THERAPEUTIC COMPOUNDS

Abstract

The invention provides compounds of formula I:

##STR00001##

or a salt thereof as described herein. The invention also provided pharmaceutical compositions comprising a compound of formula I, processes for preparing compounds of formula I, intermediates useful for preparing compounds of formula I and therapeutic methods for treating the proliferation of the HIV virus, treating AIDS or delaying the onset of AIDS or ARC symptoms in a mammal using compounds of formula I.

Claims

1-37. (canceled)

38. A compound, or pharmaceutically acceptable salt thereof, of formula Ia: ##STR00177## wherein: R.sup.1 is R.sup.1a or R.sup.1b; R.sup.5 is R.sup.5a or R.sup.5b; R.sup.1a is: a) halo; or b) H; R.sup.1b is cyano; R.sup.2 is (C.sub.1-C.sub.6)alkyl; R.sup.3 is O(C.sub.1-C.sub.6)alkyl, R.sup.3 is H; R.sup.4 is: ##STR00178## R.sup.5a is: a) H, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle, (C.sub.6-C.sub.220)aryl, heterocycle, heteroaryl, C(O)-R.sup.11, C(O)OR.sup.11, OR.sup.11 or -(C.sub.1-C.sub.6)alkyl-R.sup.11, wherein each R.sup.11 is independently H, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle, (C.sub.6-C.sub.220)aryl, heterocycle or heteroaryl, and wherein (C.sub.6-C.sub.20)aryl, heterocycle and heteroaryl are each optionally substituted with 1 to 3 Z.sup.11 groups; or b) N(R.sup.9)R.sup.10or C(O)N(R.sup.9)R.sup.10, wherein each R.sup.9 is independently H or (C.sub.1-C.sub.6)alkyl wherein each R.sup.10 is independently H, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.6-C.sub.20)aryl, heterocycle, -(C.sub.1-C.sub.6)alkyl-R.sup.11, or C(O)R.sup.11, and wherein each R.sup.11 is independently H, (C.sub.1-C.sub.6)alkyl, ((C.sub.3-C.sub.7)cycloalkyl, (C.sub.6-C.sub.20)aryl or heterocycle; R.sup.5b is: a) -(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle; or b) NR.sub.eR.sub.f; each Z.sup.11 is independently halo, (C.sub.1-C.sub.6)haloalkyl, O(C.sub.1-C.sub.6)alkyl, SO(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyl, (C.sub.6-C.sub.20)aryl, heterocycle or heteroaryl, wherein (C.sub.6-C.sub.20)aryl, heterocycle and heteroaryl are each optionally substituted with halo, (C.sub.1-C.sub.6)alkyl or COOH; each R.sub.e is independently (C.sub.1-C.sub.6)alkyl; each R.sub.f is independently -(C.sub.1-C.sub.6)alkyl-Z.sup.6; each Z.sup.6 is independently NR.sub.aR.sub.a or C(O)NR.sub.cR.sub.d; each Ra is independently (C.sub.1-C.sub.6)alkyl; and R.sub.c and R.sub.d are each independently (C.sub.1-C.sub.6)alkyl; wherein each heteroaryl has 1 to 6 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and each heterocycle has 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur.

39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein R.sup.5a is H, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.7)carbocycle, -(C.sub.1-C.sub.6)alkyl-R.sup.11, C(O)R.sup.11, N(R.sup.9)R.sup.10, C(O)N(R.sup.9)R.sup.10, heterocycle or heteroaryl, wherein heterocycle or heteroaryl is optionally substituted with 1 to 3 Z.sup.11 groups, and wherein R.sup.5b is -(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle.

40. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 is H, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.7)carbocycle, -(C.sub.1-C.sub.6)alkyl-R.sup.11, C(O)R.sup.11, N(R.sup.9)R.sup.10, C(O)N(R.sup.9)R.sup.10, heterocycle or heteroaryl, wherein heterocycle or heteroaryl is optionally substituted with 1 to 3 Z.sup.11 groups.

41. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is OC(CH.sub.3).sub.3.

42. A pharmaceutical composition comprising a compound according to claim 38, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

43. A method of treating HIV infection in a patient in need thereof comprising administering a compound as described in claim 38, or pharmaceutically acceptable salt thereof, to the patient.

44. A method for treating an HIV infection in a patient in need thereof comprising administering to the patient a compound as described in claim 38, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR.sup.4 inhibitors, gp120 inhibitors, CCR.sup.5inhibitors, capsid polymerization inhibitors, and other drugs for treating HIV, and combinations thereof.

Description

EXAMPLE 1

Preparation of tert-butoxy-[7-chloro-5-(4-chloro-phenyl)-2-methyl-quinolin-6-yl]-acetic acid (5L)

[0653] ##STR00099## ##STR00100##

[0654] (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)acetic acid (5L): A stock solution of periodic acid/chromium trioxide was prepared according to WO 99/52850 by dissolving periodic acid (11.4 g, 50.0 mmol) and chromium trioxide (23 mg, 1.2 mol %) in wet acetonitrile (0.75% H.sub.2O) to a volume of 114 mL. This stock solution (0.090 mL) was added to a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)ethanol (5K) (5 mg, 0.013 mmol) in wet acetonitrile (1.0 mL, 0.75% H.sub.2O) at 0 C. Reaction mixture was stirred for 0.5 hour at 0 C. Then more stock solution (0.2 ml) was added and the reaction mixture was stirred for 1 h at 0 C. The reaction mixture was filtered and purified by reverse phase HPLC (Gemini, 10 to 95% ACN/H.sub.2O+0.1% TFA). Product lyophilized to give a white powder. .sup.1H-NMR: 300 MHz, (CD.sub.3OD) : 9.06 (s, 1H), 7.78 (s, 1H), 7.57-7.42 (m, 4H), 5.16 (s, 1H) 2.52 (s, 3H), 0.86 (s, 9H). LCMS-ESI.sup.+: calc'd for C.sub.20H.sub.20ClNO.sup.3S: 390.0 (M+H.sup.+); Found: 390.1 (M+H.sup.+).

[0655] Preparation of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)ethanol (5K):

Step 1.

[0656] Preparation of 6-methoxy-5-methylbenzo[d]thiazol-2-amine (5A): To a solution of 4-methoxy-3-methylbenzenamine (1.05 g, 7.66 mmol) in acetic acid (30 ml) at 0 C. as added KSCN with heavy stirring. The reaction mixture was then stirred at room temperature for 45 min. The reaction was cooled to 0 C. and bromine was added dropwise. The reaction was stirred at room temperature overnight. The precipitate was collected, washed by acetic acid, dichloromethane, minimal water and dried under high vacuum to give the product as brown yellow-solid. LCMS-ESI.sup.+: calc'd for C.sub.9H.sub.10N.sub.2OS: 195.0 (M+H.sup.+): Found: 195.1 (M+H.sup.+).

Step 2.

[0657] Preparation of 6- methoxy-5-methylbenzo[d]thiazole (5B): To a solution of 6-methoxy-5-methylbenzo[d]thiazol-2-amine (5A) (1.24 g, 6.42 mmol) in H.sub.3PO.sub.4 (5 mL) at 0 C., was added NaNO.sub.2 (2.2 g, 32 mmol) in minimal amount of water. The reaction mixture was stirred at 0 C. for 20 min. The reaction mixture was then transferred to ice-cold hypophosphorous acid (50%, 5 ml) and slowly warmed to room temperature and stirred at room temperature until gas evolution ceases. Solid Na.sub.2CO.sub.3 was added to neutralize the reaction and the mixture was extracted by ethyl acetate. The organic phase was dried over MgSO.sub.4, filtered, concentrated and purified by silica gel column (0-100% ethyl acetate/hexanes). LCMS-ES.sup.+: calc'd for C.sub.9H.sub.9NOS; 180.0 (M+H.sup.+); Found: 180.1 (M+H.sup.+).

Step 3.

[0658] Preparation of 5-methylbenzo[d]thiazol-6-ol (5C): To a suspension of 6-methoxy-5-methylbenzo[d]thiazole (5B) (160 mg, 0.89 mmol) in dichloromethane (5 mL) was added boron tribromide (1 M in dichlormethane, 1.8 ml) at 0 C. The reaction mixture was stirred at 0 C. for 2 h. The reaction was quenched by adding a saturated NaHCO.sub.3 solution, extracted with dichlormethane and trace MeOH. The organic layer was dried over MgSO.sub.4, filtered, concentrated and purified by silica gel column (0-100% Ethyl acetate/hexanes). LCMS-ESI.sup.+: calc'd for C.sub.8H.sub.7NOS: 166.0 (M+H.sup.+): Found: 166.2 (M+H.sup.+).

Step 4.

[0659] Preparation of 7-bromo-5-methylbenzo[d]thiazol-6-ol (5D): To a suspension of 5-methylbenzo[d]thiazol-6-ol (5C) (140 mg, 0.84 mmol) in acetic acid (5 ml), was added, bromine (40 L) slowly. The reaction mixture was stirred at room temperature for 1 h. The precipitate was collected, washed with acetic acid, water and dried under high vacuum. LCMS-ESI.sup.+: calc'd for C.sub.8H.sub.6BrNOS: 244.0 (M+H.sup.+); Found: 244.1 (M+H.sup.+).

Step 5.

[0660] Preparation of 7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-ol (5E): The reaction mixture of 7-bromo-5-methylbenzo[d]thiazol-6-ol (5B) (90 mg, 0.37 mmol), 4-chlorophenyl boronic acid (86 mg, 0.55 mmol), Pd(PPh.sub.3).sub.4 (40 mg, 0.037 mmol), K.sub.2CO.sub.3 (153 mg, 1.11 mmol) in 1,2-dimethoxyethane (1 ml)/H.sub.2O (0.5 ml) was heated at 110 C. in the microwave for 10 min. Then the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was dried over MgSO.sub.4, filtered, concentrated and purified by silica gel column (0-100% ethyl acetate/hexanes). LCMS-ESI.sup.+: calc'd for C.sub.14H.sub.10ClNOS: 276.0 (M+H.sup.+); Found: 276.2 (M+H.sup.+).

Step 6.

[0661] Preparation of 7-(4-chlorophenyl)-5-methyl-6-vinylbenzo[d]thiazoIe (5G): To a solution of 7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-ol (5E) (107 mg, 0.39 mmol) in dichloromethane (3 mL)/pyridine (1 mL) at 0 C., was added trifluoromethanesulfonyl acid, anhydride (130 L, 0.80 mmol). The reaction mixture was stirred at 0 C. for 1 h. Then the reaction was quenched by adding saturated NaHCO.sub.3 solution, extracted by ethyl acetate. The organic layer was dried over MgSO.sub.4, filtered, concentrated to give 7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl trifluoromethanesulfonate (5F) which was used in next step without purification.

[0662] 7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl trifluoromethanesulfonate (5F) from above reaction was dissolved in DMF (3 ml). Tributylvinyltin (130 L), PdCl.sub.2(PPh.sub.3).sub.2 (27 mg, 0.039 mmol) and LiCl (49 mg, 1.17 mmol) were added. The reaction mixture was stirred at 120 C. in microwave for 30 min. The reaction mixture was diluted by ethyl acetate, washed with saturated NaHCO.sub.3 solution and extracted with ethyl acetate. The organic layer was dried over MgSO.sub.4, filtered, concentrated and purified by silica gel column (0-50% ethyl acetate hexanes). LCMS-ESI.sup.+: calc'd for C.sub.16H.sub.20ClNS: 286.0 (M+H.sup.+); Found: 286.1 (M+H.sup.+).

Step 7

[0663] Preparation of (S)-1-(7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)ethane-1,2-diol (5H): A biphasic mixture of AD mix- (1.5 g) in tert-bucanol (5 mL)/H.sub.2O (5 mL) was cooled to 0 C. and 7-(4-chlorophenyl)-5-methyl-6-vinylbenzo[d]thiazole (5G) (0.050 g, 0.175 mmol) was added. Reaction mixture was stirred overnight at 0 C. Sodium sulfite (1.5 g) was added at 0 C., then warmed to room temperature and stirred for 30 min to give a white mixture. Mixture was diluted with ethyl acetate and H.sub.2O. Extracted with ethyl acetate (3) and combined organic layer was dried (MgSO.sub.4), concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the product. LCMS-ESI.sup.+: calc'd for C.sub.16H.sub.14ClNO.sub.2S: 320.0 (M+H.sup.+): Pound: 320.1 (M+H.sup.+).

Step 8.

[0664] Preparation of (S)-2-(7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-hydroxyethyl pivalate (5H): To a solution of (S)-1-(7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)ethane-1,2-diol (5H) (0.018 g, 0.056 mmol) in pyridine (0.5 mL)/dichoromethane (1 mL) was added trimethylacetyl chloride (0.010 mL, 0.081 mmol). Reaction mixture was stirred for 1 h at room temperature and additional trimethylacetyl chloride (0.020 ml 0.081 mmol) was added and left it overnight at room temperature. More trimethylacetyl chloride (0.030 ml, 0.242 mmol) was added to the mixture and stirred at room temperature for 30 min. Reaction mixture was diluted with ethyl acetate. Organic layer was washed with saturated sodium bicarbonate solution, dried (MgSO.sub.4), concentrated and purified by flash column chromatography (silica gel, 0 to 50% ethyl acetate/hexanes)._LCMS-ESI.sup.+: calc'd for C.sub.21H.sub.22ClNO.sub.3S: 404.1 (M+H.sup.+); Found: 404.1 (M+H.sup.+).

Step 9.

[0665] Preparation of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)ethyl pivalate (5J): A solution of (S)-2-(7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-hydroxyethyl pivalate (5I) (0.016 g, 0.040 mmol) and perchloric acid, 70% (6 l, 0.1 mmol) in tert-butyl acetate (1 mL) was stirred at room temperature for 2 h. Reaction mixture was quenched with solid sodium bicarbonate (0.05 g) for 1h. Saturated sodium bicarbonate solution was added and extracted with ethyl acetate (3). The combined organic layer was dried (MgSO.sub.4), concentrated and purified by flash column chromatography (silica gel, 0 to 50% ethyl acetate/hexanes)._LCMS-ESI.sup.+: calc'd for C.sub.25H.sub.30ClNO.sub.3S: 460.2 (M+H.sup.+); Found 460.2 (M+H.sup.+).

Step 10.

[0666] Preparation of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)ethanol (5K): To a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)ethyl pivalate (5J) (8 mg, 0.0174 mmol) in MeOH (0.5 mL) and THF (1 mL) was added sodium hydroxide (2 M, 0.1 mL, 0.2 mmol) and the reaction mixture was stirred at room temperature overnight. Reaction mixture diluted with ethyl acetate and acetate and combined organic layer was dried (MgSO.sub.4), concentrated and purified by flash column chromatography (silica gel 0 to 50% ethyl acetate/hexanes). LCMS-ESI.sup.+: calc'd for C.sub.20H.sub.22ClNO.sub.2S: 376.1 (M+H.sup.+); Found: 376.1 (M+H.sup.+).

EXAMPLE 2

Preparation of 2-cyclopropyl-6-methoxy-5-methylbenzo[d]thiazole (6B)

[0667] ##STR00101##

Step 1.

[0668] To a solution of 2-bromo-6-methoxy-5-methylbenzo[d]thiazole (6A) (720 mg, 2.8 mmol) in dioxane (10 ml), was added cyclopropyl boronic acid (722 mg, 8.4 mmol), potassium phosphate (2.3 g, 10.9 mmol), PdCl.sub.2dppf (294 mg, 0.40 mmol). The mixture was reacted at 100 C. overnight. The reaction mixture was cooled to room temperature, washed with water, extracted with EtOAc. The organic phase was combined, dried over MgSO4, filtered, concentrated and purified by silica gel column, eluting by 0-50% EtOAc in hexanes. LCMS-ESI.sup.+: calc'd for C.sub.12H.sub.13NOS: 220.1 (M+H.sup.+); Found: 220.2 (M+H.sup.+).

Step 2.

[0669] Preparation of (2-bromo-6-methoxy-5-methylbenzo[d]thiazole (6A): To a solution of t-butylnitrite (5.17 ml, 43.5 mmol) in acetonitrile (50 ml) was added copper (II) bromide (7.2 g, 32.2 mmol) slowly. The reaction mixture was stirred at room temperature for half hour. Then the reaction mixture was put to a 60 C. oil bath and 6-methoxy-5-methylbenzo[d]thiazol-2-amine (5A) (4.2 g, 21.76 mmol) was added slowly. The reaction mixture was stirred at 60 C. for 1 h. The reaction was cooled to room temperature, washed with water and extracted with EtOAc. The organic phase was combined, dried over MgSO.sub.4, filtered, concentrated and purified by silica gel column, eluting by 0-50% EtOAc in hexanes. LCMS-ESI.sup.+: calc'd for C.sub.9H.sub.8BrNOS: 257.9 (M+H.sup.+); Found: 258.0 (M+H.sup.+).

EXAMPLE 3

Preparation of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2,5-dimethylbenzo[d]thiazol-6-yl)acetic acid (7)

[0670] ##STR00102##

[0671] Compound was synthesized from compound 6A according to the procedure used to prepare compound 6B (except that trimethylboxine was used instead of cyclopropyl boronic acid) followed by the procedures to convert compound 5B to compound 5L as outlined in Example 1. .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 7.69 (s, 1H), 7.65-7.51 (m, 4H), .22 (s, 1H), 2.76 (s, 3H), 2.57 (s, 3H), 0.94 (s, 9H). LCMS-ESI.sup.+: calc'd for C.sub.21H.sub.18ClNO.sub.3: 404.1 (M+H.sup.+); Found 404.1 (M+H.sup.+).

EXAMPLE 4

Preparation of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-isobutyl-5-methylbenzo[d]thiazol-6-yl)acetic acid (8J) and (S)-2-tert-butoxy-2-(2-isobutyl-5-methyl-7-phenylbenzo[d]thiazol-6-yl)acetic acid (8K).

[0672] ##STR00103## ##STR00104##

[0673] The mixture of 7-(4-chlorophenyl)-5-methyl-2-(2-methylprop-1-enyl)benzo[d]thiazol-6-ol (8E) (56 mg, 0.13 mmol), Pd/C (200 mg) in EtOH (5 ml) and EtOAc(5 ml) was stirred at room temperature under an atmosphere of H.sub.2 for 30 min, which gave a mixture of 7-(4-chlorophenyl)-2-isobutyl-5-methylbenzo[d]thiazol-6-ol (8F) and 2-isobutyl-5-methyl-7-phenylbenzo[d]thiazol-6-ol (8G). The reaction mixture was filtered over celite, concentrated and taken on to next step without purification.

[0674] The mixture was converted to a mixture of compound 8J and compound 8K by the same steps used to convert compound 5E to compound 5L as outlined in Example 1. The mixture of compounds 8J and 8K were separated by reverse phase HPLC to provide the pure compounds.

[0675] Compound 8J: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 7.72 (s, 1H), 7.64-7.50 (m, 4H), 5.22 (s, 1H), 2.92 (d, J=3.6 Hz, 2H), 2.58 (s, 3H), 2.17-2.13 (m, 1H), 1.01-0.99 (m, 6H), 0.95 (s, 9H).

[0676] LCMS-ESI.sup.+: calc'd for C.sub.21H.sub.18ClNO.sub.3: 446.1 (M+H.sup.+); Found: 446.2 (M+H.sup.+).

[0677] Compound 8K: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 7.70 (s, 1H), 7.64-7.50 (m, 5H), 5.29 (s, 1H), 2.92 (d, J=3.6 Hz, 2H), 2.57 (d, J=0.4 Hz, 3H), 2.17-2.13 (m, 1H), 1.01-0.99 (m, 6H), 0.92 (s, 9H). LCMS-ESI.sup.+: calc'd for C.sub.21H.sub.18ClNO.sub.3: 412.1 (M+H.sup.+); Found: 412.2 (M+H.sup.+).

[0678] Preparation of 7-(4-chlorophenyl)-5-methyl-2-(2-methylprop-1-enyl)benzo[d]thiazol-6-ol (8E):

Step 1.

[0679] Preparation of 7-bromo-6-methoxy-5-methylbenzo[d]thiazol-2-amine (8A). To a solution of 6-methoxy-5-methylbenzo[d]thiazol-2-amine (5A) (1.0 g, 5.15 mmol) in H.sub.2SO.sub.4 at 0 C., was added NBS (550 mg, 3.07 mmol). The reaction mixture was stirred at 0 C. for 2 h. Then the reaction mixture was poured to ice-water, neutralized by 50% KOH solution to pH about 3. The precipitation was collected, washed by water and dried over high vacuum. LCMS-ESI.sup.30 : calc'd for C.sub.9H.sub.9BrN.sub.2OS: 273.0 (M+H.sup.+); Found: 273.0 (M+H.sup.+).

Step 2.

[0680] Preparation of 7-(4-chlorophenyl)-6-methoxy-5-methylbenzo[d]thiazol-2-amine (8B). The mixture of 7-bromo-6-methoxy-5-methylbenzo[d]thiazol-2-amine (8A) (1.72 g, 6.32 mmol), 4-chlorophenyl boronic acid (1.2 g, 7.67 mmol), K.sub.2CO.sub.3 (2.63 g, 18.9 mmol), Pd(PPh.sub.3).sub.4 (364 mg, 0.315 mmol) in DME (8 ml) and H.sub.2O (4 ml) was reacted in microwave at 110 C. for 1 h. Then 4-chlorophenyl boronic acid (100 mg, 0.64 mmol), Pd(PPh.sub.3).sub.4 (100 mg, 0.086 mmol) were added and reacted in microwave at 110 C. for 0.5 h and 120 C. for 20 min. The reaction mixture was washed by water, extracted by EtOAc. The organic phase was combined, dried over MgSO.sub.4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes. LCMS-ESI.sup.+: calc'd for C.sub.15H.sub.13ClN.sub.2OS: 305.0 (M+H.sup.+); Found: 305.1 (M+H.sup.+).

Step 3.

[0681] Preparation of 2-bromo-7-(4-chlorophenyl)-6-methoxy-5-methylbenzo[d]thiazole (8C). Compound 8C was synthesized from 8B according to the procedure used to prepare compound 6A of Example 2. LCMS-ESI.sup.+: calc'd for C.sub.15H.sub.11BrClNOS: 367.9 (M+H.sup.+); Found: 368.0 (M+H.sup.+).

Step 4.

[0682] Preparation of 7-(4-chlorophenyl)-6-methoxy-5-methyl-2-(2-methylprop-1-enyl)benzo[d]thiazole (8D). The mixture of 2-bromo-7-(4-chlorophenyl)-6-methoxy-5-methylbenzo[d]thiazole (8C) (0.153 g, 0.417 mmol), 4,4,5,5-tetramethyl-2-(2-methylprop-1-enyl)-1,3,2-dioxaborolane (0.256 ml, 1.24 mmol), K.sub.3PO.sub.4 (0.35 g, 1.66 mmol), PdCl.sub.2(dppf) (45 mg, 0.062 mmol) in DME (1 ml) and H.sub.2O (0.5 ml) was reacted in microwave at 120 C. for 0.5 h. The reaction mixture was washed by water, extracted by EtOAc. The organic phase was combined, dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes. LCMS-ESI.sup.+: calc'd for C.sub.19H.sub.18ClNOS: 344.1 (M+H.sup.+); Found: 344.1 (M+H.sup.+).

Step 5.

[0683] Preparation of 7-(4-chlorophenyl)-5-methyl-2-(2-methylprop-1-enyl)benzo[d]thiazol-6-ol (8E). Compound 8E was synthesized from compound 8D according to the procedure used to prepare compound 5C of Example 1.

[0684] LCMS-ESI.sup.+: calc'd for C.sub.19H.sub.16ClNOS: 330.0 (M+H.sup.+); Found: 330.2 (M+H.sup.+).

EXAMPLE 5

Preparation of Compound (9)

[0685] ##STR00105##

[0686] Compound 9 was synthesized from 8C by the method to used convert compound 8C to compound 8J as outlined in Example 4, except that tributylvinyltin was used in first the cross coupling reaction according to the procedure used to prepare compound 5G of Example 1. .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 7.71 (s, 1H), 7.65-7.51 (m, 4H), 5.22 (s, 1H), 3.11-3.07 (m, 2H), 2.58 (s, 3H), 1.40 (t, J=7.6 Hz, 3H), 0.94 (s, 9H). LCMS-ESI.sup.+: calc'd for C.sub.21H.sub.18ClNO.sub.3: 418.1 (M+H.sup.+); Found: 418.1 (M+H.sup.+).

EXAMPLE 6

Preparation of Compound (10)

[0687] ##STR00106##

[0688] Compound 10 was synthesized from compound 8C by the method used to convert compound 8C to compound 8J as outlined in Example 4, except that cyclopropylboronic acid, was used in first the cross coupling reaction. .sup.1H-NMR: 400 MHz, (CD.sub.3OD) ; 7.63 (s, 1H), 7.61-7.49 (m, 4H), 5.20 (s, 1H), 2.55 (s, 3H), 2.41-2.36 (m, 1H), 1.26-1.22 (m, 2H), 1.14-1.10 (m, 2H), 0.94 (s, 9H).

[0689] LCMS-ESI.sup.+: calc'd for C.sub.23H.sub.18ClNO.sub.3: 430.1 (M+H.sup.+); Found: 430.1 (M+H.sup.+).

EXAMPLE 7

Preparation of Compound 12

[0690] ##STR00107##

[0691] Compound 12 was synthesized from compound 11 according to the procedure used to prepare compound 8J from compound 8D as outlined in Example 4. .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 7.62-7.49 (m, 4H), 7.34 (s, 1H), 5.15 (s, 1H), 3.27 (s, 6H), 2.53 (s, 3H), 0.94 (s, 9H). LCMS-ESI.sup.+: calc'd for C.sub.21H.sub.18ClNO.sub.3: 433.1 (M+H.sup.+); Found: 433.1 (M+H.sup.+).

[0692] Preparation of 6-methoxy-N,N,5-trimethylbenzo[d]thiazol-2-amine (11). To a solution of 2-bromo-7-(4-chlorophenyl)-6-methylbenzo[d]thiazole (8C) (135 mg, 0.37 mmol) in DMF (2 ml), was added dimethylamine in THF (2M, 0.46 ml, 0.92 mmol). The reaction mixture was stirred at 80 C. After the reaction finished, the reaction was cooled and concentrated. The residue was purified by silica gel column, eluting by 0-100% EtOAc in hexanes. LCMS-ESI.sup.+: calc'd for C.sub.17H.sub.17ClN.sub.2OS: 333.1 (M+H.sup.+); Found: 333.1 (M+H.sup.+).

EXAMPLE 8

Preparation of Compound 14

[0693] ##STR00108##

[0694] Compound 14 was synthesized from compound 13 according to the procedure used to prepare compound 8J from compound 8D as outlined in Example 4. .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 7.74 (s, 1H), 7.62-7.50 (m, 4H), 5.22 (s, 1H), 2.58 (s, 3H), 1.61-1.59 (m, 1H), 1.03-1.01 (m, 2H), 0.94 (s, 1H), 0.91-0.88 (m, 2H). LCMS-ESI.sup.+: calc'd for C.sub.21H.sub.18ClNO.sub.3: 454.1 (M+H.sup.+); Found: 454.1 (M+H.sup.+).

##STR00109##

[0695] Compound 14b was obtained as a side-product of Compound 14.

[0696] .sup.1H-NMR: 400 MHz, (CD.sub.3O.D) : 7.99 (s, 1H), 7.64-7.55 (m, 5H), 5.26 (s, 1H), 2.91 (t, J=3 Hz, 2H), 2.70 (m, 2H), 2.62 (s, 3H), 0.95 (s, 9H).

[0697] LCMS-ESI.sup.+: calc'd for C.sub.25H.sub.24ClNO.sub.4S: 470.1 (M+H.sup.+); Found: 470.1 (M+H.sup.+).

[0698] Preparation of 2-(2-cyclopropylethynyl)-6-methoxy-5-methylbenzo[d]thiazole (13). To a solution, of 2-bromo-7-(4-chlorophenyl)-6-methoxy-5-methylbenzo[d]thiazole (8C) (188 mg, 0.512 mmol) in THF (3ml), was added ethynylcyclopropane (0.09 ml, 1.2 mmol), CuI (10 mg, 0.052 mmol), Et.sub.3N (0.36 ml, 2.58 mmol) and PdCl.sub.2(dppf) (19 mg, 0.026 mmol). The reaction mixture was stirred at 60 C. for 2 hs. The reaction mixture was washed by water, extracted by EtOAc. The organic phase was combined, dried over MgSO.sub.4, filtered, concentrated and purified by silica gel column, eluting by 0-50% EtOAc in hexanes.

[0699] LCMS-ESI.sup.+: calc'd for C.sub.20H.sub.16ClNOS: 354.0 (M+H.sup.+); Found: 354.1 (M+H.sup.+).

EXAMPLE 9

Preparation of (S)-2-tert-butoxy-2-((S)-2-cyclopropyl-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid (21) and (S)-2-tert-butoxy-2-((R)-2-cyclopropyl-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid (22).

[0700] ##STR00110## ##STR00111##

[0701] Compounds 21 and 22 were prepared from compounds 19 and 20 by the method to used convert compound 5J to compound 5L as outlined in Example 1.

[0702] Compound 21: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 8.77 (d, J=3Hz, 1H), 7.87-7.80 (m, 3H), 7.40 (d, J=4.2 Hz, 1H), 5.21 (s, 1H), 4.72-4.68 (m, 2H), 3.64 (t, J=6 Hz, 2H), 2.73 (s, 3H), 2.35-2.33 (m, 1H), 1.23-1.20 (m, 2H), 1.10-4.07 (m, 2H), 0.90 (s, 9H). LCMS-ESI.sup.+: calc'd for C.sub.21H.sub.18ClNO.sub.3: 489.1 (M+H.sup.+); Found: 489.1 (M+H.sup.+).

[0703] Compound 22: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 8.66 (d, J=2.6 Hz, 1H), 8.13 (d, J=4 Hz, 1H), 7.82 (s, 1H), 7.66 (d, J=2.8 Hz, 1H), 7.39 (d, J=4 Hz, 1H), 2.52 (s, 1H), 4.66 (t, J=6 Hz, 2H), 3.57 (t, J=5.8 Hz, 2H), 2.68 (s, 3H), 2.37-2.31 (m, 1H), 1.22-1.19 (m, 2H), 1.08-1.06 (m, 2H), 0.89 (s, 9H).

[0704] LCMS-ESI.sup.+: calc'd for C.sub.21H.sub.18ClNO.sub.3: 489.1 (M+H.sup.+); Found: 489.1 (M+H.sup.+).

[0705] Preparation of compound 19 and compound 20.

Step 1.

[0706] Preparation of 7-bromo-2-cyclopropyl-5-methylbenzo[d]thiazol-6-ol (15). Compound 15 was prepared from compound 6B by the method used to prepare compound 5B from compound 5B as outlined in Example 1. LCMS-ESI.sup.+: calc'd for C.sub.141H.sub.10BrNOS: 284.0 (M+H.sup.+); Found: 284.2 (M+H.sup.+).

Step 2.

[0707] Preparation of 7-bromo-2-cyclopropyl-5-methylbenzo[d]thiazol-6-yl trifluoromethanesulfonate (16). To a solution of 7-bromo-2-cyclopropyl-5-methylbenzo[d]thiazol-6-ol (15) (500 mg, 1.766 mmol) in DCM (8 ml) and 2,6-lutine (2 ml) at 78 C. was slowly added trifluoromethanesulfonic anhydride (0.59 ml, 3.51 mmol). The temperature was allowed to slowly warm to 0 C. over 2 h. The reaction mixture was washed by saturated NaHCO.sub.3 solution, extracted with DCM. The organic phase was combined, dry over MgSO.sub.4, filtered, concentrated and purified by silica gel column, eluting by 0-50% EtOAc in hexanes. LCMS-ESI.sup.+: calc'd for C.sub.12H.sub.19BrF.sub.3NO.sub.3S.sub.2: 415.9 (M+H.sup.+); Found: 415.9 (M+H.sup.+).

Step 3.

[0708] Preparation of 7-bromo-2-cyclopropyl-5-methyl-6-vinylbenzo[d]thiazole (17). To a solution of 7-bromo-2-cyclopropyl-5-methylbenzo[d]thiazol-6-yl trifluoromethanesulfonate (16) (410 mg, 0.988 mmol) in DMF (4 ml), was added tributylvinyltin (0.43 ml, 1.47 mmol), LiCl (125 mg, 2.94 mmol) and PdCl.sub.2(PPh.sub.3).sub.2 (70 mg, 0.096 mmol). The reaction mixture was reacted at 80 C. overnight. The reaction was cooled down, washed by saturated NaHCO.sub.3 solution, extracted by EtOAc. The organic phase was combined, dry over MgSO.sub.4, filtered, concentrated and purified by silica gel column, eluting by 0-50% EtOAc in hexanes.

[0709] LCMS-ESI.sup.+: calc'd for C.sub.13H.sub.12BrNS: 294.0 (M+H.sup.+); Found: 294.1 (M+H.sup.+).

Step 4.

[0710] Preparation of (S)-2-(7-bromo-2-cyclopropyl-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (18). Compound 18 was prepared from compound 17 by the method used to convert compound 5G to compound 5J as outlined in Example 1. LCMS-ESI.sup.+: calc'd for C.sub.22H.sub.30BrNaO.sub.3S: 468.1 (M+H.sup.+); Found: 468.2 (M+H.sup.+).

Step 5.

[0711] Preparation of the (S)-2-tert-butoxy-2-(2-cyclopropyl-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)ethyl pivalate isomers (19 and 20). To a solution of (S)-2-(7-bromo-2-cyclopropyl-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (18) (23 mg, 0.047 mmol) in DMA (2 ml), was added 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid ( 25 mg, 0.099 mmol), 2N K.sub.2CO.sub.3 solution (0.11 mL 0.22 mmol) and Pd(PPh.sub.3).sub.4 ( 6 mg, 0.005 mmol). The reaction mixture was reacted at 85 C. for 2 hs. The reaction was cooled down, washed by saturated NaHCO.sub.3 solution, extracted by EtOAc. The organic phase was combined, dry over MgSO.sub.4, filtered, concentrated and purified by silica gel column, eluting by 0-50% EtOAc in hexanes. Two isomers were separated and went through the chemistry sequence as above, LCMS-ESI.sup.+: calc'd for C.sub.33H.sub.38N.sub.2O.sub.4S: 559.2 (M+H.sup.+): Found: 559.1 (M+H.sup.+).

EXAMPLE 10

Preparation of (S)-2-((S)-2-(azetidin-1-yl)-7-(253-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetic acid (35) and (S)-2-((R)-2-(azetidin-1-yl)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetic acid (36).

[0712] ##STR00112## ##STR00113##

[0713] To a solution of 34 (23 mg, 0.043 mmol) in THF (1 mL) and MeOH (1 mL) was added a solution of NaOH (2 M, 400 L). The reaction mixture was heated at 70 C. for 4 h. The reaction was brought to pH 5 with TFA and was then purified by reverse phase HPLC (MeCN/H.sub.2O containing 0.1 % TFA) to give 6 mg of compound 35 and 10 mg of compound 36.

[0714] Compound 35: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 8.75 (d, J=2.6 Hz, 1H), 7,80 (d, J=4.0 Hz, 1H), 7.72 (d, J=2.6 Hz, 1H), 7.47 (s, 1H), 7.34 (d, J=4.0 Hz, 1H), 5.13 (s, 1H), 4.67-4.65 (m, 2H), 4.17 (t, J=7.6 Hz, 4H), 3.59-3.58 (m, 2H), 2.66 (s, 3H), 2.52-2.50 (m, 2H), 0.88 (s, 9H). LCMS-ESI.sup.+: calc'd for C.sub.28H.sub.29N.sub.3O.sub.4S: 504.2 (M+H.sup.+); Found: 504.0 (M+H.sup.+).

[0715] Compound 36: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 8.67 (d, J=2.2 Hz, 1H), 8.01 (d, J=4.0 Hz, 1H), 7.49 (d, J=2.6 Hz, 1H), 7.40 (s, 1H), 7.27 (d, J=4.2 Hz, 1H), 5.18 (s, 1H), 4.60-4.57 (m, 2H), 4.27 (t, J=7.8 Hz, 4H), 3.48-3.45 (m, 2H), 2.61 (s, 3H), 2.58-2.54 (m, 2H), 0.80 (s, 9H). LCMS-ESI.sup.+: calc'd for C.sub.28H.sub.29N.sub.3O.sub.4S: 504.2 (M+H.sup.+); Found: 504.1 (M+H.sup.+).

[0716] Preparation of (2S)-ethyl 2-(2-(azetidin-1-yl)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (34).

Step 1.

[0717] Preparation of 2-bromo-5-methylcyclohexane-1,3-dione (24). To a solution of 5-methyl-1,3-cyclohexanedione (23) (45.4 g, 360 mmol) in acetic acid (540 mL) was added bromine (19.4mL, 378 mmol) over 5 min. After 30 min of stirring (with mechanical stirrer), the reaction mixture was filtered. The solid was left under high vacuum overnight and used in the subsequent step without further purification.

Step 2.

[0718] Preparation of 2-amino-5-methyl-5,6-dihydrobenzo[d]thiazol-7-(4H)-one (25). To a solution of 24 in acetic acid (540 mL) was added sodium acetate (44.3 g, 540 mmol) and thiourea (28.8 g, 378 mmol). The reaction mixture was stirred with a mechanical stirrer at 100 C. for 3 h. The reaction mixture was partially concentrated in vacuo. EtOAc was added (500 mL). The mixture was made basic with 1 M NaOH, and the layers were separated. The aqueous layer was extracted with EtOAc (2300 mL). The combined organic layers were dried, filtered, and concentrated in vacuo to give 49.3 g of 25, which was taken on without further purification. LCMS-ESI.sup.+: calc'd for C.sub.8H.sub.11N.sub.2OS: 183.1 (M+H.sup.+); Found: 183.1 (M+H.sup.+).

Step 3.

[0719] Preparation of 2-bromo-5-methyl-5,6-dlhydrobenzo[d]thiazol-7(4H)-one (26). To a solution of 25 (53.9 g, 296 mmol) in MeCN (600 mL) at 0 C., while mechanically stirred), was added copper (II) bromide (79.2 g, 355 mmol) then t-butyl nitrite (46.8 mL, 355 mmol). The reaction mixture was stirred from 0 C. to room temperature over 2 h and was then partially concentrated. EtOAc (400 mL) and a 0.5 M HCl solution were added. The layers were separated, and the organic layer was washed with a brine solution. The combined organic layers were dried, filtered, and concentrated in vacuo. The crude product was adsorbed on 150 g of silica then ran through a plug of silica with 40% EtOAc/hexanes to give 58.3 g of 26. .sup.1H-NMR: 400 MHz, (CDCl.sub.3) : 3.16 (dd, 1H, J=18, 4 Hz), 2.56 (m, 2H), 2.47 (m, 1H), 2.34 (dd, 1H, J=16, 12 Hz), 1.19 (d, 3H, J=7 Hz). LCMS-ESI.sup.+: calc'd for C.sub.8H.sub.9BrNOS: 245.9 (M+H.sup.+); Found: 246.1 (M+H.sup.+).

Step 4.

[0720] Preparation of 2-bromo-5-methylbenzo[d]thiazol-7-ol (27). To a solution of 26 (7.38 g, 30.0 mmol) in CCl.sub.4 (90 mL) was added NBS (5.61 g, 31.5 mmol) and dibenzoyl peroxide (727mg, 3.0 mmol). The reaction was heated at 90 C. in a sealed reaction vessel for about 4 h. Then DBU (6.73 mL, 45.0 mmol) in CH.sub.2Cl.sub.2 (15 mL) was added. The mixture was heated a reflux for 30 min, then a 1 M HCl solution was added. The layers were separated, and the aqueous layer was extracted with CH.sub.2Cl.sub.2. The combined organic layers were washed with a brine solution. The organic layer was then dried, filtered, and concentrated in vacuo. The crude product was adsorbed on 30 g of silica then run through a plug of silica with 40% EtOAc/hexanes to give 5.2 g of 27. .sup.1H-NMR: 400 MHz, (CD.sub.3OH) : 7.25 (s, 1H), 6.69 (s, 1H), 2.40 (s, 3H). LCMS-ESI.sup.+: calc'd for C.sub.8H.sub.7BrNOS: 243.9 (M+H.sup.+); Found: 244.1 (M+H.sup.+).

Step 5.

[0721] Preparation of ethyl 2-(2-bromo-7-hydroxy-5-methylbenzo[d]thiazol-6-yl)-2-hydroxyacetate (28). To a solution of 27 (3.90 g, 16.0 mmol) in CH.sub.2Cl.sub.2 (80 mL) at 0 C. was added triethylamine (2.45 mL, 16.8 mmol) then a solution of titanium tetrachloride in CH.sub.2Cl.sub.2 (1.0 M, 16.8 mL, 16.8 mmol). After 15 min, ethyl glyoxalate (50% in toluene, 3.49 mL, 17.6 mmol) was added. The reaction mixture was stirred for 2 h while warming to room temperature. Water (50 mL) and a saturated solution of potassium sodium tartrate (50 mL) were added. The mixture was stirred vigorously for 2 h. The layers were separated, and the aqueous layer was extracted with CH.sub.2Cl.sub.2. The combined organic layers were dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography to give 2.48 g of 28 and recovered 500 mg of 27. .sup.1-LNMR: 400 MHz, (CD.sub.3OH) : 7.33 (s, 1H), 5.69 (s, 1H), 4.17 (m, 2H), 2.50 (s, 3H), 1.18 (t, 3H, J=7 Hz). LCMS-ESI.sup.+: calc'd for C.sub.12H.sub.13BrNO.sub.4S: 346.0 (M+H.sup.+); Found: 346.1 (M+H.sup.+).

Step 6.

[0722] Preparation of ethyl 2-(2-bromo-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)-2-hydroxyacetate (29). To a solution of 28 (2.42 g, 7.00 mmol) in CH.sub.2Cl.sub.2 (30 mL) at 78 C. was added triethylamine (1.02 mL, 7.70 mmol) followed by trifluoromethanesulfonic anhydride (1.24 mL, 7.35 mmol). After 15 min, saturated NH.sub.4Cl was added. The layers were separated. The organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography to give 2.17 g of 29. .sup.1H-NMR: 400 MHz, (CDCl.sub.3) : 7.84 (s, 1H), 3.67 (s, 1H), 4.27 (m, 2H), 2.50 (s, 3H), 1.23 (t, 3H, J=7 Hz). LCMS-ESI.sup.+: calc'd for C.sub.13H.sub.12BrF.sub.3NO.sub.6S.sub.2: 477.9 (M+H.sup.+); Found: 478.2 (M+H.sup.+).

Step 7.

[0723] Preparation of ethyl 2-(2-bromo-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]triazol-6-yl)-2-oxoacetate (30). To a solution of 29 (9.85 g, 20.6 mmol) in CH.sub.2Cl.sub.2 (100 mL) was added Bess-Martin periodinane (9.61 g, 22.6 mmol). After 30 min, water (75 mL) and saturated Na.sub.2S.sub.2O.sub.4 solution (75 mL) was added. The mixture was stirred vigorously for 30 min. The layers were separated, and the aqueous layer was extracted with CH.sub.2Cl.sub.2. The combined organic layers were dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography to give 8.32 g of 30. .sup.1H-NMR: 400 MHz, (CDCl.sub.3) : 7.91 (s, 1H), 4.40 (q, 2H, J=7 Hz), 2.49 (s, 3H), 1.39 (t, 3H, J=7 Hz).

[0724] LCMS-ESI.sup.+: calc'd for C.sub.13H.sub.10BrF.sub.3NO.sub.6S.sub.2: 475.9 (M+H.sup.+); Found: 476.1 (M+H.sup.+),

Step 8.

[0725] Preparation of (S)-ethyl 2-(2-bromo-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)-2-hydroxyacetate (31). To a solution of 30 (8.30 g, 17.4 mmol) in toluene (70 mL) was added ((R)-2-methyl-CBS-oxazaborolidine (725 mg, 2.61 mmol). The reaction mixture was then cooled to 35 C. and a solution of catecholborane (freshly distilled) (1 M in toluene, 20.9 mL, 20.9 mmol) was added via addition funnel over 30 min. The reaction was stirred for 20 min while warming to 20 C. A 2 M solution of Na.sub.2CO.sub.3 was added (50 mL). The layers were separated, and the organic layer was washed with, additional N.sub.2CO.sub.3 solution (325 mL). The organic layer was dried, filtered, and concentrated in vacuo to give 31, which had analytical data to match 29. The compound was taken on to the next step without further purification.

Step 9.

[0726] Preparation of (S)-ethyl 2-(2-bromo-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)-2-tert-butoxyacetate (32). To a solution of 31 (17 mmol) in t-butylacetate (70 mL) was added perchloric acid (1.23 mL, 20.4 mmol). After 3 h, water was added (50 mL). The layers were separated. The organic layer was washed with a saturated solution of NaHCO.sub.3. The organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give 7.22 g of 32 and 1.58 g of 31. .sup.1H-NMR: 400 MHz, (CD.sub.3OH) ; 7.82 (s, 1H), 5.59 (s, 1H), 4.08-4.25 (m, 2B), 2.55 (s, 3H), 1.20 (s, 9H), 1.16 (t, 3H, J=7 Hz). LCMS-ESI.sup.+: calc'd for C.sub.17H.sub.20BrF.sub.3NO.sub.6S.sub.2: 534.0 (M+H.sup.+); Found: 534.1 (M+H.sup.+).

Step 10.

[0727] Preparation of (S)-ethyl 2-(2-(azetidin-1-yl)-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)-2-tert-butoxyacetate (33). To a solution of 32 (50 mg, 0.094 mmol) in THF (1 mL) was added azetidine (20 L). The reaction mixture was heated at 70 C. for 30 min. A saturated solution of NH.sub.4Cl (3 mL) was added, and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layer were dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give 38 mg of 33. LCMS-ESI.sup.+: calc'd for C.sub.20H.sub.25F.sub.3N.sub.2O.sub.6S.sub.2: 511.1 (M+H.sup.+); Found: 511.0 (M+H.sup.+).

Step 11.

[0728] Preparation of (2S)-ethyl 2-(2-(azetidin-1-yl)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (34). To a solution of 33 (38 mg, 0.075 mmol) in freshly distilled DME (1 mL) was added 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid hydrochloride (24 mg, 0.097 mmol), chloro(2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) methyl-t-butylether adduct, [SPhos Palladacycle] (5 mg, 0.0075 mmol), and cesium fluoride (46 mg, 0.3 mmol). The reaction mixture was heated in the microwave at 110 C. for 45 min. A saturated solution of NaHCO.sub.3 (3 mL) was added, and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layer were dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAe/hexanes) to give 21 mg of 34. LCMS-ESI.sup.+: calc'd for C.sub.30H.sub.33N.sub.3O.sub.4S: 532.2 (M+H.sup.+); Found: 532.0 (M+H.sup.+).

EXAMPLE 11

Preparation (S)-2-tert-butoxy-2-((S)-2-carbamoyl-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid (40)

[0729] ##STR00114##

[0730] Compound 46 was prepared from compound 39. To a solution of compound 39.4 (200 mg) in CH.sub.2Cl.sub.2 (5 mL) was added triethylamine (2 mL) and trifluoroacetic acid anhydride (100 L). After 3 h, a saturated solution of NH.sub.4Cl was added. The layers were separated, and the aqueous layer was extracted with CH.sub.2Cl.sub.2. The combined organic layers were dried, filtered, and concentrated in vacuo. A solution of THF and MeOH was added (1:1, 5 mL) followed by NaOH solution (2 M, 200 L). The reaction mixture was stirred at 45 C. for 6 h. The mixture was made acidic with 1 M HCl. The crude mixture was purified by reverse phase HPLC to give 10.8 mg of compound 40.

[0731] Compound 40. .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 8.79 (d, J=5.2 Hz, 1H); 8.21 (s, 1H); 7.92 (d, J=8.0 Hz, 1H); 7.87 (d, J=6.0 Hz, 1H); 7.46 (d, J=8.0 Hz, 1H); 5.27 (g, 1H); 4.74-4.72 (m, 2H); 3.68 (t, J=6.0 Hz, 2H); 2.80 (s, 3H); 0.93 (s, 9H).

[0732] LCMS-ES.sup.+: calc'd for C.sub.26H.sub.25N.sub.3O.sub.5S: 492.1 (M+H.sup.+); Found: 492.1 (M+H.sup.+).

##STR00115##

[0733] Compound 41 was a by-product in the preparation of 40.

[0734] LCMS-ESI.sup.+: calc'd for C.sub.26H.sub.24N.sub.2O.sub.6S: 493.1 (M+H.sup.+); Found: 493.1 (M+H.sup.+).

[0735] Preparation of (S)-ethyl-2-tert-butoxy-2-((S)-2-carbamoyl-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (39).

Step 1.

[0736] Preparation of (S)-ethyl 6-(1 -tert-butoxy-2-ethoxy-2-oxoethyl)-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazole-2-carboxylate (37). To a solution of (S)-ethyl 2-(2-bromo-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)-2-tert-butoxyacetate (32) (1.07 g, 2.00 mmol) in DMF (10 mL) was added tributyl(1-ethoxyvinyl)stannane (867 mg, 2.40 mmol), copper iodide (38 mg, 0.20 mmol), and Pd(PPh.sub.3).sub.4 (116 mg, 0.10 mmol). The reaction mixture was stirred at 45 C. for 2.5 h. A saturated solution of NH.sub.4Cl was added and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. Methanol and CH.sub.2Cl.sub.2 (1:1, 20 mL) added. The mixture was cooled to 78 C. and ozone (O.sub.3) was bubbled through the solution for about 15 min until the reaction mixture was blue-green. Dimethysulfide (1 mL) was added and the reaction was stirred at rt for 20 min. The mixture was concentrated in vacuo and purified by column chromatography (EtGAc/hexanes) to give 811 mg of 37. .sup.1H-NMR: 400 MHz, (CDCl.sub.3): 8.06 (s, 1H), 5.65 (s, 1H), 4.56 (q, J=7 Hz, 2H), 4.14 (m, 2H), 2.59 (s, 3H), 1.49 (t, J=7 Hz, 3H), 1.21 (s, 9H), 1.16 (t, J=7 Hz, 3H).

Step 2.

[0737] Preparation of (S)-ethyl 6-((S)-1-tert-butoxy-2-ethoxy-2-oxoethyl)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazole-2-carboxylate (38). To a solution of 37 (807 mg, 1.53 mmol) and CsF (1.02 g, 6.73 mmol) in distilled dimethoxyethane (15 mL) was added 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid (HCl salt, 770 mg, 3.06 mmol) and chloro(2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) methyl-t-butylether adduct, [SPhos Palladacycle] (206 mg, 0.31 mmol). The reaction mixture was heated at 110 C. in a sealed tube for 2 h. The reaction was cooled to rt and saturated solution of NaHCO.sub.3 was added. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. The crude material was purified by column chromagraphy (increasing EtOAc w/ 5% MeOH to hexanes) to give 224 mg of 38 and 348 mg of undesired atropisomer.

[0738] .sup.1H-NMR: 400 MHz, (CDCl.sub.3): 8.54 (d, J=4 Hz, 1H), 8.04 (s, 1H), 7.55 (d, J=8 Hz, 1H), 7.29 (d, J=4 Hz, 1H), 7.10 (d, J=8 Hz, 1H), 5.18 (s, 1H), 4.55 (m, 2H), 4.41 (q, J=7 Hz, 2H), 4.01 (m, 1H), 3.88 (m, 1H), 3.37 (m, 2H), 2.77 (s, 3H), 1.36 (t, J=7 Hz, 3H), 1.00 (t, J=7 Hz, 3H), 0.90 (s, 9H).

Step 3.

[0739] Preparation of (S)ethyl-2-tert-butoxy-2-((S)-2-carbamoyl-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (39). To a solution of 38 (224 mg) in MeOH (5 mL) was added NH.sub.4OH (500 L). The reaction mixture was stirred at rt for 2 h and then concentrated in vacuo to give 220 mg of 39.

[0740] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.28H.sub.29N.sub.3O.sub.5S: 520.2 (M+H.sup.+); Found: 520.1, 493.07 (M+H.sup.+).

EXAMPLE 12

Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(dimethylamino)-5-methylbenzo[d]thiazol-6-yl)acetic acid (42) and (S)-2-tert-butoxy-2-((R)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(dimethylamino)-5-methylbenzo[d]thiazol-6-yl)acetic acid (43).

[0741] Compounds 42 and 43 were prepared from compound 32 according to the procedure used to prepare compound 35 (except that dimethylamine was used instead of azetidine) in Example 10.

##STR00116##

[0742] Compound 42: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 8.76 (d, J=4.8 Hz, 1H); 7.82 (d, J=8.0 Hz, 1H); 7,73 (d, J=5.2 Hz, 1H); 7.50 (s, 1H); 7.35 (d, J=7.6 Hz, 1H); 5.14 (s, 1H); 4.67 (m, 2H); 3.61 (t, J=5.8 Hz, 2H); 3.13 (s, 6H); 2.66 (s, 3H); 0.89 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.27H.sub.30N.sub.3O.sub.4S: 492.20 (M+H.sup.+); Found: 492.00, 493.07(M+H.sup.+).

##STR00117##

[0743] Compound 43: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) 8.67 (d, J=4.9 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.51 (d, J=4.9 Hz, 1H), 7.45 (s, 1H), 7.30 (d, J=8.1 Hz, 1H), 5.19 (s, 1H), 4.67-4.55 (m, 2H), 3.21 (s, 6H), 2.62 (s, 3H), 0.81 (s, 9H).

[0744] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.27H.sub.29N.sub.3O.sub.4S: 492.20 (M+H.sup.+); Found: 491.98, 492.96(M+H.sup.+).

##STR00118##

[0745] Compound 42A: LCMS-ESI.sup.+ (m/z): [M+H].sup.+calcd for C.sub.19H.sub.25F.sub.3N.sub.2O.sub.6S.sub.2: 499.1 (M+H.sup.+); Found: 499.0(M+H.sup.+).

##STR00119##

[0746] Compound 42B: .sup.1H-NMR: 400 MHz, (CDCl.sub.3) : 8.75 (d, J=1.8 Hz, 1H); 7.54 (d, J=4.0 Hz, 1H), 7.48 (s, 1H), 7.11 (d, J=2.2 Hz, 1H), 7.06 (d, J=3.8 Hz, 1H), 4.94 (s, 1H), 4.54 (t, J=5.6 Hz, 2H), 4.00-4.03 (m, 2H), 3.31-3.30 (m, 2H), 3.08 (s, 6H), 2.64 (s, 3H), 1.25-1.27 (m, 3H), 0.88 (s, 9H).

[0747] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.29H.sub.33N.sub.3O.sub.4S: 520.2 (M+H.sup.+); Found: 520.0 (M+H.sup.+).

EXAMPLE 13

Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(ethyl(methyl)amino)-5-methylbenzo[d]thiazol-6-yl)acetic acid (44)

[0748] Compound 44 was prepared from compound 32 according to the procedure used to prepare compound 35 (except that methylethylamine was used instead of azetidine) in Example 10.

##STR00120##

[0749] Compound 44: .sup.1H NMR (400 MHz, CD.sub.3OD) 8.77 (d, J=5.4 Hz, 1H), 7.82 (d, J=8.1 Hz, 1H), 7.72 (d, J=5.3 Hz, 1H), 7.49 (s, 1H), 7.35 (d, J=8.1 Hz, 1H), 5.14 (s, 1H), 4.67 (t, J=5.9 Hz, 2H), 3.59 (t, J=5.9 Hz, 2H), 3.52 (dd, J=14.3, 7.1 Hz, 2H), 3.12 (s, 3H), 2.66 (s, 3H), 1.20 (t, J=7.1 Hz, 3H), 0.90 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.28H.sub.31N.sub.3O.sub.4S: 506.21 (M+H.sup.+); Found: 506.05, 507.00 (M+H.sup.+).

EXAMPLE 14

Preparation of (S)-2-tert-butoxy-2-((S)-2-(diethylamino)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid (45).

[0750] Compound 45 was prepared from compound 32 according to the procedure used to prepare compound 35 (except that diethylamine was used instead of azetidine) in Example 10.

##STR00121##

[0751] Compound 45: .sup.1H NMR (400 MHz, CD.sub.3OD) 8.90 (s, 1H), 7.90 (d, J=7.9 Hz, 2H), 7.61 (s, 1H), 7.44 (d, J=7.9 Hz, 1H), 5.17 (s, 1H), 4.71 (m, 2H), 3.66 (s, 6H), 2.73 (s, 3H), 1.95 (s, 4H), 1.29 (d, J=5.9 Hz, 6H), 0.90 (s, 8H).

[0752] LCMS-ESI.sup.+ (m/s): [M+H].sup.+ calcd for C.sub.29H.sub.34N.sub.3O.sub.4S: 520.23(M+H.sup.+); Found: 520.05, 521.13 (M+H.sup.+).

EXAMPLE 15

Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(isopropyl(methyl)amino)-5-methylbenzo[d]thiazol-6-yl)acetic acid (46) and (S)-2-tert-butoxy-2-((R)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(isopropyl(methyl)amino)-5-methylbenzo[d]thiazol-6-yl)acetic acid (47).

[0753] Compounds 46 and 47 were prepared from compound 32 according to the procedure used to prepare compound 35 (except that N-methyl-N-isopropylamine was used instead of azetidine) in Example 10.

##STR00122##

[0754] Compound 46: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) 8.76 (d, J=5.4 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.73 (d, 5.2 Hz, 1H), 7.49 (s, 1H), 7.35 (d, J=8.1 Hz, 1H), 5.14 (s, 1H), 4.67 (t, J=5.7 Hz, 2H), 4.23-4.06 (m, 1H), 3.59 (t, J=5.8 Hz, 2H), 3.00 (s, 3H), 2.67 (s, 3H), 1.23 (t, 6.5 Hz, 6H), 0.89 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.29H.sub.34N.sub.3O.sub.4S: 520.23 (M+H+); Found: 519.95, 521.00 (M+H.sup.+).

##STR00123##

[0755] Compound 47: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) 8.67 (d, J=4.9 Hz, 1H), 8.02 (d, J=8.1 Hz, 1H), 7,48 (d, J=4.6 Hz, 1H), 7.44 (s, 1H), 7.28 (d, J=8.1 Hz, 1H), 5,19 (s, 1H), 4.67-4.52 (m, 2H), 4.11-4.00 (m, 1H), 3.50-3.43 (m, 1H), 3.08 (s, 5H), 2.62 (s, 4H), 1.26 (d, J=6.1 Hz, 6H), 0.80 (s, 9H).

[0756] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.27H.sub.34N.sub.3O.sub.4S: 520.23 (M+H.sup.+); Found: 520.05, 521.08 (M+H.sup.+).

EXAMPLE 16a

Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(isobutyl(methyl)amino)-5-methylbenzo[d]thiazol-6-yl)acetic acid (48) and (S)-2-tert-butoxy-2-((R)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(isobutyl(methyl)amino)-5-methylbenzo[d]thiazol-6-yl)acetic acid (49).

[0757] Compounds 48 and 49 were prepared from compound 32 according to the procedure used to prepare compound 35 (except that N-methyl-N-isobutylamine was used instead of azetidine) in Example 10.

##STR00124##

[0758] Compound 48: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) 8.77 (d, J=5.4 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.75 (d, J=5.1 Hz, 1H), 7.49 (s, 1H), 7.36 (d, J=8.0 Hz, 1H), 5.13 (s, 1H), 4.68 (dd, J=9.9, 6.0 Hz, 2H), 3.60 (t, J=6.0 Hz, 2H), 3.27 (m, 2H), 3.13 (s, 4H), 2.66 (s, 3H), 2.08 (m, 1H), 0.89-0.87 (m, 15H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.30H.sub.35N.sub.3O.sub.4S: 534.24 (M+H.sup.+); Found: 533.9 (M+H.sup.+).

##STR00125##

[0759] Compound 49: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) 8.69 (d, J=5.0 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.54 (d, J=4.9 Hz, 1H), 7.46 (s, 1H), 7.32 (d, J=8.1 Hz, 1H), 5.19 (s, 1H), 4.62 (m, 10 Hz, 2H), 3.50 (t, J=5.8 Hz, 2H), 3,22 (s, 3H), 2.63 (s, 3H), 2.21-2.04 (m, 1H), 0.91 (d, J=6.6 Hz, 6H). 0.83 (s, 9H). LCMS-ESI.sup.30 (m/z): [M+H].sup.+ calcd for C.sub.30H.sub.36N.sub.3O.sub.4S: 534.24 (M+H.sup.+); Found: 534.04, 535.05 (M+H.sup.+).

EXAMPLE 16b

Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methyl-2-(pyrrolidin-1-yl)benzo[d]thiazol-6-yl)acetic acid (58) and (S)-2-tert-butoxy-2-((R)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methyl-2-(pyrrolidin-1-yl)benzo[d]thiazol-6-yl)acetic acid (51).

[0760] Compounds 50 and 51 were prepared from compound 32 according to the procedure used to prepare compound 35 (except that pyrrolidine was used instead of azetidine) in Example 10.

##STR00126##

[0761] Compound 50: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) 8.76 (d, J=5.3 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.69 (d, J=5.1 Hz, 1H), 7.50 (s, 1H), 7.33 (d, J=8.0 Hz, 1H), 5.15 (s, 1H), 9.03-0.64 (m, 79H), 4.70-4.60 (m, 2H), 3.56 (dd, J=13.8, 7.7 Hz, 6H), 2.68 (s, 3H), 2.10 (t, J=6.7 Hz, 4H), 0.89 (s, 10H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.23H.sub.32N.sub.5O.sub.4S: 518.21 (M+H.sup.+); Found: 517.99, 518.97(M+H.sup.+).

##STR00127##

[0762] Compound 51: .sup.1-NMR: 400 MHz, (CD.sub.3OD) 8.67 (d, J=4.7 Hz, 1H), 8,01 (d, J=8.1 Hz, 1H), 7.46 (d, J=4.8 Hz, 1H), 7.44 (s, 1H), 7.27 (d, J=8.1 Hz, 1H), 5.20 (s, 1H), 4.68-4.50 (m, 2H), 3.57 (s, 3H), 3.45 (t, J=5.8 Hz, 2H), 2.63 (s, 4H), 2.14 (t, J=6.3 Hz, 4H), 0.79 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.29H.sub.32N.sub.3O.sub.4S: 518.21 (M+H.sup.+); Found: 518.07, 519.07(M+H.sup.+).

EXAMPLE 17

Preparation of (S)-2-tert-butoxy-2-((S)-2-(3,3-difluoroazetidin-1-yl)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid (52) and (S)-2-tert-butoxy-2-((R)-2-(3,3-difluoroazetidin-1-yl)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid (53).

[0763] Compounds 52 and 53 were prepared from compound 32 according to the procedure used to prepare compound 35 (except that 2,2-difluoroazetidine was used instead of azetidine) in Example 10.

##STR00128##

[0764] Compound 52: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) 8.80 (d, J=5.6 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.83 (d, J=5.6 Hz, 1H), 7.61 (s, 1H), 7.41 (d, 8.2 Hz, 1H), 5.17 (s, 1H), 4.76-4.64 (m, 2H), 4.56-4.43 (m, 4H), 3.65 (t, J=5.9 Hz, 2H), 2.69 (s, 3H), 0.91 (s, 9H). .sup.19F NMR (377 MHz, CD.sub.3OD) 77.88 (s). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.28H.sub.28F.sub.2N.sub.3O.sub.4S: 540.18 (M+H.sup.+); Found: 539.96, 540.96 (M+H.sup.+).

##STR00129##

[0765] Compound 53: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) 8.71 (d, J=5.4 Hz, 1H), 8.14 (d, J=8.2 Hz, 1H), 7.69 (d, J=5.4 Hz, 1H), 7.57 (s, 1H), 7.40 (d, J=8.2 Hz, 1H), 5.21 (s, 1H), 4.72-4.60 (m, 2H), 4.56-4.42 (m, 4H), 3.58 (t, J=6.0 Hz, 2H), 2.65 (s, 3H), 0.91 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.28H.sub.28F.sub.2N.sub.3O.sub.4S: 540.18 (M+H.sup.+); Found: 539.98, 541.02 (M+H.sup.+).

EXAMPLE 18

Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(3-methoxyazetidin-1-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid (54) and (S)-2-tert-butoxy-2-((R)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(3-methoxyazetidin-1-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid (55).

[0766] Compounds 54 and 55 were prepared from compound 32 according to the procedure used to prepare compound 35 (except that 2-methoxyazetidine was used instead of azetidine) in Example 10.

##STR00130##

[0767] Compound 54: .sup.1H-NMR; 400 MHz, (CD.sub.3OD) : 8.78 (d, J=5.5 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.77 (d, J=6.1 Hz, 1H), 7.52 (s, 1H), 7.37 (d, J=7.8 Hz, 1H), 5.16 (s, 1H), 4.73-4.64 (m, 2H), 4.41 (ddd, J=9.9, 6.2, 3.4 Hz, 1H), 4.31 (id, J=7.7, 1.0 Hz, 2H), 4.02-3.90 (m, 2H), 3.62 (t, J=5.7 Hz, 2H), 2.68 (s, 4H), 0.91 (s, 11H), LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.29H.sub.32N.sub.3O.sub.5S; 534.21 (M+H.sup.+); Found: 533.95, 534.97(M+H.sup.+).

##STR00131##

[0768] Compound 55: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) 8.67 (d, J=5.1 Hz, 1H), 8.04 (d; J=8.2 Hz, 1H), 7.52 (d, J=4.7 Hz, 1H), 7.43 (s, 1H), 7.30 (d, J=8.1 Hz, 1H), 5.19 (s, 1H), 4.66-4.56 (m, 2H), 4.42 (m, 1H), 4.38-4.32 (m, 2H), 4.08-4.01 (m, 2H), 3.49 (t, J=6.0 Hz, 3H), 2.61 (s, 3H), 0.82 (s, 10H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.29H.sub.32N.sub.3O.sub.5S: 534.21 (M+H.sup.+); Found: 534.03, 535.08 (M+H.sup.+).

EXAMPLE 19

Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropano[4,3,2-de]quinolin-7-yl)-2-(3-fluoroazetidin-1-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid (56).

[0769] Compound 56 was prepared from compound 32 according to the procedure used to prepare compound 35 (except that 2-fluoroazetidine was used instead of azetidine) in Example 10.

##STR00132##

[0770] Compound 56: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) 8.79 (d, J=5.5 Hz, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.79 (d, J=5.1 Hz, 1H), 7.55 (s, 1H), 7.39 (d, J=7.9 Hz, 1H), 5.58-5.38 (m, 1H), 5.16 (s, 1H), 4.70 (td, J=5.9, 3.1 Hz, 2H), 4.49-4.35 (m, 2H), 4.28-4.12 (m, 2H), 3.63 (t, J=6.0 Hz, 2H), 2.68 (s, 3H), 0.91 (s, 9H).

[0771] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.28H.sub.29FN.sub.3O.sub.4S: 522.19 (M+H.sup.+); Found: 521.97, 523.02 (M+H.sup.+).

EXAMPLE 20a

Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methyl-2-(3 -methylazetidin-1-yl)benzo[d]thiazol-6-yl)acetic acid (57).

[0772] Compound 57 was prepared from compound 32 according to the procedure used to prepare compound 35 (except that 2-methylazetidine was used instead of azetidine) in Example 10.

##STR00133##

[0773] Compound 57: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 8.92 (s, 1H), 7.90 (d, J=7.6 Hz, 2H), 7.56 (s, 1H), 7.44 (d, J=7.3 Hz, 1H), 5.18 (s, 1H), 4.73 (s, 2H), 4.48 (s, 2H), 3.99 (s, 2H), 3.68 (s, 2H), 3.12 (m, 1H), 2.73 (s, 3H), 1.35 (d, J=5.6 Hz, 3H), 0.91 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.29H.sub.32N.sub.3O.sub.4S: 518.21(M+H.sup.+); Found: 518.09, 519.12(M+H.sup.+).

EXAMPLE 20b

Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methyl-2-(3-(methylsulfonyl)azetidin-1-yl)benzo[d] thiazol-6-yl)acetic acid (58).

[0774] Compound 58 was prepared from compound 32 according to the procedure used to prepare compound 35 (except that 2-methylsulfonylazetidine was used instead of azetidine) in Example 10.

##STR00134##

[0775] Compound 58: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : .sup.1H NMR (400 MHz, cd.sub.3od) 8.85 (d, J=5.3 Hz, 1H), 7.89 (t, J=6.7 Hz, 2H), 7.61 (s, 1H), 7.44 (d, J=8.1 Hz, 1H), 5.18 (s, 1H), 4.72 (dd, J=9.0, 6.2 Hz, 2H), 4.59-4.35 (m, 5H), 3.01 (s, 3H), 2.72 (s, 3H), 0.92 (s, 9H), LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.29H.sub.32N.sub.3O.sub.6S: 582.17 (M+H.sup.+); Found: 581.95, 583.02(M+H.sup.+).

EXAMPLE 21

Preparation of (S)-2-((S)-2-(((1,3-dioxolan-2-yl)methyl)(methyl)amino)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetic acid (59) and (S)-2-((R)-2-(((1,3-dioxolan-2-yl)methyl)(methyl)amino)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetic acid (60). Compounds 59 and 60 were prepared from compound 32 according to the procedure used to prepare compounds 35 (except that 1-(1,3-dioxolan-2-yl)-N-methylmethanamine was used instead of azetidine) in Example 10.

[0776] ##STR00135##

[0777] Compound 59: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 8.81 (d, J=6 Hz, 1H), 7.85 (d, J=8 Hz, 1H), 7.81 (4 J=6 Hz, 1H), 7.54 (s, 1H), 7.40 (d, J=8 Hz, 1H), 5.15 (s, 1H), 5.07 (m, 1H), 4.69 (m, 2H), 3.91 (m, 2H), 3.82 (m, 2H), 3.63 (m, 2H), 3.30 (s, 3H), 2.68 (s, 3H), 0.89 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.30H.sub.33N.sub.3O.sub.6S: 564.2 (M+H.sup.+); Found: 564.1 (M+H.sup.+).

##STR00136##

[0778] Compound 60: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 8.70 (d, J=6 Hz, 1H), 8.09 (d, J=8 Hz, 1H), 7.60 (d, J=6 Hz, 1H), 7.48 (s, 1H), 7.35 (d, J=8 Hz, 1H), 5.19 (s, 1H), 5.07 (m, 1H), 4.65 (m, 2H), 3.92 (m, 2H), 3.83 (m, 2H), 3.53 (m, 2H), 3.23 (s, 3H), 2.63 (s, 3H), 0.85 (s, 9H), LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.30H.sub.33N.sub.3O.sub.6S: 564.2 (M+H.sup.+); Found: 564.1 (M+H.sup.+).

EXAMPLE 22

Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-methylbenzo[d]thiazol-6-yl)acetic acid (61) and (S)-2-tert-butoxy-2-((R)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-methylbenzo[d]thiazol-6-yl)acetic acid (62).

[0779] Compounds 61 and 62 were prepared from compound 32 according to the procedure used to prepare compound 35 (except that N1,N1,N2-trimethylethane-1,2-diamine was used instead of azetidine) in Example 10.

##STR00137##

[0780] Compound 61: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 8.78 (d, J=6 Hz, 1H), 7.80 (m, 2H), 7.57 (s, 1H), 7.38 (d, J=8 Hz, 1H), 5.15 (s, 1H), 4.67 (m, 2H), 4.11 (m, 1H), 3.94 (s, 1H), 3.63 (t, J=6 Hz, 2H), 3.47 (m, 2H), 3.02 (s, 6H), 2.66 (s, 3H), 0.89 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.30H.sub.36N.sub.4O.sub.4S: 549.3 (M+H.sup.+); Found: 549.0 (M+H.sup.+).

##STR00138##

[0781] Compound 62: .sup.1H-NMR; 400 MHz, (CD.sub.3OD) : 8.71 (d, J=6 Hz, 1H), 8.13 (d, J=8 Hz), 7.70 (d, J=6 Hz, 2H), 7.54 (s, 1H), 7.41 (d, J=8 Hz, 1H), 5.18 (s, 1H), 4.66 (m, 2H), 4.06 (m, 1H), 3.98 (s, 1H), 3.59 (t, J=6 Hz, 2H), 3.47 (m, 2H), 3.02 (s, 3H), 3.00 (s, 3H), 2.63 (s, 3H), 0.89 (s, 9H).

[0782] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.30H.sub.36N.sub.4O.sub.4S: 549.3 (M+H.sup.+); Found: 549.0 (M+H.sup.+).

EXAMPLE 23

Preparation of (2S)-2-(2-(benzyl(methyl)amino)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetic acid (63).

[0783] Compound 63 was prepared as a mixture of atropisomers from compound 32 according to the procedure used to prepare compound 35 (except that N-methyl-N-benzylamine was used instead of azetidine) in Example 10.

##STR00139##

[0784] Compound 63: LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.33H.sub.33N.sub.3O.sub.4S: 568.2 (M+H.sup.+); Found: 568.1 (M+H.sup.+).

EXAMPLE 24

Preparation of (S)-2-tert-butoxy-2-((R)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-((2-(dimethylamino)-2-oxoethyl)(methyl)amino)-5-methylbenzo[d]thiazol-6-yl)acetic acid (64).

[0785] Compound 64 was prepared from compound 32 according to the procedure used to prepare compound 35 (except that N,N-dimethyl-2-(methylamino)acetamide was used instead of azetidine) in Example 10.

##STR00140##

[0786] Compound 64: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 8.72 (d, J=6 Hz, 1H), 8.14 (d, J=8 Hz), 7.70 (d, J=6 Hz, 2H), 7.48 (s, 1H), 7.41 (d, J=8 Hz, 1H), 5.19 (s, 1H), 4.66 (m, 2H), 3.58 (t, J=6 Hz, 2H), 3.42 (s, 2H), 3.10 (s, 3H), 3.00 (s, 3H), 2.94 (s, 3H), 2.63 (s, 3H), 0.91 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.30H.sub.34N.sub.4O.sub.5S: 563.2 (M+H.sup.+); Found: 563.1 (M+H.sup.+).

EXAMPLE 25

Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-methoxy-5-methylbenzo[d]thiazol-6-yl)acetic acid (66).

[0787] ##STR00141##

[0788] Compound 66: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 8.63 (d, J=4.4 Hz, 1H); 7.68 (d; J=8.0 Hz, 1H); 7.54 (s, 1H); 7.38 (d, J=4.8 Hz, 1H); 7.14 (d, J=7.6 Hz, 1H); 5.08 (s, 1H); 4.58-4.53 (m, 2H); 4.11 (s, 3H); 3.39 (t, J=6.0 Hz, 2H); 2.61 (s, 3H); 0.87 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.26H.sub.27N.sub.2O.sub.5S: 479.16 (M+H.sup.+); Found: 479.00, 480.02 (M+H.sup.+).

##STR00142## ##STR00143##

Step 1.

[0789] Preparation of 2-bromo-6-methyl-4-nitrophenyl trifluoromethanesulfonate (65B). To a solution of 2-bromo-6-methyl-4-nitrophenol (65A) (58.0 g, 250 mmol) in CH.sub.2Cl.sub.2 (500 mL) at 70 C. was added triethylamine (45.3 mL, 325 mmol) then trifluoromethanesulfonic acid anhydride (46.3 mL, 275 mmol). After 20 min, a solution of HCl was added (0.5 M, 500 mL). The layers were separated. The organic layer was dried, filtered, and concentrated in vacuo. The crude oil was run through a plug of SiO.sub.2 and celite with 10% EtOAc in hexanes to give 90 g of 65B.

[0790] .sup.1H-NMR: 400 MHz, (CDCl.sub.3) : 8.40 (d, J=2.4 Hz, 1H), 8.15 (d, J=2.4 Hz, 1H), 2.58 (s, 3H).

Step 2.

[0791] Preparation of 1-bromo-3-methyl-5-nitro-2-vinylbenzene (65C): The reaction mixture of 2-bromo-6-methyl-4-nitrophenyl trifluoromethanesulfonate (65B) (10.1 g, 27.7 mmol), tributylvinyltin (8.18 ml, 27.7 mmol), LiCl (1.4 g, 33.2 mmol), PdCl.sub.2dppf (607 mg, 0.83 mmol) in DMF (50 ml) was reacted at 70 C. for 3 h. Then 2N NaOH was added and stirred at 70 C. for 5 min. The reaction mixture was cooled down, washed by sat. NaHCO.sub.3, extracted by EtOAc, dry over MgSO.sub.4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in Hexanes to give 65C (1.9 g, 30%). .sup.1H-NMR: 400 MHz, (CDCl.sub.3) : 8.30 (d, J=0.8 Hz, 1H), 8.03 (d, J=1 Hz, 1H), 6.71-6.64 (dd, J=18, 12 Hz, 1H), 5.77-5.74 (d, J=12 Hz, 1H), 5.51-5.46 (d, J=18 Hz,1H), 2.48 (s, 3H).

Step 3.

[0792] Preparation of (S)-1-(2-bromo-6-methyl-4-nitrophenyl)ethane-1,2-diol (65D): The reaction mixture of 1-bromo-3-methyl-5-nitro-2-vinylbenzene (65C) (12.3 g, 50.83 mmol), AD-mix (71 g), MeSO.sub.2NH.sub.2 (4.8 g, 50.8 mmol) in t-butyl alcohol/H2O (1:1) (200 ml) was stirred at 0 C. for 3 days. Na.sub.2SO.sub.3 (6 g) was added to quench the reaction, stirred at rt for 40 min. The reaction mixture was washed by water, extracted by EtOAc, dry over MgSO.sub.4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in Hexanes to give 6.96 g of 65D and recovered 2.3 g of 65C.

[0793] .sup.1H-NMR: 400 MHz, (CDCl.sub.3) : 8.25 (d, J=2 Hz, 1H), 7.98 (d, J=2 Hz, 1H), 5.55 (m, 1H), 3.93 (dd, J=11, 9 Hz, 1H), 3.77 (dd, J=11.4 Hz), 2.66 (s, 3H).

Step 4.

[0794] Preparation of (S)-2-(2-bromo-6-methyl-4-nitrophenyl)-2-hydroxyethyl pivalate (65E): To a suspension of (S)-1-(2-bromo-6-methyl-4-nitrophenyl)ethane-1,2-diol (65D) (6.96 g, 25.22 mmol) in DCM (100 ml), was added pyridine (5 mL) at 0 C. To the solution was added pivaloyl chloride (PivCl) slowly at 0 C. The reaction mixture was stirred at 0 C. for 5 min, then raised to rt, stirred at rt for 5 h. The reaction mixture was washed by sat. NaHCO.sub.3, extracted by DCM, dry over MgSO.sub.4, filtered, purified by silica gel column, eluting by 0-40% EtOAc in Hexanes to give 9.13 g of 65E. The product taken on without full characterization.

Step 5.

[0795] Preparation of (S)-2-(2-bromo-6-methyl-4-nitrophenyl)-2-tert-butoxyethyl pivalate (65F): To a solution of (S)-2-(2-bromo-6-methyl-4-nitrophenyl)-2-hydroxyethyl pivalate (65E) in t-butyl acetate at 0 C., was added HClO.sub.4 (perchloric acid) (5.45 ml) slowly, stirred at 0 C. for 5 min, then the reaction mixture was warmed up to rt and stirred for 3 hs. The mixture was diluted by EtOAc, washed by sat NaHCO.sub.3, extracted by EtOAc, dry over MgSO.sub.4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in Hexanes to give 65F (9g, 85 %).

[0796] .sup.1H-NMR: 400 MHz, (CDCl.sub.3) : 8.23 (d, J=1 Hz, 1H), 7.96 (d, J=1.2 Hz, 1H), 5.58-5.54(m, 1H), 4.30-4.25 (m, 1 H), 4.16-4.12 (m, 1H), 2.71 (s, 3H), 1.154 (s, 9H). 1.151 (s, 9H).

Step 6.

[0797] Preparation of (S)-2-(2-amino-7-bromo-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (65H): To a solution of S)-2-(2-bromo-6-methyl-4-nitrophenyl)-2 -tert-butoxyethyl pivalate (9 g, 21.63 mmol) in EtOH (50 ml) and EtOAc (50 ml) was added Pt/C (1.5 g), attached with a balloon of H.sub.2. More Pt/ C (500 mg) was added after 3 h. Then the reaction mixture was stirred at rt for another 2 h. The reaction mixture was filtered over celite, concentrated down to give product (S)-2-(4-amino-2-bromo-6-methylphenyl)-2-tert-butoxyethyl pivalate (65G) and went to next step without purification. To a solution of (S)-2-(4-amino-2-bromo-6-methylphenyl)-2-tert-butoxyethyl pivalate (65G) (21.63 mmol) in HOAc/THF (80 ml, 1:1) was added KSCN at 0 C. The reaction mixture was stirred at 0 C. for 0.5 h. Then Br.sub.2 was added slowly, reacted at 0 C. The reaction was quenched by adding sat. NaHSO.sub.3, extracted by EtOAc, dried over MgSO.sub.4, purified by silica gel column, eluting by 0-40% EtOAc in Hexanes to give 65H (2.3 g, 24% over 2 steps).

[0798] .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 7.15 (s, 1H), 5.51 (t, J=7 Hz, 1H) 4.28 (m, 1H), 4.14 (m, 1H), 2.62 (s, 3H), 1.15 (s, 9H), 1.10 (s, 9H).

[0799] LCMS-ESI.sup.+: calc'd for C.sub.19H.sub.29BrN.sub.2O.sub.4S: 443.1 (M+H.sup.+); Found: 443.1 (M+H.sup.+).

Step 7.

[0800] Preparation of (S)-2-(7-bromo-2-chloro-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (65I): The reaction mixture of (S)-2-(2-amino-7-bromo-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (65H) (100 mg, 0.226 mmol), t-butyl nitrite (32 l, 0.271 mmol), CuCl.sub.2 (36 mg, 0.271 mmol) in acetonitrile (1.5 ml) was reacted at rt. The reaction mixture was diluted by EtOAc, washed by water, extracted by EtOAc, dried over MgSO.sub.4, filtered, concentrated down and purified by silica gel column, eluting by 0-40% EtOAc in Hexanes to give 65I (90 mg, 86 %).

[0801] LCMS-ESI.sup.+: calc'd for C.sub.19H.sub.25ClBrNO.sub.3S: 462.0 (M+H.sup.+); Found: 462.1 (M+H.sup.+).

Step 8.

[0802] Preparation of (S)-2-(7-bromo-2-methoxy-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (65J): The reaction mixture of (S)-2-(7-bromo-2-chloro-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (65I) (90 mg, 0.195 mmol), NaOMe in MeOH (25 % wt, 66 ul) in MeOH (3 ml) was heated at 50 C. for 20 min in sealed microwave vial. The reaction mixture was washed by sat. NaHCO.sub.3, extracted by EtOAc, dried over MgSO.sub.4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in Hexanes to give 65J (70 mg, 79 %).

[0803] LCMS-ESI.sup.+: calc'd for C.sub.20H.sub.28BrNO.sub.4S: 458.1 (M+H.sup.+); Found: 458.1 (M+H.sup.+).

Step 9.

[0804] Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-methoxy-5-methylbenzo[d]thiazol-6-yl)ethyl pivalate (65K): The reaction mixture of (S)-2-(7-bromo-2-methoxy-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (65K) (70 mg, 0.153 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid hydrochloride (58 mg, 0.23 mmol), 2N K.sub.2CO.sub.3 ( 380 ul), Pd(PPb.sub.3).sub.4 (17 mg, 0.015 mmol) in DME (3 ml) was heated at 90 C. overnight. The reaction mixture was washed by sat. NaHCO.sub.3, extracted by EtOAc, dried over MgSO.sub.4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in Hexanes to give 65K.

[0805] LCMS-ESI.sup.+: calc'd for C.sub.31H.sub.36N.sub.2O.sub.5S: 549.2 (M+H.sup.+); Found: 549.0 (M+H.sup.+).

Step 10.

[0806] Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-methoxy-5-methylbenzo[d]thiazol-6-yl)ethanol. The mixture of (S)-2-text-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-methoxy-5-methylbenzo[d]thiazol-6-yl)ethyl pivalate (65K) (20 mg, 0.036 mmol), 2N NaOH (360 ul) in THF/MeOH (1:1, 2 ml) was stirred at 40 C. overnight. The reaction mixture then was washed by sat. NaHCO.sub.3, extracted by EtOAc, dried over MgSO.sub.4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in Hexanes to give the product (11 mg).

[0807] LCMS-ESI.sup.+: calc'd for C.sub.26H.sub.28N.sub.2O.sub.4S: 465.2 (M+H.sup.+); Found: 465.7 (M+H.sup.+).

Step 11.

[0808] Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-methoxy-5-methylbenzo[d]thiazol-6-yl)acetic acid (66): To a solution of (S)-2-tert-butoxy-2-(S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-methoxy-5-methylbenzo[d]thiazol-6-yl)ethanol (11 mg, 0.024 mmol) in wet acetonitrile (0.75 % v H2O), was added stock solution of H.sub.6IO.sub.5/CrO.sub.3 (0.439 mmol, 500 ul) at 0 C. After the reaction was finished, the reaction was quenched by adding 1.5 M K.sub.2HPO.sub.4, extracted by EtOAc, the organic phase was washed by NaHSO.sub.3/brine(1:1), dried over MgSO.sub.4, filtered, concentrated down and purified by silica get column, eluting by 20-80% EtOAc in hexanes to give 66 (3.1 mg).

[0809] .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 8.63 (d, J=4.4 Hz, 1H); 7.68 (d, J=8.0 Hz, 1H); 7.54 (s, 1H); 7.38 (d, J=4.8 Hz, 1H); 7.14 (d, J=7.6 Hz, 1H); 5.08 (s, 1H); 4.58-4.53 (m, 2H); 4.11 (s, 3H); 3.39 (t, J=6.0 Hz, 2H); 2.61 (s, 3H); 0.87 (s, 9H) ppm.

[0810] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.26H.sub.27N.sub.3O.sub.5S: 479.16 (M+H.sup.+); Found: 479.00, 480.02(M+H.sup.+).

##STR00144##

[0811] Compound 68: .sup.1H-NMR: 400 MHz, (CDCl.sub.3) : 8.66 (d, J=4.0 Hz, 1H); 7.69 (d, J=8.4Hz, 1H); 7.29 (d, J=4.0 Hz, 1H); 7.16 (d, J=8.4 Hz, 1H); 6.97 (s, 1H); 4.94 (s, 1H); 4.59 (dd, J.sub.1=5.2 Hz, J.sub.2=9.6 HZ, 2H); 3.44 (s, 3H); 3.39 (t, J=5.6 Hz, 2H); 2.64 (2, 3H); 0.90 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.26H.sub.27N.sub.2O.sub.5S: 479-0.16 (M+H.sup.+); Found: 479.04, 480.06(M+H.sup.+).

##STR00145##

Step 1.

[0812] Preparation of (S)-2-(2-(benzyloxy)-7-bromo-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (67A): NaH (415 mg, 10.38 mmol) was added to BnOH, stirred at it for 0.5 h. The NaOBn solution was transferred to a flask charged with (S)-2-(7-bromo-2-chloro-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (65I) (1.6 g, 3.46 mmol). The reaction mixture was heated at 60 C. for 45 min. The reaction mixture was washed by sat NaHCO.sub.3, extracted by EtOAc, the organic phase was washed by brine, dry over MgSO.sub.4, filtered, concentrated down, distilled most NaOH off. The residue was purified by silica gel column, eluting by 0-50% EtOAc in hexanes.

[0813] .sup.1H-NMR: 400 MHz, (CDCl.sub.3) : 7.52-7.24 (m, 6H), 5,58 (s, 2H), 5.57-5.45 (m, 1H), 4.35-4.27 (m, 1H), 4.18-4.12 (m, 1H), 2.68 (s, 3H), 1.07 (s, 18H).

Step 2.

[0814] Preparation of (S)-2-(7-bromo-2-hydroxy-5 -methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (67B): The mixture of (S)-2-(2-(benzyloxy)-7-bromo-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (67A), Pd/C (800 mg) in EtOAc/EtOH (10 ml, 1:1) was charged into a flask with a H.sub.2 balloon, and stirred at rt for 1 h. The reaction mixture was filtered over celite, concentrated down, purified by silica gel column, eluting by 0-50% EtOAc in hexanes to give 67B (850 mg).

[0815] .sup.1H-NMR: 400 MHz, (CDCl.sub.3) : 8.99 (s, 1H), 6.88 (s, 1H), 5.45 (t, J=7 Hz, 4.26-4.22 (m, 1H), 4.14-4.09 (m, 1H), 2.62 (s, 3H), 1.13 (s, 18H).

Step 3.

[0816] Preparation of (S)-2-(7-bromo-3,5-dimethyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (67C): To a solution of (S)-2-(7-bromo-2-hydroxy-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (67B) (40 mg, 0.090 mmol) in THF (1 ml) was added KOtBu (0.14 ml, 0.135 mmol 1M in THF) slowly at 78 C. After 15 min, MeI (8.5 ul, 0.135 mmol) was added at 78 C. and stirred at 78 C. for 15 min. Then the reaction was reacted at rt for 3 hs. The reaction mixture was washed by sat, NaHCO.sub.3, extracted by EtOAc, dried over MgSO.sub.4, filtered, concentrated down and purified by silica gel column, eluting by 0-40% EtOAc in hexanes to give 67C (30 mg, 73%).

[0817] .sup.1 H-NMR: 400 MHz, (CDCl.sub.3) : 6.79 (s, 1H), 5.49-5.45 (m, 1H), 4.27-4.23 (m, 1H), 4.14-4.10 (m, 1H), 3.40 (s, 3H), 2.66 (s, 3H), 1.46 (s, 18H).

Step 4.

[0818] Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,5-dimethyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)ethyl pivalate (67D): The reaction mixture of (S)-2-(7-bromo-3,5-dimethyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (67C) (20 mg, 0.044 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid hydrochloride (16.5 mg, 0.066 mmol), 2N K.sub.2CO.sub.3 (0.12 ml, 0.22 mmol), Pd(PPh.sub.3).sub.4 (5.0 mg, 0.0044 mmol) in DME (1 ml) was heated at 120 C. in sealed microwave vial for 3 hs. The reaction mixture was washed by sat, NaHCO.sub.3, extracted by EtOAc, the organic phase was dried over MgSO.sub.4, filtered, concentrated down and purified by silica gel column, eluting by 0-60% EtOAc in hexanes to give the product (15 mg, 62%).

[0819] LCMS-ESI.sup.+: calc'd for C.sub.31H.sub.36N.sub.2O.sub.5S: 549.2 (M+H.sup.+); Found: 549.0 (M+H.sup.+).

[0820] The remainder of the synthesis of compound 68 is analogous to the preparation of compound 66 from compound 65K in example 25.

EXAMPLE 27

Preparation of compound (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-isopropoxy-5-methylbenzo[d]thiazol-6-yl)acetic acid (70).

[0821] ##STR00146##

[0822] Compound 70: .sup.1H-NMR: 400 MHz, (CDCl.sub.3) : 8.60 (d, J=4.8 Hz, 1H); 7.76 (d, J=7.6 Hz, 1H); 7.57 (s, 1H); 7.28-7.26 (m, 1H); 7.15 (d, J=8.0 Hz, 1H); 5.37-5.30 (m, 1H); 4.97 (s, 1H); 4.61-4.57 (m, 2H); 3.39 (t, J=6.2 Hz, 2H); 2.64 (s, 3H); 1.39 (dd, J.sub.1=6.4 Hz, J.sub.1=14 Hz, 6H); 0.91 (s, 9H).

[0823] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.28H.sub.31N.sub.2O.sub.5S: 507.19 (M+H.sup.+); Found: 507.01, 508.07 (M+H.sup.+).

##STR00147##

Step 1.

[0824] Preparation of (S)-2-(7-bromo-5-methyl-2-oxo-3-((2-(trimethysilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (69A): Prepared by the similar method to make (S)-2-(7-bromo-3,5-dimethyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (67C) in example 26 from 67B using 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) instead of methyl iodide.

[0825] .sup.1H-NMR: 400 MHz, (CDCl.sub.3) : 7.05 (s, 1H); 5.53-5.49 (s, 1H), 5.34 (s, 2H), 4.32-4.27 (m, 1H), 4.18-4.14 (m, 1H), 3.66 (t, J=8 Hz, 2H), 2.68 (s, 3H), 1.19 (s, 18H), 0.97-0.89 (m, 2H), 0.00 (s, 5 9H).

Step 2.

[0826] Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,5-dimethyl-2-oxo-2,3 -dihydrobenzo[d]thiazol-6-yl)ethyl pivalate (69B): prepared by the similar method to make 67D from 67C in Example 26.

[0827] LCMS-ESI.sup.+: calc'd for C.sub.36H.sub.48N.sub.2O.sub.6SSi: 665.3 (M+H.sup.+); Found: 664.9 (M+H.sup.+).

Step 3.

[0828] Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)ethyl pivalate (69C): The reaction mixture of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,5-dimethyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)ethyl pivalate (69B) (250 mg, 0.376 mmol), TBAF (1M in THF, 1.1 ml, 1.1 mmol) in DME was heated at 120 C. in sealed microwave vial for 3 h. The reaction mixture was cooled down, washed by sat. NaHCO.sub.3, extracted by EtOAc, the organic phase was dried over MgSO.sub.4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give 69C (30 mg, 15 %).

[0829] LCMS-ESI.sup.30 : calc'd for C.sub.30H.sub.34N.sub.2O.sub.5S: 535.2 (M+H.sup.+); Found: 535.0 (M+H.sup.+).

Step 4.

[0830] Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-isopropoxy-5-methylbenzo[d]thiazol-6-yl)ethyl pivalate (69D): The reaction mixture of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)ethyl pivalate (69C) (30 mg, 0.056 mmol), Ag.sub.2CO.sub.3 (50% wt on celite, 310 mg, 0.56 mmol), isopropy bromide (160 ul, 1.63 mmol) in benzene/DME (1:1, 2 ml) was heated at 70 C. overnight. The reaction mixture was washed by water, extracted by EtOAc, the organic phase was dried over MgSO.sub.4, filtered, concentrated down and purified by silica gel column, eluting by 0-60% EtOAc in hexanes to give the product (15 mg, 46%).

[0831] LCMS-ESI.sup.+: calc'd for C.sub.33H.sub.40N.sub.2O.sub.5S: 577.3 (M+H.sup.+); Found: 577.0 (M+H.sup.+).

[0832] The remainder of the synthesis of compound 78 is analogous to the preparation of compound 66 from compound 65K in example 25.

EXAMPLE 28

Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methyl-2-oxo-3-(2-(trifluoromethyl)benzyl)-2,3-dihydrobenzo[d]thiazol-6-yl)acetic acid (71).

[0833] Compound 71 was prepared from compound 69C according to the procedure used to prepare compound 67C (except that 1(bromomethyl)-2-(trifluoromethyl)benzene was used instead of methyl iodide) in Example 26, and the remainder of the synthesis of compound 71 is analogous to the preparation of compound 66 from compound 65K in example 25.

##STR00148##

[0834] Compound 71: .sup.1H-NMR: 400 MHz, (CDCl.sub.3) : 8.72 (s, 1H); 7.76-7.73 (m, 2H); 7.50 (t, J=7.6 Hz, 1H); 7.42 (t, J=7.4 Hz, 1H); 7.33 (t, J=4.0 Hz, 1H); 7.2 (d, J=8.0 Hz, 1H); 7.13 (d, J=6.8 Hz, 1H); 6.72 (s, 1H); 5.34 (s, 1H); 4.95 (s, 1H); 4.65-4.60 (m, 2H); 3.42 (t, J=5.4 Hz, 2H); 2.52 (2, 3H); 0.88 (s, 9H).

[0835] .sup.19F NMR (377 MHz, CDCl.sub.3) 60.73. LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.33H.sub.30F.sub.3N.sub.2O.sub.4S: 623.18 (M+H.sup.+); Found: 623.09, 624.09(M+H.sup.+).

EXAMPLE 29

[0836] Preparation of (S)-2-((S)-3-benzyl-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)-2-tert-butoxyacetic acid (72).

[0837] Compound 72 was prepared from compound 69C according to the procedure used to prepare compound 67C (except that benzyl bromide was used instead of methyl iodide) in Example 26, and the remainder of the synthesis of compound 71 is analogous to the preparation of compound 66 from compound 65K in example 25.

##STR00149##

[0838] Compound 72: .sup.1H-NMR: 400 MHz, (CDCl.sub.3) : 8.67 (d, J=4.0 Hz, 1H); 7.70 (d, J=8.4 Hz, 1H); 7.37-7.36 (m, 4H); 7.34-7.29 (m, 2H); 7.16 (d, J=8.4 Hz, 1H); 6.92 (s, 1H); 5.21-5.01 (dd, J.sub.1=15.6 Hz, J.sub.2=79.6 Hz, 2H); 4.92 (s, 1H); 4.63-41.56 (m, 2H); 3.39 (t, J=5.8 Hz, 2H); 2.55 (s, 3H); 0.88 (s, 9H), LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.32H.sub.31N.sub.2O.sub.5S: 555.19 (M+H.sup.+); Found: 555.08, 556.12 (M+H.sup.+).

EXAMPLE 30

Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methyl-2-oxo-3-(3-(trifluoromethyl)benzyl)-2,3-dihydrobenzo[d]thiazol-6-yl)acetic acid (73).

[0839] Compound 73 was prepared from compound 69C according to the procedure used to prepare compound 67C (except that 1-(bromomethyl)-3-(trifluoromethyl)benzene was used instead of methyl iodide) in Example 26, and the remainder of the synthesis of compound 71 is analogous to the preparation of compound 66 from compound 65K in example 25.

##STR00150##

[0840] Compound 73: .sup.1H-NMR: 400 MHz, (CDCl.sub.3) : 8.68 (s, 1H); 7.71 (d, J=7.6 Hz, 1H); 7.64 (s, 1H); 7.59 (d, J=6.4 Hz, 1H); 7.51-7.48 (m, 2H); 7.32 (d, J=3.2 Hz, 1H); 7.18 (d, J=7.6 Hz, 1H); 6.87 (s, 1H); 5.25-5.06 (dd, J.sub.1=16 Hz, J.sub.2=63.2 Hz, 2H); 4.94 (s, 1H); 4.65-4.59 (m, 2H); 3.43 (t, J=5.2 Hz, 1H); 2.56 (s, 3H); 0.88 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.27H.sub.29N.sub.3O.sub.4S: 623.18 (M+H.sup.+); Found: 623.04, 624.09 (M+H.sup.+).

EXAMPLE 31

Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methyl-2-oxo-3-(4-(trifluoromethyl)benzyl)-2,3-dihydrobenzo[d]thiazol-6-yl)acetic acid (74).

[0841] Compound 74 was prepared from compound 69C according to the procedure used to prepare compound 67C (except that 1-(bromomethyl)-4-(trifluoromethyl)benzene was used instead of methyl iodide) in Example 26, and the remainder of the synthesis of compound 71 is analogous to the preparation of compound 66 from compound 65K in example 25.

##STR00151##

[0842] Compound 74: .sup.1H-NMR: 400 MHz, (CDCl.sub.3) : 8.67 (d, J==4.4 Hz, 1H); 7.70 (d, J=8.0 Hz, 1H); 7.63 (d, J=8.0 Hz, 1H); 7.46 (d, J=7.6 Hz, 1H); 7.31 (d, J=4.0 Hz, 1H); 6.86 (s, 1H); 5.25-5.07 (dd, J.sub.1=16, J.sub.2=56.8 Hz, 2H); 4.93 (s, 1H); 4.63-4.58 (m, 2H); 3.40 (t, J=5.8 Hz, 2H); 2.56 (s, 3H); 0.88 (s, 9H). LCMS-ESI.sup.+ [M+H].sup.+ calcd for C.sub.33H.sub.30F.sub.3N.sub.2O.sub.5S: 623.18 (M+H.sup.+); Found: 623.06, 624.14 (M+H.sup.+).

EXAMPLE 32

Preparation of (S)-2-((S)-2-(azetidin-1-yl)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetic acid (76).

[0843] ##STR00152##

[0844] Compound 76: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 8.65 (d, J=4.4 Hz, 1H); 7.70 (d, J=7.6 Hz, 1H); 7.39 (d, J=4.4 Hz, 1H); 7.16 (d, J=7.6 Hz, 1H); 5.04 (s, 1H); 4.57 (t, J=6.0 Hz, 2H); 4.15-4.10 (m, 4H); 3.41 (t, J=6.0 Hz, 2H); 2.50-2.46 (m, 6H); 0.90 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.28H.sub.29FN.sub.3O.sub.4S: 522.19 (M+H.sup.+); Found: 521.99, 523.00 (M+H.sup.+).

##STR00153##

Step 1.

[0845] Preparation of (S)-ethyl 2-(2-bromo-7-hydroxy-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (75A): To a solution of (S)-ethyl 2-(2-bromo-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)-2-tert-butoxyacetate (32): (300 mg, 0.938 mmol) is THF (5 ml) was added TBAF (1.0 M in THF, 4 ml) slowly. The reaction mixture was stirred at rt for 1 h. The reaction mixture was washed by a mixture of H.sub.2O (20 ml) and HOAc (200 ul), extracted by EtOAc, the organic phase was washed by sat. NaHCO.sub.3, dried over MgSO.sub.4, filtered, concentrated down and purified, by silica gel column, eluting by 0-40% EtOAc in hexanes to give 75A (380 mg). LCMS-ESI.sup.+: calc'd for C.sub.16H.sub.20BrNO.sub.4S: 402.0 (M+H.sup.+); Found: 401.9 (M+H.sup.+).

Step 2.

[0846] Preparation of (S)-ethyl 2-(2-bromo-4-fluoro-7-hydroxy-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (75B): The reaction mixture of (S)-ethyl 2-(2-bromo-7-hydroxy-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (75A) (380 mg, 0.948 mmol), Selectfluor (1.9 g, 4.74 mmol) in acetonitrile (7 ml) was reacted at 0 C. for 5 days. The reaction mixture was washed by 1.5 M KH.sub.2O.sub.4, extracted by EtOAc, the organic phase was dried over MgSO.sub.4, filtered, concentrated down and purified by silica gel column, eluting by 0-40% EtOAc in hexanes to give 75B (137 mg, 35%). LCMS-ESI.sup.+: calc'd for C.sub.16H.sub.19FNO.sub.4S; 420.0 (M+H.sup.+); Found: 420.1 (M+H.sup.+).

Step 3.

[0847] Preparation of (S)-ethyl 2-(2-(azetidin-1-yl)-4-fluoro-7-hydroxy-5methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (75C): Prepared by the similar method to make (S)-ethyl 2-(2-azetidin-1-yl)-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)-2-tert-butoxyacetate (33) in Example 10. LCMS-ESI.sup.+: calc'd for C.sub.19H.sub.25FN.sub.2O.sub.4S: 397.2 (M+H.sup.+); Found: 397.0 (M+H.sup.+).

Step 4.

[0848] Preparation of (S)-ethyl 2-(2-(azetidin-1-yl)-4-fluoro-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)-2-tert-butoxyacetate (75B): The reaction mixture of S)-ethyl 2-(2-(azetidin-1-yl)-4-fluoro-7-hydroxy-5methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (75C) (50 mg, 0.126 mmol), N-phenyl triflimite (90 mg, 0.252 mmol), Cs.sub.2CO.sub.3 (82 mg, 0.126 mmol) in THF (2 ml) was stirred at rt. After the reaction finished, the reaction was washed by sat NaHCO.sub.3, extracted by EtOAc, the organic phase was dried over MgSO.sub.4, filtered, concentrated down and purified by silica gel column, eluting by 0-40% EtOAc in hexanes to give 75D (50 mg, 75%). LCMS-ESI.sup.+: calc'd for C.sub.20H.sub.24F.sub.4N.sub.2O.sub.6S.sub.2: 529.1 (M+H.sup.+); Found: 529.0 (M+H.sup.+).

[0849] The remainder of the synthesis of compound 76 is analogous to the preparation of compound 35 from compound 33 in example 10.

EXAMPLE 33

Preparation of (S)-2-tert-butoxy-2-((S)-2-cyclopentenyl-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid (78) and (S)-2-tert-butoxy-2-((R)-2-cyclopentenyl-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid (79).

[0850] ##STR00154##

[0851] Compound 78: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 8.78 (d, J=5.6 Hz, 1H); 7.99 (s, 1H); 7.90 (d, J=8.0 Hz, 1H); 7.85 (d, J=5.6 Hz, 1H); 7.43 (d, J=7.6 Hz, 1H); 6.58 (s, 1H); 5.23 (s, 1H); 4.72-4.69 (m, 2H); 3.66 (t, J=5.8 Hz, 2H); 2.85-2.83 (m, 2H): 2.76 (s, 3H); 2.56 (m, 2H), 2.07-2.02 (m, 2H); 0.941 (s, 9H).

##STR00155##

[0852] Compound 79: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 8.71 (d, J=5.2 Hz, 1H); 8.22 (d, J=8.0 Hz, 1H): 7.97 (s, 1H); 7.77 (d, J=6.0 Hz, 1H); 7.47 (d, J=8.0 Hz, 1H); 6.56 (s, 1H); 5.27 (s, 1H); 4.70 (t, J=6.0 Hz, 2H); 3.63 (t, J=6.2 Hz, 2H); 2.84-2.83 (m, 2H); 2.72 (s, 3H); 2.55-2.54 (m, 2H); 2.07-2.03 (m, 2H); 0.94 (s, 9H).

##STR00156##

[0853] Preparation of (S)-ethyl 2-tert-butoxy-2-(2-cyclopentenyl-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)acetate (77). To a solution of 32 (100 mg, 0.19 mmol) in toluene (1 mL), ethanol (0.5 mL), water (0.5 mL) was added potassium carbonate (77 mmol). The reaction mixture was stirred at 90 C. for 2 h. The reaction was cooled to rt and diluted with water and EtOAc. The layers were separated, dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give 96 mg of 77. .sup.1H-NMR: 400 MHz, (CDCl.sub.3) : 7.82 (s, 1H), 6.72 (m, 1H), 5.60 (s, 1H), 4.17 (m, 1H), 4.11 (m, 1H), 2.92 (m, 2H), 2.63 (m, 2H), 2.53 (s, 3H), 2.10 (m, 2H), 1.17 (s, 9H), 1.13 (t, J=7 Hz, 3H).

[0854] The remainder of the synthesis of 78 and 79 follows the same route as Example 10 from compound 33.

EXAMPLE 34

Preparation of (S)-2-tert-butoxy-2-((S)-2-cyclopentyl-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid (80) and (S)-2-tert-butoxy-2-((R)-2-cyclopentyl-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid (81).

[0855] Compound 80 was prepared from compound 78 according to the procedure used to prepare compound 8F from 8E in Example 4.

##STR00157##

[0856] Compound 80: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 8.77 (d, J=6.0 Hz, 1H): 7.96 (s, 1H); 7.88 (d, J=8.0 Hz, 1H); 7.83 (d, J=6.0 Hz, 1H); 7.42 (d, J=8.0 Hz, 1H); 5.23 (s, 1H); 4.73-4.69 (m, 2H); 3.67-3.64 (m, 2H); 3.53-3.44 (m, 1H); 2.75 (s, 1H); 2.17-2.14 (m, 2H); 1.81-1.71 (m, 6H); 0.9 (s, 9H).

[0857] Compound 81 was prepared from compound 79 according to the procedure used to prepare compound 77 from 8E in Example 4.

##STR00158##

[0858] Compound 81: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 8.67 (d, J=5.2 Hz, 1H); 8.15 (d, J=8.4 Hz, 1H); 7.90 (s, 1H); 7.68 (d, J=5.6 Hz, 1H); 7.41 (d, J=8.4 Hz, 1H); 5.27 (s, 1H); 4.69-4.65 (m, 2H); 4.67 (t, J=6.2 Hz, 2H); 3.59 (t, J=6.0 Hz, 2H); 3.50-3.42 (m, 1H); 2.71 (s, 3H); 2.16-2.13 (m, 2H); 1.78-1.70 (m, 6H); 0.90 (s, 9H).

EXAMPLE 35

Preparation of (S)-2-tert-butoxy-2-((S)-2-cyclobutyl-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid (82).

[0859] Compound 82 was prepared from compound 32 according to the procedure used to prepare compound 77 in Example 33, except cyclobutyl zinc bromide was used instead of cyclopentenylboronic acid.

##STR00159##

[0860] Compound 82: .sup.1-NMR: 400 MHz, (CD.sub.3OD) 8.79 (d, J=5.6 Hz, 1H), 7.98 (s, 1H), 7.87 (dd, J=13.1, 6.9 Hz, 2H), 7.44 (d, J=8.4 Hz, 1H), 5.23 (s, 1H), 4.71 (dl, J=11.5, 5.8 Hz, 2H), 3.9.1 (p, J=8.3 Hz, 1H), 3.67 (t, J=5.8 Hz, 3H), 2.76 (s, 3H), 2.50-2.40 (m, 2H), 2.39-2.27 (m, 2H), 2.19-2.05 (m, 1H), 0.91 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.29H.sub.31N.sub.2O.sub.4S: 503.20 (M+H.sup.+); Found: 503.07, 504.10(M+H.sup.+).

EXAMPLE 36

Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-isobutyl-5-methylbenzo[d]thiazol-6-yl)acetic acid (83) and (S)-2-tert-butoxy-2-((R)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-isobutyl-5-methylbenzo[d]thiazol-6-yl)acetic acid (84).

[0861] Compounds 83 and 84 were prepared from compound 32 according to the procedure used to prepare compound 77 in Example 33, except tributyl(2-methylprop-1-enyl)stannane was used instead of cyclopentenylboronic acid. Also, hydrogenation was performed according to the procedure used to prepare 8F from 8E in Example 4.

##STR00160##

[0862] Compound 83: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 8.74 (d, J=5.4 Hz, 1H), 7.95 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.74 (d, J=5.7 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 5.22 (s, 1H), 4.69 (m, 2H), 3.61 (t, J=5.9 Hz, 2H), 2.90 (d, J=7.2 Hz, 2H), 2.75 (s, 3H), 0.97 (d, 6.5 Hz, 6H), 0.91 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.29H.sub.33N.sub.2O.sub.4S: 505.22 (M+H.sup.+): Found: 505.06, 506.06(M+H.sup.+).

##STR00161##

[0863] Compound 84: .sup.1 H-NMR: 400 MHz, (CD.sub.3OD) 8.65 (d, J=5.2 Hz, 1H), 8.12 (d, J=8.1 Hz, 1H), 7.90 (s, 1H), 7.61 (d, J=5.1 Hz, 1H), 7.37 (d, J=8.2 Hz, 1H), 5.28 (s, 1H), 4.65 (t, J=6.1 Hz, 2H), 3.55 (t, J=5.9 Hz, 2H), 2.89 (d, J=7.2 Hz, 2H), 2.70 (s, 4H), 0.97 (dd, J=6.6, 3.2 Hz, 7H), 0.88 (s, 10H).

[0864] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.29H.sub.33N.sub.2O.sub.4S: 505.22 (M+H.sup.+); Found: 505.01, 506.07 (M+H.sup.+).

EXAMPLE 37

Preparation of (S)-2-tert-butoxy-2-((S)-2-cyclopropyl-7-(2,3-dihydrobenzo[de]chromen-7-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid (85).

[0865] Compound 85 was prepared from compound 18 according to the procedure used to prepare compounds 19 and 20 (except that 2,3-dihydrobenzo[de]chromen-7-ylboronic acid was used instead of 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid) in Example 9.

##STR00162##

[0866] Compound 85: .sup.1 H-NMR: 400 MHz, (CD.sub.3OD) : 7.70 (s, 1H); 7.29-7.19 (m, 4H), 6.95 (d, J=4 Hz, 1H), 5.07 (s, 1H), 4.48-4.45 (m, 2H), 3.29-3.27 (m, 2H), 2.64 (s, 3H), 2.32-2.28 (m, 1H), 1.20-1.18 (m, 2H), 1.056-1.03 (m, 2H), 0.96 (s, 9H).

[0867] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.29H.sub.29NO.sub.4S: 488.2 (M+H.sup.+); Found: 488.1(M+H.sup.+).

EXAMPLE 38

Preparation of (S)-2-tert-butoxy-2-((S)-7-(5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-cyclopropyl-5-methylbenzo[d]thiazol-6-yl)acetic acid (86) and (S)-2-tert-butoxy-2-((R)-7-(5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-cyclopropyl-5-methylbenzo[d]thiazol-6-yl)acetic acid (87).

[0868] Compounds 86 and 87 was prepared from compound 18 according to the procedure used to prepare compounds 19 and 29 (except that 5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylboronic acid, was used instead of 2,3-dihydroprano[4,3,2-de]quinolin-7-ylboronic acid) in Example 9.

##STR00163##

[0869] Compound 86: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 7.63 (d, J=0.4 Hz, 1H); 6.74 (d, J=4.2 Hz, 1H), 6.44 (d, J=4.2 Hz, 1H), 5.21 (s, 1H), 4.26 (t, J=4.6 Hz, 2H), 3.51-3.49 (m, 2H), 2.65 (d, J=0.4 Hz, 3H), 2.40-2.36 (m, 1H), 1.26-1.23 (m, 2H), 1.13-1.11 (m, 2H), 1.09 (s, 9H), LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.25H.sub.27ClN.sub.2O.sub.4S: 487.1 (M+H.sup.+): Found: 487.1 (M+H.sup.+).

##STR00164##

[0870] Compound 87: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 7.60 (s, 1H); 6.83-6.78 (m, 2H), 5.27 (s, 1H), 4.27-4.24 (n, 2H), 3.51-3.48 (m, 2H), 2.55 (s, 3H), 2.40-2.36 (m, 1H), 1.28-1.23 (m, 2H), 1.13-1.12 (m, 2H), 1.01 (s, 9H).

[0871] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.25H.sub.27ClN.sub.2O.sub.4S: 487.1 (M+H.sup.+); Found: 487.1(M+H.sup.+).

EXAMPLE 39

Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydroprano[4,3,2-de]quinolin-7-yl)-2-isopropyl-5-methylbenzo[d]thiazol-6-yl)acetic acid (88).

[0872] Compound 88 was prepared from compound 32 according to the procedure used to prepare compound 77 in Example 33, except propen-2-yl-(tri-n-butyl)tin was used instead of cyclopentenylboronic acid. Also, hydrogenation was performed according to the procedure used to prepare 8F from 8E in Example 4.

##STR00165##

[0873] Compound 88: .sup.1H NMR (400 MHz, CD.sub.3OD) 8.70 (d, J=5.4 Hz, 1H), 7,90 (s, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.66-7.60 (m, 1H), 7.31 (d, J=8.0 Hz, 1H), 5.20 (s, 1H), 4.70-4.61 (m, 2H), 3.59-3.51 (m, 2H), 3.15-3.09 (m, 1H), 2.72 (s, 3H), 1.36 (m, 6H), 0.90 (s, 9H). LCMS-ESI.sup.+: calc'd for C.sub.28H.sub.30N.sub.2O.sub.4S: 491.2 (M+H.sup.+); found: 491.4 (M+H.sup.+).

EXAMPLE 40

Preparation of (S)-2-((S)-2-(azetidin-1-yl)-7-(2,3-dihydroprano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)-2-(tert-pentyloxy)acetic acid (89).

[0874] ##STR00166##

[0875] Compound 89: .sup.1H NMR (400 MHz, CD.sub.3OD) 8.75 (d, J=5.1 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.71 (d, J=5.6 Hz, 1H), 7.47 (s, 1H), 7.35 (d, J=8.1 Hz, 1H), 5.09 (d, J=0.6 Hz, 1H), 4.69-4.62 (m, 2H), 4.17 (t, J=7.7 Hz, 4H), 3.61-3.55 (m, 2H), 2.66 (s, 3H), 2.58-2.42 (m, 2H), 0.87 (d, J=2.9 Hz, 6H), 0.59 (t, J=7.0 Hz, 3H). .sup.19F NMR (377 MHz, CD.sub.3OD) 77.77. LCMS: calc'd=518.64, observed: 518.08

##STR00167##

[0876] Preparation of 90: A slurry of 31 (740 mg, 1.55 mmol) in tert-amyl acetate (7.0 mL) was treated with 70% aq. HClO.sub.4 (5 L) was added at 23 C. Reaction became cloudy, but LCMS analysis indicated minimal conversion. More 70% aq. HClO.sub.4 (50 L) was introduced. After 2 h, the reaction was added dropwise over 5 min to sat. aq. NaHCO.sub.3 (20 mL). H.sub.2O (10 mL) was added, and the system was extracted with DCM (320 mL). Combined organic layers were dried (Na.sub.2SO.sub.4), filtered, concentrated, and treated with hexane (10 mL). The system was concentrated again to remove some residual t-amyl alcohol. The residue was treated with PhH and loaded onto a 12 gram gold ISCO silica gel column. Chromatography (eluent Hexanes/Ethyl Acetate) gave 90 (134 mg, 16% yield) along with some recovered 31.

[0877] .sup.1H-NMR: 400 MHz, (CDCl.sub.3) : 7.80 (s, 1H), 5.49 (s, 1H), 4.24-4.06 (m, 2H), 2.57 (s, 3H), 1.60-1.40 (m, 2H), 1.17 (s, 3H), 1.16 (t, J=7.0 Hz, 3H), 1.05 (s, 3H), 0.80 (t, J=7.0 Hz, 3H). .sup.19F-NMR: 376 MHz, (CDCl.sub.3) : 73.8.

[0878] The remainder of the synthesis of 89 follows the same route as Example 10 from compound 32.

EXAMPLE 41

Preparation of (S)-2-tert-butoxy-2-((S)-2-(difluoromethyl)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid (92).

[0879] ##STR00168##

[0880] Compound 92: .sup.1H NMR, (400 MHz, CD.sub.3OD) 8.67 (d, J=5.6 Hz, 1H), 8.08 (d, J=5.9 Hz, 1H), 7.78-7.75 (m, 1H), 7.29-7.22 (m, 1H), 7.04 (s, 1H), 6.89 (s, 1H), 5.23 (s, 1H), 4.66-4.61 (m, 2H), 3.69 (s, 1H), 3.64 (s, 2H), 3.17-3.16 (m, 1H), 3.13 (dd, J=4.1, 2.4 Hz, 2H), 2.75 (s, 3H), 0.90 (s, 9H).

##STR00169##

Step 1.

[0881] Preparation of (S)-ethyl 2-tert-butoxy-2-(5-methyl-7-(trifluoromethyl sulfonyloxy)-2-vinylbenzo[d]thiazol-6-yl)acetate (91A): A microwave vial was charged with CulI (9.4 mg, 49 mol), Pd(PPh.sub.3).sub.4 (29 mg, 25 mol), and 32 (250 mg, 0.494 mmol). The vial was sealed and placed under a vacuum. The vessel was backfilled with argon and charged with DMP (1.0 mL) followed by vinyl-(tri-n-butyl)tin (173 L, 0593 mmol). Reaction was stirred at 65 C. for 1 h, then cooled to 23 C. Sat aq. NH.sub.4Cl (40 mL) was added and the reaction was extracted with EtOAc (220 mL). Combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated. Hexane was added, and the slurry was concentrated again. The residue was treated with PhH and purified by silica gel column chromatography (eluent: Hexanes/Ethyl Acetate) giving 91A (173 mg, 77% yield). .sup.1H-NMR: 400 MHz, (CDCl.sub.3) : 7.80 (s, 1H), 7.00 (dd, J=18.6, 10.9 Hz, 1H), 6.24 (d, J=18.6 Hz, 1H), 5.82 (d, J=10.9 Hz, 1H), 5.60 (s, 1H), 4.24-4.06 (m, 2H), 2.54 (s, 3H), 1.22 (s, 9H), 1.19 (t, J=6.8 Hz, 3H). .sup.19F-NMR: 376 MHz, (CDCl.sub.3) : 73.8.

Step 2.

[0882] Preparation of (S)-ethyl 2-tert-butoxy-2-(2-formyl-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6- yl)acetate (MB): A solution of 91B): A solution of 91A (170 mg, 0.353 mmol), DCM (5.0 mL), and MeOH (5.0 mL) was cooled to 78 C. and perfused with oxygen gas for 3 min. Then, using an ozonator, a stream of O.sub.3 in oxygen gas was bubbled through the solution for 5 min. After this, the reaction was stirred for 10 min, then sparged with oxygen gas for 2 min to drive out unreached ozone in solution. While the reaction was still at 78 C., dimethylsulfide (200 L) was added and the reaction allowed to warm to 0 C. After 30 min, 1.0% w/v aq Na.sub.2S.sub.2O.sub.3 (5 mL) was added and the reaction was warmed to 23 C. and stirred for 10 min. The reaction was diluted with H.sub.2O (20 mL) and extracted with DCM (315 mL). Combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated. More DCM was added and the reaction was concentrated once more to remove residual methanol, giving 91B (165 mg, 97% yield). .sup.1H-NMR: 400 MHz, (CDCl.sub.3) : 10.04 (s, 1H), 8.00 (s, 1H), 5.60 (s, 1H), 4.22-4.00 (m, 2H), 2.51 (s, 3H), 1.16 (s, 9H), 1.14 (t, J=6.8 Hz, 3H). .sup.19F-NMR: 376 MHz, (CDCl.sub.3) : 73.6.

Step 3.

[0883] Preparation of (S)-ethyl 2-tert-butoxy-2-(2-(difluoromethyl)-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)acetate (91C): A solution of Fluolead (318 mg, 1.27 mmol) in DCM (1.0 mL) was cooled to 0 C. and treated with a solution of 91B (123 mg, 0.254 mmol) in DCM (1.5 mL). The reaction was allowed to warm to 23 C. Absolute EtOH (5 L) was added to initiate the reaction. After 1 h, additional Fluolead (318 mg, 1.27 mmol) was added. Once 4 h had passed, 0.5 M aq. NaOH (5 mL) was added, and the reaction reached a pH of 2. DCM (10 mL) was introduced. 1.0 M aq NaOH (5 mL) was added dropwise until the pH reached 12. The system was extracted with DCM (310 mL). The combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and carefully concentrated to a volume of 3 mL. The system became a suspension, which was then filtered. The filtrate was directly loaded onto a 12 gram gold ISCO silica gel column. Purification by chromatography (eluent Hexanes/Ethyl Acetate) gave 91C (67 mg, 52% yield).

[0884] .sup.1H-NMR: 400 MHz, (CDCl.sub.3) : 7.97 (s, 1H), 6.92 (t, J.sub.HF=44.5 Hz, 1H), 5.62 (s, 1H), 4.24-4.08 (m, 2H), 2.59 (s, 3H), 1.27 (s, 9H), 1,19 (t, J=6.8 Hz, 3H). .sup.19F-NMR: 376 MHz, (CDCl.sub.3) : 73.7 (3F), 110.6 (app. dd, J.sub.FF=4.0 Hz, J.sub.HF=44.5 Hz, 2F).

[0885] The remainder of the synthesis of 92 follows the same route as Example 10 from compound 33.

EXAMPLE 42

Preparation of (S)-2-((S)-2-acetamido-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetic acid (93).

[0886] ##STR00170##

[0887] Compound 93: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : .sup.1H NMR (400 MHz, cd.sub.3od) 8.73 (d, J=5.4 Hz, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.76-7.73 (m, 1H), 7.72 (d, J=5.6 Hz, 1H), 7.39 (t, J=10.0 Hz, 1H), 5.20 (s, 1H), 4.68 (m, 4H), 3.64-3.57 (m, 2H), 2.71 (s, 3H), 2.17 (s, 3H), 0.91 (s, 9H). LCMS-ESI.sup.+ (m/s): [M+H].sup.+ calcd for C.sub.27H.sub.28N.sub.3O.sub.5S: 506.17 (M+H.sup.+); Found: 506.02, 507.03(M+H.sup.+).

##STR00171##

[0888] Preparation of compound (S)-2-(2-acetamido-7-bromo-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (94). To a solution of 65H in CH.sub.2Cl.sub.2 was added pyridine, acetic anhydride, and trace DMAP. Upon consumption of starting material by LC-MS, the mixture was concentrated in vacuo and purified by column chromatography to give 94.

[0889] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.21H.sub.29BrN.sub.2O.sub.4S: 487.1 (M+H.sup.+); Found: 486.9 (M+H.sup.+).

[0890] The remainder of the synthesis of compound 93 is analogous to the preparation of compound 66 from compound 65J in example 25.

EXAMPLE 43

Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-S-methylbenzo[d]thiazol-6-yl)acetic acid (95).

[0891] Compound 95 was a by-product in the preparation of 40.

##STR00172##

[0892] Compound 95: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 9.40 (s, 1H); 8.82 (d, J=6.0 Hz, 1H); 8.17 (s, 1H); 7.93 (d, J=8.0 Hz, 1H); 7.89 (d, J=6.0 Hz, 1H); 7.46 (d, J=8.0 Hz, 1H); 5.27 (s, 1H); 4.76-4.71 (m, 2H); 3.69 (t, J=6.0 Hz, 2H); 2.81 (s, 3H); 0.92 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.25H.sub.34N.sub.2O.sub.4S: 449.2 (M+H.sup.+); Found: 449.1 (M+H.sup.+).

EXAMPLE 44

Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methyl-2-(methylcarbamoyl)benzo[d]thiazol-6-yl)acetic acid (97).

[0893] ##STR00173##

[0894] Compound 97: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 8.77 (d, J=6.0 Hz, 1H); 8.18-8.15 (m, 1H); 7.91 (m, 1H); 7.84 (d, J=5.2 Hz, 1H); 7.45 (d, J=8.4 Hz, 1H); 5.26 (s, 1H); 4.75-4.71 (m, 2H); 3.67 (t, J=6.0 Hz, 2H); 2.93 (s, 3H); 2.79 (s, 3H); 0.92 (s, 9H), LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.27H.sub.27N.sub.3O.sub.5S: 506.2 (M+H.sup.+); Found: 506.0 (M+H.sup.+).

Step 1.

[0895] Preparation of (S)-6-((S)-1-tert-butoxy-2-ethoxy-2-oxoethyl)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-methylbenzo[d]thiazole-2-carboxylic acid (96A): To a solution of compound 38 (40 mg) in THF/MeOH (1:1, 2 mL) was added a NaOH solution (2 M, 100 L). The reaction mixture was stirred at rt for 1 h. A saturated solution of NH.sub.4Cl was added, and the aqueous was extracted with EtOAc. The organic layer was dried, filtered, and concentrated in vacuo to give 95A. .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 8.63 (d, J=6 Hz, 1H), 8.05 (br s, 1H), 7.63 (d, J=8 Hz, 1H), 7.46 (d, J=6 Hz), 7.21 (d, J=8 Hz, 1H), 5.20 (s, 1H), 4.58 (m, 2H), 4.04 (m, 1H), 3.91 (m, 1H), 3.46 (m, 2H), 2.76 (s, 3H), 1.03 (t, J=7 Hz, 3H), 0.89 (s, 9H).

Step 2

[0896] To a solution of 36.4 (15 mg) in CH.sub.2Cl.sub.2 (1 mL) was added carbanyldiimidazole (10 mg) and then methylamine (solution in MeOH, 100 L). Once conversion is complete by LC-MS, the solution was concentrated to give crude 96B. Then THF/MeOH added (1:1, 1 mL) followed by NaOH solution (2 M, 100 L). The reaction mixture was stirred at 55-60 C. for 4 h. Purified by reverse phase HPLC to give 3.8 mg of 97.

##STR00174##

EXAMPLE 45

Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5 -methyl-2-(phenethylcarbamoyl)benzo[d]thiazol-6-yl)acetic acid (98).

[0897] Compound 98 was prepared from compound 96A according to the procedure used to prepare compound 97 (except that 2-phenylethanamine was used instead of methylamine) in Example 44.

##STR00175##

[0898] Compound 98: .sup.1H-NMR: 400 MHz, (CD.sub.3OD) : 8.76 (d, J=6.0 Hz, 1H); 8.17 (s, 1H); 7.90 (d, J=8 Hz, 1H); 7.82 (d, J=6 Hz, 1H); 7.43 (d, J=8 Hz, 1H); 7.20 (m, 5H), 5.26 (s, 1H); 4.71 (m, 2H); 3.64 (t, J=6 Hz, 2H); 2.91 (t, J=7 Hz, 2H), 2.77 (m, 2H), 2.72 (s, 3H), 0.92 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd. for C.sub.34H.sub.33N.sub.3O.sub.5S: 596.2 (M+H.sup.+); Found: 596.1 (M+H.sup.+).

Example 46

Preparation of (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(4-methoxybenzylcarbamoyl)-5-methylbenzo[d]thiazol-6-yl)acetic acid (99)

[0899] Compound 99 was prepared from compound 96A according to the procedure used to prepare compound 97 (except that 4-methoxybenzylamine was used instead of methylamine) in Example 44.

##STR00176##

[0900] Compound 99: LCMS-ESI.sup.+ (m/z): [M+].sup.+ calcd for C.sub.34H.sub.33N.sub.3O.sub.6S: 612.2 (M+H.sup.+); Found: 612.1 (M+H.sup.+).

Example 47

[0901] The following illustrate representative pharmaceutical dosage forms, containing a compound of Formula I (Compound X) for therapeutic or prophylactic use in humans.

TABLE-US-00002 (i) Tablet 1 mg/tablet Compound X = 100.0 Lactose 77.5 Povidone 15.0 Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesium stearate 3.0 300.0

TABLE-US-00003 (ii) Tablet 2 mg/tablet Compound X = 20.0 Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0 500.0

TABLE-US-00004 (iii) Capsule mg/capsule Compound X = 10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 600.0

TABLE-US-00005 (iv) Injection 1 (1 mg/ml) mg/ml Compound X= (free acid form) 1.0 Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0N Sodium hydroxide solution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1 mL

TABLE-US-00006 (v) Injection 2 (10 mg/ml) mg/ml Compound X = (free acid form) 10.0 Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethylene glycol 400 200.0 1.0N Sodium hydroxide solution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1 mL

TABLE-US-00007 (vi) Aerosol mg/can Compound X = 20.0 Oleic acid 10.0 Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane 10,000.0 Dichlorotetrafluoroethane 5,000.0

[0902] The above formulations may be obtained by conventional procedures well known in the

[0903] All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.