Fused ring analogues of anti-fibrotic agents

Abstract

The present invention relates to arylcarbonyl and heteroarylcarbonyl anthranilate compounds that may be useful as anti-fibrotic agents. The present invention also relates to methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment disorders.

Claims

1. A compound of Formula (I) ##STR00138## or a pharmaceutically acceptable salt or prodrug thereof, wherein: W is selected from the group consisting of: CR.sup.7 and N; A is selected from the group consisting of: CH, CH.sub.2, CH.sub.2CH.sub.2, OC(O), C(O)O, SCH.sub.2, SC(O), S(O).sub.2, C(O)S, C(O)NH, NH, NH(CO), N, and NHCH.sub.2; Z.sup.1-Z.sup.2 is selected from the group consisting of NC and CC; X.sup.1 selected from the group consisting of: CO, CF.sub.2, SO.sub.2, and PO.sub.2; X.sup.2 is selected from the group consisting of: NR.sup.13 and (CH.sub.2).sub.t, wherein t is an integer selected from the group consisting of: 0 and 1; D is selected from the group consisting of: phenyl and C.sub.2-C.sub.5 heteroaryl; R.sup.1, R.sup.4, and R.sup.7 are each independently selected from the group consisting of: H, halogen, OH, NO.sub.2, CN, NH.sub.2, optionally substituted C.sub.1-C.sub.12 alkyl, optionally substituted C.sub.2-C.sub.12 alkenyl, optionally substituted C.sub.2-C.sub.12 alkynyl, optionally substituted C.sub.1-C.sub.10 heteroalkyl, optionally substituted C.sub.3-C.sub.12 cycloalkyl, optionally substituted C.sub.3-C.sub.12 cycloalkenyl, optionally substituted C.sub.2-C.sub.12 heterocycloalkyl, optionally substituted C.sub.2-C.sub.12 heterocycloalkenyl, optionally substituted C.sub.6-C.sub.18 aryl, optionally substituted C.sub.1-C.sub.18 heteroaryl, optionally substituted C.sub.1-C.sub.12 alkyloxy, optionally substituted C.sub.2-C.sub.12 alkenyloxy, optionally substituted C.sub.2-C.sub.12 alkynyloxy, optionally substituted C.sub.1-C.sub.10 heteroalkyloxy, optionally substituted C.sub.3-C.sub.12 cycloalkyloxy, optionally substituted C.sub.3-C.sub.12 cycloalkenyloxy, optionally substituted C.sub.1-C.sub.12 heterocycloalkyloxy, optionally substituted C.sub.1-C.sub.12 heterocycloalkenyloxy, optionally substituted C.sub.6-C.sub.18 aryloxy, optionally substituted C.sub.1-C.sub.18 heteroaryloxy, optionally substituted C.sub.1-C.sub.12 alkylamino, SR.sup.14, SO.sub.3H, SO.sub.2NR.sup.15R.sup.16, SO.sub.2R.sup.14, SONR.sup.15R.sup.16, SOR.sup.14, COR.sup.14, COOH, COOR.sup.14, CONR.sup.15R.sup.16, NR.sup.15COR.sup.14, NR.sup.15COOR.sup.14, NR.sup.15SO.sub.2R.sup.14, NR.sup.15CONR.sup.15R.sup.16, NR.sup.15R.sup.16, and acyl; R.sup.5 is selected from the group consisting of: COOH, CONH.sub.2, CONHCH.sub.3, CONHOH, SO.sub.2CH.sub.3, SO.sub.2NH.sub.2, SONHCH.sub.3, and SON(CH.sub.3).sub.2, wherein the R.sup.5 substituent is ortho to X.sup.2; each R.sup.6 is independently selected from the group consisting of: H, halogen, OH, NO.sub.2, CN, optionally substituted C.sub.1-C.sub.12 alkyl, optionally substituted C.sub.2-C.sub.12 alkenyl, optionally substituted C.sub.2-C.sub.12 alkynyl, optionally substituted C.sub.1-C.sub.10 heteroalkyl, optionally substituted C.sub.3-C.sub.12 cycloalkyl, optionally substituted C.sub.3-C.sub.12 cycloalkenyl, optionally substituted C.sub.2-C.sub.12 heterocycloalkyl, optionally substituted C.sub.2-C.sub.12 heterocycloalkenyl, optionally substituted C.sub.6-C.sub.18 aryl, optionally substituted C.sub.1-C.sub.18 heteroaryl, optionally substituted C.sub.1-C.sub.12 alkyloxy, optionally substituted C.sub.2-C.sub.12 alkenyloxy, optionally substituted C.sub.2-C.sub.12 alkynyloxy, optionally substituted C.sub.1-C.sub.10 heteroalkyloxy, optionally substituted C.sub.3-C.sub.12 cycloalkyloxy, optionally substituted C.sub.3-C.sub.12 cycloalkenyloxy, optionally substituted C.sub.1-C.sub.12 heterocycloalkyloxy, optionally substituted C.sub.1-C.sub.12 heterocycloalkenyloxy, optionally substituted C.sub.6-C.sub.18 aryloxy, optionally substituted C.sub.1-C.sub.18 heteroaryloxy, optionally substituted C.sub.1-C.sub.12 alkylamino, SR.sup.14, SO.sub.3H, SO.sub.2NR.sup.15R.sup.16, SO.sub.2R.sup.14, SONR.sup.15R.sup.16, SOR.sup.14, COR.sup.14, COOH, COOR.sup.14, CONR.sup.15R.sup.16, NR.sup.15COR.sup.14, NR.sup.15COOR.sup.14, NR.sup.15SO.sub.2R.sup.14, NR.sup.15CONR.sup.15R.sup.16, NR.sup.15R.sup.16, and acyl; R.sup.2 and R.sup.3 are each independently selected from the group consisting of: OH, optionally substituted C.sub.1-C.sub.12 alkyloxy, optionally substituted C.sub.2-C.sub.12 alkenyloxy, optionally substituted C.sub.2-C.sub.12 alkynyloxy, optionally substituted C.sub.1-C.sub.10 heteroalkyloxy, optionally substituted C.sub.3-C.sub.12 cycloalkyloxy, optionally substituted C.sub.3-C.sub.12 cycloalkenyloxy, optionally substituted C.sub.1-C.sub.12 heterocycloalkyloxy, optionally substituted C.sub.1-C.sub.12 heterocycloalkenyloxy, optionally substituted C.sub.6-C.sub.18 aryloxy, and optionally substituted C.sub.1-C.sub.18 heteroaryloxy; or R.sup.2 and R.sup.3 may be fused to form a 5 or 6 membered heterocycloalkyl ring, which may be optionally substituted; R.sup.15, R.sup.16, and R.sup.17 are each independently selected from the group consisting of: H, an N-protecting group, optionally substituted C.sub.1-C.sub.12 alkyl, optionally substituted C.sub.2-C.sub.12 alkenyl, optionally substituted C.sub.2-C.sub.12 alkynyl, optionally substituted C.sub.1-C.sub.10 heteroalkyl, optionally substituted C.sub.3-C.sub.12 cycloalkyl, optionally substituted C.sub.3-C.sub.12 cycloalkenyl, optionally substituted C.sub.1-C.sub.12 heterocycloalkyl, optionally substituted C.sub.1-C.sub.12 heterocycloalkenyl, optionally substituted C.sub.6-C.sub.18 aryl, and optionally substituted C.sub.1-C.sub.18 heteroaryl; R.sup.13 is H; R.sup.14 is selected from the group consisting of H, optionally substituted C.sub.1-C.sub.12 alkyl, optionally substituted C.sub.2-C.sub.12 alkenyl, optionally substituted C.sub.2-C.sub.12 alkynyl, optionally substituted C.sub.1-C.sub.10 heteroalkyl, optionally substituted C.sub.3-C.sub.12 cycloalkyl, optionally substituted C.sub.3-C.sub.12cycloalkenyl, optionally substituted C.sub.1-C.sub.12 heterocycloalkyl, optionally substituted C.sub.1-C.sub.12 heterocycloalkenyl, optionally substituted C.sub.6-C.sub.18 aryl, and optionally substituted C.sub.1-C.sub.18 heteroaryl; m is 1; n is an integer selected from the group consisting of 1, 2, 3, and 4; and m+n is an integer selected from the group consisting of 2, 3, 4, and 5.

2. The compound of claim 1, wherein R.sup.2 is X.sup.3R.sup.18 and R.sup.3 is X.sup.4R.sup.19, wherein: R.sup.18 and R.sup.19 are the same or different and are selected from the group consisting of: H, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cyclokalkyl, C.sub.3-C.sub.10 cycloalkylmethyl, C.sub.3-C.sub.10 alkene, C.sub.3-C.sub.10 alkyne, aryl, C.sub.5-C.sub.20 alkaryl, and a hydrocarbon chain containing a heterocyclic or fused ring, any of which may be optionally substituted; and X.sup.3 and X.sup.4 are O.

3. The compound of claim 2, wherein R.sup.18 and R.sup.19 are fused to form a 5-membered or 6-membered heterocycloalkyl ring, which may be optionally substituted.

4. The compound of claim 1, wherein Z.sup.1-Z.sup.2 is CC.

5. The compound of claim 1, wherein R.sup.6 is selected from the group consisting of: H and halogen.

6. The compound of claim 1, wherein X.sup.1 is selected from the group consisting of: CO and SO.sub.2.

7. The compound of claim 1, wherein X.sup.2 is NR.sup.13.

8. The compound of claim 7, wherein W is CR.sup.7.

9. The compound of claim 8, wherein R.sup.7 is H.

10. The compound of claim 1, wherein R.sup.2 and R.sup.3 are each independently selected from the group consisting of: optionally substituted C.sub.1-C.sub.12 alkyloxy and optionally substituted C.sub.2-C.sub.12 alkynyloxy.

11. The compound of claim 10, wherein the optionally substituted C.sub.1-C.sub.12 alkyloxy is C.sub.1-C.sub.12 fluoroalkyloxy.

12. The compound of claim 10, wherein the optionally substituted C.sub.2-C.sub.12 alkynyloxy is C.sub.2-C.sub.12 alkynylalkyloxy.

13. The compound of claim 1, wherein R.sup.2 is selected from the group consisting of: H.sub.3CO, F.sub.2HCF.sub.2CO, F.sub.2HCO, F.sub.3CO, and CHCCH.sub.2O.

14. The compound of claim 1, wherein R.sup.3 is selected from the group consisting of: H.sub.3CO, F.sub.2HCF.sub.2CO, F.sub.2HCO, F.sub.3CO, and CHCCH.sub.2O.

15. The compound of claim 1, wherein R.sup.2 and R.sup.3 together are selected from the group consisting of: OCF.sub.2CF.sub.2CO, OCH.sub.2CH.sub.2O, OCF.sub.2O, and OCH.sub.2O.

16. A compound selected from the group consisting of: ##STR00139## ##STR00140## ##STR00141## ##STR00142## ##STR00143## or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1, wherein R.sup.4 is selected from the group consisting of: H and optionally substituted C.sub.1-C.sub.6 alkoxy.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1: Average % inhibition of TGF- stimulated proline incorporation by compound FT98 at 10 M, 30 M and 100 M (SEM).

(2) FIG. 2: Average % inhibition of TGF- stimulated proline incorporation by compound FT108 at 10 M, 30 M and 100 M (SEM).

(3) FIG. 3: Average % inhibition of TGF- stimulated proline incorporation by compound FT109 at 10 M, 30 M and 100 M (SEM).

(4) FIG. 4: Average % inhibition of TGF- stimulated proline incorporation by compound FT113 at 10 M, 30 M and 100 M (SEM).

(5) FIG. 5: Average % inhibition of TGF- stimulated proline incorporation by compound FT121 at 10 M, 30 M and 100 M (SEM).

(6) FIG. 6: Average % inhibition of TGF- stimulated proline incorporation by compound FT122 at 10 M, 30 M and 100 M (SEM).

(7) FIG. 7: Average % inhibition of TGF- stimulated proline incorporation by compound FT126 at 10 M, 30 M and 100 M (SEM).

(8) FIG. 8: Average % inhibition of TGF- stimulated proline incorporation by compound FT128 at 10 M, 30 M and 100 M (SEM).

(9) FIG. 9: Average % inhibition of TGF- stimulated proline incorporation by compound FT129 at 10 M, 30 M and 100 M (SEM).

(10) FIG. 10: Average % inhibition of TGF- stimulated proline incorporation by compound FT130 at 10 M, 30 M and 100 M (SEM).

(11) FIG. 11: Average % inhibition of TGF- stimulated proline incorporation by compound FT132 at 10 M, 30 M and 100 M (SEM).

(12) An average % inhibition of greater than 100% indicates cell stress or death in FIGS. 5, 6 and 9.

(13) Examples of materials and methods for use with the compounds of the present invention will now be provided. In providing these examples, it is to be understood that the specific nature of the following description is not to limit the generality of the above description.

EXAMPLES

Experimental

(14) Electrospray ionization (ESI) high resolution mass spectra (HRMS) were obtained on a Finnigan hybrid LTQ-FT mass spectrometer (Thermo Electron Corp.). Proton nuclear magnetic resonance (.sup.1H NMR) and proton decoupled carbon nuclear magnetic resonance (.sup.13C NMR) spectra were obtained on Unity 400, Innova 400 or Innova 500 instruments (Melbourne, Australia) operating at 400 or 500 MHz for .sup.1H and at 100 or 125 MHz for .sup.13C. All signals were referenced to solvent peaks (CDCl.sub.3: 7.26 ppm for .sup.1H and 77.0 ppm for .sup.13C; DMSO-d.sub.6: 2.49 ppm for .sup.1H and 39.5 ppm for .sup.13C). Infrared (IR) spectra were obtained using a PerkinElmer Spectrum One FT-IR spectrometer with zinc selenide/diamond Universal ATA Sampling Accessory. Melting points were obtained using a Reichert-Jung hot stage apparatus and are corrected. Analytical thin layer chromatography (TLC) was conducted on 2 mm thick silica. gel GF.sub.254. Compounds were visualised with solutions of 20% w/w phosphomolybdic acid in ethanol, 20% w/w potassium permanganate in water or under UV (365 nm). Flash chromatography was performed with Merck Silica Gel 60. Petrol refers to the traction boiling at 40-60 C. Ail other reagents were used as received.

Synthesis of Compounds of Formulae (I) to (IV)

(E)-3-[2-(3,4-Dimethoxyphenyl)ethenyl]-4H-1,2,4-benzothiadiazine-1,1-dioxide (FT98)

(15) ##STR00082##

(16) 2-Aminobenzenesulfonamide (0.25 g, 1.4 mmol) was added to a suspension of (E)-3-(3,4-dimethoxyphenyl)acrylic acid (0.25 g, 1.2 mmol), HBTU (0.55 g, 1.4 mmol) and NEt.sub.3 (0.67 mL, 4.8 mmol) in MeCN (5 mL) and the reaction was stirred at rt for 16 h. Extra NEt.sub.3 (0.67 mL, 4.8 mmol) in MeCN (5 mL) was added and the reaction was stirred at rt for 64 h. The solution was acidified and the precipitate was collected by filtration. Hot EtOH (15 mL) was added to the crude product and the undissolved solid was collected by hot filtration, providing (E)-3-[2-(3,4-dimethoxyphenyl)ethenyl]-4H-1,2,4-benzothiadiazine-1,1-dioxide (58 mg, 14%) as a colourless crystalline solid; mp 276-279 C.; .sub.H (500 MHz, DMSO-d.sub.6) 3.81 (s, 3H, OCH.sub.3), 3.83 (s, 3H, OCH.sub.3), 6.75 (d, J=15.6 Hz, 1H, CHCHCO), 7.05 (d, J.sub.5,6=8.0 Hz, 1H, H5), 7.29 (d, J.sub.5,6=8.0 Hz, 1H, H6), 7.31 (s, 1H, H2), 7.38 (d, J.sub.5,6=8.0 Hz, 1H, H5), 7.45 (t, J.sub.5,6=J.sub.6,7=8.0 Hz, 1H, H6), 7.68 (t, J.sub.6,7=J.sub.7,8=8.0 Hz, 1H, H7), 7.80 (d, J.sub.78=8.0 Hz, 1H, H8), 7.82 (d, J=15.6 Hz, 1H, CHCHCO), 12.13 (s, 1H, NH); .sub.C (125 MHz, DMSO-d.sub.6) 55.4, 55.6, 110.3, 111.8, 116.6, 117.6, 122.0, 122.7, 123.3, 126.3, 126.9, 133.0, 135.2, 142.2, 149.0, 151.1, 153.5; HRMS (ESI) calculated for C.sub.17H.sub.16N.sub.2O.sub.4S [M+H].sup.+ 345.0904. found 345.0900; .sub.max 756, 1134, 1263, 1513, 1568, 1600, 3024, 3117, 3163, 3200 cm.sup.1.

(E)-2-(3,4-Dimethoxystyryl)-4H-pyrido[2,3-d][1,3]oxazin-4-one (FT102)

(17) ##STR00083##

(18) A suspension of (E)-3-(3,4-dimethoxyphenyl)acrylic acid (0.25 g, 1.2 mmol) in CH.sub.2Cl.sub.2 (5 mL) was treated with oxalyl chloride (0.41 mL, 4.8 mmol). The solution was stirred at rt for 1 h and the solvent was removed under reduced pressure to give the acid chloride as a yellow solid. 3-Aminonicotinic acid (0.25 g, 1.4 mmol) was added to a solution of the acid chloride (1.2 mmol) in pyridine (2.0 mL) and the suspension was stirred at rt for 7 d. The solution was diluted with water and the precipitate was collected by filtration providing (E)-2-(3,4-dimethoxystyryl)-4H-pyrido[2,3-d][1,3]oxazin-4-one (0.16 g, 41%) as a green-yellow solid; mp 228-231 C.; .sub.H (500 MHz, DMSO-d.sub.6) 3.81 (s, 3H, OCH.sub.3), 3.84 (s, 3H, OCH.sub.3), 6.99 (d, J=16.5 Hz, 1H, CHCHCO), 7.02 (d, J.sub.5,6=8.0 Hz, 1H, H5), 7.37 (d, J.sub.5,6=8.0 Hz, 1H, H6), 7.49 (s, 1H, H2), 7.55 (dd, J.sub.4,5=8.0, J.sub.5,6=4.0 Hz, 1H, H5), 7.82 (d, J=16.5 Hz, 1H, CHCHCO), 7.47 (d, J.sub.4,5=8.0 Hz, 1H, H4), 8.95 (d, J.sub.5,6=4.0 Hz, 1H, H6); .sub.C (125 MHz, DMSO-d.sub.6) 55.6, 55.7, 110.5, 111.6, 112.9, 116.5, 123.4, 127.2, 137.3, 143.0, 149.1, 151.3, 157.1, 157.5, 159.4, 160.1; HRMS (ESI) calculated for C.sub.17H.sub.15N.sub.2O.sub.4 [M+H].sup.+ 311.1026. found 311.1025; .sub.max 798, 1024, 1417, 1563, 1757, 2836, 2958 cm.sup.1.

(E)-2-(3,4-Dimethoxystyryl)-4H-benzo[d][1,3]oxazin-4-one (FT106)

2-[(Carboxyacetyl)amino]benzoic acid

(19) ##STR00084##

(20) Anthranilic acid (300 g, 2.08 mol) was added to a solution of Meldrum's acid (272 g, 1.98 mol) in toluene (2.0 L). The reaction flask was fitted with a Dean-Stark apparatus and the suspension was heated to reflux for 3 h. The suspension was cooled, filtered, washed with toluene and dried. 2-[(Carboxyacetyl)amino]benzoic acid (381 g, 86%) was obtained as a colourless solid; mp 171-173 C.; .sub.H (500 MHz, DMSO-d.sub.6) 3.45 (br s, 2H, CH.sub.2), 7.16 (t, J.sub.3,4=J.sub.4,5=8.0 Hz, 1H, H4), 7.59 (td, J.sub.4,5=J.sub.5,6=8.0, J.sub.3,5=1.5 Hz, 1H, H5), 7.97 (dd, J.sub.3,4=8.0, J.sub.3,5=1.5 Hz, 1H, H3), 8.44 (d, J.sub.5,6=8.0 Hz, 1H, H6), 11.27 (s, 1H, NH), 12.83 (br s, 1H, CO.sub.2H), 13.57 (br s, 1H, CO.sub.2H); .sub.C (125 MHz, DMSO-d.sub.6) 45.0, 117.0, 120.3, 123.1, 131.2, 134.1, 140.4, 164.9, 169.1, 169.3; .sub.max 760, 1234, 1385, 1544, 1684, 1712, 2653, 2964, 3119 cm.sup.1.

(E)-2-[[3-(3,4-Dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (tranilast)

(21) ##STR00085##

(22) Piperidine (0.96 mL, 9.7 mmol) was added to a suspension of 3,4-dimethoxybenzaldehyde (1.6 g, 9.7 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (1.9 g, 8.6 mmol) in toluene (5.0 mL). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 4 h, then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (5.0 mL) and water (2.0 mL) at 40 C. and the solution was acidified with concentrated HCl. The precipitate was filtered, providing (E)-2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (tranilast) (2.1 g, 74%) as a yellow crystalline solid; mp 208-209 C., lit..sup.2 206 C.; .sub.H (500 MHz, DMSO-d.sub.6) 3.79 (s, 3H, OCH.sub.3), 3.82 (s, 3H, OCH.sub.3), 6.79 (d, J=15.5 Hz, 1H, CHCHCO), 6.99 (d, J.sub.5,6=8.5 Hz, 1H, H5), 7.16 (t, J.sub.3,4=J.sub.4,5=7.9 Hz, 1H, H4), 7.25 (d, J.sub.5,6=8.5 Hz, 1H, H6), 7.38 (s, 1H, H2), 7.56 (d, J=15.5 Hz, 1H, CHCHCO), 7.61 (t, J.sub.4,5=J.sub.5,6=7.9 Hz, 1H, H5), 8.00 (d, J.sub.3,4=7.9 Hz, 1H, H3), 8.62 (d, J.sub.5,6=7.9 Hz, 1H, H6), 11.30 (s, 1H, NH), 13.61 (br s, 1H, CO.sub.2H).

(E)-2-(3,4-Dimethoxystyryl)-4H-benzo[d][1,3]oxazin-4-one (FT106)

(23) ##STR00086##

(24) A solution of (E)-2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.5 g, 1.5 mmol) in acetic anhydride (3 mL) was heated to reflux and stirred for 3 h. The reaction was cooled to rt and the resulting suspension was diluted with water. The suspension was stirred at rt for 1 h and the precipitate was collected by filtration, providing (E)-2-(3,4-dimethoxystyryl)-4H-benzo[d][1,3]oxazin-4-one (0.41 g, 88%) as a yellow crystalline solid; mp 175-179 C.; .sub.H (500 MHz, DMSO-d.sub.6) 3.82 (s, 3H, OCH.sub.3), 3.85 (s, 3H, OCH.sub.3), 6.94 (d, J=16.0 Hz, 1H, CHCHCO), 7.02 (d, J.sub.5,6=8.0 Hz, 1H, H5), 7.35 (dd, J.sub.5,6=8.0, J.sub.2,6=1.5 Hz, 1H, H6), 7.47 (d, J.sub.2,6=1.5 Hz, 1H, H2), 7.58 (t, J.sub.3,4=J.sub.4,5=8.0 Hz, 1H, H4), 7.61 (d, J.sub.3,4=8.0 Hz, 1H, H3), 7.73 (d, J=16.0 Hz, 1H, CHCHCO), 7.92 (t, J.sub.4,5=J.sub.5,6=8.0 Hz, 1H, H5), 8.12 (d, J.sub.5,6=8.0 Hz, 1H, H6); .sub.C (125 MHz, DMSO-d.sub.6) 55.5, 55.6, 110.3, 111.6, 116.6, 122.9, 126.5, 127.4, 128.0, 128.0, 128.1, 136.8, 141.4, 146.8, 149.0, 150.9, 157.3, 158.8; HRMS (ESI) calculated for C.sub.18H.sub.15NO.sub.4 [M+H].sup.+ 310.1074. found 310.1073; .sub.max 1020, 1254, 1515, 1634, 1755, 2835, 2940 cm.sup.1.

(E)-2-(3-Methoxy-4-propargyloxystyryl)-4H-benzo[d][1,3]oxazin-4-one (FT107)

3-Methoxy-4-propargyloxybenzaldehyde

(25) ##STR00087##

(26) Propargyl bromide (293 mL, 80% w/v, 1.97 mol) was added to a suspension of vanillin (250 g, 1.64 mol) and potassium carbonate (681 g, 4.93 mol) in MeCN (2.0 L). The suspension was heated to reflux for 6 h and the solvent was removed under reduced pressure. Water was added and the aqueous phase was extracted with EtOAc, washed with water, brine and dried. The solvent was removed under reduced pressure to give 3-methoxy-4-propargyloxybenzaldehyde (302 g, 97%) as yellow crystalline solid; mp 95 C.; .sub.H (400 MHz, CDCl.sub.3) 2.56 (t, J=2.5 Hz, 1H, CCH), 3.95 (s, 3H, OCH.sub.3), 4.86 (d, J=2.5 Hz, 2H, OCH.sub.2), 7.14 (d, J.sub.5,6=6.8 Hz, 1H, H5), 7.44 (d, J.sub.2,6=1.4 Hz, 1H, H2), 7.47 (dd, J.sub.5,6=6.8, J.sub.2,6=1.4 Hz, 1H, H6), 9.87 (s, 1H, CHO); .sub.C (100 MHz, CDCl.sub.3) 56.0, 56.6, 77.2, 77.4, 109.4, 112.5, 126.3, 130.9, 150.0, 152.1, 190.9; HRMS (ESI) Calculated for C.sub.11H.sub.10O.sub.3 [M+H].sup.+, 191.0703. found 191.0706; .sub.max 1006, 1130, 1259, 1586, 1677, 2119, 2845, 2932, 3266 cm.sup.1.

(E)-2-[[3-(3-Methoxy-4-propargyloxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid

(27) ##STR00088##

(28) Piperidine (158 mL, 1.59 mol) was added to a suspension of 3-methoxy-4-propargyloxybenzaldehyde (302 g, 1.59 mol) and 2-[(carboxyacetyl)amino]benzoic acid (322 g, 1.44 mol) in toluene (1.5 L). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 30 min. The reaction was then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (4 L) and water (1 L) at 50 C. and the solution was acidified with 50% aqueous AcOH. The precipitate was filtered and the crude product was recrystallised from EtOH (35 mL/g), filtered and washed with cooled EtOH to afford (E)-2-[[3-(3-methoxy-4-propargyloxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (309 g, 61%) as a yellow crystalline solid; mp 201-203 C.; .sub.H (400 MHz, DMSO-d.sub.6) 3.59 (t, J=2.4 Hz, 1H, CCH), 3.84 (s, 3H, OCH.sub.3), 4.84 (d, J=2.4 Hz, 2H, OCH.sub.2), 6.81 (d, J=15.6 Hz, 1H, CHCHCO), 7.05 (d, J.sub.5,6=8.4 Hz, 1H, H5), 7.16 (t, J.sub.3,4=J.sub.4,5=8.0 Hz, 1H, H4), 7.25 (d, J.sub.5,6=8.4 Hz, 1H, H6), 7.41 (s, 1H, H2), 7.56 (d, J=15.6 Hz, 1H, CHCHCO), 7.61 (t, J.sub.4,5=J.sub.5,6=8.0 Hz, 1H, H5), 8.00 (d, J.sub.3,4=8.0 Hz, 1H, H3), 8.62 (d, J.sub.5,6=8.0 Hz, 1H, H6), 11.31 (s, 1H, NH), 13.57 (br s, 1H, CO.sub.2H); .sub.C (100 MHz, DMSO-d.sub.6) 55.6, 55.9, 78.6, 79.1, 110.8, 113.5, 116.6, 120.4, 120.4, 122.2, 122.7, 128.2, 131.2, 134.0, 141.0, 141.5, 148.3, 149.3, 164.1, 169.5; HRMS (ESI) calculated for C.sub.20H.sub.17NO.sub.5 [M+H].sup.+ 352.1179. found 352.1187; .sub.max 755, 1010, 1140, 1253, 1502, 1582, 1657, 3278, 3522 cm.sup.1.

(E)-2-(3-Methoxy-4-propargyloxystyryl)-4H-benzo[d][1,3]oxazin-4-one (FT107)

(29) ##STR00089##

(30) A solution of (E)-2-[[3-(3-methoxy-4-propargyloxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.5 g, 1.4 mmol) in acetic anhydride (3 mL) was heated to reflux and stirred for 3 h. The reaction was cooled to rt and the resulting suspension was diluted with water. The suspension was stirred at rt for 1 h and the precipitate was collected by filtration, providing (E)-2-(3-methoxy-4-propargyloxystyryl)-4H-benzo[d][1,3]oxazin-4-one (0.44 g, 93%) as a yellow crystalline solid; mp 177-178 C.; .sub.H (500 MHz, DMSO-d.sub.6) 3.59 (m, 1H, CCH), 3.85 (s, 3H, OCH.sub.3), 4.85 (s, 2H, OCH.sub.2), 6.96 (d, J=16.0 Hz, 1H, CHCHCO), 7.07 (d, J.sub.5,6=8.0 Hz, 1H, H5), 7.34 (d, J.sub.5,6=8.0, 1H, H6), 7.49 (s, 1H, H2), 7.57 (t, J.sub.3,4=J.sub.4,5=8.0 Hz, 1H, H4), 7.60 (d, J.sub.3,4=8.0 Hz, 1H, H3), 7.72 (d, J=16.0 Hz, 1H, CHCHCO), 7.91 (t, J.sub.4,5=J.sub.5,6=8.0 Hz, 1H, H5), 8.11 (d, J.sub.5,6=8.0 Hz, 1H, H6); .sub.C (125 MHz, DMSO-d.sub.6) 55.7, 55.9, 78.5, 79.0, 110.8, 113.6, 117.0, 117.2, 122.3, 126.5, 128.0, 128.1, 128.3, 136.8, 141.2, 146.8, 148.5, 149.4, 157.2, 158.8; HRMS (ESI) calculated for C.sub.20H.sub.15NO.sub.4 [M+H].sup.+ 334.1074. found 334.1074; .sub.max 970, 1136, 1270, 1471, 1743, 2135, 3268 cm.sup.1.

(E)-2-(3,4-Bis(difluoromethoxy)styryl)-4H-benzo[d][1,3]oxazin-4-one (FT108)

(E)-2-[[3,4-Bis(difluoromethoxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid

(31) ##STR00090##

(32) Piperidine (100 L, 1.01 mmol) was added to a suspension of 3,4-bis(difluoromethoxy)benzaldehyde (240 mg, 1.01 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (204 mg, 0.92 mmol) in toluene (5.0 mL). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 30 min. The reaction was then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (5 mL) and water (2 mL) and the solution was acidified with 50% aqueous AcOH. The crude product was collected by filtration and recrystallised from EtOH/water, filtered and washed with water to afford (E)-2-[[3,4-bis(difluoromethoxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (259 mg, 71%) as a colourless crystalline solid; mp 190-193 C.; .sub.H (400 MHz, DMSO-d.sub.6) 6.96 (d, J=15.6 Hz, 1H, CHCHCO), 7.18 (t, J.sub.3,4=J.sub.4,5=8.0 Hz, 1H, H4), 7.27 (t, J=73 Hz, 2H, OCHF.sub.2), 7.38 (d, J.sub.5,6=8.0 Hz, 1H, H5), 7.61 (d, J=15.6 Hz, 1H, CHCHCO), 7.62 (t, J.sub.4,5=J.sub.5,6=8.0 Hz, 1H, H5), 7.78 (d, J.sub.2,6=1.6 Hz, 1H, H2), 7.68 (dd, J.sub.5,6=8.0, J.sub.2,6=1.6 Hz, 1H, H6), 8.00 (d, J.sub.3,4=8.0 Hz, 1H, H3), 8.69 (d, J.sub.5,6=8.0 Hz, 1H, H6), 11.35 (s, 1H, NH), 13.56 (br s, 1H, CO.sub.2H); .sub.C (100 MHz, DMSO-d.sub.6) 116.3 (t, J=258 Hz), 116.5 (t, J=258 Hz), 117.0, 120.1, 120.5, 120.8, 123.0, 123.8, 126.7, 131.1, 132.8, 133.9, 139.3, 140.7, 141.9, 142.7, 163.5, 169.4; HRMS (ESI) calculated for C.sub.18H.sub.13F.sub.4NO.sub.5 [MH].sup. 398.0646. found 398.0652; .sub.max 1034, 1217, 1513, 1604, 1683, 2892, 3466 cm.sup.1.

(E)-2-(3,4-Bis(difluoromethoxy)styryl)-4H-benzo[d][1,3]oxazin-4-one (FT108)

(33) ##STR00091##

(34) A solution of (E)-2-[[3,4-bis(difluoromethoxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.5 g, 1.2 mmol) in acetic anhydride (3 mL) was heated to reflux and stirred for 3 h. The reaction was cooled to rt and the resulting suspension was diluted with water. The suspension was stirred at rt for 1 h and the precipitate was collected by filtration, providing (E)-2-(3,4-bis(difluoromethoxy)styryl)-4H-benzo[d][1,3]oxazin-4-one (0.41 g, 86%) as a colourless crystalline solid; mp 113-115 C.; .sub.H (500 MHz, DMSO-d.sub.6) 7.07 (d, J=16.0 Hz, 1H, CHCHCO), 7.29 (t, J=74 Hz, 1H, OCHF.sub.2), 7.28 (t, J=74 Hz, 1H, OCHF.sub.2), 7.39 (d, J.sub.5,6=8.0 Hz, 1H, H5), 7.60 (t, J.sub.3,4=J.sub.4,5=8.0 Hz, 1H, H4), 7.62 (d, J.sub.3,4=8.0 Hz, 1H, H3), 7.75 (d, J.sub.5,6=8.0, 1H, H6), 7.76 (d, J=16.0 Hz, 1H, CHCHCO), 7.87 (s, 1H, H2), 7.92 (t, J.sub.4,5=J.sub.5,6=8.0 Hz, 1H, H5), 8.12 (d, J.sub.5,6=8.0 Hz, 1H, H6); .sub.C (125 MHz, DMSO-d.sub.6) 116.3 (t, J=258 Hz), 116.4 (t, J=258 Hz), 116.9, 119.9, 120.6, 120.8, 126.5, 126.7, 128.1, 128.6, 132.9, 136.8, 139.0, 141.2, 142.0, 146.5, 156.5, 158.7; HRMS (ESI) calculated for C.sub.18H.sub.11F.sub.4NO.sub.4 [M+H].sup.+ 382.0697. found 382.0696; .sub.max 969, 1042, 1087, 1123, 1279, 1383, 1472, 1595, 1747 cm.sup.1.

(E)-2-(4-Acetoxy-3-methoxystyryl)-4H-benzo[d][1,3]oxazin-4-one (FT109)

(E)-2-[[3-(4-Hydroxy-3-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid

(35) ##STR00092##

(36) Piperidine (0.50 mL, 5.1 mmol) was added to a suspension of 4-hydroxy-3-methoxybenzaldehyde (0.77 g, 5.1 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (1.0 g, 4.5 mmol) in toluene (5.0 mL). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 3 h, then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (12.0 mL) and water (12.0 mL) at 40 C. and the solution was acidified with concentrated HCl. The precipitate was filtered, providing (E)-2-[[3-(4-hydroxy-3-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (1.1 g, 78%) as a yellow crystalline solid; mp 207.5-208.5 C., lit..sup.5 230-233 C.; .sub.H (500 MHz, DMSO-d.sub.6) 3.83 (s, 3H, OCH.sub.3), 6.71 (d, J=15.5 Hz, 1H, CHCHCO), 6.80 (d, J.sub.5,6=8.5 Hz, 1H, H5), 7.13 (dd, J.sub.5,6=8.5, J.sub.2,6=1.5 Hz, 1H, H6), 7.15 (t, J.sub.3,4=J.sub.4,5=8.0 Hz, 1H, H4), 7.34 (d, J.sub.2,6=1.5 Hz, 1H, H2), 7.52 (d, J=15.5 Hz, 1H, CHCHCO), 7.60 (td, J.sub.4,5=J.sub.5,6=8.0, J.sub.3,5=2.0 Hz, 1H, H5), 8.00 (dd, J.sub.3,4=8.0, J.sub.3,5=2.0 Hz, 1H, H3), 8.62 (d, J.sub.5,6=8.0 Hz, 1H, H6), 9.57 (s, 1H, OH), 11.27 (s, 1H, NH), 13.61 (br s, 1H, CO.sub.2H).

(E)-2-(4-Acetoxy-3-methoxystyryl)-4H-benzo[d][1,3]oxazin-4-one (FT109)

(37) ##STR00093##

(38) A solution of (E)-2-[[3-(4-hydroxy-3-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.5 g, 1.6 mmol) in acetic anhydride (3 mL) was heated to reflux and stirred for 3 h. The reaction was cooled to rt and the resulting suspension was diluted with water. The suspension was stirred at rt for 1 h and the precipitate was collected by filtration, providing (E)-2-(4-acetoxy-3-methoxystyryl)-4H-benzo[d][1,3]oxazin-4-one (0.52 g, 97%) as a pale brown solid; mp 185-186 C.; .sub.H (400 MHz, DMSO-d.sub.6) 2.63 (s, 3H, COCH.sub.3), 3.85 (s, 3H, OCH.sub.3), 7.08 (d, J=16.0 Hz, 1H, CHCHCO), 7.17 (d, J.sub.5,6=8.0 Hz, 1H, H5), 7.38 (d, J.sub.5,6=8.0, 1H, H6), 7.59 (t, J.sub.3,4=J.sub.4,5=8.0 Hz, 1H, H4), 7.61 (d, J.sub.3,4=8.0 Hz, 1H, H3), 7.63 (s, 1H, H2), 7.76 (d, J=16.0 Hz, 1H, CHCHCO), 7.92 (t, J.sub.4,5=J.sub.5,6=8.0 Hz, 1H, H5), 8.11 (d, J.sub.5,6=8.0 Hz, 1H, H6); .sub.C (100 MHz, DMSO-d.sub.6) 20.4, 56.0, 111.9, 116.9, 119.5, 121.4, 123.3, 126.6, 128.1, 128.4, 133.5, 136.8, 140.5, 140.9, 146.6, 151.2, 156.8, 168.4; HRMS (ESI) calculated for C.sub.19H.sub.15NO.sub.5 [M+H].sup.+ 338.1023. found 338.1023; .sub.max 1197, 1214, 1593, 1635, 1748 cm.sup.1.

(E)-2-(3-Acetoxy-4-methoxystyryl)-4H-benzo[d][1,3]oxazin-4-one (FT110)

(E)-2-[[3-(3-Hydroxy-4-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid

(39) ##STR00094##

(40) Piperidine (0.25 mL, 2.5 mmol) was added to a suspension of 3-hydroxy-4-methoxybenzaldehyde (0.39 g, 2.5 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.50 g, 2.2 mmol) in toluene (5.0 mL). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 3 h, then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (5.0 mL) and water (2.0 mL) at 40 C. and the solution was acidified with concentrated HCl. The precipitate was filtered, providing (E)-2-[[3-(3-hydroxy-4-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.53 g, 76%) as a yellow crystalline solid; mp 215-216 C., lit..sup.5 219-222 C.; .sub.H (500 MHz, DMSO-d.sub.6) 3.81 (s, 3H, OCH.sub.3), 6.59 (d, J=15.5 Hz, 1H, CHCHCO), 6.80 (d, J.sub.5,6=8.5 Hz, 1H, H5), 7.10-7.13 (m, 2H, H2, H6), 7.15 (t, J.sub.3,4=J.sub.4,5=8.0 Hz, 1H, H4), 7.47 (d, J=15.5 Hz, 1H, CHCHCO), 7.60 (td, J.sub.4,5=J.sub.5,6=8.0, J.sub.3,5=1.5 Hz, 1H, H5), 7.99 (dd, J.sub.3,4=8.0, J.sub.3,5=1.5 Hz, 1H, H3), 8.58 (d, J.sub.5,6=8.0 Hz, 1H, H6), 11.25 (s, 1H, NH), 13.56 (br s, 1H, CO.sub.2H).

(E)-2-(3-Acetoxy-4-methoxystyryl)-4H-benzo[d][1,3]oxazin-4-one (FT110)

(41) ##STR00095##

(42) A solution of (E)-2-[[3-(3-hydroxy-4-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.5 g, 1.6 mmol) in acetic anhydride (3 mL) was heated to reflux and stirred for 3 h. The reaction was cooled to rt and the resulting suspension was diluted with water. The suspension was stirred at rt for 1 h and the precipitate was collected by filtration, providing (E)-2-(3-acetoxy-4-methoxystyryl)-4H-benzo[d][1,3]oxazin-4-one (0.50 g, 93%) as a yellow solid; mp 187-190 C.; .sub.H (400 MHz, DMSO-d.sub.6) 2.80 (s, 3H, COCH.sub.3), 3.83 (s, 3H, OCH.sub.3), 6.87 (d, J=16.0 Hz, 1H, CHCHCO), 7.19 (d, J.sub.5,6=8.0 Hz, 1H, H5), 7.68 (d, J.sub.5,6=8.0, 1H, H6), 7.57 (t, J.sub.3,4=J.sub.4,5=8.0 Hz, 1H, H4), 7.60 (d, J.sub.3,4=8.0 Hz, 1H, H3), 7.66 (s, 1H, H2), 7.71 (d, J=16.0 Hz, 1H, CHCHCO), 7.89 (t, J.sub.4,5=J.sub.5,6=8.0 Hz, 1H, H5), 8.10 (d, J.sub.5,6=8.0 Hz, 1H, H6); .sub.C (100 MHz, DMSO-d.sub.6) 20.4, 56.1, 112.9, 116.7, 117.6, 122.1, 127.5, 128.0, 128.1, 128.2, 136.8, 139.6, 140.2, 146.7, 152.7, 157.0, 158.8, 168.4; HRMS (ESI) calculated for C.sub.19H.sub.15NO.sub.5 [M+H].sup.+ 338.1023. found 338.1023; .sub.max 1197, 1268, 1588, 1631, 1752 cm.sup.1.

(E)-3-(3,4-dimethoxyphenyl)-1-(indolin-1-yl)prop-2-en-1-one (FT113)

(43) ##STR00096##

(44) A suspension of (E)-3-(3,4-dimethoxyphenyl)acrylic acid (0.50 g, 2.4 mmol) in CH.sub.2Cl.sub.2 (5 mL) was treated with oxalyl chloride (0.80 mL, 9.6 mmol). The solution was stirred at rt for 2 h and the solvent was removed under reduced pressure to give the acid chloride. Indoline (0.27 g, 2.4 mmol) was added to a solution of the acid chloride (2.4 mmol) in CH.sub.2Cl.sub.2 (5 mL) and NEt.sub.3 (0.67 mL, 4.8 mmol). The mixture was stirred at rt for 16 h and concentrated under reduced pressure. The residue was diluted with water and the resulting precipitate was collected by filtration and recrystallised from EtOAc providing (E)-3-(3,4-dimethoxyphenyl)-1-(indolin-1-yl)prop-2-en-1-one (0.15 g, 20%) as a colourless crystalline solid; mp 118-120 C.; .sub.H (500 MHz, DMSO-d.sub.6) 3.18 (t, J=8.0 Hz, 2H, CH.sub.2), 3.79 (s, 3H, OCH.sub.3), 3.83 (s, 3H, OCH.sub.3), 4.33 (t, J=8.0 Hz, 2H, NCH.sub.2), 6.98-7.02 (m, 3H, CHCHCO, H5, H6), 7.16 (t, J.sub.3,4=J.sub.4,5=8.0 Hz, 1H, H4), 7.25 (d, J.sub.5,6=8.0 Hz, 1H, H5), 7.26 (dd, J.sub.56=8.0 Hz, J.sub.26=2.0 Hz, 1H, H6), 7.38 (d, J.sub.26=2.0 Hz, 1H, H2), 7.58 (d, J=15.5 Hz, 1H, CHCHCO), 8.19 (m, 1H, H3); .sub.C (125 MHz, DMSO-d.sub.6) 27.3, 47.7, 55.5, 55.6, 110.6, 111.6, 116.4, 117.5, 122.6, 123.3, 124.8, 126.9, 127.7, 132.2, 142.3, 143.1, 148.9, 150.6, 163.9; HRMS (ESI) calculated for C.sub.19H.sub.19NO.sub.3 [M+H].sup.+ 310.1438. found 310.1437; .sub.max 1025, 1145, 1262, 1398, 1510, 1646 cm.sup.1.

(E)-2-(3,4-Dimethoxystyryl)-1H-benzo[d]imidazole (FT121)

(45) ##STR00097##

(46) A mixture of (E)-3-(3,4-dimethoxyphenyl)acrylic acid (416 mg, 2.0 mmol) and o-phenylenediamine. sulfuric acid (412 mg, 2.0 mmol) in ethylene glycol (10 mL) was heated at reflux for three hours. The mixture was then cooled to room temperature and poured into water (50 mL). The pH of the solution was adjusted to >7 with NaHCO.sub.3 and extracted with DCM. The organic layer was washed with saturated aqueous NaCl solution and dried over sodium sulfate. The solvent was concentrated under a reduced pressure and the residue was purified by flash chromatography on silica gel using petroleum ether/ethyl acetate 2:1 (v:v) as eluent to give (E)-2-(3,4-dimethoxystyryl)-1H-benzo[d]imidazole (130 mg, 23%). .sup.1H-NMR (400 MHz, CDCl.sub.3) 3.78 (s, 3H), 3.88 (s, 3H), 6.80 (d, J=8.0 Hz, 1H), 6.96-7.00 (m, 2H), 7.06 (d, J=16.0 Hz, 1H), 7.25-7.29 (m, 2H), 7.59 (d, J=16.0 Hz, 1H), 7.64 (m, 2H); LC-MS (ES-API); rt 7.55 min; m/z calculated for C.sub.17H.sub.16N.sub.2O.sub.2 [M+H].sup.+ 281.1. found 281.1.

(E)-1-(2,3-Dihydrobenzo[b][1,4]oxazin-4-yl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one (FT122)

3,4-Dihydro-2H-benzo[b][1,4]oxazine

(47) ##STR00098##

(48) To a suspension of 2-aminophenol (1.0 g, 9.2 mmol) and potassium carbonate (6.36 g, 46 mmol) in dry DMF (10 mL) was added 1,2-dibromoethane (2.59 g, 13.8 mmol). The mixture was then heated at 125 C. for 15 hours. After cooling, the mixture was treated with crushed ice and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether 1:10 (v:v) as eluent to give 3,4-dihydro-2H-benzo[b][1,4]oxazine as reddish oil (0.81 g, 65%). LC-MS (ES-API); rt 7.51 min; m/z calculated for C.sub.8H.sub.3NO [M+H].sup.+ 136.1. found 136.1.

(E)-1-(2,3-Dihydrobenzo[b][1,4]oxazin-4-yl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one (FT122)

(49) ##STR00099##

(50) To a solution of (E)-3-(3,4-dimethoxyphenyl)acrylic acid (0.46 g, 2.22 mmol) and 3,4-dihydro-2H-benzo[b][1,4]oxazine (0.20 g, 1.48 mmol) in DCM (15 mL) was added EDC.HCl (0.71 g, 3.70 mmol), HOBt (0.60 g, 3.70 mmol) and Et.sub.3N (0.37 g, 3.70 mmol). The mixture was stirred at room temperature overnight then diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate 5:1 (v:v) as eluent to give (E)-1-(2,3-dihydrobenzo[b][1,4]oxazin-4-yl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one (230 mg, 32%). .sup.1H-NMR (400 MHz, CDCl.sub.3) 3.88 (s, 3H), 3.91 (s, 3H), 4.08 (m, 2H), 4.37 (m, 2H), 6.86 (d, J=8.4 Hz, 1H), 6.90 (m, 1H), 6.92 (d, J=15.2 Hz, 1H), 6.96 (dd, J=8.0, 1.6 Hz, 1H), 6.99 (d, J=2.0 Hz, 1H), 7.08-7.13 (m, 2H), 7.20 (br d, J=7.6 Hz, 1H), 7.02 (d, J=15.6 Hz, 1H); LC-MS (ES-API); rt 8.72 min; m/z calculated for C.sub.13H.sub.13NO.sub.4 [M+H].sup.+ 326.1. found 326.1.

(E)-1-(3-(3,4-Dimethoxyphenyl)acryloyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (FT123)

(E)-3-(3,4-Dimethoxyphenyl)acryloyl chloride

(51) ##STR00100##

(52) To a suspension of 3-(3,4-dimethoxyphenyl)acrylic acid (416 mg 2 mmol) in toluene (10 mL) was added thionyl chloride (1.45 mL, mmol). The solution was heated at 50 C. for 1 hour and then the solvent was removed under reduced pressure to give (E)-3-(3,4-dimethoxyphenyl)acryloyl chloride, which was used directly in the next step without purification.

(E)-1-(3-(3,4-Dimethoxyphenyl)acryloyl)-1H-benzo[d]imidazol-2(3H)-one

(53) ##STR00101##

(54) To a solution of 1H-benzo[d]imidazol-2(3H)-one (268 mg, 2 mmol) in DMF (10 mL) at 0 C. was added 60% oily sodium hydride (88 mg, 2.2 mmol). When hydrogen evolution had ceased, a solution of (E)-3-(3,4-dimethoxyphenyl)acryloyl chloride (240 mg, 0.75 mmol) in DMF (3 mL) was added and the reaction mixture allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched by addition of 1N hydrochloric acid, and extracted with DCM. The combined organic phases were washed with brine and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by flash column (hexane-EtOAc, 25:10) to give (E)-1-(3-(3,4-dimethoxyphenyl)acryloyl)-1H-benzo[d]imidazol-2(3H)-one (240 mg, 37%). LC-MS (ES-API); rt 9.02 min; m/z calculated for C.sub.18H.sub.16N.sub.2O.sub.4 [M+H].sup.+ 325.1. found 325.0 and 347.0 ([M+Na].sup.+).

(E)-1-(3-(3,4-Dimethoxyphenyl)acryloyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (FT123)

(55) ##STR00102##

(56) A mixture of (E)-1-(3-(3,4-dimethoxyphenyl)acryloyl)-1H-benzo[d]imidazol-2(3H)-one (240 mg, 0.75 mmol), iodomethane (68 uL, 1.1 mmol) and K.sub.2CO.sub.3 (204 mg, 1.5 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction was quenched with water and extracted with DCM. The combined organic phases were washed with brine, dried over sodium sulfate and the solvent removed under reduced pressure. The residue was purified by recrystallisation from EtOH to afford (E)-1-(3-(3,4-dimethoxyphenyl)acryloyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (200 mg, 79%). .sup.1H-NMR (400 MHz, CDCl.sub.3) 3.46 (s, 3H), 3.96 (s, 3H), 3.98 (s, 3H), 6.91 (d, J=8.4 Hz, 1H), 7.01 (dd, J=7.6, 0.8 Hz, 1H), 7.19-7.28 (m, 4H), 7.98 (d, J=15.6 Hz, 1H), 8.15 (d, J=15.6 Hz, 1H) 8.32 (dd, J=8.0, 0.8 Hz, 1H); LC-MS (ES-API); rt 9.05 min; m/z calculated for C.sub.19H.sub.18N.sub.2O.sub.4 [M+H].sup.+ 339.1. found 339.0 and 361.0 ([M+Na].sup.+).

(E)-3-(3-(3,4-Dimethoxyphenyl)acryloyl)benzo[d]oxazol-2(3H)-one (FT124)

(57) ##STR00103##

(58) To a solution of (E)-3-(3,4-dimethoxyphenyl)acrylic acid (208 mg, 1.0 mmol) and benzo[d]oxazol-2(3H)-one (162 mg, 1.2 mmol) in DCM (10 mL) was added EDC.HCl (230 mg, 1.2 mmol), HOBt (196 mg, 1.2 mmol) and Et.sub.3N (304 mg, 3.0 mmol). The mixture was stirred at room temperature overnight then diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography using petroleum ether/ethyl acetate 3:2 (v:v) to give (E)-3-(3-(3,4-d)acryloyl)benzo[d]oxazol-2(3H)-one (225 mg, 70%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 3.84 (s, 6H), 7.09 (d, J=8.4 Hz, 1H), 7.31-7.38 (m, 4H), 7.44-7.46 (m, 1H), 7.76 (d, J=15.6 Hz, 1H), 7.95 (d, J=16 Hz, 1H), 8.03-8.06 (m, 1H); LC-MS (ES-API); rt 9.08 min; m/z calculated for C.sub.18H.sub.15NO.sub.5 [M+Na] 348.1. found 348.1.

(E)-4-(3-(3,4-Dimethoxyphenyl)acryloyl)-3,4-dihydroquinoxalin-2(1H)-one (FT125)

3,4-Dihydroquinoxalin-2(1H)-one

(59) ##STR00104##

(60) To a solution of o-phenylenediamine (1.08 g, 10 mmol) in DMF (50 mL) was added Et.sub.3N (2.9 mL, 21 mmol), and ethyl 2-bromoacetate (1.2 mL, 11 mmol). The reaction mixture was stirred at room temperature for 16 h, then at 80 C. for 3 h. The DMF was evaporated under reduced pressure and the reaction mixture partitioned between H.sub.2O and EtOAc. The EtOAc layer was washed with sat. NaHCO.sub.3, brine, and dried over Na.sub.2SO.sub.4. The solvent was evaporated under reduced pressure and the crude residue purified by flash chromatography eluting with petroleum ether/EtOAc (4/1) to give 3,4-dihydroquinoxalin-2(1H)-one (560 mg, 38%) as yellow solid. LC-MS (ES-API); rt 7.40 min; m/z calculated for C.sub.8H.sub.8N.sub.2O [M+H].sup.+ 149.0. found 149.0.

(E)-4-(3-(3,4-Dimethoxyphenyl)acryloyl)-3,4-dihydroquinoxalin-2(1H)-one (FT125)

(61) ##STR00105##

(62) To a stirred solution of 3,4-dihydroquinoxalin-2(1H)-one (142 mg, 0.96 mmol) and triethylamine (0.16 mL, 1.14 mmol) in anhydrous THF (15 mL) at 0 C. was added a solution of (E)-3-(3,4-dimethoxyphenyl)acryloyl chloride in THF (2 mL) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched by addition of 1N hydrochloric acid, and extracted with DCM. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the crude product which was purified by flash chromatography (hexane-EtOAc, 25:10) to give (E)-4-(3-(3,4-dimethoxyphenyl)acryloyl)-3,4-dihydroquinoxalin-2(1H)-one (160 mg, 47%). .sup.1H-NMR (400 MHz, CDCl.sub.3) 3.86 (s, 3H), 3.90 (s, 3H), 4.63 (br s, 2H), 6.71 (d, J=15.2 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 7.02 (dd, J=7.6, 1.2 Hz, 1H), 7.07-7.13 (m, 2H), 7.22 (dd, J=7.6, 1.2 Hz, 1H), 7.28 (br d, J=8.0 Hz, 1H), 7.76 (d, J=15.6 Hz, 1H), 8.89 (s, 1H); LC-MS (ES-API); rt 8.14 min; m/z calculated for C.sub.19H.sub.18N.sub.2O.sub.4 [M+H].sup.+ 339.1. found 339.0.

2-(5,6-Dimethoxy-1H-indene-2-carboxamido)benzoic acid (FT126)

2-Iodo-4,5-dimethoxybenzaldehyde

(63) ##STR00106##

(64) To a solution of 3,4-dimethoxybenzaldehyde (2.00 g, 12.0 mmol) in EtOH (100 mL) under nitrogen was added iodine (3.65 g, 14.4 mmol) and silver sulfate (4.49 g, 14.4 mmol) and the mixture was stirred for 3 hours at room temperature. The solvent was removed, water was added and the mixture was extracted with DCM. The organic extracts were washed with brine, dried over sodium sulfate and the solvent was removed under reduce pressure. The residue was purified by flash chromatography using petroleum ether/ethyl acetate 2:1 (v:v) as eluent to give 2-iodo-4,5-dimethoxybenzaldehyde (2.81 g, 80%). LC-MS (ES-API); rt 8.52 min; m/z calculated for C.sub.9H.sub.9IO.sub.3 [M+H].sup.+ 293.0. found 293.0.

Methyl 5,6-dimethoxy-1H-indene-2-carboxylate

(65) ##STR00107##

(66) 2-Iodo-4,5-dimethoxybenzaldehyde (292 mg, 1.0 mmol), CoCl.sub.2(dppe) complex (26.4 mg, 0.05 mmol), dppe (19.9 mg, 0.05 mmol) and zinc power (179.8 mg, 2.75 mmol) were placed in a vial, which was sealed with a septum and flushed several times with nitrogen. Acetonitrile (3 mL) and methyl acrylate (172 mg, 2.0 mmol) were then sequentially added and the mixture was heated at 80 C. overnight. Water was then added and the mixture was extracted with ethyl acetate. The organic extracts were concentrated under reduced pressure and the residue was purified by flash chromatography using petroleum ether/ethyl acetate 8:1 (v:v) as eluent to give methyl 5,6-dimethoxy-1H-indene-2-carboxylate (50 mg, 21%). LC-MS (ES-API); rt 7.89 min; m/z calculated for C.sub.13H.sub.14O.sub.4 [M+H].sup.+ 235.1. found 235.1.

5,6-Dimethoxy-1H-indene-2-carboxylic acid

(67) ##STR00108##

(68) To a stirred solution of methyl 5,6-dimethoxy-1H-indene-2-carboxylate (330 mg, 1.41 mmol) in THF (8 mL) and MeOH (4 mL) was added 2 N NaOH solution (3.5 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 hours and the reaction was quenched with 1N HCl solution. Then mixture was diluted with water and the resulting suspension was filtered and the solid was dried under vacuum to give 5,6-dimethoxy-1H-indene-2-carboxylic acid (150 mg, 48%). LC-MS (ES-API); rt 8.44 min; m/z calculated for C.sub.12H.sub.12O.sub.4 [MH].sup. 219.1. found 219.1.

Methyl 2-(5,6-dimethoxy-1H-indene-2-carboxamido)benzoate

(69) ##STR00109##

(70) To a stirred mixture of 5,6-dimethoxy-1H-indene-2-carboxylic acid (230 mg, 1.05 mmol) and DMF (20 L) in DCM (10 mL) was added oxalyl chloride (267 mg, 2.10 mmol) dropwise at room temperature. The resulting mixture was stirred for 2 hours then concentrated and dried under high vacuum. The resulting acid chloride was then taken up into DCM (10 mL) and added dropwise to a stirred mixture of methyl 2-aminobenzoate (174 mg, 1.16 mmol) and triethylamine (159.1 mg, 1.58 mmol) in DCM (10 mL) 0 C. The mixture was then stirred overnight at room temperature before adding water and extracting with DCM. The organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography with petroleum ether/ethyl acetate 5:1 (v:v) as eluent to give methyl 2-(5,6-dimethoxy-1H-indene-2-carboxamido)benzoate (140 mg, 38%). LC-MS (ES-API); rt 9.35 min; m/z calculated for C.sub.20H.sub.19NO.sub.5 [M+H].sup.+ 354.1. found 354.1.

2-(5,6-Dimethoxy-1H-indene-2-carboxamido)benzoic acid (FT126)

(71) ##STR00110##

(72) To a stirred solution of methyl 2-(5,6-dimethoxy-1H-indene-2-carboxamido)benzoate (120 mg, 0.34 mmol) in THF (6 mL) and MeOH (3 mL) was added 2 N NaOH solution (0.85 mL) dropwise. The resulting mixture was stirred at room temperature for 2 h, then quenched with 1N HCl solution and extracted with DCM. The organic extracts were washed with a saturated aqueous NaCl solution and dried over sodium sulfate. The solvent was then removed under reduced pressure to give 2-(5,6-dimethoxy-1H-indene-2-carboxamido)benzoic acid (100 mg, 87%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 3.72 (br s, 2H), 3.79 (s, 3H), 3.81 (s, 3H), 7.15 (m, 1H), 7.24 (s, 1H), 7.26 (s, 1H), 7.55-7.66 (m, 2H), 8.04 (dd, J=8.0, 1.6 Hz, 1H), 8.70 (dd, J=8.4, 1.2 Hz, 1H), 11.91 (s, 1H); LC-MS (ES-API); rt 9.23 min; m/z calculated for C.sub.19H.sub.17NO.sub.5 [MH].sup. 338.1. found 338.1.

2-(5,6-Dimethoxy-1H-benzo[d]imidazole-2-carboxamido)benzoic acid (FT127)

Methyl 2-aminobenzoate

(73) ##STR00111##

(74) To a stirred solution of 2-aminobenzoic acid (2.0 g, 14.59 mmol) in MeOH (70 mL) at 0 C. was added SOCl.sub.2 (7.4 g, 145.9 mmol) dropwise. The mixture was heated at reflux overnight and was then concentrated under reduced pressure. DCM and saturated aqueous NaHCO.sub.3 were added and the aqueous phase extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to afford methyl 2-aminobenzoate (2.05 g, 93%). LC-MS (ES-API); rt 8.46 min; m/z calculated for C.sub.8H.sub.9NO.sub.2 [M+H].sup.+ 152.0. found 152.1.

Methyl 2-(2-chloroacetamido)benzoate

(75) ##STR00112##

(76) To a stirred solution of methyl 2-aminobenzoate (906 mg, 6.0 mmol) and NaHCO.sub.3 (554.4 mg, 6.6 mmol) in THF (12 mL) and water (12 mL) at 0 C. was added 2-chloroacetyl chloride (806 mg, 7.2 mmol) dropwise. After 2 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the crude product. The residue was purified by flash chromatography to give methyl 2-(2-chloroacetamido)benzoate (1.31 g, 96%). LC-MS (ES-API); rt 8.65 min; m/z calculated for C.sub.10H.sub.10ClNO.sub.3 [M+Na].sup.+ 250.0. found 250.0.

Methyl 2-(5,6-dimethoxy-1H-benzo[d]imidazole-2-carboxamido)benzoate

(77) ##STR00113##

(78) A mixture of 4,5-dimethoxybenzene-1,2-diamine (1.08 g, 4.5 mmol), NaHCO.sub.3 (756 mg, 9.0 mmol) methyl 2-(2-chloroacetamido)benzoate (1.03 g, 4.5 mmol) and sulfur (216 mg, 6.75 mmol) in CH.sub.3CN (27 mL) was stirred in a microwave reactor for 2 hours at 140 C. The mixture was concentrated and purified by flash column chromatography to give the desired methyl 2-(5,6-dimethoxy-1H-benzo[d]imidazole-2-carboxamido)benzoate (190 mg, 12%). LC-MS (ES-API); rt 9.12 min; m/z calculated for C.sub.18H.sub.17N.sub.3O.sub.6 [M+Na].sup.+378.1. found 378.1.

2-(5,6-Dimethoxy-1H-benzo[d]imidazole-2-carboxamido)benzoic acid (FT127)

(79) ##STR00114##

(80) To a stirred solution of methyl 2-(5,6-dimethoxy-1H-benzo[d]imidazole-2-carboxamido)benzoate (200 mg, 0.56 mmol) in THF (10 mL) and MeOH (5 mL) was added 2N NaOH solution (1.4 mL) dropwise. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched by addition of 1N HCl solution and extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give 2-(5,6-dimethoxy-1H-benzo[d]imidazole-2-carboxamido)benzoic acid (90 mg, 47.1%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 3.82 (s, 6H), 6.97 (s, 1H), 7.13-7.34 (m, 2H), 7.64 (m, 1H), 8.08 (d, J=9.6 Hz, 1H), 8.78 (d, J=7.6 Hz, 1H), 12.90 (s, 1H), 13.27 (s, 1H); LC-MS (ES-API); rt 8.74 min; m/z calculated for C.sub.17H.sub.15N.sub.3O.sub.5 [MH].sup. 340.1. found 340.1.

2-(1,1-Dioxo-5,6-dimethoxybenzo[b]thiophene-2-carboxamido)benzoic acid (FT128)

Methyl 5,6-dimethoxybenzo[b]thiophene-2-carboxylate

(81) ##STR00115##

(82) To a stirred solution of 2-fluoro-4,5-dimethoxybenzaldehyde (1.10 g, 6 mmol) in DMF (50 mL) was added methyl 2-mercaptoacetate (0.58 mL, 6.6 mmol) and potassium carbonate (2.48 g, 18 mmol). The resulting mixture was then heated at 60 C. for 15 hours. The DMF was removed via rotary evaporation and the residue was diluted with water and extracted with DCM. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure to afford methyl 5,6-dimethoxybenzo[b]thiophene-2-carboxylate as a light yellow solid (1.0 g, 67%). LC-MS (ES-API); rt 8.48 min; m/z calculated for C.sub.12H.sub.12O.sub.4S [M+Na].sup.+ 275.0. found 275.0.

5,6-Dimethoxybenzo[b]thiophene-2-carboxylic acid

(83) ##STR00116##

(84) To a stirred solution of methyl 5,6-dimethoxybenzo[b]thiophene-2-carboxylate (1.0 g, 4 mmol) in MeOH (20 mL) and THF (10 mL) was added 2N NaOH (10 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 hours before adjusting the pH value to 3 with 1 N HCl and diluting with water. The resulting suspension was filtered and the solid was dried under vacuum to afford 5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid as a white solid (890 mg, 94%). LC-MS (ES-API); rt 8.17 min; m/z calculated for C.sub.11H.sub.10O.sub.4S [M+Na].sup.+ 261.0. found 260.9.

Methyl 2-(5,6-dimethoxybenzo[b]thiophene-2-carboxamido)benzoate

(85) ##STR00117##

(86) To a stirred solution of 5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid (714 mg, 3 mmol) and DMF (20 l) in anhydrous DCM (20 mL) was added oxalyl chloride (0.5 mL, 6 mmol) dropwise at 0 C. The mixture was then allowed to warm to room temperature and stirring was continued until the acid was consumed completely (about 1 h). The solvent was removed under reduced pressure and the crude 5,6-dimethoxybenzo[b]thiophene-2-carbonyl chloride was used directly in the next step. To a stirred solution of methyl 2-aminobenzoate (500 mg, 3.3 mmol) and Et.sub.3N (1.25 mL, 9 mmol) in anhydrous DCM (20 mL) was added 5,6-dimethoxybenzo[b]thiophene-2-carbonyl chloride in anhydrous DCM (2 mL) dropwise at 0 C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with DCM. The organic extract was dried over sodium sulfate, the solvent was removed under reduced pressure and the crude product was purified by re-crystallization from EtOH to give methyl 2-(5,6-dimethoxybenzo[b]thiophene-2-carboxamido)benzoate as a white solid (650 mg, 55%). LC-MS (ES-API); rt 9.38 min; m/z calculated for C.sub.19H.sub.17NO.sub.5S [M+H].sup.+ 372.1. found 372.1.

2-(5,6-Dimethoxybenzo[b]thiophene-2-carboxamido)benzoic acid

(87) ##STR00118##

(88) To a stirred solution of methyl 2-(5,6-dimethoxybenzo[b]thiophene-2-carboxamido)benzoate (650 mg, 1.75 mmol) in MeOH (9 mL) and THF (20 mL) was added 2N NaOH (9 mL) dropwise at room temperature. The resulting solution was stirred at room temperature for 2 hours. The reaction was quenched with 1N HCl and diluted with water. The resulting suspension was filtered and the solid was dried under vacuum to afford 2-(5,6-dimethoxybenzo[b]thiophene-2-carboxamido)benzoic acid (550 mg, 88%). LC-MS (ES-API); rt 9.22 min; m/z calculated for C.sub.18H.sub.15NO.sub.5S [M+Na].sup.+380.1. found 380.0.

2-(1,1-Dioxo-5,6-dimethoxybenzo[b]thiophene-2-carboxamido)benzoic acid (FT128)

(89) ##STR00119##

(90) To a stirred solution of 2-(5,6-dimethoxybenzo[b]thiophene-2-carboxamido)benzoic acid (500 mg, 1.4 mmol) in CH.sub.3COOH (100 mL), CH.sub.3CN (50 mL) and DCM (50 mL) was added m-Chloroperoxybenzoic acid (1.2 g, 7 mmol) at room temperature. The resulting solution was stirred at room temperature for 48 hours until the starting material was consumed completely by TLC analysis. The reaction was quenched with water and extracted with DCM. The combined organic phase was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash column using DCM/MeOH (from 30:1 to 10:1) as eluent. Further purification by re-crystallization from CH.sub.3CN provided 2-(1,1-dioxo-5,6-dimethoxybenzo[b]thiophene-2-carboxamido)benzoic acid (220 mg, 40%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 3.89 (s, 3H), 3.92 (s, 3H), 7.26 (app t, J=7.6 Hz, 1H), 7.48 (s, 1H), 7.61 (s, 1H), 7.67 (m, 1H), 8.05 (dd, J=8.0, 1.2 Hz, 1H), 8.14 (s, 1H), 8.47 (d, J=8.4 Hz, 1H), 11.87 (s, 1H); LC-MS (ES-API); rt 8.91 min; m/z calculated for C.sub.18H.sub.15NO.sub.7S [M+H].sup.+ 390.1. found 390.1.

2-(6,7-Dimethoxy-1,2-dihydronaphthalene-3-carboxamido)benzoic acid (FT129)

6,7-Dimethoxy-1,2,3,4-tetrahydronaphthalen-1-ol

(91) ##STR00120##

(92) To a stirred solution of 6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-one (3.09 g, 15 mmol) in MeOH (50 mL) was added NaBH.sub.4 (680 mg, 18 mmol) portion wise over 0.5 hour. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with 1N HCl, diluted with water and extracted with DCM. The combined organic phase was washed with brine, dried over sodium sulfate and the solvent was removed under reduced pressure to afford 6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-ol as a yellow oil (2.9 g, 93%). LC-MS (ES-API); rt 7.96 min; m/z calculated for C.sub.12H.sub.16O.sub.3 [M+Na].sup.+ 231.1. found 231.1.

6,7-Dimethoxy-3,4-dihydronaphthalene-2-carbaldehyde

(93) ##STR00121##

(94) A solution of 6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-ol (208 mg, 1 mmol) in dry DMF (5 mL) was cooled in an ice bath and phosphoryl chloride (0.2 mL, 2.3 mmol) was added dropwise. The reaction mixture was heated at 90 C. for 3 hours, then cooled and treated with a cold saturated aqueous solution of sodium acetate (2 mL) and stirred at room temperature for 10 min. Water was added and the mixture was extracted with DCM. The combined organic phase was washed with brine and dried over sodium sulfate. The solvent was then removed under reduced pressure to afford 6,7-dimethoxy-3,4-dihydronaphthalene-2-carbaldehyde as white solid (160 mg, 46%). LC-MS (ES-API); rt 8.23 min; m/z calculated for C.sub.13H.sub.14O.sub.3 [M+H].sup.+ 219.1. found 219.0.

6,7-Dimethoxy-3,4-dihydronaphthalene-2-carboxylic acid

(95) ##STR00122##

(96) A mixture of 6,7-dimethoxy-3,4-dihydronaphthalene-2-carbaldehyde (2.2 g, 10 mmol) in EtOH (30 mL) was treated with a solution of silver nitrate (5.0 g, 30 mmol) in water (16 mL). A solution of NaOH (6.0 g, 150 mmol) in water (50 mL) was then added with continuous stirring and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then extracted with DCM and combined organic phase was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash column using petroleum ether/ethyl acetate (from 6:1 to 3:1, v:v) as the eluent to give 6,7-dimethoxy-3,4-dihydronaphthalene-2-carboxylic acid (1.8 g, 77%). LC-MS (ES-API); rt 8.23 min; m/z calculated for C.sub.13H.sub.14O.sub.4 [M+H].sup.+ 235.1. found 235.0.

Methyl 2-(6,7-dimethoxy-1,2-dihydronaphthalene-3-carboxamido)benzoate

(97) ##STR00123##

(98) A mixture of 6,7-dimethoxy-3,4-dihydronaphthalene-2-carboxylic acid (476 mg, 2 mmol) and SOCl.sub.2 (1.5 mL, mmol) in toluene (20 mL) was heated at 50 C. for 1 hour. The solvent was then removed under reduced pressure to give 6,7-dimethoxy-3,4-dihydronaphthalene-2-carbonyl chloride which was used directly in the next step without further purification. To a stirred solution of methyl 2-aminobenzoate (332 mg, 2.2 mmol) and Et.sub.3N (0.8 mL, 6 mmol) in anhydrous DCM (20 mL) was added 6,7-dimethoxy-3,4-dihydronaphthalene-2-carbonyl chloride in anhydrous DCM (2 mL) dropwise at 0 C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with DCM. The combined organic phase was dried over sodium sulfate, the solvent was removed under reduced pressure and the residue was purified by flash column, eluting with petroleum ether/ethyl acetate (10:1) to give methyl 2-(6,7-dimethoxy-1,2-dihydronaphthalene-3-carboxamido)benzoate (330 mg, 45%). LC-MS (ES-API); rt 9.27 min; m/z calculated for C.sub.21H.sub.21NO.sub.5 [M+Na].sup.+390.1. found 390.1.

2-(6,7-Dimethoxy-1,2-dihydronaphthalene-3-carboxamido)benzoic acid (FT129)

(99) ##STR00124##

(100) To a stirred solution of methyl 2-(6,7-dimethoxy-3,4-dihydronaphthalene-2-carboxamido) benzoate (440 mg, 1.2 mmol) in MeOH (6 mL) and THF (3 mL) was added 2N NaOH (3 mL) dropwise at room temperature. The resulting solution was stirred at room temperature for 2 hours, then quenched with 1N HCl and diluted with water. The resulting suspension was filtered and the solid was dried under vacuum to give 2-(6,7-dimethoxy-1,2-dihydronaphthalene-3-carboxamido)benzoic acid (350 mg, 83%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 2.59 (t, J=8.4 Hz, 2H), 2.83 (t, J=8.4 Hz, 2H), 3.75 (s, 3H), 3.79 (s, 3H), 6.90 (s, 1H), 6.97 (s, 1H), 7.15 (app t, J=7.6 Hz, 1H), 7.39 (s, 1H), 7.62 (m, 1H), 8.03 (dd, J=8.0, 1.6 Hz, 1H), 8.69 (d, J=8.4 Hz, 1H), 11.89 (s, 1H); LC-MS (ES-API); rt 9.22 min; m/z calculated for C.sub.20H.sub.19NO.sub.6 [M+Na].sup.+ 376.1. found 376.1.

2-(6,7-Dimethoxy-1,2,3,4-tetrahydronaphthalene-3-carboxamido)benzoic acid (FT130)

(101) ##STR00125##

(102) A mixture of 2-(6,7-dimethoxy-3,4-dihydronaphthalene-2-carboxamido)benzoic acid (350 mg, 1 mmol) and 10% Pd/C (35 mg) in MeOH (50 mL) and THF (50 mL) was stirred at room temperature under H.sub.2 overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 2-(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalene-3-carboxamido)benzoic acid (250 mg, 71%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 1.70-1.85 (m, 1H), 2.10-2.21 (m, 1H), 2.64-2.82 (m, 3H), 2.82-3.00 (m, 2H), 3.71 (s, 6H), 6.66 (s, 1H), 6.68 (s, 1H), 7.16 (app t, J=7.6 Hz, 1H), 7.60 (app t, J=8.0 Hz, 1H), 8.00 (d, J=7.2 Hz, 1H), 8.53 (d, J=8.4 Hz, 1H), 11.32 (s, 1H); LC-MS (ES-API); rt 8.96 min; m/z calculated for C.sub.20H.sub.21NO.sub.5 [M+H].sup.+ 356.1. found 356.1.

(Z)-2-(2-(6,7-Dimethoxy-1-oxo-2,3-dihydroisoquinolin-4(1H)-ylidene)acetamido)benzoic acid (FT131)

2-Iodo-4,5-dimethoxybenzoic acid

(103) ##STR00126##

(104) To a stirred solution of 2-iodo-4,5-dimethoxybenzaldehyde (1.0 g, 3.42 mmol) in CH.sub.3CN (25 mL) was added a solution of KMnO.sub.4 (0.76 g, 4.79 mmol) in water (15 mL) dropwise at 0 C. The resulting mixture was stirred at room temperature overnight. After the reaction was complete, the pH was adjusted to <7 with 1N HCl. The mixture was extracted with DCM and the organic layers combined, washed with brine, dried over sodium sulfate, and evaporated to give 2-Iodo-4,5-dimethoxybenzoic acid (0.89 g, 85%).

Ethyl 2-(2-iodo-4,5-dimethoxybenzamido)acetate

(105) ##STR00127##

(106) To a stirred solution of 2-iodo-4,5-dimethoxybenzoic acid (24.6 g, 80 mmol), ethyl 2-aminoacetate hydrochloride (11 g, 88 mmol), EDCl (17 g, 88 mmol) and HOBt (14 g, 88 mmol) in dry DCM (500 mL) was added Et.sub.3N (55 mL, 400 mmol) dropwise at rt. The resulting mixture was stirred at room temperature overnight then the reaction was quenched with water, and thoroughly extracted with DCM. The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using petroleum ether/ethyl acetate 3:1 (v:v) as eluent to give ethyl 2-(2-iodo-4,5-dimethoxybenzamido)acetate (29 g, 95%).

N-(2-Hydroxyethyl)-2-iodo-4,5-dimethoxybenzamide

(107) ##STR00128##

(108) LiBH.sub.4 (63 mg, 3 mmol) was added to a stirred solution of ethyl 2-(2-iodo-4,5-dimethoxybenzamido)acetate (379 mg, 1 mmol) in THF (2 mL) at 10 C. The reaction was stirred for 5 min then methanol (0.22 mL) was added dropwise. The reaction mixture was warmed to room temperature, stirred for 30 minutes and quenched by addition of water. The THF was removed under reduced pressure and the aqueous residue was thoroughly extracted with DCM. The combined organic phases were washed with brine, dried over sodium sulphate and evaporated to give the crude product which was purified by re-crystallization from EtOAc and hexane to give N-(2-hydroxyethyl)-2-iodo-4,5-dimethoxybenzamide (280 mg, 80%) LC-MS (ES-API); rt 7.60 min; m/z calculated for C.sub.11H.sub.14INO.sub.4 [M+H].sup.+ 352.0. found 352.0.

(Z)-Ethyl 4-(2-iodo-4,5-dimethoxybenzamido)but-2-enoate

(109) ##STR00129##

(110) A solution of dry DMSO (0.453 mL, 6.4 mmol) in DCM (2 mL) was added dropwise to a solution of oxalyl chloride (0.338 mL, 4 mmol) in DCM (5 mL) at 78 C. The reaction was stirred for 30 min at 78 C. then a solution of N-(2-hydroxyethyl)-2-iodo-4,5-dimethoxybenzamide (702 mg, 2 mmol) in DCM (3 mL) was added via cannula. The mixture was stirred at 78 C. for 1 hour then dry Et.sub.3N (1.7 mL, 12 mmol) was added slowly. Stirring was continued at 78 C. for 1 hour by which time the formation of the aldehyde was complete (monitored by TLC). Solid Ph.sub.3PCHCOOEt (1.0 g, 3 mmol) was then added and the reaction was allowed to warm slowly to room temperature overnight. The solvent was removed under reduced pressure and the crude product was purified by flash column using petroleum ether/ethyl acetate (from 6:1 to 3:1) as eluent to give (Z)-ethyl 4-(2-iodo-4,5-dimethoxybenzamido)but-2-enoate (280 mg, 34%). LC-MS (ES-API); rt 8.46 min; m/z calculated for C.sub.15H.sub.181 NO.sub.5 [M+H].sup.+ 420.0. found 420.0.

(Z)-Ethyl 2-(6,7-dimethoxy-1-oxo-2,3-dihydroisoquinolin-4(1H)-ylidene)acetate

(111) ##STR00130##

(112) A stirred solution of Pd(OAc).sub.2 (16 mg, 0.07 mmol), PPh.sub.3 (61 mg, 0.23 mmol), Et.sub.3N (0.58 mL, 4.2 mmol) and (Z)-ethyl 4-(2-iodo-4,5-dimethoxybenzamido)but-2-enoate (860 mg, 2.1 mmol) in dry CH.sub.3CN (20 mL) was heated at 70 C. overnight under an argon atmosphere. The reaction was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by flash chromatography using DCM/MeOH 100:1 (v:v) as eluent to give (Z)-ethyl 2-(6,7-dimethoxy-1-oxo-2,3-dihydroisoquinolin-4(1H)-ylidene)acetate (510 mg, 83%). LC-MS (ES-API); rt 7.56 min; m/z calculated for C.sub.15H.sub.17NO.sub.5 [M+H].sup.+ 292.1. found 292.1.

(Z)-2-(6,7-Dimethoxy-1-oxo-2,3-dihydroisoquinolin-4(1H)-ylidene)acetic acid

(113) ##STR00131##

(114) To a stirred solution of (Z)-ethyl 2-(6,7-dimethoxy-1-oxo-2,3-dihydroisoquinolin-4(1H)-ylidene)acetate (1.45 g, 5 mmol) in MeOH (20 mL) and THF (40 mL) was added 2N LiOH (5 mL) dropwise at room temperature and the resulting mixture was stirred at room temperature overnight. The reaction was quenched by addition of 1N HCl and the solvents were removed under reduced pressure. The mixture was diluted with water and cooled and the precipitate collected by filtration to afford (Z)-2-(6,7-dimethoxy-1-oxo-2,3-dihydroisoquinolin-4(1H)-ylidene)acetic acid (1.0 g, 77%). LC-MS (ES-API); rt 7.21 min; m/z calculated for C.sub.13H.sub.13NO.sub.5 [MH].sup. 262.0. found 262.1.

(Z)-Methyl 2-(2-(6,7-dimethoxy-1-oxo-2,3-dihydroisoquinolin-4(1H)-ylidene)acetamido)benzoate

(115) ##STR00132##

(116) To a stirred solution of (Z)-2-(6,7-dimethoxy-1-oxo-2,3-dihydroisoquinolin-4(1H)-ylidene)acetic acid (789 mg, 3 mmol), methyl 2-aminobenzoate (544 mg, 3.6 mmol), HOBt (587 mg, 3.6 mmol), EDCl (688 mg, 3.6 mmol) and DMAP (439 mg, 3.6 mmol) in dry DMF (30 mL) was added Et.sub.3N (2 mL, 15 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature overnight then the reaction was quenched with water and extracted with DCM. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated to give the crude product which was purified by flash chromatography using DCM/MeOH 40:1 (v:v) as eluent to give (Z)-methyl 2-(2-(6,7-dimethoxy-1-oxo-2,3-dihydroisoquinolin-4(1H)-ylidene)acetamido)benzoate (280 mg, 80%) LC-MS (ES-API); rt 8.39 min; m/z calculated for C.sub.21H.sub.20N.sub.2O.sub.6 [M+Na].sup.+ 419.1. found 419.1.

(Z)-2-(2-(6,7-Dimethoxy-1-oxo-2,3-dihydroisoquinolin-4(1H)-ylidene)acetamido)benzoic acid (FT131)

(117) ##STR00133##

(118) To a stirred solution of (4-methyl 2-(2-(6,7-dimethoxy-1-oxo-2,3-dihydroisoquinolin-4(1H)-ylidene)acetamido)benzoate (140 mg, 0.35 mmol) in MeOH (4 mL) and THF (8 mL) was added 2N LiOH (0.7 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature overnight then the reaction was quenched by addition of 1N HCl and the solvent was removed under reduced pressure. The mixture was diluted with water, cooled and the precipitate collected by filtration to afford (2)-2-(2-(6,7-dimethoxy-1-oxo-2,3-dihydroisoquinolin-4(1H)-ylidene)acetamido)benzoic acid (125 mg, 93%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 3.80, (s, 3H), 3.84 (s, 2H), 3.85 (s, 3H), 7.00 (s, 1H), 7.10 (m, 1H), 7.22 (d, J=6.0 Hz, 1H), 7.56 (m, 1H), 7.61 (s, 1H), 7.90 (dd, J=8.0, 1.6 Hz, 1H), 8.57 (dd, J=8.4, 0.8 Hz, 1H), 11.38 (d, J=5.6 Hz, 1H), 13.54 (br s, 1H); LC-MS (ES-API); rt 8.27 min; m/z calculated for C.sub.20H.sub.18N.sub.2O.sub.6 [M+H].sup.+ 383.1. found 383.1.

(E)-2-(3,4-Dimethoxystyryl)benzo[d]oxazole-4-carboxylic acid (FT132)

Methyl 2-amino-3-hydroxybenzoate

(119) ##STR00134##

(120) To a stirred solution of 2-amino-3-hydroxybenzoic acid (1.22 g, 8.0 mmol) in MeOH (80 mL) was added SOCl.sub.2 (9.52 g, 80.0 mmol) dropwise at 0 C. The mixture was then heated at reflux overnight. Most of the methanol was removed and the residue was partitioned between DCM and saturated aqueous NaHCO.sub.3. The organic phase was washed with brine, dried over sodium sulfate and the solvent was removed under reduced pressure to give methyl 2-amino-3-hydroxybenzoate (1.27 g, 95%). LC-MS (ES-API); rt 8.09 min; m/z calculated for C.sub.8H.sub.9NO.sub.3 [M+H].sup.+ 168.1. found 168.1.

Methyl 2-methylbenzo[d]oxazole-4-carboxylate

(121) ##STR00135##

(122) A solution of methyl 2-amino-3-hydroxybenzoate (167 mg, 1.0 mmol), acetyl chloride (86 mg, 1.1 mmol) and triethylamine (101 mg, 1.1 mmol) in xylene (10 mL) was stirred at 0 C. for 2 h. Pyridine (mg, 0.25 mmol) and TsOH (43 mg, 0.25 mmol) were then added and the mixture was heated at reflux overnight. The mixture was then cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, then dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography using petroleum ether/ethyl acetate 5:1 (v:v) as eluent to give methyl 2-methylbenzo[d]oxazole-4-carboxylate (151 mg, 79%). LC-MS (ES-API); rt 8.08 min; m/z calculated for C.sub.10H.sub.9NO.sub.3 [M+H].sup.+ 192.1. found 192.1.

(E)-Methyl 2-(3,4-dimethoxystyryl)benzo[d]oxazole-4-carboxylate

(123) ##STR00136##

(124) A solution of methyl 2-methylbenzo[d]oxazole-4-carboxylate (0.63 g, 4.12 mmol) and 3,4-dimethoxybenzaldehyde (0.68 g, 4.12 mmol) in THF (25 mL) and t-BuOH (5 mL) was cooled to 50 C. under nitrogen and treated with a solution of t-BuOK in THF (1.0 mol/L, 4.94 mL, 4.94 mmol) at such a rate that the internal reaction temperature did not exceed 46 C. After 2 hours at 50 C., the cooling bath was removed and the mixture was stirred at room temperature for 12 h in the dark. Water was added and the mixture was made slightly acidic by addition of a 1N HCl solution then extracted with DCM. The organic layers were combined, washed with water and brine then dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography using petroleum ether:ethyl acetate 2:1 (v:v) as eluent to give (E)-methyl 2-(3,4-dimethoxystyryl)benzo[d]oxazole-4-carboxylate (0.30 g, 27%). LC-MS (ES-API); rt 9.25 min; m/z calculated for C.sub.19H.sub.17NO.sub.5 [M+H].sup.+ 340.1. found 340.1.

(E)-2-(3,4-Dimethoxystyryl)benzo[d]oxazole-4-carboxylic acid (FT132)

(125) ##STR00137##

(126) To a stirred solution of (E)-methyl 2-(3,4-dimethoxystyryl)benzo[d]oxazole-4-carboxylate (240 mg, 0.71 mmol) in THF (10 mL) and MeOH (5 mL) was added 2 N NaOH solution (1.77 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for two hours then quenched with a 1 N HCl solution. The mixture was then extracted with DCM and the organic phase was washed with saturated aqueous NaCl solution and dried over sodium sulfate. The solvent was then removed under reduced pressure to give (E)-2-(3,4-Dimethoxystyryl)benzo[d]oxazole-4-carboxylic acid (170 mg, 74%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 3.81 (s, 3H), 3.85 (s, 3H), 7.03 (d, J=8.0 Hz, 1H), 7.33-7.39 (m, 2H), 7.46 (app t, J=8.0 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.80 (d, J=16.0 Hz, 1H), 7.87 (dd, J=8.0, 1.2 Hz, 1H), 7.93 (dd, J=8.0, 1.2 Hz, 1H); LC-MS (ES-API): rt 8.88 min; m/z calculated for C.sub.18H.sub.15NO.sub.5 [MH].sup. 324.1. found 324.1.

(127) 1097 Rat Mesangial Cells

(128) A well-characterised cloned rat mesangial cell line (Kakizaki Y, Kraft N, Atkins R C: Differential control of mesangial cell proliferation by interferon-gamma. Clin Exp Immunol 85:157-163, 1991) was cultured in DMEM (5 mM glucose) with 5% FBS, 100U/mL penicillin, and 100 ug/mL streptomycin in humidified 5% CO2 atmosphere at 37 C. Cells were used up to passage 40.

(129) Proline Incorporation Assay

(130) Cells were plated into 24-well culture dishes in DMEM/5% FBS and allowed to adhere overnight. The subconfluent cells were then starved overnight in DMEM/0.1% FBS and 150 uM L-ascorbic acid, prior to pre-treatment with or without FibroTech compounds for 4 hours at 10, 30 or 100 uM in 0.1% DMSO, final concentration. TGF-beta 1 at 5 ng/mL (Peprotech) and tritiated proline (Perkin-Elmer, (2,3,4,5-.sup.3H)-proline) at 1 uCi/mL were added and the incubation continued for a further 44 hours. Treatments were performed in triplicate.

(131) After the incubation, cells were placed on ice and washed three times with ice cold PBS. They were then incubated on ice with 10% TCA for 30 minutes, followed by a final wash in cold 10% TCA. The cells were solubilized in 0.75 mL of 1M NaOH at 37 C for 45 minutes, or overnight at 4 C. Aliquots of the solubilized cells were neutralized in an equal amount of 1M HCl and counted in scintillant in a beta counter. Aliquots of neutralized solubilized cells were assayed for protein using the BioRad Bradford Protein Assay. Proline incorporation was normalized for protein content (cpm .sup.3H-proline incorporated per ug protein).

(132) In order to compare the results of experiments performed on different days, the percentage inhibition of proline incorporation was calculated for each treatment by setting the TGF treatment at 0% inhibition and the control (incubation with media alone) at 100% inhibition.

(133) Mesangial Cells

(134) Percentage Reduction of TGF-Beta 1 Stimulated Proline Incorporation:

(135) TABLE-US-00001 Tox. Rank FT 10 M 30 M 100 M (4 = non-toxic) 98 30% 70% 70% 4 102 0 0 10%, ppt 4 106 0 0, sick dead 1@100 uM 2@30 uM 107 0 0 0, ppt 4 (yellow floating patches @ 30 & 100 uM) 108 75% 95% 100+% 4 (yellow jellylike patches @ 30 & 100 uM) 109 3% 16% 75%, ppt 4 110 0 0 0, ppt 3@100 uM (cells elongated) 113 20% 67% 44% 4 121 ~60% 100+% dead 1@100 uM 3@30 uM 122 ~25% ~80% dead 1@100 uM 4@30 uM 123 0 0, ppt, sick 0, ppt, dead 1 to 2 124 0, ppt 0, ppt, sick 0, ppt, sick 2 125 0 0, sick 0, sick 2 126 ~55% ~75% ~100% 4 127 0 0 ~50% 4 128 ~20% ~20% ~40% 3@100 uM (some death) 129 ~10% ~75% dead 1@100 uM 2@30 uM 130 ~10% ~30% ~50% 2@100 uM 131 ~20% ~10% ~10% 4 132 ~2% ~75%, ppt ~75%, ppt 3@100 uM (some death) ppt indicates compound precipitated during assay.

(136) The details of specific embodiments described in this invention are not to be construed as limitations. Various equivalents and modifications may be made without departing from the essence and scope of this invention, and it is understood that such equivalent embodiments are part of this invention.