Combinations comprising biphenyl derivatives for use in the treatment of HCV

Abstract

The present disclosure is generally directed to antiviral compounds, and more specifically directed to combinations of compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such combinations, and methods for inhibiting the function of the NS5A protein.

Claims

1. A combination comprising an NS5A-targeting compound and an NS5A synergist, which, when administered, provides synergistic anti-HCV activity against variants that contain mutation(s) conferring resistance to the NS5A-targeting compound alone, wherein the NS5A-targeting compound is BMS-790052: ##STR00119## and wherein the NS5A synergist is a compound of formula (I): ##STR00120## or a pharmaceutically acceptable salt thereof, wherein A and B are independently selected from ##STR00121## R.sup.1 is selected from alkoxy, alkyl, haloalkyl, and hydroxy; R.sup.2 is hydrogen; or, alternatively, R.sup.1 and R.sup.2, together with the carbon atoms to which they are attached, form a dioxolanyl ring, wherein the dioxolanyl-ring is optionally substituted with one or two methyl groups; R.sup.1′ is selected from alkoxy, alkyl, haloalkyl, and hydroxy; R.sup.2′ is hydrogen; or, alternatively, R.sup.1′ and R.sup.2′, together with the carbon atoms to which they are attached, form a dioxolanyl ring, wherein the dioxolanyl ring is optionally substituted with two methyl groups; and R.sup.3 and R.sup.3′ are independently selected from alkoxy, hydroxy, and —NR.sup.aR.sup.b; R.sup.a and R.sup.b are independently selected from hydrogen, alkoxycarbonylalkyl, alkyl, polycycloalkyl, (polycycloalkyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, hydroxyalkyl, —NR.sup.cR.sup.d, (NR.sup.cR.sup.d)alkyl, (NR.sup.cR.sup.d)carbonylalkyl, phenylalkyl, and pyranyl, wherein the cycloalkyl, the cycloalkyl part of the (cycloalkyl)alkyl, and the phenyl part of the phenylalkyl is optionally substituted with one or two groups independently selected from alkoxy, alkoxyalkyl, aminocarbonyl, cyano, halo, hydroxy, and phenyl; and wherein the alkyl part of the (NR.sup.cR.sup.d)alkyl is optionally substituted with a hydroxy group; or, alternatively, R.sup.a and R.sup.b, together with the nitrogen atom to which they are attached, form a ring selected from morpholine, piperidine, and piperazine wherein each ring is optionally substituted with one or two groups selected from alkoxycarbonyl, alkyl, halo, oxo, and phenyl optionally substituted with halo; and one of R.sup.c and R.sup.d is selected from hydrogen and alkyl and the other is selected from hydrogen, alkoxycarbonyl, and alkyl; or, alternatively, R.sup.c and R.sup.d, together with the nitrogen atom to which they are attached, form an oxazolidinone ring.

2. The combination of claim 1 wherein the compound of formula (I) is selected from ##STR00122## ##STR00123## ##STR00124## ##STR00125## ##STR00126## ##STR00127## ##STR00128## TABLE-US-00008 R ##STR00142## TABLE-US-00009 R ##STR00148## TABLE-US-00010 R ##STR00163## TABLE-US-00011 R R.sub.1 ##STR00168## TABLE-US-00012 R or a pharmaceutically acceptable salt thereof.

3. A composition comprising the combination of claim 1 and one or more pharmaceutically acceptable carriers.

4. The composition of claim 3 further comprising one or two additional compounds having anti-HCV activity.

5. The composition of claim 4 wherein at least one of the additional compounds is an interferon or a ribavirin.

6. The composition of claim 5 wherein the interferon is selected from interferon alpha 2B, pegylated interferon alpha, pegylated interferon lambda, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.

7. The composition of claim 4 wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection.

8. A method of treating an HCV infection in a patient, comprising administering to the patient a therapeutically effective amount of a combination of claim 1, or a pharmaceutically acceptable salt thereof.

9. The method of claim 8 further comprising administering one or two additional compounds having anti-HCV activity prior to, after or simultaneously with the combination, or a pharmaceutically acceptable salt thereof.

10. The method of claim 9 wherein at least one of the additional compounds is an interferon or a ribavirin.

11. The method of claim 10 wherein interferon is selected from interferon alpha 2B, pegylated interferon alpha, pegylated interferon lambda, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.

12. The method of claim 9 wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection.

Description

EXAMPLE MD-1

(1) ##STR00007##

EXAMPLE MD-1

Step a

(2) ##STR00008##

(3) To a suspension of 1,1′-([1,1′-biphenyl]-4,4′-diyl)bis(2-bromoethanone) (500 mg, 1.262 mmol) and (R)-2-(2-(tert-butoxy)-2-oxoethyl)-5,5,5-trifluoropentanoic acid (700 mg, 2.052 mmol) (prepared according to the procedure described in WO2012129353-A1) in anhydrous ACN (15 mL) at 0° C. was slowly added DIEA (485 μL, 2.78 mmol). The reaction was flushed well with N.sub.2, securely capped and allowed to stir for 18 h while slowly warming to room temp. The solvent was removed in vacuo and the crude product was purified by flash column chromatography (80 g Teledyne Isco Silica Flash Column, 100% hexanes to 60% ethyl acetate/hexanes over 10 column volumes) to afford the title compound (880 mg) as a white solid. .sup.1H NMR (500 MHZ, CDCl.sub.3) δ 8.04 (d, J=8.4 Hz, 4H), 7.76 (d, J=8.4 Hz, 4H), 5.53 (d, J=16.4 Hz, 2H), 5.34 (d, J=16.3 Hz, 2H), 3.16-2.99 (m, 2H), 2.83 (dd, J=16.4, 8.2 Hz, 2H), 2.58-2.22 (m, 6H), 2.14-1.86 (m, 4H), 1.48 (s, 18H).

EXAMPLE MD-1

Step b

(4) ##STR00009##

(5) To a 48 ml, pressure bottle under N.sub.2 was added material from Example MD-1, step a (880 mg, 1.136 mmol), ammonium acetate (2.65 g, 34.4 mmol), imidazole (462 mg, 6.79 mmol) and anhydrous toluene (18 mL). The reaction was flushed with N.sub.2, capped and heated at 110° C. for 18 h. The reaction was diluted with EtOAc (300 mL) and the organic layer was washed with saturated aqueous NaHCO.sub.3 (70 mL), water (2×50 mL), brine (1×50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness in vacuo. The crude product was purified by flash column chromatography (80 g Teledyne Isco Silica Flash Column, 100% dichloromethane to 100% ethyl acetate over 12 column volumes) to afford the title compound (510 mg) as a white solid. LC/MS Condition MD-1: [M+H].sup.+ 735, R.sub.t=3.401 min; .sup.1H NMR (500 MHZ, CDCl.sub.3) δ 7.73 (br. s., 2H), 7.60 (br. s., 4H), 7.32-7.15 (m, 4H), 3.33-3.23 (m, 2H), 2.78-2.50 (m, 4H), 2.18-1.75 (m, 8H), 1.43-1.24 (m, 18H).

EXAMPLE MD-1

Step c

(6) ##STR00010##

(7) To a suspension of material from Example MD-1, step b (508 mg, 0.691 mmol) in anhydrous dichloromethane (8 mL) with vigorous swirling was added TFA (10.0 mL, 130 mmol). The reaction was allowed to stand at room temp for 125 min, then the volatiles were removed under a gentle stream of N.sub.2. The residue was suspended in toluene (30 mL) and the solvent was removed in vacuo to give the title compound (785 mg) as a tris TFA salt as a tan solid. LC/MS Condition MD-1: [M+H].sup.+ 623, R.sub.t=3.02 min; .sup.1H NMR (500 MHZ, DMSO-d.sub.6) δ 14.6 (m, 3H), 12.5 (m, 1H), 8.19 (s, 2H), 8.00-7.96 (m, 4H), 7.96-7.87 (m, 4H), 3.62-3.52 (m, 2H), 3.05-2.90 (m, 4H), 2.42-2.20 (m, 4H), 2.09-1.96 (m, 4H); .sup.19F NMR (470 MHZ, DMSO-d.sub.6) δ −64.84 (s, 6F), −74.51 (s, 9F).

EXAMPLE MD-1

(8) To a mixture of material from Example MD-1, step c (44.3 mg, 0.046 mmol), (S)-methyl 2-amino-3-methylbutanoate, HCl (67.8 mg, 0.4.4 mmol), and HOAT (18.7 mg, 0.137 mmol) in anhydrous dichloromethane (3 mL) under N.sub.2 was added EDC (62.4 mg, 0.326 mmol) and DIEA (130 μL, 0.744 mmol). The reaction was flushed with N.sub.2, securely capped and stirred at room temp for 18 h. DMAP (23.4 mg, 0.192 mmol) was added and the reaction was allowed to stir at room temp for 4 days. The solvent was evaporated under a gentle stream of N.sub.2, and the crude product was purified by reverse phase preparative HPLC conditions MD-1 using a gradient from 20% solvent B/80% solvent A to 100% solvent B over 11 min to give the title compound (16.8 mg) as a bis TFA salt as a white solid. LC/MS Condition MD-1: [M+H].sup.+ 849, R.sub.t=3.31 min; .sup.1H NMR (500 MHZ, CD.sub.3OD) δ 7.90 (s, 2H), 7.90-7.85 (m, 8H), 4.29 (d, J=6.0 Hz, 2H), 3.72 (s, 6H), 3.71-3.66 (m, 2H), 3.03-2.97 (m, 2H), 2.97-2.90 (m, 2H), 2.42-2.31 (m, 2H), 2.24-2.09 (m, 8H), 0.91 (d, J=6.9 Hz, 6H), 0.89 (d, J=6.9 Hz, 6H).

(9) Analytical HPLC MD-A: R.sub.t=27.37 min, λ=220 nm

(10) Analytical HPLC MD-B: R.sub.t=27.12 min, λ=220 nm

(11) Analytical HPLC MD-C: R.sub.t=5.65 min, λ=254 nm

(12) Analytical HPLC MD-D: R.sub.t=6.29 min, λ=254 nm

EXAMPLE MD-2

(13) ##STR00011##

(14) To a mixture of material from Example MD-1, step c (47 mg, 0.049 mmol), 4-fluoropiperidine, HCl (76 mg, 0.544 mmol) and HOAT (19.6 mg, 0.144 mmol) in anhydrous dichloromethane (4 mL) under N.sub.2 was added EDC (83 mg, 0.433 mmol) and DIEA (160 μL, 0.916 mmol). The reaction was flushed with N.sub.2, securely capped and stirred at room temp for 18 h. Imidazole (150 mg, 2.203 mmol) and additional EDC (190 mg, 0.991 mmol) was added and the reaction was allowed to stir at room temp for 18 h. The solvent was evaporated under a gentle stream of N.sub.2, and the crude product was purified by reverse phase preparative HPLC conditions MD-1 using a gradient from 30% solvent B/70% solvent A to 100% solvent B over 11 min to give the impure title compound as a tris TFA salt as a white solid. LC/MS Condition MD-1: [M+H].sup.+ 793, R.sub.t=3.2 min. The impure title compound was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-70% B over 25 min, then a 5-min hold at 100% B; Flow: 20 mL/min. to give the pure title compound (11.4 mg). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) δ 7.81 (br. s., 4H), 7.69 (br. s., 4H), 7.55 (br. s., 2H), 4.95-4.78 (m, 2H), 3.67-3.42 (m, 10H), 2.96 (dd, J=16.0, 7.3 Hz, 2H), 2.69 (d, J=16.0 Hz, 2H), 2.32-2.23 (m, 2H), 2.22-2.12 (m, 2H), 1.97-1.80 (m, 7H), 1.76-1.52 (m, 5H).

EXAMPLE MD-3

(15) ##STR00012##

(16) To a mixture of material from Example MD-1, step c (70 mg, 0.073 mmol), 2-methylpropan-1-amine (65.7 mg, 0.898 mmol) and HOAT (14 mg, 0.103 mmol) in anhydrous DMF (4 mL) was added EDC (90 mg, 0.469 mmol). The reaction was flushed with N.sub.2, securely capped and stirred at 55° C. for 18 h. The volatiles were evaporated off under a gentle stream of N.sub.2 and the crude product was purified by reverse phase preparative HPLC conditions MD-1 using a gradient from 25% solvent B/75% solvent A to 100% solvent B over 10 min to give the TFA salt of the title compound (9.0 mg) as a white solid. LC/MS Condition MD-1: [M+H].sup.+ 733, R.sub.t=3.38 min; .sup.1H NMR (500 MHZ, CD.sub.3OD) δ 7.90 (s, 2H), 7.90-7.85 (m, 8H), 3.76-3.59 (m, 2H), 3.06-3.00 (m, 2H), 2.98-2.92 (m, 2H), 2.91-2.81 (m, 4H), 2.40-2.30 (m., 2H), 2.26-2.10 (m, 6H), 1.73 (m, J=6.7 Hz, 2H), 0.88 (d, J=6.7 Hz, 6H), 0.87 (d, J=6.7 Hz, 6H); .sup.19F NMR (470 MHZ, CD.sub.3OD) δ −67.89 (s, 6F), −77.10 (s, 6F).

EXAMPLE MD-4

(17) ##STR00013##

(18) Also isolated from the reaction described in Example MD-3 was the TFA salt of the title compound (16.9 mg) shown above as a white solid. LC/MS Condition MD-1: [M+H].sup.+ 678, R.sub.t=3.17 min; .sup.1H NMR (500 MHZ, CD.sub.3OD) δ 7.91 (s, 1H), 7.90 (s, 1H), 7.89-7.86 (m, 8H), 3.74-3.63 (m, 2H), 3.06-2.99 (m, 3H), 2.98-2.86 (m, 3H), 2.39-2.30 (m, 2H), 2.23-2.12 (m, 6H), 1.72 (dquart, J=6.7 Hz, 1H), 0.87 (d, J=6.7 Hz, 3H), 0.86 (dd, J=6.7 Hz, 3H); .sup.19F NMR (470 MHZ, CD.sub.3OD) δ −67.33 (s, 3F), −68.74 (s, 3F), −77.07 (s, 6F).

EXAMPLE MD-5

(19) ##STR00014##

EXAMPLE MD-5

Step a

(20) ##STR00015##

(21) To a rapidly stirred solution of (R)-dibenzyl 2-hydroxysuccinate (prepared according to the procedure described in J. Chem. Soc., Perkin Trans. 1: Organic and Bio-Organic Chemistry (1972-1999), 1995, #22, p. 2877-2882) (1.0 g, 3.18 mmol) in iodoethane (60 mL) was added silver(I) oxide (3.90 g, 16.83 mmol). The reaction was flushed with nitrogen and heated to 80° C. for 48 h. The solid was filtered off, the solvent was removed in vacuo and the crude product was purified by flash column chromatography (80 g Teledyne Isco Silica Flash Column, 100% hexanes to 35% ethyl acetate/65% hexanes over 10 column volumes) to afford the title compound (682 mg) as colorless oil. LC/MS Condition MD-2: [M+H].sup.+ 343, R.sub.t=3.36 min; .sup.1H NMR (500 MHZ, CDCl.sub.3) δ 7.42-7.30 (m, 10H), 5.21-5.10 (m, 4H), 4.37 (dd, J=8.2, 4.9 Hz, 1H), 3.74 (dq, J=9.0, 7.0 Hz, 1H), 3.50 (dq, J=9.1, 7.0 Hz, 1H), 2.91-2.78 (m, 2H), 1.19 (t, J=7.0 Hz, 3H).

EXAMPLE MD-5

Step b

(22) ##STR00016##

(23) To a rapidly stirred solution of material from MD-5, step a (682 mg, 1.992 mmol) in methanol (40 mL) was added 30% Pd/C (385 mg). The resulting black suspension was flushed with nitrogen, securely capped, purged very well with H.sub.2 and stirred overnight at room temperature under H.sub.2. The reaction was flushed with N.sub.2, the catalyst was filtered off thru a small pad of Celite and the solvent was removed in vacuo to give the title compound (323 mg) as a white solid. .sup.1H NMR (500 MHZ, CDCl.sub.3) δ 4.31 (dd, J=7.0, 4.7 Hz, 1H), 3.86-3.74 (m, 1H), 3.72-3.59 (m, 1H), 3.02-2.84 (m, 2H), 1.27 (t, J=6.9 Hz, 3H).

EXAMPLE MD-5

Step c

(24) ##STR00017##

(25) To a rapidly stirred solution of material from MD-5, step b (273 mg, 1.684 mmol) in anhydrous dichloromethane (15 mL) was added trifluoroacetic anhydride (20 mL, 142 mmol). The resulting pale yellow solution was stirred at room temp for 20 min, and then the solvent was removed in vacuo. The residue was redissolved in anhydrous dichloromethane (7 mL) and evaporated to dryness to give the title compound (243 mg) as a TFA salt. .sup.1H NMR (400 MHZ, CDCl.sub.3) δ 4.51 (dd, J=8.5, 5.5 Hz, 1H), 4.04 (dq, J=9.3, 7.0 Hz, 1H), 3.70 (dq, J=9.0, 7.0 Hz, 1H), 3.26 (dd, J=18.7, 8.7 Hz, 1H), 2.96 (dd, J=18.7, 5.6 Hz, 1H), 1.27 (t, J=7.0 Hz, 3H).

EXAMPLE MD-5

Step d

(26) ##STR00018##

(27) To a rapidly stirred solution of material from MD-5, step c (243 mg, 1.684 mmol) in THF (1.5 mL) was added benzyl alcohol (185 μL, 1.78 mmol). The reaction was flushed well with N.sub.2, securely capped and placed in a 60° C. sand-bath for 24 h. The solvent was removed in vacuo, the residue was redissolved in dichloromethane (10 mL) and the solvent was again removed in vacuo to give the title compound (425 mg). .sup.1H NMR (500 MHZ, CDCl.sub.3) δ 7.48-7.31 (m, 5H), 5.29-5.17 (m, 2H), 4.34 (dd, J=8.2, 4.7 Hz, 1H), 3.84-3.74 (m, 1H), 3.56 (dq, J=9.1, 7.0 Hz, 1H), 2.92-2.77 (m, 2H), 1.23 (t, J=6.9 Hz, 3H).

EXAMPLE MD-5

Step e

(28) ##STR00019##

(29) To a solution of material from MD-5, step d (212 mg, 0.842 mmol), methyl 2-isopropylhydrazinecarboxylate (117 mg, 0.885 mmol), and 1-hydroxy-7-azabenzotriazole (10 mg, 0.073 mmol) in anhydrous dichloromethane (1.5 mL) was added EDC (200 mg, 1.043 mmol), followed immediately by DIEA (190 μL, 1.088 mmol). The reaction was flushed briefly with N.sub.2, capped and stirred at room temp for 18 h. The reaction was diluted with dichloromethane (200 mL) and the organic layer was washed with saturated aqueous NaHCO.sub.3 (50 mL), water (50 mL), brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness in vacuo. The crude product was purified by flash column chromatography (40 g Teledyne Isco Silica Flash Column, 100% dichloromethane to 75% ethyl acetate/dichloromethane over 12 column volumes) to afford the title compound (161 mg) as a colorless film. LC/MS Condition MD-1: [M+H].sup.+ 367; [M+Na].sup.+ 389, R.sub.t=3.32 min; LC/MS Condition MD-2: [M+H].sup.+ 367; [M−H].sup.− 365, R.sub.t=2.62 min; .sup.1H NMR (500 MHZ, CDCl.sub.3) δ 7.48-7.31 (m, 5H), 5.21 (s, 2H), 4.80 (ddd, J=19.6, 13.2, 6.6 Hz, 1H), 4.57-4.32 (m, 1H), 3.64-3.40 (m, 1H), 3.09-2.83 (m, 1H), 2.74-2.50 (m, 1H), 1.28-0.95 (m, 10H).

EXAMPLE MD-5

Step f

(30) ##STR00020##

(31) To a solution of material from MD-5, step e (161 mg, 0.439 mmol) in a mixture of dioxane (2.15 mL) and water (1.3 mL) was added sodium hydroxide (21.0 mg, 0.91 mmol) over 40 min. After the addition was complete, the resulting solution was stirred at room temp for 95 min, cooled briefly, and quenched with 1.0 M aq. HCl (1 mL, 1.0 mmol). The reaction was diluted with dichloromethane (60 mL) and the water layer was back-extracted with dichloromethane (3×25 mL). The organic layers were combined, dried over Na.sub.2SO.sub.4 and MgSO.sub.4, filtered and evaporated to dryness in vacuo to give the title compound (190 mg) as a colorless oil. LC/MS Condition MD-1: [M+H].sup.+ 277; [M+Na].sup.+299, R.sub.t=2.39 min.

EXAMPLE MD-5

Step g

(32) ##STR00021##

(33) To a solution of material from MD-5, step f (121 mg, 0.438 mmol), 1,1′-([1,1′-biphenyl]-4,4′-diyl)bis(2-bromoethanone) (77 mg, 0.194 mmol) in anhydrous ACN (5 mL) at 0° C. was slowly added DIEA (120 μL, 0.687 mmol). The reaction was flushed well with N.sub.2, securely capped and allowed to stir for 18 h while slowly warming to room temp. The solvent was removed in vacuo and the crude product was purified by flash column chromatography (24 g Teledyne Isco Silica Flash Column, 100% dichloromethane to 100% EtOAc over 12 column volumes) to afford the title compound (133.2 mg) as a colorless oil. LC/MS Condition MD-1: [M+H].sup.+ 787, R.sub.t=3.91 min; .sup.1H NMR (500 MHZ, CDCl.sub.3) δ 8.04 (t, J=8.9 Hz, 4H), 7.77 (d, J=6.3 Hz, 4H), 5.72-5.33 (m, 4H), 4.95-4.74 (m, 2H), 4.69-4.52 (m, 2H), 3.97-3.74 (m, 8H), 3.71-3.48 (m, 2H), 3.26 (dd, J=14.5, 9.5 Hz, 1H), 3.04 (d, J=9.6 Hz, 1H), 2.87-2.64 (m, 2H), 1.34-0.98 (m, 18H).

EXAMPLE MD-5

(34) To a solution of material from MD-5, step g (67.3 mg, 0.086 mmol) in anhydrous toluene (3.1 mL) was added ammonium acetate (268.7 mg, 3.49 mmol) and imidazole (37.8 mg, 0.555 mmol). The reaction was flushed with N.sub.2, securely capped and placed in 90° C. oil bath for 2 h 45 min. After heating, the reaction was stirred at room temp for 18 h, heated to 100° C. for 75 min., and then DIEA (150 μL, 0.859 mmol) was added and heating continued at 100° C. for an additional 3 h 45 min. The solvent was evaporated off under a gentle stream of N.sub.2 and the residue was purified by reverse phase preparative HPLC conditions MD-1 using a gradient from 20% solvent B/80% solvent A to 100% solvent B over 12 min to give the impure title compound (9.2 mg) as a TFA salt. LC/MS Condition MD-1: [M+H].sup.+ 747, R.sub.t=3.06 min.

(35) The impure title compound was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over 20 min, then a 5-min hold at 100% B; Flow: 20 mL/min. to give the pure title compound (2.6 mg). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) δ 12.45-12.12 (m, 2H), 9.71 (br. s., 2H), 7.97-7.43 (m, 10H), 4.86 (d, J=6.7 Hz, 2H), 4.68-4.42 (m, 2H), 3.75-3.64 (m, 14H), 1.09-0.89 (m, 18H).

EXAMPLE MD-6

(36) ##STR00022##

EXAMPLE MD-6

Step a

(37) ##STR00023##

(38) To a solution of material from MD-5, step d (212 mg, 0.842 mmol) isobutylamine (115 μL, 1.148 mmol), and HOAT (20 mg, 0.147 mmol) in anhydrous dichloromethane (1.6 mL) was added EDC (200 mg, 1.043 mmol), followed immediately by DIEA (200 μl, 1.145 mmol). The reaction was flushed briefly with N.sub.2, capped and stirred at room temp for 1 h, and then the solvent was removed under a gentle stream of N.sub.2 overnight. The crude product was dissolved in dichloromethane (5 mL) and purified by flash column chromatography (24 g Teledyne Isco Silica Flash Column, 100% dichloromethane to 100% ethyl acetate over 12 column volumes) to afford the title compound (161 mg) as colorless film. LC/MS Condition MD-1: [M+H].sup.+ 308; [M+Na].sup.+330, R.sub.t=3.50 min; .sup.1H NMR (500 MHZ, CDCl.sub.3) δ 7.50-7.32 (m, 5H), 6.08 (br. s., 1H), 5.29-5.13 (m, 2H), 4.32 (dd, J=8.6, 3.7 Hz, 1H), 3.76 (dd, J=9.2, 7.0 Hz, 1H), 3.62-3.44 (m, 1H), 3.13 (dt, J=13.2, 6.5 Hz, 1H), 3.08-2.98 (m, 1H), 2.74-2.66 (m, 1H), 2.62-2.52 (m, 1H), 1.76 (dt, J=13.4, 6.7 Hz, 1H), 1.24 (t, J=7.0 Hz, 3H), 0.92 (dd, J=6.6, 0.4 Hz, 6H).

EXAMPLE MD-6

Step b

(39) ##STR00024##

(40) To a solution of material from MD-6, step a (177 mg, 0.576 mmol) in methanol (75 mL) was added 30% palladium on carbon (78 mg). The reaction was flushed with N.sub.2, securely capped, then purged well with H.sub.2 gas and allowed to stir at room temp for 18 h under an atmosphere of H.sub.2. The reaction was filtered through a 45μ frit and the solvent was removed in vacuo to afford the title compound (126.9 mg) as colorless oil. LC/MS Condition MD-1: [M+Na].sup.+240, R.sub.t=2.39 min; .sup.1H NMR (500 MHZ, CDCl.sub.3) δ 7.88-7.43 (brs, 1H), 6.45 (t, J=5.3 Hz, 1H), 4.26 (dd, J=7.1, 4.8 Hz, 1H), 3.87-3.73 (m, 1H), 3.64-3.48 (m, 1H), 3.23-3.02 (m, 2H), 2.80 (dd, J=15.2, 4.8 Hz, 1H), 2.67 (dd, J=15.3, 7.2 Hz, 1H), 1.80 (dt, J=13.4, 6.7 Hz, 1H), 1.25 (t, J=7.0 Hz, 3H), 0.93 (d, J=6.7 Hz, 6H).

EXAMPLE MD-6

Step c

(41) ##STR00025##

(42) To a suspension of 1,1′-([1,1′-biphenyl]-4,4′-diyl)bis(2-bromoethanone) (51 mg, 0.129 mmol) and material from MD-6, step b (62.1 mg, 0.286 mmol) in anhydrous ACN (3.5 mL) at 0° C. was slowly added DIEA (80 μL, 0.458 mmol). The resulting off white suspension was flushed well with N.sub.2, securely capped and allowed to stir for 18 h while slowly warming to room temp. The solvent was removed in vacuo and the crude product was purified by flash column chromatography (80 g Teledyne Isco Silica Flash Column, 100% dichloromethane to 100% ethyl acetate over 11 column volumes) to afford the title compound (79.7 mg) as white solid. LC/MS Condition MD-1: [M+Na].sup.+669, R.sub.t=3.93 min; .sup.1H NMR (500 MHZ, CDCl.sub.3) δ 8.12-7.98 (m, 4H), 7.84-7.69 (m, 4H), 6.18 (t, J=5.7 Hz, 2H), 5.58-5.38 (m, 4H), 4.51 (dd, J=8.4, 4.1 Hz, 2H), 3.93-3.82 (m, 2H), 3.62 (dq, J=9.0, 7.1 Hz, 2H), 3.24-3.06 (m, 4H), 2.89 (dd, J=14.8, 4.1 Hz, 2H), 2.72 (dd, J=14.9, 8.3 Hz, 2H), 1.80 (dt, J=13.4, 6.7 Hz, 2H), 1.29 (t, J=7.0 Hz, 6H), 0.95 (d, J=6.7 Hz, 12H).

EXAMPLE MD-6

(43) To a 48 mL pressure bottle under N.sub.2 was added material from Example MD-6, step c (42.3 mg, 0.063 mmol), ammonium acetate (170 mg, 2.205 mmol), imidazole (25 mg, 0.367 mmol) and anhydrous toluene (3 mL). The reaction was flushed with N.sub.2, securely capped and heated at 100° C. for 6 h. The solvent was evaporated off under a gentle stream of N.sub.2 and the crude product was purified by reverse phase preparative HPLC conditions MD-1 using a gradient from 30% solvent B/70% solvent A to 100% solvent B over 10 min to give the TFA salt of the title compound (8.3 mg) as white solid. LC/MS Condition MD-1: [M+H].sup.+ 629, R.sub.t=3.21 min; .sup.1H NMR (500 MHZ, CD.sub.3OD) δ 7.94 (s, 2H), 7.89 (s, 8H), 5.18 (t, J=6.5 Hz, 2H), 3.71-3.61 (m, 4H), 3.05-3.01 (m, 4H), 2.95 (dd, J=8.2, 6.6 Hz, 4H), 1.78 (dt, J=13.5, 6.7 Hz, 2H), 1.27 (t, J=6.9 Hz, 6H), 0.92 (dd, J=6.6, 0.7 Hz, 12H).

(44) Analytical HPLC MD-A: R.sub.t=25.67 min, λ=220 nm

(45) Analytical HPLC MD-B: R.sub.t=25.32 min, λ=220 nm

(46) Analytical HPLC MD-C: R.sub.t=8.90 min, λ=254 nm

EXAMPLE MD-7

(47) ##STR00026##

EXAMPLE MD-7

Step a

(48) ##STR00027##

(49) To a suspension of 1,1′-([1,1′-biphenyl]-4,4′-diyl)bis(2-bromoethanone) (800 mg, 2.02 mmol) and (4R,5R)-5-(methoxycarbonyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (BMCL, 2003, vol. 13, No. 10 p. 1713-1716) (950 mg, 4.65 mmol) in anhydrous ACN (25 mL) at 0° C. was slowly added DIEA (850 μL, 4.87 mmol). The resulting off-white suspension was flushed well with N.sub.2, securely capped and allowed to stir for 18 h while slowly warming to room temp. The solvent was removed in vacuo and the crude product was purified by flash column chromatography (80 g Teledyne Isco Silica Flash Column, 100% hexanes to 70% ethyl acetate/hexanes over 11 column volumes) to afford the title compound (1.11 g) as a white solid. LC/MS Condition MD-1: [M+Na].sup.+665, R.sub.t=3.79 min. .sup.1H NMR (500 MHZ, CDCl.sub.3) δ 8.04 (d, J=8.7 Hz, 4H), 7.77 (d, J=8.5 Hz, 4H), 5.61 (d, J=16.2 Hz, 2H), 5.44 (d, J=16.2 Hz, 2H), 5.12 (d, 2H, J=5.3 Hz), 5.07 (d, 2H, J=5.3 Hz), 3.88 (s, 6H), 1.60 (s, 6H), 1.56 (s, 6H).

EXAMPLE MD-7

Step b

(50) ##STR00028##

(51) To a microwave vial under N.sub.2 was added material from Example MD-7, step a (108.1 mg, 0.168 mmol), ammonium acetate (330 mg, 4.28 mmol), and anhydrous toluene (4 mL). The reaction was flushed with N.sub.2, securely capped and heated at 110° C. for 45 min. The reaction was then heated at 106° C. for 5 h, followed by 60° C. for 18 h. The solvent was evaporated off under a gentle stream of N.sub.2, and the residue was partitioned between EtOAc and aq. satd. NaHCO.sub.3. The water layer was back extracted with EtOAc, the organic layers were combined, washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The crude product was purified by reverse phase preparative HPLC conditions MD-1 using a gradient from 25% solvent B/75% solvent A to 100% solvent B over 11 min to give the title compound (26.8 mg) as a TFA salt as a white solid. LC/MS Condition MD-1: [M+H].sup.+ 603, R.sub.t=2.88 min. .sup.1H NMR (500 MHZ, CD.sub.3OD) δ 8.00 (s, 2H), 7.93-7.86 (m, 8H), 5.67 (d, J=6.7 Hz, 2H), 4.98 (d, J=6.7 Hz, 2H), 3.87 (s, 6H), 1.64 (s, 6H), 1.55 (s, 6H).

EXAMPLE MD-7

(52) To a 2-5 mL microwave vial under N.sub.2 was added material from Example MD-7, step b (18 mg, 0.022 mmol), 2-methylpropan-1-amine (100 mg, 1.367 mmol) and anhydrous MeOH (2 mL). The reaction was flushed with N.sub.2, securely capped and heated in a microwave heating unit at 155° C. for 90 min under high power, followed by additional heating at 130° C. for 16 h under high power. The volatiles were removed under a gentle stream of N.sub.2 and the crude product was purified by reverse phase preparative HPLC conditions MD-1 using a gradient from 20% solvent B/80% solvent A to 100% solvent B over 10 min to give the title compound (7.8 mg) as a TFA salt as a white solid. LC/MS Condition MD-1: [M+H].sup.+ 685, R.sub.t=3.31 min; .sup.1H NMR (400 MHZ, CD.sub.3OD) δ 8.00 (s, 2H), 7.89 (s, 8H), 5.45 (d, J=7.7 Hz, 2H), 4.79 (d, J=7.7 Hz, 2H), 3.22-3.14 (m, 2H), 3.12-3.06 (m, 2H), 1.89 (m, 2H), 1.67 (s, 6H), 1.61 (s, 6H), 0.98-0.93 (m, 12H).

(53) Analytical HPLC MD-A: R.sub.t=25.18 min, λ=220 nm

(54) Analytical HPLC MD-B: R.sub.t=25.07 min, λ=220 nm

(55) Analytical HPLC MD-C: R.sub.t=10.66 min, λ=254 nm

(56) Analytical HPLC MD-D: R.sub.t=11.83 min, λ=254 nm

EXAMPLE MD8

(57) ##STR00029##

EXAMPLE MD-8

Step a

(58) ##STR00030##

(59) To a suspension of (4R,5R)-5-(methoxycarbonyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (BMCL, 2003, vol. 13, #10 p. 1713-1716) (610 mg, 2.99 mmol), methyl 2-isopropylhydrazinecarboxylate (375.5 mg, 2.84 mmol), and HOAT (62 mg, 3.19 mmol) in anhydrous dichloromethane (5 mL) was added EDC (612 mg, 3.19 mmol), followed immediately by DIEA (600 μl, 1.209 mmol). The reaction was flushed briefly with N2, capped and stirred at room temp for 18 h. The reaction was diluted with dichloromethane (50 mL) and the organic layer was washed with aq. saturated NaHCO.sub.3 (1×50 mL), water (1×25 mL), brine (1×50 mL), dried over Na.sub.2SO4, filtered and the solvent removed in vacuo. The crude product was dissolved in dichloromethane (10 mL) and purified by flash column chromatography (120 g Teledyne Isco Silica Flash Column, 100% dichloromethane to 80% ethyl acetate/dichloromethane over 10 column volumes) to afford the title compound (320 mg) as a white solid. LC/MS Condition MD-1: [M+H].sup.+ 319, R.sub.t=2.71 min; LC/MS Condition MD-2: [M+H].sup.+ 319; [M−H].sup.− 317, R.sub.t=2.09 min; .sup.1H NMR (500 MHZ, CDCl.sub.3) δ 5.30-5.20 (m, 1H), 5.02-4.67 (m, 2H), 3.87-3.76 (m, 6H), 1.55-1.41 (m, 6H), 1.29-1.10 (m, 6H).

EXAMPLE MD-8

Step b

(60) ##STR00031##

(61) To a solution of material from MD-8, step a (315 mg, 0.990 mmol) in a mixture of dioxane (5 mL) and water (3 mL) was added sodium hydroxide (47.4 mg, 2.06 mmol) slowly over 30 min. The reaction was stirred at room temp for 1 h, cooled briefly in a −20° C. freezer and quenched with 1.0 N HCl (1.4 mL). The reaction was diluted with dichloromethane (80 mL) and water (4 mL), the organic layer was separated, dried over Na.sub.2SO.sub.4/MgSO.sub.4, filtered and the solvent removed in vacuo to give the title compound (255 mg) as a white solid. LC/MS Condition MD-1: [M+Na].sup.+327, R.sub.t=2.38 min.

EXAMPLE MD-8

Step c

(62) ##STR00032##

(63) To a suspension of 1,1′-([1,1′-biphenyl]-4,4′-diyl)bis(2-bromoethanone) (130 mg, 0.328 mmol) and material from MD-8, step b (250 mg, 0.822 mmol) in anhydrous ACN (15 mL) at 0° C. was slowly added DIEA (200 μL, 1.145 mmol). The reaction was flushed well with N.sub.2, securely capped and allowed to stir for 18 h while slowly warming to room temp. The reaction was diluted with dichloromethane (10 mL), cooled to −20° C. for 1 h and the white precipitate was filtered off to give the title compound (184 mg) as a white solid. LC/MS Condition MD-1: [M+Na].sup.+865, R.sub.t=3.708 min.

EXAMPLE MD-8

(64) To a dry 5-10 mL microwave vial under N.sub.2 was added material from MD-8, step c (82 mg, 0.097 mmol), ammonium acetate (280 mg, 3.63 mmol), imidazole (40 mg, 0.588 mmol) and anhydrous toluene (3.5 mL). The resulting suspension was flushed well with N.sub.2, securely capped, stirred at room temp for 5 min, then heated to 100° C. for 3.5 h, and then stirred at room temp for 18 h. The resulting crude solid was washed with toluene (3×2 mL), the solvent removed under a gentle stream of N.sub.2 and the resulting crude solid was purified by reverse phase preparative HPLC conditions MD-1 using a gradient from 20% solvent B/80% solvent A to 100% solvent B over 11 min to give the title compound (10.8 mg) as a TFA salt as a white solid. LC/MS Condition MD-1: [M+H].sup.+803, R.sub.t=3.32 min. .sup.1H NMR (500 MHZ, CD.sub.3OD) δ 7.97 (s, 2H), 7.89 (s, 8H), 5.84 (d, J=6.7 Hz, 2H), 4.96 (d, J=6.7 Hz, 2H), 4.73 (m, 2H), 3.64 (s, 6H), 1.61 (s, 6H), 1.56 (s, 6H), 1.17 (d, J=6.7 Hz, 6H), 1.12 (d, J=6.7 Hz, 6H)

(65) Analytical HPLC MD-A: R.sub.t=23.35 min, λ=220 nm

(66) Analytical HPLC MD-B: R.sub.t=23.79 min, λ=220 nm

(67) Analytical HPLC MD-C: R.sub.t=9.31 min, λ=254 nm

(68) Analytical HPLC MD-D: R.sub.t=10.05 min, λ=254 nm

EXAMPLE MD-9

(69) ##STR00033##

(70) To a 48 mL pressure bottle under N.sub.2 was added material from MD-7, step a (226 mg, 0.352 mmol), ammonium acetate (850 mg, 11.03 mmol) and anhydrous toluene (8 mL). The reaction was flushed with N.sub.2, securely capped and heated at 110° C. for 18 h. The supernatant was removed and the resulting crude solid was via preparative LC/MS with the following conditions: Column: XBridge C18, 19×mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 30-80% B over 25 min, then a 5-min hold at 100% B; Flow: 20 mL/min to give the title compound (13.1 mg). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) δ 7.86 (br. s., 3H), 7.71 (br. s., 5H), 7.57-7.41 (m, 4H), 5.13 (d, J=7.3 Hz, 2H), 4.87 (br. s., 2H), 2.55 (s, 4H), 1.47 (br. s., 12H).

EXAMPLE MD-10

(71) ##STR00034##

(72) Also isolated from the reaction described in Example MD-9 was the compound shown above (7.4 mg). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) δ 7.84 (d, J=7.7 Hz, 4H), 7.71 (d, J=7.7 Hz, 4H), 7.62 (s, 1H), 7.54 (br. s., 1H), 7.47 (br. s., 1H), 5.13 (d, J=7.0 Hz, 1H), 5.12-5.10 (d, J=7.3 Hz, 1H), 4.89 (d, J=7.0 Hz, 1H), 4.81 (d, J=7.3 Hz, 1H), 2.55 (s, 2H), 2.51 (br. s., 2H), 1.47 (br. s., 6H), 1.43 (d, 6H).

EXAMPLE MD-11

(73) ##STR00035##

EXAMPLE MD-11

Step a

(74) ##STR00036##

(75) To an ice-cold suspension of 1,1′-([1,1′-biphenyl]-4,4′-diyl)bis(2-bromoethanone) (1.2 g, 3.03 mmol), (R)-4-(tert-butoxy)-2-methyl-4-oxobutanoic acid (prepared according to the procedure described in J. Org. Chem., V. 64 (1999), issue 17, p. 6411-6417) (1.72 g, 9.14 mmol) in anhydrous acetonitrile (30 mL) was slowly added DIEA (1.6 mL, 9.16 mmol). The reaction was flushed well with N.sub.2, securely capped and allowed to stir for 18 h while slowly warming to room temp. The solvent was removed in vacuo and the crude product was purified by flash column chromatography (120 g Teledyne Isco Silica Flash Column, 100% hexanes to 100% ethyl acetate over 11 column volumes) to afford the title compound (980 mg) as a white solid. LC/MS Condition MD-1: [M+Na].sup.+633, R.sub.t=4.42 min; .sup.1H NMR (400 MHZ, CDCl.sub.3) δ 8.03 (d, J=8.3 Hz, 4H), 7.75 (d, J=8.5 Hz, 4H), 5.57-5.39 (m, 2H), 5.37-5.25 (m, 2H), 3.19-2.98 (m, 2H), 2.79 (dd, J=16.4, 7.7 Hz, 2H), 2.43 (dd, J=16.3, 6.5 Hz, 2H), 1.51-1.45 (m, 18H), 1.35 (d, J=7.3 Hz, 6H).

EXAMPLE MD-11

Step b

(76) ##STR00037##

(77) To a dry 48 mL pressure bottle under N.sub.2 was added material from MD-11, step a (807 mg, 1.321 mmol), ammonium acetate (3.06 g, 39.7 mmol), imidazole (540 mg, 7.93 mmol) and anhydrous toluene (20 mL). The reaction was flushed well with N.sub.2, securely capped and stirred at room temp for 5 min, then heated at 110° C. oil for 18 h. Evaporate off the solvent under a gentle stream of N.sub.2 while warming to 60° C. for 7 h. The residue was dissolved in a mixture of ethyl acetate (425 mL) and water (50 mL) and the organic layer was extracted with water (5×50 mL), brine (1×50 mL), dried over Na.sub.2SO.sub.4, filtered and the solvent removed in vacuo. The crude product was purified by flash column chromatography (24 g Teledyne Isco Silica Flash Column (equilibrated with 1% triethylamine in dichloromethane), 100% dichloromethane to 100% ethyl acetate over 10 column volumes) to afford the title compound (448 mg) as a yellow solid. LC/MS Condition MD-1: [M+H].sup.+ 571, R.sub.t=3.15 min. .sup.1H NMR (500 MHZ, CDCl.sub.3) δ 10.15 (br. s., 1H), 9.91-9.71 (m, 1H), 7.85 (d, J=6.4 Hz, 3H), 7.72-7.45 (m, 6H), 7.25 (br. s., 1H), 3.55-3.34 (m, 2H), 2.82-2.61 (m, 4H), 1.55-1.41 (m, 24H).

EXAMPLE MD-11

Step c

(78) ##STR00038##

(79) To a rapidly swirled solution of material from MD-11, step b (141.6 mg, 0.248 mmol) in anhydrous dichloromethane (5 mL) was added TFA (8 mL, 104 mmol). The resulting red/orange solution was allowed to stand at room temp for 90 min, and then the volatiles were removed under a gentle stream of N.sub.2. The residue was suspended in dichloromethane (20 mL) and the solvent was removed under a gentle stream of N.sub.2. The residue was suspended in toluene (25 mL), sonicated briefly and the solvent was removed in vacuo to give the title compound (182.7 mg) as a tan solid as a TFA salt. LC/MS Condition MD-1: [M+H].sup.+ 4591, R.sub.t=2.35 min; .sup.1H NMR (500 MHZ, DMSO-d.sub.6) δ 8.17 (s, 2H), 8.03-7.87 (m, 8H), 3.71-3.53 (m, 2H), 2.95 (dd, J=17.1, 8.4 Hz, 2H), 2.87-2.77 (m, 2H), 1.41 (d, J=7.0 Hz, 6H).

EXAMPLE MD-11

(80) To a suspension of material from MD-11, step c (15 mg, 0.022 mmol) in anhydrous DMF (600 μL) was added isobutylamine (25 μL, 0.250 mmol), DIEA (40 μL, 0.229 mmol) and HATU (85 mg, 0.224 mmol). The resulting solution was flushed well with N.sub.2, securely capped and stirred at room temp for 80 min. The reaction was diluted with DMF (1.4 mL), filtered thru a 45μ frit, and purified by reverse phase preparative HPLC conditions MD-1 using a gradient from 20% solvent B/80% solvent A to 100% solvent B over 10 min to give the title compound (8.5 mg) as a TFA salt as a white solid. LC/MS Condition MD-1: [M+H].sup.+ 569, R.sub.t=3.02 min. .sup.1H NMR (500 MHZ, CD.sub.3OD) δ 7.94-7.78 (m, 10H), 3.77-3.65 (m, 2H), 3.07-2.94 (m, 4H), 2.88-2.77 (m, 4H), 1.76 (dt, J=13.5, 6.8 Hz, 2H), 1.52 (d, J=7.2 Hz, 6H), 0.90 (dd, J=6.7, 1.8 Hz, 12H).

EXAMPLE MD-12

(81) ##STR00039##

EXAMPLE MD-12

Step a

(82) ##STR00040##

(83) To a rapidly swirled solution of material from MD-11, step a (103 mg, 0.169 mmol) in anhydrous dichloromethane (4 mL) was added TFA (5.5 mL, 71.4 mmol). The resulting clear, colorless solution was allowed to stand at room temp for 1 h, and then the solvent was removed in vacuo. The residue was dissolved in dichloromethane and the solvent was removed in vacuo. The residue was dissolved in toluene and the solvent was removed in vacuo to give the title compound (84.7 mg) as a white solid. LC/MS Condition MD-1: [M+Na].sup.+ 521, R.sub.t=3.43 min.

EXAMPLE MD-12

Step b

(84) ##STR00041##

(85) To a dichloromethane (2 mL) solution of material from MD-12, step a (84.7 mg, 0.170 mmol), methyl 2-isopropylhydrazinecarboxylate (60 mg, 0.454 mmol), and HOAT (10 mg, 0.073 mmol) was added EDC (51 mg, 0.266 mmol) and DIEA (150 μL, 0.037 mmol). The reaction was flushed with N.sub.2, securely capped and allowed to stir at room temp for 18 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography (24 g Teledyne Isco Silica Flash Column, 100% dichloromethane to 100% ethyl acetate over 11 column volumes) to afford the title compound (136.5 mg) as a colorless film. LC/MS Condition MD-1: [M+H].sup.+ 727, R.sub.t=3.85 min.

EXAMPLE MD-12

(86) To a dry 10-20 mL microwave vial under N.sub.2 was added material from MD-12, step b (136.5 mg, 0.188 mmol), ammonium acetate (455 mg, 5.90 mmol), imidazole (83 mg, 1.219 mmol) and anhydrous toluene (3.0 mL). The reaction was flushed with N.sub.2, securely capped and placed in a 110° C. oil bath for 18 h. The crude reaction was purified by reverse phase preparative HPLC conditions MD-1 using a gradient from 25% solvent B/75% solvent A to 100% solvent B over 10 min to give the impure title compound (15.3 mg) as a TFA salt as a pale yellow solid. LC/MS Condition MD-1: [M+H].sup.+ 687, R.sub.t=2.83 min.

(87) The impure title compound was then further purified by via preparative LC/MS with the following conditions: Column: XBridge C18, 19×mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 5-min hold at 100% B; Flow: 20 mL/min to give the pure title compound (3.1 mg) as a white film. .sup.1H NMR (500 MHZ, CD.sub.3OD) δ 7.89-7.56 (m, 8H), 7.32 (d, J=8.2 Hz, 2H), 4.80-4.61 (m, 2H), 3.80 (d, J=19.8 Hz, 6H), 3.54 (dt, J=14.0, 6.8 Hz, 2H), 3.00 (dd, J=16.3, 7.9 Hz, 1H), 2.88 (dd, J=16.4, 8.3 Hz, 1H), 2.67 (dd, J=16.4, 5.9 Hz, 1H), 2.54 (dd, J=16.2, 6.7 Hz, 1H), 1.38 (d, J=7.0 Hz, 6H), 1.19-0.96 (m, 12H).

EXAMPLE MD-13

(88) ##STR00042##

(89) To a dry vial under N.sub.2 was added material from MD-11, step c (25 mg, 0.036 mmol), 4,4-difluoropiperidine, 1.00 HCl (50 mg, 0.317 mmol), HOAT (15 mg, 0.110 mmol), anhydrous dichloromethane (2.5 mL), EDC (50 mg, 0.261 mmol), and DIEA (105 μL, 0.601 mmol). The reaction was flushed briefly with N.sub.2, capped, stirred at room temp for 80 min, and then treated with DMAP (19 mg, 0.156 mmol) and allowed to stir at room temp for 70 h. The reaction was then treated with additional EDC (56 mg, 0.292 mmol) and DIEA (105 μL, 0.601 mmol), flushed with N.sub.2 and allowed to stir at room temp for 24 h. The solvent was removed under a gentle stream of N.sub.2 and the residue was diluted with DMF (1.4 mL), filtered thru a 45μ frit, and purified by reverse phase preparative HPLC conditions MD-1 using a gradient from 20% solvent B/80% solvent A to 100% solvent B over 11 min to give the impure TFA salt of the title compound (18 mg) as a colorless film. LC/MS Condition MD-1: [M+H].sup.+ 665, R.sub.t=3.03 min.

(90) The impure title compound was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 7-min hold at 100% B; Flow: 20 mL/min. to give the pure title compound (6.0 mg). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) δ 12.13 (br. s., 1H), 11.86 (br. s., 1H), 8.00-7.40 (m, 10H), 3.62 (d, J=7.3 Hz, 10H), 2.99 (dd, J=15.1, 6.9 Hz, 2H), 2.62 (dd, J=15.4, 6.9 Hz, 2H), 2.09-1.81 (m, 8H), 1.29 (d, J=6.7 Hz, 6H).

EXAMPLE MD-14

(91) ##STR00043##

EXAMPLE MD-14

Step a

(92) ##STR00044##

(93) To a solution of (4R,5R)-5-(ethoxycarbonyl)-1,3-dioxolane-4-carboxylic acid (prepared according to the procedure described in BOMCL, 2002, vol. 10, #5, 1567-1580) (200 mg, 1.052 mmol), 2-methylpropan-1-amine (100 mg, 1.367 mmol), HOAT (40 mg, 0.294 mmol) in dichloromethane (8 mL) was added EDC (250 mg, 1.304 mmol) and DIEA (220 μL, 1.260 mmol). The reaction was flushed with N.sub.2, securely capped and stirred at room temp for 18 h. The reaction was washed once with water, once with brine, dried over Na.sub.2SO.sub.4, filtered and the solvent was removed in vacuo to give the title compound (240 mg) as colorless oil. LC/MS Condition MD-1: [M+H].sup.+ 246, R.sub.t=2.99 min.

EXAMPLE MD-14

Step b

(94) ##STR00045##

(95) To a solution of material from MD-14, step a (240 mg, 0.979 mmol) in a mixture of dioxane (5 mL) and water (3 mL) was slowly added sodium hydroxide (45 mg, 1.125 mmol). The reaction was stirred at room temp for 80 min, cooled to −20° C. and quenched with aq. 1N HCl (1.5 mL, 1.50 mmol). The reaction was diluted with dichloromethane (80 mL) and the organic layer was washed with water (3 mL). The water layer was back extracted with additional dichloromethane (30 mL), the organic layers were combined, dried over Na.sub.2SO.sub.4/MgSO.sub.4, filtered and the solvent was removed in vacuo to give the title compound (152 mg) as a white solid. LC/MS Condition MD-1: [M+H].sup.+ 218, R.sub.t=2.33 min. .sup.1H NMR (500 MHZ, CDCl.sub.3) δ 6.84 (br. s., 1H), 5.26 (s, 1H), 5.24 (s, 1H), 4.62 (d, J=6.7 Hz, 1H), 4.56 (d, J=6.7 Hz, 1H), 3.26-3.16 (m, 2H), 1.87 (m, 1H), 0.97 (d, J=6.7 Hz, 6H).

EXAMPLE MD-14

Step c

(96) ##STR00046##

(97) To an ice cold suspension of 1,1′-([1,1′-biphenyl]-4,4′-diyl)bis(2-bromoethanone) (125 mg, 0.316 mmol), material from MD-14, step b (152 mg, 0.700 mmol) in anhydrous acetonitrile (7 mL) was slowly added DIEA (180 μL, 1.031 mmol). The reaction was flushed well with N.sub.2, securely capped and allowed to stir for 60 h while slowly warming to room temp. The solvent was removed in vacuo and the crude product was purified by flash column chromatography (40 g Teledyne Isco Silica Flash Column, 100% dichloromethane to 100% ethyl acetate over 9 column volumes) to afford the title compound (173 mg) as a white solid. LC/MS Condition MD-1: [M+H].sup.+ 669, R.sub.t=3.72 min; .sup.1H NMR (500 MHZ, CDCl.sub.3) δ 8.03 (d, J=8.4 Hz, 4H), 7.77 (d, J=8.4 Hz, 4H), 6.68 (t, J=5.9 Hz, 2H), 5.66 (d, J=16.3 Hz, 2H), 5.43 (d, J=16.3 Hz, 2H), 5.35 (s, 2H), 5.31 (s, 2H), 5.08 (d, J=3.5 Hz, 2H), 5.02 (d, J=3.5 Hz, 2H), 3.18 (m, 4H), 1.84 (m, 2H), 0.96 (d, J=6.7 Hz, 12H).

EXAMPLE MD-14

(98) To a 48 mL pressure bottle under N.sub.2 was added material from MD-14, step c (88 mg, 0.132 mmol), ammonium acetate (350 mg, 4.54 mmol), imidazole (50.8 mg, 0.746 mmol) and anhydrous toluene (4 mL). The reaction was flushed well with N.sub.2, securely capped and heated at 110° C. for 10 h. The solvent was removed in vacuo and the crude product was purified by reverse phase preparative HPLC conditions MD-1 using a gradient from 30% solvent B/70% solvent A to 100% solvent B over 11 min to give the TFA salt of the title compound (6.9 mg) as a white solid. LC/MS Condition MD-1: [M+H].sup.+ 629, R.sub.t=3.14 min. .sup.1H NMR (500 MHZ, CD.sub.3OD) δ 7.95 (s, 2H), 7.89 (m, 8H), 5.54 (d, J=4.9 Hz, 2H), 5.50 (s, 2H), 5.25 (s, 2H), 4.89 (d, J=4.9 Hz, 2H), 3.14 (d, J=7.0 Hz, 4H), 2.67 (s, 2H), 1.94-1.86 (m, 2H), 0.96 (d, J=6.7 Hz, 12H). Analytical HPLC MD-A: R.sub.t=23.22 min, λ=220 nm

(99) Analytical HPLC MD-B: R.sub.t=23.62 min, λ=220 nm.

(100) Analytical HPLC MD-C: R.sub.t=8.49 min, λ=254 nm

(101) Analytical HPLC MD-D: R.sub.t=9.42 min, λ=254 nm

EXAMPLE MD-15

(102) ##STR00047##

EXAMPLE MD-15

Step a

(103) ##STR00048##

(104) To an ice cold suspension of 1,1′-([1,1′-biphenyl]-4,4′-diyl)bis(2-bromoethanone) (870 mg, 2.197 mmol), (4R,5R)-5-(ethoxycarbonyl)-1,3-dioxolane-4-carboxylic acid (prepared according to the procedure described in BOMC, 2002, vol. 10, No.#5, 1567-1580) (1.25 g, 6.57 mmol) in anhydrous acetonitrile (25 mL) was slowly added DIEA (1.3 mL, 7.44 mmol). The reaction was flushed well with N.sub.2, securely capped and allowed to stir for 18 h while slowly warming to room temp. The solvent was removed in vacuo and the crude product was purified by flash column chromatography (80 g Teledyne Isco Silica Flash Column, 100% hexanes to 70% ethyl acetate/hexanes over 11 column volumes) to afford the title compound (865 mg) as a white solid. LC/MS Condition MD-1: [M+Na].sup.+ 637, R.sub.t=3.65 min .sup.1H NMR (500 MHZ, CDCl.sub.3) δ 8.04 (d, J=8.5 Hz, 4H), 7.78 (d, J=8.5 Hz, 4H), 5.62 (d, J=16.3 Hz, 2H), 5.46 (d, J=16.3 Hz, 2H), 5.37 (s, 2H), 5.35 (s, 2H), 5.11 (d, J=3.4 Hz, 2H), 5.00 (d, J=3.4 Hz, 2H), 4.33 (q, J=7.2 Hz, 4H), 1.37 (t, J=7.2 Hz, 6H).

EXAMPLE MD-15

(105) To a dry 10-20 mL microwave vial under N.sub.2 was added material from Example MD-15, step a (100 mg, 0.163 mmol), ammonium acetate (365 mg, 4.74 mmol) and anhydrous toluene (4 mL). The reaction was flushed well with N.sub.2, securely capped and heated at 60° C. for 18 h. The reaction was heated further at 80° C. for 3 h, then 90° C. for 2.5 h. The solvent was removed under a gentle stream of N.sub.2 and the crude product was purified by reverse phase preparative HPLC conditions MD-1 using a gradient from 20% solvent B/80% solvent A to 100% solvent B over 11 min to give the TFA salt of the impure title compound (18 mg) as an off-white solid. The impure title compound was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over 20 min, then a 5-min hold at 100% B; Flow: 20 mL/min to give the pure title compound (5.4 mg). LC/MS Condition MD-1: [M+H].sup.+ 575, R.sub.t=2.76 min; .sup.1H NMR (500 MHZ, DMSO-d.sub.6) δ 12.86 (br. s., 1H), 12.53 (br. s., 1H), 8.09-7.56 (m, 10H), 5.33-5.02 (m, 8H), 4.21 (d, J=7.0 Hz, 4H), 1.23 (t, J=7.0 Hz, 6H).

EXAMPLE MD-16

(106) ##STR00049##

(107) To a dry 10-20 mL microwave vial under N.sub.2 was added material from Example MD-15, step a (100 mg, 0.163 mmol), ammonium acetate (330 mg, 4.74 mmol) and anhydrous toluene (4 mL). The reaction was flushed well with N.sub.2, securely capped, stirred at room temp for 10 min, and then placed in a 110° C. oil bath for 4.5 h. The reaction was partitioned between EtOAc and aq. satd. NaHCO.sub.3, organic layer was removed and evaporated to dryness. LC/MS Condition MD-2: [M+H].sup.+ 575, [M−H].sup.− 573; R.sub.t=2.58 min.

(108) The resulting residue was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 30-70% B over 20 min, then a 5-min hold at 100% B; Flow: 20 mL/min to give the title compound (1.0 mg); .sup.1H NMR (500 MHZ, DMSO-d.sub.6) δ 12.86 (br. s., 1H), 12.53 (br. s., 1H), 8.09-7.56 (m, 10H), 5.33-5.02 (m, 8H), 4.21 (d, J=7.0 Hz, 4H), 1.23 (t, J=7.0 Hz, 6H).

EXAMPLE MD-17

(109) ##STR00050##

EXAMPLE MD-17

Step a

(110) ##STR00051##

(111) To a solution of (4R,5R)-5-(ethoxycarbonyl)-1,3-dioxolane-4-carboxylic acid (prepared according to the procedure described in BOMC, 2002, vol. 10, No. 5, 1567-1580) (490 mg, 2.58 mmol), methyl 2-isopropylhydrazinecarboxylate (388 mg, 1.139 mmol), HOAT (80 mg, 0.588 mmol) in dichloromethane (6 mL) was added EDC (600 mg, 3.13 mmol) and DIEA (600 μL, 3.44 mmol). The reaction was flushed with N.sub.2, securely capped and stirred at room temp for 18 h. The solvent was evaporated off under a gentle stream of N2 and the crude product was purified by flash column chromatography (120 g Teledyne Isco Silica Flash Column, 100% dichloromethane to 80% ethyl acetate/hexanes over 11 column volumes) to afford the title compound (60 mg) as a white solid. LC/MS Condition MD-1: [M+Na].sup.+327, R.sub.t=2.54 min.

EXAMPLE MD-17

Step b

(112) ##STR00052##

(113) To a solution of material from MD-17, step a (60 mg, 0.197 mmol) in a mixture of dioxane (3 mL) and water (1 mL) was added sodium hydroxide (11 mg, 0.275 mmol). The reaction was securely capped, stirred at room temp for 1 h, cooled to −20° C. and quenched with 1 N HCl (400 μL). The reaction was diluted with dichloromethane (70 mL) and water (3 mL), the organic layer was removed, dried over Na.sub.2SO.sub.4/MgSO.sub.4, filtered and the solvent was removed in vacuo to give the title compound (52 mg) as a colorless solid. LC/MS Condition MD-1: [M+H].sup.+ 277, [M+Na].sup.+299; R.sub.t=1.96 min.

EXAMPLE MD-17

Step c

(114) ##STR00053##

(115) To an ice cold suspension of 1,1′-([1,1′-biphenyl]-4,4′-diyl)bis(2-bromoethanone) (37 mg, 0.093 mmol), material from MD-17, step b (52 mg, 0.188 mmol) in anhydrous acetonitrile (3 mL) was slowly added DIEA (60 μL, 0.344 mmol). The reaction was flushed well with N.sub.2, securely capped and allowed to stir for 18 h while slowly warming to room temp. The solvent was removed in vacuo and the crude product was purified by flash column chromatography (12 g Teledyne Isco Silica Flash Column, 100% hexanes to 70% ethyl acetate/hexanes over 10 column volumes) to afford the title compound (35 mg) as a white solid. LC/MS Condition MD-1: [M+H].sup.+ 787, [M+Na].sup.+809; R.sub.t=3.42 min.

EXAMPLE MD-17

(116) To 15 ml, pressure bottle under N.sub.2 was added material from MD-17, step c (35 mg, 0.044 mmol), ammonium acetate (115 mg, 1.492 mmol) and anhydrous toluene (4 mL). The reaction was flushed with N.sub.2 and immediately put in a 79° C. oil bath which was ramping up to 101° C. The reaction was heated at 101° C. for 5 h. The solvent was removed under a gentle stream of N.sub.2 and the crude product was purified by reverse phase preparative HPLC conditions MD-1 using a gradient from 30% solvent B/70% solvent A to 100% solvent B over 11 min to give the TFA salt of the title compound (7.0 mg) as a white solid. LC/MS Condition MD-1: [M+H].sup.+ 747, R.sub.t=2.94 min; .sup.1H NMR (500 MHZ, CD.sub.3OD) δ 8.03-7.76 (m, 10H), 5.77-5.08 (m, 8H), 4.77-4.66 (m, 2H), 3.81-3.53 (m, 6H), 1.29-1.07 (m, 12H).

(117) Analytical HPLC MD-A: R.sub.t=20.63 min, λ=220 nm

(118) Analytical HPLC MD-B: R.sub.t=21.73 min, λ=220 nm

(119) Analytical HPLC MD-C: R.sub.1=7.04 min, λ=254 nm

(120) Analytical HPLC MD-D: R.sub.t=7.50 min, λ=254 nm

EXAMPLE MD-18

(121) ##STR00054##

EXAMPLE MD-18

Step a

(122) ##STR00055##

(123) To an ice cold suspension of 1,1′-([1,1′-biphenyl]-4,4′-diyl)bis(2-bromoethanone) (750 mg, 1.894 mmol), (S)-4-(tert-butoxy)-2-isopropyl-4-oxobutanoic acid (prepared according to the procedure described in J. Org. Chem, 1999, 64, 6411-6417) (859 mg, 3.97 mmol) in anhydrous acetonitrile (20 mL) was slowly added DIEA (1.1 mL, 6.30 mmol). The reaction was flushed well with N.sub.2, securely capped and allowed to stir for 18 h while slowly warming to room temp. The solvent was removed in vacuo and the crude product was purified by flash column chromatography (80 g Teledyne Isco Silica Flash Column, 100% hexanes to 60% ethyl acetate/hexanes over 10 column volumes) to afford the title compound (1.23 g) as a white solid. LC/MS Condition MD-1: [M+Na].sup.+666; R.sub.t=4.76 min; .sup.1H NMR (500 MHZ, CDCl.sub.3) δ 8.04 (d, J=8.4 Hz, 4H), 7.75 (d, J=8.5 Hz, 4H), 5.51 (d, J=16.2 Hz, 2H), 5.30 (d, J=16.3 Hz, 2H), 2.94-2.87 (m, 2H), 2.75 (dd, J=16.6, 10.5 Hz, 2H), 2.43 (dd, J=16.6, 4.1 Hz, 2H), 2.24-2.14 (m, 2H), 1.47 (s, 18H), 1.08/1.06 (two overlapping doublets, J=6.8, 7.0 Hz, 12H).

EXAMPLE MD-18

Step b

(124) ##STR00056##

(125) To 15 mL pressure bottle under N.sub.2 was added material from MD-18, step a (232 mg, 0.348 mmol), ammonium acetate (812 mg, 10.53 mmol), imidazole (141 mg, 2.071 mmol) and anhydrous toluene (5.5 mL). The reaction was flushed with N.sub.2 and immediately put in a 78° C. oil bath which was programmed for 120° C. The reaction was heated at 120° C. for 18 h. The solvent was removed under a gentle stream of N.sub.2 and the crude product was purified by flash column chromatography (24 g Teledyne Isco Silica Flash Column, 100% dichloromethane to 100% ethyl acetate over 12 column volumes) to afford the title compound (80.2 mg) as a yellow solid. LC/MS Condition MD-1: [M+H].sup.+ 627; R.sub.t=3.42 min; .sup.1H NMR (500 MHZ, CD.sub.3OD) δ 7.89-7.63 (m, 8H), 7.34 (br. s., 2H), 3.07 (ddd, J=10.3, 7.8, 5.5 Hz, 2H), 2.87-2.69 (m, 4H), 2.61-2.46 (m, 2H), 1.99 (dd, J=14.2, 6.9 Hz, 2H), 1.32 (s, 18H), 1.04 (d, J=6.7 Hz, 6H), 0.88 (d, J=6.9 Hz, 6H).

EXAMPLE MD-18

Step c

(126) ##STR00057##

(127) To a solution of material from MD-18, step b (80.2 mg, 0.128 mmol) in anhydrous dichloromethane (5 mL) was added TFA (8 mL) with vigorous swirling. The resulting solution was allowed to stand at room temp for 70 min, then the volatiles were removed under a gentle stream of N.sub.2 to give the title compound (134.8 mg) as a TFA salt as a yellow film. LC/MS Condition MD-1: [M+H].sup.+ 515; R.sub.t=2.97 min.

EXAMPLE MD-18

Step d

(128) ##STR00058##

(129) Regiochemistry of cyclization onto the imidazole was not determined

(130) To a suspension of material from MD-18, step c (460 mg, 0.537 mmol) in dichloromethane (14 mL) was added DIEA (540 μL, 3.09 mmol), followed immediately by HATU (877 mg, 2.306 mmol). The resulting suspension was flushed briefly with N2, capped, sonicated briefly and stirred at room temp for 1.5 h. The reaction was filtered thru a 45μ frit and purified by flash column chromatography (80 g Teledyne Isco Silica Flash Column, 100% dichloromethane to 50% dichloromethane:50% ethyl acetate over 5 column volumes) to afford the title compound (170 mg) as a pale yellow solid. LC/MS Condition MD-1: [M+H].sup.+ 479; R.sub.t=4.23 min; .sup.1H NMR (400 MHZ, CDCl.sub.3) δ 7.97-7.88 (m, 4H), 7.78-7.66 (m, 4H), 7.55 (s, 2H), 3.39 (ddd, J=8.2, 5.3, 3.1 Hz, 2H), 3.29-3.19 (m, 2H), 2.92 (dd, J=18.6, 3.3 Hz, 2H), 2.38-2.24 (m, 2H), 1.13 (d, J=6.8 Hz, 6H), 1.03 (d, J=6.8 Hz, 6H).

EXAMPLE MD-18

(131) A dry 0.5-2.0 mL microwave vial under N.sub.2 was charged with material from MD-18, step d (20.2 mg, 0.042 mmol), pivalic acid (44 μL, 0.378 mmol), 2,2-dimethylpropan-1-amine (29.2 mg, 0.355 mmol) and anhydrous NMP (700 μL). The reaction was flushed briefly with N.sub.2, securely capped and placed in a 75° C. sand bath for 10 min. The reaction was then heated in a microwave heating unit for 1 min. at 110° C. under high power. LC/MS Condition MD-1: [M+H].sup.+ 653; R.sub.t=3.52 min. The reaction was diluted with DMF (700 μL) and purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-100% B over 15 min, then a 10-min hold at 100% B; Flow: 20 mL/min. to give the title compound (22.8 mg). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) δ 12.32-11.66 (m, 2H), 7.98-7.57 (m, 10H), 7.49 (br. s., 2H), 3.21-3.09 (m, 2H), 2.88 (dd, J=13.4, 6.7 Hz, 2H), 2.82-2.67 (m, 4H), 2.56 (br. s., 2H), 2.00-1.88 (m, 2H), 0.87 (dd, J=14.2, 6.6 Hz, 12H), 0.74 (s, 18H).

EXAMPLE MD-19

(132) ##STR00059##

(133) To a solution material from Example MD-18, step d (24 mg, 0.050 mmol) and pivalic acid (52 μL, 0.450 mmol) in anhydrous NMP (600 μL) is added (2-chlorophenyl)methanamine (54 mg, 0.381 mmol). The reaction is flushed briefly with argon, securely capped and heated to 85° C. for 3.25 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-80% B over 15 min, then a 5-min hold at 100% B; Flow: 20 mL/min to give the pure title compound (28 mg). LC/MS Condition MD-2: [M+H].sup.+ 761, 763, [M−H].sup.− 759, 761; R.sub.t=3.62 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.12 (br. s., 1H), 11.82 (br. s., 1H), 8.45 (t, J=5.8 Hz, 2H), 7.84 (d, J=8.3 Hz, 3H), 7.78-7.56 (m, 5H), 7.50 (s, 1H), 7.41-7.24 (m, 2H), 7.19-6.98 (m, 2H), 6.96-6.77 (m, 3H), 4.46-4.21 (m, 2H), 4.06 (dd, J=16.7, 4.9 Hz, 2H), 3.21-3.00 (m, 2H), 2.93-2.69 (m, 2H), 2.55 (dd, J=14.7, 4.9 Hz, 2H), 2.02-1.78 (m, 2H), 0.87/0.83 (two overlapping doublets, J=6.8, 6.8 Hz, 12H).

EXAMPLE MD-20 to MD-32

(134) Example MD-20 to MD-32 are prepared using the general procedure as outlined in Example MD-19. In the Examples below, all LC/MS data were obtained under LC/MS Condition MD-2.

(135) TABLE-US-00002 0 Obs. Obs. Mass Mass ion Example R RT (min) ion (M + H).sup.+ (M − H).sup.− MD-20 2.81 737.8 735.9 MD-21 4.2 785.8 783.9 MD-22 4.03 809.7 807.8 MD-23 4.05 857.8 855.8 MD-24 2.96 767.7 765.7 MD-25 2.85 767.8 — MD-26 3.7 709.8 707.9 MD-27 3.18 879.7 877.8 MD-28 3.89 901.7 899.8 MD-29 0 2.93 831.6 829.7 MD-30 2.7 711.6 709.7 MD-31 2.81 643.5 641.6 MD-32 3.97 865.6 863.8

EXAMPLE MD-33

(136) ##STR00074##

(137) To a solution of Example MD-19, step a (17.0 mg, 0.036 mmol) and pivalic acid (36.4 μL, 0.313 mmol) in anhydrous NMP is added 1-aminocyclopropanecarbonitrile/1.0 HCl (35 mg, 0.295 mmol), followed by DIEA (52 μL, 0.298 mmol). The reaction is flushed with N.sub.2, securely capped, and placed in a 75° C. sand bath for 2 h and 45 min. The reaction is further heated in a microwave reactor at 100° C. for 1 h under high power. The crude material was purified via preparative HPLC with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over 15 min, then a 5-min hold at 100% B; Flow: 20 mL/min to give the pure title compound (3.4 mg). LC/MS Condition MD-2: [M+H].sup.+ 661, [M−H].sup.− 659; R.sub.t=2.71 min.

EXAMPLE MD-34

(138) ##STR00075##

(139) To a solution of (1S,1′S)-1,1′-(5,5′-([1,1′-biphenyl]-4,4′-diyl)bis(1H-imidazole-5,2-diyl))bis(2,2-dimethylpropan-1-amine)/4.0 HCl (see patent application WO2013106520; 110 mg, 0.183 mmol), material from Example MD-6, step b (32.4 mg, 0.149 mmol) and HATU (70 mg, 0.184 mmol) in anhydrous CH.sub.2Cl.sub.2 (3 mL) is added DIEA (100 μL, 0.573 mmol). The reaction is flushed briefly with argon, securely capped and allowed to stir at room temp for 18 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-80% B over 15 min, then a 5-min hold at 100% B; Flow: 20 mL/min to give the pure title compound (26.4 mg). LC/MS Condition MD-1: [M+H].sup.+ 855, R.sub.t=3.79 min. .sup.1H NMR (600 MHZ, DMSO-d.sub.6) δ 12.12 (br. s., 2H), 7.94-7.50 (m, 12H), 4.89 (d, J=9.5 Hz, 2H), 4.23 (d, J=6.6 Hz, 2H), 3.64-3.48 (m, 4H), 3.03-2.77 (m, 4H), 2.50-2.29 (m, 4H), 1.66 (dt, J=13.3, 6.6 Hz, 2H), 1.18 (t, J=6.6 Hz, 6H), 0.95 (s, 18H), 0.83 (d, J=6.6 Hz, 12H).

EXAMPLE MD-35

(140) ##STR00076##

(141) To a suspension of material from Example MD-18, step c (64 mg, 0.066 mmol) in dichloromethane (4 mL) is added HOAT (50 mg, 0.367 mmol), isobutylamine (65.2 μL, 0.656 mmol), EDC (95 mg, 0.496 mmol) and DIEA (115 μL, 0.658 mmol). The resulting solution is flushed briefly with N.sub.2, capped and stirred at room temp for 18 h. Additional EDC (60 mg, 0.313 mmol), DIEA (70 μL, 0.401 mmol) and isobutylamine (200 μL, 2.01 mmol) is added, the reaction is flushed reaction briefly with N.sub.2, securely capped and stirred at room temp for 18 h. The solvent is removed under a gentle stream of N.sub.2 and the crude product is purified by preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 60-100% B over 30 min, then a 5-min hold at 100% B; Flow: 20 mL/min. to give the title compound (4.5 mg). LC/MS Condition MD-1: [M+H].sup.+ 625; R.sub.t=3.32 min.

EXAMPLE MD-36 TO MD-40

(142) Example MD-36 to MD-40 were prepared using the general procedure outlined in Example MD-13, except using material from Example MD-11, step c. Note: in Example MD-38 and Example MD-40, THF was used as the solvent in place of dichloromethane. For the Examples below, all LC/MS data was obtained under Condition MD-1.

(143) TABLE-US-00003 Example R R.sub.t (min) Obs. Mass ion (M + H).sup.+ MD-36 2.82 653.4 MD-37 2.58 597.4 MD-38 0 2.90 565.4 MD-39 2.65 625.4 MD-40 2.96 665.4

EXAMPLE MD-41 TO MD-54

(144) Example MD-41 to MD-54 were prepared using the general procedure outlined in Example MD-19, except using material from Example MD-18, step d. Note: In the examples where the reagent was a salt, DIEA (8.3 mole equivalents) was added to the reaction. For the Examples below, all LC/MS data was obtained using Condition MD-1.

(145) TABLE-US-00004 Example R R.sub.t (min) Obs. Mass ion (M + H).sup.+ MD-41 3.03 657.6 MD-42 3.12 685.6 MD-43 3.20 625.5 MD-44 3.61 705.6 MD-45 3.71 681.5 MD-46 3.81 738.6 MD-47 0 3.75 777.6 MD-48 3.25 739.6 MD-49 3.55 681.6 MD-50 2.83 709.6 MD-51 3.00 711.5 MD-52 3.69 777.6 MD-53 2.90 707.5 MD-54 3.14 681.5

EXAMPLE MD-55

(146) ##STR00098##

EXAMPLE MD-55

Step a

(147) ##STR00099##

(148) Regiochemistry of cyclization onto the imidazole was not determined

(149) Following the general procedure as described in Example MD-18, step d, except using the material from Example MD-1, step C (290 mg, 0.301 mmol), the title compound is obtained as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.02-7.84 (m, 4H), 7.81-7.65 (m, 4H), 7.57 (s, 2H), 3.60-3.37 (m, 4H), 2.86 (dd, J=17.9, 2.9 Hz, 2H), 2.80-2.64 (m, 2H), 2.54-2.35 (m, 2H), 2.24-2.08 (m, 4H). LC/MS Condition MD-1; [M+H].sup.+ 651.4, R.sub.t=3.18 min.

EXAMPLE 55

(150) Example MD-55 was prepared using the general procedure outlined in Example MD-19. LC/MS Condition MD-1; [M+H].sup.+ 761.6, R.sub.t=3.3.60 min.

EXAMPLE MD-56 TO MD-57

(151) Example MD-56 was prepared using the general procedure outlined in Example MD-19, except using material from Example MD-55, step a and N-isopropylcyclopropanamine Note that because of isopropylamine contamination in the amine precursor, Example MD-57 was also isolated. For the Examples below, R.sub.t was obtained using LC/MS Condition MD-1.

(152) TABLE-US-00005 00 Example R R.sub.1 R.sub.t (min) Obs. Mass ion (M + H).sup.+ MD-56 01 02 3.50 785.6 MD-57 03 04 3.40 745.5

EXAMPLE MD-58

(153) ##STR00105##

(154) The title compound was prepared following the general procedure described in Example MD-3. Note: in this example, DIEA (200 μL, 1.15 mmol) was added to the reaction. LC/MS Condition MD-1: [M+H].sup.+903.5, R.sub.t=3.22 min.

EXAMPLE MD-59 TO MD-60

(155) ##STR00106##

(156) To a dry microwave vial under N.sub.2 is added Example MD-18, step d (20 mg, 0.042 mmol), pivalic acid (43.1 μL, 0.371 mmol) and anhydrous NMP (700 μL). The reaction is flushed with N.sub.2, then treated with N-(propan-2-yl)cyclopropanamine (23 μl, 0.169 mmol). The reaction was securely capped and placed in a 75° C. sand bath for 10 min, and then heated with a microwave unit for 3 h at 130° C. under high power. The crude material was purified via preparative LC/MS with the following conditions to afford Example MD-59 and MD-60: Column: XBridge C18, 19×mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 40-100% B over 16 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Note that the origin of the final products is likely because of contamination of the starting amine.

(157) Example MD-59: LC/MS Condition MD-1: [M+H].sup.+ 597.5, R.sub.t=3.22 min.

(158) Example MD-60: LC/MS Condition MD-1: [M+H].sup.+ 637.6, R.sub.t=3.36 min.

EXAMPLE MD-61

(159) ##STR00107##

(160) The title compound was prepared according to the general procedure as described in Example MD-2. LC/MS Condition MD-1: [M+H].sup.+ 789.5, R.sub.t=3.09 min.

EXAMPLE B1

(161) ##STR00108##

EXAMPLE B1

Step a

(162) ##STR00109##

(163) To a solution of diethyl 2-(tert-butyl)malonate (1.5 g, 6.94 mmol) in ethanol (5 mL) was added solution of KOH (0.389 g, 6.94 mmol) in ethanol (1 mL). Reaction mixture was allowed to stir at RT for overnight. The volatile component was removed in vacuo. The residue was diluted with water, extracted with hexane to remove impurities. The aqueous layer was acidified with 1.5 N HCl and extracted with in ethyl acetate (25 mL×2), washed with water (15 mL) and brine (20 mL), dried with Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford title compound (0.9 g) as colorless gummy material. .sup.1HNMR (CDCl.sub.3, δ=7.26 ppm, 400 MHz): δ 4.26 (q, J=4.80 Hz, 2H), 3.26 (s, 1H), 1.31 (t, J=7.20 Hz, 3H), 1.14 (s, 9H).

EXAMPLE B1

Step b

(164) ##STR00110##

(165) To a solution of 1,1′-([1,1′-biphenyl]-4,4′-diyl)bis(2-bromoethanone) (1.052 g, 2.66 mmol) in DMF (10 mL) was added Example B1, Step a (1 g, 5.31 mmol) and DIEA (5.57 mL, 31.9 mmol). The reaction mixture was stirred at RT for 3 h. The volatile component was removed in vacuo and the residue was diluted with water and extracted with DCM (10 ml×2), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Crude reaction mixture was purified by ISCO (40 g Redisep silica column, 34% ethyl acetate/hexanes) to afford Example B1, Step b (1.6 g) as colorless gummy material. .sup.1HNMR (MeOD, δ=3.34 ppm, 400 MHz): δ 8.09 (dd, J=1.6, 4.8 Hz, 4H), 7.87 (dd, J=2.00, 6.80 Hz, 4H), 5.43-5.56 (m, 4H), 4.20 (q, J=7.20 Hz, 4H), 3.47 (s, 2H), 1.28 (t, J=7.20 Hz, 6H), 1.19 (s, 18H).

EXAMPLE B1

Step c

(166) ##STR00111##

(167) To a solution of Example B1, Step b (1.6 μm, 1.637 mmol) in Xylene (20 mL) was added ammonium acetate (2.52 g, 32.7 mmol) and imidazole (0.669 g, 9.82 mmol). Reaction mixture was purged with argon for 30 min and allowed to stir at 130° C. for overnight in a sealed tube. The volatile component was removed in vacuo, diluted with water and extracted with DCM, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Crude material was purified by ISCO (40 g Redisep silica column, 48% ethyl acetate/hexanes) to afford diethyl Example B1, Step c (0.49 g) as yellow solid. LC/MS Condition B-12: R.sub.t=2.54 min, .sup.1H NMR (MeOD, δ=3.34 ppm, 400 MHz): δ 7.81 (dd, J=2.00, 6.60 Hz, 4H), 7.70 (dd, J=2.00, 6.60 Hz, 4H), 7.44 (s, 2H), 4.33-4.16 (m, 4H), 3.85 (s, 2H), 1.37-1.21 (m, 6H), 1.11 (s, 18H), LC/MS: Anal. Calcd. for [M+2H].sup.+ C.sub.21H.sub.21BrN.sub.3O.sub.2: 570.3. found 571.0 (M+1).

EXAMPLE B1

Step d

(168) ##STR00112##

(169) To a solution of diethyl Example B1, Step c (0.49 g, 0.859 mmol) in THF (5 mL) and methanol (5 mL) mixture was added KOH (0.482 g, 8.59 mmol) in water (5 mL). The reaction mixture was stirred at RT for 2 days. The volatile component was removed in vacuo, the aqueous layer was acidified with 1.5 N HCl, extracted with ethyl acetate (10 ml×2), washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford Example B1, Step d (0.35 g) as yellow solid. LC/MS (Condition B-12): R.sub.t=1.637 min, .sup.1H NMR (DMSO-d.sub.6, δ=2.50 ppm, 400 MHz): δ 7.88-7.52 (m, 8H), 7.47-7.26 (m, 2H), 3.28-3.14 (m, 2H), 1.09-0.89 (m, 18H) LC/MS: Anal. Calcd. for [M+2H].sup.+ C.sub.21H.sub.21BrN.sub.3O.sub.2: 514.2. found 515.2 (M+1).

EXAMPLE B1

(170) To a solution of Example B1, Step d (0.04 g, 0.063 mmol) in DMF (2 mL) was added 2-methylpropan-2-amine (0.023 g, 0.315 mmol), DIEA (0.088 mL, 0.504 mmol) and HATU (0.050 g, 0.132 mmol). After being stirred for overnight at RT, the volatile component was removed in vacuo and the residue was dissolved in DCM (5 mL×2), washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude was submitted to reverse phase HPLC purification to afford Example B1 in a free base form as a mixture of stereoisomers (5.9 mg). LC (Condition 32 and 35): >98% homogeneity index. LC/MS (Condition 12): R.sub.t=2.717 min. LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.42H.sub.54N.sub.10O.sub.6S: 624.4. found 625.4. .sup.1H NMR (MeOD, δ=3.34 ppm, 400 MHz): δ 7.81 (d, J=8.0 Hz, 4H), 7.71 (d, J=8.5 Hz, 4H), 7.42 (s, 2H), 3.50 (s, 2H), 1.37 (br. s., 18H), 1.13 (br. s., 18H).

(171) TABLE-US-00006 Example Form R LC & LC/MS data B2 Free base LC (Condition B-32 and B-35): >99% homogeneity index. LC/MS (Condition B- 12): R.sub.t = 3.01 min. LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.54N.sub.10O.sub.6S: 732.2; found 733.2. .sup.1H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.91-7.79 (m, 6 H), 7.72 (d, J = 8.5 Hz, 4 H), 7.52-7.43 (m, 4 H), 7.33 (t, J = 8.3 Hz, 2 H), 7.13 (ddd, J = 1.0, 2.0, 8.0 Hz, 2 H), 3.77 (s, 2 H), 1.16 (s, 18 H). B3 Free base LC (Condition B-32 and B-35): >99% homogeneity index. LC/MS (Condition B- 12): R.sub.t = 2.49 min. LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.54N.sub.10O.sub.6S: 624.4; found 625.4. .sup.1H NMR (DMSO-d.sub.6, δ = 2.50 ppm, 400 MHz): δ 11.50 (br. s., 2 H), 7.84 (s, 4 H), 7.72-7.59 (m, 4 H), 7.47 (s, 2 H), 4.03 (s, 2 H), 3.70-3.44 (m, 5 H), 3.26- 3.20 (m, 2 H), 3.13 (m, 2 H), 1.14 (br. s., 30 H). B4 Free base LC (Condition B-32 and B-35): >99% homogeneity index. LC/MS (Condition 12): R.sub.t = 2.35 min. LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.54N.sub.10O.sub.6S: 620.4; found 621.5. .sup.1H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.86-7.78 (m, 4 H), 7.76- 7.66 (m, 4 H), 7.45 (s, 2 H), 4.10 (s, 2 H), 3.78-3.63 (m, 4 H), 3.50 (dt, J = 3.0, 6.8 Hz, 4 H), 2.12-1.84 (m, 8 H), 1.14 (s, 18 H). B5 Free base LC (Condition B-32 and B-35): >99% homogeneity index. LC/MS (Condition 12): R.sub.t = 2.81 min. LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.54N.sub.10O.sub.6S: 676.4; found 677.4. .sup.1H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.81 (d, J = 8.0 Hz, 4 H), 7.70 (d, J = 8.5 Hz, 4 H), 7.42 (s, 2 H), 3.82-3.67 (m, 2 H), 3.55 (s, 2 H), 2.01- 1.72 (m, 8 H), 1.66 (d, J = 12.5 Hz, 2 H), 1.49-1.18 (m, 12 H), 1.10 (s, 18 H).

Biological Activity

(172) The NS5A synergistic inhibitory effect of test compounds can be determined using various amounts of an NS5A-targeting compound with titration of a second compound of interest. Both the NS5A-targeting compound and the second compound of interest, when tested individually versus HCV variants, are understood to be essentially inactive or weakly active and only regain synergistic inhibitory potency of 3-fold or greater inhibition when tested in combination versus HCV variants. In one embodiment, compound BMS-790052, as an NS5A-targeting compound, can be held constant at a fixed concentration of 200 nM with subsequent titration of the test compound on a variant of HCV. In one embodiment, the HCV genotype strain can be genotype 1a containing a change at amino acid 30 of the NS5A protein consisting of glutamine to glutamate. The test compound can be chosen from compounds listed above or from others present in the literature. One skilled in the art can readily test compounds in the HCV replicon cell based assay as has been demonstrated previously in the art and one can readily determine the effective concentration for 50% inhibition (EC.sub.50) of a particular compound.

(173) For illustration, Compound P-55, which is noted below, can be titrated in the HCV replicon cell-based assay consisting of the genotype-1a variant with glutamine 30 changed to glutamate in the NS5A protein. Titration of BMS-790052 singly would yield an EC.sub.50 value ˜200 nM while titration of P-55 singly would yield an EC.sub.50 value >200 nM. The titration of P-55 in the presence of a fixed amount of BMS-790052 at 200 nM afforded an EC.sub.50 values of ˜2 nM for P-55 demonstrating a synergistic inhibitory effect for the combination of >100-fold. Similarly, the titration of BMS-790052 in the presence of a fixed amount of P-55 at 200 nM afforded an EC.sub.50 values of ˜2 nM for BMS-790052, demonstrating a reciprocal synergistic inhibitory effect ˜100-fold for the combination (PCT/US2011/043785, filed Jul. 13, 2011), Table 3). Additional compounds can be tested in a similar manner and a ranking of synergist activities determined; these rankings for the genotype 1a Q.fwdarw.E variant are shown for selected compounds in the table below.

(174) ##STR00118##

(175) It is understood that the genotype is not limited to the genotype 1a variant but can encompass all genotypic variants of HCV including but not limited to HCV variants of 1b, 2a, 3a, 4a, 5a, 6a as demonstrated in commonly owned WO2012/009394. It is also understood that the synergy effect is not limited to BMS-790052 or P-55 combinations but can be derived from other combinations of NS5A-targeting compounds that by themselves have reduced or no potency towards HCV variants.

(176) TABLE-US-00007 Fold Synergistic (1a- Example number QE) MD-1 >10 MD-1, step b >100 MD-1, step c <10 MD-2 >100 MD-3 >10 MD-4 <10 MD-5 >10 MD-6 >10 MD-7 <10 MD-7, step b <10 MD-8 <10 MD-9 <10 MD-10 <10 MD-11 >100 MD-12 >10 MD-13 >100 MD-14 <10 MD-15 <10 MD-16 <10 MD-17 <10 MD-18 >10 MD-19 >100 MD-20 >10 MD-21 >100 MD-22 >100 MD-23 >100 MD-24 >10 MD-25 >10 MD-26 >10 MD-27 >10 MD-28 >100 MD-29 <10 MD-30 <10 MD-31 <10 MD-32 >100 MD-33 <10 MD-34 >100 MD-35 >10 MD-36 >10 MD-37 >10 MD-38 >100 MD-39 >10 MD-40 >100 MD-41 >10 MD-42 >10 MD-43 >10 MD-44 >10 MD-45 >100 MD-46 >10 MD-47 >100 MD-48 <10 MD-49 >10 MD-50 <10 MD-51 >10 MD-52 >100 MD-53 <10 MD-54 >10 MD-55 <10 MD-56 <10 MD-57 >10 MD-58 >10 MD-59 >10 MD-60 >10 MD-61 <10 B1 >100 B2 <10 B3 >10 B4 <10 B5 <10

(177) It will be evident to one skilled in the art that the present disclosure is not limited to the foregoing illustrative examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.