80-7.86 (m, 479.2 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.76-6.84 (m, 2H), 6.62 (s, 1H), 6.58 (d, J = 8.5 Hz, 1H), 4.26 (t, J = 6.3 Hz, 2H), 3.54-3.66 (m, 4H), 3.20 (t, J = 6.2 Hz, 3H), 2.13 (s, 3H), 1.78-1.87 (m, 2H). 337 (DMSO-d6): 12.36 (s, 1H), 10.61 (br. s, 1H), 10.54 (s, 1H), 8.24 (d, J = 3.8 Hz, 477.4 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.55-7.70 (m, 4H), 6.89-6.95 (m, 2H), 4.38 (d, J = 4.8 Hz, 2H), 4.29 (t, J = 6.3 Hz, 2H), 3.62-3.55 (m, 2H), 3.39 (s, 1H), 2.76 (d, J = 4.6 Hz, 6H), 2.32 (s, 3H), 1.80-1.89 (m, 2H). 338 (DMSO-d6): 12.23 (s, 1H), 8.78 (d, J = 7.5 Hz, 1H), 8.29 (d, J = 4.1 Hz, 1H), 8.01 386.4 (s, 1H), 7.19 (dd, J = 7.9, 4.7 Hz, 1H), 6.77 (s, 1H), 4.20 (t, J = 5.8 Hz, 2H), 2.73 (s, 6H), 2.53-2.58 (m, 2H), 2.24 (s, 6H), 1.90 (s, 3H). 339 (DMSO-d6): 8.71 (d, J = 7.1 Hz, 1H), 8.27 (d, J = 4.6 Hz, 1H), 7.89 (s, 1H), 7.15 428.4 (dd, J = 7.8, 4.6 Hz, 1H), 6.37 (s, 1H), 4.10 (t, J = 5.9 Hz, 3H), 3.76-3.82 (m, 4H), 2.81-2.88 (m, 4H), 2.45-2.55 (m, 2H), 2.24 (s, 6H), 1.88 (s, 3H). 340 (DMSO-d6): 12.23 (br. s, 1H), 8.17 (d, J = 3.7 Hz, 1H), 7.80 (s, 1H), 7.67-7.74 492.4 (m, 1H), 7.08-7.17 (m, 1H), 6.78-6.84 (m, 1H), 6.70-6.78 (m, 1H), 6.60 (s, 1H), 6.53-6.58 (m, 1H), 5.81 (br. s, 1H), 4.71-4.79 (m, 1H), 4.21-4.30 (m, 2H), 3.59-3.67 (m, 2H), 3.15-3.25 (m, 2H), 2.55-2.60 (m, 2H), 2.21 (s, 6H), 2.12 (s, 3H), 1.90 (s, 3H). 341 (DMSO-d6): 12.28 (br. s, 1H), 10.45 (s, 1H), 8.18 (dd, J = 1.38, 4.64 Hz, 1H), 7.70- 429.1 7.76 (m, 2H), 7.55 (d, J = 8.03 Hz, 1H), 7.43 (s, 1H), 7.36 (d, J = 7.78 Hz, 1H), 6.85 (s, 1H), 6.77 (dd, J = 4.64, 7.91 Hz, 1H), 4.27 (q, J = 7.03 Hz, 2H), 4.17 (s, 2H), 2.28 (s, 3H), 1.30 (t, J = 7.15 Hz, 3H) 342 (DMSO-d6): 12.19 (br. s., 1H), 9.17 (s, 1H), 8.12-8.24 (m, 3H), 7.82 (d, J = 8.03 490.2 Hz, 1H), 7.66 (s, 1H), 7.21-7.40 (m, 3H), 6.78 (dd, J = 4.64, 7.91 Hz, 1H), 6.72 (s, 1H), 4.29 (t, J = 5.77 Hz, 2H), 3.52 (s, 2H), 2.65-2.73 (m, 2H), 2.30 (s, 6H), 2.23 (s, 9H). 343 (DMSO-d6): 12.39 (br. s, 1H), 9.93 (br. s, 1H), 8.28 (dd, J = 1.26, 4.52 Hz, 1H), 463.9 7.86 (s, 1H), 7.33 (d, J = 8.53 Hz, 2H), 7.10-7.19 (m, 2H), 7.00 (dd, J = 2.76, 8.53 Hz, 1H), 5.49 (br. s, 1H), 5.04-5.17 (m, 1H), 4.99 (t, J = 5.40 Hz, 1H), 4.12 (t, J = 4.89 Hz, 2H), 3.81 (q, J = 4.94 Hz, 2H), 2.23 (s, 3H), 1.28 (d, J = 6.27 Hz, 6H)
(902) TABLE-US-00016 TABLE 2-6 344 (DMSO-d6): 12.33 (s, 1H), 10.07 (s, 1H), 8.93 (d, J = 7.8 Hz, 1H), 8.33 (d, J = 399.0 3.6 Hz, 1H), 8.11 (s, 1H), 7.22 (dd, J = 8.0, 4.6 Hz, 1H), 6.86 (s, 1H), 4.11 (t, J = 6.7 Hz, 2H), 3.76-3.86 (s, 4H), 3.02-3.13 (s, 4H), 1.60-1.72 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 345 (DMSO-d6): 12.34 (s, 1H), 10.07 (s, 1H), 8.92 (d, J = 7.5 Hz, 1H), 8.33 (d, J = 413.4 3.3 Hz, 1H), 8.11 (d, J = 2.5 Hz, 1H), 7.22 (dd, J = 8.0, 4.7 Hz, 1H), 6.86 (s, 1H), 3.94 (d, J = 6.6 Hz, 2H), 3.75-3.87 (m, 4H), 3.00-3.15 (m, 4H), 1.88-2.02 (m, 1H), 0.95 (d, J = 6.7 Hz, 6H). 346 (DMSO-d6): 12.02 (br. s, 1H), 8.89 (d, J = 7.7 Hz, 1H), 8.32 (d, J = 3.4 Hz, 1H), 401.4 8.07 (s, 1H), 7.21 (dd, J = 8.0, 4.7 Hz, 1H), 6.77 (s, 1H), 4.15 (t, J = 5.4 Hz, 2H), 3.73-3.87 (m, 4H), 3.63 (t, J = 5.4 Hz, 2H), 3.17 (s, 1H), 2.95-3.07 (m, 4H). 347 (DMSO-d6): 12.35 (s, 1H), 10.09 (s, 1H), 8.94 (d, J = 7.9 Hz, 1H), 8.33 (d, J = 411.3 3.5 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H), 7.22 (dd, J = 8.0, 4.7 Hz, 1H), 6.87 (s, 1H), 4.02 (d, J = 7.1 Hz, 2H), 3.72-3.90 (m, 4H), 3.00-3.16 (m, 4H), 1.12-1.23 (m, 1H), 0.48-0.58 (m, 2H), 0.26-0.37 (m, 2H). 348 (DMSO-d6): 12.34 (s, 1H), 10.08 (s, 1H), 8.93 (d, J = 7.7 Hz, 1H), 8.33 (d, J = 425.4 4.5 Hz, 1H), 8.12 (d, J = 2.6 Hz, 1H), 7.22 (dd, J = 8.0, 4.7 Hz, 1H), 6.82 (s, 1H), 5.15-5.22 (m, 1H), 3.75-3.87 (m, 4H), 3.02-3.13 (m, 4H), 1.83-1.96 (m, 2H), 1.63-1.78 (m, 4H), 1.50-1.62 (m, 2H). 349 (DMSO-d6): 12.24 (br. s, 1H), 10.20 (br. s, 1H), 8.88 (d, J = 7.9 Hz, 1H), 8.32 413.6 (d, J = 3.5 Hz, 1H), 8.07 (s, 1H), 7.21 (dd, J = 8.0, 4.7 Hz, 1H), 6.72 (s, 1H), 4.94-4.79 (m, 1H), 3.74-3.88 (m, 4H), 2.90-3.14 (m, 4H), 1.48-1.70 (m, 2H), 1.23 (d, J = 6.2 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H). 350 (DMSO-d6): 12.48-12.19 (m, 1H), 10.04 (br. s, 1H), 8.93 (s, 1H), 8.33 (d, J = 413.4 3.7 Hz, 1H), 8.10 (s, 1H), 7.22 (dd, J = 7.9, 4.7 Hz, 1H), 6.81 (s, 1H), 4.80-4.96 (m, 1H), 3.74-3.87 (m, 4H), 3.01-3.14 (m, 4H), 1.50-1.68 (m, 2H), 1.24 (d, J = 6.2 Hz, 3H), 0.91 (t, J = 7.3 Hz, 3H). 351 (DMSO-d6): 12.34 (br. s, 1H), 9.86 (br. s, 1H), 8.97 (d, J = 7.8 Hz, 1H), 8.33 (d, 480.2 J = 3.4 Hz, 1H), 8.11 (s, 1H), 7.25 (dd, J = 8.0, 4.7 Hz, 1H), 6.80 (s, 1H), 5.00- 5.09 (m, 1H), 3.30-3.40 (m, 2H), 3.01-3.13 (m, 4H), 2.81-2.94 (m, 4H), 1.27 (d, J = 6.3 Hz, 6H). 352 (DMSO-d6): 12.35 (br. s, 1H), 8.62 (br. s, 1H), 8.40 (dd, J = 8.0, 1.3 Hz, 1H), 398.0 8.32 (d, J = 4.6 Hz, 1H), 8.01 (s, 1H), 7.21 (dd, J = 7.9, 4.7 Hz, 1H), 6.86 (s, 1H), 4.99-5.13 (m, 1H), 4.18-4.31 (m, 1H), 3.87-3.99 (m, 2H), 3.39-3.54 (m, 2H), 1.80-1.97 (m, 4H), 1.27 (d, J = 6.3 Hz, 6H). 353 (DMSO-d6): 12.36 (s, 1H), 10.43 (br. s, 1H), 8.88 (d, J = 6.5 Hz, 1H), 8.35 (d, 447.2 J = 3.5 Hz, 1H), 8.14 (s, 1H), 7.17 (dd, J = 8.0, 4.7 Hz, 1H), 6.86 (s, 1H), 4.99- 5.11 (m, 1H), 3.47-3.62 (m, 4H), 3.35-3.42 (m, 4H), 1.27 (d, J = 6.2 Hz, 6H). 354 (DMSO-d6): 12.36 (br. s, 1H), 8.39 (d, J = 7.9 Hz, 1H), 8.33 (d, J = 4.7 Hz, 1H), 460.2 8.07 (s, 1H), 7.16-7.26 (m, 2H), 6.80-6.92 (m, 3H), 5.01-5.12 (m, 1H), 4.94 (br. s, 2H), 3.83-4.02 (m, 2H), 3.76 (s, 3H), 3.00 (t, J = 5.7 Hz, 2H), 1.27 (d, J = 6.2 Hz, 6H). 355 (DMSO-d6): 13.04 (br. s, 1H), 8.40 (dd, J = 7.9, 1.4 Hz, 1H), 8.33 (dd, J = 4.6, 444.2 1.3 Hz, 1H), 8.07 (s, 1H), 7.22 (dd, J = 7.9, 4.7 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.08 (d, J = 7.1 Hz, 2H), 6.87 (s, 1H), 5.00-5.12 (m, 1H), 4.93 (br. s, 2H), 3.88-3.98 (m, 2H), 3.03 (t, J = 5.5 Hz, 2H), 2.30 (s, 3H), 1.89 (s, 3H), 1.28 (d, J = 6.2 Hz, 6H). 356 (DMSO-d6): 11.33 (br. s, 1H), 8.39 (dd, J = 7.9, 1.4 Hz, 1H), 8.33 (dd, J = 4.6, 464.2 1.3 Hz, 1H), 8.09 (s, 1H), 7.42 (s, 1H), 7.32 (s, 2H), 7.22 (dd, J = 7.9, 4.7 Hz, 1H), 6.88 (s, 1H), 4.94-5.11 (m, 3H), 3.87-4.00 (m, 2H), 3.07 (t, J = 5.7 Hz, 2H), 1.89 (s, 3H), 1.27 (t, J = 6.0 Hz, 6H). 357 (MeOD): 9.17 (s, 1H), 8.16-8.34 (m, 3H), 7.19-7.27 (m, 3H), 6.94-7.04 (m, 448.0 2H), 5.14-5.28 (m, 1H), 4.93 (br. s, 2H), 3.99 (t, J = 5.8 Hz, 2H), 3.05 (t, J = 5.5 Hz, 2H), 1.37 (d, J = 6.3 Hz, 6H). 358 (DMSO-d6): 12.36 (s, 1H), 8.39 (d, J = 7.9 Hz, 1H), 8.33 (d, J = 4.6 Hz, 1H), 8.06 460.2 (s, 1H), 7.18-7.28 (m, 2H), 6.81-6.94 (m, 3H), 5.00-5.11 (m, 1H), 4.96 (s, 2H), 3.91-4.06 (m, 2H), 3.81 (s, 3H), 2.94 (t, J = 5.7 Hz, 2H), 1.28 (d, J = 6.2 Hz, 6H). 359 (DMSO-d6): 12.34 (br. s, 1H), 8.39 (dd, J = 7.9, 1.1 Hz, 1H), 8.33 (dd, J = 4.6, 460.4 1.1 Hz, 1H), 8.06 (s, 1H), 7.17-7.25 (m, 2H), 6.82-6.90 (m, 3H), 5.00-5.10 (m, 1H), 4.89 (br. s, 2H), 3.84-4.00 (m, 2H), 3.76 (s, 3H), 3.05 (t, J = 5.7 Hz, 2H), 1.27 (d, J = 6.2 Hz, 6H).
(903) Biological activities of several compounds of the present invention were measured according to the methods mentioned blow.
(904) [Preparation and Storage of Solutions of Test Compounds]
(905) A test compound was dissolved or suspended in DMSO so as to be at 10 mM or 1 mM, thereby making a stock solution, which was stored at 20 C. in the dark before being tested.
Test Example 1
(906) [Inhibitory Effect on Cdc7 Protein Kinase]
(907) Measurement of kinase activity was carried out using an MSA assay kit (QuickScout Screening Assist Kit, Carna Biosciences, Inc.).
(908) Assay buffer (20 mM HEPES, 0.01% Triton X-100, 2 mM dithiothreitol, pH 7.5) was used to prepare a substrate mixture solution comprising 4 M of a kinase-reaction substrate (FITC-labeled MCM2 peptide), 40 mM MgCl.sub.2, and 20 M ATP.
(909) The enzyme supplied in the kit (human Cdc7/human ASK complex protein) was diluted in the assay buffer so as to be at 7 nM, thereby preparing an enzyme solution.
(910) The stock solution of each test compound was diluted in DMSO to prepare diluted DMSO solutions of 10 concentrations (0.00003 mM, 0.0001 mM, 0.0003 mM, 0.001 mM, 0.003 mM, 0.01 mM, 0.03 mM, 0.1 mM, 0.3 mM, 1 mM), each of which was further diluted 25 times in the assay buffer to make a drug solution (a solution containing 4% DMSO).
(911) The kinase reaction was performed in wells of a polypropylene 384-well plate in which 5 l of each of the drug solutions or of a solvent (assay buffer containing 4% DMSO), 5 l of the substrate mixture solution, and 10 l of the enzyme solution were mixed. The assay buffer, instead of the enzyme solution, was added to blank wells. After the reaction at room temperature for 5 hours, 60 l of the termination buffer supplied in the kit was added to each well to stop the reaction. The percent inhibition of each reaction was determined using a LabChip EZ Reader II system (manufactured by Caliper Life Sciences), according to the protocol provided with the assay kit. In this case, the peak heights of the separated substrate and the phosphorylated substrate were represented as S and P, respectively, and the percent inhibition (%) by a tested compound was calculated according to the following formula:
Percent inhibition(%)=(1(CA)/(BA))100
wherein A denotes P/(P+S) for a blank well, B denotes P/(P+S) for a solvent well, and C denotes P/(P+S) for a compound-added well.
(912) The IC.sub.50 value of a tested compound was calculated by regression analysis of the percent inhibition values versus the (logarithmic) concentrations of the tested compound.
(913) The IC.sub.50 values of several compounds of the present invention against Cdc7 were all less than 1 M, as shown in Table 4 below.
Test Example 2
(914) [Inhibitory Effect on Phosphorylation Using Cells]
(915) Cultured Cells
(916) COLO205 cells derived from human colon adenocarcinoma (RCB2127, RIKEN BRC) were cultured in 10 cm dishes using RPMI-1640 medium (SIGMA, R8758) supplemented with 10% FCS (Equitech-bio) and 5% penicillin/streptomycin (GIBCO, 15140). After the cells were cultured to a confluence of 70 to 90%, the medium was removed, and the cells were treated with trypsin (2 mL, TrypLE Express, GIBCO, 12604-021) and then harvested using a new medium.
(917) Addition of Drugs to Cultured Cells
(918) COLO205 cells were seeded in 6-well plates (FALCON, 35046) to 2.510.sup.5 cells (1 ml) per well and cultured overnight in a 5% CO.sub.2 incubator. A drug solution, which was prepared by adding 1.5 l of a 0.1-mM stock solution in DMSO of a test compound to 500 l of medium, was added to each well (to a final drug concentration of 0.1 M), and then cultured for another 24 hours.
(919) Determination of Inhibitory Effect on MCM2 Phosphorylation
(920) Cells were cultured for 24 hours in the presence of a test compound, harvested using a similar way as described above, washed with PBS, and then pelletized and stored at 80 C. The frozen cells were thawed, subsequently suspended immediately in 2SDS-PAGE electrophoresis buffer (110.sup.5 cells per 10 l), and heated at 95 C. for 10 minutes, leading to the dissolution and denaturation of the proteins. The resulting sample solutions were subjected to SDS-PAGE using a 5-20% gradient acrylamide gel (e-PAGEL (5-20%), ATTO, E-T520L). After the electrophoresis was completed, the gel was immersed in tris-glycine buffer supplemented with 20% methanol, and the proteins in the gel were transferred onto a PVDF membrane (MILLIPORE, Immobilon-P, IPVH00010) using a semi-dry transfer apparatus (TRNS-BLOT SD SEMI-DRY TRANSFER CELL, BIO RAD).
(921) The transferred PVDF membrane was blocked with 5% skim milk (Difco Skim Milk, BD, 232100), and then subjected to reaction with an anti-MCM2 goat antibody (N-19, Santa Cruz, sc-9839) or anti-phosphorylated MCM2 rabbit antibody (S53) (Bethyl, A300-756A) as a primary antibody and additionally with an anti- tubulin mouse antibody (Clone DM 1A, SIGMA, 9026) as an internal control. Each band was detected by chemiluminescence using an HRP-labeled anti-goat IgG donkey antibody (Santa Cruz, sc2020), anti-rabbit IgG sheep antibody (Roche, 12015218001), or anti-mouse IgG donkey antibody (Jackson ImmunoResearch, 715-035-151) as a secondary antibody. The combinations of and the diluted concentrations of the primary and secondary antibodies were as indicated below.
(922) TABLE-US-00017 TABLE 3 Primary antibody Secondary antibody (diluted concentration) (diluted concentration) 1 Anti-MCM2 goat antibody Anti-goat IgG donkey (1/500) antibody (1/10000) 2 Anti-phosphorylated MCM2 Anti-rabbit IgG sheep rabbit antibody (S53) antibody (1/5000) (1/500) 3 Anti--tubulin mouse Anti-mouse IgG donkey antibody (1/1000) antibody (1/100000)
(923) The bands which were detected were normalized using the amount of endogenous -tubulin as a reference, and the percent phosphorylation of MCM2 was calculated for each of the tested compounds. Their inhibitory effects on MCM2 phosphorylation were indicated by a triple asterisk (***) in the case where the percent phosphorylation of MCM2 was less than 20%, by a dual asterisk (**) in the case where the percent phosphorylation of MCM2 was not less than 20% and less than 50%, and by a single asterisk (*) in the case where the percent phosphorylation of MCM2 was not less than 50% and less than 70%.
(924) It was found from this testing that as shown in Table-4, the tested compounds of the present invention inhibited the phosphorylation of MCM2 at a concentration of 0.1 M.
(925) TABLE-US-00018 TABLE 4 Test Example 2 Test Example 1 Inhibitory effect on Example Cdc7 IC.sub.50 value (M) MCM2 phosphorylation 15 0.002 ** 22 0.010 * 63 0.006 *** 68 0.004 *** 78 0.011 *** 81 0.005 *** 89 0.003 *** 91 0.004 *** 102 0.004 *** 126 0.003 *** 129 0.009 *** 142 0.003 ** 157 0.003 ** 173 0.003 *** 226 0.004 *** 233 0.002 ** 239 0.001 ** 242 0.001 *** 244 0.004 *** 245 0.008 *** 246 0.008 ***
INDUSTRIAL APPLICABILITY
(926) The compounds provided by the present invention are capable of controlling the growth of cells through their inhibitory effects on Cdc7. Therefore, the compounds of the present invention which have an inhibitory effect on Cdc7 will be useful as a medicine, especially an agent for the treatment of diseases derived from abnormal growth of cells, such as cancers.