N-acyl-arylsulfonamide derivatives as aminoacyl-tRNA synthetase inhibitors

Abstract

The present invention relates to novel N-acyl-diarysulfonamides acting as inhibitors of bacterial aminoacyl-tRNA synthetase. These can be used as medicines or as constituent of medicines for the treatment of bacterial infections. ##STR00001##

Claims

1. A compound selected from the following compounds and pharmaceutically acceptable salts thereof: ##STR00204## ##STR00205## ##STR00206## ##STR00207## ##STR00208## ##STR00209## ##STR00210##

2. A compound selected from compounds of the following formula: ##STR00211## and pharmaceutically acceptable salts thereof, wherein: R1 is C.sub.1-4alkyl; R2 is C.sub.1-4alkyl or H; R3 is C.sub.1-4alkyl or H; R1, R2 or R1, R3 together with the atoms to which they are attached may form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; provided that R2 and R3 are not both hydrogen; wherein the radical: ##STR00212## wherein: R9 is independently H, halo, C.sub.1-6alkyl, phenyl, or CN, wherein said alkyl is optionally substituted with 1 to 3 substituents selected from halo; R10 is independently H, halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, pyridyl, pyrimidyl, triazinyl, tetrazolyl, purinyl, phenyl, CN, C(═O)R.sup.e, C(═O)OR.sup.e, C(═O)N(R.sup.e)R.sup.f, OR.sup.e, or S(O).sub.0-2R.sup.e, wherein said alkyl is optionally substituted with 1 to 3 substituents selected from halo, and wherein said pyridyl, pyrimidyl, triazinyl, tetrazolyl, purinyl, and phenyl are optionally substituted with 1 or 2 substituents independently selected from OR.sup.e, N(R.sup.e)R.sup.f, halo, SR.sup.e, methyl, ethyl, and phenyl; R11 is independently H, halo, C.sub.2-6alkyl, phenyl, or CN; R12 is independently H or halo; R13 is independently H, halo, or C.sub.1-6alkyl; R.sup.e and R.sup.f are independently H, C.sub.1-8alkyl, or phenyl, wherein said alkyl is optionally substituted by 1 to 3 substituents selected from halo; with the proviso that the compound is not: ##STR00213##

3. A compound according to claim 2, wherein R9 is independently H, halo, C.sub.1-6alkyl, or phenyl.

4. A compound according to claim 2, wherein R9 is independently H, F, Cl, isopropyl, or phenyl.

5. A compound according to claim 2, wherein R10 is independently H, halo, pyridyl, pyrimidyl, triazinyl, phenyl, or purinyl, wherein said pyridyl, pyrimidyl, triazinyl, purinyl, and phenyl are optionally substituted by 1 or 2 substituents independently selected from NH.sub.2, NMe.sub.2, SMe, methyl, ethyl, halo, OH, OC.sub.1-4alkyl, and phenyl.

6. A compound according to claim 2, wherein R10 is independently halo, pyridyl, pyrimidyl, triazinyl, phenyl, or purinyl, wherein said pyridyl, pyrimidyl, triazinyl, purinyl, and phenyl are optionally substituted by 1 or 2 substituents independently selected from NH.sub.2, NMe.sub.2, SMe, methyl, ethyl, halo, OH, OC.sub.1-4alkyl, and phenyl.

7. A compound according to claim 2, wherein R10 is halo.

8. A compound according to claim 2, wherein R11 is independently H, C.sub.2-6alkyl, or phenyl.

9. A compound according to claim 2, wherein R11 is independently H, butyl, isopropyl, or phenyl.

10. A compound according to claim 2, wherein R12 is halo.

11. A compound according to claim 2, wherein R13 is independently H or C.sub.1-6alkyl.

12. A compound according to claim 2, wherein R13 is independently H, butyl, or isopropyl.

13. A compound according to claim 2, wherein: R9 is independently H, halo, C.sub.1-6alkyl, or phenyl; R10 is independently H, halo, pyridyl, pyrimidyl, triazinyl, purinyl or phenyl, wherein said pyridyl, pyrimidyl, triazinyl, purinyl, and phenyl are optionally substituted by 1 or 2 substituents independently selected from NH.sub.2, NMe.sub.2, SMe, methyl, ethyl, halo, OH, OC.sub.1-4alkyl, and phenyl; R11 is independently H, C.sub.2-6alkyl, or phenyl; R12 is independently H or halo; and R13 is independently H, halo, or C.sub.1-6alkyl.

14. A compound according to claim 2, wherein: R9 is independently H, halo, C.sub.1-6alkyl, or phenyl; R10 is independently halo, pyridyl, pyrimidyl, triazinyl, purinyl or phenyl, wherein said pyridyl, pyrimidyl, triazinyl, purinyl, and phenyl are optionally substituted by 1 or 2 substituents independently selected from NH.sub.2, NMe.sub.2, SMe, methyl, ethyl, halo, OH, OC.sub.1-4alkyl, and phenyl; R11 is independently H, C.sub.2-6alkyl, or phenyl; R12 is independently H or halo; and R13 is independently H, halo, or C.sub.1-6alkyl.

15. A compound according to claim 2, wherein: R9 is independently H, F, Cl, isopropyl, or phenyl; R10 is independently H, halo, pyridyl, pyrimidyl, triazinyl, phenyl, or purinyl, wherein said pyridyl, pyrimidyl, triazinyl, purinyl and phenyl are optionally substituted by 1 or 2 substituents independently selected from NH.sub.2, NMe.sub.2, methyl, ethyl, halo, OH, OC.sub.1-4alkyl, and phenyl; R11 is independently H, butyl, isopropyl, or phenyl; R12 is independently H or halo; and R13 is independently H, F, C, or isopropyl.

16. A compound according to claim 2, wherein: R9 is independently H, F, Cl, isopropyl, or phenyl; R10 is independently halo, pyridyl, pyrimidyl, triazinyl, phenyl, or purinyl, wherein said pyridyl, pyrimidyl, triazinyl, purinyl and phenyl are optionally substituted by 1 or 2 substituents independently selected from NH.sub.2, NMe.sub.2, methyl, ethyl, halo, OH, OC.sub.1-4alkyl, and phenyl; R11 is independently H, butyl, isopropyl, or phenyl; R12 is independently H or halo; and R13 is independently H, F, Cl, or isopropyl.

17. A compound according to claim 2, wherein: R9 is H; R10 is halo; R11 is H; R12 is H; and R13 is H.

18. A pharmaceutical composition comprising at least one compound according to claim 2 in admixture with one or more pharmaceutically acceptable carriers and/or excipients.

19. A pharmaceutical composition comprising at least one compound according to claim 1 in admixture with one or more pharmaceutically acceptable carriers and/or excipients.

Description

EXAMPLES OF SPECIFIC EMBODIMENTS

(1) The following examples further illustrate the invention, but should not be construed to limit the scope of the invention in any way.

(2) The following N-acyl-arylsulfonamide derivatives 5.1-5.52 were prepared as examples of the current invention:

(3) TABLE-US-00001 ID Cmpd. No Structure IK-698 5.1. IK-713 5.2. IK-718 5.3. LL-20 5.4. LL-19 5.5. 0 EO-99 5.6. LL-23 5.7. MZ-377 5.8. IK-681 5.9. DL-23-340 5.10. IK-707 5.11. IK-719 5.12. IK-666 5.13. IK-665 5.14. DG-500 5.15. 0 MZ-335 5.16. MZ-343 5.17. MZ-370 5.18. KS-1189 5.19. MZ-375 5.20. C-2724 5.21. C-2775 5.22. MZ-368 5.23. IK-603 5.24. AC-486 5.25. 0 C-2727 5.26. DG-459 5.27. DG-457 5.28. DG-460 5.29. IK-656 5.30. DG-466 5.31. DG-470 5.32. IK-685 5.33. DG-469 5.34. IK-580 5.35. 0 IK-617 5.36. IK-587 5.37. K-615 5.38. IK-621 5.39. BM-13 5.40. IK-625, 5.41. IK-636 5.42. IK-634 5.43. IK-635 5.44. IK-627 5.45. 0 DG-435 5.46. DG-437 5.47. DG-440 5.48. DG-444 5.49. DG-445 5.50. DG-455 5.51. DG-453 5.52.
General Synthesis

(4) Compounds included as examples to the invention were prepared according to general Scheme 1. Sulfonyl chlorides 1 were transformed to sulfonamides 2 which were N-acylated with protected amino acids 3a-g to give N-acylsulfonamides 4. Deprotection provided final compounds 5.1-5.25, 5.27-5.52.

(5) ##STR00058##

(6) Several sulfonamides 2.23-2.25, 2.35 were prepared according to schemes 2-5.

(7) ##STR00059##

(8) ##STR00060## ##STR00061##

(9) ##STR00062##

(10) ##STR00063##

(11) Several protected N-acyl sulphonamides were prepared from intermediates 4.53-4.55 by coupling these with pinacolate diborane to give boronic acid derivatives 20.27, 20.30, 20.40 which were then transferred to protected N-acyl sulphonamides 4.27-4.30, 4.35-4.49, 4.51, 4.52 according to Scheme 6.

(12) ##STR00064##

(13) N-Acylsulfonamide 4.50 was prepared by hydrolytic replacement of chloride in the chloropyrimidine derivative 4.49 according to Scheme 7.

(14) ##STR00065##

(15) Acylsulfonamide 5.26 was prepared by partial hydrogenation of isoquinoline ring in compound 5.22 according to scheme 8.

(16) ##STR00066##

General Method A. Exemplified by the Synthesis of 3-bromobenzenesulfonamide (2.53)

(17) ##STR00067##

(18) To a solution of 3-bromobenzene-1-sulfonyl chloride (1.53) (4.073 g, 15.94 mmol) in DCM (67 ml) at ice bath temperature was added 25% NH.sub.4OH solution in water (3.7 ml, 57.15 mmol). The reaction mixture was stirred at this temperature for 0.5 h followed by stirring for 6 h at room temperature. The precipitated solid material was filtered, washed with water, and dried in vacuo over P.sub.2O.sub.5 to give 3-bromobenzene-sulfonamide (2.53) (3.270 g, 87%) as white crystals. .sup.1H NMR (DMSO-d.sub.6) δ: 7.97 (t, J=1.9 Hz, 1H), 7.84-7.80 (m, 2H), 7.54 (t, J=7.9 Hz, 1H), 7.50 (b s, 2H). LCMS (ESI) m/z: 235.98 [M−H].sup.−.

(19) By a method analogous to Method A, the following compounds were obtained:

(20) TABLE-US-00002 Com- pound No Procedure Precursor Structure 2.1 A 1.1 2.2. A 1.2 2.3. A 1.3 0 2.4. A 1.4 2.5. A 1.5 2.6 A 1.6 2.7 A 1.7 2.8 A 1.8 2.9 A 1.9 2.11 A 1.11 2.12 A 1.12 2.13 A 1.13 2.14 A 1.14 0 2.16 A 1.16 2.17 A 1.17 2.18 A 1.18 2.19 A 1.19 2.20 A 1.20 2.21 A 1.21 2.22 A 1.22 2.53 A 1.53

General Method B. Exemplified by the Synthesis of (S)-tert-butyl (1-(3-bromophenylsulfonamido)-4-methyl-1-oxopentan-2-yl)carbamate (4.53)

(21) ##STR00089##

(22) To a solution of BOC-L-leucine monohydrate 3a (0.592 g, 2.37 mmol) in DMF (5 ml) successively were added 3-bromobenzenesulfonamide 2.53 (0.561 g, 2.37 mmol), HBTU (0.900 g, 2.37 mmol), TEA (0.66 ml, 4.75 mmol), and a catalytic amount of DMAP (0.029 g, 0.237 mmol). The reaction mixture was stirred for 24 h and poured into water (70 ml). The mixture was extracted with EtOAc (3×75 ml), the combined organic extracts were washed with 1N HCl (20 ml), water (2×100 ml), saturated solution of NaCl (100 ml), and dried (Na.sub.2SO.sub.4). The volatiles were evaporated and the residue (0.988 g) was purified by Biotage purification system (C18HS 40+M column, eluent water-methanol, gradient from 1:1 to 0:100) to afford 0.660 g (61.8%) of (5)-tert-butyl (1-(3-bromophenylsulfonamido)-4-methyl-1-oxopentan-2-yl)carbamate (4.53) as a foam. .sup.1H NMR (CDCl.sub.3) δ: 9.57 (b s, 1H), 8.16 (t, J=1.8 z, 1H), 8.00 (d, J=7.9 Hz, 1H), 7.75 (ddd, J=7.9, 1.8, 1.0 Hz, 1H), 7.40 (t, J=7.9 Hz, 1H), 4.70 (unresolved d, J=6.4 Hz, 1H), 4.06-3.92 (m, 1H), 1.70-1.52 (m, 3H), 1.44 (s, 9H), 0.91 (d, J=6.3 Hz, 3H), 0.87 (d, J=6.3 Hz, 3H). LCMS (ESI) m/z: 449.2 [M−H].sup.−.

(23) Following a method analogous to Method B, the following compounds were obtained:

(24) TABLE-US-00003 Compound No Method Precursor Structure 4.1 B 2.1 0 4.2 B 2.2 4.3 B 2.3 4.4 B 2.4 4.5 B 2.5 4.6 B 2.6 4.7 B 2.7 4.8 B 2.8 4.9 B 2.9 4.10 B 2.9 4.11 B 2.11 00 4.12 B 2.12 01 4.13 B 2.13 02 4.14 B 2.14 03 4.15 B 2.14 04 4.16 B 2.16 05 4.17 B 2.17 06 4.18 B 2.18 07 4.19 B 2.19 08 4.20 B 2.20 09 4.21 B 2.21 0 4.22 B 2.22 4.23 B 2.23 4.24 B 2.24 4.25 B 2.25 4.31 B 2.35 4.32 B 2.35 4.33 B 2.35 4.34 B 2.35 4.35 B 2.35 4.53 B 2.53 0 4.54 B 2.53 4.55 B 2.53

General Method C1. Exemplified by the Synthesis of (S)-2-amino-N-((3-(2-amino-6-methylpyrimidin-4-yl)phenyl)sulfonyl)-4-methylpentanamide (5.35)

(25) ##STR00123##

(26) (S)-tert-Butyl (1-(3-(2-amino-6-methylpyrimidin-4-yl)phenylsulfonamido)-4-methyl-1-oxopentan-2-yl)carbamate (4.35) (0.246 g, 0.515 mmol) was dissolved in a 5% TFA solution in dichloromethane (12 ml) and the obtained solution was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the oily brown residue (0.396 g) was purified by Biotage purification system (C18HS 40+M column, eluent water-acetonitrile, gradient from 95:5 to 60:40) to afford 0.162 g (83%) of (5)-2-amino-N-((3-(2-amino-6-methylpyrimidin-4-yl)phenyl)sulfonyl)-4-methylpentanamide (5.35) as white crystals, m.p. 241-242° C. (dec.). (DMSO-d.sub.6, HMDSO) δ: 8.50 (t, J=1.7 Hz, 1H), 8.05 (ddd, J=7.8, 1.7, 1.2 Hz, 1H), 7.88 (ddd, J=7.8, 1.7, 1.2 Hz, 1H), 7.67 (b s, 3H), 7.50 (t, J=7.8 Hz, 1H), 7.01 (s, 1H), 6.63 (s, 2H), 3.37-3.30 (m, 1H, overlapped with water), 2.31 (s, 3H), 1.73-1.60 (m, 1H), 1.58 (ddd, J=13.7, 8.4, 5.6 Hz, 1H), 1.38 (ddd, J=13.7, 8.3, 5.8 Hz, 1H), 0.83 (d, J=6.3 Hz, 3H), 0.81 (d, J=6.3 Hz, 3H). LCMS (ESI) m/z: 378.2 [M+H].sup.+. Anal. Calcd for C.sub.17H.sub.23N.sub.5O.sub.3S×0.09 CF.sub.3COOH (2.5%)×1.12H.sub.2O (4.9%): C, 50.59, H, 6.26, N, 17.17. Found: C, 50.59, H, 6.32, N, 17.23.

General Method C2. Exemplified by the Synthesis of (S)-2-amino-4-methyl-N-(phenylsulfonyl)pentanamide hydrochloride (5.1)

(27) ##STR00124##

(28) To a solution tert-butyl (S)-(4-methyl-1-oxo-1-(phenylsulfonamido)pentan-2-yl)carbamate (4.1) (0.160 g, 0.43 mmol) in dioxane (5 mL) under argon 4N HCl dioxane solution (2.5 mL) was added dropwise and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was triturated with diethyl ether (4×5 mL). The solid material was filtered, washed with diethyl ether (5 mL) and dried in vacuo over P.sub.2O.sub.5 to give 0.076 g (57%) of compound (5.1) as white crystals, mp 192° C. .sup.1H NMR (DMSO-d.sub.6) δ: 13.05 (b s, 1H), 8.43 (b s, 3H), 7.98-7.94 (m, 2H), 7.76-7.70 (m, 1H), 7.67-7.61 (m, 2H), 3.93-3.83 (m, 1H), 1.67-1.48 (m, 3H), 0.82 (d, J=6.0 Hz, 3H), 0.81 (d, J=6.1 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 169.1, 138.9, 133.9, 129.2, 127.6, 51.3, 23.4, 22.6, 21.7. LCMS (ESI) m/z: 271.2 [M+H].sup.+. Anal. Calcd for C.sub.12H.sub.18N.sub.2O.sub.3S×HCl (11.8%)×0.06H.sub.2O (0.4%): C, 46.81, H, 6.26, N, 9.10. Found: C, 46.81, H, 6.21, N, 9.02.

General Method C3. Exemplified by the Synthesis (S)-2-amino-N-((5-(dimethylamino)naphthalen-1-yl)sulfonyl)-4-methylpentanamide hydrochloride (5.16)

(29) ##STR00125##

(30) tert-Butyl (S)-(1-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-methyl-1-oxopentan-2-yl)carbamate (4.16) (0.155 g, 0.33 mmol) was dissolved in dioxane (6.5 mL). The solution was cooled to 0-5° C. and 4N HCl solution in dioxane (1.95 mL) was added dropwise. The solution was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by Biotage purification system (C18HS 40+M column, eluent water-acetonitrile, gradient from 100:0 to 50:50) to afford 0.099 g of compound 5.16 (77%) as white powder, mp 178-180° C. .sup.1H NMR (DMSO-d.sub.6) δ: 8.65 (d, J=8.3 Hz, 1H), 8.40-8.32 (m, 2H), 8.29 (b s, 3H), 7.74 (t, J=8.0 Hz, 1H), 7.71 (t, J=8.1 Hz, 1H), 7.45 (d, J=7.5 Hz, 1H), 3.82 (m, overlapped with water, 1H), 2.92 (s, 6H), 1.46-1.25 (m, 3H), 0.70 (d, J=5.8 Hz, 3H), 0.65 (d, J=5.8 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 168.9, 154.8, 143.8, 133.9, 131.6, 130.5, 128.7, 128.4, 127.9, 124.3, 117.1, 51.3, 45.5, 23.2, 22.5, 21.6. LCMS (ESI) m/z: 364.3 [M+H].sup.+. Anal. Calcd for C.sub.18H.sub.25N.sub.3O.sub.3S×2.9 HCl (21.9%)×0.75H.sub.2O (2.8%): C, 44.79, H, 6.14, N, 8.70. Found: C, 44.77, H, 6.14, N, 8.47.

General Method C4. Exemplified by the Synthesis of 8-(N-(L-Leucyl)sulfamoyl)isoquinoline-3-carboxamide (5.24)

(31) ##STR00126##

(32) tert-Butyl (S)-(4-methyl-1-oxo-1-((3-((2,4,4-trimethylpentan-2-yl)carbamoyl)isoquinoline)-8-sulfonamido)pentan-2-yl)carbamate (4.24) (0.042 g, 0.073 mmol) was dissolved in TFA (2 mL) and the obtained solution was stirred at 40° C. for 5 days. The reaction mixture was concentrated in vacuo and the oily brown residue was purified by Biotage purification system (C18HS 40+M column, eluent water-acetonitrile, gradient from 95:5 to 80:20) to afford 0.016 g (60%) of compound (5.24) as white crystals, m.p. 222.9° C. (detection by OptiMelt). .sup.1H NMR (DMSO-d.sub.6) δ: 10.11 (s, 1H), 8.56 (s, 1H), 8.27 (d, J=2.0 Hz, 1H), 8.24 (d, J=7.3 Hz, 1H), 8.24 (d, J=8.3 Hz, 1H), 7.87 (t, J=7.8 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.63 (b s, 3H), 3.31 (dd, J=7.7, 5.6 Hz, 1H), 1.52-1.44 (m, 2H), 1.26-1.19 (m, 1H), 0.74 (d, J=5.9 Hz, 3H), 0.71 (d, J=5.9 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 173.2, 166.2, 150.4, 143.8, 142.3, 136.0, 131.1, 130.0, 129.7, 124.5, 119.8, 53.4, 40.6, 23.7, 22.5, 21.8. LCMS (ESI) m/z: 365.2 [M+H].sup.+. Anal. Calcd for C.sub.16H.sub.20N.sub.4O.sub.4S×0.08 CF.sub.3COOH (2.3%)×1.1H.sub.2O (5.0%): C, 49.34, H, 5.71, N, 14.24, S, 8.15. Found: C, 49.34, H, 5.77, N, 14.16, S, 7.92.

(33) Following a method analogous to Method C, the following compounds were obtained:

(34) TABLE-US-00004 Compound No Procedure Precursor Structure 5.1 C2 4.1 5.2 C2 4.2 5.3 C2 4.3 5.4 C2 4.4 0 5.5 C2 4.5 5.6 C2 4.6 5.7 C2 4.7 5.8 C3 4.8 5.9 C2 4.9 5.10 C2 4.10 5.11 C2 4.11 5.12 C2 4.12 5.13 C2 4.13 5.14 C2 4.14 0 5.15 C2 4.15 5.16 C3 4.16 5.17 C3 4.17 5.18 C3 4.18 5.19 C2 4.19 5.20 C3 4.20 5.21 C2 4.21 5.22 C2 4.22 5.23 C3 4.23 5.24 C4 4.24 0 5.25 C2 4.25 5.27 C3 4.27 5.28 C3 4.28 5.29 C3 4.29 5.30 C3 4.30 5.31 C3 4.31 5.32 C3 4.32 5.33 C2 4.33 5.34 C3 4.34 5.35 C1 4.35 0 5.36 C1 4.36 5.37 C1 4.37 5.38 C1 4.38 5.39 C1 4.39 5.40 C1 4.40 5.41 C1 4.41 5.42 C2 4.42 5.43 C2 4.43 5.44 C2 4.44 5.45 C2 4.45 0 5.46 C2 4.46 5.47 C2 4.47 5.48 C2 4.48 5.49 C2 4.49 5.50 C2 4.50 5.51 C2 4.51 5.52 C2 4.52

Synthesis of 4-((tert-Butyldimethylsilyl)oxy)naphthalene-1-sulfonamide (2.23) (Scheme 2)

Method D

(35) 4-(Chlorosulfonyl)naphthalen-1-yl acetate (6) (prepared from sodium 4-hydroxynaphthalene-1-sulfonate as described in literature [Thea, S. et al. J. Org. Chem. 1985, 50, 2158]) (1.22 g; 4.29 mmol) was dissolved in dichloromethane (20 mL). The solution was cooled to 0-5° C. and 25% NH.sub.4OH water solution (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 4 h and evaporated to dryness in vacuo. The residue was taken up in EtOAc/H.sub.2O (50 ml/20 ml). The organic layer was separated, washed with brine (20 ml), dried, evaporated. The residue was purified by chromatography on silica gel, eluent: CH.sub.2Cl.sub.2/EtOH gradient from 100/0 to 100/2. To give intermediate 7, yield—0.62 g (65.3%). .sup.1H NMR (DMSO-d.sub.6) δ: 11.07 (s, 1H), 8.55 (d, J=8.5 Hz, 1H), 8.21 (dd, J=8.3, 1.5 Hz, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.66 (ddd, J=8.5, 6.9, 1.5 Hz, 1H), 7.57 (ddd, J=8.3, 6.9, 1.1 Hz, 1H), 7.35 (s, 2H), 6.90 (d, J=8.2 Hz, 1H). LCMS (ESI) m/z: 224 [M+H]..sup.+

Method E

(36) Intermediate 7 was transformed to 4-((tert-butyldimethylsilyl)oxy)naphthalene-1-sulfonamide (2.23) Prepared according to the procedure described in a patent [Corbett, T. H. et al. PCT Int. Appl., 2002098848, 12 Dec. 2002] used for the preparation of 4-(tert-butyl-dimethylsilanyloxi)-benzene-1-sulfonic acid amide. Yield 74.3%. .sup.1H NMR (DMSO-d.sub.6) δ: 8.63-8.57 (m, 1H), 8.26-8.20 (m, 1H), 8.04 (d, J=8.2 Hz, 1H), 7.70 (ddd, J=8.5, 6.9, 1.7 Hz, 1H), 7.66 (ddd, J=8.3, 6.9, 1.5 Hz, 1H), 7.48 (s, 2H), 7.04 (d, J=8.2 Hz, 1H), 1.06 (s, 9H), 0.34 (s, 6H). LCMS (ESI) m/z: 338 [M+H].sup.+.

Synthesis of 8-sulfamoyl-N-(2,4,4-trimethylpentan-2-yl)isoquinoline-3-carboxamide (4.24) (Scheme 3)

Method F. 1,2-Bis(bromomethyl)-3-iodobenzene (9)

(37) To a solution of 1-iodo-2,3-dimethylbenzene (8) [prepared according to Chen, Y et al. Org. Lett. 2007, 9, 1899] (1.93 g, 8.32 mmol) in carbon tetrachloride (40 mL) was added NBS (3.67 g, 20.62 mmol), AIBN (0.070 g, 0.43 mmol) and the resulting mixture was gently refluxed by irradiation with a halogen lamp (500 W) for 4 h. The precipitate was filtered and washed with a small amount of carbon tetrachloride. The filtrate was concentrated under reduce pressure, the obtained residue was dissolved in EtOAc (100 ml), successively washed with 10% NaOH solution (20 mL), water (2×20 ml), 10% Na.sub.2S.sub.2O.sub.3 solution (20 mL), water (20 mL), brine (20 mL), and dried (Na.sub.2SO.sub.4). The solvent was evaporated and the residue was purified by column chromatography on silica gel (eluent petroleum ether) to give 1.89 g (58.3%) of compound 9. .sup.1H NMR (CDCl.sub.3) δ: 7.84 (dd, J=8.1, 1.1 Hz, 1H), 7.33 (dd, J=7.6, 1.1 Hz, 1H), 6.97 (t, J=7.8 Hz, 1H), 4.85 (s, 2H), 4.66 (s, 2H). The product contained ca. 15-20% of an inseparable impurity (supposedly 1-bromo-2,3-bis(bromomethyl)benzene).

Method G. Diethyl 2-acetyl-8-iodo-1,4-dihydroisoquinoline-3,3(2H)-dicarboxylate (10)

(38) A mixture of 1,2-bis(bromomethyl)-3-iodobenzene (9) (2.50 g, 6.41 mmol), diethyl 2-acetamidomalonate (1.39 g, 6.41 mmol), and K.sub.2CO.sub.3 (2.22 g, 16.06 mmol) in acetonitrile (40 mL) was refluxed for 70 h. The mixture was allowed to cool to ambient temperature, the precipitate was filtered and washed with a small amount of acetonitrile. The filtrate was concentrated under reduce pressure, the obtained residue was dissolved in EtOAc (100 mL), washed successively with saturated NaHCO.sub.3 solution (30 mL), water (2×30 mL), brine (30 mL), and dried (Na.sub.2SO.sub.4). The solvent was evaporated and the residue was purified by column chromatography on silica gel (eluent petroleum ether-ethyl acetate, gradient from 20:1 to 20:6) to give 2 g of oil. The oil was dissolved in diethyl ether and kept in a refrigerator overnight. The precipitate was filtered and dried to give 0.4 g (14%) of a regioisomer diethyl 2-acetyl-5-iodo-1,4-dihydroisoquinoline-3,3(2H)-dicarboxylate. .sup.1H NMR (CDCl.sub.3) δ: 7.76 (d, J=8.0 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 6.94 (t, J=7.7 Hz, 1H), 4.65 (s, 2H), 4.19 (q, J=7.1 Hz, 2H), 4.16 (q, J=7.1 Hz, 2H), 3.56 (s, 2H), 2.28 (s, 3H), 1.22 (t, J=7.1 Hz, 3H), 1.22 (t, J=7.1 Hz, 3H). LCMS (ESI) m/z: 446 [M+H].sup.+. The filtrate was evaporated and the residue was purified by column chromatography on silica gel (eluent petroleum ether-ethyl acetate, gradient from 20:1 to 20:6) to give 0.95 g (33.2%) of compound (10). .sup.1H NMR (CDCl.sub.3) δ: 7.73 (dd, J=7.9, 1.0 Hz, 1H), 7.14 (d, J=7.5 Hz, 1H), 6.95 (t, J=7.7 Hz, 1H), 4.67 (s, 2H), 4.17 (q, J=7.1 Hz, 2H), 4.15 (q, J=7.1 Hz, 2H), 3.40 (s, 2H), 2.33 (s, 3H), 1.17 (t, J=7.1 Hz, 3H), 1.17 (t, J=7.1 Hz, 3H). LCMS (ESI) m/z: 446 [M+H].sup.+. The structures of the regioisomers were determined by NOESY spectra. The product contained ca. 15-20% of an inseparable impurity (supposedly the corresponding bromo derivative diethyl 2-acetyl-8-bromo-1,4-dihydroisoquinoline-3,3(2H)-dicarboxylate). LCMS (ESI) m/z: 398 [M+H].sup.+.

Method H. 8-Iodo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (11)

(39) A solution of diethyl 2-acetyl-8-iodo-1,4-dihydroisoquinoline-3,3(2H)-dicarboxylate (10) (0.585 g, 1.31 mmol) in 6N HCl (10 mL) was refluxed for 5 h. The mixture was cooled and conc. NH.sub.4OH water solution was added until pH of the medium was −7. The precipitate was filtered, washed with a small amount of water, and dried to give 0.305 g (76.7%) of compound (11). Because of a low solubility of the product in common deuterated organic solvents and deuterium oxide, the .sup.1H NMR spectrum was not informative. LCMS (ESI) m/z: 304 [M+H].sup.+. The product contained ca. 15-20% of an inseparable impurity (supposedly the corresponding bromo derivative 8-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid). LCMS (ESI) m/z: 256 [M+H].sup.+.

Method I. Methyl 8-iodo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (12)

(40) To a suspension of 8-iodo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (11) (0.645 g, 2.13 mmol) in methanol (18 mL) slowly SOCl.sub.2 (1.07 ml, 14.92 mmol) was added within 10 min. The reaction mixture was stirred at room temperature for 16 h, evaporated, and the residue was dissolved in a mixture of 1N NaHCO.sub.3 solution (30 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×15 mL). The organic extracts were combined, washed successively with water (20 mL), brine (20 mL), and dried (Na.sub.2SO.sub.4). The solvents were evaporated to give compound 12 (0.570 g, 84%) which was used in the next step without further purification. .sup.1H NMR (CDCl.sub.3) δ: 7.67 (d, J=7.8 Hz, 1H), 7.10 (d, J=7.5 Hz, 1H), 6.87 (t, J=7.7 Hz, 1H), 4.07 (d, 16.6 Hz, 1H), 3.87 (d, J=16.6 Hz, 1H), 3.78 (s, 3H), 3.71 (dd, J=9.4, 5.0 Hz, 1H), 3.04 (dd, J=16.5, 5.0 Hz, 1H), 2.97 (dd, J=16.5, 9.4 Hz, 1H). LCMS (ESI) m/z: 318 [M+H].sup.+. The product contained ca. 15-20% of an inseparable impurity (supposedly the corresponding bromo derivative methyl 8-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate). LCMS (ESI) m/z: 270 [M+H].sup.+.

Method J. Methyl 8-iodoisoquinoline-3-carboxylate (13)

(41) A mixture of methyl 8-iodo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (12) (0.570 g, 1.8 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.449 g, 2.0 mmol) in toluene (20 mL) was refluxed for 6 h. To the reaction mixture was added another portion of DDQ (0.100 g, 0.45 mmol) and the refluxing was continued for 16 h. The mixture was allowed to cool to room temperature; the precipitate was filtered and washed with a small amount of toluene. The filtrate was evaporated and the residue was purified by column chromatography on silica gel (eluent petroleum ether-ethyl acetate, gradient from 100:0 to 100:15) to give 0.34 g (60%) of compound 13. .sup.1H NMR (CDCl.sub.3) δ: 9.50 (t, J=0.8 Hz, 1H), 8.46 (dd, J=0.8, 0.4 Hz, 1H), 8.28 (dd, J=7.4, 1.0 Hz, 1H), 7.96 (dtd, J=8.2, 0.9, 0.4 Hz, 1H), 7.48 (dd, J=8.2, 7.4 Hz, 1H), 4.07 (s, 3H). LCMS (ESI) m/z: 314 [M+H].sup.+. The product contained ca. 15-20% of an inseparable impurity (supposedly the corresponding bromo derivative methyl 8-bromoisoquinoline-3-carboxylate). LCMS (ESI) m/z: 266 [M+H].sup.+.

Method K. 8-Iodoisoquinoline-3-carboxylic acid (14)

(42) A mixture of methyl 8-iodoisoquinoline-3-carboxylate (13) (0.237 g, 0.757 mol), 1M NaOH solution (1.14 mL, 1.14 mmol), and methanol (15 mL) was stirred in a closed vessel at 40° C. for 16 h. The reaction mixture was evaporated, mixed with water (10 mL), and 2N HCl solution was added until pH of the medium was −5. The mixture was extracted with EtOAc (25 mL, 2×10 mL), the combined extracts were washed with water (10 mL), brine (10 mL), and dried (Na.sub.2SO.sub.4). The solvent was evaporated and the residue was dried in vacuo to give 0.210 g (92%) of compound 14. .sup.1H NMR (CDCl.sub.3) δ: 9.43 (s, 1H), 8.56 (s, 1H), 8.34 (dd, J=7.4, 0.9 Hz, 1H), 8.03 (d, J=8.2 Hz, 1H), 7.55 (dd, J=8.2, 7.4 Hz, 1H). LCMS (ESI) m/z: 300 [M+H].sup.+. The product contained ca. 15-20% of an inseparable impurity (supposedly the corresponding bromo derivative 8-bromoisoquinoline-3-carboxylic acid). LCMS (ESI) m/z: 352 [M+H].sup.+.

Method L. 8-Iodo-N-(2,4,4-trimethylpentan-2-yl)isoquinoline-3-carboxamide (15)

(43) To a suspension of 8-iodoisoquinoline-3-carboxylic acid (14) (0.150 g, 0.500 mmol) in dichloromethane (12 mL) under argon atmosphere was added HOBt (0.111 g, 0.625 mmol) followed by EDC chloride (0.157 g, 0.625 mmol) and the resulting mixture was stirred at room temperature for 45 min. To the mixture was added tert-octylamine (0.106 g, 0.625 mmol) and stirring was continued for 2 h. The volatiles were evaporated and the residue (0.609 g) was purified by column chromatography on silica gel (eluent petroleum ether-ethyl acetate, 4:1) to give 0.163 g (79%) of compound 15. .sup.1H NMR (CDCl.sub.3) δ: 9.33 (t, J=0.8 Hz, 1H), 8.45 (s, 1H), 8.31 (b s, 1H), 8.21 (dd, J=7.4, 1.0 Hz, 1H), 7.95 (d, J=8.2 Hz, 1H), 7.43 (dd, J=8.2, 7.4 Hz, 1H), 1.92 (s, 2H), 1.60 (s, 6H), 1.05 (s, 9H). LCMS (ESI) m/z: 411.21 [M+H].sup.+. The product contained ca. 15-20% of an inseparable impurity (supposedly the corresponding bromo derivative 8-bromo-N-(2,4,4-trimethylpentan-2-yl)isoquinoline-3-carboxamide). LCMS (ESI) m/z: 363.18 [M+H].sup.+.

Method M. S-(3-((2,4,4-Trimethylpentan-2-yl)carbamoyl)isoquinolin-8-yl) benzothioate (16)

(44) A mixture of 8-iodo-N-(2,4,4-trimethylpentan-2-yl)isoquinoline-3-carboxamide (15) (0.160 g, 0.39 mmol), thiobenzoic acid (0.065 g, 0.47 mmol), 1,10-phenanthroline (0.014 g, 0.078 mmol), DIPEA (0.100 g, 0.78 mmol), CuI (0.007 g (0.039 mmol), and toluene (3 mL) was stirred under argon atmosphere in a closed vessel at 110° C. temperature for 18 h. The mixture was evaporated and the residue was purified by column chromatography on silica gel (eluent petroleum ether-ethyl acetate, gradient from 6:1) to give 0.103 g (62.8%) of compound 16. .sup.1H NMR (CDCl.sub.3) δ: 9.51 (t, J=0.8 Hz, 1H), 8.63 (d, J=0.7 Hz, 1H), 8.30 (b s, 1H), 8.12-8.09 (m, 3H), 7.91 (dd, J=7.2, 1.1 Hz, 1H), 7.80 (dd, J=8.2, 7.2 Hz, 1H), 7.70-7.65 (m, 1H), 7.57-7.52 (m, 2H), 1.90 (s, 2H), 1.58 (s, 6H), 1.04 (s, 9H). LCMS (ESI) m/z: 421.26 [M+H].sup.+.

Method N. 8-Sulfamoyl-N-(2,4,4-trimethylpentan-2-yl)isoquinoline-3-carboxamide (2.24)

(45) To a solution of S-(3-((2,4,4-trimethylpentan-2-yl)carbamoyl)isoquinolin-8-yl) benzothioate (16) (0.060 g, 0.143 mmol), benzyltriethylammonium chloride (0.110 g, 0.485 mmol), and water (0.0064 g, 0.356 mmol) in acetonitrile (2 ml) at 0° C. within 1 min. was added trichloroisocyanuric acid (0.040 g, 0.172 mmol) as a solid. The reaction mixture was stirred at this temperature for 30 min. and then 25% NH.sub.4OH solution (0.40 ml, 0.858 mmol) was added. The stirring was continued at room temperature for 1 h and the mixture was diluted with acetonitrile (8 ml). The mixture was filtered, the filtrate was evaporated and the residue was purified by column chromatography on silica. gel (eluent hexane-ethyl acetate, 1:1) to give 0.042 g (81%) of compound 2.24. LCMS (ESI) m/z: 364.20 [M+H].sup.+.

Synthesis of chromane-8-sulfonamide (2.25) (Scheme 4)

Method O. Chromane-8-sulfonyl chloride (18)

(46) 8-Bromochromane (17) was prepared from commercial 2,6-dibromophenol according to the literature procedure [Kerrigan, F.; Martin, C; Thomas, G. H. Tetrah. Lett. 1998, 39, 2219]. To 8-bromochromane (17) (0.18 g, 0.84 mmol) in dry tetrahydrofuran (2 mL) at −78° C. under argon 2.5 M n-BuLi in hexanes (0.34 ml, 0.85 mmol) was added slowly. The reaction was stirred at this temperature for 30 min and then SO.sub.2 (g) was bubbled through the solution for 3 minutes. The reaction was stirred at −78° C. then warmed to room temperature and the solvent was evaporated. The residue was dissolved in 2 ml of DCM and NCS (0.112 g, 0.84 mmol) was added at r.t., the reaction mixture stirred for 1 h, then diluted with 15 mL DCM, washed with water, brine, dried over sodium sulfate and the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel (eluent petroleum ether-ethyl acetate, 3:1) to give 0.054 g (30%) of compound 18. Compound was unstable under GCMS and LCMS conditions. .sup.1H NMR (CDCl.sub.3) δ: 7.78-7.75 (m, 1H), 7.39-7.36 (m, 1H), 6.95 (t, J=7.8 Hz, 1H), 4.46 (t, J=5.4 Hz, 2H), 2.88 (t, J=6.5 Hz, 2H), 2.16-2.09 (m, 2H).

Method P. Chromane-8-sulfonamide (2.25)

(47) To chromane-8-sulfonyl chloride (18) (0.053 g, 0.23 mmol) in acetonitrile (2 ml) was added aq. NH.sub.4OH (1 mL) and the mixture was stirred for 10 min, then the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent chloroform-methanol, 30:1) to give 0.044 g (91%) of compound 2.25. .sup.1H NMR (DMSO-d.sub.6) δ: 7.51 (dd, J=7.8, 1.6 Hz, 1H), 7.28 (dd, J=7.6, 1.6 Hz, 1H), 6.96 (b s, 2H), 6.95 (t, J=7.7 Hz, 1H), 4.28 (t, J=5.3 Hz, 2H), 2.80 (t, J=6.4 Hz, 2H), 1.98-1.91 (m, 2H). LCMS (ESI) m/z: 213.0 [M−H].sup.−.

Synthesis of (3-(2-amino-6-methylpyrimidin-4-yl)benzenesulfonamide (2.35) (Scheme 5)

Method Q. 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (19)

(48) Through a mixture of 3-bromobenzenesulfonamide (2.53) (0.620 g, 2.63 mmol), KOAc (1.032 g, 10.52 mmol), and PdCl.sub.2(dppf).sub.2 (0.100 g, 0.137 mmol) in dioxane (20 mL) was bubbled argon for 10 min. To the reaction mixture was added bis(pinacolato)diboron (1.000 g, 3.94 mmol), the reaction vessel was closed, and the content was stirred at 110° C. for 24 h. The mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (eluent petroleum ether-ethyl acetate, gradient from 4:1 to 1:1) to give 0.663 g (89%) of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (19) as a white solid. .sup.1H NMR (DMSO-d.sub.6, HMDSO) δ: 8.14 (ddd, J=2.0, 1.1, 0.5 Hz, 1H), 7.93 (ddd, J=7.9, 2.0, 1.3 Hz, 1H), 7.85 (td, J=1.2, 7.4 Hz, 1H), 7.59 (ddd, J=7.9, 7.4, 0.5 Hz, 1H), 1.32 (s, 12H). LCMS (ESI) m/z: 284.0 [M+H].sup.+.

Method R. (3-(2-Amino-6-methylpyrimidin-4-yl)benzenesulfonamide (2.35)

(49) To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (19) (0.030 g, 0.106 mmol) in dioxane (3 mL) were added successively 2-amino-4-chloro-6-methylpyrimidine (0.015 g, 0.105 mmol), Na.sub.2CO.sub.3 (0.034 g, 0.321 mmol), and water (0.15 mL). Through the obtained mixture for 10 min was bubbled argon, to the mixture was added PdCl.sub.2(dppf).sub.2 (0.004 g, 0.005 mmol), the reaction vessel was closed, and the content was stirred at 100° C. for 16 h. The mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (eluent chloroform-methanol, gradient from 100:5 to 90:10) to give 0.014 g (50%) of 3-(2-amino-6-methylpyrimidin-4-yl)benzenesulfonamide (2.35). .sup.1H NMR (DMSO-d.sub.6, HMDSO) δ: 8.54 (t, J=1.6 Hz, 1H), 8.23 (ddd, J=7.8, 1.5, 1.1 Hz, 1H), 7.92 (ddd, J=7.8, 1.7, 1.1 Hz, 1H), 7.69 (t, J=7.8 Hz, 1H), 7.42 (s, 2H), 7.09 (s, 1H), 6.67 (s, 2H), 2.32 (s, 3H). LCMS (ESI) m/z: 265.1 [M+H].sup.+.

General Method S. Exemplified by the Synthesis of (S)-tert-butyl (4-methyl-1-oxo-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylsulfonamido)pentan-2-yl)carbamate (20.27)

(50) ##STR00178##

(51) Through a mixture of (S)-tert-butyl (1-(3-bromophenylsulfonamido)-4-methyl-1-oxopentan-2-yl)carbamate (4.53) (1.000 g, 2.23 mmol), KOAc (0.874 g, 8.9 mmol), and PdCl.sub.2(dppf).sub.2 (0.18 g, 0.22 mmol) in dioxane (40 ml) was bubbled argon for 10 min. To the reaction mixture was added bis(pinacolato)diboron (0.85 g, 3.35 mmol), the reaction vessel was closed, and the content was stirred at 110° C. for 17 h. The mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated and the dark oily residue (3.0 g) was purified by column chromatography on silica gel (eluent petroleum ether-ethyl acetate, gradient from 4:1 to 1:1) to give 1.281 g of a mixture of (S)-tert-butyl (4-methyl-1-oxo-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylsulfonamido)pentan-2-yl)carbamate (20.27) and (S)-(3-(N-(2-((tert-butoxycarbonyl)amino)-4-methylpentanoyl)sulfamoyl) phenyl)boronic acid (20.27a) as a glass-like material. The obtained mixture was utilized in the next step without further purification. LCMS (ESI) m/z: 495.28 [M−H].sup.− (20.27, retention time 3.939 min.) and 413.22 [M−H].sup.− (20.27a, retention time 2.750).

(52) Following a method analogous to Method S the following compounds were obtained:

(53) TABLE-US-00005 Compound No Method Precursor Structure 20.27 S 4.53 20.30 S 4.54 0 20.40 S 4.55

General Method T. Exemplified by the Synthesis of (S)-tert-butyl (1-(3-(2-amino-6-methylpyrimidin-4-yl)phenylsulfonamido)-4-methyl-1-oxopentan-2-yl)carbamate (4.35)

(54) ##STR00182##

(55) The mixture of (S)-tert-butyl (4-methyl-1-oxo-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylsulfonamido)pentan-2-yl)carbamate (20.27) and (S)-(3-(N-(2-((tert-butoxycarbonyl)amino)-4-methylpentanoyl)sulfamoyl)phenyl)boronic acid (20.27a) (0.600 g), obtained in the preceding step, was dissolved in dioxane (34 mL) and to the prepared solution were added 2-amino-4-chloro-6-methylpyrimidine (0.174 g, 1.21 mmol), Na.sub.2CO.sub.3 (0.385 g, 3.63 mmol), and water (1.7 mL). Through the obtained mixture for 10 min was bubbled argon, to the mixture was added PdCl.sub.2(dppf).sub.2 (0.045 g, 0.061 mmol), the reaction vessel was closed, and the content was stirred at 110° C. for 18 h. The mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated and the residue (0.76 g) was purified by column chromatography on silica gel (eluent chloroform-methanol, gradient from 100:1 to 100:2) to give 0.246 g (49.4%, calculated with respect to 3.1) of (S)-tert-butyl (1-(3-(2-amino-6-methylpyrimidin-4-yl)phenylsulfonamido)-4-methyl-1-oxopentan-2-yl)carbamate (4.35). .sup.1H NMR (DMSO-d.sub.6) δ: 12.33 (b s, 1H), 8.58 (s, 1H), 8.31 (d, J=7.9 Hz, 1H), 7.97 (d, J=7.9 Hz, 1H), 7.71 (t, J=7.9 Hz, 1H), 7.08 (s, 1H), 7.01 (b s, 1H), 6.70 (s, 2H), 4.00-3.90 (m, 1H), 2.32 (s, 3H), 1.63-1.19 (m, 3H), 1.28 (s, 9H), 0.80 (d, J=6.7 Hz, 3H), 0.78 (d, J=6.7 Hz, 3H). LCMS (ESI) m/z: 478.36 [M+H].sup.+.

(56) Following a method analogous to Method T the following compounds were obtained:

(57) TABLE-US-00006 Compound No Method Precursor Structure 4.27 T 20.27 4.28 T 20.27 4.29 T 20.27 4.30 T 20.30 4.35 T 20.27 4.36 T 20.27 4.37 T 20.27 4.38 T 20.27 0 4.39 T 20.27 4.40 T 20.27 4.41 T 20.27 4.42 T 20.27 4.43 T 20.27 4.44 T 20.27 4.45 T 20.27 4.46 T 20.27 4.47 T 20.27 4.48 T 20.27 00 4.49 T 20.27 01 4.51 T 20.27 02 4.52 T 20.27 03

Method U. Synthesis of (S)-tert-butyl (1-(3-(2-hydroxypyrimidin-4-yl)phenylsulfonamido)-4-methyl-1-oxopentan-2-yl)carbamate (4.50)

(58) To a solution of (S)-tert-butyl (1-(3-(2-chloropyrimidin-4-yl)phenylsulfonamido)-4-methyl-1-oxopentan-2-yl)carbamate (4.49) (0.189 g, 0.39 mmol) in THF (2 mL) was added 1 N aq. NaOH (22 mL) and the obtained emulsion was stirred at 55° C. for 1.5 h. The mixture was cooled to 0° C. and acidified to pH 3-4 by adding cold 2N aq. HCl (11 mL). The precipitate was filtered, the filtrate was extracted with EtOAc (3×25 mL), and the extract was dried (N.sub.2SO.sub.4). The solvents were evaporated, the residue was combined with the precipitate and purified by column chromatography on silica gel (eluent chloroform-methanol, 10:3) to give 0.110 g (60.5%) of (S)-tert-butyl (1-(3-(2-hydroxypyrimidin-4-yl)phenylsulfonamido)-4-methyl-1-oxopentan-2-yl)carbamate (4.50) as a foam. .sup.1H NMR (DMSO-d.sub.6, HMDSO) δ: 12.38 (b s, 1H), 12.05 (s, 1H), 8.63 and 8.58 (s and s, altogether 1H), 8.40-8.28 (m, 1H), 8.10 (d, J=6.3 Hz, 1H), 8.03 (d, J=7.5 Hz, 1H), 7.71 (t, J=7.7 Hz, 1H), 7.01 (d, J=6.3 Hz, 1H), 6.85 and 6.53 (b s and b s, altogether 1H), 3.94-3.85 and 3.84-3.73 (m and m, altogether 1H), 1.66-1.18 (m, 3H), 1.28 (s, 9H), 0.80 (d, J=6.2 Hz, 3H), 0.78 (d, J=6.2 Hz, 3H). LCMS (ESI) m/z: 465.4 [M+H].sup.+.

Method U. (S)-2-amino-4-methyl-N-((1,2,3,4-tetrahydroisoquinolin-8-yl)sulfonyl) pentanamide trifluoroacetate (5.26)

(59) A mixture of (S)-2-amino-N-(isoquinolin-8-ylsulfonyl)-4-methylpentanamide trifluoroacetate (5.22) (0.050 g, 0.11 mmol) and 10% Pd/C (5 mg) in methanol (2 mL) was hydrogenated at 5 atm. for 4 h. The catalyst was removed by filtration, the solvent was evaporated under vacuum, and the residue was purified by Biotage purification system (C18HS 40+M column, eluent water-acetonitrile, gradient from 95:5 to 60:40) to give 0.030 g (59%) of compound 5.26, mp 90-92° C. .sup.1H NMR (DMSO-d.sub.6, HMDSO) δ: 0.86 (3H, d, J=6.2 Hz), 0.88 (3H, d, J=6.2 Hz), 1.43 (1H, ddd, J=5.5, 8.8, 13.8 Hz), m), 1.62 (1H, ddd, J=5.2, 8.7, 13.8 Hz), 1.67-1.77 (1H, m), 3.04 (2H, t, J=6.3 Hz), 3.29-3.40 (3H, m, overlapped with water), 4.67 (2H, s), 7.30 (1H, dd, J=1.8, 7.6 Hz), 7.33 (1H, t, J=7.5 Hz), 7.72 (3H, b s), 7.75 (1H, dd, J=1.8, 7.4 Hz), 9.03 (2H, b s). LCMS (ESI) m/z: 326.2 [M+H].sup.+. Anal. Calcd for C.sub.15H.sub.23N.sub.3O.sub.3S×1.24 CF.sub.3COOH (30.3 C, 44.98, H, 5.23, N, 9.00. Found: C, 44.99, H, 5.38, N, 9.23.

(60) All compounds were characterized by .sup.1H-NMR and occasionally by .sup.13C-NMR spectroscopy performed on Varian Mercury spectrometer (400 MHz) with chemical shifts values (6) in ppm relative to internal standard, by tandem LC/MS spectrometer on Water Acquity UPLC with SQ mass selective detector, by elemental analyses, and occasionally by melting points. Physicochemical characterization of compounds 5.1-5.52.

(61) TABLE-US-00007 Compound Compound ID No Physicochemical characterization IK-698 5.1. m.p. 192° C., .sup.1H NMR (DMSO-d.sub.6) δ: (DMSO-d.sub.6) δ: 13.05 (b s, 1H), 8.43 (b s, 3H), 7.98-7.94 (m, 2H), 7.76-7.70 (m, 1H), 7.67- 7.61 (m, 2H), 3.93-3.83 (m, 1H), 1.67-1.48 (m, 3H), 0.82 (d, J = 6.0 Hz, 3H), 0.81 (d, J = 6.1 Hz, 3H); .sup.13C NMR (DMSO-d.sub.6) δ: 169.1, 138.9, 133.9, 129.2, 127.6, 51.3, 23.4, 22.6, 21.7. LCMS ESI (m/z): 271.2 [M + H].sup.+ Anal. Calcd. for C.sub.12H.sub.18N.sub.2O.sub.3S × HCl (11.8%) × 0.06 H.sub.2O (0.4%)): C 46.81, H 6.26, N 9.10. Found: C 46.81, H 6.21, N 9.02 IK-713 5.2. m.p. 224-225° C. .sup.1H NMR (DMSO-d.sub.6) δ: 8.38 (b s, 3H), 7.94 (distorted d, J = 9.0 Hz, 2H), 7.49 (distorted dd, J = 8.5, 7.4 Hz, 2H), 7.28 (distorted t, J = 7.4 Hz, 1H), 7.16-7.11 (m, 4H), 3.84 (b s, 1H), 1.65-1.47 (m, 3H), 0.84 (d, J = 6.0 Hz, 3H), 0.83 (d, J = 6.1 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 169.0, 161.7, 154.5, 132.6, 130.5, 125.2, 120.3, 117.2, 51.3, 23.4, 22.6, 21.7. LCMS ESI.sup.+ (m/z): 363.2 [M + H].sup.+. Anal. Calcd for C.sub.18H.sub.22N.sub.2O.sub.4S × HCl (9.1%) × 0.15 H.sub.2O (0.7%)): C 53.83, H 5.85, N 6.98, S 7.98; Found: C 53.80, H 5.85, N 6.98, S 7.62. IK-718 5.3. m.p. 143° C. (dec.). .sup.1H NMR (DMSO-d.sub.6) δ: 12.50 (b s, 1H), 8.11 (d, J = 7.3 Hz, 1H), 7.92 (b s, 3H), 7.65-7.46 (m, 2H), 7.46-7.30 (m, 5H), 7.27-7.18 (m, 1H), ~3.5-3.2 (1H, overlapped with water), 1.72-1.58 (m, 1H), 1.44-1.28 (m, 2H), 0.85 (d, J = 6.4 Hz, 3H), 0.81 (d, J = 6.4 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 171.0, 140.2, 132.2, 129.6, 129.4, 127.3, 127.1, 52.3, 23.5, 23.0, 21.1. LCMS ESI.sup.+ (m/z): 347.26 [M + H].sup.+. Anal. Calcd for C.sub.18H.sub.22N.sub.2O.sub.3S × HCl (9.0%) × 1.2 H.sub.2O (5.3%)): C 53.45, H 6.33, N 6.93, S 7.93. Found: C 53.52, H 6.03, N 6.76, S 7.41. LL-20 5.4. .sup.1H NMR (CD.sub.3OD) δ: 7.92 (s, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.55- 7.39 (m, 2H), 3.55 (t, J = 6.8 Hz, 1H), 1.81-1.60 (m, 2H), 1.52 (t, J = 8.3 Hz, 1H), 0.94 (d, J = 6.0 Hz, 3H), 0.92 d, J = 6.0 Hz, 3H). LCMS ESI.sup.+ (m/z): 305.8 [M + H].sup.+ LL-19 5.5. .sup.1H NMR (CD.sub.3OD) δ: 8.22 (dd, J = 7.9, 1.5 Hz, 1H), 7.75-7.58 (m, 2H), 7.53 (ddd, J = 7.8, 6.6, 2.0 Hz, 1H), 4.00-3.80 (m, 1H), 1.77-1.59 (m, 2H), 1.34-1.22 (m, 1H), 0.97 (d, J = 6.5, 6H). LCMS ESI.sup.+ (m/z): 305.8 [M + H].sup.+ EO-99 5.6. .sup.1H NMR (CD.sub.3OD) δ: δ 8.04 (td, J = 7.6, 1.8 Hz, 1H), 7.86- 7.66 (m, 1H), 7.49-7.24 (m, 2H), 3.86 (d, J = 3.1 Hz, 1H), 1.77- 1.57 (m, 3H), 1.05-0.89 (m, 6H). LCMS ESI.sup.+ (m/z): 289.34 [M + H].sup.+ LL-23 5.7. .sup.1H NMR (CD.sub.3OD) δ: 7.94 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 3.86 (t, J = 6.8 Hz, 1H), 2.70 (t, J = 7.7 Hz, 2H), 1.70- 1.46 (m, 4H), 1.44-1.21 (m, 3H), 1.02-0.76 (m, 9H). LCMS ESI.sup.+ (m/z): 327.46 [M + H].sup.+ MZ-377 5.8. m.p. 235-236° C. .sup.1H NMR (DMSO-d.sub.6) δ: 7.84 (distorted dd, J = 8.9, 5.6 Hz, 2H), 7.68 (b s, 3H), 7.21 (distorted t, J = 8.9 Hz, 2H), 3.32 (dd, J = 8.4, 5.7 Hz, 1H), 1.74-1.60 (m, 1H), 1.56 (ddd, J = 13.8, 8.3, 5.7 Hz, 1H), 1.38 (ddd, J = 13.8, 8.4, 6.0 Hz, 1H), 0.83 (d, J = 6.4 Hz, 3H), 0.82 (d, J = 6.4 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 172.7, 163.0 (.sup.1J.sub.CF = 246.9 Hz), 141.8 (.sup.4J.sub.CF = 2.9 Hz), 129.7 (.sup.3J.sub.CF = 8.9 Hz), 114.5 (.sup.2J.sub.CF = 22.1 Hz), 53.4, 40.5, 23.7, 22.7, 21.8. LCMS ESI.sup.+ (m/z): 289.3 [M + H].sup.+. Anal. Calcd for C.sub.12H.sub.17FN.sub.2O.sub.3S × 0.11 H.sub.2O (0.7%)): C 49.65, H 5.98, N 9.65; Found: C 49.66, H 6.01, N 9.61. IK-681 5.9. m.p. 149° C. (dec.). .sup.1H NMR (DMSO-d.sub.6) δ: 8.19 (b s, 3H), 8.16 (q, J = 1.5 Hz, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.72-7.68 (m, 2H), 7.56-7.51 (m, 2H), 7.48-7.43 (m, 1H), 3.86-3.74 (m, 1H), 1.64-1.45 (m, 3H), 0.82 (d, J = 6.0 Hz, 3H), 0.81 (d, J = 6.0 Hz, 3H). LCMS ESI (m/z): 347.1 [M + H].sup.+. Anal. Calcd. for C.sub.18H.sub.22N.sub.2O.sub.3S × HCl (8.3%) × 0.12 H.sub.2O (0.5%) × 0.6 C.sub.4H.sub.8O.sub.2 (12.1%)): C 55.95, H 6.45, N 6.40, S 7.32. Found: C 55.94, H 6.45, N 6.61, S 7.52. DL-23-340 5.10. m.p. 214.4° C. (single point, detected by OptiMelt). .sup.1H NMR (CD.sub.3OD) δ: 8.31 (td, J = 1.9, 0.5 Hz, 1H), 8.03 (ddd, J = 7.9, 1.9, 1.1 Hz, 1H), 7.99 (ddd, J = 7.9, 1.9, 1.1 Hz, 1H), 7.70 (td, J = 7.9, 0.5 Hz, 1H), 7.69-7.64 (m, 2H), 7.53-7.47 (m, 2H), 7.46-7.40 (m, 1H), 3.93 (t, J = 6.3 Hz, 1H), 1.75 (dt, J = 14.6, 6.8 Hz, 1H), 1.72 (ddd, J = 14.6, 6.9, 6.2 Hz, 1H), 0.68-0.57 (m, 1H), 0.51- 0.36 (m, 2H), 0.10-0.00 (m, 2H). .sup.13C NMR (CD.sub.3OD) δ: 169.1, 143.6, 140.8, 140.3, 133.7, 130.8, 130.3, 129.5, 128.1, 127.9, 127.9, 55.3, 36.7, 6.8, 5.3, 4.8. LCMS ESI.sup.+ (m/z): 345.31 [M + H].sup.+. Anal. Calcd for C.sub.18H.sub.20N.sub.2O.sub.3S × HCl (9.5%) × 0.16 H.sub.2O (0.8%)): C 56.34, H 5.60, N 7.30; Found: C 56.33, H 5.46, N 7.22. IK-707 5.11. m.p. 212° C. (dec.). .sup.1H NMR (DMSO-d.sub.6) δ: 8.17 (b s, 3H), 8.01 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H), 7.76-7.71 (m, 2H), 7.56-7.50 (m, 2H), 7.48-7.43 (m, 1H), 3.87-3.73 (m, 1H), 1.66- 1.46 (m, 3H), 0.84 (d, J = 6.2 Hz, 3H), 0.84 (d, J = 6.2 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 169.2, 145.3, 138.3, 137.7, 129.2, 128.7, 128.4, 127.3, 127.1, 51.4, 23.4, 22.6, 21.6. LCMS ESI.sup.+ (m/z): 347.3 [M + H].sup.+. Anal. Calcd. for C.sub.18H.sub.22N.sub.2O.sub.3S × 1.15 HCl (9.2%) × 0.75 H2O (3.4%)): C 54.54, H 6.23, N 7.07, S 8.09. Found: C 54.54, H 6.34, N 7.23, S 7.37. IK-719 5.12. m.p. 217° C. .sup.1H NMR (DMSO-d.sub.6) δ: 7.67 (b s, 3H), 7.01 (s, 2H), 4.58 (septet, J = 6.4 Hz, 2H), 3.36-3.27 (m, 1H, overlapped with water), 2.82 (septet, J = 6.6 Hz, 1H), 1.83-1.63 (m, 2H), 1.48-1.34 (m, 1H), 1.22-1.08 (m, 18H), 0.87 (d, J = 5.8 Hz, 6H). .sup.13C NMR (DMSO-d.sub.6) δ: 172.4, 148.8, 148.6, 139.6, 122.0, 53.0, 40.8, 33.3, 28.0, 24.8, 23.7, 23.0, 21.2. LCMS ESI+ (m/z): 397.43 [M + H]+ Anal. Calcd. for C.sub.21H.sub.36N.sub.2O.sub.3S × 0.3 HCl (2.7%)): C 61.89, H 8.98, N 6.87, S 7.87. Found %: C 62.03, H 9.03, N 6.65, S 7.48. IK-666 5.13. .sup.1H NMR (DMSO-d.sub.6) δ: 8.64 (d, J = 8.2 Hz, 1H), 8.33-8.20 (m, 2H), 8.08 (d, J = 7.8 Hz, 1H), 7.96 (b s, 3H), 7.76-7.62 (m, 3H), 3.72-3.58 (m, 1H), 1.50-1.36 (m, 2H), 1.31-1.19 (m, 1H), 0.73 (d, J = 5.7 Hz, 3H), 0.70 (d, J = 5.7 Hz, 3H). LCMS ESI (m/z): 321.2 [M + H].sup.+. IK-665 5.14. m.p. 215° C. (dec). .sup.1H NMR (DMSO-d.sub.6) δ: 13.08 (bs, 1H), 8.65 (d, J = 1.9 Hz, 1H), 8.31 (bs, 3H), 8.24 (d, J = 8.1 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.92 (dd, J = 8.8, 1.9 Hz, 1H), 7.75 (ddd, J = 8.1, 6.9, 1.4 Hz, 1H), 7.70 (ddd, J = 8.1, 6.9, 1.4 Hz, 1H), 3.91-3.81 (m, 1H), 1.64-1.44 (m, 3H), 0.81 (d, J = 6.1 Hz, 6H). .sup.13C NMR (DMSO-d.sub.6) δ: 169.2, 136.0, 134.7, 131.4, 129.6, 129.5 (2), 129.3, 129.2, 127.8, 122.5, 51.4, 40.0, 23.4, 22.6, 21.5. LCMS ESI (m/z): 321.2 [M + H].sup.+. Anal. Calcd. for C.sub.16H.sub.20N.sub.2O.sub.3S × HCl (9.5%) × 0.3 C.sub.4H.sub.8O.sub.2 (6.9%) × 0.1 H.sub.2O (0.5%)): C 53.65, H 6.18, N 7.27, S 8.33. Found: C 53.65, H 6.21, N 7.34, S 8.56. DG-500 5.15. m.p. 229.7° C. (224.6-237.4° C.). .sup.1H NMR (DMSO-d.sub.6) δ: 13.07 (b s, 1H), 8.66 (d, J = 1.9 Hz, 1H), 8.36 (b s, 3H), 8.24 (d, J = 8.2 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.92 (dd, J = 8.8, 1.9 Hz, 1H), 7.75 (ddd, J = 8.2, 7.0, 1.4 Hz, 1H), 7.70 (ddd, J = 8.2, 7.0, 1.4 Hz, 1H), 3.80 (b s, 1H), 1.91-1.79 (m, 1H), 1.28-1.15 (m, 1H), 1.07-0.92 (m, 1H), 0.79 (d, J = 7.0 Hz, 3H), 0.71 (t, J = 7.4 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 168.1, 135.9, 134.7, 131.4, 129.5, 129.4, 129.2, 129.2, 127.8, 127.7, 122.5, 56.8, 36.0, 23.6, 14.5, 11.1. LCMS ESI (m/z): 321.2 [M + H].sup.+. Anal. Calcd. for C.sub.16H.sub.20N.sub.2O.sub.3S × HCl (9.1%) × H.sub.2O (4.5%) × 0.3 C.sub.4H.sub.8O.sub.2 (6.6%)): C 51.48, H 6.38, N 6.98. Found: C 51.50, H 6.02, N 6.70. MZ-335 5.16. m.p. 178-180° C. .sup.1H NMR (DMSO-d.sub.6) δ: 8.65 (d, J = 8.3 Hz, 1H), 8.40-8.32 (m, 2H), 8.29 (b s, 3H), 7.74 (t, J = 8.0 Hz, 1H), 7.71 (t, J = 8.1 Hz, 1H), 7.45 (d, J = 7.5 Hz, 1H), 3.82 (m, overlapped with water, 1H), 2.92 (s, 6H), 1.46-1.25 (m, 3H), 0.70 (d, J = 5.8 Hz, 3H), 0.65 (d, J = 5.8 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 168.9, 154.8, 143.8, 133.9, 131.6, 130.5, 128.7, 128.4, 127.9, 124.3, 117.1, 51.3, 45.5, 23.2, 22.5, 21.6. LCMS ESI.sup.+ (m/z): 364.3 [M + H].sup.+. Anal. Calcd for C.sub.18H.sub.25N.sub.3O.sub.3S × 2.9 HCl (21.9%) × 0.75 H2O (2.8%)): C 44.79, H 6.14, N 8.70; Found: C 44.77, H 6.14, N 8.47. MZ-343 5.17. m.p. 230-232° C. .sup.1H NMR (DMSO-d.sub.6) δ: 8.28 (s, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.81 (dd, J = 8.7, 1.6 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.67 (b s, 3H), 7.34 (d, J = 2.5 Hz, 1H), 7.21 (dd, J = 9.0, 2.5 Hz, 1H), 3.33 (dd, J = 8.4, 5.6 Hz, 1H, overlapped with water), 1.76-1.62 (m, 1H), 1.58 (ddd, J = 13.8, 8.3, 5.6 Hz, 1H), 1.38 (ddd, J = 13.8, 8.4, 5.9 Hz, 1H), 0.83 (d, J = 6.4 Hz, 3H), 0.82 (d, J = 6.4 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 172.5, 158.3, 140.4, 135.0, 130.3, 127.0, 126.7, 126.0, 124.6, 119.1, 105.8, 55.3, 53.4, 40.6, 23.7, 22.7, 21.8. LCMS ESI.sup.+ (m/z): 351.2 [M + H].sup.+. Anal. Calcd. for C.sub.17H.sub.22N.sub.2O.sub.4S × 1.02 H.sub.2O (5.0%)): C 55.36, H 6.57, N 7.60. Found: C 55.35, H 6.48, N 7.60. MZ-370 5.18. m.p. 253-255° C. .sup.1H NMR (DMSO-d.sub.6) δ: 8.74 (ddd, J = 8.5, 1.4, 0.7 Hz, 1H), 8.16 (ddd, J = 8.2, 1.6, 0.7 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.60 (b s, 3H), 7.54 (ddd, J = 8.5, 6.8, 1.6 Hz, 1H), 7.49 (ddd, J = 8.2, 6.8, 1.4 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 3.26 (dd, J = 8.0, 5.7 Hz, 1H), 1.63-1.49 (m, 1H), 1.50 (ddd, J = 13.5, 8.0, 6.0 Hz, 1H), 1.21 (ddd, J = 13.5, 8.0, 5.7 Hz, 1H), 0.77 (d, J = 6.3 Hz, 3H), 0.73 (d, J = 6.3 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 172.3, 156.6, 133.3, 129.5, 128.7, 126.7, 126.4, 125.1, 124.9, 121.7, 102.3, 55.9, 53.4, 40.6, 23.7, 22.5, 21.8. LCMS ESI.sup.+ (m/z): 351.4 [M + H].sup.+. Anal. Calcd for C.sub.17H.sub.22N.sub.2O.sub.4S): C 58.27, H 6.33, N 7.99. Found: C 58.30, H 6.31, N 7.99. KS-1189 5.19. .sup.1H NMR (DMSO-d.sub.6) δ 9.12 (dd, J = 4.2, 1.6 Hz, 1H), 8.59 (dd, J = 8.4, 1.7 Hz, 1H), 8.52 (dd, J = 7.4, 1.4 Hz, 1H), 8.40 (dd, J = 8.2, 1.4 Hz, 1H), 8.27 (bs, 1H), 8.15 (bs, 3H), 7.83 (t, J = 7.8 Hz, 1H), 7.76 (dd, J = 8.3, 4.2 Hz, 1H), 1.52-1.29 (m, 2H), 1.27-1.13 (m, 1H), 0.76 (d, J = 5.5 Hz, 3H), 0.69 (d, J = 5.6 Hz, 3H). MZ-375 5.20. m.p. 203-205° C. .sup.1H NMR (DMSO-d.sub.6) δ: 8.76-8.73 (m, 1H), 8.50 (b s, 3H), 8.18-8.11 (m, 2H), 7.77-7.70 (m, 1H), 3.89 (b s, 1H), 1.76-1.50 (m, 3H), 0.86 (d, J = 8.5 Hz, 3H), 0.86 (d, J = 8.5 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 169.6, 155.5, 150.2, 138.8, 128.2, 123.4, 51.3, 39.5, 23.4, 22.7, 21.7. LCMS ESI.sup.+ (m/z): 372.3 [M + H].sup.+. Anal. Calcd. for C.sub.11H.sub.17N.sub.3O.sub.3S × HCl (11.8%)): C 42.93, H 5.89, N 13.65. Found, C 43.00, H 6.04, N 13.23. C-2724 5.21. m.p. 55-57° C. .sup.1H NMR (DMSO-d.sub.6) δ: 0.73 (3H, d, J = 6.2 Hz), 0.74 (3H, d, J = 6.2 Hz), 1.20-1.34 (1H, m), 1.41-1.52 (2H, m), 3.48 (1H, m), 7.79 (3H, b s), 8.01 (1H, dd, J = 7.3, 8.2 Hz), 8.18 (1H, d, J = 5.8 Hz), 8.28 (1H, d, J = 8.2 Hz), 8.34 (1H, dd, J = 1.1, 7.3 Hz), 8.68 (1H, d, J = 5.8 Hz), 10.15 (1H, s). LCMS ESI (m/z): 322.1 [M + H].sup.+. Anal. Calcd. for C.sub.15H.sub.19N.sub.3O.sub.3S × 2.7 CF.sub.3COOH (46.4%) × H.sub.2O (2.7%) × 0.12 Leu (2.4%)): C 38.26, H 3.84, N 6.59. Found, %: C 38.32, H 3.86, N 6.41. C-2775 5.22. m.p. 137-139° C. .sup.1H NMR (DMSO-d.sub.6) δ: 10.12 (1H, s), 8.74 (1H, d, J = 5.9 Hz), 8.27 (1H, d, J = 7.9 Hz), 8.14 (1H, d, J = 7.9 Hz), 8.06 (1H, dd, J = 5.9, 08 Hz), 7.73 (3H, b s), 3.47-3.37 (1H, m), 1.56-1.40 (2H, m), 1.30-1.20 (1H, m), 0.74 (3H, d, J = 6.3 Hz), 0.73 (3H, d, J = 6.3 Hz). LCMS ESI (m/z): 400.0 [M + H].sup.+. Anal. Calcd. For C.sub.15H.sub.18BrN.sub.3O.sub.3S × 1.22 CF.sub.3COOH (25.6%) × 0.2 H.sub.2O (0.7%): C 38.58, H 3.64, N 7.74. Found: C 38.60, H 3.66, N 7.74. MZ-368 5.23. m.p. 250-252° C. .sup.1H NMR (DMSO-d.sub.6) δ: 10.60 (b s, 1H), 8.91 (ddd, J = 8.4, 1.2, 0.6 Hz, 1H), 8.15 (ddd, J = 8.2, 1.6, 0.6 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.60 (b s, 3H), 7.50 (ddd, J = 8.4, 6.8, 1.6 Hz, 1H), 7.44 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 3.27 (dd, J = 7.7, 5.8 Hz, 1H), 1.64-1.46 (m, 2H), 1.23 (ddd, J = 13.3, 8.0, 5.8 Hz, 1H), 0.77 (d, J = 6.2 Hz, 3H), 0.73 (d, J = 6.2 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 172.1, 155.6, 131.6, 130.1, 129.0, 126.5, 126.2, 124.6, 124.4, 122.0, 105.8, 53.4, 40.7, 23.7, 22.5, 21.8. LCMS ESI.sup.+ (m/z): 337.3 [M + H].sup.+. Anal. Calcd. for C.sub.16H.sub.20N.sub.2O.sub.4S × 0.2 H.sub.2O (1.0%) × 0.2 HCl (2.1%) × 0.17 CH.sub.3CN (2.0%)): C 55.40, H 6.01, N 8.58. Found, C 55.31, H 5.98, N 8.76. IK-603 5.24. m.p. 222.9° C. .sup.1H NMR (DMSO-d.sub.6) δ: 10.11 (s, 1H), 8.56 (s, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 7.3 Hz, 1H), 8.24 (d, J = 8.3 Hz, 1H), 7.87 (t, J = 7.8 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.63 (b s, 3H), 3.31 (dd, J = 7.7, 5.6 Hz, 1H), 1.52-1.44 (m, 2H), 1.26-1.19 (m, 1H), 0.74 (d, J = 5.9 Hz, 3H), 0.71 (d, J = 5.9 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 173.2, 166.2, 150.4, 143.8, 142.3, 136.0, 131.1, 130.0, 129.7, 124.5, 119.8, 53.4, 40.6, 23.7, 22.5, 21.8. LCMS ESI (m/z): 365.2 [M + H].sup.+. Anal. Calcd. for C.sub.16H.sub.20N.sub.4O.sub.4S × 0.08 CF.sub.3COOH (2.3%) × 1.1 H2O (5.0%)): C 49.34, H 5.71, N 14.24, S 8.15. Found: C 49.34, H 5.77, N 14.16, 87.92 AC-486 5.25. m.p. 165° C. (dec.) .sup.1H NMR (DMSO-d.sub.6) δ: 0.87 (3H, d, J = 6.3 Hz), 0.88 (3H, d, J = 6.3 Hz), 1.38 (1H, ddd, J = 5.9, 8.7, 14.0 Hz), 1.65 (1H, ddd, J = 5.7, 8.7, 14.0 Hz), 1.75 (1H, m), 1.84-1.91 (2H, m), 2.73 (2H, t, J = 6.5 Hz), 3.28 (1H, dd, J = 5.7, 8.7 Hz, overlapped with water), 4.06-4.13 (2H, m), 6.76 (1H, t, J = 7.6 Hz), 7.06 (1H, d, J = 7.5 Hz), 7.54 (1H, dd, J = 7.8, 1.7 Hz), 7.62 (3H, b s). LCMS ESI (m/z): 327.1 [M + H]+. Anal. Calcd for C.sub.15H.sub.22N.sub.2O.sub.4S × 1.2 C.sub.2HF.sub.3O.sub.2 (28.6%) × 0.8 H.sub.2O (3.0%)): C 43.75, H 5.23, N 5.86; Found: C 43.78, H 4.98, N 6.30. C-2727 5.26. m.p. 90-92° C. .sup.1H NMR (DMSO-d.sub.6) δ: 0.86 (3H, d, J = 6.2 Hz), 0.88 (3H, d, J = 6.2 Hz), 1.43 (1H, ddd, J = 5.5, 8.8, 13.8 Hz), m), 1.62 (1H, ddd, J = 5.2, 8.7, 13.8 Hz), 1.67-1.77 (1H, m), 3.04 (2H, t, J = 6.3 Hz), 3.29-3.40 (3H, m, overlapped with water), 4.67 (2H, s), 7.30 (1H, dd, J = 1.8, 7.6 Hz), 7.33 (1H, t, J = 7.5 Hz), 7.72 (3H, b s), 7.75 (1H, dd, J = 1.8, 7.4 Hz), 9.03 (2H, b s). LCMS ESI (m/z): 326.2 [M + H].sup.+. Anal. Calcd. for C.sub.15H.sub.22N.sub.3O.sub.3S × 1.24 CF.sub.3COOH (30.3%)): C 44.98, H 5.23, N 9.00. Found C 44.99, H 5.38, N 9.23. ‘DG-459 5.27. .sup.1H NMR (DMSO-d.sub.6) δ: 12.62 (b s, 1H), 8.65 (b s, 1H), 8.19 (s, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.74 (b s, 3H), 7.60 (t, J = 7.7 Hz, 1H), ~8.2-7.1 (b s, 2H), 6.44 (s, 1H), 3.44-3.26 (m, 1H, overlapped with water), 2.91 (d, J = 4.6 Hz, 3H), 1.77-1.61 (m, 1H), 1.58 (ddd, J = 13.8, 8.1, 5.7 Hz, 1H), 1.41 (ddd, J = 13.8, 8.2, 6.2 Hz, 1H), 0.83 (d, J = 6.3 Hz, 3H), 0.82 (d, J = 6.3 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 172.9, 170.1, 163.7, 163.6, 158.3, 158.1, 146.4, 129.7, 128.7, 128.2, 125.0, 53.4, 40.4, 27.5, 23.7, 22.7, 21.9. LCMS ESI (m/z): 393.2 [M + H].sup.+. Anal. Calcd for C.sub.17H.sub.24N.sub.6O.sub.3S × HCl (8.3%) × 0.6 H.sub.2O (2.5%)): C 46.43, H 6.01, N 19.11. Found: C 46.46, H 6.22, N 19.02. DG-457 5.28. .sup.1H NMR (DMSO-d.sub.6) δ: 12.63 (b s, 1H), 8.29 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.76 (b s, 3H), 7.58 (t, J = 7.8 Hz, 1H), 7.34 (b s, 2H), 6.59 (s, 1H), 3.45-3.30 (m, 1H, overlapped with water), 3.19 (s, 6H), 1.79-1.63 (m, 1H), 1.59 (ddd, J = 13.7, 8.2, 5.7 Hz, 1H), 1.41 (ddd, J = 13.7, 8.2, 6.0 Hz, 1H), 0.84 (d, J = 6.2 Hz, 3H), 0.83 (d, J = 6.2 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 172.8, 162.7, 162.6, 146.2, 129.6, 128.8, 128.4, 125.1, 91.4, 53.3, 40.4, 37.5, 23.7, 22.7, 21.8. LCMS ESI (m/z): 407.3 [M + H].sup.+. Anal. Calcd for for C.sub.18H.sub.26N.sub.6O.sub.3S × HCl (7.8%) × H.sub.2O (3.8%) × 0.1 C.sub.4H.sub.8O.sub.2 (1.9%)): C 47.04, H 6.39, N 17.89. Found: C 46.95, H 6.33, N 17.79. DG-460 5.29. .sup.1H NMR (DMSO-d.sub.6) δ: 8.51 (s, 1H), 8.07 (d, J = 7.4 Hz, 1H), 7.87 (d, J = 7.4 Hz, 1H), 7.68 (b s, 3H), 7.50 (t, J = 7.4 Hz, 1H), 7.00 (s, 1H), 6.80 (b s, 2H), 3.50-3.25 (m, 1H, overlapped with water), 2.52 (s, 3H), 1.77-1.51 (m, 2H), 1.45-1.31 (m, 1H), 0.83 (d, J = 6.2 Hz, 3H), 0.82 (d, J = 6.2 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 172.7, 171.1, 162.9, 161.8, 145.9, 136.5, 128.9, 128.5, 128.0, 125.5, 102.2, 53.4, 40.5, 23.7, 22.7, 21.8, 11.8. LCMS ESI (m/z): 410.2 [M + H].sup.+. Anal. Calcd for C.sub.17H.sub.23N.sub.5O.sub.3S.sub.2 × 0.5 HCl (3.8%) × 0.12 C.sub.16H.sub.20ClN.sub.5O.sub.3S (10.0%)): C 47.79, H 5.49, N 16.50. Found C 48.04, H 5.65, N 16.46 IK-656 5.30. m.p. >192° C. (dec). .sup.1H NMR (DMSO-d.sub.6) δ: 8.76 (t, J = 1.8 Hz, 1H), 8.47 (d, J = 8.0 Hz, 1H), 8.43 (b s, 3H), 8.19 (d, J = 7.8 Hz, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.56 (s, 1H), ~9-7 (b s, 3H), 4.03- 3.91 (m, 1H), 2.50 (s, 3H, overlapped with DMSO), 1.72 (td, J = 6.7, 14.4 Hz, 1H), 1.60 (td, J = 6.8, 14.4 Hz, 1H), 0.69-0.57 (m, 1H), 0.33-0.16 (m, 2H), 0.04-−0.13 (m, 2H). .sup.13C NMR (DMSO- d.sub.6) δ: 168.8, 168.7, 140.0, 138.1, 135.8, 132.9, 131.1, 130.2, 126.9, 125.8, 106.2, 53.2, 34.9, 20.4, 5.8, 4.5, 4.0. LCMS ESI (m/z): 376.2 [M + H].sup.+. Anal. Calcd for C.sub.17H.sub.21N.sub.5O.sub.3S × 2.5 HCl (18.5%) × 1.5 H.sub.2O (5.5%)): C 41.37, H 5.41, N 14.19. Found: C 41.35, H 5.31, N 14.27. DG-466 5.31. .sup.1H NMR (DMSO-d.sub.6) δ: 8.75 (t, J = 1.7 Hz, 1H), 8.48 (ddd, J = 7.9, 1.6, 1.0 Hz, 1H), 8.43 (b s, 3H), 8.20 (ddd, J = 7.9, 1.9, 1.0 Hz, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.63 (s, 1H), 9.1-7.5 (b s, 2H), 3.90- 3.79 (m, 1H), 2.52 (s, 3H), 2.27 (septet, J = 7.7 Hz, 1H), 1.96- 1.76 (m, 4H), 1.76-1.53 (m, 3H), 1.45 (quintet, J = 9.0 Hz, 1H). .sup.13C NMR (DMSO-d.sub.6) δ: 168.9, 166.6, 162.1, 157.4, 140.1, 135.5, 133.0, 131.3, 130.2, 126.9, 106.3, 51.5, 37.1, 30.4, 27.7, 27.3, 20.0, 17.8. LCMS ESI (m/z): 390.2 [M + H].sup.+. Anal. Calcd. for C.sub.18H.sub.23N.sub.5O.sub.3S × 2.5 HCl (17.2%) × 0.36 C.sub.4H.sub.8O.sub.2 (6.0%) × 1 H.sub.2O (3.4%)): C 44.03, H 5.77, N 13.20. Found: C 44.29, H 5.74, N 12.71. DG-470 5.32. .sup.1H NMR (DMSO-d.sub.6) δ: (DMSO-d.sub.6) δ: 8.75 (s, 1H), 8.48 (d, J = 7.6 Hz, 1H), 8.39 (b s, 3H), 8.18 (d, J = 7.9 Hz, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7.65-7.56 (m, 1H), ~9.1-7.3 (b s, 2H), 3.87-3.74 (m, 1H), 2.52 (s, 3H), 1.85-1.68 (m, 1H), 1.68-1.49 (m, 3H), 1.49-1.35 (m, 2H), 1.15-0.86 (m, 5H) .sup.13C NMR (DMSO-d.sub.6) δ: (DMSO-d.sub.6) δ: 168.6, 166.9, 162.8, 158.1, 140.5, 136.0, 133.3, 131.7, 130.6, 127.3, 106.7, 57.3, 39.4, 28.3, 27.8, 25.8, 25.7, 25.7, 20.6. LCMS ESI (m/z): 404.2 [M + H].sup.+ Anal. Calcd. for C.sub.19H.sub.25N.sub.5O.sub.3S × 2.7 HCl (16.6%) × 1.1 H.sub.2O (3.3%) × 0.8 C.sub.4H.sub.8O.sub.2 (11.9%)): C 45.02, H 6.18, N 11.83, S 5.41; Found: C 45.03, H 6.19, N 12.15, S 4.99. IK-685 5.33. m.p. 158° C. (dec.). .sup.1H NMR (DMSO-d.sub.6) δ: 8.73 (s, 1H), 8.43 (d, J = 7.8 Hz, 1H), 8.35 (b s, 3H), 8.15 (d, J = 7.8 Hz, 1H), 7.95 (s, 1H), 7.84 (distorted t, J = 7.8 Hz, 1H), 7.45 (b s, 1H), ~8.8-7.0 (b s, 2H), 3.32-3.17 (m, 1H), 2.46 (s, 3H), 0.97-0.87 (m, 1H), 0.85- 0.73 (m, 1H), 0.63-0.49 (m, 2H), 0.48-0.40 (m, 1H). LCMS ESI (m/z): 362.2 [M + H].sup.+. Anal. Calcd. for C.sub.16H.sub.19N.sub.5O.sub.3S × 2 HCl (14.6%) × 1.7 H2O (6.1%) × 0.4 C4H8O2): C 42.26, H 5.56, N 14.00, S 6.41. Found: C 42.18, H 5.33, N 13.84, S 6.44. DG-469 5.34. .sup.1H NMR (DMSO-d.sub.6) δ: 8.75 (t, J = 1.7 Hz, 1H), 8.48 (d, J = 8.1 Hz, 1H), 8.45 (b s, 3H), 8.18 (ddd, J = 7.7, 1.7, 0.8 Hz, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.61 (s, 1H), ~9.3-7.5 (b s, 2H), 4.00-3.90 (m, 1H), 2.52 (s, 3H), 1.62-1.45 (m, 7H), 1.27-1.14 (m, 1H), 1.14- 0.97 (m, 3H), 0.87-0.68 (m, 2H). .sup.13C NMR (DMSO-d.sub.6) δ: 169.4, 166.6, 162.3, 157.5, 140.1, 135.6, 132.9, 131.2, 130.2, 126.9, 106.2, 50.8, 37.8, 32.6, 32.2, 32.0, 25.7, 25.5, 25.3, 20.1. LCMS ESI (m/z): 418.2 [M + H].sup.+. Anal. Calcd for C.sub.20H.sub.27N.sub.5O.sub.3S × 2.8 HCl (17.1%) × 0.45 H2O (1.4%) × 0.8 C4H8O2 (11.8%)): C 46.58, H 6.25, N 11.71. Found, %: C 46.61, H 6.29, N 11.42. IK-580 5.35. m.p. 241-242° C. (dec.). .sup.1H NMR (DMSO-d.sub.6, HMDSO) δ: 8.50 (t, J = 1.7 Hz, 1H), 8.05 (ddd, J = 7.8, 1.7, 1.2 Hz, 1H), 7.88 (ddd, J = 7.8, 1.7, 1.2 Hz, 1H), 7.67 (b s, 3H), 7.50 (t, J = 7.8 Hz, 1H), 7.01 (s, 1H), 6.63 (s, 2H), 3.37-3.30 (m, 1H, overlapped with water), 2.31 (s, 3H), 1.73-1.60 (m, 1H), 1.58 (ddd, J = 13.7, 8.4, 5.6 Hz, 1H), 1.38 (ddd, J = 13.7, 8.3, 5.8 Hz, 1H), 0.83 (d, J = 6.3 Hz, 3H), 0.81 (d, J = 6.3 Hz, 3H). LCMS (ESI) m/z: 378.2 [M + H].sup.+. Anal. Calcd for C.sub.17H.sub.23N.sub.5O.sub.3S × 0.09 CF.sub.3COOH (2.5%) × 1.12 H.sub.2O (4.9%): C 50.59, H 6.26, N 17.17. Found: C 50.59, H 6.32, N 17.23. IK-617 5.36. m.p. 87-88° C. (dec.). .sup.1H NMR (DMSO-d.sub.6) δ: 8.60 (1H, br s), 8.40-7.90 (5H, br m), 7.73 (1H, unresolved t, J~7.5 Hz), 7.50- 6.75 (2H, m), 6.66 (1H, br s), 3.89 (3H, br s), 3.78 (1H, br s), 1.68-1.40 (3H, m), 0.93-0.71 (6H, br s). .sup.13C NMR (DMSO-d.sub.6) δ: 171.4, 169.7, 163.0, 158.5, 158.2, 140.3, 137.2, 131.6, 129.6, 129.3, 125.9, 92.7, 53.5, 51.7, 23.4, 22.6, 21.3. LCMS (ESI) m/z: 394.2 [M + H].sup.+. Anal. Calcd for C.sub.17H.sub.23N.sub.5O.sub.4S × 2.6 CF.sub.3COOH (42.7%) × 0.25 H.sub.2O (0.6%): C 38.40, H 3.79, N 10.09. Found: C 38.42, H 4.16, N 9.70. IK-587 5.37. m.p. 224-226° C. (dec.). .sup.1H NMR (DMSO-d.sub.6, HMDSO) δ: 0.81 (3H, d, J = 6.5 Hz), 0.83 (3H, d, J = 6.5 Hz), 1.38 (1H, ddd, J = 5.8, 8.3, 13.7 Hz), 1.58 (1H, ddd, J = 5.6, 8.3, 13.7 Hz), 1.67 (1H, m), 3.32 (1H, dd, J = 5.6, 8.3 Hz, overlapped with water), 6.75 (2H, s), 7.09 (1H, d, J = 5.2 Hz), 7.52 (1H, t, J = 7.8 Hz), 7.67 (3H, b s), 7.89 (1H, ddd, J = 0.9, 1.6, 7.8 Hz), 8.06 (1H, ddd, J = 0.9, 1.6, 7.8 Hz), 8.33 (1H, d, J = 5.2 Hz), 8.53 (1H, t, J = 1.6 Hz). .sup.13C NMR (DMSO-d.sub.6) δ: 21.8, 22.7, 23.7, 40.5, 53.4, 105.8, 125.3, 125.4, 128.3, 128.9, 136.6, 146.0, 159.3, 163.0, 163.9, 172.7. LCMS (ESI) m/z: 364.1 [M + H].sup.+. Anal. Calcd for C.sub.16H.sub.21N.sub.5O.sub.3S × 0.05 CF.sub.3COOH (1.5%) × 0.85 H.sub.2O (4.0%): C 50.30, H 5.96, N 18.22. Found: C 50.31, H 5.98, N 18.17. K-615 5.38. m.p. 117° C. (dec.). .sup.1H NMR (DMSO-d.sub.6) δ: 9.32 (1H, s), 9.03 (1H, d, J = 7.6 Hz), 8.25 (1H, s), 8.16 (3H, b s), 8.10 (1H, d, J = 7.6 Hz), 7.83 (1H, t, J = 7.6 Hz), 6.8-3.4 (broad water signal) 3.82 (1H, b s), 1.64-1.42 (3H, m), 0.84-0.76 (6H, b m). .sup.13C NMR (DMSO-d.sub.6) δ: 169.4, 160.0, 156.0, 150.5, 142.0, 139.5, 136.7, 134.0, 129.5, 129.4, 128.1, 123.6, 51.6, 23.4, 22.6, 21.3. LCMS (ESI) m/z: 404.2 [M + H].sup.+. Anal. Calcd for C.sub.17H.sub.21N.sub.7O.sub.3S × 2.65 CF.sub.3COOH (42.6%) × 0.2 H.sub.2O (0.5%): C 37.77, H 3.42, N 13.82, S 4.52. Found: C 37.87, H 3.46, N 13.76, S 4.00. IK-621 5.39. m.p. 246° C. .sup.1H NMR (DMSO-d.sub.6, HMDSO) δ: 9.11 (d, J = 1.1 Hz, 1H), 8.61 (t, J = 1.6 Hz, 1H), 8.21 (ddd, J = 7.8, 1.6, 1.1 Hz, 1H), 7.98 (s, 1H), 7.94 (ddd, J = 7.8, 1.5, 1.1 Hz, 1H), 7.67 (b s, 3H), 7.58 (t, J = 7.8 Hz, 1H), 3.36-3.34 (m, 1H, overlapped with water), 2.55 (s, 3H), 1.67 (nonet, J = 6.6 Hz, 1H), 1.59 (ddd, J = 13.7, 8.1, 5.7 Hz, 1H), 1.38 (ddd, J = 13.7, 8.1, 5.9 Hz, 1H), 0.83 (d, J = 6.6 Hz, 3H), 0.81 (d, J = 6.6 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 173.2, 168.4, 162.1, 158.8, 146.8, 136.1, 129.8, 128.9, 128.9, 126.0, 116.8, 53.8, 41.0, 24.2, 24.1, 23.1, 22.2. LCMS (ESI) m/z: 363.1 [M + H].sup.+. Anal. Calcd for C.sub.17H.sub.22N.sub.4O.sub.3S × 0.3 H.sub.2O (1.5%): C 55.51, H 6.19, N 15.23. Found: C 55.51, H 6.25, N 15.19. BM-13 5.40. m.p. 97° C. .sup.1H NMR (DMSO-d.sub.6, HMDSO) δ 8.67 (t, J = 1.7 Hz, 1H), 8.32 (d, J = 7.8 Hz, 1H), 8.04 (ddd, J = 7.8, 1.7, 1.0 Hz, 1H), 7.95 (b s, 3H), 7.73 (t, J = 7.8 Hz, 1H), 7.24 (s, 1H), 7.20 (b s, 3H), 3.76-3.68 (m, 1H), 2.38 (s, 3H), 1.86-1.75 (m, 1H), 1.25- 1.14 (m, 1H), 1.09-0.96 (m, 1H), 0.79 (d, J = 7.0 Hz, 3H), 0.73 (t, J = 7.4 Hz, 3H). LCMS (ESI) m/z: 378.2 [M + H].sup.+. Anal. Calcd for C.sub.17H.sub.23N.sub.5O.sub.3S × 2.56 CF.sub.3COOH (43.1%) × 0.4 H.sub.2O (1.1%): C 39.27, H 3.93, N 10.35. Found: C 39.28, H 3.91, N 10.44. IK-625 5.41. m.p. 186-188° C. (dec). .sup.1H NMR (DMSO-d.sub.6, HMDSO) δ: 8.76 (s, 1H), 8.54-8.48 (m, 1H), 8.25-8.19 (m, 2H), 8.08-7.94 (m, 4H), 7.79-7.72 (m, 2H), 7.57-7.52 (m, 3H), 6.91 (b s, 2H), 3.76- 3.65 (m, 1H, overlapped with water), 1.65-1.42 (m, 3H), 0.83 (d, J = 6.2 Hz, 3H), 0.82 (d, J = 6.2 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 169.6, 165.3, 163.9, 163.1, 158.5, 158.1, 138.1, 136.9, 132.1, 130.8, 129.6, 129.4, 128.7, 127.0, 126.0, 102.1, 51.6, 23.4, 22.6, 21.3. LCMS (ESI) m/z: 440.3 [M + H].sup.+. Anal. Calcd for C.sub.22H.sub.25N.sub.5O.sub.3S × 2.1 CF.sub.3COOH (34.3%) × 1.05 H.sub.2O (2.7%): C 45.09, H 4.22, N 10.03. Found: C 45.05, H 4.26, N 9.83. IK-636 5.42. m.p. 151° C. (dec). .sup.1H NMR (DMSO-d.sub.6, HMDSO) δ: 9.01 (b s, 2H), 8.49 (b s, 3H), 8.44 (s, 1H), 8.39 (b s, 2H), 8.33 (d, J = 7.2 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.89 (t, J = 7.4 Hz, 1H), ~9.4-7.2 (b s, 1H), 3.93 (b s, 1H), 1.68-1.51 (m, 3H), 0.83 (d, J = 5.7 Hz, 3H), 0.82 (d, J = 6.0 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 169.9, 153.2, 143.7, 140.9, 136.2, 133.6, 131.1, 130.3, 127.2, 124.7, 51.8, 23.9, 22.9, 22.2. LCMS (ESI) m/z: 348.2 [M + H].sup.+. Anal. Calcd for C.sub.17H.sub.21N.sub.3O.sub.3S × 2 HCl (15.9%) × 2.1 H.sub.2O (8.3%): C 44.56, H 5.98, N 9.17. Found: C 44.54, H 5.57, N 9.06. IK-634 5.43. m.p. 141° C. (dec). .sup.1H NMR (DMSO-d.sub.6, HMDSO) δ: 13.86 (b s, 1H), 8.36-8.02 (m, 9H), 7.80 (t, J = 7.3 Hz, 1H), 7.36-7.31 (m, 1H), 7.22 (dd, J = 6.7, 1.6 Hz, 1H), 8.36-7.10 (b s, 1H), 3.74 (m, overlapped with water, 1H), 1.67-1.43 (m, 3H), 0.82 (d, J = 6.2 Hz, 3H), 0.82 (d, J = 6.3 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 170.0, 154.4, 152.2, 141.1, 136.7, 136.1, 131.9, 130.4, 129.4, 125.9, 110.4, 110.2, 51.7, 23.4, 22.5, 21.7. LCMS (ESI) m/z: 363.2 [M + H].sup.+. Anal. Calcd for C.sub.17H.sub.22N.sub.4O.sub.3S × 3 HCl (22.0%) × 1.45 H.sub.2O (5.2%): C 41.01, H 5.65, N 11.25. Found: C 41.01, H 5.62, N 11.20. IK-635 5.44. m.p. 148° C. (dec). .sup.1H NMR (DMSO-d.sub.6, HMDSO) δ: 8.42 (t, J = 1.7 Hz, 1H), 7.96 (ddd, J = 7.8, 1.7, 1.1 Hz, 1H), 7.77 (ddd, 7.7, 1.7, 1.1 Hz, 1H), 7.65 (b s, 3H), 7.47 (dd, J = 8.1, 7.5 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.01 (dd, J = 7.5, 0.7 Hz, 1H), 6.43 (dd, J = 8.1, 0.7 Hz, 1H), 6.05 (b s, 2H), 3.35-3.29 (m, overlapped with water, 1H), 1.75-1.61 (m, 1H), 1.59 (ddd, J = 13.8, 8.4, 5.4 Hz, 1H), 1.38 (ddd, J = 13.8, 8.5, 5.8 Hz, 1H), 0.83 (d, J = 6.7 Hz, 3H), 0.81 (d, J = 6.7 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 172.6, 159.6, 153.7, 146.7, 138.9, 138.0, 127.7, 127.7, 126.8, 125.0, 108.3, 107.3, 53.4, 40.6, 23.7, 22.7, 21.8. LCMS (ESI) m/z: 363.2 [M + H].sup.+. Anal. Calcd for C.sub.17H.sub.22N.sub.4O.sub.3S × 0.36 HCl (3.5%): C 54.37, H 6.00, N 14.92. Found: C 54.39, H 6.10, N 14.82. IK-627 5.45. m.p. 234° C. (dec). .sup.1H NMR (DMSO-d.sub.6, HMDSO) δ: 13.11 (b s, 1H), 8.51 (b s, 1H), 8.31 (b s, 3H), 8.28 (s, 1H), 8.22 (d, J = 7.9 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.84 (t, J = 7.9 Hz, 1H), 8.70- 7.50 (b s, 4H), 6.53 (s, 1H), 3.87 (b s, 1H), 1.69-1.49 (m, 3H), 0.85 (d, J = 6.0 Hz, 3H), 0.84 (d, J = 6.1 Hz, 3H). LCMS (ESI) m/z: 379.2 [M + H].sup.+. Anal. Calcd for C.sub.16H.sub.22N.sub.6O.sub.3S × 3 HCl (20.4%) × 2.7 H.sub.2O (9.1%): C 35.82, H 5.71, N 15.67. Found: C 35.78, H 5.62, N 15.22. DG-435 5.46. .sup.1H NMR (DMSO-d.sub.6, HMDSO) δ: 8.71 (unresolved d, J = 0.7 Hz, 1H), 8.63 (b s, 2H), 8.44 (t, J = 1.8 Hz, 1H), 8.29 (b s, 3H), 8.23 (ddd, J = 8.0, 1.8, 1.0 Hz, 1H), 8.15 (ddd, J = 8.0, 1.8, 1.0 Hz, 1H), 7.85 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 0.7 Hz, 1H), ~9.5-7.0 (b s, 1H), 3.84 (b s, 1H, overlapped with water), 1.68-1.47 (m, 3H), 0.84 (d, J = 6.2 Hz, 3H), 0.83 (d, J = 6.3 Hz, 3H). LCMS (ESI) m/z: 364.2 [M + H].sup.+. Anal. Calcd for C.sub.16H.sub.21N.sub.5O.sub.3S × 3 HCl (22.0%) × 1.3 H.sub.2O (4.7%): C 38.73, H 5.40, N 14.11. Found: C 39.07, H 5.28, N 13.64. DG-437 5.47. .sup.1H NMR (DMSO-d.sub.6, HMDSO) δ: 8.50 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.67 (b s, 3H), 7.50 (t, J = 7.7 Hz, 1H), 7.00 (s, 1H), ~9.0-6.9 (b s, 1H), 6.64 (s, 2H), 3.45-3.25 (m, 1H, overlapped with water), 2.59 (q, J = 7.6 Hz, 2H), 1.77- 1.52 (m, 2H), 1.44-1.33 (m, 1H), 1.22 (t, J = 7.6 Hz, 3H), 0.85- 0.79 (m, 6H). .sup.13C NMR (DMSO-d.sub.6) δ: 173.2, 172.7, 163.8, 163.1, 146.0, 136.9, 128.7, 128.3, 128.0, 125.3, 104.0, 53.4, 40.5, 30.3, 23.7, 22.7, 21.8, 12.8. LCMS (ESI) m/z: 392.2 [M + H].sup.+. DG-440 5.48. .sup.1H NMR (DMSO-d.sub.6, HMDSO) δ: 8.91 (t, J = 1.8 Hz, 1H), 8.66 (s, 1H), 8.62 (ddd, J = 7.9, 1.6, 1.1 Hz, 1H), 8.39 (unresolved d, J~5.9 Hz, 3H), 8.16 (ddd, J = 7.9, 2.0, 1.1 Hz, 1H), 7.93 (b s, 1H), 7.88 (b s, 1H), 7.82 (t, J = 7.9 Hz, 1H), ~9.5-7.0 (b s, 1H), 3.91 (m, 1H, overlapped with water), 1.63-1.49 (m, 3H), 0.81 (d, J = 6.1 Hz, 3H), 0.81 (d, J = 6.1 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 169.1, 168.1, 166.5, 166.4, 139.3, 136.6, 133.0, 131.1, 129.9, 127.3, 51.3, 23.4, 22.5, 21.7. LCMS (ESI) m/z: 365.2 [M + H].sup.+. Anal. Calcd for C.sub.15H.sub.20N.sub.6O.sub.3S × 3 HCl (20.6%) × 0.3 Et.sub.2O (4.2%) × 0.4 C.sub.4H.sub.8O.sub.2 (6.6%): C 40.24, H 5.54, N 15.82. Found: C 40.64, H 5.63, N 15.99. DG-444 5.49. m.p. 231-238° C. (dec). .sup.1H NMR (DMSO-d.sub.6, HMDSO) δ: 8.93 (d, J = 5.2 Hz, 1H), 8.73 (t, J = 1.8 Hz, 1H), 8.52 (ddd, J = 7.9, 1.7, 1.0 Hz, 1H), 8.34 (b s, 3H), 8.27 (d, J = 5.2 Hz, 1H), 8.17 (ddd, J = 7.9, 1.9, 1.0 Hz, 1H), 7.86 (t, J = 7.9 Hz, 1H), 3.91-3.80 (m, 1H), 1.65-1.47 (m, 3H), 0.83 (d, J = 6.1 Hz, 6H). .sup.13C NMR (DMSO-d.sub.6) δ: 169.5, 164.3, 161.9, 160.6, 140.4, 135.4, 132.5, 130.8, 130.3, 126.2, 116.6, 66.3, 51.5, 23.4, 22.5, 21.6. LCMS (ESI) m/z: 383.2 [M + H].sup.+. Anal. Calcd for C.sub.16H.sub.19ClN.sub.4O.sub.3S × HCl (8.6%) × 0.3 H.sub.2O (1.3%): C 45.25, H 4.89, N 13.19. Found: C 45.48, H 4.72 N 12.73. DG-445 5.50. m.p. 191-221° C. (dec). .sup.1H NMR (DMSO-d.sub.6, HMDSO) δ: 8.65 (unresolved t, J = 1.7 Hz, 1H), 8.49-8.38 (m, 4H), 8.21 (d, J = 6.3 Hz, 1H), 8.15 (d, J = 7.7 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 6.3 Hz, 1H), ~8.8-7.0 (b s, 1H), 3.95-3.86 (m, 1H), 1.66-1.50 (m, 3H), 0.81 (d, J = 5.9 Hz, 1H), 0.81 (d, J = 5.9 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 169.2, 168.6, 155.7, 149.7, 139.5, 136.3, 133.1, 130.7, 130.1, 126.7, 100.7, 51.3, 23.4, 22.5, 21.7. LCMS (ESI) m/z: 365.2 [M + H].sup.+. Anal. Calcd for C.sub.16H.sub.20N.sub.4O.sub.4S × 2 HCl (15.2%) × 1.5 H.sub.2O (5.6%) × 0.2 Et.sub.2O (3.1%): C 42.11, H 5.68, N 11.69. Found: C 41.93, H 5.21, N 11.23. DG-455 5.51. .sup.1H NMR (DMSO-d.sub.6) δ: 8.48 (t, J = 1.7 Hz, 1H), 8.00 (ddd, J = 7.8, 1.6, 1.0 Hz, 1H), 7.85 (ddd, J = 7.8, 1.6, 1.0 Hz, 1H), 7.60 (b s, 3H), 7.46 (t, J = 7.8 Hz, 1H), 6.66 (b s, 2H), 6.45 (s, 1H), 5.31 (septet, J = 6.2 Hz, 1H), 3.40-3.27 (m, 1H, overlapped with water), 1.74-1.61 (m, 1H), 1.58 (ddd, J = 13.7, 8.3, 5.5 Hz, 1H), 1.38 (ddd, J = 13.7, 8.3, 5.9 Hz, 1H), 1.29 (d, J = 6.2 Hz, 6H), 0.83 (d, J = 6.5 Hz, 3H), 0.82 (d, J = 6.5 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 172.9, 170.2, 164.2, 163.6, 145.8, 136.8, 128.5, 128.1, 127.9, 125.3, 92.4, 67.6, 53.4, 40.7, 23.7, 22.7, 21.9, 21.8. LCMS (ESI) m/z: 422.2 [M + H].sup.+. Anal. Calcd for C.sub.19H.sub.27N.sub.5O.sub.4S × 0.4 HCl (3.3%): C 52.33, H 6.33, N 16.06. Found: C 52.56, H 6.41, N 15.99. DG-453 5.52. .sup.1H NMR (DMSO-d.sub.6, HMDSO) δ: 8.63 (t, J = 1.6 Hz, 1H), 8.36 (ddd, J = 8.1, 1.6, 1.0 Hz, 1H), 8.32 (b s, 3H), 8.10 (ddd, J = 7.8, 1.6, 1.0 Hz, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.46 (distorted t, J = 7.8 Hz, 2H), 7.27 (distorted t, J = 7.4 Hz, 1H), (distorted d, J = 7.6 Hz, 2H), 6.89 (s, 1H), 3.94-3.82 (m, 1H, overlapped with water), 3.8- 3.2 (2H, overlapped with water), 1.67-1.47 (m, 3H), 0.83 (d, J = 5.7 Hz, 3H), 0.83 (d, J = 5.7 Hz, 3H). .sup.13C NMR (DMSO-d.sub.6) δ: 171.4, 169.3, 161.6, 161.0, 152.2, 139.7, 135.4, 132.4, 130.1, 130.1, 129.9, 126.2, 125.7, 121.7, 94.2, 66.4, 51.4, 23.4, 22.6, 21.6. LCMS (ESI) m/z: 456.3 [M + H].sup.+. Anal. Calcd for C.sub.22H.sub.25N.sub.5O.sub.4S × 2 HCl (12.9%) × 2 H.sub.2O (6.4%): C 46.81, H 5.54, N 12.41. Found: C 46.89, H 5.36, N 12.01.
In Vitro Assay

(62) The compounds have been tested for antibacterial activity in vitro as aminoacyl-tRNA synthetases (aaRS) inhibitors following the following process.

(63) Targeted aaRSs

(64) Leucyl-, valyl- and isoleucyl-tRNA synthetases (LRS, VRS and IRS, respectively) from Escherichia coli (Eco) and Staphylococcus aureus (Sau).

(65) Protein Expression and Purification

(66) Escherichia coli M15 cells transformed with plasmid pQE-60, or pQE-70, containing the open-reading frame sequence of one targeted aaRS were induced with 1 mM IPTG (Isopropyl β-D-1-thiogalactopyranoside) for 3 h at 37° C. Bacterial cells were harvested and lysed with 20 mM NaH.sub.2PO.sub.4 (pH 8.0), 200 mM NaCl, 10 mM imidazole and protease inhibitor cocktail (Roche). Pathogenic aaRS was purified by nickel affinity standard chromatography. Protein concentration was determined by spectrophotometry.

(67) In Vitro tRNA Transcription

(68) tRNA.sup.Leu, tRNA.sup.Val and tRNA.sup.Ile from E. coli and S. aureus were transcribed in vitro for 4 h at 37° C. using T7 RNA polymerase. Transcription reaction contained 40 mM Tris-HCl (pH 8.0), 22 mM MgCl2, 1 mM spermidine, 5 mM DTT, 0.01% Triton X-100, 4 mM GTP, 4 mM ATP, 4 mM UTP, 4 mM CTP, 16 mM GMP, 250 μM T7 RNA polymerase and 150 μg BstNI digested plasmid. Once finished, the reaction was applied on a 6% polyacrylamide-8 M urea denaturing gel to purify the transcribed tRNA and discard any impurities. Purified tRNA was quantified with Nanodrop 2000 (Thermo Scientific).

(69) Determination of IC.sub.50

(70) The aminoacylation reaction catalyzed by aminoacyl-tRNA synthetases (aaRS) takes place in two steps. In the first step, aaRS activates its cognate amino acid with ATP; and in the second step the activated amino acid is loaded to its corresponding tRNA. This reaction can be summarized as follows:
ARS+aa+ATP=ARS-aa-AMP+PPi  [1]
ARS-aa-AMP+tRNA=aa-tRNA+AMP+ARS  [2]
(ARS, Aminoacyl-tRNA synthetase; aa, amino acid; ARS-aa-AMP, enzyme-bound to aminoacyl-adenylate; aa-tRNA, aminoacyl-tRNA).

(71) The activity of the pathogenic aaRSs was monitored by measuring the ATP consumption rate, since this consumption is directly proportional to the activity of the aaRS. If the tested compound, at a single point concentration of 50 μM, is inhibiting the aminoacylation reaction, there is a decrease in the ATP consumption, compared to the control reaction without compound, allowing the calculation of an inhibition ratio.

(72) When the inhibition ratio for a given compound was above 80%, IC.sub.50 determination was performed with the same enzymatic assay (using the commercial kit Kinase RR from BioThema AB, Sweden) in the presence of serial dilutions of inhibitor. Known inhibitors of LRS, VRS or IRS were used as a positive control of the assay. The IC.sub.50 was calculated based on nonlinear regression analysis.

(73) IC.sub.50 values of for selected inhibitors of aminoacyl-tRNA synthethases

(74) TABLE-US-00008 IC50 IC50 IC50 IC50 IC50 IC50 Cmpd EcoLRS EcoIRS EcoVRS SauLRS SauIRS SauVRS No ID (μM) (μM) (μM) (μM) (μM) (μM) IK-698 5.1. 0.035 i.a. i.a. 5.4 i.a. i.a. IK-713 5.2. 0.713 i.a i.a 16.3 i.a i.a IK-718 5.3. 0.159 i.a i.a 14.8 i.a i.a LL-20 5.4. 0.031 i.a i.a 0.92 i.a i.a LL-19 5.5. 0.121 i.a i.a 13.2 i.a i.a EO-99 5.6. 0.233 i.a i.a 17.0 i.a i.a LL-23 5.7. 0.668 i.a i.a 4.9 i.a i.a IK-681 5.9. 0.032 i.a i.a 0.65 i.a i.a DL-23-340 5.10. 47.6 i.a i.a i.a i.a i.a IK-707 5.11. 27.6 i.a i.a 11.3 i.a i.a IK-719 5.12. 32.7 i.a i.a i.a i.a i.a IK-666 5.13. 0.059 i.a i.a 16.1 i.a i.a IK-665 5.14. 0.065 i.a i.a 1.0 i.a i.a DG-500 5.15. i.a i.a i.a i.a i.a i.a MZ-335 5.16. 4.1 i.a i.a i.a i.a i.a MZ-343 5.17. 0.92 i.a i.a 2.0 i.a i.a KS-1189 5.19. 0.78 i.a i.a 16.8 i.a i.a C-2724 5.21. 0.483 i.a i.a 3.42 i.a i.a C-2775 5.22. 2.4 i.a i.a 11.5 i.a i.a IK-603 5.24. 0.011 i.a i.a 8.5 i.a i.a AC-486 5.25. 0.149 i.a i.a 14.1 i.a i.a C-2727 5.26. 0.176 i.a i.a 20.0 i.a i.a DG-459 5.27. 0.051 i.a i.a 0.26 i.a i.a DG-457 5.28. 1.6 i.a i.a 4.8 i.a i.a DG-460 5.29. 0.021 i.a i.a 1.2 i.a i.a IK-656 5.30. 14.0 i.a i.a i.a i.a i.a DG-466 5.31. 6.2 i.a i.a i.a i.a i.a DG-470 5.32. 38.0 i.a i.a i.a 65.2 i.a IK-685 5.33. 40%@50 i.a i.a i.a i.a i.a uM DG-469 5.34. i.a i.a i.a i.a i.a i.a IK-580 5.35. 0.014 n.d. i.a. 4.34 i.a. i.a. IK-617 5.36. 0.012 n.d. i.a. 3 i.a. i.a. IK-587 5.37. 0.054 n.d. i.a. 2.18 i.a. i.a. K-615 5.38. 0.084 n.d. i.a. 1.11 i.a. i.a. IK-621 5.39. 0.045 n.d. i.a. 2.0 i.a. i.a. BM-13 5.40. 21.8 n.d. i.a. i.a. i.a. i.a. IK-625 5.41. 0.22 n.d. i.a. 3.0 i.a. i.a. IK-636 5.42. 0.013 n.d. i.a. 0.81 i.a. i.a. IK-634 5.43. 0.002 n.d. i.a. 0.33 i.a. i.a. IK-635 5.44. 0.006 n.d. i.a. 1.64 i.a. i.a. IK-627 5.45. 0.02 n.d. i.a. 0.72 i.a. i.a. DG-435 5.46. 0.01 n.d. i.a. 1.3 i.a. i.a. DG-437 5.47. 0.011 n.d. i.a. 2.15 i.a. i.a. DG-440 5.48. 0.0034 n.d. i.a. 0.53 i.a. i.a. DG-444 5.49. 0.064 n.d. i.a. 6.23 i.a. i.a. DG-445 5.50. 0.063 n.d. i.a. 13.9 i.a. i.a. DG-455 5.51. 102%@50 μM n.d. n.d. n.d. n.d. n.d. DG-453 5.52. 104%@50 μM n.d. n.d. n.d. n.d. n.d. i.a.—inactive at a concentration below 50 uM; n.d.—not determined
Terms and Definitions

(75) Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings that are commonly understood by those of ordinary skill in the art.

(76) The term “alkyl”, alone or in combination, means an acyclic, saturated hydrocarbon group of the formula CnH2n+1 which may be linear or branched. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl and hexyl and the like. Unless otherwise specified, an alkyl group comprises from 1 to 6 carbon atoms. The carbon atom content of alkyl and various other hydrocarbon-containing moieties is indicated by a prefix designating a lower and upper number of carbon atoms in the moiety, that is, the prefix Ci-j indicates a moiety of the integer “i” to the integer “j” carbon atoms, inclusive. Thus, for example, C.sub.1-6alkyl refers to alkyl of one to six carbon atoms, inclusive. The terms “cycloalkyl” and “carbocyclic” are synonyms and each means a monocyclic, saturated hydrocarbon group of the formula CnH2n−1. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Unless otherwise specified, a cycloalkyl group comprises from 3 to 8 carbon atoms.

(77) The terms “heterocyclic”, and “heterocyclo” are synonyms and each means a saturated or unsaturated (but not aromatic) monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system. Monocyclic heterocyclic rings contain from about 3 to 12 ring atoms, with from 1 to 5 heteroatoms selected from N, O, and S, and preferably from 3 to 7 member atoms, in the ring. In this context, the prefixes (e.g., C.sub.3-20, C.sub.5-7, C.sub.5-6, etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term “C.sub.5-6heterocyclyl” as used herein, pertains to a heterocyclyl group having 5 or 6 ring atoms. Examples of heterocyclic groups include cyclic ethers (oxiranes) such as ethyleneoxide, tetrahydrofuran, dioxane. Heterocycles containing nitrogen are groups such as pyrrolidine, piperidine, piperazine, tetrahydrotriazine, tetrahydropyrazole. Typical sulfur containing heterocycles include tetrahydrothiophene, dihydro-1,3-dithiol-2-yl, and hexahydrothiophen-4-yl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO.sub.2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothiophene. Other commonly employed heterocycles include dihydro-oxathiol-4-yl, dihydro-1H-isoindole, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl and thiomorpholinyl.

(78) As used herein, the term “alkenyl” as a group or a part of a group refers to a linear or branched hydrocarbon group containing one or more carbon-carbon double bonds and containing the indicated number of carbon atoms. Examples of such groups include ethenyl, propenyl, butenyl, pentenyl or hexenyl and the like.

(79) As used herein, the term “alkynyl” as a group or a part of a group refers to a linear or branched hydrocarbon group containing one or more carbon-carbon triple bonds and containing the indicated number of carbon atoms. Examples of such groups include ethynyl, propynyl, butynyl, pentynyl or hexynyl and the like.

(80) The term “oxo” means a doubly bonded oxygen.

(81) The term “halo” means, fluoro, chloro, bromo or iodo.

(82) As used herein, the term “aryl”, pertains to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, said compound having one ring, or two or more rings (e.g., fused), wherein at least one of said ring(s) is an aromatic ring. Preferably, each ring has from 5 to 7 ring atoms. In this context, the prefixes (e.g., C.sub.3-20, C.sub.5-7, C.sub.5-6, etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term “C.sub.5-6aryl,” as used herein, pertains to an aryl group having 5 or 6 ring atoms. Examples of groups of aryl groups include C.sub.3-20aryl, C.sub.5-7aryl, C.sub.5-6aryl.

(83) The ring atoms may be all carbon atoms, as in “carboaryl groups” (e.g., C.sub.5-20carboaryl). Examples of carboaryl groups include, but are not limited to, those derived from benzene (i.e., phenyl) (C6), naphthalene (C10), azulene (C10), anthracene (C14), phenanthrene (C14), naphthacene (C18), and pyrene (C16).

(84) Examples of aryl groups which comprise fused rings, at least one of which is an aromatic ring, include, but are not limited to, groups derived from indene (C9), isoindene (C9), and fluorene (C13).

(85) Alternatively, the ring atoms may include one or more heteroatoms, including but not limited to oxygen, nitrogen, and sulfur, as in “heteroaryl groups.” In this case, the group may conveniently be referred to as a “C.sub.5-20heteroaryl” group, wherein “C.sub.5-20” denotes ring atoms, whether carbon atoms or heteroatoms. Preferably, each ring has from 5 to 7 ring atoms, of which from 0 to 4 are ring heteroatoms.

(86) Examples of monocyclic heteroaryl groups include, but are not limited to, those derived from:

(87) N1: pyrrole (azole) (C5), pyridine (azine) (C6);

(88) O1: furan (oxole) (C5);

(89) S1: thiophene (thiole) (C5);

(90) N1O1: oxazole (C5), isoxazole (C5), isoxazine (C6);

(91) N2O1: oxadiazole (furazan) (C5);

(92) N3O1: oxatriazole (C5);

(93) N1S1: thiazole (C5), isothiazole (C5);

(94) N2: imidazole (1,3 diazole) (C5), pyrazole (1,2 diazole) (C5), pyridazine (1,2 diazine) (C6), pyrimidine (1,3 diazine) (C6) (e.g., cytosine, thymine, uracil), pyrazine (1,4 diazine) (C6);

(95) N3: triazole (C5), triazine (C6); and,

(96) N4: tetrazole (C5).