NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF

Abstract

Described herein are neuroactive steroids of the Formula (I):

##STR00001##

or a pharmaceutically acceptable salt thereof; wherein R.sup.1, R.sup.2, R.sup.a G, X, Y, Z, and n are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. Also provided are pharmaceutical compositions comprising a compound described herein and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia.

Claims

1-66. (canceled)

67. A compound of Formula (I): ##STR00228## or a pharmaceutically acceptable salt thereof, wherein each X, Y, and Z is independently CH or N; G is C(R.sup.3a)(R.sup.3b)(OR.sup.1); R.sup.1 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkenyl, C.sub.1-C.sub.6 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R.sup.2 is C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkoxy; each of R.sup.3a and R.sup.3b is independently H, D, or C.sub.1-C.sub.6 alkyl; R.sup.a is cyano, halogen, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, S(O).sub.mR.sup.b, NR.sup.cR.sup.d, C(O)R.sup.e, or C(O)OR.sup.f; R.sup.b is C.sub.1-C.sub.6 alkyl, NR.sup.cR.sup.d, or OR.sup.f; each of R.sup.c and R.sup.d is independently H, C.sub.1-C.sub.6 alkyl, C(O)R.sup.e, or C(O)OR.sup.f; R.sup.e is C.sub.1-C.sub.6 alkyl or NR.sup.gR.sup.h; R.sup.f is H or C.sub.1-C.sub.6 alkyl; each of R.sup.g and R.sup.h is independently H or C.sub.1-C.sub.6 alkyl; m is 0, 1, or 2; and n is 0, 1, 2, 3, or 4; with the proviso that at least one of R.sup.3a and R.sup.3b is D or C.sub.1-C.sub.6 alkyl.

68. The compound or pharmaceutically acceptable salt of claim 67, wherein R.sup.1 is C.sub.1-C.sub.6 alkyl.

69. The compound or pharmaceutically acceptable salt of claim 68, wherein R.sup.1 is CH.sub.3, CH.sub.2CH.sub.3, or CH(CH.sub.3).sub.2.

70. The compound or pharmaceutically acceptable salt of claim 67, wherein R.sup.2 is C.sub.1-C.sub.6 alkyl.

71. The compound or pharmaceutically acceptable salt of claim 67, wherein one of R.sup.3a and R.sup.3b is D or C.sub.1-C.sub.6 alkyl, and the other of R.sup.3a and R.sup.3b is H.

72. A compound selected from ##STR00229## ##STR00230## or pharmaceutically acceptable salt thereof.

73. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of claim 67, and a pharmaceutically acceptable excipient.

74. A method of treating a CNS-related disorder related to GABA function in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt of claim 67.

75. The method of claim 74, wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus; or wherein the subject is a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome.

76. The method of claim 74, wherein the CNS-related disorder is epilepsy or status epilepticus.

77. The method of claim 76, wherein the CNS-related disorder is status epilepticus, and the status epilepticus is convulsive status epilepticus or non-convulsive status epilepticus.

78. The method of claim 74, wherein the CNS-related disorder is seizure.

79. The method of claim 74, wherein the CNS-related disorder is tremor.

80. The method of claim 79, wherein the tremor is essential tremor.

81. The method of claim 74, wherein the CNS-related disorder is a mood disorder or an anxiety disorder.

82. The method of claim 74, wherein the CNS-related disorder is depression.

83. The method of claim 78, wherein the depression is a major depressive disorder.

84. The method of claim 74, wherein the compound or pharmaceutically acceptable salt is administered orally, intravenously, or intramuscularly.

85. The method of claim 74, wherein the compound or pharmaceutically acceptable salt is administered chronically.

86. The method of claim 74, wherein the compound or pharmaceutically acceptable salt is administered in combination with another therapeutic agent.

87. A method of inducing sedation and/or anesthesia in a subject in need thereof, comprising administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt of claim 67 to the subject.

Description

SYNTHETIC METHODS

Example 1. Synthesis of Compounds 1 and 2

[0323] ##STR00174##

[0324] To a solution of C1 (1 g, 2.26 mmol) in acetone (150 mL) was added K.sub.2CO.sub.3 (937 mg) and 5-chloro-2H-benzo[d][1,2,3]triazole (520 mg, 3.39 mmol). The mixture was stirred at 25 C. for 2 hrs. The solvent was removed by rotary evaporator. To the mixture was added water (80 mL) and EtOAc (120 mL). The organic layer was separated. The aqueous phase was extracted with EtOAc (2100 mL). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product, which was purified by preparative HPLC to give two compounds. The further purification was conducted by SFC to afford compound 2 (157 mg, 13%) and compound 1 (100 mg, 9%).

[0325] 1: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.99 (d, J=9.3 Hz, 1H), 7.37-7.31 (m, 2H), 5.44-5.30 (m, 2H), 3.54 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 3.22 (d, J=9.3 Hz, 1H), 2.74-2.66 (m, 1H), 2.28-1.71 (m, 8H), 1.70-1.46 (m, 9H), 1.45-1.20 (m, 9H), 0.71 (s, 3H). LCMS R.sub.t=0.943 min in 1.5 min chromatography, MS ESI calcd. for C.sub.29H.sub.41ClN.sub.3O.sub.3 [M+H].sup.+ 514, found 514.

[0326] 2: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.05 (d, J=1.5 Hz, 1H), 7.44 (dd, J=8.7 Hz, 1.6 Hz, 1H), 7.24-7.29 (m, 1H), 5.46-5.31 (m, 2H), 3.53 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 3.21 (d, J=9.0 Hz, 1H), 2.74-2.63 (m, 1H), 2.38-1.67 (m, 9H), 1.57-1.06 (m, 17H), 0.69 (s, 3H). LCMS R.sub.t=0.945 min in 1.5 min chromatography, MS ESI calcd. for C.sub.29H.sub.41ClN.sub.3O.sub.3 [M+H].sup.+ 514, found 514.

Example 2. Synthesis of Compounds 7 and 8

[0327] ##STR00175##

[0328] The synthesis of compounds 7 and 8 were carried out in a similar manner to the protocol outlined in Example 1.

[0329] 7: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.41-7.34 (m, 1H), 7.08-7.04 (m, 1H), 5.41-5.34 (m, 2H), 3.55 (d, J=9.2 Hz, 1H), 3.48-3.41 (m, 2H), 3.26 (d, J=9.2 Hz, 1H), 2.73-2.68 (m, 1H), 2.25-2.10 (m, 2H), 2.00-1.90 (m, 2H), 1.85-1.35 (m, 17H), 1.30-1.10 (m, 8H), 0.69 (s, 3H). LCMS R.sub.t=2.503 min in 3 min chromatography, MS ESI calcd. for C.sub.30H.sub.40F.sub.2N.sub.3O.sub.2 [M+HH.sub.2O].sup.+512, found 512.

[0330] 8: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.66-7.63 (m, 1H), 7.32-7.25 (m, 1H), 5.58-5.50 (m, 2H), 3.56 (d, J=9.2 Hz, 1H), 3.48-3.41 (m, 2H), 3.26 (d, J=9.2 Hz, 1H), 2.70-2.61 (m, 1H), 2.25-2.10 (m, 2H), 2.00-1.90 (m, 2H), 1.85-1.35 (m, 17H), 1.30-1.10 (m, 8H), 0.72 (s, 3H). LCMS R.sub.t=2.168 min in 3 min chromatography, MS ESI calcd. for C.sub.30H.sub.40F.sub.2N.sub.3O.sub.2 [M+HH.sub.2O].sup.+512, found 512.

Example 3. Synthesis of Compounds 9 and 10

[0331] ##STR00176##

[0332] To a solution of C1 (1 g, 2.26 mmol) in acetone (150 mL) was added K.sub.2CO.sub.3 (937 mg, 6.78 mmol) and 4,6-difluoro-2H-benzo[d][1,2,3]triazole (525 mg, 3.39 mmol). The mixture was stirred at 25 C. for 2 hrs. The solvent was removed by rotary evaporator. To the mixture was added water (80 mL) and EtOAc (120 mL). The organic layer was separated. The aqueous phase was extracted with EtOAc (2100 mL). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to afford crude product, which was purified by preparative HPLC to give a mixture of two compounds. The further purification was conducted by SFC to give 9 (168.9 mg, crude) and 10 (25 mg, 2%). Compound 9 was purified by SFC second time to afford compound 9 (91.3 mg, 8%).

[0333] 9: .sup.1H NMR (400 MHz, CDCl.sub.3) 6.86 (dt, J=1.8, 9.5 Hz, 1H), 6.79 (dd, J=1.6, 7.4 Hz, 1H), 5.44-5.30 (m, 2H), 3.52 (d, J=9.0 Hz, 1H), 3.32 (s, 3H), 3.21 (d, J=9.0 Hz, 1H), 2.74-2.64 (m, 1H), 2.26-1.64 (m, 9H), 1.59-1.05 (m, 17H), 0.68 (s, 3H). LCMS Rt=0.929 min in 1.5 min chromatography, MS ESI calcd. for C.sub.29H.sub.38F.sub.2N.sub.3O.sub.2 [M+HH.sub.2O].sup.+498, found 498.

[0334] 10: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.31 (dd, J=1.8, 8.3 Hz, 1H), 6.95-6.87 (m, 1H), 5.57-5.44 (m, 2H), 3.55 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 3.21 (d, J=9.0 Hz, 1H), 2.69-2.60 (m, 1H), 2.28-1.65 (m, 7H), 1.56-1.08 (m, 19H), 0.73 (s, 3H). LCMS Rt=1.389 min in 2 min chromatography, MS ESI calcd. for C.sub.29H.sub.38F.sub.2N.sub.3O.sub.2 [M+HH.sub.2O].sup.+498, found 498.

Example 4. Synthesis of Compounds 11, 12, and 13

[0335] ##STR00177##

[0336] To a solution of C1 (200 mg, 0.453 mmol) in acetone (4 mL) was added K.sub.2CO.sub.3 (186 mg) and 6-chloro-2H-[1,2,3]triazolo[4,5-b]pyridine (104 mg, 0.679 mmol). The mixture was stirred at 25 C. for 4 hrs. The solvent was removed by rotary evaporator. To the mixture was added water (4 mL) and EtOAc (5 mL). The organic layer was separated. The aqueous phase was extracted with EtOAc (25 mL). The combined organic layers was washed with brine (7 mL), dried over Na.sub.2SO.sub.4. The solvent was removed by the rotary evaporator, and the residue was purified by preparative HPLC to give compound 11 (89.6 mg, 38%), compound 12 (28.2 mg, 12%) and compound 13 (33.6 mg, 14%).

[0337] 11: (400 MHz, CDCl.sub.3) 8.68 (d, J=2.0 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 5.53-5.45 (m, 1H), 5.40-5.32 (m, 1H), 3.54 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 3.22 (d, J=9.0 Hz, 1H), 2.78-2.69 (m, 1H), 2.29-2.12 (m, 2H), 2.02-1.61 (m, 9H), 1.55-1.11 (m, 15H), 0.70 (s, 3H). LCMS Rt=0.906 min in 1.5 min chromatography, MS ESI calcd. for C.sub.28H.sub.38ClN.sub.4O.sub.2 [M+HH.sub.2O].sup.+497, found 497.

[0338] 12: (400 MHz, CDCl.sub.3) 8.58 (d, J=2.0 Hz, 1H), 8.37 (d, J=2.0 Hz, 1H), 5.56-5.42 (m, 2H), 3.55 (d, J=9.0 Hz, 1H), 3.34 (s, 3H), 3.23 (d, J=9.0 Hz, 1H), 2.78-2.69 (m, 1H), 2.29-2.17 (m, 2H), 2.02-1.62 (m, 8H), 1.55-1.10 (m, 16H), 0.72 (s, 3H). LCMS Rt=0.932 min in 1.5 min chromatography, MS ESI calcd. for C.sub.28H.sub.38ClN.sub.4O.sub.2 [M+HH.sub.2O].sup.+497, found 497.

[0339] 13: (400 MHz, CDCl.sub.3) 8.73 (d, J=2.3 Hz, 1H), 8.22 (d, J=2.3 Hz, 1H), 5.59-5.47 (m, 2H), 3.54 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 3.21 (d, J=9.0 Hz, 1H), 2.70-2.59 (m, 1H), 2.28-1.62 (m, 9H), 1.56-1.08 (m, 17H), 0.73 (s, 3H). LCMS Rt=0.928 min in 1.5 min chromatography, 5-95AB, purity 100%, MS ESI calcd. for C.sub.28H.sub.38ClN.sub.4O.sub.2 [M+HH.sub.2O].sup.+497, found 497.

Example 5. Synthesis of Compounds 14 and 15

[0340] ##STR00178##

[0341] To a solution of C1 (150 mg, 0.339 mmol) in acetone (3 mL) was added K.sub.2CO.sub.3 (139 mg) and 6-fluoro-2H-indazole (69.1 mg, 0.508 mmol). The mixture was stirred at 25 C. for 4 hrs. The solvent was removed by rotary evaporator. To the mixture was added water (4 mL) and EtOAc (5 mL). The organic layer was separated. The aqueous phase was extracted with EtOAc (25 mL). The combined organic layers was washed with brine (7 mL), dried over Na.sub.2SO.sub.4. The solvent was removed by the rotary evaporator, and the residue was purified by preparative HPLC to give compound 14 (11.5 mg, 7%) and 15 (60.2 mg, 36%).

[0342] 14: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.93 (s, 1H), 7.63 (dd, J=5.3, 9.0 Hz, 1H), 7.31-7.22 (m, 1H), 6.95-6.83 (m, 1H), 5.25-5.07 (m, 2H), 3.53 (d, J=9.0 Hz, 1H), 3.32 (s, 3H), 3.20 (d, J=9.0 Hz, 1H), 2.62 (t, J=8.5 Hz, 1H), 2.28-2.15 (m, 1H), 2.15-2.06 (m, 1H), 2.01-1.67 (m, 8H), 1.56-1.07 (m, 16H), 0.69 (s, 3H). LCMS Rt=0.915 min in 1.5 min chromatography, MS ESI calcd. for C.sub.30H.sub.42FN.sub.2O.sub.3 [M+H].sup.+ 497, found 497.

[0343] 15: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.01 (s, 1H), 7.68 (dd, J=5.0, 8.8 Hz, 1H), 6.93 (dt, J=2.0, 9.0 Hz, 1H), 6.84 (d, J=9.0 Hz, 1H), 5.14-5.00 (m, 2H), 3.54 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 3.21 (d, J=9.0 Hz, 1H), 2.67-2.56 (m, 1H), 2.25-2.06 (m, 2H), 1.98-1.86 (m, 2H), 1.82-1.62 (m, 5H), 1.58-1.06 (m, 17H), 0.70 (s, 3H). LCMS Rt=0.935 min in 1.5 min chromatography, MS ESI calcd. for C.sub.30H.sub.42FN.sub.2O.sub.3 [M+H].sup.+ 497, found 497.

Example 6. Synthesis of Compounds 16 and 17

[0344] ##STR00179##

[0345] To a solution of C1 (150 mg, 0.339 mmol) in acetone (3 mL) was added K.sub.2CO.sub.3 (139 mg) and 5-fluoro-2H-indazole (69.1 mg, 0.508 mmol). The mixture was stirred at 25 C. for 4 hrs. The solvent was removed by rotary evaporator. To the mixture was added water (4 mL) and EtOAc (5 mL). The organic layer was separated. The aqueous phase was extracted with EtOAc (25 mL). The combined organic layers was washed with brine (7 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product, which was purified by preparative HPLC to give compound 16 (20.4 mg, 12%) and compound 17 (69.3 mg, 41%).

[0346] 16: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.89 (s, 1H), 7.67 (dd, J=4.5, 9.3 Hz, 1H), 7.28-7.21 (m, 1H), 7.14-7.06 (m, 1H), 5.27-5.12 (m, 2H), 3.54 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 3.20 (d, J=9.0 Hz, 1H), 2.67-2.58 (m, 1H), 2.27-2.06 (m, 2H), 2.02-1.62 (m, 10H), 1.51-1.11 (m, 14H), 0.69 (s, 3H). LCMS Rt=0.913 min in 1.5 min chromatography, MS ESI calcd. for C.sub.30H.sub.42FN.sub.2O.sub.3 [M+H].sup.+ 497, found 497.

[0347] 17: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.00 (s, 1H), 7.40-7.33 (m, 1H), 7.18-7.11 (m, 2H), 5.18-5.06 (m, 2H), 3.54 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 3.21 (d, J=9.0 Hz, 1H), 2.61 (t, J=8.9 Hz, 1H), 2.24-2.06 (m, 2H), 2.02-1.85 (m, 3H), 1.82-1.62 (m, 4H), 1.56-1.06 (m, 17H), 0.69 (s, 3H). LCMS Rt=0.939 min in 1.5 min chromatography, MS ESI calcd. for C.sub.30H.sub.42FN.sub.2O.sub.3 [M+H].sup.+ 497, found 497.

Example 7. Synthesis of Compounds 18 and 19

[0348] ##STR00180##

[0349] To a solution of C1 (150 mg, 0.339 mmol) in acetone (3 mL) was added K.sub.2CO.sub.3 (139 mg) and 2H-benzo[d][1,2,3]triazole (60.5 mg, 0.508 mmol). The mixture was stirred at 25 C. for 4 hrs. The solvent was removed by rotary evaporator. To the mixture was added water (4 mL) and EtOAc (5 mL). The organic layer was separated. The aqueous phase was extracted with EtOAc (25 mL). The combined organic layers was washed with brine (7 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to give crude product, which was purified by preparative HPLC to afford compound 18 (51.9 mg, 32%) and compound 19 (8.9 mg, 6%).

[0350] 18: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.07 (d, J=8.3 Hz, 1H), 7.52-7.44 (m, 1H), 7.41-7.29 (m, 2H), 5.46-5.35 (m, 2H), 3.53 (d, J=9.0 Hz, 1H), 3.32 (s, 3H), 3.21 (d, J=9.0 Hz, 1H), 2.73-2.64 (m, 1H), 2.14 (d, J=12.0 Hz, 2H), 2.00-1.86 (m, 2H), 1.81-1.62 (m, 6H), 1.55-1.10 (m, 16H), 0.70 (s, 3H). LCMS Rt=0.894 min in 1.5 min chromatography, MS ESI calcd. for C.sub.29H.sub.42N.sub.3O.sub.3 [M+H].sup.+ 480, found 480.

[0351] 19: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.93-7.83 (m, 2H), 7.45-7.35 (m, 2H), 5.57-5.46 (m, 2H), 3.55 (d, J=9.0 Hz, 1H), 3.34 (s, 3H), 3.21 (d, J=9.0 Hz, 1H), 2.69-2.60 (m, 1H), 2.29-2.11 (m, 2H), 1.99-1.87 (m, 2H), 1.84-1.63 (m, 5H), 1.57-1.10 (m, 17H), 0.74 (s, 3H). LCMS Rt=0.931 min in 1.5 min chromatography, MS ESI calcd. for C.sub.29H.sub.40N.sub.3O.sub.2 [M+HH.sub.2O].sup.+462, found 462.

Example 8. Synthesis of Compound 20

[0352] ##STR00181##

[0353] To a solution of C1 (200 mg, 0.453 mmol) in acetone (4 mL) was added K.sub.2CO.sub.3 (186 mg) and 5-fluoro-2H-benzo[d][1,2,3]triazole (137 mg, 0.679 mmol). The mixture was stirred at 25 C. for 4 hrs. The solvent was removed by rotary evaporator. To the mixture was added water (5 mL) and EtOAc (6 mL). The organic layer was separated. The aqueous phase was extracted with EtOAc (26 mL). The combined organic layers was washed with brine (7 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to give crude product, which was purified by preparative HPLC to afford compound 20 (34.3 mg, 13%).

[0354] 20: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.91 (d, J=9.3 Hz, 1H), 7.72 (s, 1H), 7.30-7.25 (m, 1H), 5.58-5.44 (m, 2H), 3.55 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 3.21 (d, J=9.0 Hz, 1H), 2.70-2.61 (m, 1H), 2.31-2.09 (m, 2H), 1.95-1.63 (m, 6H), 1.59-1.06 (m, 18H), 0.73 (s, 3H). LCMS Rt=1.035 min in 1.5 min chromatography, MS ESI calcd. for C.sub.30H.sub.39F.sub.3N.sub.3O.sub.3 [M+HH.sub.2O].sup.+546, found 546.

Example 9. Synthesis of Compounds 21 and 22

[0355] ##STR00182##

[0356] Step 1. To a solution of C1 (300 mg, 0.679 mmol) in acetone (6 mL) was added K.sub.2CO.sub.3 (280 mg) and 4-(methylthio)-1H-pyrazole (115 mg, 1.01 mmol). The mixture was stirred at 25 C. for 4 hrs. The solvent was removed by rotary evaporator. To the mixture was added water (6 mL) and EtOAc (8 mL). The organic layer was separated. The aqueous phase was extracted with EtOAc (28 mL). The combined organic layers was washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to give a residue, which was purified by preparative HPLC to afford compound 21 (30.3 mg, 75%).

[0357] 21: (400 MHz, CDCl.sub.3) 7.53 (s, 1H), 7.41 (s, 1H), 4.94-4.87 (m, 1H), 4.86-4.78 (m, 1H), 3.53 (d, J=9.0 Hz, 1H), 3.32 (s, 3H), 3.18 (d, J=9.0 Hz, 1H), 2.61-2.52 (m, 1H), 2.34 (s, 3H), 2.24-2.13 (m, 1H), 2.08-1.99 (m, 1H), 1.96-1.86 (m, 2H), 1.79-1.61 (m, 8H), 1.52-1.35 (m, 5H), 1.27 (s, 9H), 0.66 (s, 3H). LCMS Rt=0.900 min in 1.5 min chromatography, MS ESI calcd. for C.sub.27H.sub.42N.sub.2O.sub.3SN.sub.a [M+Na].sup.+497, found 497.

[0358] Step 2. To a solution of compound 21 (105 mg, 0.221 mmol) in DCM (20 mL) was added MCPBA (42 mg, 0.243 mmol) at 78 C. The reaction mixture was stirred at 78 C. for 6 hrs. The reaction was quenched with saturated aqueous Na.sub.2S.sub.2O.sub.3 (15 mL) and extracted with EtOAc (240 mL). The combined organic phase was washed with saturated aqueous NaHCO.sub.3 (20 mL) and brine (240 mL), dried over Na.sub.2SO.sub.4, and concentrated in vacuum. The residue was purified by column chromatograph on silica gel (PE/EtOAc=5/1 to EtOH/MeOH=9/1) to give compound 22 (60 mg, 56%).

[0359] 22: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.84-7.77 (m, 2H), 5.06-4.83 (m, 2H), 3.56-3.48 (m, 1H), 3.31 (s, 3H), 3.18 (d, J=9.0 Hz, 1H), 2.88 (d, J=1.5 Hz, 3H), 2.63-2.54 (m, 1H), 2.26-2.12 (m, 1H), 2.08-1.65 (m, 9H), 1.54-1.38 (m, 6H), 1.34-1.03 (m, 10H), 0.65 (s, 3H). LCMS Rt=1.075 min in 2 min chromatography, MS ESI calcd. for C.sub.27H.sub.41N.sub.2O.sub.3S [M+HH.sub.2O].sup.+473, found 473.

Example 10. Synthesis of Compounds 23 and 24

[0360] ##STR00183##

[0361] To a solution of C1 (150 mg, 0.339 mmol) in acetone (3 mL) was added K.sub.2CO.sub.3 (139 mg) and 5-chloro-4-fluoro-2H-benzo[d] (87.1 mg, 0.508 mmol). The mixture was stirred at 25 C. for 4 hrs. The solvent was removed by rotary evaporator. To the mixture was added water (3 mL) and EtOAc (4 mL). The organic layer was separated. The aqueous phase was extracted with EtOAc (24 mL). The combined organic layers was washed with brine (6 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to give the crude product, which was purified by preparative HPLC to give compound 23 (69.2 mg, 38%) and compound 24 (40.3 mg, 22%).

[0362] 23: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.47 (dd, J=6.1, 8.7 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 5.48-5.33 (m, 2H), 3.53 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 3.22 (d, J=9.3 Hz, 1H), 2.74-2.66 (m, 1H), 2.27-2.09 (m, 2H), 2.02-1.88 (m, 2H), 1.85-1.58 (m, 7H), 1.52-1.09 (m, 15H), 0.70 (s, 3H). LCMS Rt=1.378 min in 2 min chromatography, MS ESI calcd. for C.sub.29H.sub.38ClFN.sub.3O.sub.2 [M+HH.sub.2O].sup.+514, found 514.

[0363] 24: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.63 (d, J=9.0 Hz, 1H), 7.36 (dd, J=6.5, 9.0 Hz, 1H), 5.57-5.46 (m, 2H), 3.55 (d, J=9.0 Hz, 1H), 3.34 (s, 3H), 3.21 (d, J=9.0 Hz, 1H), 2.70-2.60 (m, 1H), 2.29-2.09 (m, 2H), 1.96-1.60 (m, 7H), 1.56-1.13 (m, 17H), 0.73 (s, 3H). LCMS Rt=1.431 min in 2 min chromatography, MS ESI calcd. for C.sub.29H.sub.38ClFN.sub.3O.sub.2 [M+HH.sub.2O].sup.+514, found 514.

Example 11. Synthesis of Compounds 25, 26, and 27

[0364] ##STR00184##

[0365] To a solution of C1 (200 mg, 0.453 mmol) in acetone (4 mL) was added K.sub.2CO.sub.3 (186 mg) and 5-methoxy-2H-benzo[d][1,2,3]triazole (101 mg, 0.679 mmol). The mixture was stirred at 25 C. for 4 hrs. The solvent was removed by rotary evaporator. To the mixture was added water (5 mL) and EtOAc (6 mL). The organic layer was separated. The aqueous phase was extracted with EtOAc (26 mL). The combined organic layers was washed with brine (7 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to give crude product, which was purified by preparative HPLC to afford compound 25 (50.8 mg, 22%) and compound 26 (20.5 mg, 9%), compound 27 (28 mg, 12%).

[0366] 25: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.92 (d, J=9.0 Hz, 1H), 7.26 (s, 1H), 7.04-6.99 (m, 1H), 6.60 (d, J=2.0 Hz, 1H), 5.42-5.24 (m, 2H), 3.86 (s, 3H), 3.54 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 3.21 (d, J=9.0 Hz, 1H), 2.73-2.63 (m, 1H), 2.29-2.11 (m, 2H), 1.97-1.64 (m, 6H), 1.57-1.05 (m, 17H), 0.71 (s, 3H). LCMS Rt=0.886 min in 1.5 min chromatography, MS ESI calcd. for C.sub.30H.sub.44N.sub.3O.sub.4 [M+H].sup.+ 510, found 510.

[0367] 26: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.37 (d, J=1.8 Hz, 1H), 7.22-7.17 (m, 1H), 7.16-7.10 (m, 1H), 5.41-5.29 (m, 2H), 3.88 (s, 3H), 3.53 (d, J=9.0 Hz, 1H), 3.32 (s, 3H), 3.21 (d, J=9.0 Hz, 1H), 2.71-2.61 (m, 1H), 2.28-2.07 (m, 2H), 1.97-1.61 (m, 8H), 1.55-1.08 (m, 16H), 0.69 (s, 3H). LCMS Rt=0.885 min in 1.5 min chromatography, MS ESI calcd. for C.sub.30H.sub.44N.sub.3O.sub.4 [M+H].sup.+ 510, found 510.

[0368] 27: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.76-7.70 (m, 1H), 7.10-7.04 (m, 2H), 5.49-5.37 (m, 2H), 3.88 (s, 3H), 3.55 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 3.20 (d, J=9.0 Hz, 1H), 2.66-2.57 (m, 1H), 2.28-2.08 (m, 2H), 2.02-1.59 (m, 8H), 1.54-1.11 (m, 16H), 0.72 (s, 3H). LCMS Rt=1.319 min in 2 min chromatography, MS ESI calcd. for C.sub.30H.sub.44N.sub.3O.sub.4 [M+H].sup.+ 510, found 510.

Example 12. Synthesis of Compounds 28, 29, and 30

[0369] ##STR00185##

[0370] To a solution of C1 (150 mg, 0.339 mmol) in acetone (3 mL) was added K.sub.2CO.sub.3 (140 mg) and 4-methoxy-2H-benzo[d][1,2,3]triazole (75.7 mg, 0.508 mmol). The mixture was stirred at 25 C. for 4 hrs. The solvent was removed by rotary evaporator. To the mixture was added water (3 mL) and EtOAc (4 mL). The organic layer was separated. The aqueous phase was extracted with EtOAc (25 mL). The combined organic layers was washed with brine (8 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product, which was purified by preparative HPLC to give compound 29 (10.4 mg, 6%), compound 28 (15.6 mg, 9%) and compound 30 (11.1 mg, 6%).

[0371] 28: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.40 (t, J=8.0 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.72 (d, J=7.8 Hz, 1H), 5.38 (s, 2H), 4.14 (s, 3H), 3.56 (d, J=9.0 Hz, 1H), 3.35 (s, 3H), 3.23 (d, J=9.0 Hz, 1H), 2.74-2.63 (m, 1H), 2.28-2.12 (m, 2H), 1.99-1.89 (m, 2H), 1.83-1.69 (m, 4H), 1.58-1.43 (m, 7H), 1.34-1.29 (m, 6H), 0.97-0.81 (m, 5H), 0.70 (s, 3H). LCMS Rt=0.892 min in 1.5 min chromatography, MS ESI calcd. for C.sub.30H.sub.44N.sub.3O.sub.4 [M+H].sup.+ 510, found 510.

[0372] 29: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.63 (d, J=8.3 Hz, 1H), 7.25-7.21 (m, 1H), 6.76 (d, J=7.5 Hz, 1H), 5.57 (s, 2H), 3.89 (s, 3H), 3.56 (d, J=9.0 Hz, 1H), 3.34 (s, 3H), 3.21 (d, J=9.0 Hz, 1H), 2.71-2.61 (m, 1H), 2.26-2.08 (m, 2H), 1.93 (d, J=6.3 Hz, 2H), 1.84-1.63 (m, 5H), 1.53-1.10 (m, 17H), 0.75-0.68 (m, 3H). LCMS Rt=0.898 min in 1.5 min chromatography, MS ESI calcd. for C.sub.30H.sub.44N.sub.3O.sub.4 [M+H].sup.+ 510, found 510.

[0373] 30: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.43 (d, J=8.5 Hz, 1H), 7.34-7.27 (m, 1H), 6.64 (d, J=7.5 Hz, 1H), 5.49 (s, 2H), 4.07-4.00 (m, 3H), 3.55 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 3.19 (d, J=9.0 Hz, 1H), 2.65-2.58 (m, 1H), 2.26-2.08 (m, 2H), 1.97-1.62 (m, 8H), 1.54-1.36 (m, 8H), 0.95-0.79 (m, 8H), 0.72 (s, 3H). LCMS Rt=2.092 min in 3 min chromatography, MS ESI calcd. for C.sub.30H.sub.44N.sub.3O.sub.4 [M+H].sup.+ 510, found 510.

Example 13. Synthesis of Compounds 31, 32, and 33

[0374] ##STR00186##

[0375] To a solution of C1 (150 mg, 0.339 mmol) in acetone (3 mL) was added K.sub.2CO.sub.3 (139 mg) and 5-chloro-4-fluoro-2H-benzo[d] (87.1 mg, 0.508 mmol). The mixture was stirred at 25 C. for 4 hrs. The solvent was removed by rotary evaporator. To the mixture was added water (3 mL) and EtOAc (4 mL). The organic layer was separated. The aqueous phase was extracted with EtOAc (24 mL). The combined organic layers was washed with brine (6 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product, which was purified by preparative HPLC to give compound 31 (5.2 mg, 3%), compound 32 (40.3 mg, 22%) and compound 33 (33, 69.2 mg, 38%).

[0376] 31: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.80 (d, J=8.8 Hz, 1H), 7.35 (dd, J=6.4, 8.7 Hz, 1H), 5.58-5.46 (m, 2H), 3.55 (d, J=9.0 Hz, 1H), 3.34 (s, 3H), 3.22 (d, J=9.0 Hz, 1H), 2.71 (t, J=8.9 Hz, 1H), 2.27-2.09 (m, 2H), 2.03-1.62 (m, 7H), 1.44-1.12 (m, 16H), 0.88 (t, J=6.7 Hz, 1H), 0.72 (s, 3H). LCMS Rt=1.328 min in 2 min chromatography, MS ESI calcd. for C.sub.29H.sub.38ClFN.sub.3O.sub.2 [M+HH.sub.2O].sup.+514, found 514.

[0377] 32: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.63 (d, J=9.0 Hz, 1H), 7.36 (dd, J=6.5, 9.0 Hz, 1H), 5.57-5.46 (m, 2H), 3.55 (d, J=9.0 Hz, 1H), 3.34 (s, 3H), 3.21 (d, J=9.0 Hz, 1H), 2.70-2.60 (m, 1H), 2.29-2.09 (m, 2H), 1.96-1.60 (m, 7H), 1.56-1.13 (m, 17H), 0.73 (s, 3H). LCMS Rt=1.431 min in 2 min chromatography, MS ESI calcd. for C.sub.29H.sub.38ClFN.sub.3O.sub.2 [M+HH.sub.2O].sup.+514, found 514.

[0378] 33: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.47 (dd, J=6.1, 8.7 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 5.48-5.33 (m, 2H), 3.53 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 3.22 (d, J=9.3 Hz, 1H), 2.74-2.66 (m, 1H), 2.27-2.09 (m, 2H), 2.02-1.88 (m, 2H), 1.85-1.58 (m, 7H), 1.52-1.09 (m, 15H), 0.70 (s, 3H). LCMS Rt=1.378 min in 2 min chromatography, MS ESI calcd. for C.sub.29H.sub.38ClFN.sub.3O.sub.2 [M+HH.sub.2O].sup.+514, found 514.

Example 14. Synthesis of Compounds 34 and 35

[0379] ##STR00187##

[0380] Step 1. To a solution of A1 (300 mg, 0.679 mmol) in acetone (6 mL) was added K.sub.2CO.sub.3 (280 mg, 2.03 mmol) and 4-(methylthio)-1H-pyrazole (115 mg, 1.01 mmol). The mixture was stirred at 25 C. for 4 hrs. The solvent was removed by rotary evaporator. To the mixture was added water (6 mL) and EtOAc (8 mL). The organic layer was separated. The aqueous phase was extracted with EtOAc (28 mL). The combined organic layers was washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to afford a crude product, which was purified by preparative HPLC to give compound 34 (120 mg, 36%).

[0381] 34: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.52 (s, 1H), 7.41 (s, 1H), 4.95-4.77 (m, 2H), 3.49-3.43 (m, 1H), 3.40-3.34 (m, 1H), 3.28 (s, 3H), 2.58 (t, J=8.7 Hz, 1H), 2.34 (s, 3H), 2.26-2.14 (m, 1H), 2.07-1.98 (m, 2H), 1.77-1.63 (m, 4H), 1.57-1.44 (m, 5H), 1.41-0.79 (m, 14H), 0.69 (s, 3H). LCMS Rt=0.927 min in 1.5 min chromatography, MS ESI calcd. for C.sub.27H.sub.42N.sub.2O.sub.3SN.sub.a [M+Na].sup.+497, found 497.

[0382] Step 2. To a solution of compound 34 (50 mg, 0.105 mmol) in DCM (20 mL) was added MCPBA (19.8 mg, 0.115 mmol) at 78 C. The reaction mixture was stirred at 78 C. for 6 hrs. The reaction was quenched with saturated Na.sub.2S.sub.2O.sub.3 (15 mL). The reaction mixture was extracted with EtOAc (240 mL). The combined organic phase was washed with saturated NaHCO.sub.3 (20 mL), brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by column chromatograph on silica gel (PE/EtOAc=5/1) to give compound 35 (27.5 mg, 53%).

[0383] 35: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.80 (d, J=3.0 Hz, 2H), 5.06-4.84 (m, 2H), 3.49-3.43 (m, 1H), 3.40-3.34 (m, 1H), 3.28 (s, 3H), 2.89 (d, J=0.8 Hz, 3H), 2.60 (t, J=8.8 Hz, 1H), 2.28-2.15 (m, 1H), 2.08-1.97 (m, 2H), 1.81-1.60 (m, 7H), 1.50-0.80 (m, 16H), 0.69 (s, 3H). LCMS Rt=0.812 min in 1.5 min chromatography, MS ESI calcd. for C.sub.27H.sub.41N.sub.2O.sub.3S [M+HH.sub.2O].sup.+473, found 473.

Example 15. Synthesis of Compound 36

[0384] ##STR00188##

[0385] To a solution of A1 (150 mg, 0.339 mmol) in acetone (3 mL) was added 1H-imidazole-2-carbonitrile (47.2 mg, 0.508 mmol), followed by K.sub.2CO.sub.3 (93.7 mg, 0.678 mmol). The resulting reaction mixture was stirred at 40 C. for 16 hrs. To the mixture was added water (10 mL) and extracted with EtOAc (38 mL). The combined organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated to give a residue, which was purified by combi-flash (PE: EtOAc=100% 80%) to compound 36 (57 mg, 37%) as a white solid.

[0386] 36: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.24 (s, 1H), 7.03 (s, 1H), 4.96-4.83 (m, 2H), 3.48-3.35 (m, 2H), 3.28 (s, 3H), 2.62 (t, J=8.8 Hz, 1H), 2.22-2.01 (m, 4H), 1.85-1.63 (m, 4H), 1.62-1.10 (m, 16H), 1.05-0.86 (m, 2H), 0.72 (s, 3H). LCMS Rt=1.256 min in 2 min chromatography, MS ESI calcd. for C.sub.27H.sub.40N.sub.3O.sub.3 [M+H].sup.+ 454, found 454.

Example 16. Synthesis of Compound 37

[0387] ##STR00189##

[0388] To a solution of A1 (150 mg, 0.339 mmol) in acetone (3 mL) was added 4-methoxy-1H-pyrazole (49.8 mg, 0.508 mmol), followed by K.sub.2CO.sub.3 (93.7 mg, 0.678 mmol). The resulting reaction mixture was stirred at 40 C. for 16 hrs. To the mixture was added water (10 mL) and extracted with EtOAc (38 mL). The combined organic phase was concentrated to give a residue, which was purified by preparative HPLC to give compound 37 (10 mg, 7%),

[0389] 37: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.28 (s, 1H), 7.09 (s, 1H), 4.87-4.75 (m, 2H), 3.76 (s, 3H), 3.47-3.31 (m, 2H), 3.28 (s, 3H), 2.56 (t, J=8.8 Hz, 1H), 2.17-2.01 (m, 4H), 1.71-1.42 (m, 8H), 1.41-0.92 (m, 12H), 0.91-0.84 (m, 2H), 0.69 (s, 3H). LCMS Rt=1.256 min in 2 min chromatography, MS ESI calcd. for C.sub.27H.sub.43N.sub.2O.sub.4 [M+H].sup.+ 459, found 459.

Example 17. Synthesis of Compound 38

[0390] ##STR00190##

[0391] To a solution of A1 (150 mg, 0.339 mmol) in acetone (3 mL) was added 4-isopropoxy-1H-pyrazole (64 mg, 0.508 mmol), followed by K.sub.2CO.sub.3 (93.7 mg, 0.678 mmol). The resulting reaction mixture was stirred at 40 C. for 16 hrs. To the mixture was added water (10 mL) and extracted with EtOAc (38 mL). The combined organic phases was concentrated to give a residue, which was purified by preparative HPLC to yield compound 38 (36 mg, 22%) as an off-white solid.

[0392] 38: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.26 (s, 1H), 7.06 (s, 1H), 4.84-4.77 (m, 2H), 4.18-4.14 (m, 1H), 3.47-3.35 (m, 2H), 3.28 (s, 3H), 2.55 (t, J=8.8 Hz, 1H), 2.04-1.70 (m, 3H), 1.68-1.45 (m, 10H), 1.41-1.01 (m, 17H), 0.98-0.83 (m, 2H), 0.69 (s, 3H). LCMS Rt=1.338 min in 2 min chromatography, MS ESI calcd. for C.sub.29H.sub.46N.sub.2O.sub.4Na [M+Na].sup.+509, found 509.

Example 18. Synthesis of Compound 39

[0393] ##STR00191##

[0394] To a solution of A1 (150 mg, 0.339 mmol) in acetone (2 mL) was added (1H-pyrazol-4-yl)methanol (49.8 mg, 0.508 mmol), followed by K.sub.2CO.sub.3 (93.7 mg, 0.678 mmol). The resulting reaction mixture was stirred at 40 C. for 2 hrs. To the mixture was added water (10 mL) and extracted with EtOAc (38 mL). The combined organic phases was concentrated to give a residue, which was purified by preparative HPLC to give compound 39 (6 mg, 4%) as an off-white solid.

[0395] 39: (yield 4%): .sup.1H NMR (400 MHz, CDCl.sub.3) 7.54 (s, 1H), 7.41 (s, 1H), 4.96-4.61 (m, 2H), 4.61 (s, 2H), 3.47-3.36 (m, 2H), 3.28 (s, 3H), 2.59 (t, J=9.2 Hz, 1H), 2.05-2.01 (m, 4H), 1.71-1.58 (m, 4H), 1.56-0.84 (m, 19H), 0.69 (s, 3H). LCMS Rt=0.813 min in 1.5 min chromatography, MS ESI calcd. for C.sub.27H.sub.42N.sub.2O.sub.4Na [M+Na].sup.+481, found 481.

Example 19. Synthesis of Compounds 40 and 41

[0396] ##STR00192##

[0397] To a solution of A1 (300 mg, 0.679 mmol) in acetone (4 mL) was added K.sub.2CO.sub.3 (280 mg, 2.03 mmol) and 7-methoxy-2H-indazole (149 mg, 1.01 mmol). The mixture was stirred at 25 C. for 4 hrs. The solvent was removed by rotary evaporator. To the mixture was added water (5 mL) and EtOAc (6 mL). The organic layer was separated. The aqueous phase was extracted with EtOAc (26 mL). The combined organic layers was washed with brine (7 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to afford a residue, which was purified by preparative HPLC to give compound 40 (44.6 mg, 13%) and compound 41 (28.6 mg, 8%).

[0398] 40: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.89 (s, 1H), 7.22 (d, J=8.5 Hz, 1H), 6.98 (t, J=7.9 Hz, 1H), 6.54 (d, J=7.3 Hz, 1H), 5.27-5.14 (m, 2H), 3.99 (s, 3H), 3.49-3.44 (m, 1H), 3.40-3.35 (m, 1H), 3.29 (s, 3H), 2.63 (t, J=8.7 Hz, 1H), 2.26-2.00 (m, 3H), 1.78-1.66 (m, 5H), 1.51-1.06 (m, 16H), 1.04-0.79 (m, 2H), 0.72 (s, 3H). LCMS Rt=1.345 min in 2 min chromatography, MS ESI calcd. for C.sub.31H.sub.45N.sub.2O.sub.4 [M+H].sup.+ 509, found 509.

[0399] 41: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.96 (s, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.02 (t, J=7.8 Hz, 1H), 6.68 (d, J=7.5 Hz, 1H), 5.49-5.42 (m, 1H), 5.37-5.30 (m, 1H), 3.86 (s, 3H), 3.51-3.46 (m, 1H), 3.41-3.35 (m, 1H), 3.30 (s, 3H), 2.61 (t, J=8.9 Hz, 1H), 2.25-2.01 (m, 3H), 1.79-1.61 (m, 6H), 1.54-1.46 (m, 3H), 1.38-1.06 (m, 12H), 1.03-0.80 (m, 2H), 0.72 (s, 3H). LCMS Rt=1.374 min in 2 min chromatography, MS ESI calcd. for C.sub.31H.sub.45N.sub.2O.sub.4 [M+H].sup.+ 509, found 509.

Example 20. Synthesis of Compounds 42 and 43

[0400] ##STR00193##

[0401] To a solution of A1 (300 mg, 0.679 mmol) in acetone (4 mL) was added K.sub.2CO.sub.3 (280 mg, 2.03 mmol) and 5-methoxy-2H-indazole (149 mg, 1.01 mmol). The mixture was stirred at 25 C. for 4 hrs. The solvent was removed by rotary evaporator. To the mixture was added water (5 mL) and EtOAc (6 mL). The organic layer was separated. The aqueous phase was extracted with EtOAc (26 mL). The combined organic layers was washed with brine (7 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to afford a residue, which was purified by preparative HPLC to give compound 42 (37.2 mg, 11%) and compound 43 (71.6 mg, 21%).

[0402] 42: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.79 (s, 1H), 7.59 (d, J=9.5 Hz, 1H), 6.99 (dd, J=2.3, 9.5 Hz, 1H), 6.87 (d, J=2.0 Hz, 1H), 5.23-5.07 (m, 2H), 3.83 (s, 3H), 3.48 (s, 1H), 3.40-3.35 (m, 1H), 3.29 (s, 3H), 2.62 (t, J=8.8 Hz, 1H), 2.28-2.17 (m, 1H), 2.13-1.98 (m, 2H), 1.80-1.61 (m, 5H), 1.57-1.07 (m, 16H), 1.03-0.80 (m, 2H), 0.72 (s, 3H). LCMS Rt=1.333 min in 2 min chromatography, MS ESI calcd. for C.sub.31H.sub.45N.sub.2O.sub.4 [M+H].sup.+ 509, found 509.

[0403] 43: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.94 (s, 1H), 7.13-7.02 (m, 3H), 5.15-5.03 (m, 2H), 3.85 (s, 3H), 3.50-3.44 (m, 1H), 3.40-3.34 (m, 1H), 3.29 (s, 3H), 2.62 (t, J=8.8 Hz, 1H), 2.27-1.99 (m, 3H), 1.80-1.61 (m, 5H), 1.56-1.06 (m, 16H), 1.03-0.79 (m, 2H), 0.73 (s, 3H). LCMS Rt=1.347 min in 2 min chromatography, MS ESI calcd. for C.sub.31H.sub.45N.sub.2O.sub.4 [M+H].sup.+ 509, found 509.

Example 21. Synthesis of Compounds 44 and 45

[0404] ##STR00194##

[0405] To a solution of A1 (300 mg, 0.679 mmol) in acetone (4 mL) was added K.sub.2CO.sub.3 (280 mg, 2.03 mmol) and 4-methoxy-2H-indazole (149 mg, 1.01 mmol). The mixture was stirred at 25 C. for 4 hrs. The solvent was removed by rotary evaporator. To the mixture was added water (5 mL) and EtOAc (6 mL). The organic layer was separated. The aqueous phase was extracted with EtOAc (26 mL). The combined organic layers was washed with brine (7 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to afford a residue, which was purified by preparative HPLC to give compound 44 (35.2 mg, 10%) and compound 45 (65.5 mg, 19%).

[0406] 44: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.98 (s, 1H), 7.28 (s, 1H), 7.23-7.15 (m, 1H), 6.33 (d, J=7.3 Hz, 1H), 5.23-5.09 (m, 2H), 3.93 (s, 3H), 3.51-3.43 (m, 1H), 3.40-3.35 (m, 1H), 3.29 (s, 3H), 2.63 (t, J=8.8 Hz, 1H), 2.28-2.17 (m, 1H), 2.13-1.99 (m, 2H), 1.80-1.61 (m, 5H), 1.56-1.07 (m, 16H), 1.04-0.79 (m, 2H), 0.72 (s, 3H). LCMS Rt=1.342 min in 2 min chromatography, MS ESI calcd. for C.sub.31H.sub.45N.sub.2O.sub.4 [M+H].sup.+ 509, found 509.

[0407] 45: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.10 (s, 1H), 7.32-7.27 (m, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.48 (d, J=7.5 Hz, 1H), 5.14-5.03 (m, 2H), 4.00-3.93 (m, 3H), 3.50-3.44 (m, 1H), 3.40-3.34 (m, 1H), 3.29 (s, 3H), 2.62 (t, J=8.7 Hz, 1H), 2.25-1.99 (m, 3H), 1.81-1.59 (m, 6H), 1.55-1.06 (m, 15H), 1.04-0.79 (m, 2H), 0.73 (s, 3H). LCMS Rt=1.361 min in 2 min chromatography, MS ESI calcd. for C.sub.31H.sub.45N.sub.2O.sub.4 [M+H].sup.+ 509, found 509.

Example 22. Synthesis of Compounds 46 and 47

[0408] ##STR00195##

[0409] To a solution of 2H-pyrazolo[3,4-c]pyridine (80.8 mg, 0.679 mmol) in THF (3 mL) was added NaH (32.4 mg, 1.35 mmol) at 25 C. The mixture was stirred at 20 C. for 30 mins, then a solution of C1 (200 mg, 0.453 mmol) in THF (2 mL) was added. The reaction mixture was stirred at 20 C. for 16 hrs. The mixture was quenched with water (10 mL), extracted with EtOAc (215 mL). The combined organic phase was washed with brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuum. The residue was purified by preparative TLC (eluted with EtOAc) to give compound 46 (9.9 mg, 5%) and compound 47 (17.3 mg, 8%).

[0410] 46: .sup.1H NMR (400 MHz, CDCl.sub.3) 9.31 (s, 1H), 8.19 (d, J=6.0 Hz, 1H), 8.00 (s, 1H), 7.62-7.52 (m, 1H), 5.38-5.18 (m, 2H), 3.54 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 3.21 (d, J=9.0 Hz, 1H), 2.71-2.61 (m, 1H), 2.29-2.10 (m, 2H), 1.98-1.60 (m, 9H), 1.50-1.27 (m, 11H), 1.22-1.09 (m, 2H), 0.91-0.76 (m, 2H), 0.70 (s, 3H). LCMS Rt=1.039 min in 2 min chromatography, MS ESI calcd. for C.sub.29H.sub.42N.sub.3O.sub.3 [M+H].sup.+ 480, found 480.

[0411] 47: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.79 (s, 1H), 8.34 (d, J=5.5 Hz, 1H), 8.10 (s, 1H), 7.64 (dd, J=1.1, 5.6 Hz, 1H), 5.31-5.19 (m, 2H), 3.54 (d, J=9.0 Hz, 1H), 3.34 (s, 3H), 3.22 (d, J=9.0 Hz, 1H), 2.71-2.63 (m, 1H), 2.27-2.09 (m, 2H), 1.98-1.87 (m, 2H), 1.83-1.61 (m, 6H), 1.56-1.40 (m, 8H), 1.37-1.27 (m, 6H), 1.22-1.10 (m, 2H), 0.71 (s, 3H). LCMS Rt=1.069 min in 2 min chromatography, MS ESI calcd. for C.sub.29H.sub.42N.sub.3O.sub.3 [M+H].sup.+ 480, found 480.

Example 23. Synthesis of Compound 48 and 49

[0412] ##STR00196##

[0413] To a solution of A1 (300 mg, 0.679 mmol) in acetone (4 mL) was added K.sub.2CO.sub.3 (280 mg, 2.03 mmol) and 6-methoxy-2H-indazole (149 mg, 1.01 mmol). The mixture was stirred at 25 C. for 4 hrs. The solvent was removed by rotary evaporator. To the mixture was added water (5 mL) and EtOAc (6 mL). The organic layer was separated. The aqueous phase was extracted with EtOAc (26 mL). The combined organic layers was washed with brine (7 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to afford a residue, which was purified by preparative HPLC to give compound 49 (3.3 mg, 0.2%) and compound 48 (81.2 mg, 1%).

[0414] 48: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.82 (s, 1H), 7.52 (d, J=9.0 Hz, 1H), 6.94 (s, 1H), 6.77 (dd, J=2.3, 9.0 Hz, 1H), 5.19-5.03 (m, 2H), 3.85 (s, 3H), 3.50-3.44 (m, 1H), 3.40-3.34 (m, 1H), 3.29 (s, 3H), 2.62 (t, J=8.8 Hz, 1H), 2.27-2.17 (m, 1H), 2.13-1.99 (m, 2H), 1.78-1.67 (m, 4H), 1.50-1.12 (m, 16H), 1.02-0.81 (m, 3H), 0.72 (s, 3H). LCMS Rt=1.326 min in 2 min chromatography, MS ESI calcd. for C.sub.31H.sub.45N.sub.2O.sub.4 [M+H].sup.+ 509, found 509.

[0415] 49: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.93 (s, 1H), 7.58 (d, J=8.8 Hz, 1H), 6.81 (dd, J=2.0, 8.8 Hz, 1H), 6.53 (s, 1H), 5.13-4.99 (m, 2H), 3.84 (s, 3H), 3.51-3.44 (m, 1H), 3.41-3.34 (m, 1H), 3.29 (s, 3H), 2.63 (t, J=8.8 Hz, 1H), 2.25-2.01 (m, 3H), 1.79-1.65 (m, 5H), 1.55-1.10 (m, 16H), 1.04-0.79 (m, 2H), 0.74 (s, 3H). LCMS Rt=1.341 min in 2 min chromatography, MS ESI calcd. for C.sub.31H.sub.45N.sub.2O.sub.4 [M+H].sup.+ 509, found 509.

Example 24. Synthesis of Compound 50

[0416] ##STR00197##

[0417] To a solution of C1 (200 mg, 0.453 mmol) and 6-chloro-2H-indazole (103 mg, 0.679 mmol) in acetone (5 mL) was added K.sub.2CO.sub.3 (93.8 mg, 0.679 mmol). The reaction mixture was stirred at 25 C. for 2 hrs. The reaction mixture was diluted with EtOAc (50 mL), washed with H.sub.2O (20 mL), brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to afford crude product, which was purified by preparative HPLC to give compound 50 (10 mg, 5%).

[0418] 50: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.03 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.22 (s, 1H), 7.15 (d, J=8.5 Hz, 1H), 5.20-5.03 (m, 2H), 3.57 (d, J=9.0 Hz, 1H), 3.36 (s, 3H), 3.23 (d, J=9.0 Hz, 1H), 2.65 (t, J=8.7 Hz, 1H), 2.30-2.09 (m, 2H), 1.99-1.91 (m, 2H), 1.77-1.45 (m, 14H), 1.34-1.14 (m, 8H), 0.73 (s, 3H). LCMS t.sub.R=3.185 min in 4 min chromatography, MS ESI calcd. for C.sub.30H.sub.42ClN.sub.2O.sub.3 [M+H].sup.+ 513, found 513.

Example 25. Synthesis of Compound 51

[0419] ##STR00198##

[0420] To a solution of A1 (200 mg, 0.47 mmol) in acetone (2 mL) was added 5-chloro-4-fluoro-2H-benzo[d][1,2,3]triazole (0.116 g, 0.68 mmol), followed by K.sub.2CO.sub.3 (0.124 g, 0.906 mmol). The resulting reaction mixture was stirred at 25 C. for 16 hrs. To the mixture was added water (4 mL) and extracted with EtOAc (32 mL). The combined organic phase was concentrated to give a residue, which was purified by preparative HPLC to give compound 51 (65.9 mg, 27%)

[0421] 51: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.48 (dd, J=6.0, 8.8 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 5.46-5.36 (m, 2H), 3.50-3.48 (m, 1H), 3.40-3.37 (m, 1H), 3.30 (s, 3H), 2.72 (t, J=8.6 Hz, 1H), 2.30-2.01 (m, 3H), 1.80-1.70 (m, 4H), 1.69-1.48 (m, 7H), 1.39-1.10 (m, 10H), 1.09-0.76 (m, 2H), 0.74 (s, 3H). LCMS Rt=1.374 min in 2 min chromatography, MS ESI calcd. for C.sub.29H.sub.40ClFN.sub.3O.sub.3 [M+H].sup.+ 532, found 532.

Example 26. Synthesis of Compound 52

[0422] ##STR00199##

[0423] To a solution of C1 (100 mg, 0.226 mmol) in acetone (5 mL) was added K.sub.2CO.sub.3 (62.4 mg, 0.452 mmol) and 5-fluoro-1H-imidazole (29.1 mg, 0.339 mmol) at 15 C. The mixture was stirred at 45 C. for 12 h, then treated with water (20 mL) and extracted with EtOAc (230 mL). The organic phase was washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, and concentrated in vacuum prior to being purified by preparative HPLC to afford compound 52 (18.3 mg) as an off-white solid.

[0424] 52: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.00 (s, 1H), 6.37 (dd, J=1.2 Hz, 8.0 Hz, 1H), 4.60-4.59 (m, 2H), 3.50 (d, J=8.8 Hz, 1H), 3.31 (s, 3H), 3.21 (d, J=8.8 Hz, 1H), 2.57-2.55 (m, 1H), 2.23-2.10 (m, 1H), 1.91-1.85 (m, 3H), 1.80-1.1.65 (m, 6H), 1.64-1.14 (m, 16H), 0.65 (s, 3H). LCMS Rt=0.861 min in 1.5 min chromatography, MS ESI calcd. for C.sub.26H.sub.40FN.sub.2O.sub.3 [M+H].sup.+ 447, found 447.

Example 27. Synthesis of Compound 53

[0425] ##STR00200##

[0426] To a solution of A1 (600 mg, 1.35 mmol) in 3 mL of acetone was added 4-nitro-1H-pyrazole (197 mg, 1.75 mmol) and K.sub.2CO.sub.3 (373 mg, 2.7 mmol) at 25 C. After stirring at 55 C. for 3 hrs, the reaction mixture was poured into ice-cold water, extracted with EtOAc (250 mL), washed with brine (230 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated under vacuum to give 500 mg of the crude product, which was purified by prep-HPLC to obtain compound 53 (30.0 mg, 23%) as an off-white solid.

[0427] 53: .sup.1H NMR (400 MHz, CDCl.sub.3): 8.17 (s, 1H), 8.08 (s, 1H), 5.00-4.86 (m, 2H), 3.48-3.44 (m, 1H), 3.37 (d, J=9.8 Hz, 1H), 3.28 (s, 3H), 2.61 (t, J=8.8 Hz, 1H), 2.26-2.18 (m, 1H), 2.03 (d, J=13.4 Hz, 2H), 1.77-1.69 (m, 4H), 1.55-1.47 (m, 4H), 1.46-1.04 (m, 13H), 1.03-0.95 (m, 1H), 0.90-0.81 (m, 1H), 0.69 (s, 3H). LCMS Rt=2.859 min in 4.0 min chromatography, MS ESI calcd. for C.sub.26H.sub.38N.sub.3O.sub.4 [MH.sub.2O+H].sup.+456, found 456.

Example 28. Synthesis of Compounds 54 and 55

[0428] ##STR00201##

[0429] Step 1. To a stirred solution of 53 (400 mg, 0.844 mmol) in 20 mL of MeOH was added Pd/C (200 mg). The reaction was stirred under H.sub.2 at 25 C. for 3 hrs, then the reaction mixture was filtered, washed with MeOH (20 mL) and evaporated under vacuum to give a crude product (300 mg), which was purified by HPLC to obtain compound 54 (15 mg, 90%) as an off-white solid.

[0430] 54: .sup.1H NMR .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.00 (br. s., 2H), 7.90 (s, 1H), 7.55 (s, 1H), 5.21-5.00 (m, 2H), 3.37-3.30 (m, 2H), 3.24-3.15 (m, 3H), 2.77-2.62 (m, 2H), 2.33 (br. s., 1H), 2.04 (d, J=9.6 Hz, 2H), 1.92-1.50 (m, 10H), 1.48-1.01 (m, 10H), 0.99-0.88 (m, 1H), 0.83-0.72 (m, 1H), 0.64-0.47 (m, 3H). LCMS Rt=1.984 min in 4.0 min chromatography, MS ESI calcd. for C.sub.26H.sub.42N.sub.3O.sub.3 [M+H].sup.+ 444.2, found 444.2.

[0431] Step 2. To a stirred solution of compound 54 (200 mg, 0.450 mmol) in 5 mL of DCM was added Ac.sub.2O (45.9 mg, 0.450 mmol) and TEA (0.124 mL, 0.9 mmol) and DMAP (109 mg, 0.9 mmol) at 25 C. After stirring at 25 C. for 0.5 hrs, the reaction mixture was poured into water (20 mL), extracted with EtOAc (250 mL), washed with brine (230 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated in vacuum. The crude product was purified by prep-HPLC to obtain compound 55 (30.7 mg, 14%) as an off-white solid.

[0432] 55: .sup.1H NMR (400 MHz, CDCl.sub.3): 7.89 (brs, 1H), 7.42 (brs, 1H), 7.30 (brs, 1H), 4.94-4.77 (m, 2H), 3.48-3.42 (m, 1H), 3.39-3.34 (m, 1H), 3.28 (s, 3H), 2.57 (brs, 1H), 2.23-2.10 (m, 4H), 2.06-1.99 (m, 2H), 1.76-1.62 (m, 9H), 1.51 (dd, J=12.6, 4.5 Hz, 3H), 1.33 (t, J=13.6 Hz, 2H), 1.25-1.18 (m, 5H), 1.16-1.05 (m, 2H), 1.02-0.92 (m, 1H), 0.83 (t, J=9.6 Hz, 1H), 0.68 (s, 3H). LCMS Rt=2.631 min in 4.0 min chromatography, MS ESI calcd. for C.sub.28H.sub.44N.sub.3O.sub.4 [M+H].sup.+486.3, found 486.3.

Example 29. Synthesis of Compound 56

[0433] ##STR00202##

[0434] To a stirred solution of C1 (90 mg, 0.203 mmol) in 3 mL of acetone was added 1H-imidazole-2-carbonitrile (24.4 mg, 0.263 mmol) and K.sub.2CO.sub.3 (56.1 mg, 0.406 mmol) at 25 C. After stirring at 55 C. for 4 hrs, the reaction mixture was poured into ice-cold water, extracted with EtOAc (250 mL), washed with brine (230 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated under vacuum. The crude product was purified by preparative HPLC to obtain compound 56 (25.6 mg, 28%) as an off-white solid.

[0435] 56: .sup.1H NMR (400 MHz, CDCl.sub.3): 7.26 (s, 1H), 7.13-6.98 (m, 1H), 5.02-4.79 (m, 2H), 3.57-3.50 (m, 1H), 3.33 (s, 3H), 3.20 (d, J=9.0 Hz, 1H), 2.62 (br. s., 1H), 2.22 (d, J=8.6 Hz, 1H), 2.08 (d, J=10.6 Hz, 1H), 1.92 (br. s., 2H), 1.79-1.57 (m, 11H), 1.52-1.42 (m, 4H), 1.29 (s, 5H), 1.24-1.09 (m, 2H), 0.70 (s, 3H). LCMS Rt=2.553 min in 4.0 min chromatography, MS ESI calcd. for C.sub.27H.sub.40N.sub.3O.sub.3 [M+H].sup.+ 454.3, found 454.3.

Example 30. Synthesis of Compound 57

[0436] ##STR00203##

[0437] To a stirred solution of C1 (80 mg, 0.181 mmol) in 3 mL of acetone was added 4-isopropoxy-1H-pyrazole (29.6 mg, 0.235 mmol) and K.sub.2CO.sub.3 (50 mg, 0.362 mmol) at 25 C. After stirring at 55 C. for 4 hrs, the reaction mixture was poured into ice-cold water, extracted with EtOAc (250 mL, washed with brine (230 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated under vacuum. The crude product was purified by preparative HPLC to obtain compound 57 (16.3 mg, 19%) as an off-white solid.

[0438] 57: .sup.1H NMR (400 MHz, CDCl.sub.3): 7.26 (s, 1H), 7.06 (s, 1H), 4.84-4.72 (m, 2H), 4.17 (dt, J=12.2, 6.2 Hz, 1H), 3.54 (d, J=9.0 Hz, 1H), 3.32 (s, 3H), 3.18 (d, J=9.0 Hz, 1H), 2.54 (t, J=8.8 Hz, 1H), 2.22-2.13 (m, 1H), 2.03 (d, J=11.6 Hz, 1H), 1.91 (d, J=5.8 Hz, 2H), 1.80-1.66 (m, 4H), 1.56-1.34 (m, 11H), 1.33-1.26 (m, 9H), 1.24 (br. s., 4H), 0.65 (s, 3H). LCMS Rt=2.758 min in 4.0 min chromatography, MS ESI calcd. for C.sub.29H.sub.47N.sub.2O.sub.4 [M+H].sup.+ 487.4, found 487.4.

Example 31. Synthesis of Compound 58

[0439] ##STR00204##

[0440] To a stirred solution of C1 (80 mg, 0.181 mmol) in 3 mL of acetone was added 4-ethoxy-1H-pyrazole (26.3 mg, 0.235 mmol) and K.sub.2CO.sub.3 (50 mg, 0.362 mmol) at 25 C. After stirring at 55 C. for 4 hrs, the reaction mixture was poured into ice-cold water, extracted with EtOAc (250 mL), washed with brine (230 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated under vacuum. The crude product was purified by preparative HPLC to obtain compound 58 (12.3 mg, Yield:14%) as an off-white solid.

[0441] 58: .sup.1H NMR (400 MHz, CDCl.sub.3): 7.27 (br. s., 1H), 7.06 (s, 1H), 4.86-4.70 (m, 2H), 3.94 (q, J=6.8 Hz, 2H), 3.58-3.49 (m, 1H), 3.32 (s, 3H), 3.23-3.13 (m, 1H), 2.53 (t, J=8.4 Hz, 1H), 2.22-2.14 (m, 1H), 2.07-1.97 (m, 2H), 1.91 (d, J=4.8 Hz, 2H), 1.79-1.59 (m, 7H), 1.51-1.33 (m, 8H), 1.32-1.15 (m, 9H), 0.65 (s, 3H). LCMS Rt=2.686 min in 4.0 min chromatography, MS ESI calcd. for C.sub.28H.sub.45N.sub.2O.sub.4 [M+H].sup.+ 473.3, found 473.3.

Example 32. Synthesis of Compound 59

[0442] ##STR00205##

[0443] To a solution of A1 (100 mg, 226 mol) in acetone (5 mL) was added K.sub.2CO.sub.3 (62.4 mg, 452 mol) and 5-fluoro-1H-imidazole (23.3 mg, 271 mol) at 55 C. The mixture was stirred at 55 C. for 12 hrs, at which point H.sub.2O (10 mL) was added. The mixture was extracted with EtOAc (220 mL), and the combined organic layer was washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC to afford compound 59 (22 mg, 22%) as an off-white solid.

[0444] 59: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.02 (s, 1H), 6.39 (dd, J=1.8, 8.0 Hz, 1H), 4.69-4.54 (m, 2H), 3.53-3.36 (m, 2H), 3.31 (s, 3H), 2.59 (t, J=8.9 Hz, 1H), 2.30-2.16 (m, 1H), 2.09-2.00 (m, 1H), 1.99-1.91 (m, 1H), 1.82-1.68 (m, 4H), 1.67-1.61 (m, 2H), 1.56-1.45 (m, 3H), 1.45-1.30 (m, 3H), 1.29-1.20 (m, 6H), 1.19-1.09 (m, 3H), 1.06-0.82 (m, 2H), 0.70 (s, 3H). LCMS Rt=0.992 min in 2 min chromatography, MS ESI calcd. for C.sub.26H.sub.40FN.sub.2O.sub.3 [M+H].sup.+ 447, found 447.

Example 33. Synthesis of Compound 60

[0445] ##STR00206##

[0446] To a solution of A1 (200 mg, 0.453 mmol) in acetone (5 mL) was added K.sub.2CO.sub.3 (93.8 mg, 0.679 mmol) and 4-methyl-1H-pyrazole (44.5 mg, 0.543 mmol) at 50 C. The mixture was stirred at 50 C. for 12 hrs, then poured into water (10 mL) and extracted with EtOAc (220 mL). The combined organic layer was washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give compound 60 (107 mg, 53%) as an off-white solid.

[0447] 60: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.38 (s, 1H), 7.20 (s, 1H), 4.97-4.82 (m, 2H), 3.51-3.35 (m, 2H), 3.30 (s, 3H), 2.63-2.55 (m, 1H), 2.28-2.16 (m, 1H), 2.12 (s, 3H), 2.08-2.00 (m, 2H), 1.79-1.66 (m, 5H), 1.63-1.56 (m, 3H), 1.53-1.47 (m, 3H), 1.42-1.30 (m, 2H), 1.27-1.19 (m, 6H), 1.18-1.07 (m, 2H), 1.05-0.92 (m, 1H), 0.91-0.80 (m, 1H), 0.71 (s, 3H). LCMS Rt=1.028 min in 2 min chromatography, MS ESI calcd. for C.sub.27H.sub.43N.sub.2O.sub.3 [M+H].sup.+ 443, found 443.

Example 34. Synthesis of Compound 61

[0448] ##STR00207##

[0449] To a solution of A1 (80 mg, 0.181 mmol) in acetone (3 mL) was added 4-ethoxy-1H-pyrazole (30.3 mg, 0.271 mmol) and K.sub.2CO.sub.3 (49.9 mg, 0.362 mmol) at 15 C. The mixture was stirred at 40 C. for 15 hrs, then was diluted with DCM (10 mL) and filtered. The filtrate was concentrated to get the crude product, which was purified by preparative HPLC to afford compound 61 (17.6 mg, 21%).

[0450] 61: .sup.1H NMR (400 MHz, CD.sub.3OD) 7.30 (s, 1H), 7.24 (s, 1H), 4.64 (br. s., 2H), 3.96 (q, J=7.0 Hz, 2H), 3.54-3.40 (m, 2H), 3.31 (s, 3H), 2.72-2.64 (m, 1H), 2.22-1.94 (m, 5H), 1.82-1.12 (m, 19H), 1.09-0.81 (m, 4H), 0.71 (s, 3H). LCMS R.sub.t=1.840 min in 3.0 min chromatography, MS ESI calcd. for C.sub.28H.sub.45N.sub.2O.sub.4 [M+H].sup.+ 473, found 473.

Example 35. Synthesis of Compounds 62 and 63

[0451] ##STR00208## ##STR00209##

[0452] Step 1. To a solution of D1 (2 g, 6.01 mmol) in 40 mL of anhydrous dichloromethane was added PCC (2.58 g, 12 mmol) at 25 C. The mixture was stirred at 25 C. for 2 hrs. The solution was filtered and the filter cake was washed with DCM (250 mL). The combined filtrate was concentrated in vacuum. The residue was purified by silica gel column eluted with (PE/EtOAc=10/1) to afford D2 (1.6 g 77%) as an off-white solid.

[0453] D2: .sup.1H NMR (400 MHz, CDCl.sub.3) 9.75 (s, 1H), 5.17-5.08 (m, 1H), 2.42-2.28 (m, 2H), 2.26-2.12 (m, 1H), 2.04-1.80 (m, 3H), 1.78-1.67 (m, 1H), 1.67-1.59 (m, 6H), 1.58-1.45 (m, 6H), 1.40-1.33 (m, 3H), 1.32-1.25 (m, 4H), 1.24-1.07 (m, 3H), 0.93 (s, 3H).

[0454] Step 2. To a solution of D2 (1.2 g, 3.63 mmol) in MeOH (10 mL) and THF (10 mL) was added NaBD.sub.4 (227 mg, 5.44 mmol) at 25 C. The reaction mixture was stirred at 25 C. for 2 hrs. The reaction was poured into water (100 mL) and extracted with (250 mL). The combined organic layer was washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to afford D3 (1.1 g, crude) as an off-white solid.

[0455] D3: .sup.1H NMR (400 MHz, CDCl.sub.3) 5.18-5.06 (m, 1H), 3.54-3.48 (m, 1H), 2.41-2.31 (m, 1H), 2.29-2.11 (m, 2H), 2.01-1.84 (m, 2H), 1.82-1.71 (m, 1H), 1.67-1.59 (m, 5H), 1.54-1.34 (m, 5H), 1.33-1.08 (m, 12H), 0.85 (s, 3H).

[0456] Step 3. To a solution of D3 (1 g, 2.99 mmol) in DMF (15 mL) was added NaH (358 mg, 8.97 mmol, 60%) at 25 C. The mixture was stirred at 25 C. for 30 mins. Me.sub.2SO.sub.4 (377 mg, 2.99 mmol, 100 mg/mL in THF) was added and the reaction mixture was stirred at 25 C. for 12 h. The mixture was poured into ice water (20 mL) and extracted with EtOAc (230 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (PE/EtOAc=10/1) to afford D4 (506 mg, 44%) as a colorless oil.

[0457] D4: .sup.1H NMR (400 MHz, CDCl.sub.3) 5.19-5.00 (m, 1H), 3.36 (s, 3H), 2.44-2.12 (m, 3H), 2.02-1.88 (m, 2H), 1.85-1.71 (m, 1H), 1.66-1.40 (m, 10H), 1.41-1.12 (m, 12H), 0.96-0.82 (m, 5H).

[0458] Step 4. To a solution of D4 (506 mg, 1.45 mmol) in THF (3 mL) was added drop wise a solution of BH.sub.3-Me.sub.2S (1.44 mL, 14.4 mmol) at 0 C. The solution was stirred at 25 C. for 16 hrs. After cooling to 0 C., a solution of NaOH (4.8 mL, 3M) was added very slowly. After the addition, H.sub.2O.sub.2 (3 mL, 33%) was added slowly and the inner temperature was maintained below 10 C. The resulting solution was stirred at 25 C. for 2 hrs. The resulting solution was extracted with EtOAc (220 mL). The combined organic layer was washed with saturated Na.sub.2S.sub.2O.sub.3 (250 mL), brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give D5 (410 mg, crude) as an off-white solid, which was used for the next step without further purification.

[0459] D5: .sup.1H NMR (400 MHz, CDCl.sub.3) 3.78-3.72 (m, 1H), 3.35 (s, 3H), 3.18 (m, 1H), 1.96-1.94 (m, 3H), 1.59-1.45 (m, 11H), 1.29-1.10 (m, 16H), 0.88-0.75 (m, 1H), 0.75-0.56 (m, 3H).

[0460] Step 5. To a solution of D5 (410 mg, 1.12 mmol) in THF (2 mL) and DCM (8 mL) was added PCC (481 mg, 2.24 mmol) at 25 C. The mixture was stirred at 25 C. for 2 hrs. The solution was filtered and the filter cake was washed with DCM (250 mL). The combined filtrate was concentrated in vacuum, and the residue was purified by silica gel column eluted with (PE/EtOAc=6/1) to afford D6 (242 mg, 56%) as an off-white solid.

[0461] D6: .sup.1H NMR (400 MHz, CDCl.sub.3) 3.52-3.15 (m, 4H), 2.52 (t, J=8.9 Hz, 1H), 2.20-2.08 (m, 4H), 2.04-1.84 (m, 3H), 1.81-1.60 (m, 4H), 1.55-1.34 (m, 8H), 1.31-1.05 (m, 10H), 0.60 (s, 3H).

[0462] Step 6. To a solution of D6 (242 mg, 0.665 mmol) and HBr (0.05 mL, 48% in water) in MeOH (5 mL) was added bromine (127 mg, 0.798 mmol). The reaction mixture was stirred at 25 C. for 2 hrs. The reaction was quenched by saturated NaHCO.sub.3 (20 mL) and pH was adjusted to 7-8. The mixture was extracted with EtOAc (230 mL). The combined organic layers was washed with brine (50 mL), dried over Na.sub.2SO.sub.4 filtered and concentrated in vacuum. The residue was purified by silica gel column eluted with (PE/EtOAc=10/1) to afford D7 (180 mg, 58%) as an off-white solid.

[0463] D7: .sup.1H NMR (400 MHz, CDCl.sub.3) 3.95-3.85 (m, 2H), 3.52-3.14 (m, 4H), 2.85-2.77 (m, 1H), 2.24-2.10 (m, 1H), 1.96-1.85 (m, 3H), 1.81-1.66 (m, 3H), 1.57-1.35 (m, 6H), 1.31-1.09 (m, 11H), 0.92-0.81 (m, 2H), 0.62 (s, 3H).

[0464] Step 7. To a solution of D7 (180 mg, 0.406 mmol) in acetone (3 mL) was added K.sub.2CO.sub.3 (112 mg, 0.812 mmol) and 5-methyl-2H-tetrazole (84.9 mg, 1.01 mmol). The mixture was stirred at 25 C. for 12 hrs. The mixture was poured into water (30 mL) and extracted with EtOAc (230 mL). The combined organic layers was washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by preparative HPLC to give compounds 62 (40 mg, 22%) and 63 (33 mg, 18%) as an off-white solid.

[0465] 62: .sup.1H NMR (400 MHz, CDCl.sub.3) 5.34 (s, 2H), 3.52-3.19 (m, 4H), 2.65-2.59 (m, 1H), 2.57 (s, 3H), 2.28-2.15 (m, 1H), 2.10-2.05 (m, 1H), 1.98-1.87 (m, 2H), 1.84-1.70 (m, 3H), 1.67-1.62 (m, 1H), 1.60-1.40 (m, 8H), 1.37-1.09 (m, 10H), 0.70 (s, 3H). LCMS Rt=0.979 min in 2.0 min chromatography, MS ESI calcd. for C.sub.25H.sub.38DN.sub.4O.sub.2 [M+HH.sub.2O].sup.+428, found 428.

[0466] 63: .sup.1H NMR (400 MHz, CDCl.sub.3) 5.19-5.01 (m, 2H), 3.50-3.20 (m, 4H), 2.69-2.61 (m, 1H), 2.47 (s, 3H), 2.26-2.14 (m, 1H), 2.10-2.05 (m, 1H), 1.98-1.87 (m, 2H), 1.85-1.71 (m, 3H), 1.68-1.62 (m, 2H), 1.61-1.59 (m, 1H), 1.57-1.41 (m, 7H), 1.39-1.10 (m, 9H), 0.67 (s, 3H). Rt=0.897 min in 2.0 min chromatography, MS ESI calcd. for C.sub.25H.sub.38DN.sub.4O.sub.2 [M+HH.sub.2O].sup.+428, found 428.

Example 36. Synthesis of Compound 64

[0467] ##STR00210##

[0468] To a solution of C1 (110 mg, 249 mol) in acetone (5 mL) was added K.sub.2CO.sub.3 (51.5 mg, 373 mol) and 2-methyl-1H-imidazole (24.4 mg, 298 mol) at 25 C. The mixture was stirred at 25 C. for 2 hrs. The mixture was poured into water (10 mL) and extracted with EtOAc (220 mL). The combined organic layer was washed with brine (10 mL), dried over Na.sub.2SO.sub.4 filtered and concentrated under reduced pressure to give the crud product, which was purified by HPLC to give compound 64 (9.5 mg, 9%) as an off-white solid.

[0469] 64: .sup.1H NMR (400 MHz, DMSO-d6) 6.86 (s, 1H), 6.70 (s, 1H), 4.98-4.69 (m, 2H), 3.47 (d, J=9.3 Hz, 1H), 3.20 (s, 3H), 3.15 (d, J=9.0 Hz, 1H), 2.67 (m, 1H), 2.07 (s, 3H), 2.02-1.56 (m, 7H), 1.56-1.32 (m, 8H), 1.32-0.96 (m, 11H), 0.53 (s, 3H). LCMS Rt=0.742 min in 2.0 min chromatography, MS ESI calcd. for C.sub.27H.sub.43N.sub.2O.sub.3 [M+H].sup.+ 443, found 443.

Example 37. Synthesis of Compounds 65 and 66

[0470] ##STR00211##

[0471] Step 1. To a solution of C1 (450 mg, 1.01 mmol) in acetone (20 mL) was added K.sub.2CO.sub.3 (208 mg, 1.51 mmol) and 4-nitro-1H-pyrazole (136 mg, 1.21 mmol) at 25 C. The mixture was stirred at 25 C. for 2 hrs. The mixture was poured into water (10 mL) and extracted with EtOAc (220 mL). The combined organic layer was washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the crude product (450 mg), of which 150 mg which was purified by preparative HPLC to give compound 65 (36.9 mg, 7%) as an off-white solid.

[0472] 65: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.20 (s, 1H), 8.10 (s, 1H), 5.04-4.88 (m, 2H), 3.55 (d, J=8.8 Hz, 1H), 3.35 (s, 3H), 3.23 (d, J=9.2 Hz, 1H), 2.68-2.58 (m, 1H), 2.29-2.18 (m, 1H), 2.12-2.02 (m, 1H), 1.97-1.89 (m, 2H), 1.85-1.73 (m, 3H), 1.71-1.59 (m, 3H), 1.56-1.44 (m, 7H), 1.40-1.15 (m, 9H), 0.69 (s, 3H). LCMS Rt=1.030 min in 2.0 min chromatography, MS ESI calcd. for C.sub.26H.sub.38N.sub.3O.sub.4 [M+HH.sub.2O].sup.+ 456, found 456.

[0473] Step 2. To a solution of 65 (300 mg, 633 mol) in MeOH (5 mL) was added Pd/C (10%, 300 mg) under N.sub.2. The suspension was degassed under vacuum and purged with H.sub.2 several times. The mixture was stirred under H.sub.2 (15 psi) at 25 C. for 12 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give the crude product (300 mg), 150 mg of which was purified by preparative HPLC to give 66 (17 mg, 6%) as an off-white solid.

[0474] 66: .sup.1H NMR (400 MHz, DMSO-d6) 6.97 (s, 1H), 6.92 (s, 1H), 4.90-4.72 (m, 2H), 4.25 (s, 1H), 3.84 (br. s., 2H), 3.49 (d, J=9.2 Hz, 1H), 3.25 (s, 3H), 3.17 (d, J=9.2 Hz, 1H), 2.62-2.54 (m, 1H), 2.08-1.96 (m, 2H), 1.88-1.73 (m, 3H), 1.72-1.56 (m, 3H), 1.55-1.44 (m, 4H), 1.43-1.32 (m, 4H), 1.30-1.00 (m, 9H), 0.55 (s, 3H). LCMS Rt=0.604 min in 2.0 min chromatography, MS ESI calcd. for C.sub.26H.sub.41N.sub.3O.sub.3Na [M+Na].sup.+466, found 466.

Example 38. Synthesis of Compound 67

[0475] ##STR00212##

[0476] To a solution of C1 (110 mg, 249 mol) in acetone (5 mL) was added K.sub.2CO.sub.3 (51.5 mg, 373 mol) and 4-(trifluoromethyl)-1H-pyrazole (40.5 mg, 298 mol) at 25 C. The mixture was stirred at 25 C. for 2 hrs. The mixture was poured into water (10 mL) and extracted with EtOAc (220 mL), and the combined organic layer was washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the crud product, which was purified by HPLC to give 67 (33.8 mg, 27%) as an off-white solid.

[0477] 67: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.74 (s, 2H), 5.06-4.86 (m, 2H), 3.56 (d, J=9.2 Hz, 1H), 3.35 (s, 3H), 3.22 (d, J=8.8 Hz, 1H), 2.66-2.57 (m, 1H), 2.28-2.03 (m, 2H), 1.98-1.90 (m, 2H), 1.84-1.72 (m, 3H), 1.57-1.39 (m, 9H), 1.38-1.10 (m, 10H), 0.69 (s, 3H). LCMS Rt=1.083 min in 2.0 min chromatography, MS ESI calcd. for C.sub.27H.sub.40F.sub.3N.sub.2O.sub.3 [M+H].sup.+ 497, found 497.

Example 39. Synthesis of Compounds 68, 69, and 70

[0478] ##STR00213##

[0479] Step 1. To a mixture of propan-2-ol (27.7 g, 462 mmol) and TEA (46.6 g, 462 mmol) in DCM (100 mL) was added sulfurous dichloride (25 g, 210 mmol) dropwise at 0 C. The reaction mixture was stirred at 70 C. for 3 hrs. The reaction mixture was cooled to 15 C., washed with water (2200 mL), brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to give diisopropyl sulfite (28.0 g, crude) as a brown oil. .sup.1H NMR (400 MHz, CDCl.sub.3) 4.82-4.73 (m, 2H), 1.38-1.26 (m, 12H).

[0480] Step 2. To a solution of diisopropyl sulfite (24 g, 144 mmol) in CCl.sub.4 (20 mL), MeCN (20 mL) and water (30 mL) was added sodium periodate (92.4 g, 432 mmol) in portions followed by ruthenium(III) chloride (8.96 mg, 43.2 mmol) at 15 C. The reaction mixture was stirred at 15 C. for 1 h. The reaction mixture was filtered. The filtered cake was washed with EtOAc (4250 mL). The organic layer was separated and washed with water (220 mL), saturated Na.sub.2S.sub.2O.sub.3 (3220 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give diisopropyl sulfate (26 g, 99%) as colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) 4.88 (sept, J=6.4 Hz, 2H), 1.42 (d, J=6.4 Hz, 12H).

[0481] Step 3. NaH (251 mg, 6.30 mmol) was added to a solution of D1 (300 mg, 1.05 mmol) in THF (35 mL) at 0 C. under nitrogen. After that, diisopropyl sulfate (765 mg, 4.20 mmol) was added portion wise. The mixture was slowly warmed to room temperature and heated to 65 C. The reaction mixture was stirred at 65 C. for 2 hrs. The mixture was diluted with water (200 mL) and extracted with EtOAc (3200 mL). The combined organic layers were washed with saturated NH.sub.4Cl (100 mL), dried with anhydrous sodium sulfate and filtered. The solvents were removed under reduced pressure and the residue was purified by column chromatography on silica gel (PE/EtOAc=4/1) to afford D8 (300 mg, 76%) as an off-white solid.

[0482] D8: .sup.1H NMR (400 MHz, CDCl.sub.3) 5.10 (q, J=6.8 Hz, 1H), 3.58 (d, J=9.2 Hz, 1H), 3.47-3.41 (m, 1H), 3.21 (d, J=9.2 Hz, 1H), 2.41-2.29 (m, 1H), 2.28-2.09 (m, 2H), 2.00-1.85 (m, 2H), 1.83-1.70 (m, 1H), 1.68-1.38 (m, 14H), 1.37-1.16 (m, 9H), 1.13 (d, J=6.0 Hz, 6H), 0.85 (s, 3H).

[0483] Step 4. To a solution of D8 (380 mg, 1.01 mmol) in THE (15 mL) was added dropwise a solution of BH.sub.3-Me.sub.2S (1.01 mL, 10 M, 10.1 mmol) at 0 C. The solution was stirred at 25 C. for 12 hrs. After cooling to 0 C., NaOH aqueous (3.36 mL, 3M, 10.1 mmol) was added slowly. After the addition, hydrogen peroxide (1.03 g, 33% w/w in water, 10.1 mmol) was added slowly and the inner temperature maintained below 10 C. The resulting solution was stirred at 25 C. for 2 hrs. The resulting solution was extracted with EtOAc (380 mL). The combined organic solution was washed with saturated Na.sub.2S.sub.2O.sub.3 (280 mL), brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuum to give D9 (401 mg, crude) as a white solid, which was used for the next step without further purification.

[0484] Step 5. To a solution of D9 (401 mg, 1.02 mmol) in DCM (30 mL) was added PCC (393 mg, 1.83 mmol) and MgSO.sub.4 (612 mg, 5.10 mmol) at 15 C. The reaction mixture was stirred at 15 C. for 4 hrs. The reaction mixture was filtered. The filtrate was concentrated under vacuum to give a residue, which was purified by silica gel chromatography (PE/EtOAc=4/1) to afford D10 (280 mg, 70%) as an off-white solid.

[0485] D10: .sup.1H NMR (400 MHz, CDCl.sub.3) 3.59-3.51 (m, 1H), 3.49-3.41 (m, 1H), 3.22-3.19 (m, 1H), 2.53 (t, J=8.8 Hz, 1H), 2.20-2.08 (m, 4H), 2.05-1.95 (m, 1H), 1.94-1.85 (m, 2H), 1.82-1.70 (m, 2H), 1.69-1.40 (m, 10H), 1.39-1.16 (m, 10H), 1.13 (d, J=6.0 Hz, 6H), 0.60 (s, 3H).

[0486] Step 6. To a solution of D10 (150 mg, 384 mol) in MeOH (20 mL) was added HBr (1 drop, 48% w/w in water) at 15 C. Liquid bromine (67.4 mg, 422 mol) was added at 15 C. The reaction mixture was stirred at 15 C. for 2 hrs. The mixture was quenched by saturated NaHCO.sub.3 aqueous (20 mL) at 0 C. The mixture was extracted with EtOAc (380 mL), and the combined organic phase was washed with water (100 mL), brine (100 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated under vacuum to give a residue, which was purified by silica gel chromatography (PE/EtOAc=5/1) to afford D11 (220 mg, impure) as an off-white solid.

[0487] D11: .sup.1H NMR (400 MHz, CDCl.sub.3) 3.96-3.83 (m, 2H), 3.53 (d, J=8.8 Hz, 1H), 3.45 (m, 1H), 3.21 (d, J=8.8 Hz, 1H), 2.81 (t, J=8.8 Hz, 1H), 2.24-2.09 (m, 1H), 1.98-1.85 (m, 3H), 1.82-1.67 (m, 3H), 1.65-1.31 (m, 11H), 1.29-1.16 (m, 8H), 1.12 (d, J=6.0 Hz, 6H), 0.63 (s, 3H).

[0488] Step 7. To a solution of D11 (145 mg, 0.3088 mmol) in acetone (10 mL) was added 4,5-difluoro-2H-benzo[d][1,2,3]triazole (71.8 mg, 0.4632 mmol), followed by K.sub.2CO.sub.3 (85.2 mg, 0.6176 mmol) at 15 C. The reaction mixture was stirred at 15 C. for 16 hrs, and the organic phase was washed with water (2100 mL), brine (120 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated under vacuum to give a residue, which was purified by preparative HPLC to afford 68 (37.7 mg, 22%), 69 (4.6 mg, 3%) and 70 (20.8 mg, 12%).

[0489] 68: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.45-7.30 (m, 1H), 7.10-7.00 (m, 1H), 5.49-5.33 (m, 2H), 3.54 (d, J=8.8 Hz, 1H), 3.49-3.45 (m, 1H), 3.25 (d, J=8.8 Hz, 1H), 2.76-2.66 (m, 1H), 2.28-2.09 (m, 2H), 1.99-1.87 (m, 2H), 1.85-1.71 (m, 3H), 1.69-1.34 (m, 11H), 1.34-1.16 (m, 8H), 1.14 (d, J=6.0 Hz, 6H), 0.71 (s, 3H). LCMS R.sub.t=4.647 min in 7 min chromatography, MS ESI calcd. For C.sub.31H.sub.42F.sub.2N.sub.3O.sub.2 [M+HH.sub.2O].sup.+526, found 526.

[0490] 69: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.85-7.75 (m, 1H), 7.25-7.15 (m, 1H), 5.57-5.47 (m, 2H), 3.54 (d, J=8.8 Hz, 1H), 3.49-3.45 (m, 1H), 3.25 (d, J=8.8 Hz, 1H), 2.70-2.62 (m, 1H), 2.29-2.09 (m, 2H), 1.99-1.86 (m, 2H), 1.84-1.69 (m, 3H), 1.69-1.17 (m, 19H), 1.14 (d, J=6.0 Hz, 6H), 0.74 (s, 3H). LCMS R.sub.t=4.835 min in 7 min chromatography, MS ESI calcd. for C.sub.31H.sub.44F.sub.2N.sub.3O.sub.3 [M+H].sup.+ 544, found 544.

[0491] 70: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.70-7.60 (m, 1H), 7.35-7.27 (m, 1H), 5.60-5.44 (m, 2H), 3.54 (d, J=9.2 Hz, 1H), 3.49-3.45 (m, 1H), 3.25 (d, J=9.2 Hz, 1H), 2.70-2.62 (m, 1H), 2.29-2.09 (m, 2H), 1.99-1.86 (m, 2H), 1.84-1.69 (m, 3H), 1.69-1.17 (m, 19H), 1.14 (d, J=6.0 Hz, 6H), 0.74 (s, 3H). LCMS R.sub.t=5.104 min in 7 min chromatography, MS ESI calcd. for C.sub.31H.sub.42F.sub.2N.sub.3O.sub.2 [M+HH.sub.2O].sup.+526, found 526.

Example 40. Synthesis of Compounds 71 and 72

[0492] ##STR00214##

[0493] To a solution of D11 (170 mg, 0.3620 mmol) in acetone (15 mL) was added 2H-tetrazole (38.0 mg, 0.543 mmol), followed by K.sub.2CO.sub.3 (99.9 mg, 0.724 mmol) at 15 C. The reaction mixture was stirred at 15 C. for 16 hrs. The reaction mixture was diluted with DCM (80 mL), washed with water (350 mL), brine (60 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give a solid, which was purified by preparative HPLC to give 71 (33 mg, 20%) as a white solid and crude 72 (45 mg, impure) which was further purified by silica gel chromatography (PE:EtOAc=3:1) to give 72 (13 mg, 8%) as an off-white solid.

[0494] 71: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.74 (s, 1H), 5.38-5.12 (m, 2H), 3.52 (d, J=8.8 Hz, 1H), 3.50-3.40 (m, 1H), 3.24 (d, J=8.8 Hz, 1H), 2.66 (t, J=8.4 Hz, 1H), 2.30-2.15 (m, 1H), 2.10-2.00 (m, 1H), 1.97-1.86 (m, 2H), 1.85-1.71 (m, 3H), 1.69-1.41 (m, 10H), 1.40-1.16 (m, 9H), 1.13 (d, J=6.0 Hz, 6H), 0.66 (s, 3H). LCMS R.sub.t=3.394 min in 7 min chromatography, MS ESI calcd. for C.sub.26H.sub.41N.sub.4O.sub.2 [M+HH.sub.2O].sup.+441, found 441.

[0495] 72: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.57 (s, 1H), 5.45 (s, 2H), 3.53 (d, J=9.0 Hz, 1H), 3.50-3.40 (m, 1H), 3.24 (d, J=9.0 Hz, 1H), 2.69-2.59 (m, 1H), 2.27-2.15 (m, 1H), 2.15-2.00 (m, 1H), 1.99-1.86 (m, 2H), 1.85-1.70 (m, 3H), 1.68-1.33 (m, 13H), 1.33-1.18 (m, 6H), 1.13 (d, J=6.0 Hz, 6H), 0.71 (s, 3H). LCMS R.sub.t=3.670 min in 7 min chromatography, MS ESI calcd. for C.sub.26H.sub.41N.sub.4O.sub.2 [M+HH.sub.2O].sup.+441, found 441.

Example 41. Synthesis of Compounds 73 and 74

[0496] ##STR00215## ##STR00216## ##STR00217##

[0497] Step 1. To a solution of D7 (3 g, 8.99 mmol) in DCM (50 mL) was added PCC (3.84 g, 17.9 mmol) at 25 C. The mixture was stirred at 25 C. for 2 hrs. The solution was filtered and the filter cake was washed with DCM (250 mL). The combined filtrate was concentrated in vacuum. The residue was purified by silica gel column eluted with (PE/EtOAc=8/1) to afford D12 (2.7 g, 86%, D/H=7/1) as an off-white solid.

[0498] D12: .sup.1H NMR (400 MHz, CDCl.sub.3) 9.75 (s, 0.14H), 5.16-5.10 (m, 1H), 2.44-2.26 (m, 2H), 2.24-2.11 (m, 1H), 2.03-1.77 (m, 4H), 1.75-1.63 (m, 6H), 1.59-1.45 (m, 6H), 1.40-1.26 (m, 7H), 1.24-1.08 (m, 3H), 0.93 (s, 3H).

[0499] Step 2. To a solution of D12 (2.7 g, 8.14 mmol) in MeOH (20 mL) and THE (20 mL) was added NaBD.sub.4 (510 mg, 12.2 mmol) at 25 C. The reaction mixture was stirred at 25 C. for 2 hrs. The reaction was poured into water (100 mL) and extracted with EtOAc (2100 mL). The combined organic layer was washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to afford D13 (2.6 g, crude, D/H=7/1) as an off-white solid.

[0500] D13: .sup.1H NMR (400 MHz, CDCl.sub.3) 5.16-5.12 (m, 1H), 2.39-2.29 (m, 1H), 2.28-2.25 (m, 2H), 1.98-1.95 (m, 2H), 1.67-1.66 (m, 1H), 1.65-1.64 (m, 6H), 1.63-1.52 (m, 6H), 1.52-1.21 (m, 12H), 0.87 (s, 3H).

[0501] Step 3. To a solution of D13 (2.6 g, 7.77 mmol) in DCM (40 mL) was added PCC (3.33 g, 15.5 mmol) at 25 C. The mixture was stirred at 25 C. for 2 hrs. The solution was filtered and the filter cake was washed with DCM (250 mL). The combined filtrate was concentrated in vacuum. The residue was purified by silica gel column eluted with (PE/EtOAc=8/1) to afford D14 (2.2 g, 81%, D/H=40/1) as an off-white solid.

[0502] D14: .sup.1H NMR (400 MHz, CDCl.sub.3) 9.77 (s, 0.024H), 5.18-5.13 (m, 1H), 2.43-2.36 (m, 3H), 1.97-1.94 (m, 4H), 1.69-1.61 (m, 12H), 1.56-1.49 (m, 7H), 1.33-1.21 (m, 3H), 0.95 (s, 3H).

[0503] Step 4. To a solution of D14 (2.2 g, 6.63 mmol, D/H=40/1)) in MeOH (20 mL) and THF (20 mL) was added NaBD.sub.4 (416 mg, 9.94 mmol) at 25 C. The reaction mixture was stirred at 25 C. for 2 hrs. The reaction was poured into water (100 mL) and extracted with EtOAc (250 mL). The combined organic layer was washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to afford D15 (1.8 g, crude) as an off-white solid.

[0504] D15: .sup.1H NMR (400 MHz, CDCl.sub.3) 5.13-5.10 (m, 1H), 2.38-2.23 (m, 3H), 1.95-1.92 (m, 2H), 1.64-1.63 (m, 1H), 1.62-1.50 (m, 12H), 1.47-1.19 (m, 12H), 0.84 (s, 3H).

[0505] Step 5. To a solution of D15 (1.8 g, 5.38 mmol) in DMF (20 mL) was added NaH (643 mg, 16.1 mmol, 60%) at 25 C. The mixture was stirred at 25 C. for 30 min. Me.sub.2SO.sub.4 (678 mg, 5.38 mmol) was added to the mixture. The reaction mixture was stirred at 25 C. for 12 hrs. The mixture was poured into ice water (50 mL) and extracted with EtOAc (250 mL). The combined organic phase was washed with saturated brine (50 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel (PE/EtOAc=10/1) to afford D16 (800 mg, 34%) as colorless oil.

[0506] D16: .sup.1H NMR (400 MHz, CDCl.sub.3) 5.13-5.08 (m, 1H), 3.33 (s, 3H), 2.32-2.23 (m, 3H), 1.92-1.91 (m, 2H), 1.65-1.64 (m, 1H), 1.57-1.48 (m, 8H), 1.45-1.22 (m, 15H), 0.85 (s, 3H).

[0507] Step 6. To a solution of D16 (800 mg, 2.29 mmol) in THF (10 mL) was added drop wise a solution of BH.sub.3-Me.sub.2S (2.29 mL, 22.9 mmol) at 0 C. The solution was stirred at 25 C. for 16 hrs. After cooling to 0 C., a solution of NaOH (7.63 mL, 3M) was added very slowly. After the addition was complete, H.sub.2O.sub.2 (4.7 mL, 33%) was added slowly and the inner temperature was maintained below 10 C. The resulting solution was stirred at 25 C. for 2 hrs. The resulting solution was extracted with EtOAc (220 mL). The combined organic layer was washed with saturated aqueous Na.sub.2S.sub.2O.sub.3 (250 mL), brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give D17 (780 mg, crude) as an off-white solid. The crude product was used for the next step without further purification.

[0508] Step 7. To a solution of D17 (780 mg, 2.12 mmol) in THE (5 mL) and DCM (20 mL) was added PCC (911 mg, 4.24 mmol) at 25 C. The mixture was stirred at 25 C. for 2 hrs. The solution was filtered and the filter cake was washed with DCM (250 mL). The combined filtrate was concentrated in vacuum. The residue was purified by silica gel column eluted with (PE/EtOAc=6/1) to afford D18 (340 mg, 40%) as an off-white solid.

[0509] D18: .sup.1H NMR (400 MHz, CDCl.sub.3) 3.33 (s, 3H), 2.55-2.53 (m, 1H), 2.19-2.10 (m, 4H), 2.07-1.88 (m, 3H), 1.81-1.60 (m, 4H), 1.57-1.51 (m, 3H), 1.50-1.35 (m, 5H), 1.30-1.07 (m, 10H), 0.60 (s, 3H).

[0510] Step 8. To a solution of D18 (340 mg, 0.932 mmol) and HBr (0.1 mL, 48% in water) in MeOH (8 mL) was added drop wise bromine (177 mg, 1.11 mmol). The reaction mixture was stirred at 25 C. for 2 hrs. The reaction was quenched by saturated aqueous NaHCO.sub.3 (20 mL) and the pH was adjusted to 7-8. The mixture was extracted with EtOAc (230 mL), and the combined organic layers was washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by silica gel column eluted with (PE/EtOAc=8/1) to afford D19 (240 mg, 52%) as colorless oil.

[0511] D19: .sup.1H NMR (400 MHz, CDCl.sub.3) 3.94-3.86 (m, 2H), 3.32 (s, 3H), 2.84-2.79 (m, 1H), 2.23-2.13 (m, 1H), 1.97-1.87 (m, 3H), 1.82-1.67 (m, 3H), 1.54-1.35 (m, 7H), 1.31-1.10 (m, 9H), 0.91-0.83 (m, 3H), 0.63 (s, 3H).

[0512] Step 9. To a solution of D19 (120 mg, 0.27 mmol) in acetone (3 mL) was added K.sub.2CO.sub.3 (74.6 mg, 0.54 mmol) and 5-methyl-2H-tetrazole (34 mg, 0.405 mmol) at 25 C. The mixture was stirred at 25 C. for 3 hrs. The mixture was poured into water (30 mL) and extracted with ethyl acetate (230 mL). The combined organic layers was washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by preparative HPLC to give 73 (23.8 mg, 20%) and 74 (30.3 mg, 25%) as an off-white solid.

[0513] 73: .sup.1H NMR (400 MHz, CDCl.sub.3) 5.34 (s, 2H), 3.33 (s, 3H), 2.65-2.58 (m, 1H), 2.56 (s, 3H), 2.27-2.14 (m, 1H), 2.11-2.03 (m, 1H), 1.98-1.87 (m, 2H), 1.84-1.69 (m, 3H), 1.67-1.56 (m, 3H), 1.52-1.38 (m, 6H), 1.37-1.09 (m, 10H), 0.70 (s, 3H). LCMS Rt=0.954 min in 2.0 min chromatography, MS ESI calcd. for C.sub.25H.sub.37D.sub.2N.sub.4O.sub.2 [M+HH.sub.2O].sup.+429, found 429.

[0514] 74: .sup.1H NMR (400 MHz, CDCl.sub.3) 5.16-5.02 (m, 2H), 3.33 (s, 3H), 2.67-2.63 (m, 1H), 2.47 (s, 3H), 2.29-2.14 (m, 1H), 2.10-2.02 (m, 1H), 1.97-1.85 (m, 2H), 1.84-1.70 (m, 3H), 1.67-1.57 (m, 3H), 1.49-1.40 (m, 6H), 1.38-1.08 (m, 10H), 0.67 (s, 3H). LCMS Rt=0.886 min in 2.0 min chromatography, MS ESI calcd. for C.sub.25H.sub.37D.sub.2N.sub.4O.sub.2 [M+HH.sub.2O].sup.+429, found 429.

Example 42. Synthesis of Compound 75

[0515] ##STR00218##

[0516] To a solution of A1 (200 mg, 453 mol) in acetone (2 mL) was added 5-fluoro-2H-pyrazolo[3,4-c]pyridine (74.4 mg, 543 mol) and K.sub.2CO.sub.3 (125 mg, 906 mol) at 25 C. The mixture was stirred at 25 C. for 12 hrs, poured into water (10 mL), and extracted with EtOAc (220 mL). The combined organic solution was washed with brine (10 mL) and dried over Na.sub.2SO.sub.4. The organic layer was filtered and concentrated under reduced pressure to give crude product, which was purified by preparative HPLC to give 75 (17 mg, 7%) as an off-white solid.

[0517] 75: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.93 (s, 1H), 7.97 (s, 1H), 7.07 (s, 1H), 5.35-5.17 (m, 2H), 3.51-3.35 (m, 2H), 3.30 (s, 3H), 2.68 (t, J=8.9 Hz, 1H), 2.29-2.00 (m, 3H), 1.80-1.69 (m, 4H), 1.55-1.38 (m, 8H), 1.35-1.09 (m, 9H), 1.06-0.83 (m, 2H), 0.73 (s, 3H). LCMS Rt=1.018 min in 1.5 min chromatography, MS ESI calcd. for C.sub.29H.sub.41FN.sub.3O.sub.3 [M+H].sup.+ 498, found 498.

Example 43. Synthesis of Compound 76

[0518] ##STR00219## ##STR00220##

[0519] Step 1. To a solution of E1 (6 g, 19.7 mmol) in toluene (100 mL) was added pyridine hydrochloride (453 mg, 3.94 mmol) and ethane-1,2-diol (6.1 g, 98.4 mmol). The mixture was stirred at 130 C. for 16 hrs, then concentrated in vacuum. The residue was purified by silica gel column eluted with (PE/EtOAc=5/1) to afford E2 (5.4 g, 66%) as an off-white solid.

[0520] E2: .sup.1H NMR (400 MHz, CDCl.sub.3) 3.98-3.80 (m, 9H), 3.58-3.55 (m, 1H), 2.10-2.01 (m, 1H), 1.99-1.91 (m, 2H), 1.84-1.60 (m, 5H), 1.59-1.33 (m, 10H), 1.30-1.17 (m, 4H), 1.15-1.02 (m, 1H), 0.82 (s, 3H).

[0521] Step 2. To a solution of E2 (5.3 g, 13.5 mmol) in DCM (60 mL) was added PCC (4.34 g, 20.2 mmol) at 25 C. The mixture was stirred at 25 C. for 30 mins. The solution was filtered and the filtered cake was washed with DCM (2100 mL). The combined filtrate was washed with saturated NaHCO.sub.3 (100 mL) and brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by silica gel column eluted with (PE/EtOAc=8/1) to afford E3 (3.1 g, 53%) as a colorless oil.

[0522] E3: .sup.1H NMR (400 MHz, CDCl.sub.3) 9.58 (s, 1H), 4.00-3.84 (m, 8H), 2.25-2.15 (m, 1H), 2.03-1.88 (m, 2H), 1.84-1.59 (m, 7H), 1.56-1.32 (m, 10H), 1.30-1.17 (m, 1H), 1.13-0.99 (m, 1H), 0.92 (s, 3H).

[0523] Step 3. To a solution of E3 (3 g, 7.68 mmol) in THE (50 mL) was added MeMgBr (5.1 mL, 15.3 mmol, 3M in ethyl ether) at 0 C. The mixture was stirred at 25 C. for 2 hrs. The reaction was poured into water (100 mL) and extracted with EtOAc (2100 mL). The combined organic layer was washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to afford E4 (2.8 g, 81%) as colorless oil.

[0524] E4: .sup.1H NMR (400 MHz, CDCl.sub.3) 4.42 (m, 1H), 3.97-3.81 (m, 8H), 2.03-1.92 (m, 2H), 1.90-1.74 (m, 5H), 1.71-1.64 (m, 1H), 1.60-1.34 (m, 9H), 1.30-1.22 (m, 4H), 1.21-1.11 (m, 5H), 0.87 (s, 3H).

[0525] Step 4. To a solution of E4 (2.7 g, 6.64 mmol) in DMF (20 mL) was added NaH (795 mg, 19.9 mmol, 60%) at 25 C. The mixture was stirred at 50 C. for 30 mins. MeI (2.82 g, 19.9 mmol) was added drop wise to the reaction. The mixture was stirred at 50 C. for 2 hrs, followed by addition of another aliquot of MeI (2.82 g, 19.9 mmol). The mixture was stirred at 50 C. for 1 h, then poured into ice water (50 mL) and extracted with EtOAc (260 mL). The combined organic phase was washed with saturated brine (100 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel (PE/EtOAc=10/1) to afford E5 (2 g, 64%) as an off-white solid.

[0526] E5: .sup.1H NMR (400 MHz, CDCl.sub.3) 3.97-3.83 (m, 8H), 3.79-3.74 (m, 1H), 3.29 (s, 3H), 2.08-1.93 (m, 2H), 1.91-1.75 (m, 3H), 1.73-1.57 (m, 3H), 1.54-1.36 (m, 8H), 1.31-1.05 (m, 9H), 0.88 (s, 3H).

[0527] Step 5. To a solution of E5 (2 g, 4.75 mmol) in THF (30 mL) was added aq. HCl (4.75 mL, 4M, 19 mmol). The mixture was stirred at 25 C. for 16 hrs, then poured into water (100 mL) and extracted with EtOAc (250 mL). The combined organic layers were washed with saturated aqueous NaHCO.sub.3 (50 mL), brine (50 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuum to afford E6 (1.4 g, 80%) as an off-white solid.

[0528] E6: .sup.1H NMR (400 MHz, CDCl.sub.3) 3.86-3.82 (m, 1H), 3.31 (s, 3H), 2.77-2.67 (m, 1H), 2.54-2.43 (m, 1H), 2.32-2.19 (m, 3H), 2.16-1.94 (m, 4H), 1.91-1.78 (m, 3H), 1.75-1.60 (m, 4H), 1.55-1.35 (m, 2H), 1.30-1.16 (m, 4H), 1.10-1.05 (m, 3H), 0.93 (s, 3H).

[0529] Step 6. To a solution of BHT (5.56 g, 25.2 mmol) in toluene (50 mL) was added dropwise AlMe.sub.3 (6.3 mL, 12.6 mmol, 2 M in toluene) at 0 C. The mixture was stirred at 25 C. for 1 h. A solution of E6 (1.4 g, 4.21 mmol) in toluene (20 mL) was added drop wise to the mixture at 65 C. After stirring at 65 C. for 1 h, MeMgBr (4.19 mL, 12.6 mmol, 3M in ethyl ether) was added drop wise at 65 C. The resulting solution was stirred at 65 C. for 3 hrs. The reaction was quenched by saturated aqueous NH.sub.4Cl (50 mL) at 65 C. After stirring at 25 C. for 0.5 h, the resulting mixture was filtered through a celite pad and the pad was washed with EtOAc (100 mL). The combined organic layer was separated, washed with brine (2100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The crude product was purified by silica gel column eluted with PE/EtOAc=5/1 to give E7 (1.1 g, 68%) as an off-white solid.

[0530] E7: .sup.1H NMR (400 MHz, CDCl.sub.3) 3.80-3.75 (m, 1H), 3.29 (s, 3H), 2.48-2.41 (m, 1H), 2.15-2.02 (m, 1H), 2.00-1.77 (m, 4H), 1.74-1.63 (m, 4H), 1.57-1.33 (m, 7H), 1.29-1.13 (m, 9H), 1.08 (d, J=6.4 Hz, 3H), 0.89 (s, 3H). LCMS Rt=0.954 min in 2.0 min chromatography, MS ESI calcd. For C.sub.21H.sub.31O [M+HH.sub.2O-MeOH].sup.+ 299, found 299.

[0531] Step 7. To a solution of PPh.sub.3EtBr (3.18 g, 8.58 mmol) in THF (15 mL) was added t-BuOK (962 mg, 8.58 mmol) at 25 C. After stirring at 60 C. for 1 h, a solution of E7 (1 g, 2.86 mmol) in THF (5 mL) was added dropwise at 60 C. The reaction mixture was stirred at 60 C. for 16 hrs, and the mixture was poured into ice-water (100 mL) and extracted with EtOAc (250 mL). The organic layer was washed with brine (50 mL), dried over Na.sub.2SO.sub.4 and filtered, concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc=15/1 to afford E8 (1 g, 78%) as an off-white solid.

[0532] E8: .sup.1H NMR (400 MHz, CDCl.sub.3) 5.18-4.99 (m, 1H), 3.83-3.71 (m, 1H), 3.30 (s, 3H), 2.45-2.09 (m, 3H), 2.01-1.81 (m, 3H), 1.68-1.58 (m, 6H), 1.58-1.37 (m, 7H), 1.31-1.12 (m, 10H), 1.08-1.03 (m, 3H), 0.91 (s, 3H).

[0533] Step 8. To a solution of E8 (1 g, 2.77 mmol) in THE (20 mL) was added dropwise a solution of BH.sub.3-Me.sub.2S (2.77 mL, 27.7 mmol) at 0 C. The solution was stirred at 25 C. for 16 hrs. After cooling to 0 C., a solution of NaOH (9.23 mL, 3M) was added very slowly. After the addition was complete, H.sub.2O.sub.2 (4.5 mL, 33%) was added slowly and the inner temperature was maintained below 10 C. The resulting solution was stirred at 25 C. for 2 hrs. The resulting solution was extract with EtOAc (220 mL), and the combined organic layer was washed with saturated aqueous Na.sub.2S.sub.2O.sub.3 (250 mL), brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give E9 (0.9 g, crude) as an off-white solid. The crude product was used for the next step without further purification.

[0534] Step 9. To a solution of E9 (800 mg, 2.11 mmol) in DCM (10 mL) was added PCC (907 mg, 4.22 mol) at 25 C. The mixture was stirred at 25 C. for 2 hrs. The solution was filtered and the filter cake was washed with DCM (250 mL). The combined filtrate was concentrated in vacuum. The residue was purified by silica gel column eluted with (PE/EtOAc=5/1) to afford 76 (600 mg, 68%) as a white solid.

[0535] 76: .sup.1H NMR (400 MHz, CDCl.sub.3) 3.78-3.74 (m, 1H), 3.27 (s, 3H), 2.56-2.51 (m, 1H), 2.22-2.16 (m, 1H), 2.12 (s, 3H), 2.06-1.94 (m, 2H), 1.91-1.79 (m, 1H), 1.74-1.61 (m, 6H), 1.50-1.32 (m, 6H), 1.29-1.10 (m, 10H), 1.06 (d, J=6.0 Hz, 3H), 0.64 (s, 3H). LCMS Rt=1.067 min in 2.0 min chromatography, MS ESI calcd. For C.sub.23H.sub.35O [M+HH.sub.2O-MeOH].sup.+ 327, found 327.

Example 44. Synthesis of Compounds 77 and 78

[0536] ##STR00221##

[0537] Step 1. To a solution of 76 (300 mg, 0.796 mmol) and HBr (0.1 mL, 48% in water) in MeOH (5 mL) was added drop wise bromine (190 mg, 1.19 mmol). The reaction mixture was stirred at 25 C. for 2 hrs. The reaction was quenched by saturated aqueous NaHCO.sub.3 (20 mL) and the pH was adjusted to 78. The mixture was extracted with EtOAc (230 mL), and the combined organic layers was washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by silica gel column eluted with (PE/EtOAc=8/1) to afford E10 (240 mg, 60%) as an off-white solid.

[0538] E10: .sup.1H NMR (400 MHz, CDCl.sub.3) 3.98-3.86 (m, 2H), 3.77-3.73 (m, 1H), 3.26 (s, 3H), 2.85-2.83 (m, 1H), 2.27-2.13 (m, 1H), 2.02-1.83 (m, 3H), 1.77-1.61 (m, 5H), 1.54-1.33 (m, 7H), 1.31-1.11 (m, 8H), 1.08-1.02 (m, 3H), 0.91-0.80 (m, 2H), 0.67 (s, 3H).

[0539] Step 2. To a solution of E10 (120 mg, 0.263 mmol) in acetone (3 mL) was added K.sub.2CO.sub.3 (72.5 mg, 0.526 mmol) and 5-methyl-2H-tetrazole (44.2 mg, 0.526 mmol) at 25 C. The mixture was stirred at 25 C. for 16 hrs. The mixture was poured into water (30 mL) and extracted with EtOAc (230 mL). The combined organic layers was washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by preparative HPLC to give 77 (15 mg, 12%) and 78 (32 mg, 27%) as an off-white solid.

[0540] 77: .sup.1H NMR (400 MHz, CDCl.sub.3) 5.43-5.29 (m, 2H), 3.79-3.74 (m, 1H), 3.27 (s, 3H), 2.65-2.60 (m, 1H), 2.57 (s, 3H), 2.30-2.16 (m, 1H), 2.11-2.08 (m, 1H), 2.01-1.95 (m, 1H), 1.76-1.65 (m, 1H), 1.80-1.63 (m, 6H), 1.52-1.34 (m, 6H), 1.33-1.10 (m, 10H), 1.07 (d, J=6.4 Hz, 3H), 0.74 (s, 3H). LCMS Rt=0.990 min in 2.0 min chromatography, MS ESI calcd. for C.sub.26H.sub.41N.sub.4O.sub.2 [M+HH.sub.2O].sup.+ 441, found 441.

[0541] 78: .sup.1H NMR (400 MHz, CDCl.sub.3) 5.21-5.02 (m, 2H), 3.79-3.74 (m, 1H), 3.28 (s, 3H), 2.71-2.61 (m, 1H), 2.48 (s, 3H), 2.29-2.17 (m, 1H), 2.09-2.06 (m, 1H), 2.03-1.93 (m, 1H), 1.90-1.87 (m, 1H), 1.83-1.62 (m, 6H), 1.53-1.41 (m, 6H), 1.39-1.11 (m, 10H), 1.07 (d, J=6.4 Hz, 3H), 0.71 (s, 3H). LCMS Rt=0.910 min in 2.0 min chromatography, MS ESI calcd. for C.sub.26H.sub.41N.sub.4O.sub.2 [M+HH.sub.2O].sup.+ 441, found 441.

Example 45. Synthesis of Compounds 79 and 80

[0542] ##STR00222##

[0543] To a solution of A1 (6 g, 13.5 mmol) in acetone (60 mL) was added K.sub.2CO.sub.3 (3.73 g, 27.0 mmol) and ethyl 2H-1,2,3-triazole-4-carboxylate (2.85 g, 20.2 mmol). The mixture was stirred at 25 C. for 2 hrs, then filtered. The filtrate was washed with brine (40 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE/EtOAc=2/11/1) to give 79 (2.26 g, crude) and 80 (2.47 g, crude) as an off-white solid. 100 mg of crude 79 and 80 were purified by preparative HPLC to give 79 (20 mg) and 80 (20 mg). .sup.1H NMR (400 MHz, CDCl.sub.3) 8.10 (s, 1H), 5.33-5.23 (m, 2H), 4.42 (q, J=7.2 Hz, 2H), 3.48-3.36 (m, 2H), 3.28 (s, 3H), 2.61-2.59 (m, 1H), 2.21-0.84 (m, 29H), 0.72 (s, 3H). LCMS Rt=1.314 min in 2 min chromatography, 10-80AB; MS ESI calcd. for C.sub.28H.sub.43N.sub.3O.sub.5 [M+Na]+524, found 524.

[0544] 80: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.16 (s, 1H), 5.30-5.14 (m, 2H), 4.43 (q, J=7.2 Hz, 2H), 3.48-3.36 (m, 2H), 3.28 (s, 3H), 2.67-2.60 (m, 1H), 2.22-2.00 (m, 4H), 1.75-0.86 (m, 25H), 0.68 (s, 3H). LCMS R.sub.t=1.247 min in 2 min chromatography, MS ESI calcd. for: C.sub.28H.sub.44N.sub.3O.sub.5 [M+H].sup.+ 502, found 502.

Example 46. Synthesis of Compound 81

[0545] ##STR00223##

[0546] To a solution of 79 (4 g, 7.97 mmol) in EtOH/H.sub.2O (30 mL/30 mL) was added LiOH.Math.H.sub.2O (1.33 g, 31.8 mmol). The mixture was stirred at 25 C. for 2 hrs, at which point H.sub.2O (30 mL) was added. The mixture was acidified to pH=3 with 2N HCl, followed by removal of EtOH by evaporation. The aqueous phase was extracted with EtOAc (320 mL), and the combined organic layer was washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give 81 (3.6 g, crude). 100 mg of crude 81 was purified by preparative-HPLC to give 81 (21.2 mg, 21%).

[0547] 81: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.16 (s, 1H), 5.35-5.26 (m, 2H), 3.47-3.36 (m, 2H), 3.28 (s, 3H), 2.62-2.60 (m, 1H), 2.20-0.85 (m, 27H), 0.72 (s, 3H). LCMS R.sub.t=1.185 min in 2 min chromatography, MS ESI calcd. for C.sub.26H.sub.39N.sub.3O.sub.5Na [M+Na].sup.+496, found 496.

Example 47. Synthesis of Compound 82

[0548] ##STR00224##

[0549] To a solution of 80 (3.7 g, 7.37 mmol) in EtOH/H.sub.2O (30 mL/30 mL) was added lithium hydroxide hydrate (1.23 g, 29.4 mmol). The mixture was stirred at 25 C. for 2 hrs, at which point H.sub.2O (30 mL) was added. The mixture was acidified to pH=3 with 2N HCl, then EtOH was removed under evaporation. The aqueous layer was extracted with EtOAc (350 mL), and the combined organic layer was washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give 82 (2.34 g, crude). 100 mg of crude 82 was purified by preparative HPLC to give 82 (21 mg 21%).

[0550] 82: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.25 (s, 1H), 5.32-5.17 (m, 2H), 3.48-3.36 (m, 2H), 3.29 (s, 3H), 2.68-2.64 (m, 1H), 2.35-2.03 (m, 4H), 1.76-1.40 (m, 4H), 1.39-1.28 (m, 8H), 1.25-0.87 (m, 11H), 0.69 (s, 3H). LCMS R.sub.t=1.135 min in 2 min chromatography, MS ESI calcd. for C.sub.26H.sub.40N.sub.3O.sub.5 [M+H].sup.+ 474, found 474.

Example 48. Synthesis of Compound 83

[0551] ##STR00225##

[0552] To a solution of 81 (200 mg, 0.42 mmol) in DCM (20 mL) was added TEA (213 mg, 2.11 mmol) and HATU (240 mg, 0.63 mmol). After stirring for 30 mins at 25 C., NH.sub.4Cl (35.7 mg, 0.675 mmol) was added and the mixture was stirred for another 30 mins. The reaction mixture was washed with water (220 mL) and the organic layer was concentrated in vacuum to give 83 (150 mg, crude). 50 mg of crude 83 was purified by preparative HPLC to give 83 (21, 42%).

[0553] 83: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.13 (s, 1H), 6.57 (br, 1H), 5.50 (br, 1H), 5.29-5.17 (m, 2H), 3.49-3.36 (m, 2H), 3.29 (s, 3H), 2.64-2.60 (m, 1H), 2.21-2.02 (m, 3H), 1.76-1.40 (m, 4H), 1.39-1.28 (m, 8H), 1.25-0.87 (m, 11H), 0.73 (s, 3H). LCMS R.sub.t=1.243 min in 2 min chromatography, MS ESI calcd. for C.sub.26H.sub.40N.sub.4O.sub.4Na [M+Na].sup.+495, found 495.

Example 49. Synthesis of Compound 84

[0554] ##STR00226##

[0555] To a solution of 82 (200 mg, 0.422 mmol) in DCM (20 mL) was added TEA (213 mg, 2.11 mmol) and HATU (240 mg, 0.63 mmol). After stirring 30 min at 25 C., NH.sub.4Cl (35.7 mg, 0.675 mmol) was added and the mixture was stirred for another 30 min. The reaction mixture was washed with water (220 mL) and the organic layer was concentrated under vacuum to give 84 (150 mg, crude). 50 mg of crude 84 was purified by preparative HPLC to give 84 (20 mg, 40%).

[0556] 84: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.13 (s, 1H), 7.03 (br, 1H), 5.59 (br, 1H), 5.28-5.12 (m, 2H), 3.48-3.36 (m, 2H), 3.29 (s, 3H), 2.67-2.63 (m, 1H), 2.27-2.04 (m, 3H), 1.76-1.40 (m, 4H), 1.39-1.28 (m, 8H), 1.25-0.87 (m, 11H), 0.69 (s, 3H). LCMS R.sub.t=1.201 min in 2 min chromatography, MS ESI calcd. for C.sub.26H.sub.39N.sub.4O.sub.3 [M+HH.sub.2O].sup.+455, found 455.

Example 50. Synthesis of Compound 85

[0557] ##STR00227##

[0558] To a stirred solution of A1 (100 mg, 0.226 mmol) in acetone (10 mL) was added K.sub.2CO.sub.3 (62.4 mg, 0.452 mmol) and (1H-1,2,3-triazol-4-yl)methanol (33.5 mg, 0.339 mmol) at 25 C. The reaction mixture was stirred for 2 hrs at 25 C., at which point the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give 85 (66 mg, 64%) as a white solid.

[0559] 85: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.65 (s 1H), 5.25-5.14 (m, 2H), 4.80-4.75 (m, 2H), 2.61-2.59 (m, 1H), 2.19-2.05 (m, 4H), 1.72-1.40 (m, 16H), 1.38-1.05 (m, 10H), 1.04-0.85 (m, 2H), 0.72 (s, 3H). LCMS R.sub.t=1.231 min in 2 min chromatography, MS ESI calcd. for C.sub.26H.sub.41N.sub.3O.sub.4Na [M+Na].sup.+482, found 482.

[0560] Assay Methods

[0561] Compounds provided herein can be evaluated using various assays; examples of which are described below.

[0562] Steroid Inhibition of TBPS Binding

[0563] TBPS binding assays using rat brain cortical membranes in the presence of 5 M GABA has been described (Gee et al., J. Pharmacol. Exp. Ther. 1987, 241, 346-353; Hawkinson et al., Mol. Pharmacol. 1994, 46, 977-985; Lewin, A. H. et al., Mol. Pharmacol. 1989, 35, 189-194).

[0564] Briefly, cortices are rapidly removed following decapitation of carbon dioxide-anesthetized Sprague-Dawley rats (200-250 g). The cortices are homogenized in 10 volumes of ice-cold 0.32 M sucrose using a glass/teflon homogenizer and centrifuged at 1500g for 10 min at 4 C. The resultant supernatants are centrifuged at 10,000g for 20 min at 4 C. to obtain the P2 pellets. The P2 pellets are resuspended in 200 mM NaCl/50 mM NaK phosphate pH 7.4 buffer and centrifuged at 10,000g for 10 min at 4 C. This washing procedure is repeated twice and the pellets are resuspended in 10 volumes of buffer. Aliquots (100 L) of the membrane suspensions are incubated with 3 nM [.sup.35S]-TBPS and 5 aliquots of test drug dissolved in dimethyl sulfoxide (DMSO) (final 0.5%) in the presence of 5 GABA. The incubation is brought to a final volume of 1.0 mL with buffer. Nonspecific binding is determined in the presence of 2 M unlabeled TBPS and ranged from 15 to 25%. Following a 90 min incubation at room temp, the assays are terminated by filtration through glass fiber filters (Schleicher and Schuell No. 32) using a cell harvester (Brandel) and rinsed three times with ice-cold buffer. Filter bound radioactivity is measured by liquid scintillation spectrometry. Non linear curve fitting of the overall data for each drug averaged for each concentration is done using Prism (GraphPad). The data are fit to a partial instead of a full inhibition model if the sum of squares is significantly lower by F-test. Similarly, the data are fit to a two component instead of a one component inhibition model if the sum of squares is significantly lower by F-test. The concentration of test compound producing 50% inhibition (IC.sub.50) of specific binding and the maximal extent of inhibition (Lim) are determined for the individual experiments with the same model used for the overall data and then the meansSEM.s of the individual experiments are calculated. Picrotoxin serves as the positive control for these studies as it has been demonstrated to robustly inhibit TBPS binding.

[0565] Various compounds are or can be screened to determine their potential as modulators of [.sup.35S]-TBPS binding in vitro. These assays are or can be performed in accordance with the above discussed procedures.

[0566] For Table 2, A indicates an IC.sub.50<10 nM, B indicates an IC.sub.50 of 10 nM to 50 nM, C indicates an IC.sub.50 of 50 nM to 100 nM, D indicates an IC.sub.50 of 100 nM to 500 nM, and E indicates IC.sub.50>500 nM.

TABLE-US-00002 TABLE 2 35S-TBPS Radioligand Compound Displacement (IC.sub.50) 1 A 2 A 7 A 8 A 9 A 10 A 11 A 12 A 13 A 14 A 15 A 16 A 17 B 18 A 19 A 20 A 21 A 22 D 23 A 24 A 25 A 26 A 27 A 28 A 29 A 30 A 34 B 35 E 36 D 37 D 38 C 40 C 41 C 42 B 43 C 44 B 45 C 46 B 47 B 48 C 49 C 51 A 52 B 59 D 60 D 61 D 62 B 63 D 64 D 65 A 66 B 67 B 68 A 69 A 70 A 71 B 72 A 73 B 74 D 75 D 80 D 81 E 82 E 83 D 84 D 85 E