WO2013163466A1

WO2013163466A1 - Inhibitors of hepatitis c virus

Info

Publication number: WO2013163466A1
Application number: PCT/US2013/038275
Authority: WO
Inventors: Min Zhong; Leping Li
Original assignee: Presidio Pharmaceuticals, Inc.
Priority date: 2012-04-25
Filing date: 2013-04-25
Publication date: 2013-10-31

Abstract

A class of compounds that inhibit Hepatitis C Virus (HCV) is disclosed, along with compositions containing the compound, and methods of using the composition for treating individuals infected with HCV. The invention is intended to include all isotopically labeled analogs of the compounds of the invention. Isotopes include those atoms having the same atomic number but different mass.

Description

INHIBITORS OF HEPATITIS C VIRUS

Field

[001] The invention relates to compounds useful for inhibiting hepatitis C virus ("HCV") replication, particularly functions of the non-structural 5B ("NS5B") protein of HCV.

Background

[002] HCV is a single-stranded RN A virus that is a member of the Flaviviridae family. The virus shows extensive genetic heterogeneity as there are currently seven identified genotypes and more than 50 identified subtypes. In HCV infected cells, viral RNA is translated into a polyprotein that is cleaved into ten individual proteins. At the amino terminus are structural proteins: the core (C) protein and the envelope glycoproteins, El and E2, p7, an integral membrane protein, follows El and E2. Additionally, there are six non-structural proteins, NS2, NS3, NS4A, NS4B, NS5A and NS5B, which play functional roles in the HCV life cycle, (see, for example, B.D. Lindenbach and CM. Rice, Nature. 436:933-938, 2005). NS5B is the RNA polymerase or replicase of the virus and is responsible for replication of both positive and negative-strand genomic RNA during the viral replicative cycle. NS5B plays an essential and critical role in viral replication, and a functional NS5B replicase is required for HCV replication and infection. Thus, inhibition of NS5B RNA-dependent polymerase activity is believed to be an effective way of treating HCV infection.

[003] Infection by HCV is a serious health issue. It is estimated that 170 million people worldwide are chronically infected with HCV. HCV infection can lead to chronic hepatitis, cirrhosis, liver failure and hepatocellular carcinoma. Chronic HCV infection is thus a major worldwide cause of liver-related premature mortality.

[004 [ The current standard of care treatment regimen for HCV infection involves interferon- alpha, alone, or in combination with ribavirin and a protease inhibtor. The treatment is cumbersome and sometimes has debilitating and severe side effects and many patients do not durably respond to treatment. New and effective methods of treating HCV infection are urgently needed.

i Summary

[005] Essential functions of the NS5B protein in HCV replication make it an attractive intervention target for treating HCV infection. The present disclosure describes a class of compounds targeting the NS5B protein and methods of their use to treat HCV infection in humans.

[006] More particularly, the present disclosure describes a class of heterocyclic compounds targeting HCV NS5B polymerase and methods of their use to treat HCV infection in humans.

[007 [ In a first aspect of the invention is a compound that has the structure:

wherein,

L¹, L² and-NCSQzR¹²)- together with the attached carbons of the aromatic ring to form a 5-12 member ring, containing 1-4 heteroatoms of N, O, S, P and/or Si;

L'or L² is independently selected from the group consisting of a bond, -0-, -C(R^I5R¹⁶)-, -NR³-, - S(O _» -P(0 , -Si(R⁴R⁵K -C(O)-, -C(0)0-, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide;

n is 0, 1, or 2; and

R¹ is selected from hydrogen, halide, -CF₃, -CN, -C(0)H, -C(0)OR⁶, -C(0)NHR⁷, - 7, -C(=NOR')NHR⁷, -C(CF₃)NHR⁸, -C(CN)NHR⁹, -S(0)₂NHR¹⁰, -

R' is selected from hydrogen, -(CH₂CHzO)o-8-Me, C₂.24 alkyl optionally containing 0-6 heteroatoms of O, NR^N and/or S, and 3-8 cycloalkyl optionally containing 0-2 heteroatora of O, NR^N, and/or S;

R² is an aryl or heteroaryl having one or more R¹⁷ substituents;

R³ is selected from the group of hydrogen, alkylcarbonyl, cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl, alkylsulfonyl and cycloalkylsulfonyl; R⁴ and R⁵ are independently methyl, ethyl, or cyclopropyl;

R¹² is independently C].₃ alkyl, cyclopropyl, -OMe, or -NHMe;

R¹⁵, R¹⁶ is independently hydrogen, hydroxyl, azide, C₂- alkeny!,

CM alkyl, cyclopropyl, C alkoxy, or cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon are 3-6 member ring optionally containing 0-3 heteroatoms of O, NR^N and or S; and

R^,7 is F, Cl or CN.

(008] The compound of this embodiment may have an inhibitory activity with respect to HCV,

R^v is selected from hydrogen, -NR'R", alkoxyls, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl;

R^w and R* are indenpendrntry selected from hydrogen, -C(0)H, -C(0)R^Hi, -C(0)OR^iv-, - C^NR'H", alkoxyls, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl; optionally, R^v and R together form a C4.8 member ring;

R^y and R^z are independently selected from hydrogen, alkoxyls, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl; optionally, R^y and R^z together form a 3-8 member ring;

R' and R" are indenpendently selected from hydrogen, -Me, -Et, c-Pr-, c-Butyl;

R"¹ is selected from alkyoxyl, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl;

R^lv is selected from alkyoxyl, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl; and R^v and R^VI are indenpendently selected from hydrogen, aUcyoxyl, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl.

[010] In one general embodiment, the compound has the structural formula:



ο-_ά&^F #o o#°T#_°,o#o

^■o

X' is selected from

and

R'₃ is selected from -CH₃ and -OCH₃.

[011[ In a more specific embodiment of the compound above, is para-F, R'₂is as above, X' is =0, and R'₃ is -CH₃.

[012] The compound may be selected from the group consisting of B243, B244, B245, B246, B248, B249, B252, B253, B255, B256, B257, B258, B259, B260, B261, B262,B263, B264, B265, B266, B267, B268, B269, B270, B271, B272, B273, B274, B275, B276, B277, B278, B279, B280, B281, B282, B283, B284, B285, B286, B287, B288, B289, B290, B291, B293, B294, B295, B296, B297, B298, B299, B300, B301, B302, B303, B304, B305, B306, B307, B308, B309, B310, B311, B312, B313, B314, B315, B316, B317, B318, B319, B320, B321, B322, B323, B326, B327, B328, B329, B330, B333, B334, B335, B336, B337, B338, B339, B340, B341, B342, B343, B344, B345, B346, B347, B348, B349, B350, B351, B352, B353, B354, B355, B356, B357, B358, B360, B36i, B362, B363, B364, B365, B366, B367, B368, B369, B370, B371, B372, B373, B374, B375, B376, B377, B378, B379, B380, B381, B382, B383, B384, B385, B386, B387, B388, B389, B390, B391, B392, B393, B394, B395, B396, B397, B398, B399, B400, B401, B402, B403, B404, B405, B406, B407, B408, B409, B410, B411, B412, B413, B414, B415, B416, B417, B418, B419, B420, B421, B422, B423, B424, B425, B426, B427, B428, B429, B430, B431, B432, B433, B434, B435, B436, B437, B438, B439, B440, B441, B442, B443, B444, B446, B447, B448, B449, B450, B451, B452, B453, B454, B455, B456, B457, B458, B459, B460, B461, B462, B463, B464, B465, B466, B467, B468, B469, B470, B471, B472, B473, B474, B475, B476, B477, B478, B479, B480, B481, B482, B483, B484, B485, B486, B487, B488, B489, B490, B491, B492, B493, B494, B495, B496, B497, B498, B499, B500, B501, B502, B503, B504, B505, B506, B507, B508, B509, B510, B511, B512, B513, B514, B515, B516, B517, B518, B51 , B520, B521, B522, B523, B524, B525, B526, B527, B528, B529, B530, B531, B532, B533, B534, B535, B536, B537, B538, B539, B540, B541, B542, B543, B544, B545, B546, B547, B548, B549, B550, B551, B552,

B563, B564, B565, B566, B567, B568, and B577.

hemical structure shown below:

[014] In one general embodiment, indicted as Group 1 herein, the compound has have the structural formula:

wherein:

i t



Χ' is selected from =0, =N-OH,

and «N-0(CH₂)i-23CH₃, and R'₃ is selected firom -CH₃ and -OCH3. [01 SJ The above compound may have the same structural formula, wherein R'i is pa a-F, R^u-0- is as above, and X^* is =0, and R^ is -C¾.

[016] The compound in this group may be selected from the group consisting of B243, B244, B245, B246, B248, B249, B252, B253, B255, B256, B257, B258, B259, B260, B261, B262,B263, B264, B265, B266, B267, B268, B269, B270, B271, B272, B273, B274, B275, B276, B277, B278, B279, B280, B281, B282, B285, B286, B289, B300, B302, B306, B307, B308, B309, B310, B311, B314, B316, B317, B318, B319, B320, B333, B335, B336, B337, B338, B343, B344, B345, B346, B347, B348, B349, B350, B351, B352, B353, B354, B373, B378, B379, B381, B383, B384, B385, B386, B388, B389, B390, B391, B392, B394, B395, B397, B399, B400, B401, B402, B404, B405, and B409.

cated herein as Group 2, the compound has the

wherein:

R'i is selected from -H, -F, -CI, -Br, -I,

[018J R^v-S(OV, wherein n = 0, 1, 2, is selected from

o#o θ ^HO^#O - #o ^~ D o -o#,

IS

*nr"£. °cr¾, T¾, 0^"¾, ° T¾

X' is selected

and R'₃ is selected from -CH₃ and -OCH3.

[019J The compound in this group may have the same structure where R'i is para-F, R^v-S(0)„-, are as above, X' is =0, and R'3 is -CH3. [020J Specific compounds in this group (Group 2) are selected from the group consisting of B283, B284, B287, B288, B290, B291, B293, B422, B423, B424, B426, B432, B443, B446, B447, B455, B456, B459, B463, B464, B466, B467, B470, B478, B479, B487, B488, B489, B491, B492, B493, B494, B495, B496, B497, B498, B499, B500, B501, B502, B503, B504, B505, B506, B507, B508, B509, B510, B511, B512, B513, B514, B515, B516, B517, B518, B519, B520, B521, B522, B523, B524, B525, B526, B527, B528, B529, B530, B531, B532, B533, B534, B535, B536, B537, B538, B539, B540, B541, B542, B543, B544, B545, B546, B547, B548, B549, B550, B551, B552, B553, B554, B555, B556, B557, B558, B561, B562, B563, B564, B565, B566, B567, B568, B569, B570, B571, B572, B573, B574, B575, B576, and B577.

[021] In another general embodiment, indicated herein as Group 3, the compound of the invention has the structural formula:

0*§ CH₃ wherein:

X' is selected

and

R'3 is selected from -C¾ and -OCH3.

[023] The compound in this group may have the same structural formula wherein: R'i is para-Έ, R R*N- is selected as above, X' is =0, and R'₃ is -C¾.

[024J Specific compounds in this group (Group 3) are selected from the group consisting of B294, B295, B296, B297, B298, B299, B301, B303, B304, B305, B312, B313, B315, B321, B322, B323, B326, B327, B328, B329, B330, B334, B339, B340, B341, B342, B355, B356, B357, B358, B360, B361, B362, B363, B364, B365, B366, B367, B368, B369, B370, B371, B372, B374, B375, B376, B377, B380, B382, B387, B393, B396, B398, B403, B406, B407, B408, B410, B411, B412, B413, B414, B415, B416, B417, B418, B419, B420, B421, B425, B427, B428, B429, B430, B431, B433, B434, B435, B436, B437, B438, B439, B440, B441, B442, B444, B448, B449, B450, B451, B452, B453, B454, B457, B458, B460, B461, B462, B465, B468, B471, B472, B473, B474, B475, B476, B477, B480, B481, B482, B483, B484, B485, B486, and B490.

of the invention has the structural formula:

wherein:

R'_l is selected from para-F

R'₂ is selected from -OH and -S0₂Me; and R'₃ is selected from -CH₃ and -OCH₃, as exemplified by B324, B325, B331, and B332.

[026] In still another aspect, the compound of the invention has the structural formula:

wherein:

R' i is selected from para-F

;

R'₂ is selected from -OH and -S0₂Me; and R^* ₃ is selected from -CH₃ and -OCH3, as exemplified by compound B359. [027] Also forming part of the invention is a pharmaceutical composition comprising a compound of any one of compounds above, or its pharmaceutically acceptable salts, together with one or more pharmaceutically acceptable excipients or vehicles, and optionally other therapeutic and/or prophylactic ingredients. The composition may further includes additional one, two or three anti-HCV agent(s) selected from the group consisting of interferon-alpha, ribavirin, cyclosporine derivatives, HCV NS3 protease inhibitors, HCV NS4B inhibitors, HCV NS5 A inhibitors, HCV NS5B polymerase inhibitors, and p7 inhibitors.

In still another aspect, the invention includes a method of treating HCV infection in a subject comprising administering to the subject, a pharmaceutically acceptable dose of the compound above, and continuing the administering until a selected reduction in the subject's HCV titer is achieved

[028] The method may use a compound selected from the group consisting of B243, B244, B245, B246, B248, B249, B252, B253, B255, B256, B257, B258, B259, B260, B261, B262,B263, B264, B265, B266, B267, B268, B269, B270, B271, B272, B273, B274, B275, B276, B277, B278, B279, B280, B281, B282, B283, B284, B285, B286, B287, B288, B289, B290, B291, B293, B294, B295, B296, B297, B298, B299, B300, B301, B302, B303, B304, B305, B306, B307, B308, B309, B310, B311, B312, B313, B314, B315, B316, B317, B 18, B319, B320, B321, B322, B323, B326, B327, B328, B329, B330, B333, B334, B335, B336, B337, B338, B339, B340, B341, B342, B343, B344, B345, B346, B347, B348, B349, B350, B351, B352, B353, B354, B355, B356, B357, B358, B360, B361, B362, B363, B364, B365, B366, B367, B368, B369, B370, B371, B372, B373, B374, B375, B376, B377, B378, B379, B380, B381, B382, B383, B384, B385, B386, B387, B388, B389, B390, B391, B392, B393, B394, B395, B396, B397, B398, B399, B400, B401, B402, B403, B404, B405, B406, B407, B408, B409, B410, B411, B412, B413, B414, B415, B416, B417, B418, B419, B420, B421, B422, B423, B424, B425, B426, B427, B428, B429, B430, B431. B432, B433, B434, B435, B436, B437, B438, B439, B440, B441, B442, B443, B444, B446, B447, B448, B449, B450, B451, B452, B453, B454, B455, B456, B457, B458, B459, B460, B461, B462, B463, B464, B465, B466, B467, B468, B469, B470, B471, B472, B473, B474, B475, B476, B477, B478, B479, B480, B481, B482, B483, B484, B485, B486, B487, B488, B489, B490, B491, B492, B493, B494, B495, B496, B497, B498, B499, B500, B501, B502, B503, B504, B505, B506, B507, B508, B509, B510, B511, B512, B513, B514, B515, B516, B517, B518, B519, B520, B521, B522, B523, B524, B525, B526, B527, B528, B529, B530, B531, B532, B533, B534, B535, B536, B537, B538, B539, B540, B541, B542, B543, B544, B545, B546, B547, B548, B549, B550, B551, B552, B553, B554, B555, B556, B557, B558, B561, B562, B563, B564, B565, B566, B567, B568, B569, B570, B571, B572, B573, B574, B575, B576, and B577.

[029] In one embodiment of the method, the compound is selected from the group (Group 1 ) consisting of B243, B244, B245, B246, B248, B249, B252, B253, B255, B256, B257, B258, B259, B260, B261, B262.B263, B264, B265, B266, B267, B268, B269, B270, B271, B272, B273, B274, B275, B276, B277, B278, B279, B280, B281, B282, B285, B286, B289, B300, B302, B306, B307, B308, B309, B310, B311, B314, B316, B317, B318, B319, B320, B333, B335, B336, B337, B338, B343, B344, B345, B346, B347, B348, B349, B350, B351, B352, B353, B354, B373, B378, B379, B381, B383, B384, B385, B386, B388, B389, B390, B391, B392, B394, B395, B397, B399, B400, B401, B402, B404, B405, and B409.

[030] In another embodiment of the method, the compound is selected from the group (Group 2) consisting of B283, B284, B287, B288, B290, B291, B293, B422, B423, B424, B426, B432, B443, B446, B447, B455, B456, B459, B463, B464, B466, B467, B470, B478, B479, B487, B488, B489, B491, B492, B493, B494, B495, B496, B497, B498, B499, B500, B501, B502, B503, B504, B505, B506, B507, B508, B509, B510, B511, B512, B513. B514, B515, B516, B517, B518, B519, B520, B521, B522, B523, B524, B525, B526, B527, B528, B529, B530, B531, B532, B533, B534, B535, B536, B537, B538, B539, B540, B541, B542, B543, B544, B545, B546, B547, B548, B549, B550, B551, B552, B553, B554, B555, B556, B557, B558, B561, B562, B563, B564, B565, B566, B567, B568, B569, B570, B571, B572, B573, B574, B575, B576, and B577.

[031] In still another embodiment of the method, the compound is selected from the group (Group 3) consisting of B294, B295, B296, B297, B298, B299, B301, B303, B304, B305, B312, B313, B315, B321, B322, B323, B326, B327, B328, B329, B330, B334, B339, B340, B341, B342, B355, B356, B357, B358, B360, B361, B362, B363, B364, B365, B366, B367, B368, B369, B370, B371, B372, B374, B375, B376, B377, B380, B382, B387, B393, B396, B398, B403, B406, B407, B408, B410, B411, B412, B413, B414, B415, B416, B417, B418, B419, B420, B421, B425, B427, B428, B429, B430, B431, B433, B434, B435, B436, B437, B438, B439, B440, B441, B442, B444, B448, B449, B450, B451, B452, B453, B454, B457, B458, B460, B461, B462, B465, B468, B471, B472, B473, B474, B475, B476, B477, B480, B481, B482, B483, B484, B485, B486, and B490.

[032] The method may be practiced by administering the compound orally.

[033] Also disclosed is one or more of the above compounds for use in treating HCV infection in an infected subject.

[034] Further disclosed is the use of a compound as set forth herein, such as one of the compounds identified by ID NOS, in the preparation of a medicament for the treatment of HCV in an HCV-infected subject

[035] Some of the compounds of the invention possess chiral carbons. The invention included all stereoisomeric forms, including enantiomers and diastereomers as well as mixtures of stereoisomers such as racemates. The stereoisomers or their precursors can be either

asymmetrically synthesized or obtained by separations of the racemates according to methods commonly known in the art.

[036] The invention is intended to include all isotopically labeled analogs of the compounds of the invention. Isotopes include those atoms having the same atomic number but different mass. For example, isotopes of hydrogen include ²H(D) and ³H(T) and isotopes of carbon include ^,3C and ¹⁴C. Isotopically labeled compounds of the invention can be prepared according to methods commonly known in the art. Such compounds may have various potential uses as, but not limited to, standards and reagents in determining biological/pharmacological activities. For those stable isotopically labeled compounds of the invention, they may have the potential to favorably modulate biological, pharmacological, or pharmacokinetic properties.

[037] Additional embodiments of the compounds, compositions, methods, uses and the like will be apparent from the following description, examples, and claims. As can be appreciated from the foregoing and following description, each and every feature described herein, and each and every combination of two or more of such features, is included within the scope of the present disclosure provided that the features included in such a combination are not mutually inconsistent. In addition, any feature or combination of features may be specifically excluded from any embodiment of the present invention. Additional aspects and advantages of the present invention are set forth in the following description, particularly when considered in conjunction with the accompanying examples.

Detailed Description

[038] Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Definition of standard chemistry terms may be found in reference works, including Carey and Sundberg (2007) "Advanced Organic Chemistry 5^th Ed." Vols. A and B, Springer Science+Business Media LLC, New York. The practice of the present invention will employ, unless otherwise indicated, conventional methods of synthetic organic chemistry, mass spectroscopy, preparative and analytical methods of chromatography, protein chemistry, biochemistry, recombinant DNA techniques and

pharmacology.

[039] The term "alkanoyl" as used herein contemplates a carbonyl group with a lower alkyl group as a substituent.

[040] The term "alkenyl" as used herein contemplates substituted or unsubstituted, straight and branched chain alkene radicals, including both the E- and Z-forms, containing from two to eight carbon atoms. The alkenyl group may be optionally substituted with one or more substituents selected from the group consisting ofhalogen, -CN, -N(¼, CC¾R, C(0)R, -O-R, -N(R^N)₂, - N(R^N)C(0)R, -N(R^N)S(0)₂R, -SR, -C(0)N(R^N)₂, -OC(0)R,

-OC(0)N(R^N) , S(0)R, S0₂R, -S0₃R, -S(0)₂N(R^N)₂, phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.

[041] The term "alkoxy" as used herein contemplates an oxygen with a lower alkyl group as a substituent and includes methoxy, ethoxy, butoxy, trifluromethoxy and the like. It also includes divalent substituents linked to two separated oxygen atoms such as, without limitation, -0-CF₂-0-, -0-(CH₂)M-0-(CH₂CH₂-0)M- and -(0-CH₂C¾-0)_M-.

[042] The term "alkoxycarbonyl" as used herein contemplates a carbonyl group with an alkoxy group as a substituent. {043] The term "alkyl" as used herein contemplates substituted or unsubstituted, straight and branched chain alkyl radicals containing from one to fifteen carbon atoms. The term "lower alkyP as used herein contemplates both straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl and the like. The alkyl group may be optionally substituted with one or more substituents selected from halogen, -CN, -N0₂, -C(0)₂R, -C(0)R, -O-R, -N(R^N)₂, -N(R^N)C(0)R, - N(R^N)S(0)2R, -SR, -C(0)N(R^N)₂, -OC(0)R, -OC(0)N(R^N)₂, -SOR, -S0₂R, -SO3R, -S(0)2N(R^N)_2i phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.

[044] The term "alkylene," "alkenylene" and "alkynylene" as used herein refers to the groups "alkyl," "alkenyl" and "alkynyl" respectively, when they are divalent, ie, attached to two atoms. 1045] The term "alkylsulfonyl" as used herein contemplates a sulfonyl group which has a lower alkyl group as a substituent.

[046] The term "alkynyl" as used herein contemplates substituted or unsubstituted, straight and branched carbon chain containing from two to eight carbon atoms and having at least one carbon- carbo triple bond. The term alkynyl includes, for example ethynyl,

1-propynyl, 2- propynyl, 1-butynyl, 3-methyl- 1 -butynyl and the like. The alkynyl group may be optionally substituted with one or more substituents selected from halo, -CN, -N0₂, -C0₂R, - C(0)R, -O-R, -N(R^N)₂, -N(R^N)C(0)R, -N(R^N)S(0)₂R, -SR, -C(0)N(R^N)₂, -OC(0)R,

-OC(0)N(R^N)₂, -SOR, -S0₂R, -SO3R, -S(0)₂N(R^N)₂, phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.

[047] The term "amino" as used herein contemplates a group of the structure -NR^N ₂.

of the structure

D or the L configuration and includes but is not limited to the twenty "standard" amino acids: isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartate, cysteine, glutamate, glutamtne, glycine, proline, serine, tyrosine, arginine and histidine. The present invention also includes, without limitation, D-configuration amino acids, beta-amino acids, amino acids having side chains as well as all non-natural amino acids known to one skilled in the art.

[049] The term "aralkyl" as used herein contemplates a lower alkyl group which has a substituent on an aromatic group, which aromatic group may be substituted or unsubstituted. The aralkyl group may be optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -CO2R, -C(0)R, -O-R, -N(R^N)2, -N(R^N)C(0)R, -N(R^N)S(0)₂R, -SR,

-C(0)N(R^N)₂, -OC(0)R, -OC(0)N(R^N)₂, -SOR, -S0₂R, -SO3R, -S(0)₂N(R^N)2, phosphate, phosphonate, cyctoalkyl, cycloalkenyl, aryl and heteroaryl.

[050] The terms "aryl," "aromatic group" or "aromatic ring" as used herein contemplates substituted or unsubstituted single-ring and multiple aromatic groups (for example, phenyl, pyridyl and pyrazole, etc.) and polycyclic ring systems (naphthyl and quinolinyl, etc.). The polycyclic rings may have two or more rings in which two atoms are common to two adjoining rings (the rings are "fused") wherein at least one of the rings is aromatic, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls. The aryl group may be optionally substituted with one or more substituents selected from halogen, alkyl, -CN, -NO2, - CC¾R, -C(0)R, -O-R, -N(R^N)₂, -N(R^N)C(0)R, -N(R^N)S(0)₂R, -SR, -C(0)N(R^N)₂, -OC(0)R, - OC(0)N(R^N)₂, -SOR, -S0₂R, -SO3R, -SiO^N^ , -SiR₃, -P(0)R, phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.

[051] The term "arylsulfonyl" as used herein contemplates a sulfonyl group which has as a substituent an aryl group. The term is meant to include, without limitation, monovalent as well as multiply valent aryls (eg, divalent aryls).

"carbamoyl" as used herein contemplates a group of the structure

[053] The term "carbonyl" as used herein contemplates a group of the structure

"carboxyl" as used herein contemplates a group of the structure

[055] The term "cycloalkyt" as used herein contemplates substituted or unsubstituted cyclic alkyl radicals containing from three to twelve carbon atoms and includes cyclopropyl, cyclopentyl, cyclohexyl and the like. The term "cycloalkyl" also includes polycyclic systems having two rings in which two or more atoms are common to two adjoining rings (the rings are "fused"). The cycloalkyl group may be optionally substituted with one or more substituents selected from halo, -CN, -NO₂, -CO2R, -C(0)R, -O-R, -N( ^N>₂, -N(R^N)C(0)R, -N(R^N)S(0)₂R, -SR, -C(0)N(R^N>2, - OC(0)R, -OC(0)N(R^N)₂, -SOR, -S0₂R, -S(0)₂N(R^N)₂, phosphate, phosphonate, alkyl,

cycloalkenyl, aryl and heteroaryl.

[056] The term "cycloalkenyl" as used herein contemplates substituted or unsubstituted cyclic alkenyl radicals containing from four to twelve carbon atoms in which there is at least one double bond between two of the ring carbons and includes cyclopentenyl, cyclohexenyl and the like. The term "cycloalkenyl" also includes polycyclic systems having two rings in which two or more atoms are common to two adjoining rings (the rings are "fused"). The cycloalkenyl group may be optionally substituted with one or more substituents selected from halo, -CN, -NO₂, -C0₂R, - C(0)R, -O-R, -N(R^N)₂, -N(R^N)C(0)R, -N(R^N)S(0)₂R, -SR, -C(0)N(R^N)₂, -OC(0)R, - OC(0)N(R^N)₂, -SOR, -S0₂R, -S(0)₂N(R^N)₂, phosphate, phosphonate, alkyl, cycloalkenyl, aryl and heteroaryl.

[057] The term "halo" or "halogen" as used herein includes fluorine, chlorine, bromine and iodine.

[058] The term "heteroalkyl" as used herein contemplates an alkyl with one or more

heteroatoms.

[059] The term "heteroatom", particularly within a ring system, refers to N, O and S.

[060] The term "heterocyclic group," "heterocycle" or "heterocyclic ring" as used herein contemplates substituted or unsubstituted aromatic and non-aromatic cyclic radicals having at least one heteroatom as a ring member. Preferred heterocyclic groups are those containing five or six ring atoms which includes at least one hetero atom and includes cyclic amines such as morpholtno, piperidino, pyrrolidino and the like and cyclic ethers, such as tetrahydrofuran, tetrahydropyran and the like. Aromatic heterocyclic groups, also termed "heteroaryl" groups, contemplates single-ring hetero-aromatic groups that may include from one to three heteroatoms, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, oxodiazole, thiadiazole, pyridine, pyrazine, pyridazine, pyrimidine and the like. The term heteroaryl also includes polycyclic hetero-aromatic systems having two or more rings in which two or more atoms are common to two adjoining rings (the rings are "fused") wherein at least one of the rings is a heteroaryl, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls. Examples of polycyclic heteroaromatic systems include quinoline, isoquinoline, cinnoline, tetrahydroisoquinoline, quinoxaline, quinazoline, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, indazole, purine, benzotriazole, pyrrolepyridine, pyrrazolopyridine and the like. The heterocyclic group may be optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, -CN, -NO₂, -CO2R, -C(0)R, - O-R, -N(R^N)₂, -N(R^N)C(0)R, -N(R^N)S(0)₂R, -SR, -C(0)N(R^N>2, -OC(0)R, -OC(0)N(R^N)₂, -SOR, -SO2R, -SO3R, -S(0)₂N(R^N)₂, -S1R3, -P(0)R, phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.

[061] The term "oxo" as used herein contemplates an oxygen attached with a double bond.

[062] By "pharmaceutically acceptable" or ''pharmacologically acceptable" is meant a material which is not biologically or otherwise undesirable, i.e., the material may be administered to an individual without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention which is made with counterions understood in the art to be generally acceptable for pharmaceutical uses and which possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid,

hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, rumaric acid, tartaric acid, citric acid, benzoic acid, 3 -(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid,

2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid,

2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid,

4-methylbicyclo-oct-2-ene- 1 -carboxylic acid, glucoheptonic acid, 3 -pheny .propionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, bydroxynaphtfaoic acid, salicylic acid, stearic acid, muconic acid and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, piperidine, dimethylamine, diethylamine and the like. Also included are salts of amino acids such as arginates and the like, and salts of organic acids like glucurmic or galactunoric acids and the like {see, e.g., Berge etal., 1977, J. Pharm. Sci. 66:1-19).

[063] The terms "phosphate" and "phosphonate" as used herein refer to the moieties having the following structures, respectively:

[064] The terms "salts" and "hydrates" refers to the hydrated forms of the compound that would favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, absorption, distribution, metabolism and excretion. Other factors, more practical in nature, which those skilled in the art may take into account in the selection include the cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity, flowability and manufacturability of the resulting bulk drug.

sulfonamide as used herein contemplates a group having the structure

"sulfonate" as used herein contemplates a group having the structure

wherein R" is selected from the group consisting of hydrogen, Ci-Cio alkyl, Cj-

Cio alkenyl, C2-C10 alkynyl, Ci-C_!0 aikanoyl, or C|-Cjo alkoxycarbonyl. [067 [ The term "sulfonyl" as used herein contemplates a group having the structure

"Substituted sulfonyl" as used herein contemplates a group having the structure

including, but not limited to alkylsulfonyl and arylsulfonyl.

[069] The term "thiocarbonyl," as used herein, means a carbonyl wherein an oxygen atom has been replaced with a sulfur.

[070[ Each R is independently selected from hydrogen, -OH, -CN, -N0₂, halogen, d to C₎₂ alkyl, C| to heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide, amino, and oxo.

[071] Each R^N is independendy selected from the group consisting of hydrogen, -OH, Ci to Cu alkyl, Cj toC heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and sulfonamide. Two R^N may be taken together with C, O, N or S to which they are attached to form a five to seven membered ring which may optionally contain a further heteroatom.

[072 [ The compounds of the present invention may be used to inhibit or reduce the activity of HCV, particularly HCV's NS5B protein. In these contexts, inhibition and reduction of activity of the NS5B protein refers to a lower level of the measured activity relative to a control experiment in which the cells or the subjects are not treated with the test compound. In particular aspects, the inhibition or reduction in the measured activity is at least a 10% reduction or inhibition. One of skill in the art will appreciate that reduction or inhibition of the measured activity of at least 20%, 50%, 75%, 90% or 100%, or any number in between, may be preferred for particular applications.

I. Compounds of the Invention

[073] In a first aspect of the invention is a compound that has the structure:

wherein,

L¹, L² and-N(S0₂R¹²)- together with the attached carbons of the aromatic ring to form a 5-12 member ring, containing 1-4 heteroatoms of N, O, S, P and/or Si;

L'or L² is independently selected from the group consisting of a bond, -0-, -C(R¹⁵R^I6 _> -NR³-, - S(0)„-, -P(O)-, -SifR^⁵)-, -C(O)-, -C(0)0-, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide;

is 0, 1, or 2; and

R¹ is selected from hydrogen, faalide, -CF₃, -CN, -C(0)H, -C(0)OR⁶, -C(0)NHR⁷, - 7, -C(=NOR')NHR⁷, -C(CF₃)NHR⁸, -C(CN)NHR⁹, -S(0)₂NHR¹⁰, -

R* is selected from hydrogen, -(CH2CH₂0)o^-Me, C₂-24 alkyl optionally containing 0-6 heteroatoms of O, NR^N and/or S, and 3-8 cycloalkyl optionally containing 0-2 heteroatom of O, NR^N, and/or S;

R² is an aryl or heteroaryl having one or more Rⁱ⁷ substituents;

R³ is selected from the group of hydrogen, alkylcarbonyl, cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl, alkylsulfonyl and cycloalkylsulfonyl;

R⁴ and R⁵ are independently methyl, ethyl, or cyclopropyl;

R¹² is independently C1.3 alkyl, cyclopropyl, -OMe, or -NHMe;

R¹⁵, R¹⁶ is independently hydrogen, hydroxyl, azide, C2-4 alkenyl, C2-₄alkynyl, C alkyl, cyclopropyl, CM alkoxy, or cyclopropoxy or R¹³ and R¹⁶ together are a carbonyl or C

alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon are 3-6 member ring optionally containing 0-3 heteroatoms of O, NR^N and/or S; and

R¹⁷ is F, Cl orCN. [074] The compound of this aspect may have an inhibitory activity with respect to HCV, as measured by the concentration of the compound effective to produce a half-maximal inhibition of HCVlb replication (EC₅₀) in a lb_Huh-Luc Neo-ET cell line in culture, of lOO nM or less.

R^u is selected from hydrogen, -C(0)H, -C(0)Rⁱⁿ, -C(0)OR^iv, -CiONR'R , alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl;

R^w and R* are independrntly selected from hydrogen, -C(0)H, -C(0)R^Ui, -C(0)OR^iv-, - C(0)NR^vR^vi, alkoxyls, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl; optionally, R^v and R^w together form a C4.8 member ring;

R^y and R^z are independently selected from hydrogen, alkoxyls, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl; optionally, R^y and R^x together form a 3-8 member ring;

R' and R^u are indenpendently selected from hydrogen, -Me, -Et, oPr-, c-Butyl;

R'" is selected from alkyoxyl, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl;

R^1V is selected from alkyoxyl, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl; and

R^v and R^VI are indenpendently selected from hydrogen, alkyoxyl, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl.

33





[077] The compound of this aspect may have the structure in which R¹²0 is one of



40

41

42

R¹ in mis aspect may be

[0811 R² in this aspect may be a phenyl substituted with one or more R¹⁷ substituents.

[082] R² in this aspect may be a 4-phenoxyphenyl and the phenoxy group is substituted with one or mor ¹⁷ substituents.

[083]

[084] The compound may have the particular sterochemical structure shown below:

(085 [ In one general embodiment, indicted as Group 1 herein, the compound has have the structural formula:

wherein:

selected from -H, -F, -CI, -Br, -I, and



[086] The above compound may have the same structural formula, wherein R' 1 is para-Έ, R^u-0- is as above, and X' is =0, and R'₃ is -CH₃.

[087] The compound in this group may be selected from the group consisting of B243, B244, B245, B246, B248, B249, B252, B253, B255, B256, B257, B258, B259, B260, B261, B262.B263, B264, B265, B266, B267, B268, B269, B270, B271, B272, B273, B274, B275, B276, B277, B278, B279, B280, B281, B282, B285, B286, B289, B300, B302, B306, B307, B308, B309, B310, B311, B314, B316, B317, B318, B319, B320, B333, B335, B336, B337, B338, B343, B344, B345, B346, B347, B348, B349, B350, B351, B352, B353, B354, B373, B378, B379, B381, B383, B384, B385, B386, B388, B389, B390, B391, B392, B394, B395, B397, B399, B400, B401, B402, B404, B405, and B409.

[088] In another geneal embodiment, indicated herein as Group 2, the compound has the structural formula:

wherein:

R'_I is selected from -H, -F, -CI, -Br, -I,

H₃C-S-_:

v-S(0)„-, wherein n = 0, 1 , 2, is selected from n n / n



X' is selected

and ^«N-0(CH₂)j-23CH₃, and

R'₃ is selected from -C¾ and -OCH3.

[090] The compound in Ms group may have the same structure where R'i is para-V, R^v-S(0)a-, are as above, X' is =0, and R'₃ is -CH₃.

[091[ Specific compounds in this group (Group 2) are selected from the group consisting of B283, B284, B287, B288, B290, B291, B293, B422, B423, B424, B426, B432, B443, B446, B447, B455, B456, B459, B463, B464, B466, B467, B470, B478, B479, B487, B488, B489, B491, B492, B493, B494, B495, B496, B497, B498, B499, B500, B501, B502, B503, B504, B505, B506, B507, B508, B509, B510, B511, B512, B513, B514, B515, B516, B517, B518, B519, B520, B521, B522, B523, B524, B525, B526, B527, B528, B529, B530, B531, B532, B533, B534, B535, B536, B537, B538, B539, B540, B541, B542, B543, B544, B545, B546, B547, B548, B549, B550, B551, B552, B553, B554, B555, B556, B557, B558, B561, B562, B563, B564, B565, B566, B567, B568, B569, B570, B571, B572, B573, B574, B575, B576, and B577.

[092] In another general embodiment, indicated herein as Group 3, the compound of the invention has the structural formula:

51

X' is selected from=0, =N-OH, =N-0(CH₂CH₂0)o-8CH3, and =N-0(CH₂)|.₂₃CH₃, and

R*3 is selected from -C¾ and -OCH3.

[094] The compound in this group may have the same structural formula wherein: R' ₁ is para-V, R^XR* - is selected as above, X' is =0, and R'₃ is -CH_¾.

[095] Specific compounds in this group (Group 3) are selected from the group consisting of B294, B295, B296, B297, B298, B299, B301, B303, B304, B305, B312, B313, B315, B321, B322, B323, B326, B327, B328, B329, B330, B334, B339, B340, B341, B342, B355, B356, B357, B358, B360, B361, B362, B363, B364, B365, B366, B367, B368, B369, B370, B371, B372, B374, B375, B376, B377, B380, B382, B387, B393, B396, B398, B403, B406, B407, B408, B410, B411, B412, B413, B414, B415, B416, B417, B418, B419, B420, B421, B425, B427, B428, B429, B430, B431 , B433, B434, B435, B436, B437, B438, B439, B440, B441, B442, B444, B448, B449, B450, B451, B452, B453, B454, B457, B458, B460, B46I, B462, B465, B468, B471, B472, B473, B474, B475, B476, B477, B480, B481, B482, B483, B484, B485, B486, and B490.

[096] The compounds above can be prepared in accordance with the synthetic schemes detailed below,

[097] In another aspect the compound of the invention has the structural formula:

S3 ,

wherein:

R'i is selected

R*2 is selected from -OH and -SOaMe; and R'3 is selected from -CH3 and -OCH3, as exemplified by B324, B325, B331, and B332. This compound can be prepared in accordance with Scheme 40 detailed below.

098] In still another aspect, the compound of the invention has the structural formula:

wherein:

R'2 is selected from -OH and -SOaMe; and R'j is selected from -CH3 and -OCH3, as exemplified by compound B359. This compound can be prepared in accordance with Scheme 39 detailed below.

II. Synthesis of Compounds of the Invention

]099] The compounds of the invention may be prepared by a variety of synthetic routes, samples of which are illustrated in the synthetic schemes outlined below. In general, the synthesis starts with constructing the central scaffolds such as benzofuran, benzothiophene, imidazopyridine or pyrazolopyridine by employing various synthetic techniques known to those skilled in the art. (e.g. in Heterocyclic Chemistry, J. A. Joule and K. Mills, J Wiley and Sons, 2010.) . Once the properly substituted cores are made, further functional group manipulations including but not limited to chain elongation, amidation, esterification, cyclization are performed as necessary to lead to the target molecules. When being allowed chemically and in some cases necessary, the central cores may preferably be introduced toward the end of the synthesis. Often, protection-deprotection and, in some cases, orthogonal protection-deprotection strategies are required to accomplish the desired transformation. More comprehensive descriptions of these synthetic methodologies and techniques can be in found in these and other references: Comprehensive Organic

Transformations, R. C. Larock Ed., Wiley-RCH, 1999. Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^ri ed. J Willey and Sons, 1999.

[0100] The following abbreviations are used throughout this application:

ACN Acetonitrile

AcOH Acetic acid

aq Aqueous

Boc terr-Butoxycarbonyl

Bu Butyl

Cbz Benzoxylcarbonoyl

Coned. Concentrated

GDI 1 , 1 '-Carbonyldiimidazole

DCM Dichloromethane

DffiA (DIPEA) Diisopropylethylamine

DMA MW-Dimethylacetamide

DMAP N^V-dimethyI-4-aminopyridine

DME 1 ,2-Dimethoxyethane

DMF ACiV-Dimethylformamide

DMSO Dimethylsulfoxide

dppf 1 , 1 '-Bis(diphenylphosphino)ferrocene

DCI l-Ethyl-3-[3-(dimethyIamino) propyl]carbodiimide hydrochloride ECso Effective concentration to produce 50% of the maximal effect

ESI Electrospray Ionization

EtjN, TEA Triethylamine

EtOAc, EtAc Ethyl acetate

EtOH Ethanol

g Gram(s)

h or hr Hour(s)

HATU 2-(7-Aza- lH-benzotriazole- 1 -yl 1 , 1 ,3.3-tetramethyluronium hexafluorophosphate

Hex Hexanes

HOBt 1-Hydroxybenzotriazole

HPLC High performance liquid chromatography

IC50 The concentration of an inhibitor that causes a 50 % reduction in a measured activity

LC-MS Liquid Chromatography-Mass Spectrometry

μΜ Micromolar(s)

Mel Methyl Iodide

MeOH Methanol

min Minute(s)

mM Millimolar(s)

mmol Millimole(s)

MoNP 2-Methoxy-2-(l-naphthyl)propionic acid

Ms Mesyl, Methylsulfonyl, Methanesulfonyl

MSH 0-(Mesitylsulfonyl)hydroxyamine

mw Microwave

NBS W-Bromosuccinimide

NIS iV-Iodosuccinimide

nM Nanomoiar(s)

NMO V-MethyIraorpholine-iV-oxide

NMP iV-Methylpyrrolidinone NMR Nuclear magnetic resonance

PE Petroleum ether

PPA Polyphosphoric Acid

PPh₃ Triphenylphosphine

PPTs Pyridinium / oluenesulfonate

Py. Pyr Pyridine

rt Room temperature

Sat. Saturated

TBAF Tetra-n-butylammonium fluoride

TEA Triethylamine

TfOH Trifluoromethanesulfonic acid

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TLC Thin Layer Chromatography

TMSOTf Trimethylsilyl trifluoromethanesulfonate

t_R Retention time

Ts Tosyl, Methylphenylsulfonyl

TsOH Tosylic acid, -Methylphenylsulfonic acid

w/w Weight/weight

v/v Volume volume

[0101] Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). Ή NMR spectra were recorded on a Broker 400 MHz or 500 MHz NMR spectrometer. Significant peaks are tabulated in the order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet), coupling constants) in Hertz (Hz) and number of protons. Electrospray spray ionization (ESI) mass spectrometry analysis was conducted on a Hewlett-Packard 1100 MSD electrospray mass spectrometer using the HP 1 100 HPLC for sample delivery. Mass spectrometry results are reported as the ratio of mass over charge, followed by the relative abundance of each ion (in parentheses) or a single m z value for the M + H (or, as noted, M - H) ion containing the most common atomic isotopes. Isotope patterns correspond to the expected formula in all cases. Normally the analyte was dissolved in methanol at 0.1 mg mL and 5 microliter was infused with the delivery solvent into the mass spectrometer, which scanned from 100 to 1500 daltons. All compounds could be analyzed in the positive ESI mode, using an acetonitrile/water gradient (10% ~ 90%) acetonitrile in water with 0.1% formic acid as delivery solvent. The compounds provided below could also be analyzed in the negative ESI mode, using 2 mM N¾OAc in

acetonitrile/water as delivery solvent. Enantiomeric purity was determined using a Hewlett- Packard Series 1050 system equipped with a chiral HLPC column (ChiraiPak AD, 4.6 mm x 150 mm) and isocratic etution using isopropanol/hexane = 5/95 (v/v) as mobile phase.



These compounds may be synthesized in accordance with the synthetic schemes disclosed below.

In another aspect, the compound of the invention includes a compound having the structural formula:

wherein:

R'_l is selected from para-

R^* ₂ is selected from -OH and -S0₂Me; and R'3 is selected from -CH^ and -OCH3, as exemplified by B324, B325, B331, and B332. This compound can be synthesized in accordance with the scheme 40 below. 0102] In another aspect, the compound of the invention has the structural formula:

wherein:

R' I is selected from para-Έ

;

R'₂ is selected from -OH and -S0₂Me; and R'3 is selected from -CH₃ and -OCH3, as exemplified by compound B359.

This compound can be synthesized in accordance with Scheme 39 below.

(0118] The following examples illustrate the preparation and antiviral evaluation of compounds within the scope of the invention. These examples and preparations which follow are provided to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.

Scheme 4

[0119] Step 1. Refer to Scheme 4. To a solution of compound 3-1 (prepared by following the procedures described in WO200759421 with some modifications) (4.00 g, 10.3 mmol) in CH₂C1₂ (30 mL) was added BC1₃ (I N in CH₂C1₂, 20.6 mmol) at 0 °C. After stirring at rt for 1 hr, the reaction mixture was added ice water (100 mL). The mixture was extracted with CH₂C1₂ (800 mL x 2) and the combined organic extracts were washed with water and brine and dried with anhydrous Na₂SO_}. The solvent was removed and the residue was dried in vacuo to give crude compound 4-1 (3.4 g, 96% yield) as a yellow solid. LC-MS (ESI): mlz 346 [M + H]⁺.

10120] Step 2. To a solution of compound 4-1 (3.4 g, 9.8 mmol) in CH₂C1₂ (100 mL) were added DMAP (120 mg, 0.980 mmol) and D1EA (1.52 g, 11.8 mmol), followed Tf_zO (3.20 g, 1 1.3 mmol) at 0 °C. After stirring at 0 °C for 2 hrs, the reaction mixture was added ice water (100 mL). The organic layer was separated, washed with water and brine, and dried with anhydrous Na₂S0₄. The solvent was removed and the residue was dried in vacuo to give crude compound 4-2 (4.6 g, quantitative yield) as a yellow solid. LC-MS (ESI): mlz 478 [M + H]⁺.

10121 [ Step 3. To a solution of 4-2 (2.0 g, 4.2 mmol) in 20 mL DMF was added 4-3 (0.44 g, 6.3 mmol), Cul (0.16 g, 0.84 mmol), Pd(PPh₃)₂Cl₂ (0.29 g, 0.42 mmol) and Et₃N (20 mL). The resulting mixture was flushed with Ar, stirred at rt for 1 hr and poured into ice water ( 100 mL). The mixture was extracted with EtOAc (50 mL x 5) and the combined organic extracts were washed with water and dried with anhydrous Na₂S0₄. The solvent was removed and the residue was purified by silica gel column chromatography (Petroleum ether/acetone = 4/1 (v/v) to 3/2 (v/v)) to give compound 4-4 (1.10 g, 69% yield) as a gray solid. LC-MS (ESI): mlz 398 [M + H]⁺. 10122] Step 4.To a solution of compound 4-4 (2.00 g, 5.03 mmol) in EtOAc (150 mL) was added 10% Pd C (2.0 g). The resulting mixture was flushed with H₂ and stirred at rt for 1.5 hrs.

Subsequently, the reaction mixture was filtered through Celite^®545 and the filtrate was concentrated and dried in vacuo to give compound 4-5 (1.8 g, 97% yield). LC-MS (ESI): mlz 372 [M+H ; Ή NMR (500 MHz, CDC1₃): δ 7.98 - 8.01 (m, 2H), 7.70 (s, 1H), 7.12 - 7.16 (m, 2H), 6.82 (s, 1H), 4.39 (dd, J, = 14.5 Hz, J₂ = 7 Hz, 2H), 3.73 (t, J= 6 Hz, 3H), 2.66 (t, J= 7.5 Hz, 2H), 1.69 - 1.80 (m, 4H), 1.40 (t, J= 7 Hz, 3H) ppm.

10123] Step 5. To a solution of compound 4-5 (1.80 g, 4.85 mmol) in CH₂C1₂ (50 mL) was added DMAP (6 mg) and anhydrous pyridine (3.07 g, 38.8 mmol), followed by MsCl (1.60 g, 14.5 mmol) at 0 °C. After stirring at rt for 2 hrs, the reaction mixture was added ice water (50 mL). The organic layer was separated, washed with water and brine and dried with anhydrous NajSO-j, The solvent was removed and the residue was purified by silica gel column chromatography (Petroleum ether/acetone = 5/1 (v/v)) to give compound 4-6 (1.4 g, 55% yield) as a yellow solid. LC-MS (ESI): mlz 449 [M - Ms + H]⁺; ^lH NMR (500 MHz, CDC1₃): δ 8.02 - 8.05(m, 2H), 7.90 (s, l H), 7.71 (s, 1H), 7.16 - 7.19 (m, 2H), 6.61 (s, 1H), 4.42 (dd, J_s= 14 Hz, J₂ = 7.0 Hz, 2H), 4.34 (t, J= 5.5 Hz, 2H), 3.04 - 3.08 (m, 6H), 2.83 (t, J= 8.0 Hz, 2H), 1.81 - 1.92 (m, 4H), 1.41 (t, J- 7.0 Hz, 3H) ppm.

[0124] Step 6. To a suspension of NaH (0.21 g, 60% in mineral oil, 5.31 mmol) in anhydrous THF (160 mL) was added a solution of compound 4-6 (1.40 g, 2.65 mmol) in anhydrous THF (40 mL) at 0 °C. After stirring at rt for 2 hrs, the reaction mixture was added sat. aq. NH4CI (10 mL). The resulting mixture was concentrated and the residue was diluted with EtOAc (100 mL). The mixture was washed with water and brine and dried with anhydrous NaiSC The solvent was removed and the residue was purified by silica gel column chromatography (Petroleum

ether/acetone = 5/ 1 (v/v)) to give compound 4-7 (1.1 g, 96% yield) as a yellow solid. LC-MS (ESI): mlz 432 [M + H]⁺; H NMR (500 MHz, CDCI3): δ 8.02 - 8.06 (m, 2H), 7.90 (s, 1H), 7.60 (s, 1H), 7.15 - 7.20 (m, 2H), 4.42 (dd,J/ = 14 Hz, J₂ = 6.5 Hz, 2H), 3.69 (t, J= 6.0 Hz, 2H), 3.07 (s, 3H), 3.02 (t, J = 6.0 Hz, 2H), 1.94 (dd, J, = 11 Hz, J₂ = 5.5 Hz, 2H), 1.77 (br s, 2H), 1.40 - 1.43 (m, 3H) ppm.

10125] Step 7. To a solution of compound 4-7 (50 mg, 0.12 mmol) in MeOH THF (2 mL/4 mL) was added LiOH (2.0 N, 0.46 mmol). The resulting mixture was stirred at 70 °C for 2 hrs, cooled to rt and acidified with 1 N aq. HC1 (5 mL). Subsequently, the suspension was filtered and the solid was washed with waster and dried in vacuo to give crude compound 4-8 (46 mg, 95% yield) as a white solid, which was used directly for the next step without further purification. LC-MS (ESI): mlz 404 [M + H]⁺.

|0126] Step 8. To a solution of compound 4-8 (46 mg, 0.12 mmol) in DMF (2 mL) was added HATU (54 mg, 0.14 mmol). The resulting mixture was stirred at rt for 30 min and added D1EA (154 mg, 1.20 mmol) and MeNH₂ HC1 (41 mg, 0.60 mmol). After stirring at rt for 20 min, the reaction mixture was poured into ice water (50 mL). The suspension was filtered and the solid was purified by silica gel column chromatography (Petroleum ether/acetone = 3/1 (v/v)) to give compound 4-9 (30 mg, 61% yield) as a white solid. LC-MS (ESI): mlz M [M + H]⁺; 1H NMR (500 MHz, CDCI3): 5 7.89 - 7.92 (m, 2H), 7.68 (s, 1H), 7.59 (s, 1 H), 7.19 (t, J= 9.0 Hz, 2H), 5.80 (d, J= 4.0 Hz, 1H), 3.69 (<L J= 6.0 Hz, 2H), 3.06 (s, 3H), 2.98-3.03 (m, 5H), 1.93 (dd, J/= 11 Hz, J₂ = 5.5 Hz, 2H), 1.75 (d, J= 2.5 Hz, 2H) ppm.

|0127] Synthesis of compound 4-10. A mixture of compound 4-8 (50 mg, 0.12 mmol) in SOCl₂ (1.5 mL) was stirred at 80 °C for 2 hrs. The solvent was removed and the residue dried in vacuo to give the crude acid chloride, which was used for the next step without further purification. Subsequently, the crude acid chloride was dissolved in anhydrous pyridine (1.5 mL), followed by 0-methylhydroxylamine hydrochloride ( 124 mg, 0.490 mmol). After stirring at 100 °C for 1 5 hrs, the reaction mixture was concentrated and the residue was purified by preparative HPLC to give compound 4-10 (20 mg, 37% yield) as a white powder. LC-MS (ESI): mlz 433 [M + H ; Ή NMR (500 MHz, CDCI₃): δ 8.31 (s, 1H), 7.90 - 7.93 (m, 2H), 7.66 (s, 1 H), 7.20 (t, J= 8.5 Hz, 2H), 3.85 (s, 3H), 3.03 (s, 3H), 2.97 - 3.00 (m, 2H), 1.93 - 1.96 (m, 2H), 1.69 - 1.76 (m, 2H) ppm.

[0128] Step 1. Refer to Scheme 8. To a stirred solution of compound 4-2 (9.00 g, 18.9 mmol) in DMF (100 mL) were added Et₃N (7.84 mL, 56.6 mmol), Pd(OAc)₂ (212 mg, 0.94 mmol), dppp (469 mg, 1.13 mmol) and butyl vinyl ether (12.1 mL, 94.4 mmol) under an atmosphere of Ar. After stirring at 100 °C for 2 hrs, the reaction mixture was concentrated. The residue was diluted with EtOAc (250 mL) and the resulting mixture was washed with water (100 mL x 3) and dried with anhydrous Na2SC>4. The solvent was removed and the residue was purified by silica gel column chromatography (Petroleum ether EtOAc = 16/1 (v/v)) to give compound 8-1 (3.9 g, 48% yield) as a yellow solid. LC-MS (ESI): mlz 427 [M + H)⁺.

[0129] Step 2. A solution of compound 8-1 (3.90 g, 9.13 mmol) in THF (60 mL) was added 1 N aq. HC1 (10 mL) at rt. After stirring at rt for 15 min, the reaction mixture was concentrated and the residue was diluted with DCM (100 mL). The resulting mixture was washed with brine and dried with anhydrous Na₂S04. The solvent was removed and the residue was dried in vacuo to give crude compound 8-2 (3.27 g, 96% yield) as a yellow solid, which was used for the next step without further purification. LC-MS (ESI): mlz 372 [M + H]⁺.

[0130] Step 3. To a stirred solution of compound 8-2 (2.00 g, 5.38 mmol) in EtOAc (50 mL) was added SnCl₂2H₂0 (3.47 g, 16.2 mmol). After stirring at 80 °C for 1 hr, the reaction mixture was added sat. aq. NaHC0₃ (50 mL) and the resulting mixture was stirred at rt for 30 min.

Subsequently, the mixture was filtered through Celite^®545 and the the filtered cake was washed with EtOAc (50 mL x 3). The organic layer of the filtrate was washed with brine and dried with anhydrous Na₂S0₄. The solvent was removed and the residue was dried in vacuo to give crude compound 8-3 (1.8 g, 98% yield) as a brown solid, which was used for the next step without further purification. LC-MS (ESI): mlz 342 [M + H]⁺.

10131] Step 4. To a stirred solution of compound 8-3 (900 mg, 2.64 mmol) in anhydrous pyridine (15 mL) was added MsCl (0.25 mL, 3.17 mmol) at 0 °C. After stirring at rt for 1 hr, the reaction mixture was diluted with EtOAc (100 mL) and the resulting mixture was washed with 2 N aq. HC1 (20 mL x 2) and H₂0 (50 mL x 3) and dried with anhydrous Na₂S0₄. The solvent was removed and the residue was purified by silica gel column chromatography (Petroleum

ether DCM/EtOAc = 8/4/1 (v/v)) to compound 8-4 (520 mg, 47% yield) as a yellow solid. LC-MS (ESI): m/2442 [M + Naf.

[0132] Step 5. To a solution of compound 8-4 (380 mg, 0.91 mmol) in MeOH (10 mL) and THF (10 mL) was added NaBH₄( 172 mg, 4.54 mmol) in several portions at 0 °C. After stirring at 0 °C for 15 min, the reaction was quenched by adding acetone (1 mL). The mixture was concentrated and the residue was diluted with EtOAc (100 mL). The resulting mixture was washed with 2 N aq. HC1 (20 mL) and H₂0 (50 mL x 3) and dried with anhydrous Na₂S0₄. The solvent was removed

13 and the residue was dried in vacuo to give crude compound 8-5 (240 mg, 63% yield), which was used for the next step without further purification. LC-MS (ESI): mlz 444 [M + Na]⁺.

[0133J Step 6. To a stirring solution of compound 8-5 (50 mg, 0.12 mmol) in THF (15 mL) was added NaH (24 mg, 0.6 mmol) at 0 °C under an atmosphere of Ar. After stirring at rt for 15 min, the mixture was added compound 8-6 (106 mg, 0.24 mmol) (prepared following the procedure described in Angew. Chem. Intl. Ed. 2008, 47, 3784) at 0 °C and the resulting mixture was stirred at 0 °C for 3 hrs and rt overnight. Subsequently, saturated aq. NH₄CI (10 mL) was added to quench the reaction and the mixture was concentrated. The residue was diluted with EtOAc (50 mL) and the mixture was washed with brine ( 10 mL) and dried with anhydrous Na₂SC«4. The solvent was removed and the residue was purified by silica gel column chromatography

(Petroleum ether/Acetone = 4/1 (v/v)) to give compound 8-7 (30 mg, 56% yield) as a white solid. LC-MS (ESI): mlz 448 [M + H]⁺.

[0134] Step 7. To a solution of compound 8-7 (40 mg, 0.09 mmol) in MeOH THF (2 mL/4 mL) was added 2.0 N aq. LiOH (0.18 mmol, 0.36 mmol). After stirring at 75 °C for 3 hrs, the reaction mixture was cooled to 0 °C and acidified with 2N aq. HC1 adjust pH value to 5~6. Subsequently, the suspension was filtered and the solid was washed with water and dried in vacuo to give compound 8-8 (38 mg, 97% yield) as a white solid, which was used for the next step without further purification. LC-MS (ESI): mlz 442 [M + Na .

[0135] Step 8. To a solution of compound 8-8 (40 mg, 0.10 mmol) in DMF (3 mL) was added HATU (43 mg, 0.12 mmol). The resulting mixture was stirred at rt for 60 min and DIE A (0.16 mL, 0.95 mmol) and MeNH₂ HCl (20 mg, 0.29 mmol) were added. After stirring at rt for 15 min, the reaction mixture was added into water (30 mL). The suspension was filtered and the solid was washed with water and dried in vacuo. The residue was dissolved in DCM (1.5 mL) and the solution was added into hexane (40 mL). The resulting suspension was filtered and the solid was dried in vacuo to give compound 8-9 (23 mg, 56% yield). LC-MS (ESI): mlz 433 [M+H]⁺; Ή NMR (500 MHz, CDCI3): δ 7.88 - 7.91 (m, 3H), 7.62 (s, 1 H), 7.20 (t,J= 8.5 Hz, 2H), 5.80 (br s, 1 H), 4.96 (q, J= 6.5 Hz, 1H), 4.15 - 4.18 (m, 1 H), 4.02 - 4.09 (m, 2H), 3.29 - 3.34 (m, 1H), 3.15 (s, 3H), 3.01 (d, J= 5.0 Hz, 3H), 1.74 (d, J= 6.5 Hz, 3H) ppm. Compound 8-9 was separated into a pair of enantiomers: enantiomer 8-9 A (t_R = 3.34 min) and enantiomer 8-9_B (.R = 3.89 min) detected by UV absorption at 214 run on a Daicel CHIRALPAK AS-H column (eluent:

MeOH/liquid CO2 = 10/90 (v V), flow rate: 60 g/min and back pressure: 100 bar).

[0136] Step 1. Refer to Scheme 15. To a solution of NaH (80 g, 60% mineral oil dispersion, 2 mol) in toluene (1.2 L) was added diethyl carbonate (295 g, 2.50 mol) at 0 °C. After stirring at rt for 2 hrs, the mixture was added drop wise to a solution of compound 15-1 (99 g, 0.50 mol) in toluene (400 mL) at reflux. After refluxing overnight, the reaction mixture was cooled to rt and sequentially treated with HOAc (140 mL) and aq. HC1 (2 M, 864 mL). The resulting mixture was extracted with EtOAc (400 mL x 3) and the combined organic extracts were washed with water (500 mL x 4) and brine (200 mL x 2) and dried with anhydrous Na₂SO.i. The solvent was removed and the residue was dried in vacuo to give compound 15-2 (122 g, 90% yield) as an oil. LC-MS (ESI): m/z 271.0 [M + H]^'

[0137 J Step 2. To a solution of compound 15-2 (100 g, 369 mmol) in DMF (70 mL) was added /?-benzoquinone (40 g, 369 mmol), followed by ZnCl₂ (50 g, 369 mmol) in portions at rt. After stirring at 105 °C for 3.5 hrs, the reaction mixture was partitioned between water (800 mL) and EtOAc (800 mL) and filtered. The aqueous phase was extracted with EtOAc (500 mL x 2). The combined organic extracts were washed with water (1000 mL x 2) and dried with anhydrous Na₂S0₄. The solvent was removed and the residue was purified by silica gel column

chromatography (Petroleum ether/Acetone = 10/l(v/v)) to give compound 15-3 (26 g, 20% yield) as a yellow solid. LC-MS (ESI): m/z 361.0 [M + H]⁺.

[0138] Step 3. To a solution of compound 15-3 (26 g, 72 mmol) in NMP (200 mL) was added Cs₂C0₃ (47.0 g, 144 mmol). After stirring at rt for 20 min, 2-bromopropane (20.0 ml, 216 mmol) was added. The resulting mixture was stirred at 80 °C for 4 hrs, then diluted with ammonia and agitated for 30 min. The mixture was diluted with water (200 mL) and the aqueous phase was extracted with EtOAc (150 mL x 3). The combined organic extracts were washed with water (200 mL x 3) and dried with anhydrous Na₂S0₄. The solvent was removed and the residue was dried in vacuo to give compound 15-4 (27.5 g, 95% yield) as a colorless oil. LC-MS (ESI): m/z 403.0 [M

|0139[ Step 4. To a solution of HN0₃ (cone. 66 mL, 0.89 mol) and CH₂C1₂ (300 mL) a solution of compound 15-4 was added drop wise (27.5 g, 68.2 mmol) in CH₂C1₂ (120 mL) at 0 °C over 1 nr. After stirring at rt for 30 min, the reaction mixture was diluted with water (200 mL) and extracted with DCM (150 mL x 3). The combined organic extracts were washed with water (200 mL x 3) and dried with anhydrous Na₂S0 . The solvent was removed and the residue was re- crystallized in methyl /-butyl ether (MTBE) to give compound 15-5 (24.6 g, 80% yield) as a pale yellow solid. LC-MS (ESI): m/z 448.0 [M + H]⁺; 1H NMR (500 MHz, CDC1₃): δ 7.92 (d, J= 8.5 Hz, 2H), 7.87 (m, 2H), 7.76 (s, 1H), 7.65 (d, J = 8.5 Hz, 2H), 4.69 - 4.74 (m, 1H), 4.40 - 4.44 (m, 2H), 1.54 (s, 6H), 1.41 - 1.45 (t, 3H) ppm.

|0140] Step 5. A mixture of compound 15-5 (5.0 g, 1 1.2 mmol), 4-fluorophenol (1.7 g, 14.5 mmol), Pd(OAc)₂ (250 mg, 1.12 mmol), -BuXphose (380 mg, 0.9 mmol) and K₃PO₄ (4.8 g, 22.4 mmol) in toluene (50 mL) was stirred at 100°C under an atmosphere of Ar and monitored by LC- MS. After 2 hrs, the reaction mixture was concentrated and the residue was diluted with water (100 mL). The mixture was extracted with EtOAc ( 100 mL x 3) and the combined organic extracts were washed with water (100 mL x 2) and dried with anhydrous Na₂S0 . The solvent was removed and the residue was dried in vacuo to give crude compound 15-6 (4.8 g, 90% yield) as a yellow powder. LC-MS (ESI): m/z 480.1 [M + H]⁺. [0141| Step 6. To a solution of compound 15-6 (2.0 g, 4.2 mmol) in DCM (30 mL) drop wise was added BCU (8.4 mL, 8.4 mmol) at -78 °C. After stirring at -40 °C for 1 hr, the reaction was quenched by adding sat. aq. NH4CI (20 mL). The resulting mixture was extracted with DCM (50 mL x 2) and the combined organic extracts were washed with water (50 mL x 3) and brine (50 mL) and dried with anhydrous Na₂S0₄. The solvent was removed and the residue was dried in vacuo to give crude compound 15-7 (1.6 g, 90% yield) as a yellow solid. LC-MS (ESI): /z 438.1 [M + H]⁺.

|0142[ Step 7. To a solution of compound 15-7 (1.6 g, 3.9 mmol) and DMAP (24 mg, 0.2 mmol) in DCM (30 mL) at 0 °C was added Et₃N (790 mg, 7.8 mmol), followed by Tf₂0 (1.6 g, 5.82 mmol). After stirring at rt for 1 hr, LC-MS analysis indicated that the reaction went completion. The mixture was diluted with DCM (100 mL), washed water (50 mL x 3) and brine (50 mL) and dried with anhydrous Na₂S0₄. The solvent was removed and the residue was dried in vacuo to give crude compound 15-8 (1.8 g, 94% yield) as a yellow solid. LC-MS (ESI): m/z 570.0 [M +

H]⁺.

[01431 Step 8. To a solution of compound 15-8 (1.8 g, 3.2 mmol) in CH3CN (50 mL) was added NaOAc (1.6 g, 16 mmol.), dppf (180 mg, 0.32 mmol), and Pd(OAc)₂ (150 mg, 0.64 mmol), and the resulting mixture was saturated with Ar. After l-(vinyloxy)butane (1.6 g, 16 mmol) was added, the mixture was stirred at 100 °C for 2 hrs under an atmosphere of Ar. Subsequently, the reaction mixture was cooled to rt, concentrated, and diluted with EtOAc (100 mL). The resulting mixture was washed with water (50 mL x 2) and brine (100 mL) and dried with anhydrous Na₂S0₄. The solvent was removed and the residue was dissolved in THF (50 mL) and aq. HC1 (2 N, 12 mL). After refluxing for 1 hr, the mixture was cooled to rt and concentrated to remove most of the organic solvent. The resulting mixture was extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with water (50 mL x 3) and brine (50 mL) and dried with anhydrous Na₂S0₄. The solvent was removed and the residue was dried in vacuo to give crude compound 15-9 (1.4 g, 98% yield). LC-MS (ESI): m/z 464.1 [M + Hf.

[0144[ Step 9. To a solution of compound 15-9 (1.4 g, 3.4 mmol) in EtOAc (50 mL) was added SnCl₂2H₂0 (2.8 g, 13.6 mmol) at rt and the resulting mixture was stirred at 80 °C for 1 hr. The mixture was cooled to rt and d its pH value was adjusted to 8 ~ 9 by adding saturated aq.

NaHC0₃. The mixture was filtered and the filtrate was extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with water (50 mL x 3) and brine (50 mL) and dried with anhydrous Na₂S0₄. The solvent was removed and the residue was dried in vacuo to give crude compound 15-10 (1.1 g, 85% yield) as a yellow solid. LC-MS (ESI): mlz 434.1 [M + H]⁺.

[0145] Step 10. To a solution of compound 15-10 (1.1 g, 2.5 mmol) in anhydrous pyridine (20 mL) was added MsCl ( 1.8 mL) at 0 °C. After the mixture was stirred at 30 °C for 2 hrs, LC-MS analysis indicated that the reaction went to completion. The mixture was diluted with water (100 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with sat. aq. NH₄C1 (50 mL x 3) and brine (50 mL) and dried with anhydrous Na₂S0₄. The solvent was removed and the residue was dried in vacuo to give crude compound 15-11 (1.1 g, 90% yield) as a yellow solid. LC-MS (ESI): mlz 512.1 [M + H]⁺.

[0146] Step 11. To a solution of compound 15-11 (1.1 g, 2.1 mmol) in THF (30 mL) was added aBH₄ (560 mg, 14.7 mmol) in portions at 0 °C. After stirring at 0 °C for 30 min, LC-MS analysis indicated that the reaction went to completion and acetone (2 mL) was added to quench excess amount of NaB¾. The mixture was concentrated and the residue was diluted with EtOAc (100 mL). The resulting mixture was washed with water (50 mL x 3) and brine (50 mL) and dried with anhydrous Na₂SO.t. The solvent was removed and the residue was dried in vacuo to give compound 15-12 (0.9 g, 90% yield) as a yellow solid. LC-MS (ESI): mlz 514.1 [M + H]⁺.

[0147] Step 12. To a solution of compound 15-12 (0.9g, 1.7 mmol) in anhydrous DCM (30 mL) was added NaH (60% in paraoil, 200 mg, 5 mmol) at 0 °C, followed by compound 8-6 ( 1.1 g, 2.55 mmol). After stirring at 0 °C for 3 hrs and at it for 12 hrs, the reaction was quenched by adding saturated aq. NH₄C1 (10 mL). The resulting mixture was extracted with DCM (30 mL x 3) and the combined organic extracts were washed with brine (50 mL) and dried with anhydrous Na₂S0₄. The solvent was removed and the residue was purified by silica gel column

chromatography (Petroleum ether/EtOAc = 67l(v/v)) to give compound 15-13 (520 mg, 55% yield) as a white solid. LC-MS (ESI): mlz 540.1 [M + H]⁺.

[0148] Step 13. To a solution of compound 15-13 (520 mg, 0.96 mmol) in MeOH/THF (4 mL/8 mL) was added aq. LiOH (2.0 M, 2 mL) at rt. After stirring at 80 °C for 12 hrs, the reaction mixture was cooled to rt and adjusted its pH value to 2 ~ 3 by adding aq. HC1 (2.0 M). The organic solvent was removed and the residue was diluted with EtOAc (50 mL). The organic layer was isolated, washed with brine (25 mL) and dried with anhydrous Na2SC>4. The solvent was removed and the residue was dried in vacuo to give crude compound 15-14 (442 mg, 90% yield) as a white solid. LC-MS: (ESI): mlz 512.1 [M + H]⁺.

[0149] Step 14. Compound 15-14 (442 mg, 0.86 mmol) was dissolved in DMF (5 mL), followed by addition of HATU (450 mg, 1.17 mmol). After stirring at rt for I hr, the reaction mixture was added DIPEA (503 mg, 3.9 mmol) and MeNH₂ HCl (157 mg, 2.34 mmol). The resulting mixture was stirred at rt for another 1 hr before being concentrated The residue was diluted with water (25 mL) and EtOAc (50 mL). The organic layer was isolated, washed with brine (25 mL), and dried with anhydrous Na₂S0 . The solvent was removed and the residue was purified by silica gel column chromatography (Petroleum ether/EtOAc = 5/1 (v V)) to give compound 15-15 (360 mg, 80% yield) as a white solid. LC-MS (ESI): mlz 525.1 [M + Hf ; Ή NMR (500 MHz, CDC1₃): δ 7.89 (s, I H), 7.82 - 7.84 (m, 2H), 7.26 (s, I H), 7.04 - 7.12 (m, 6H), 5.85 (m, lH), 4.94 - 4.98 (m, I H), 4.14 - 4.18 (m, 1 H), 4.02 - 4.06 (m, 2H), 3.31 (m, 1 H), 3.15 (d, J = 8.5 Hz, 3H), 3.00 (<L J = 5.0 Hz, 3H), 2.07 - 1.73 (d, J = 6.5 Hz, 3H) ppm. Compound 15-15 was separated into a pair of enantiomers: enantiomer 15-15a (tR = 3.66 min) and enantiomer 15-15b (fe = 4.25 min) detected by UV absorption at 214 nm on a 4.6 mm x 250 mm x 5 μιη Daicel CHIRALPAK AS-H column (column temperature: 39.7 °C; eluent: MeOH/liquid CO2 = 20/80 (vV); CO2 flow rate: 2.4 g min and co-solvent flow rate: 0.6 g min; front pressure: 198 bar and back pressure: 150 bar).

Scheme 28

[0150] Synthesis of compound 28-3a. Refer to Scheme 28. Following the same procedure as that for the praparation of compound 27-3a from 15-11 described in Scheme 27 and replacing 3- bromo-2-methylpropene with allyl bromide, compound 28-3a was obtained as a white solid. LC- MS (ESI): m/z 732.1 [M + Naf.

[0151] Synthesis of compound 28-5a. Following the same procedure as that for the praparation of compound 27-5a from 27-3 a described in Scheme 27 and replacing compound 27-3a with 28- 3a, compound 28-5a was obtained as a white solid. LC-MS (ESI): m/z 539.2 [M + H]⁺; Ή NMR (500 MHz, CDCb): δ 7.89 and 7.78 (s, s, lH), 7.83 (dd, J, = 6.5 Hz, J₂ = 8.5 Hz, 2H), 7.61 and 7.58 (br s, s, 1 H), 7.04 - 7.12 (m, 6H), 5.83 (d, J = 4.0 Hz, IH), 5.18 and 4.98 (dd, dd, J_/ = 13.5 Hz, J₂ = 6.5 Hz, 1H), 4.13 - 4.16 and 3.78 - 3.81 (m, m, 2H), 3.15 and 3.12 (s, s, 3H), 3.12 and 2.85 (m, m, 1 H), 3.00 (d, J = 5.0 Hz, 3H), 1.73 (t, J= 6.5 Hz, 3H), 1.23 and 1.17 (d, d, J= 6.5 Hz, 3H) ppm. Alternatively, compound 28-5a can be obtained using compound 28-7a as the starting material described in Scheme 28.

[0152] Synthesis of compound 28-5b. Following the same procedure as that for the preparation of compound 28-5a described in Scheme 27 and replacing compound 27-3a with 28-3b,

compound 28-5b was obtained as a white soUd. LC-MS (ESI): m/z 447.1 [M + H ; Ή NMR (500 MHz, CDCb): δ 7.89 - 7.92 (m, 2H), 7.87 (s, 1H), 7.59 (s, 1H), 7.20 (t, J= 8.5 Hz, 2H),

5.78 (m, 1H), 4.98 (m, 1H), 4.14 (m, 2H), 3.15 and 3.12 (s, s, 3H), 3.01 (d, J = 4.5 Hz, 3H), 2.83 (m, 1 H), 1.73 and 1.71 (d, d, J = 7.0 Hz, 3H), 1.23 and 1.18 (d, d, J = 6.5 Hz, 3H) ppm.

Alternatively, compound 28-5b can be obtained using compound 28-7b as the starting material described in Scheme 28.

[0153] Synthesis of compound 8-6a. To a solution of compound 28-3a (2.1 g, 3.0 mmol) in DCM (200 mL) was added m-CPBA (563 mg, 3.3 mmol) at 0 °C. After stirring at 0°C for 30 min, the reaction mixture was washed with saturated aq. NaHCCb solution and water. The organic layer was dried over anhydrous Na₂S04 and concentrated to dryness to give crude compound 28- 6a as a red solid, which was used in the next step without further purification. LC-MS (ESI): m/z 748.1 [M + Naf.

[0154] Synthesis of compound 28-7a. Compound 28-6a (375 mg, 0.52 mmol) was dissolved in dry toluene (300 mL) and the resulting solution was added DBU (4.2 mL, 28.1 mmol) at 0 °C. After stirring at 100 °C for 45 min under an atmosphere of N2, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (PE/EtOAc = 5/1 to 3/1 (v/v)) to give compound 28-7a (248 mg, 87% yield) as an off white solid. LC-MS (ESI): m/z 552.1 [M + H]⁺; Ή NMR (500 MHz, d*-DMSO): δ 8.05 (d, J= 9.0 Hz, 2H), 8.00 (s, 1H),

7.79 (s, IH), 7.31 (m, 2H), 7.21 - 7.23 (m, 2H), 7.12 (d, J = 9.0 Hz, 2H), 5.46 (q, J= 6.0 Hz, 1H), 4.67 (d, J = 14.0 Hz, 1H), 4.46 (s, 1H), 4.40 (s, IH), 4.36 (q, J= 7.0 Hz, 2H), 4.20 (d, J= 14.0 Hz, 1H), 3.24 (s, 3H), 1.72 (d, J= 6.0 Hz, 3H), 1.36 (t, J= 7.0 Hz, 3H) ppm.

[0155] Synthesis of compound 28-8a. Under an atmosphere of N₂, ZnEt₂ (IM in hexane, 7.40 mL, 7.40 mmol) was added to dry DCM (20 mL) at -78 °C, followed by CH₂I₂ (1.2 mL, 14.8 mmol) over 10 tnin. The resulting mixture was stirred at -78 °C for 30 min and then at -10 °C for 30 min. The mixture was cooled to -78 °C and a solution ofTFA (137 μί, 1.9 mmol) in DCM (I mL) was added dropwise. After stirring at -78 °C for 30 min, the mixture was added dropwise a solution of compound 28-7a (340 mg, 0.62 mmol) in DCM (2 mL) at -78 °C. The resulting mixture was stirred at -78 °C for 10 min, 0 °C for 1 hr, and 25 °C for 4 hrs. Subsequently, saturated aq. NH4CI solution (10 mL) was added and the mixture was concentrated. The residue was extracted with DCM (20 mL x 3). The combined organic extracts were washed with saturated aq. NaHC03 solution and water and dried over anhydrous Na₂S04. The solvent was removed and the residue was purified by silica gel column chromatography (PE EtOAc = 10/1 to 4/1 (vA>)) to give compound 28-8a (230 mg, 66% yield) as a white solid. LC-MS (ESI): m/z 566.2 [M + Hf; Ή NMR (500 MHz,

δ 8.06 - 8.08 (m, 2H), 8.01 (s, IH), 7.88 (s, IH), 7.30 - 7.34 (m, 2H), 7.21 - 7.24 (m, 2H), 7.12 - 7.14 (m, 2H), 5.09 (q, J = 6.0 Hz, IH), 4.36 (q, J = 7.5 Hz, 2H), 3.69 (d, J= 15.0 Hz, IH), 3.57 (d, J= 15.0 Hz, IH), 3.32 (s, 3H), 1.57 (d, J = 6.0 Hz, 3H), 1.35 (t, J= 7.5 Hz, 3H), 0.71 - 0.96 (m, 4H) ppm.

[0156] Synthesis of compound 28-9a. Following the same procedure as that for the praparation of 1-16 described in Scheme 1 (W02012/058125) and replacing compound 1-14 with 28-8a, compound 28-9a was obtained as a white solid. LC-MS (ESI): m/z 551.2 [M+Hf ; Ή NMR (500

MHz, i^-DMSO): δ 8.50 (d, J= 4.5 Hz, IH), 7.92 (d, J= 9 Hz, 2H), 7.83 (s, IH), 7.56 (s, IH),

7.28 - 7.32 (m, 2H), 7.17 - 7.20 (m, 2H), 7.12 (d, J= 8.5 Hz, 2H), 5.06 (dd, J, = 12.5 Hz, J₂ =

6.5 Hz, IH), 3.67 (d, J = 15.5 Hz, IH), 3.56 (d, J= 14.5 Hz, IH), 3.31 (s, 3H), 2.84 (d, J= 4.5 Hz,

3H), 1.54 (d, J= 6 Hz, 3H), 0.70 - 0.93 (m, 4H) ppm. Compound 28-9a was separated into a pair of enantiomers: enantiomer 28-9a_A (t_¾ = 4.13 min) and enantiomer 28-9a_B (tR = 5.05 min) detected by UV absorption at 214 nm on a 4.6 mm x 250 mm x 5 μπι Regis ( ?^? Whelk-ol column (column temperature: 39.3 °C; eluent: MeOHAiquid CO2 = 50/50 (v/v); CO2 flow rate: 1.5 g/min and co-solvent flow rate: 1.5 g/min; front pressure: 218 bar and back pressure: 152 bar).

[0157] Synthesis of compound 28-9b. Following the same procedure as that for the praparation of compound 28-9a described in Scheme 28 and replacing compound 15-11 with 8-4, compound

28-9b was obtained as a white solid. LC-MS (ESI): m/z 459.1 [M + Hf; Ή NMR (500 MHz, t -

DMSO): δ 8.53 (m, IH), 7.97 (dd, J, = 5.5 Hz, J₂ = 8.7 Hz, 2H), 7.85 (s, IH), 7.58 (s, IH), 7.41 (t,

J = 8.5 Hz, 2H), 5.06 (q, J = 6.5 Hz, IH), 3.68 (d, J = 14.5 Hz, IH), 3.57 (<L J= 14.5 Hz, IH), 3.32 (s, 3H), 2.84 (d, J= 4.5 Hz, 3H), 1.54 (d, J= 6.5 Hz, 3H), 0.93 (m, 1H), 0.84 - 0.86 (m, 2H), 0.70 (m, 1H) ppm. Compound 28-9b was separated into a pair of enantiomers: enantiomer 28- 9b_A (t_R = 4.36 min) and enantiomer 28-9b_B (t_R = 6.09 min) detected by UV absorption at 214 nm on a 4.6 mm x 250 mm 5 μιη ChiralPak^® AD-H column (column temperature: 39.8 °C;

eluent: MeOH/liquid CO2 = 30/70 (v/v); CO₂ flow rate: 2.1 g min and co-solvent flow rate: 0.9 g min; back pressure: 150 bar).

[0158] Synthesis of compound 28-10a. To a solution of compound 28-7a (680 mg, 1.2 mmol) in THF (10 mL) was added BH3 THF (7.4 mL, 7.4 mmol) at 0°C. After stirring at rt for 3 hrs, the reaction mixture was added 3 N aq. NaOH (7 mL) at 0°C, followed by 30% aq. H2O2 (7 mL). The reaction mixture was stirred at rt overnight and the added iced water (30 mL). The mixture was extracted with EtOAc (25 mL x 2). The combined organic extracts were washed with water (20 mL x 2), dried over anhydrous Na₂SC>4, and concentrated. The residue was purified by silica gel column chromatography (DCM/Acetone = 50/1 (v/v)) to give compound 28-10a (560 mg, 80% yield) as a white solid. LC-MS (ESI): mlz 592.2 [M + Naf.

[0159] Synthesis of compound 28-10b. Following the same procedure as that for the praparation of compound 28-10a and replacing compound 28-7a with 28-7b, compound 28-10b was obtained as a white solid. LC-MS (ESI): mlz 500.1 [M + Naf.

[0160] Synthesis of compound 28-1 la. Following the same procedure as that for the praparation of compound 1-16 described in Scheme 1 and replacing compound 1-14 with 28-10a, compound 28-1 la was obtained as a white solid. LC-MS (ESI): mlz 555.2 [M + H ; H NMR (500 MHz, <?- DMSO): δ 8.42 - 8.50 (m, IH), 7.90 - 7.93 (m, 2H), 7.82 and 7.77 (s, s, 1H), 7.56 and 7.54 (s, s, 1H), 7.27 - 7.31 (m, 2H), 7.17 -7.19 (m, 2H), 7.1 1 (d, J= 8.5 Hz, 2H), 5.17 and 4.88 (m, m, IH), 4.78 (m, IH), 4.18 and 3.99 (m, m, IH), 3.93 (m, IH), 3.45 (m, IH), 3.47 (m, IH), 3.38 and 3.36 (s, s, 3H), 2.84 (<L J = 4.5 Hz, 3H), 2.83 (m, IH), 1.62 and 1.60 (d, d, J= 6.5 Hz, 3H) ppm.

[0161] Synthesis of compound 28-1 lb. Following the same procedure as that for the praparation of compound 28-1 la described in Scheme 28 and replacing compound 28-10a with 28-10b, compound 28-1 lb was obtained as a white solid. LC-MS (ESI): mlz 463.1 [M + H]⁺; ^lH NMR (500 MHz, i -DMSO): δ 8.52 (m, IH), 7.95 - 7.98 (m, 2H), 7.83 and 7.79 (s, s, IH), 7.58 and 7.57 (s, s, IH), 7.40 (t, J= 9.0 Hz, 2H), 4.88 (q, J = 6.5 Hz, IH), 4.78 (t, J= 5.5 Hz, IH), 4.19 (d,

S3 J= 15 Hz, 1H), 3.92 (m, 1H), 3.43 - 3.48 (m, 1H), 3.39 (s, 3H), 3.26 - 3.31 (m, 1H), 2.84 (<L J= 4.5 Hz, 3H), 2.83 (m, 1H), 1.62 and 1.60 (d, d, J= 6.0 Hz, 3H) ppm.

[0162] Synthesis of compound 28-12a. To a solution of compound 28-10a (200 mg, 0.35 mmol), DMAP (21 mg, 0.18 mmol) and Et₃N (0.15 mL, 1.1 mmol) in CH₂C1₂ (5 mL) was added TsCl ( 100 mg, 0.53 mmol) at 0 °C. After stirring at rt for 2 hrs, the reaction mixture was added ice water (10 mL) and DCM (25 mL). The organic layer was washed with saturated aq. NaHCOi (10 mL x 2), water (10 mL x 2) and brine ( 10 mL), dried over anhydrous NajSO-j, and concentrated. The residue was purified by silica gel column chromatography (PE EtOAc = 6/1 to 2/1 (v/v)) to give the tosylate as a white solid (230 mg, 91% yield). LC-MS (ESI): mlz 746.2 [M+Na] ⁺.

Subsequently, a mixture of the tosylate (140 mg, 0.19 mmol), MeSC^Na (59 mg, 0.58 mmol) and KI (964 mg, 0.581 mmol) in DMF (2 mL) was stirred at 120 °C for 2 hrs. The mixture was then poured into water (15 mL). The resulting precipitate was filtered and the white was washed with water (15 mL x 3) and dried in vacuo to give compound 28-12a (100 mg, 82% yield). LC-MS (ESI); mlz 654.1 [M + Naf.

[0163] Synthesis of compound 28-12b. Following the same procedure as that for the praparation of compound 28-12a described in Scheme 28 and replacing compound 28-10a with 28-10b, compound 28-12b was obtained as a white solid. LC-MS (ESI): mlz 562.1 [M + Hf.

[0164] Synthesis of compound 28-13a. Following the same procedure as that for the praparation of compound 1-16 described in Scheme 1 and replacing compound 1-14 with 28-12a, compound 28-13a was obtained as a white solid. LC-MS (ESI): mlz 617.1 [M + H]⁺; Ή NMR (500 MHz, CDCb): δ 7.94 (s, IH), 7.81 (dd, J, = 2.5 Ez, J₂ = 8.5 Hz, 2H), 7.61 (s, 1H), 7.05 - 7.13 (m, 6H), 5.82 (m, IH), 5.09 (q, J= 8.5 Hz, 1H), 4.59 (t, J= 1 1.5 Hz, 1H), 4.24 (d, J= 18.5 Hz, IH), 3.16 (s, 3H), 3.05 - 3.13 (m, 3H), 3.07 (s, 3H), 2.98 (d, J= 6.0 Hz, 3H), 1.78 (d, J= 8.5 Hz, 3H) ppm. Alternatively, compound 28-13a can be obtained using compound 28-1 la as the starting material as described in Scheme 28.

[0165] Synthesis of compound 28-13b. Following the same procedure as that for the praparation of compound 28-13a described in Scheme 28 and replacing compound 28-12a with 28-12b, compound 28-13b was obtained as a white solid. LC-MS (ESI): mlz 525.1 [M + Hf ; Ή NMR (500 MHz, tZ-DMSO): δ 8.52 (m, IH), 7.95 - 7.99 (m, 2H), 7.87 (s, IH), 7.61 (s, IH), 7.40 (t, J = 8.5 Hz, 2H), 4.98 (q, J = 6.0 Hz, 1 H), 4.39 (t, J = 9.0 Hz, IH), 4.20 (d, J= 14.0 Hz, 1H), 3.37 (s, 3H), 3.29 - 3.32 (m, 2H), 3.04 (s, 3H), 2.89 (m, 1H), 2.85 (d, J =4.5 Hz, 3H), 1.66 (d, J=

3H) ppm. Alternatively, compound 28-13b can be obtained using compound 28-1 lb as th

[0166] Step 1. Refer to Scheme 29. To a solution of compound 4-2 (9.0 g, 18.9 mmol) in DME (200 mL) and H₂0 (400 mL) were added ₂C0₃ (7.8 g, 56.6 mmol), Pd(dppf)Cl₂ (1.5 g, 1.9 mmol) and 4,4,5,5-tetramethyl-2-vinyl- 1 ,3,2-dioxaborolane (4.4 g, 28.3 mmol). After stirring at 60 °C for 2 hrs under an atmosphere of Ar, the reaction mixture was concentrated and the residue was partitioned between water (150 mL) and EtOAc (150 mL). The aqueous phase was extracted with EtOAc ( 100 mL x 3) and the combined organic extracts were washed with water ( 100 mL x 3) and brine (100 mL) and dried over anhydrous Na₂S0₄. The solvent was removed and the residue was purified by silica gel column chromatography (PE/EtOAc = 15/1 (vV)) to give compound 29-1 (5.0 g, 75% yield) as a yellow solid. LCMS (ESI): m/z 356.1 [M + H ,

[0167] Step 2. To a solution of compound 29-1 (1.2 g, 3.4 mmol) in THF (50 mL), EtOH (20 mL) and HOAc (40 mL) was slowly added Zn ( 1.3 g, 20.1 mmol) at 0 °C. After stirring at rt for 2 hrs, the reaction mixture was filtered and the filtrate was concentrated. The residue was partitioned between water (80 mL) and EtOAc (80 mL) and the organic layer was extracted with EtOAc (60 mL x 3). The organic extracts were combined and washed with water (80 mL x 2), sat. aq, NaHC0₃ (80 mL) and brine (80 mL) and dried over anhydrous Na₂S0₄. The solvent was concentrated and the residue was dried in vacuo to give crude compound 29-2 (1.0 g, 91% yield) as a yellow solid. LC-MS (ESI): m/z 326.1 [M + H]⁺. [0168] Step 3. To a solution of compound 29-2 (1.0 g, 3.1 mmol) in anhydrous pyridine (5 mL) was treated with DMAP (20 mg), followed by a solution ofMsCl (I. I g, 9.2 mmol) in DCM (3 mL) at 0 °C. After stirring at rt for 3 hrs, the reaction mixture was concentrated and the residue was partitioned between water (20 mL) and EtOAc (20 mL). The aqueous layer was extracted with DCM (30 mL x 3) and the combined organic extracts were washed with water (60 mL x 2) and brine (60 mL) and dried over anhydrous Na₂S0₄. The solvent was removed and the residue was dried in vacuo to give crude compound 29-3 (1.1 g, 88% yield) as a yellow solid. LC-MS (ESI): m/z 404.1 [M + Hf.

[0169] Step 4. To a solution of compound 29-3 (700 mg, 1.7 mmol) in DMF (30 mL) were added K2C(¼ (719 mg, 5.2 mmol) and I (144 mg, 0.87 mmol), followed by 2-bromobenzyl chloride (534 mg, 2.6 mmol). After stirring at 70 °C for 3 hrs, the reaction mixture was concentrated and the residue was partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (3 x 40 mL) and the combined organic extracts were washed with water (80 mL x 3) and brine (50 mL) and dried over anhydrous NaaSO-j. The solvent was removed and the residue was purified by silica gel column chromatography (Petroleum ether EtOAc = 15/1 (vV)) to give compound 29-4 (800 mg, 87% yield) as a yellow solid. LC-MS (ESI): m/z 574.0 [M + H]⁺.

[0170] Step 5. To a solution of compound 29-4 (770 mg, 1.34 mmol) in CH₃CN (25 ml) were added Et₃N (4.6 mL), and Pd(PPh₃)₄(l.55 g, 1.34 mmol). After stirring at 80 °C for several hours under an atmosphere of Ar, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (Petroleum ether/EtOAc = 10/1 (vV)) to give compound 29-5 (260 mg, 40% yield) as a yellow solid. LC-MS (ESI): m/z 492.1 [M + H]⁺.

[0171] Step 6. To a solution of compound 29-5 (150 mg, 0.31 mmol) in EtOH (30 mL) was added 5% Pd/C (w w, 200 mg). After stirring at 50 °C for several hours under an atmosphere of ¾, the reaction mixture was filtered through a pad of Celite^®545. The filtered cake was washed with EtOH (15 mL x 2). The filtrate was concentrated and the residue was dried in vacuo to give crude compound 29-6 (149 mg, 99% yield) as a yellow solid. LC-MS (ESI): m/z 494.1 [M + H]⁺.

[0172] Step 7. Following the same procedure as that for for the preparation of compound 1-16 described in Scheme 1 and replacing compound 1-14 with 29-6, compound 29-7 was obtained (130 mg, 90% yield) as a pale brown solid. LC-MS (ESI): m/z 479.1 [M + Hf; 'H NMR (500 MHz, CDC1₃): δ 7.85 - 7.88 (m, 2H), 7.78 (s, 1H), 7.71 (s, IH), 7.30 (d, 2H), 7.15 - 7.24 (m, 5H), 5.76 (ore, 2H), 5.12 (d, J= 16 Hz, 2H), 4.95 (d, J= 16 Hz, 5H), 4.57 - 4.62 (dd, J, = 15 Hz, J₂ = 7 Hz, 1H), 2.72 (d, J = 5 Hz, 3H), 2.73 (s, 3H), 1.80 (d, J = 8 Hz, 3H) ppm. Compound 29-7 was separated into a pair of enantiomers: enantiomer 29-7_A (t_R = 4.16 min) and enantiomer 29-7 B (t_R = 6.05 min) detected by LTV absorption at 214 nm on a 4.6 mm x 250 mm 5 μηι ChiralPak® OD-H column (column temperature: 40.4 °C; eluent: MeOH/liquid C0₂ = 30/70 (v/v); CO2 flow rate: 2.1 g/min and co-solvent flow rate: 0.9 g/min; front pressure: 205 bar and back pressure: 148 bar).

B R = F 30-2· R » F

b R - 4-F-PhO- 30-2b R« 4-F-PhO-

(0173] Chiral separation of compound 8-5. Compound 8-5 (3.8 g) was separated into a pair of enantiomers: (Λ)-8-5 (t_R = 2.61 min, 1.6 g, 84% yield) and (S)-8-5 (t_R = 3.14 min, 1.6 g, 84% yield) detected by UV absorption at 214 nm on a 4.6 mm x 250 mm x 5 μπι ChiralPak® AD-H column (column temperature: 40.2 °C; eluent: MeOH (0.1% DEA)/liquid C0₂ = 30/70 (v/v); C0₂ flow rate: 2.1 g/min and co-solvent flow rate: 0.9 g/min; front pressure: 206 bar and back pressure: 149 bar).

[0174] Chiral separation of compound 15-12. Using the same prep-chiral HPLC condition as that used for separating compound 8-5, Compound 15-12 (5.6 g) was separated into a pair of enantiomers: (fl)-15-12 (t_R = 5.71 min, 1.1 g, 39% yield) and (S)- 15-12 (t_R = 6.58 min, 1.0 g, 36% yield).

[0175] Synthesis of compound 30-1 a. To a solution of the enantiomer came out first from the chiral separation of compound 8-5 (t_R = 2.61 min) (30 mg, 0.07 mmol) and (Λ)-ΜαΝΡ (18.4 mg, 0.08 ramol) in CH₂Cl₂ (2 mL) was added DCC (72.1 mg, 0.35 mmol), followed by DMAP (17.1 mg, 0.14 mmol). After stirring at rt for 20 hrs, the reaction mixture was concentrated and the residue was diluted with EtOAc (45 mL). The solution was washed with water (20 mL) and brine (20 mL), dried with anhydrous Na₂S0 , and concentrated. The residue was purified by prep- HPLC to give compound 30-la (15 mg) as a white powder. LC-MS: (ESI) miz 656.2 [M + Naf; Ή NMR (500 MHz, CDC1₃): 6 8.1 1 - 8.13 (m, 2H), 7.74 - 7.77 (m, 2H), 7.60 (<L J = 7.0 Hz, 2H). 7.47 (t, J= 8.0 Hz, 1H), 7.45 (s, 1H), 7.22 (t, J= 9.0 Hz, 2H ), 7.08 (s, 1H), 7.00 (t, J = 7.0 Hz, 1H), 6.76 (t, J= 8.0 Hz, 1H), 6.07 (q, J= 7.0 Hz, 1H), 4.23 - 4.36 (m, 2H), 3.05 (s, 3H), 2.98 (s,

= 7.0 Hz, 3H), 1.27 (t, J = 7.0 Hz, 3H) ppm.

[0176] Synthesis of compound 30-2a. Following the same procedure as that used for preparing compound 30-la and replacing (Λ)-ΜαΝΡ with (S)-MaNP, compound 30-2a was obtained. LC- MS: (ESI) mlz 656.2 [M + Naf;Ή NMR (500 MHz, CDC1₃): δ 8.06 - 8.09 (m, 2H), 7.95 (d, J= 8.5 Hz, lH), 7.87 (s, 1H), 7.82 (d, J= 8.0 Hz, 1H), 7.78 (d, J= 8.0 Hz, 1H), 7.73 (s, IH), 7.67 (s, 1H), 7.64 (d, J = 7.0 Hz, 1H), 7.47 (t, J= 8.0 Hz, 1H), 7.28 (t, J= 7.5 Hz, 1H), 7.20 (t, J = 7.5 Hz, 2H), 7.06 (t, J = 7.5 Hz, IH), 6.12 (q, J= 6.5 Hz, 1H), 4.35 - 4.41 (m, 2H), 3.12 (s, 3H), 3.00 (s,

= 6.5 Hz, 3H), 1.27 (t, J = 7.0 Hz, 3H) ppm.

[0177J Synthesis of compound 30-lb. Following the same procedure as that used for preparing compound 30-la and using the enantiomer came out first from the chiral separation of compound 15-12 (t_R = 5.71 min), compound 30-lb was obtained. LC-MS: (ESI) miz 748.2 [M + Naf; Ή NMR (500 MHz, CD₃C1): δ 8.08 - 8.10 (m, 2H), 7.06 - 7.1 1 (m, 7H), 6.99 (t, 7= 7.0 Hz, 1H), 6.75 (dt, J, = 1.0 Hz, J₂ = 8.0 Hz, 1H), 6.06 (q, J= 7.0 Hz, 1H), 4.24 -4.35 (m, 2H), 3.05 (s, 3H),

J= 7.0 Hz, 3H), 1.27 (t, J= 7.0 Hz, 3H) ppm.

10178) Synthesis of compound 30-2b. Following the same procedure as that used for preparing compound 30-lb and replacing (Λ)-ΜαΝΡ with (5)-ΜαΝΡ, compound 30-2b was obtained. LC- MS: (ESI) miz 748.2 [M + Naf; Ή NMR (500 MHz, CD₃C1): 5 8.06 (d, J= 7.0 Hz, 2H), 7.93 (d, J= 8.5 Hz, 1H), 7.85 (s, 1H , 7.83 (d, J= 8.0 Hz, 1H), 7.78 (d, J= 8.0 Hz, 1H), 7.69 (s, 1H), 7.63 - 7.66 (m, 2H), 7.46 (t, J= 8.0 Hz, 1H), 7.29 (t, J= 8.0 Hz, 1H), 7.04 - 7.10 (m, 7H), 6.10 (q, J= 7.0 Hz, 1H), 4.36 - 4.39 (m, 2H), 3.13 (s, 3H), 2.99 (s, 3H), 1.91 (s, 3H), 1.48 (d, J= 7.0 Hz, 3H),

= 7.0 Hz, 3H) ppm.

101791 Determination of chiraliry. Refer to Scheme 31. Based on the general rule of chemical shfits of a pair of diastereomeric esters derived from an alcohol with (Λ)-ΜαΝΡ and (5)-MaNP, the chiraliry of the benzylic carbon in the enantiomer came out first (t_¾ = 2.61 min) from the chiral separation of compound 8-5 was determined as R. Accordingly, the chirality of the benzylic carbon in the enantiomer came out first (t_R = 5.71 min) from the chiral separation of compound 15-12 was determined as R.

{01801 Synthesis of compound (J?)-8-5. Refer to scheme 32. A 25 mL flask was charged with triethylamine (76 mg, 0.75 mmol, 7 eq.) in an ice bath, followed by adding formic acid (35 mg, 0.75 mmol, 7 eq.) dropwise. After stirring at rt for 20 min, a solution of compound 8-4 (45 mg, 0.107 mmol, 1 equiv.) in DMF (6 mL) and RuCl[(R,i.)-Tsdpen](p-cymene) (1.6 mg, 0.0029 mmol 0.024 equiv.) were added. The resulting dark red reaction mixture was stirred at 40 °C overnight and then concentrated. The residue was purified by silica column chromatography (EtOAc/PE = 1 :1 (v/v)) to give compound (Jf)-8-5 (30 mg, 66% yield, 95.5%?<?) as a white solid. The absolute configuration of the sample (tR = 2.59 min) was determined as R by taking chiral HPLC along with compound 8-5 following chiral HPLC the condition in Scheme 30.

101811 Synthesis of compound (S)-8-5. Following the same procedure as described for the preparation of compound (Jf)-8-5 and replacing RuCl[(i?^?)-Tsdpen](p-cymene) with RuCl[(S,S)- Tsdpen](p-cymene), compound (S)-8-5 (28 mg, 66% yield, 94.0%ee, t_R = 3,12 min, S

configuration) was obtained from compound 8-4 (42 mg, 0.1 mmol).

]0182| Synthesis of compound (Jf)-15-12. Following the same procedure as described for the preparation of compound (R)S-5 and replacing compound 8-4 with compound 15-11 (50 mg, 0.1 mmol), compound (S)-8-12 (38 mg, 75% yield, 95.9%ee, t_R = 5.76 min, R configuration).

101831 Synthesis of compound (S)-15-12. Following the same procedure as described for the preparation of compound ( ?)-15-12 and replacing RuCl[(i?,/?)-Tsdpen](p-cymene) with

RuCl[(.?^S)-Tsdpen](p-cymene), compound (5)-15-12 (70 mg, 70% yield, 96.6% ee, t_R = 6.70 min, S configuration) was obtained from compound 15-11 (100 mg, 0.2 mmol). 10184] Synthesis of compound (Λ)-8-9. Using compound (J?)-8-5 as the starting material and following the same procedure for the preparation of compound 8-9 described in Scheme 8, compound (J?)-8-9 was obtained. Chiral HPLC analysis determined that compound (Ji)-8-9 and enantiomer 8-9_A obtained from chiral separation of compound 8-9 are identical.

{01851 Synthesis of compound (J?)- 15- 15. Using compound (Λ)-15-12 as the starting material and following the same procedure for the preparation of compound 15-15 described in Scheme 15, compound (Λ)-15-15 was obtained. Chiral HPLC analysis determined that compound (Λ)-15-15 and enantiomer 15~15_A obtained from chiral separation of compound 15-15 are identical.

10186) Syntheses of diastereomers of compounds 28-1 la and -13a. Using either compounds (Jf)-15-12 or 0-0-15-12 as the starting material and following the procedure for the preparation of compounds 28-1 la and -13a described in Scheme 28, those diastereomers of compounds 28-1 la and -13a were obtained, respectively. The absolute configurations of those diastereomers were determined by 2D-COSY and NOESY spectra.

]0187I Syntheses of diastereomers of compounds 28-1 lb and -13b. Using either compounds (Λ)-8-5 or (-5)-8-5 as the starting material and following the procedure for the preparation of compounds 28-llb and -13b described in Scheme 28, those diastereomers of compounds 28-1 lb and -13b were obtained, respectively. The absolute configurations of those diastereomers were determined by 2D-COSY and NOESY spectra.

Scheme 34

<5S,7S)-3 -2a R - F (SS.7R> 4-2a R = F

(5S.7S)-3 -2b R - 4-F-PhO- (SS m-3**b R - 4JF-PHQ-

|0188| Step 1. Refer to Scheme 34. To a solution of compound (5)-15-12 (5.13 g, lO mmol) in

DMF (40 mL) was added K₂C0₃ (2.07 g, 15 mmol), the resulting mixture was stirred at rt for 30 min. Subsequently, a solution of racemic 2-(bromomethyl)oxirane (1.23 mL, 15 mmol) in DMF

(10 mL) was dropwise added to the mixture. After stirring at 60 °C overnight, the reaction mixture was concentrated. The residue was diluted with H₂0 (100 mL) and EtOAc (150 mL). The aqueous layer was extracted with EtOAc (150 mL x 2). The combined organic extracts were washed with H2O (100 mL x 2) and brine (100 mL), dried over anhydrous a2S >4, filtrated and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether/EtOAc = 1/1 (vV)) to give compound 3 -lb (4.8 g, 84% yield) as a white solid. LC-MS

101891 Step 2. To a solution ofTsOH (91 mg, 0.53 mmol) in DCM (10 mL) at rt was added compound 34-lb (150 mg, 0.26 mmol). After stirring at rt overnight, the reaction mixture was concentrated and the residue was dissolved in DCM (50 mL). The mixture was washed with sat. aq. NaHCC>3 (25 mL x 2) and brine (25 mL), dried over anhydrous Na₂S0₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether/EtOAc = 1/1 (v v)) to give a mixture of compounds (55,75>34-2b and (55,7 ?)-34-2b (120 mg, 81% yield) as white solid in a ratio of 1/1 as determined by comparing the integrations of the benzylic carbons at 5.08 ppm for compound (5S,7S)-34-2b and 5.20 ppm for compound (5S,7R)- 34-2b, respectively. LC-MS (ESI): mlz 570.1 [M + H]⁺. Compound (5S,7S)-34-2b: Ή NMR (500 MHz, CDCI3): 5 8.14 (s, 1H), 8.04 (m, 2H), 7.58 (s, 1H), 7.03 - 7.1 1 (m, 6H), 5.08 (q, J= 6.5 Hz, 1H), 4.42 (q, J= 7.0 Hz, 2H), 4.13 - 4.19 (m, 2H), 3.73 (dd, J, = 3.5 Hz, J₂ = 11.5 Hz, 1H), 3.53 (dd, Jj = 6.0 Hz, J. = 11.8 Hz, 1H), 3.18 (s, 1H), 3.12 (m, 1H), 1.92 (bs, 1H), 1.77 (d, J= 7.0 Hz, 3H), 1.44 (t, J= 6.5 Hz, 3H) ppm. Compound (5S,7/?)-34-2b: Ή NMR (500 MHz, CDC1₃): δ 7.94 - 7.97 (m, 3H), 7.52 (s, 1H), 6.96 - 7.03 (m, 6H), 5.20 (q, J= 6.5 Hz, 1H), 4.35 (q, J= 7.0 Hz, 2H), 3.94 (brm, 1H), 3.71 (dd, J, =4.5 Hz, J₂ = 1 1.8 Hz, 1H), 3.58 - 3.66 (m, 4H), 3.08 (s, 3H), 1.92 (bs, 1H), 1.67 (d, J= 7.0 Hz, 3H), 1.36 (t, J= 7.0 Hz, 3H) ppm. Further chiral HPLC analyses showed that although better ratios were achieved when performing the cyclization at elevated temperatures, racemization of the chirality at the benzylic carbon was observed and a racemic synlanti mixture of the cyclized products was obtained.

|0190| Comparison of the stereoselectivity of the acid catalyzed epoxide-opening-ring-formation step

Temperature

Starting

Acid Solvent and reaction ratio of compound 34-2 material

time

34-la TsOH (0.3 eq.) DCM 0 °C, 1.0/3.0 ((5S,75)-34-2a (55,7/?)-34-2a)

overnight 34-la TsOH (2.0 eq.) DCM rt, overnight 1.0/11.0 ((55,75)-■34-2a (55,7*)-34-2a)

34-la TsOH (2.0 eq.) DCE 60 °C, 4 hr 4.0/11.0 ((±)-syn- 34-2a/(±)-a/ift-34-2a)

34-lb TsOH (0.3 eq.) DCM 0 °C, 1.0/3 Ϊ.0 ((55,75)· ■34-2b/(55,7i?)-34-2b) overnight

34-lb TsOH (2.0 eq.) DCM rt, overnight 1.0/1 1.0 ((55,75)· ■34-2b/(55,7i¾)-34-2b)

34-lb TsOH (2.0 eq.) DCE 60 °C, 4 hr 6.5/1 1.0 i(± -syn-■34-2b/(±)- n/ -34-2b)

34-lb TsOH (2.0 eq.) Toluene 100 °C, 4 hr 7.5/11.0 {(±)sytt- 34-2b/(±)-an/i-34-2b)

34-lb TsOH (2.0 eq.) DMF 150 °C, 2 for 3.0/210 ((±)-syn- 34-2b/(±)-an/ -34-2b)

(5S,7S)-3 -3a

|0191J Step 1. Refer to Scheme 34a. To a stirred solution of compound 8-5 (15.0 g, 35.6 mmol) in toluene (250 mL) at 70 °C was added PPTs (3.56 g, 14.2 mol). After refluxing overnight, the reaction mixture was concentrated and the residue was dissolved in DCM (200 mL). The resulting mixture was washed with sat, aq. NaHC0₃ (300 mL) and brine (200 mL), and dried over anhydrous Na2SC> . The solvent was removed and the residue was purified by silica gel column chromatography (Petroleum ether/Acetone = 10/1 (vV)) to give compound 29-3 (10.0 g, 70% yield) as a pale yellow solid. LC-MS (ESI): mlz 404.1 [M + Hf; Ή NMR (500 MHz, CDC1₃): δ 8.14 (s, 1H), 8.07 - 8.04 (m, 2H), 7.72 (s, 1H), 7.18 ( = 8.5 Hz, 2H), 6.97 (dd, J_t = 11 Hz, J₂ = 17 Ηζ,ΙΗ), 6.60 (s, 1H), 5.78 (d, J = 17 Hz, 1H), 5.53 (d, J= 11 Hz, 1H), 4.42 (q, J= 7.0 Hz, 2H), 3.02 (s, 3H), 1.42 (t, J= 7.0 Hz, 3H) ppm.

101921 Step 2. To a solution of compound 29-3 (100 mg, 0.25 mmol) in DMF (2 mL) were added K2CO3 (103 mg, 0.75 mmol) and (J?)-3-chloropropane-l,2-diol (82 mg, 0.744 mmol). After stirring at 110°C overnight, the reaction mixture was cooled to rt and poured into water (50 mL). The suspension was filtered; the solid was washed with water (20 mL), dried, and purified by silica gel column chromatography (DCM / MeOH = 100/1 (v V)) to give compound 34a-l (100 mg, 84% yield) as a white solid. LC-MS (ESI): mlz 500.1 [M + Na]⁺.

10193] Step 3. To a stirred solution of compound 34a-l (94.0 mg, 0.20 mmol) in DCE (20 mL) at 85°C was added TsOH (94 mg, 0.49 mmol). After refluxing overnight, the reaction mixture was concentrated. The residue was diluted with DCM (50 mL) and the resulting mixture was washed with sat. aq. NaHCCb (50 mL) and brine (50 mL), and dried over anhydrous Na2S(> . The solvent was removed and the residue was purified by silica gel column chromatography (Petroleum ether/EtOAc = 2/1 (v V)) to give a mixture of compounds (55,75 34-2a and (5/?,7S)-34-2a with a ratio of 7.8/1 (75 mg, 80% yield) as a white solid. LC-MS (ESI): mlz 500.1 [M + Naf.

10194] Synthesis of compound 34a-2. Method A. To a solution of compound 29-3 (1.0 g, 2.5 mmol) in DMF (25 mL) were added K₂C0₃ (1.04 g, 7.5 mmol) and ( ?)-(2,2-dimethyl-l,3- dioxolan-4-yl)methyl 4-methylbenzenesulfonate (1.42 g, 5.0 mmol). After stirring at 90°C for 48 hr, the reaction mixture was cooled, diluted with EtOAc (100 mL), and filtered through

Celite^®545. The filtered cake was washed with EtOAc (100 mL). The filtrate was concentrated and the residue was diluted with EtOAc (100 mL). The mixture was washed with water (50 mL x 2) and brine (50 mL), and dried with anhydrous Na2SC>4. The solvent was removed and the residue was purified by silica gel column chromatography (Petroleum ether/EtOAc = 5/1 (v/V)) to give compound 34a-2 (0.95 g, 74% yield) as a yellow solid. LC-MS (ESI): m/∑ 540.2 [M + Naf. |0195| Synthesis of compound 34a-2. Method B. To a solution of compound 29-3 (1.2 g, 3.0 mmol) in dry toluene (20 mL) were added n-BujP (1.4 mL, 6 mmol) and DIAD (1.2 mL, 6 mmol) under an atmosphere of N₂. After stirring at 0 °C for 30 min, the reaction mixture was added a solution of (5)-(2,2-dimethyl-l,3-dioxolan-4-yl)methanol (0.56 mL, 4.5 mmol) in toluene (5 mL). The resulting reaction mixture was stirred at 90 °C overnight and then concentrated. The residue was diluted with DCM (200 mL), washed with water (50 mL x 2) and brine (50 mL), and dried over anhydrous Na₂SC>4. The solvent was removed and the residue was purified by silica gel column chromatography (Petroleum ether/EtOAc = 4/1 (v/v)) to give compound 34a-2 (1.3 g, 83% yield) as a yellow solid. LC-MS (ESI): m/z 540.2 [M + Naf.

10196] Synthesis of compound (5S,75)-34-2a from compound 34a-2. To a stirred solution of compound 34a-2 (0.95 g, 1.8 mmol) in DCE (40 mL) at 85°C was added TsOH (0.86 g, 4.5 mmol). After reflux ing overnight, the reaction mixture was concentrated. The residue was diluted with DCM (200 mL) and the resulting mixture was washed with sat. aq. NaHC0₃ (50 mL x 2) and brine (50 mL), and dried over anhydrous Na₂SC>4. The solvent was removed and the residue was purified by silica gel column chromatography (Petroleum ether/EtOAc = 2/1 (v/v)) to give a mixture of compounds (5S,7S)-34-2a and (5«,7S)-34-2a with a ratio of 7.8/1 (0.64 g, 74% yield) as a white solid. LC-MS (ESI): m/z 500.1 [M + Naf. The mixture was dissolved in DCE at reflux and slowly cooled to rt. The resulting suspension was filtered. The solid was washed with cold DCE and dried in vacuo to give compound (55,75)-34-2a with a diastereomeric purity of > 99% in 75% yield.

101971 Step 1. Refer to Scheme 34b. To a stirred solution of compound 34b-l (3.0 g, 17.2 mmol) in dry THF (20 mL) was added L1AIH₄ (1.3 g, 34.4mmol) in portions at 0 °C. After stirring at rt overnight, the reaction was quenched by slowly adding isopropanol (10 mL) at 0 °C. The suspension was filtered through Celite^®545 and the filtrate was concentrated. The residue was dried in vacuo to give crude compound 34b-2 (2.0 g) as a white solid, which was used directly for the next step without further purification. LC-MS (ESI): miz 147.1 [M + H]⁺, ^]H NMR (500 MHz, CDClj): 54.04 - 4.01 (m, 1H), 3.82 (dd, J_/ = 4.5 Hz, J₂= 14.0 Hz, 1H), 3.67 - 3.64 (m, 1H), 3.61 (dd, J_/ = 4.5 Hz, J ₂= 14.0 Hz, 1H), 2.17 (br, 1H), 1.43 (s,3H), 1.41 (s, 3H), 1.30 (d, J= 6.0 Hz, 3H) ppm.

|0198| Step 2. To a stirred solution of compound 34b-2 (2.0 g, 13.6 mmol) in dry DCM (20 mL) and pyridine (5 mL) was added TsCl (3.8 g, 20.5mmol) in portions at 0 °C. After stirring at rt overnight, the reaction mixture was added water (20 mL). The mixture was extracted with DCM (50 mL x 3) and the combined organic extracts were washed with saturated aq. NH₄CI and brine, and dried over anhydrous Na₂SC>4. The solvent was removed and the residue was purified by silica gel column chromatography (Petroleum ether/EtOAc = 10/1 (v/v)) to give compound 34b-3 (3.4 g, 85% yield) as a white solid. LC-MS (ESI): miz 323.1 [M + Naf; Ή NMR (500 MHz, CDCI3): δ 7.80 (d, J = 8.0Hz, 2H), 7.35 (d, J= 8.5Hz, 2H), 4.10 -4.08 (m, 2H), 3.93 - 3.92 (m, 1H), 3.71 - 3.69 (m, 1H), 2.46 (s, 3H), 1.38 (s, 3H), 1.31 (s, 3H), 1.28 (d, J= 6.0 Hz, 3H) ppm. (0199| Step 3. To a stirred solution of compound 34b-3 (600 mg, 2.0 mmol) and 29-3 (1.0 g, 2.5 mmol) in dry DMF (4 mL) was added K₂C0₃ (0.7 g, 5 mmol) at rt. After stirring at 100 °C under an atmosphere of Ar for 18 hr, the reaction mixture was cooled to rt and added water (40 mL). The suspension was filtered and the solid was washed with water and further purified by silica gel column chromatography (Petroleum ether/EtOAc = 10/1 (v/v)) to give compound 34b-4 (350 mg, 32% yield) as a white solid. LC-MS (ESI): miz 554.2 [M + Na] ⁺.

10200} Step 4. To a refluxed solution of compound 34Ϊ (350 mg, 0.66 mmol) in dry DCE (4 mL) was slowly added /?-TsOH (113 mg, 0.66 mmol). After stirring was stirred at reflux for another 30 min, the reaction mixture was concentrated. The residue was added water (25 mL) and the suspension was filtered. The solid was washed with water and dried in vacuo to give a mixture (270 mg, 83% yield) of two diastereomers with a ratio of 3.5/1 (the desired diastereomer as a major product) based on chiral HPLC analysis. This mixture was separated by chiral HPLC to give compound 34b-5 (70 mg, 26% yield) as a white solid. LC-MS (ESI): miz 514.1 [M + Naf; Ή NMR (500 MHz, CDCI3): S 8.14 (s, 1H), 8.07 (dd, J/ = 6.5 Hz, J 2= 1 1.5 Hz, 2H), 7.19 (t, J=10.5 Hz, IH), 5.06 (q, J= 6.0 Hz, IH), 4.42 (q, J= 9.0 Hz, 2H), 4.19 (d, J= 17.0 Hz, 1H), 3.82 - 3.80 (m, IH), 3.65 - 3.59 (m, IH), 3.18 (s, 3H), 3.15 - 3.10 (m, IH), 2.30 (br, IH), 1.78 (d, J = 8.0 Hz, 3H), 1.43 (t, J= 9.5 Hz, 3H), 1.28 (d, J= 8.0 Hz, 3H) ppm.

[02011 Step 5. Following the same procedure used for preparing compound 4-9 shown in Scheme 4 and replacing compound 4-7 with 34b-5, compound 34b-7 was obtained as a white solid. LC- MS (ESI): mlz 499.1 [M + Na]⁺; 'H NMR (500 MHz, i/-DMSO): δ 8.54 (q, J= 4.5 Hz, IH), 7.97 (dd, J, = 9.0 Hz, J₂= 5.5 Hz, 2H), 7.83 (s, IH), 7.58 (s, IH), 7.40 (t, J = 9.0 Hz, 2H), 4.86 (q, J= 7.0 Hz, IH), 4.62 (d, J= 5.0 Hz, IH), 4.22 (d, J = 10.0 Hz, IH), 3.80- 3.75 (m, IH), 3.68 - 3.65 (m, lH), 3.36 (s, 3H), 2.88 - 2,84 (m, IH), 2.84 (d, 7= 5.0 Hz, 3H), 1.63 (d, J= 6.0 Hz, 3H), 1.04 (d, J= 6.0 Hz, 3H) ppm.

Scheme 3S

10202] Synthesis of compound (55,75)-35-lb. Refer to Scheme 35. To a solution of compound (55,75)-34-3b (120 mg, 0.22 mmol) and DMAP (159 mg, 1.3 mmol) in DCM (2 mL) was added diphenyl phosphorochloridate (291 mg, 1.08 mmol) at 0 °C under an atmosphere of Ar. After stirring rt overnight, the reaction mixture was added ice water (10 mL) and DCM (10 mL). The organic layer was washed with saturated aq. NaHCQj (10 mL x 3) and water (10 mL x 3), dried over anhydrous Na₂SC>4, filtered and concentrated. The residue was dried in vacuo to give crude compound (5S,7S)-35-lb (120 mg, 71% yield) as a white solid. LC-MS (ESI): miz 787.2 [M + H]⁺.

102031 Synthesis of compound (5S,7S)-35-2b. To a solution of compound (5S,7S)-35-lb (120 mg, 0.15 mmol) in THF (5 mL) was added PtC (50 mg). The resulting mixture was flushed with ¾ and stirred at rt overnight. Subsequently, the mixture was diluted with THF (25 mL) and filtered through Celite®545. The filtrate was concentrated and the residue was diluted with water (25 mL). The suspension was filtered; the solid was washed with water (10 mL) and C¾CN (10 mL) and dried in vacuo to give compound (55,75)-35-2b (50 mg, 52% yield) as a white solid. LC-MS (ESI): miz 635.2 [M + Hf; ^lU NMR (500 MHz, ^-DMSO): S 8.50 (d, J= 4.5 Hz, 1 H), 7.91 (d, J= 8.5 Hz, 2H),7.81 (s, 1H), 7.56 (s, 1H), 7.29 (d, J = 8.5 Hz, 2H), 7.15 - 7.18 (m, 2H), 7.10 (d, J= 8.5 Hz, 2H), 4.89 (d, J- 5.5 Hz, 1H), 4.10- 4.16 (m, 1H), 4.03 (br, lH), 3.77 (br, 1H), 3.58 - 3.60 (m, 1 H), 3.47 (br, 2H), 3.36 (s, 3H), 2.89 (br, 1H), 2.83 (d, J= 4.5 Hz, 3H), 1.60 (d, J= 5.5 Hz, 3H) ppm.

] 02041 Synthesis of compound (55,75 35-3b. To a solution of N, N-dimethylglycine (45 mg, 0.43 mmol), DCC ( 149 mg, 0.72 mmol) and compound (55,75)-34-3b (80 mg, 0.14 mmol) in CH₂C1₂ (2 mL) was added DMAP (89 mg, 0.72 mmol) at rt. After stirring at rt overnight, the reaction mixture was filtered and the filtrated was concentrated. The residue was purified by preparative HPLC and product was converted to its HCl salt to give compound (5S,7S)-35-3b (50 mg, 54% yield) as a white solid. LC-MS (ESI): miz 640.2 [M + Hf; ^!H NMR (500 MHz, a⁶- DMSO): δ 10.32 (br, 1H), 8.51 (d, J= 5.0 Hz, 1H), 7.91 (d, J= 9.0 Hz, 2H),7.86 (s, 1H), 7.57 (s, 1H), 7.30 (t, J= 8.5 Hz, 2H), 7.17 - 7.20 (m, 2H), 7.12 (d, J= 9.0 Hz, 2H), 4.92 (q, J= 6.5 Hz, 1H), 4.19 -4.26 (m, 6H), 3.04 (s, 1H), 3.00 (br, 1 H), 2.83 (s, 9H), 1.64 (d, J= 6.0 Hz, 3H) ppm. J0205I Synthesis of compound (5S,7S)-35-4c. To a solution of /V-Boc-L- Alanine (68 mg, 0.36 mmol), DCC (149 mg, 0.72 mmol) and compound (55,75 -34-3b (100 mg, 0.18 mmol) in CH₂C1₂ (2 mL) was added DMAP (89 mg, 0.72 mmol) at rt. After stirring at rt overnight, the reaction mixture was filtered; the filtrate was concentrated and the residue was dried in vacuo to give crude compound (5S,7S)-35-4c (105 mg, 80% yield) as a white solid. LC-MS (ESI): miz 626.1 [M - Boc + 2H .

102061 Synthesis of compound (5S,7S)-35-5c. A mixture of compound (5S,7S)-35-4c (100 mg, 0.14 mmol) in 4.0 N HCl in 1 ,4-dioxane (3 mL) was stirred at rt for 2 hr. The solvent was removed and the residue was purified by prep-HPLC to give compound (55,75)-35-5c (50 mg, 58% yield) as a white solid. LC-MS (ESI): m/z 626.1 [M + H] ⁺; Ή NMR (500 MHz, t -DMSO): δ 8.48 - 8.51 (m, 1H), 8.40 (s, 2H), 7.90 (d, J = 8.5 Hz, 2H), 7.81 (s, 1H), 7.56 (s, 1H), 7.31 (t, J = 8.5 Hz, 2H), 7.16 - 7.20 (m, 2H), 7.12 (d, 7= 9.0 Hz, 2H), 4.91 (q, 7= 6.5 Hz, 1H), 4.09 - 4.26 (m, 5H), 4.00 (s, 3H), 2.95 (br, 1H), 2.83 (d, 7 = 6.5 Hz, 1H), 1.61 (d, 7 = 4.5 Hz, 3H), 1.40 (d, 7 = 7.0 Hz, 3H) ppm.

[0207] Synthesis of compound (5S,7S)-35-5d. Following the same procedure as that used for preparing compound (55,75)-35-5c and replacing N-Boc-L-Alanine with N-Boc-L-Valine, compound (5S,75)-35-5d was obtained as a white solid in 69% yield. LC-MS (ESI): m/z 654.2 [M + Hf; Ή NMR (500 MHz,

δ 8.49 - 8.5 l(m, 1H), 8.08 (br, 2H), 7.91 (cL 7 = 9.0 Hz, 2H), 7.86 (s, 1H), 7.57 (s, 1H), 7.30 (t, 7= 9.0 Hz, 2H), 7.17 - 7.20 (m, 2H), 7.12 (d, 7 = 9.0 Hz, 2H), 4.93 (d, 7= 6.5 Hz, 1H), 4.15 - 4.20 (m, 4H), 3.87 (s, 1 H), 3.36 (s, 3H), 2.95 (br, 1H), 2.84 (d, 7 = 4.0 Hz, 3H), 2.13 - 2.16 (m, 1H), 2.16 (d, 7= 6.5 Hz, 3H), 1.00 (d, 7= 6.5 Hz, 3H), 0.95 (d, 7= 6.5 Hz, 3H) ppm.

[0208] Synthesis of analogs of compound (55,7£)-35-2, -3, and -5. Following the same synthetic strategy described in Scheme 35, the following analogs were readily obtained.

3H), 1.41 (d,J=7Hz,3H)

10.43 (br, IH), 8.53 (q,J=4.5 Hz, IH), 7.96 (t, J = 4.5 Hz, 2H), 7.87 (s, IH), 7.60 (s, IH), 7.41 (t,J=9.0 Hz, 2H), 4.93 (q,J = r 548.2

6.5 Hz, IH), 4.18-4.26 (m, 6H), 3.41 (s, 3H), 2.97 (t,J= 9.0 Hz, IH), 2.80-2.85 (m , 9H), 2.54 (s, IH), 1.64 (d,J=6.5Hz,3H)

8.54 (q, J = 4.0 Hz, IH), 8.38 (br, 3H), 7.95 (q,J=5.5 Hz, 2H), 7.87 (s, IH), 7.60 (s, IH), 7.41 (t, J =8.5 Hz, 2H), 4.92 (q,

0.

520.1 J- 6.0 Hz, IH), 4.17-4.24 (m,

BocHN—'

4H),3.82 (d,J=5.5 Hz, 2H), 3.41 (s, 3H), 2.98 (t,J= 12.5 Hz, IH), 2.84 (d, J =4.5 Hz, 3H), 1.65 (d, J =6.5 Hz, 3H)

8.54 (q, J =3.5 Hz, IH), 7.88 (d, J=8.5Hz,2H), 7.80 (s, IH), 7.61 (s, IH), 7.30 (t,J=9.0 Hz, 2H), 7.17- 7.19 (m, 2H), 7.13

VOH 612.2 (d, J= 9.0 Hz, 2H), 4.93 (q, J = BocHN-'

o P 6.5 Hz, IH), 4.24-4.30 (m, 2H),

3.76 (s, 2H), 3.36 (s, 3H), 3.00- 3.03 (m, 1H),2.86 (d,J=4.0 Hz, 3H), 1.65 (d,J = 6.5 Hz, 3H)

J= 6.5 Hz, 3H)

8.62 (bra, 3H), 8.55 (q, J =4.5 Hz, IH), 7.97 (dd, J = 9.0 Hz, J₂ = 5.0 Hz, 2H), 7.89 (s, IH), 7.59 (s, lH),7.42(t,J=9.0 Hz, 2H), 7.25 - 7.31 (m, 5H), 4.89 (q,J= 6.0 Hz, IH), 4.28 (t,J = 6.5 Hz, lH),4.16(d,J = 10.0 Hz, 2H),

610.2 4.08 (dd,J; = 12.0 Hz, J₂= 6.5

Hz, 2H),3.92(d,J = 15.0 Hz, 1H),3.41 (s, 3H),3.19(dd,J,= 14.0 Hz, J₂ = 5.5 Hz, 1H),3.50 (dd, J/ = 14.0 Hz, J; = 7.5 Hz, IH), 2.85 (d,J=5.0 Hz, 3H), 2.85 (m,lH), 1.63 (d,J=6.5 Hz,3H)

8.53 (q,J = 4.5 Hz, IH), 8.27 (brs, 2H), 7.95 (dd, J, = 8.8 Hz, J₂ = 5.0Hz,2H), 7.88 (s, IH), 7.59 (s, 1H),7.41 (t,J = 9.0 Hz, 2H), 6.61 (d,J=4.5 Hz, IH), „NHBoc

~OH 564.2 4.91 (q,J=6.0 Hz, IH), 4.17- 4.25 (m, 4H), 4.04 (m, IH), 3.95 (m, 1H),3.40 (s,3H), 2.98 (m, lH),2.84(d,J=4.5 Hz,3H), 1.63 (d, J = 7.0 Hz, 3H), 1.20 (d, J= 6.5 Hz, 3H)

im 8.53 (q, 7 = 4.5 Hz, IH), 8.46

(brs, 2H), 7.94 - 7.97 (m, 2H), 7.88 (s, IH), 7.59 (s, IH), 7.41 (t,J=9.0Hz,2H),5.60 (brs,

550.2 IH), 4.92 (q,J=6.0 Hz, IH),

4.13 -4.24 (m5H), 3.79 (m, 2H), 3.41 (s, 3H), 2.98 (m, IH), 2.84 (d, J= 4.5 Hz, 3H), 1.64 (d, J =6.5 Hz, 3H)

8.54 (m,4H), 7.96 (dd,Jj =9.0 Hz,y₂ = 5.0 Hz, 2H), 7.89 (s, IH), 7.60 (s, lH),7.42(t,J=9.0 Hz, 2H), 4.92 (q,J=6.0Hz, IH), 4.36 (d,J= 11.5 Hz, IH),

_\ NHBoc

562.2 4.20-4.22 (m, 2H),3.91 -4.12

(m, 5H), 3.42 (s, 3H), 2.98 (m, IH), 2.85 (d,J=4.5 Hz, 3H), 2.18(m, IH), 1.63 (d, J =6.5 Hz,3H), 0.98 (d, J = 7.0 Hz, 3H), 0.96 (d,J=7.0 Hz, 3H)

8.61 (brs,3H), 8.54 (m, IH), 7.97 (dd, J; = 8.5 Hz,J₂=5.5 Hz,2H), 7.88 (s, 1H),7.60 (s, HBoc lH),7.42(t,J=8.0 Hz), 2H),

564.2 4.94 (m, IH), 4.17-4.36 (m,

-" "°"

5H), 3.74 (m, 2H), 3.55 (s, 3H), 3.41 (s, 3H), 2.97 (m, IH), 2.85 (d,J=5.0 Hz, 3H), 1.65 (d,J= 6.5 Hz)

|0209| Synthesis of compound (S$,7¾-3Sa-lb, Refer to Scheme 35a. To a solution of compound (5S,7S)-34-3b (60 mg, 0.1 1 mmol), DMAP ( 10 mg) and EtjN (0.5 mL) in DCM (2 mL) at 0 °C was added dihydrofuran-2,5-dione ( 108 mg, 1.1 mmol). After stirring at rt for 2 hr, the reaction mixture was concentrated and the residue was purified by preparative HPLC to give compound (5S,7.S)-35a-lb (40 mg, 56.5% yield) as a white solid. LC-MS (ESI): m/z 655.1 [M + Hf; Ή NMR (500 MHz, cADMSO): δ 12.29 (br , I H), 8,51 (q, J = 5.5 Hz, I H), 7.92 (t, J - 4.5 Hz, 2H), 7.84 (s, 1 H), 7.57 (s, 1 H), 7.30 (t, J = 8.5 Hz, 2H), 7.20 - 7.17 (m ,2H), 7.12 (d, J - 8.0 Hz, 2H), 4.90 (q, J = 6.5 Hz, 1 H), 4.12 4.15 (m, 2H), 4.04 (s, 2H), 3.39 (s, 3H), 2.90 (t, J = 4.5 Hz, I H), 2.84 (d , J - 4.0 Hz, 3H), 2.46 - 2.50 (m, 4 H), 1.63 (d, J ^« 6.5 Hz, 3H) ppm.

|0210| Synthesis of compound (5$, 7$) -35a- la. Following the same procedure as that used to prepare compound (5S,7S)-35a-lb and replacing compound (5S,7S)-34-3b with (5S,7S)-34-3a, compound (55,75>35a-la was obtained as a white solid. LC-MS (ESI): m/z 563 1 [M + Hf; Ή NMR (500 MHz, tADMSO): δ 8.55 (q, J = 5.0 Hz, I H), 7.97 (dd, J, - 9.0 Hz, J> = 5 5 Hz, 2H), 7.86 (s, I H), 7.59 (s, I H), 7.41 (t, J= 9.0 Hz, 2H), 4.90 (q, J - 6.5 Hz, I H), 4.13 4.16 (m, 2H), 4.40 (m, 2H), 3.39 (s, 3H), 2.89 - 2.94 (m, 1 H), 2.84 (d, J - 4 5 Hz, 3H), 2.43 2.48 (m, 4H), 1.63 (d, J = 6.0 Hz) ppm.

(SS,7S 38b-2 R = 4-F-PhO- im |021 11 Synthesis of compound (5_S,7.S)-35b-2a. Refer to Scheme 35b. To a stirred solution of compound (5S,7S)-34-3a (60 mg, 0.13 mmol) in THF (5 mL) was added Ι ,Γ- carbonyldiimidazole (CDl) (63 mg, 0.39 mmol) at rt. After stirring at rt overnight, compound (5S,75 -34-3a was completely converted to compound (5S,7-V)-35b-la determined by LC-MS. Subsequently, l ,4'-bipiperidine (327 mg, 1.95 mmol) was added into the reaction mixture. After stirring at rt for 10 hrs, the reaction mixture was concentrated and the residue was dissolved in DCM (25 mL). The mixture was washed with brine and dried with anhydrous Na₂S0 . The solvent was removed and the residue was purified by preparative HPLC to give compound (5S,7S)-3Sb~2a (50 mg, 59% yield) as a white solid. LC-MS (ESI): m/z 657.1 [M + Hj⁺; ^! H NMR (500 MHz, ( -DMSO): δ 8.52 (q, J = 4.0 Hz, 1 H), 7.95 - 7.98 (m, 2H), 7.84 (s, 1 H), 7.85 (s, 1 H), 7.40 (t, J - 8.5 Hz, 2H), 4.90 (q. J = 6.5 Hz, 1 H), 3.95 - 4.14 (m, 6H), 3.38 (s, 3H), 2.91 (br, 1 H), 2.84 (d , 7 = 5.0 Hz, 3H), 2.80 (br, 2H), 2.37 (br, 5H), 1.62 1 68 (m, 5H), 1.27 - 1.46 (m, 8H) ppm.

(5S7S)-3 -3a R = F <SS.7S>-36a-1a R - F

(5S.7S)-34-3b R ^» 4-F PhO (SS,7S»-3«a-1b R = 4-F-PhO-

|02I2| Synthesis of compound (&S,7S)-36a-lb Refer to Scheme 36a. To a solution of compound (5S,7S)-34-3b (40 mg, 0.0724 mmol), and NaOH (0.5 mL, 40% (wAv) in H₂0) in acetone (3 mL) was added dimethyl sulfate (0.6 mL) at rt. After stirring at rt overnight, the reaction mixture was concentrated and the residue was diluted with DCM (50 mL). The organic layer was washed with brine and dried over anhydrous Na₂SCV The solvent was removed that the residue was purified by preparative HPLC to give compound (5S,75)-36a-lb (20 mg, 49% yield) as a white solid. LC MS (ESI): m z 569.2 [M + Hf ; ^! H NMR (500 MHz, i -DMSO): δ 8.50 (q, J 4.5 Hz, 1 H), 7 92 (d, J ÷ 15 0 Hz, 2H), 7 82 (s, I H), 7 56 (s, I H), 7.29 (t, J= 17.5 Hz, 2H), 7.17 7.20 (m, 2H), 7.12 (d, J 17.5 Hz, 2H), 4.89 (q, J - 6.5 Hz, I H), 4.13 (d, J = 10.5 Hz, I H), 4.07 (t, J - 4.5 Hz, I H), 3.37 3.40 (m ,1 H), 3.37 (s, 3H), 3.27 - 3.30 (m, I H), 3.25 (s, 3H), 2.84 (d, J 4.5 Hz, 3H), 1.62 (d, J 6.5 Hz, 3H) ppm

|0213| Synthesis of compound (5S,7S)-36a-la. Following the same procedure as that used to prepare compound (5S,7S)-36a-lb and replacing compound (55,7S)-34~3b with (55,75)-34-3a, compound (5S,7S)-36a-la was obtained as a white solid. LC-MS (ESI): m/.r 477.1 [M + Hf; Ή NMR (500 MHz, </-D SO): δ 8,52 (q,J~ 3.5 Hz, S H), 7.97 (dd, Ji^■■■■ 8.8 Hz, J₂ ==· 5,5 Hz, 2H), 7.84 (s, IH), 7.59 (s, IH), 7.40 (t, J = 8.0 Hz, 2H), 4.90 (q, J ^:: 6.0 Hz, I H), 4,07 4,16 (m,2H), 3.39 (s, 3H), 3.27 - 338 (m, 2H), 3.27 (s, 3H), 2.84 - 2.88 (m, I H), 2.84 (d, J - 4.5 Hz, 3H), 1.62 (d,J= 6.5 Hz, 3H) ppm.

|0214| Following either Approach A or B described in Scheme 36b, the following analogs were

in

Π4

IH), 4.06 (s,2H),3.58~

3.43 (m,2H),3.37(s,3H),

3.30-3.27(m, iH), 300- 2.92(oi, 4H), 2,84 (d,J^; 4.5 Hz, 3H), 3.78 (s, 2H), 1.62 (d,J ^« 60 Hz, 3H)

B 546.2 8.52 (q, 7 = 4.5 Hz, iH), prepared in u

7.97 (dd, J! - 6.5 Hz, J₂ =

9.0 Hz, 2H), 7.83 (s, IH), obiained b ireaiing ihe

7.59 (s, IH), 7,40 (t, 7 = 9.0 compound shown in Enir 1

wish aq. HCHO in ihe Hz,2H), 4.89 (q,J = 6.5 Hz, presence of NaBHjCN and IH), 4.13(d,J = 13.5 Hz,

AcOH in eOH IH), 4.04 - 4.02 (m, IH),

3.99-3.94(01, IH), 340

3 Ί_*j "IQ (m ill, \ i H ΓΪ¾ j 1.j Πf icS, U\

3.32 ~ 3.29 (m,2H), 2.90-

2.88 (m, IH), 2.84 (d,J- 5

Hz, 3H), 2.57 ~2.52 (m,

IH), 2.43 2.41 (m, IH),

2.30- 2.26 (m, IH), 2.20 {s,

3H), 2.00- 1.93 (m, IH), i.62 {d,J 65 Hz,3H)

B 546.2 8.52- 8.50 (m, IH), 7.97

(dd,Ji -6,0 Hz,J₂ 85 ob!ained by ireaiing ihe Hz,2H), 7.83 (s, iH), 7.59 compound shown in Eniry 13 (s, IH), 7.40 (t,J 8,5 Hz, wiJh eOC(0)CI in ihe 2H), 4.89 {q, J =* 60 Hz, presence of Ei₃N in DCIVI

iH), 4.i3{d,J-9.5 Hz, !H), 4.06 (s, IH), 3.57 (s,

Scheme 33c

|021S| Step 1. Refer to Scheme 36c. To a stirred solution of compound (5S,75)-36b-3a (50 mg, 0.08 mmol) in dry DMF (2 mL) was added Cs₂C0₃ (26 mg, 0, 16 mmol) and 2 -methyl- 1 H~ imidazole ( 13 mg, 0.16 mmol). After stirring at 50 °C for 12 hrs, the reaction mixture was concentrated. The residue was diluted with water (25 mL) and the resulting suspension was extracted with EtOAc (20 mL ^x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous NajS0 , and concentrated. The residue was dried in vacuo to give crude compound (55,7 ?)-36c-l (50 mg) as light yellow solid, which was used directly for the next step without further purification LC MS (ESI) m z 542 2 [M + Hf.

|0216| Step 2. Following the same procedure as that used for converting compound 1-14 to 1-15 shown in Scheme 1 (WO2012/058125) and replacing compound 1-14 with (5S,7/?)-36c-l, compound (55,7 ?)-36c-2 was obtained as a light yellow solid. LC-MS (ESI): m/z 514.1 [M + Hf . |0217| Step 3. Following the same procedure as that used for converting compound 1-15 to 1-16 shown in Scheme 1 and replacing compound 1-15 with (5i',7/?)-36c-2, compound (5S,7/?)-36c-3 was obtained as a white solid. LC-MS (ESI): m/z 527.2 [M + Hf; Ή NMR (500 MHz, tt- DMSO); S 8.53 (q, J = 4.5 Hz, 1 H), 7.96 (t, J - 4 5 Hz, 2H), 7.84 (s, 1 H), 7.56 (s, I H), 7.40 (t, J 8.5 Hz, 2H), 7.07 (s, 1 H), 6.74 (s, 1 H), 4 86 (q, J^■« 6.5 Hz, 1 H), 4.23 - 4.16 (m, 2H), 4.08 (d, J - 18.0 Hz, 1 H), 3.90 (dd, J, 15.0 Hz, J? 7 0 Hz, I H), 3.51 (s, 3H), 2.84 - 2.79 (m, I H), 2.79 (s,

(d, J - 7.0 Hz, 3H) ppm

(5S,7 38s-4

|0218| Synthesis of compound (5£,7i?)-36c-4. Following the same procedure as that used for preparing compound (5S,7/?)-36c-3 shown in Scheme 36c and replacing 2-methyl-lH-imidazole with I H-pyrazole, compound (5S,7,R)-36c-4 was obtained as a white solid. LC-MS (ESI): m/z 513.2 [M + Hf; Ή NMR (500 MHz, i/-DMSO): 6 8.51 (q, J - 5.0 Hz, I H), 7.98 - 7.95 (m, 2H), 7.84 (s, I H), 7.66 (s, I H), 7.57 (s, IH), 7.45 (s, I H), 7.40 (t, J 8.5 Hz, 2H), 6.23 (s, I H), 4.86 (q, J = 6.0 Hz, 1 H), 4.26 - 4.12 (m, 4H), 3.36 (s, 3H), 2.84 (d, J - 5.0 Hz, 3H), 1 .54 (d, 7 - 6.5 Hz, 3H) ppm.

|0219| Synthesis of compound (55,7i?)-36c-5. Following the same procedure as that used for preparing compound (55,7 ?)-36c-3 shown in Scheme 36c and replacing 2-methyl-S //-imidazole with pyrrolidin-2-one, compound (5S,7/?)-36c-5 was obtained as a white solid. LC-MS (ESI): /z 530.2 [M + Hf; Ή NMR (500 MHz, i -DMSO): δ 8.52 (q, J 4.5 Hz, 1 H), 7.97 (dd, J, 5.5 Hz, J2 = 8.5 Hz. 2H), 7.85 (s, I H), 7.59 (s, IH), 7.40 (t, J 8.5 Hz, 2H), 4.88 (q, J 6.5 Hz, I H), 4.08 4 06 (m, 2H), 3 52 - 3.47 (m, 2H), 3.38 (s, 3H), 3.10 - 3.06 (m, 2H), 2.84 (d, J = 4.5 Hz, 3H),

2 1 (m, 2H), 1.94 - 1 .89 (m, 2H), 1.62 (d, J = 6.0 Hz, 3H) ppm.

|0220| Synthesis of compound (5S,7/f)-36c-6. Following the same procedure as that used for preparing compound (5S R) 36c-3 shown in Scheme 36c and replacing 2-methyl- 1 H-imidazole with oxazo!idin-2-one, compound (55,7/?)-36c-6 was obtained as a white solid. LC-MS (ESI): mlz 532.1 [M + H] ; Ή NMR (500 MHz, -DMSO): δ 8.5 1 (q, J - 4.5 Hz, 1 H), 7.97 (dd, J, = 4.5 Hz, j₂ = 7.5 Hz, 2H), 7 85 (s, I H), 7 59 (s, 1 H), 7.40 (t, J, = 8.5Hz, 2H), 4.90 (q, J - 6.5 Hz, 1 H), 4.28 ~ 4.24 (m, 2H), 4.13 - 4.1 1 (d, J ^« 9.5 Hz, 2H), 3.70 - 3.68 (m, 2H), 3.57 - 3.55 (m, 2H), 3.39 (s,

2.84 (d, J = 4.5 Hz, 3H), 1 .63 (d, J - 6.0 Hz, 3H) ppm.

|0221 | Synthesis of compound (&S,7/f)-36c-7, Following the same procedure as that used for preparing compound (5S,7 ?)-36c-3 shown in Scheme 36c and replacing 2-methyl- 1 H-imidazole with 1 ,3-oxazinam 2 one, compound (55,7/?)-36c-7 was obtained as a white solid. LC-MS (ESI): mlz 546.2 [M + Η] ; Ή NMR (500 MHz, J³ DMSO): δ 8.52 (q, J = 4.5 Hz, I H), 7.97 (dd, J, - 5.5 Hz, J2 - 8.5 Hz, 2H), 7.84 (s, 1 H), 7.59 (s, 1 H), 7.39 (t, J = 8.5 Hz, 2H), 4.90 (q, J - 6.5 Hz, 1 H), 4.21 - 4.05 (m, 4H), 3.48 - 3.40 (m, 4H), 3.38 (s, 3H), 3 08 - 3.01 (br, I H), 2.84 (d, J ~ 4 5

(d, J 6.0 Hz, 3H) ppm.

|0222| Synthesis of compound (5S,7iV)-36c-8. Following the same procedure as that used for preparing compound (5_?,7i?)-36c-3 shown in Scheme 36c and replacing 2-methyl- 1 H-imidazole with morpholin 3-one, compound (55,7 ?)-36c-8 was obtained as a white solid. LC-MS (ESI): m! 546,2 [M + H]⁺; Ή NMR (500 MHz, tt DMSO): δ 8.53 (q, J^■ 4.5 Hz, I H), 7.97 (dd, Jj - 5.5 Hz, J₂ - 8.5 Hz, 2H), 7.87 (s, I H), 7.60 (s, 1 H), 7.40 (t, J 8.5 Hz, 2H), 4.90 (q, J - 6.5 Hz, I H), 4.18 4.01 (m, 4H), 3.81 ~ 3.78 (t, J- 45 Hz, 2H), 3.61 356 (m, 1H), 3.52 - 3.48 (m, 2H), , 1 H), 284 (d, J - 45 Hz, 3H), 1.62 (d, J = 6.0 Hz, 3H) ppm.

| 2231 Synthesis of compound (5S,7i?)-36c-9. Following the same procedure as that used for preparing compound (55,7?) 36c-3 shown in Scheme 36c and replacing 2-methyl- 1 H-imidazole with piperidin-2-one, compound (5S,7/?)-36c-9 was obtained as a white solid. LC-MS (ESI) miz

5442 [M + Hf ; Ή NMR (500 MHz, (t DMSO): δ 8.52 (q, J^■·^»■ 4.5 Hz, 1H), 7.97 (dd, J\ - 5.5 Hz, Ji - 8.5 Hz, 2H), 7.85 (s, IH), 7.58 (s, IH), 7.39 (t,J=8.5 Hz, 2H), 4.86 (q, J -6.5 Hz, 1H),413 4.05 (m, 2H), 361 355 (m, IH), 3.44 3.41 (m, 2H), 3.36 (s, 3H), 3.02-2.90 (m, IH), 2.84 - 4.5 Hz, 3H), 224 - 2.21 (m, 2H), 1.74- I 61 (m, 4H), 1.60 (d, J - 6.0 Hz, 3H) ppm.

|0224| Synthesis of compound (5S,7/r 36c-10. Following the same procedure as that used for preparing compound (5S,7?)-36e-3 shown in Scheme 36c and replacing 2-methyl- 1 H-imidazole with 1 , 1 -dioxo-isothiazolidme, compound (5S,7/?)-36c-10 was obtained as a white solid LC MS (ESI): miz = 566.1 [M + Hf ; ^lH NMR (500 MHz, ./-DMSO): δ 8.51 (q,J 45 Hz, IH), 7.97 (dd, Ji = 5.5 Hz, J2 - 8.5 Hz, 2H), 7.85 (s, 1 H), 7.59 (s, 1 H), 7.40 (t, J = 90 Hz, 2H), 4.90 (q, J ^« 6.5 Hz, IH), 4.20 -4.10 (m, 2H), 3.38 (s, 3H),3.21 -3.11 (m, 4H), 3.10 3.02 (m, 1H),2.89

- 4.5 Hz, 3H), 2.25 -2.18 (m, 2H), 1.65 (d, J - 6.0 Hz, 3H) ppm.

|0225| Synthesis of compound (5S R)-36c-\l. Following the same procedure as that used for preparing compound (55,7/?)-36c-3 shown in Scheme 36c and replacing 2-methyl- 1 H imidazole with 1 , l-dioxo-tetrahydro-2H- 1 ,2-thiazine, compound (55,7?)-36c-l 1 was obtained as a white solid. LC-MS (ESI): miz = 580.2 [M + Hj⁺;Ή NMR (500 MHz, i^-DMSO): δ 8.51 (q, J 45 Hz, IH), 7.97 (dd, J, - 5.5 Hz, J₂ - 8.5 Hz, 2H), 7.85 (s, 1 H), 7.59 (s, IH), 7.40 (t, J - 90 Hz, 2H), 4.90 (q, J 6,5 Hz, 1 H), 4.14 ~ 4 07 (m, 2H), 3.43 - 3 40 (m, 2H), 3.37 (s, 3H), 3.16 - 3 06 (m, 4H), 2.85 (d, J 4,5 Hz, 3H), 2 84 (m, S H), 2 0 i (m, 2H), 1.64 (d, J - 6.0 Hz, 3H), 1 54 {m, 2H) ppm.

|0226| Step 1. Refer to Scheme 36d. To a stirred solution of compound (5S,7S)-36b-3b ( 1 10 mg, 0.18 mmoi) in DMF (3 mL) at 65 °C was added NaNj ( 140 mg, 2.15 mmol) in portions After stirring at 65 °C for 4 hrs, the reaction mixture was cooled to rt and diluted with water (20 mL) and EtOAc (60 mL). The organic layer was washed with saturated aq. NaHCOj (20 mL), dried over anhydrous Na₂SCXi, and concentrated. The residue was purified by silica gel column chromatography to give compound (5S,7 ?)-36d-l (71 mg, 81 % yield) as a white solid. LC-MS (ESI): mlz 525.1 [M + Na]⁺.

|0227| Step 2. To a solution of trimethylsilylacetylene (85 μί, 0.597 mmol) and compound (5S,7/?)-36d-I ( 100 mg, 0.2 mmol) in DMF (5 mLVH₂0 (2 mL) was added Oil ( 1 14 mg, 0.60 mmol) and Et¾N (61 mg, 0.60 mmol). After stirring at rt for 24 hrs, the reaction mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous NaiSttj, and concentrated. The residue was dried in vacuo to give crude compound (55,7/?)-36d-2 (91 mg, 76% yield) as a white solid, which was used directly for the next step without further purification. LC-MS (ESI): mlz 601.2 [M + Hf ,

|0228| Step 3. Following the same procedure as that used for converting compound 1-14 to 1-15 shown in Scheme 1 (WO2012/058125) and replacing compound 1-14 with (5S,7/?)-36d-2, compound (5S,7 ?)-36d-3 (66 mg, 70%) was obtained as a white solid. LC-MS (ESI): miz 573.2 [M + Hf .

|0229| Step 4. Following the same procedure as that used for converting compound 1-15 to 1-16 shown in Scheme 1 (WO2012/058125) and replacing compound 1-15 with (5S,7/?)-36d-3, compound (55,7 ?)-36d-4 (56 mg, 83% yield) was obtained as a white solid. LC-MS (ESI): miz 586.2 [M + Hf.

|0230| Step 5. A solution of compound (5S,7/?)-36d-4 (56 mg, 0.1 mmo!) in 4 N HC1 in 1 ,4- dioxane (5 mL) was stirred at 60 °C for 4 hrs. Subsequently, the reaction mixture was concentrated and the residue was purified by preparative HPLC to give compound (5-?,7 ?)-36d-5 (5.5 mg, 1 1% yield) as a white solid. LC-MS (ESI): miz 514.1 [M + H]⁺; Ή NMR (500 MHz, ct- DMSO): 6 8.51 (q, J = 4.5 Hz, 1 H), 8.05 (s, 1 H), 7.96 (dd, J, - 5.5 Hz, J₂ = 9.0 Hz, 2H), 7.85 (s, 1 H), 7.73 (s, I H), 7.57 (s, 1 H), 7.40 (t, J - 9.0 Hz, 1 H), 4.87 (q, J - 6.5 Hz, I H), 4.62 (d, J - 1 1.0 Hz, 1 H), 4.39 - 4.23 (m, 3H), 3.38 (s, 3H), 2.88 - 2.85 (m, 1 H), 2.83 (d, J ^« 4,5 Hz, 3H), 1.52 (d, J - 6.0 Hz, 3H) ppm.

102311 Step 1. Refer to Scheme 36e. To a stirred solution of compound (5S,7S)-34-3a (2.0 g, 4.3 mmol), DMAP (52 g, 0.43 mmol) and Et₃N ( 1 mL, 8.3 mmol) in DCM (40 mL) at 0 °C was added a solution of TsCI ( 1.24 g, 6.5 mmol) in DCM (20 mL). After stirring at rt overnight, the reaction mixture was quenched by adding ice-water (50 mL). The organic layer was separated and washed with saturated aq. NaHCOi solution (20 mL x 3) and water (20 mL x 3), dried over anhydrous Na₂SC>4, and concentrated. The residue was purified by silica gel column chromatography

(Petroleum ether/EtOAc = 2/1 (v/v)) to give compound (55,75)-36e-l (1 .8 g, 68% yield) as a light yellow solid. LC-MS (ESI): m/z 617.1 [M + Hf.

102321 Step 2. To a stirred solution of compound (5S,7S)-36e-l (1 .8 g, 3.0 mmol) in DMF (40 mL) at 65 °C was added NaNj (0.6 g, 9.0 mmol) portion-wise. After stirring at 65 ^UC for 2 hrs, the reaction mixture was cooled to rt and added ice- water (50 mL). The mixture was extracted with EtOAc (50 mL * 3). The combined organic extracts were washed with saturated aq. NaHCOj solution ( 10 mL x 3) and water ( 10 mL x 3), dried over anhydrous Na₂S0₄, and concentrated. The residue was dried in vacuo to give crude compound (55,7/?)-36e-2 ( 1 .42 g, quantitative yield) as a white solid, which was used directly for the next step without further purification. LC-MS (ESI): m/z- 488.1 [M + Hf.

102331 Step 3. To a stirred solution of compound (5S,7/?)-36e-2 ( 1.42 g, 3.0 mmol) in THF (40 mL) and H₂0 (2 mL) was added PPhj ( 1.57 g, 6 mmol) at rt under an atmosphere of N₂, After refluxing for 4 hrs, the reaction mixture was cooled to rt and added 1 .0 N aq. HCl solution (6 mL). The resulting mixture was stirred at rt for 1 hr and concentrated. The residue was diluted with water (20 mL) and extracted with hexane (20 mL x 3). Subsequently, the aq. phase was treated with 1 .0 N aq. NaOH solution to adjust the pH value > 9.0. The basic suspension was extracted with EtOAc (25 mL x 3). The combined organic extracts were dried with anhydrous Na₂S0₄ and concentrated. The residue was dried in vacuo to give compound (55,7/?)-36e-3 (810 mg, 60% yield) as a white solid. LC-MS (ESI): m/z 462.1 [M + Hf.

102341 Step 4. To a stirred solution of 4-chlorobutanoic acid (74 mg, 0.6 mmol) in DMF (2 mL) was added HATU (456 mg, 1 .2 mmol). After stirring at rt for 30 min, the mixture was added DIPEA ( 193 mg, 1 .5 mmol) and compound (55,7/?)-36e-3 ( 192 mg, 0.4 mmol). The resulting reaction mixture was stirred at rt for 3 hrs and then poured into water (20 mL). The suspension was filtered; the solid was washed with water ( 10 mL x 2) and dried in vacuo to give crude compound (5S,7/?)-36e-4 (180 mg, 63% purity based on LC-MS) as a white solid, which was used directly for the next step without further purification. LC-MS (ESI): mlz 566.1 [M + H] . |0235| Step 5. To a stirred solution of compound (5S,7/?)-36e-4 ( 180 mg, 0.31 mmol) in dry THF (50 mL) was added ₂CO₁ (483 mg, 3.5 mmol). After re fluxing for 6 hrs, the reaction mixture was cooled to rt and filtered. The filtrate was concentrated and the residue was purified by preparative HPLC to give (5£,7i?)-36e-5 (28 mg, 17 yield) as a white solid. LC-MS (ESI): mlz 530.2 [M + Hf.

|0236| Synthesis of compound (&S,7 ?)-36e-6. To a stirred solution ofCDI ( 162 mg, 1.0 mmol) in DMF (2 mL) was added compound (55,7Λ)-36β-3 (92 mg, 0.2 mmol) portion-wise at rt. After stirring at 60 ^UC for 3 hrs, the reaction mixture was added 3-ch!oro- 1 -propylamine HC1 salt (260 mg, 2.0 mmol). The reaction mixture was stirred at 60 °C overnight and then concentrated. The residue was diluted with water (20 mL) and EtOAc (20 mL) and the aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with brine (25 mL), dried over anhydrous

and concentrated. The residue was dried in vacuo to give crude compound (5S,7/?)-36e-6 (99 mg, 86% yield) as a white solid, which was used directly for the next step without further purification. LC-MS (ESI): mlz 581.2 [M + Hf.

|0237| Synthesis of compound (&_»,7i?)-36e-7. To a solution of compound (5S,7/?)-36e-6 (99 mg, 0.17 mmol) in DMF (6 mL) was added ₂C0₃ (71 mg, 0.51 mmol). After stirring at 80 ^UC overnight, the reaction mixture was cooled to rt, diluted with EtOAc (20 mL), and filtered through C elite* 545. The filtered cake was washed with EtOAc (20 mL x 2). Subsequently, the filtrate was washed with H2O (20 mL x 3) and brine (20 mL), dried over anhydrous Na₂S0₄, and concentrated. The residue was purified by preparative HPLC to give compound (5S,7/?)-36e-7 (35 mg, 38% yield) as a white solid. LC-MS (ESI): mlz 545.2 [M + Hf; Ή NMR (400 MHz, c ~ DMSO): δ 8.52 (q, J = 5.5 Hz, 1 H), 7.96 (dd, J, =1 1.0 Hz, J₂ = 7.0 Hz, 2H), 7.84 (s, 1 H), 7.58 (s, 1 H), 7.40 (t, J = 1 1.0 Hz, 2H), 4.87 (q, J = 7.5 Hz, 1 H), 4.28 - 3.98 (m, 4H), 3.36 (s, 3H), 3 35 (s, 1 H), 3.23 (s, 2H), 3.05 (d, J - 17.0 Hz, 2H), 2.84 (d, J = 5.5 Hz, 3H), 2.81 - 2.76 (m, 1 H), 1 86 (br, 2H), 1.63 (d, J = 9.0 Hz, 3H) ppm.

|0238| Step 1. Refer to Scheme 36f. A solution of compound (5S,7S)-36e-l (62 mg, 0.1 mmol) in 70% EtNH₂ in water (5 mL) was stirred at 80 °C in a microwave reactor for 2 hrs. The reaction mixture was concentrated and the residue was diluted with water (30 mL). Subsequently, the resulting mixture was extracted with EtOAc (20 mL x 3); the combined organic extracts were dried over anhydrous NaiSO* and concentrated. The residue was dried in vacuo to give crude compound (5S,7/?)-36f-l (35 mg, 72% yield) as a white solid. LC-MS (ESI): mlz 490.2 [M + Hf. |0239| Step 2. To a solution of compound (5S,7/?)-36f-l (35 mg, 0.07 mmol) in DCM (5 mL) and Eti ( i mL) was added methyl chloroformate (6.7 mg, 0.07 mmol) at 0 °C. After stirring at rt overnight, the reaction mixture was added several drops of saturated aq. NaHCOj solution.

Subsequently, the mixture was concentrated and the residue was added water ( 15 mL). The resulting mixture was extracted with EtOAc ( 15 mL x 3); the combined organic extracts were dried over anhydrous Na₂S0 and concentrated. The residue was purified by preparative HPLC to give compound (5S,7/?)-36f-2 (7 mg, 18% yield) as a white solid. LC-MS (ESI); mlz 548.2 [M + Hf; Ή NMR (500 MHz, c/-DMSO): 8 8.52 (q, J= 4.0 Hz, 1 H), 7.97 (dd, J, = 8.0 Hz, J₂ ^» 8.5 Hz, 2H), 7.85 (s, 1 H), 7.59 (s, 1 H), 7.41 (t, J= 9.0 Hz, 2H), 4.89 (q, J = 6.5 Hz, I H), 4.10 - 4.06 (m, 2H), 3.60 (s, 3H), 3.45 - 3.38 {m, 4H), 3 12 3,09 (br, I H), 2 85 (d, J 5.5 Hz, 3H), 2 85 2.79 (m, 1 H), 1.62 (d, J- 6.5 Hz, 3H), 1.06 (t, J 7.0 Hz, 3H) ppm.

|0240| Synthesis of compound 36g-2 Refer to Scheme 36g To a stirred solution of CDI (300 mg, 1 .85 mmol) in dry DMF (5 mL) was added (/?)-tetrahydrofuran-3-ol ( 163mg, 1.85 mmol) at rt. After stirring at rt for 4 hrs, the reaction mixture was added compound (5-?,7 ?)-36e-3 (47 mg,

0.1 mmol) and TEA ( 1 mL, 6.6 mmol). The resulting reaction mixture was stirred at 60 °C overnight and then concentrated. The residue was diluted with water (20 mL) and extracted with

EtOAc (20 mL x 3). The combined organic extracts were washed with water (25 mL) and brine

(25 mL), dried over anhydrous Na₂S0₄, and concentrated The residue was purified by

preparative HPLC to give compound 36g~2 (12 mg, 21%) as a white solid. LC MS (ESI): mlz

576.2 [M + Hf; ^f H NMR (500 MHz, DM SO): 8 8 52 (q,J 5.0 Hz, 1 H), 7 96 (dd, J, ^»= 5 5 Hz, J2 = 9.0 Hz, 2H), 7.84 (s, I H), 7.59 (s, 1 H), 7 40 (t, J - 9 0 Hz, 2H), 7.28(t, J - 4.5 Hz, I H), 5.10 (br, 1 H), 4.86(q, J - 5.0 Hz, 1 H), 4.09 (d, J 17 0 Hz , I H), 3 95 - 3.90 (m, 1 H), 3.74 - 3.65 (m, 4H), 3.10 - 2.95 (m, 2H), 2.94 (s, 3H), 2.84 (d, J 4 5 Hz, 3H), 2.65 - 2.60 (m, 1 H), 2.09 - 2.07

-1.85 (m, I H), 1 .60 (d, J 6.5 Hz, 3H) ppm.

|0241 | Synthesis of compound 36g-3. Following the same procedure as that used for preparing compound 36g-2 shown in Scheme 36g and replacing (/?) tetrahydrofuran-3-ol with (S)- tetrahydrofuran-3-ol, compound 36g-3 was obtained as a white solid. LC-MS (ESI): mlz 576.2 [M

+ Hf ; Ή NMR (500 MHz, i -DMSO): δ 8 51 (q, J - 5.0 Hz, 1 H), 7.98 (dd, J, = 5.5 Hz, J₂ = 9.0 Hz, 2H), 7.84 (s, I H), 7.58 (s, I H), 7.40 (t, J 9.0 Hz , 2H), 7.27 (s, I H), 5.1 1 (t, J - 6.0 Hz, I H), 4.87(d, J = 5.0 Hz, 1 H), 4.13 (d, J = 17.0 Hz, I H), 3.98 - 3.92 (m, 1 H), 3.77 - 3.65 (m, 4H), 3.36 (s, 3H), 3.09 - 2.97 (m, 2H), 2.84 (d, J = 4.5 Hz, 3H), 2.80 2.73 (m, I H), 2. 15 - 2.05 (m, 1 H), - 1.82 (m, I H), 1.63 (d, J - 6.5 Hz, 3H) ppm.

|0242| Synthesis of compound 36g-4. Following the same procedure as that used for preparing compound 36g-2 shown in Scheme 36g and replacing ( ?)-tetrahydrofuran-3-ol with tetrahydro- 2H-pyran-4-ol, compound 36g-4 was obtained as a white solid LC-MS (ESI): mh 590.2 [M + H]⁺; ¹ H NMR (500 MHz, </-DMSO): δ 8,5 1 (q, J - 5 0 Hz, I H), 7.97 (dd, J, = 5.5 Hz, J₂ ^» 9.0 Hz, 2H), 7.84 (s, 1 H), 7.59 (s, 1 H), 7.40 (t, J - 9 0 Hz , 2H), 7 20 (s, 1 H), 4.87 (q, J 6.0 Hz, 1 H), 4.71 - 4.67 (m, 1 H), 4.12 (d, J ÷ 15.5 Hz, 1 H), 3.96 (m, I H), 3.81 - 3.79 (m, 2H), 3.46 -3 39 (m, 2H), 3.35 (s, 3H), 3.03 - 3.00 (m, 2H), 2.84 (d, J 4 5 Hz, 3H), 2.80 - 2.70 (m, I H), 1 .85™ 1 .82 (m, 2H), 1.62 (d, J - 6.5 Hz, 3H), 1.60 1 .40 (m, 2H) ppm

102431 104321 Step 1. Refer to Scheme 36h. To a stirred suspension of Cs₂C0₃ (63 mg, 0.19 mmol) in dry DMF (2 mL) was added /<?r/-butyl thiazol-2-ylcarbamate (30 mg, 0.14 mmol) at rt under an atmosphere of Ar. The mixture was stirred at rt for 30 min and then (5S,7S)-36e-I (60mg, 0.1 mmol) was added. After stirring at 60 °C overnight, the reaction mixture was concentrated. The residue was diluted with water ( 15 mL) and EtOAc ( 15 mL). The aqueous phase was extracted with EtOAc ( 15 mL x 3). Subsequently, the combined organic extracts were washed with saturated aq. NaHC{¾ solution (20 mL x 2) and brine (20 mL), dried over anhydrous and concentrated. The residue was dried in vacuo to give crude compound (5S,7/?)-36h- 1 , which was used for the next step without further purification. LC-MS (ESI): mlz 645.2 [M +

Hf.

1024 1 Step 2. A mixture of compound (5S,7fl)-36h-l (50 mg, 0.08 mmol) in saturated HC1 in EtOAc (5 mL) was stirred at rt for 5 hrs. The mixture was concentrated and the residue was purified by preparative HPLC to give compound (55,7 ?)-36h-2 (13 mg, 31 % yield) as a white solid. LC-MS (ESI): mlz 545.1 [M + Hf; Ή NMR (500 MHz,

δ 8.5 i (q, J - 4.5 Hz. 1 H), 7.98 - 7.95 (m, 2H), 7.84 (s, 1 H), 7.59 (s, 1 H), 7.60 - 7.57 (m, 1 H), 7.40 (t, J - 9.0 Hz, 2H), 7.00 (s, I H), 6.60 (s, 1 H), 4.90 (q, J 6.5 Hz, 1 H), 4 18 {d, J* 10.5 Hz, S H), 4.12 4J 0 {m, 1 H), 3.39 ~ 3.31 (m, 2H), 3,35 (s, 3H), 2.84 (d, J 4 5 Hz, 3H), 2.89 - 2.84 (m, S H), 1.65 (d, J ^« 6 5 Hz, 3H) ppm.

102451 Synthesis of compound (§£,7$)-36h-3. Following the same procedure as that used for preparing compound (5S,7/?)-36h-2 shown in Scheme 36h and replacing te/7-butyl thiazol-2- y I carbamate with ten-butyl benzo[i/]thiazol-2-ylcarbamate, compound (5S,7 ?)-36h-3 was obtained as a white solid. LC-MS (ESI): mlz 595.1 [M + Hf, Ή NMR (500 MHz, tA DMSO) δ 8.51 (q, J - 4.5 Hz, 1 H), 8. 10 (t, J 5.0 Hz, 1 H), 7 96 (dd, J, 9.0 Hz, J₂ 5.0 Hz, 2H), 7.85 (s, 1 H), 7.66 (d, J - 7.5 Hz, 1 H), 7.60 (s, 1 H), 7.42™ 7.37 (m, 3H), 7.22 (t, J *^» 7.0 Hz, 1 H), 7 02 (t, J = 7.5 Hz, 1 H), 4.92 (q, J = 6.5 Hz, 1 H), 4.25 4.18 (m, 2H), 3.53 - 3.39 (m, 2H), 3.41 (s, 3H), 2.90 (m, 1 H), 2.84 (d, J = 5.0 Hz, 3H), 1.66 (d, J - 6.0 Hz, 3H) ppm.

|0246| Synthesis of compound (&S,7J?)-36fa-4, Following the same procedure as that used for preparing compound (5S,7 ?)-36h-2 shown in Scheme 36h and replacing terf-butyl thiazol-2- ylcarbamate with ierf-butyl 2-(terf-butoxycarbonylamino)- 1 //-imidazole- 1 -carboxylate, compound (5S,7/?)-36h-4 was obtained as a white solid. LC-MS (ESI): m/z 528.2 [M + Hf; Ή NMR (500 MHz, -DMSO): 5 8.51 (q, J = 5.0 Hz, 1 H), 8.30 (s, 1 H), 7.97 (dd, J, - 9.0 Hz, J₂ = 5.0 Hz, 2H), 7.82 (s, I H), 7.59 (s, I H), 7.40 (t, J - 9.0 Hz, 2H), 6.48 (s, 2H), 5.25 (m, 1 H), 4.91 (q, J = 6.5 Hz, 1 H), 4.1 6 (m, 1 H), 4.06 (m, 1 H), 3.35 (s, 3H), 3.21 - 3.12 (m, 2H), 2.88 - 2.84 (m,

= 5.0 Hz, 3H), 1.66 (d, J = 6.0 Hz, 3H) ppm.

|0247| Synthesis of compound (&S,7/?)-36h-5. Following the same procedure as that used for preparing compound (5S,7 ?)-36h-2 shown in Scheme 36h and replacing terf-butyl thiazol-2- ylcarbamate with terf-butyl 1 -methyl- 1 H.imidazol-2-ylcarboxylate, compound (SS,7/?)-36h-5 was obtained as a white solid. LC MS (ESI): m/z 542 2 [M + H]⁺; Ή NMR (500 MHz, t- DMSO): 6 8.51 (q, J = 5.0 Hz, I H), 8.30 (s, 1 H), 7.97 (dd, J_\ - 9.0 Hz, J₂ - 5.0 Hz, 2H), 7.83 (s, I H), 7.59 (s, 1 H), 7.40 (t, J 9.0 Hz, 2H), 6 61 (s, 1 H), 6.43 (s, 1 H), 5.25 (m, 1 H), 4.90 (q, J 7.0 Hz, l H), 4.20 (m, I H), 4. I O (m, I H), 3.34 (s, 3H), 3 23 3 19 (m, 2H), 2.88 - 2.84 (m, I H),

= 4.0 Hz, 3H), 1.63 (d, J 7.0 Hz, 3H) ppm.

|0248| Synthesis of compound (5S,7/?)-36h-6 Following the same procedure as that used for preparing compound (55,7 ?)-36h-2 shown in Scheme 36h and replacing terf-butyl thiazol-2- ylcarbamate with terf-butyl 2-(½rf-butoxycarbonylamino)- 1 //-benzo[<7) imidazole- 1 -carboxylate, compound (55,7 ?)-36h-6 was obtained as a white solid. LC MS (ESI): m/z 578.2 [M + Hf ; Ή NMR (500 MHz, -DMSO): 5 8.51 (q, J - 5.0 Hz, 1 H), 8.1 7 (s, 1 H), 7.96 (dd, J, = 9.0 Hz, J₂ ^¾ 5.0 Hz, 2H), 7.84 (s, 1 H), 7 60 (s, 1 H), 7. 13 (t, J 4.0 Hz, 2H), 6.86 (m, 2H), 6.52 (m, 1 H), 4.93 (q, J™ 7 0 Hz, I H), 4 23 (m, 1 H), 4 15 (m, 1 H), 3.43 - 3.39 (m, 2H), 3.35 (s, 3H), 2.92 - 2.89 fm,

, 1.63 (d, J 6.5 Hz, 3H) ppm

|0249| Synthesis of compound (&S,7 i)-36h-7 Following the same procedure as that used for preparing compound (5S,7 ?)-36h-2 shown in Scheme 36h and replacing rerr-butyl thiazol-2- ylcarbamate with tert butyl pyrimidin-2-ylcarbamate, compound (5S,7/?)-36h-7 was obtained as a white solid. LC-MS (ESI): miz 540.2 [M + H] ^', Ή NMR (500 MHz, (/-DMSO): S 8.51 (q, J ~ 4.0 Hz, 1 H), 8.28 (d, J 5.0 Hz, 2H), 7 95 (dd, J_/ 9.5 Hz, J₂ 5.0 Hz, 2H), 7.83 (s, 1 H), 7.59 (s, 1 H), 7.40 (t, J 9.0 Hz, 2H), 7 08 (t, J - 7 0 Hz, 1 H), 6 59 (t, J, - 4.5 Hz, 1 H), 4.90 (q, J = 7.0 Hz, I H), 4.10 - 4.05 (m, 2H), 3.40 (s, 3H), 3.45 - 3.35 (m, 2H), 2.92 - 2.85 (m 1 H), 2.84 (d, J =

- 7.0 Hz, 3H) ppm.

|0250| Synthesis of compound (&S",7J?)-36h-8. Following the same procedure as that used for preparing compound (5S,7 ?)-36h-2 shown in Scheme 36h and replacing reri-butyl thiazol-2- ylcarbamate with ieri-butyl 5-fluoropyridin-2-ylcarbamate, compound (5S,7 ?)-36h-8 was obtained as a white solid. LC-MS (ESS): miz 557.2 [M + H] ; Ή NMR (500 MHz, /"-DMSO): δ 8.51 (q, J = 4.5 Hz, I H), 7.98 ~ 7.92 (m, 3H), 7.83 (s, 1 H), 7 59 (s, I H), 7.41 - 7.32 (m, 3H), 6.58 - 6.52 (m, 2H), 4.90 ( 1 , J = 7.0 Hz, 1 H), 4.15 - 4.05 (m, 2H), 3 35 (s, 3H), 3.36 - 3.30 (m, 2H), - 2.85 (m I H), 2.84 (d, J = 4.5 Hz, 3H), 1.64 (d, J 7.0 Hz, 3H) ppm.

|02511 Synthesis of compound (&S,7i?)-36h-9. Following the same procedure as that used for preparing compound (5S,7/?)-36h-2 shown in Scheme 36h and replacing r/-butyl thiazol-2- ylcarbamate with /eri-butyl 5-chloropyridin-2-ylcarbamate, compound (5S,7 ?)-36h-9 was obtained as a white solid. LC MS (ESS); mh 573 1 [M + H] ; Ή NMR (500 MHz, (ADMSO): S 8.51 (q, J = 4.0 Hz, 1 H), 7.96 (dd, J, - 8 5 Hz, J₂ 6 0 Hz, 3H), 7.83 (s, 1 H), 7.59 (s, 1 H), 7.43 ~ 7.38 (m, 3H). 6.80 (t, J 5.0 Hz, I H), 6 58 (d, J 9,0 Hz, I H), 4.90 (q, J 6.5 Hz, 1 H), 4.10 4.05 (m, 2H), 3.34 (s, 3H), 3.35 - 3 30 (m, 2H), 2 92 2 85 (m 1 H), 2.84 (d, J 4.5 Hz, 3H),

- 6.5 Hz, 3H) ppm.

102521 Synthesis of compound (&S,7J?)-36h-10, Following the same procedure as that used for preparing compound (5S,7 ?)-36h-2 shown in Scheme 36h and replacing terf-butyl thiazol-2- ylcarbamate with terf-butyl 5 trifluoromethylpyridin 2 ylcarbamate, compound (5S,7 ?)-36h-10 was obtained as a white solid. LC MS (ESI): mlz 607.2 [M + Hf; ¹ H NMR (500 MHz, if

DMSO): δ 8.51 (q, J ^~ 4.0 Hz, 1 H), 8.30 (s, 1 H), 7.96 (dd, J, = 8.5 Hz, = 5.5 Hz. 3H), 7.84 (s, 1 H), 7.63 (m, 1 H), 7.59 (s, I H), 7 42 - 7.36 (m, 3H). 6 66 (d, J = 9.0 Hz, 1 H), 4.90 (q, J ~ 6.5 Hz, I H), 4.18— 4.10 (m, 2H), 3.43 3,38 (m, 2H), 3.35 (s, 3H), 2.92 - 2.85 (m 1 H), 2.84 (d, J - 4.5

3H) ppm

|0253| Synthesis of compound (5S,7i?)-36h-U. Following the same procedure as that used for preparing compound (5S,7 ?) 36h-2 shown in Scheme 36h and replacing fer/ butyl thiazoL2 ylcarbamate with ten butyl 4- fluoropyridtn 2 -ylcarbamate, compound (5S.7 ?) 36h-U was obtained as a white solid. LC MS (ESI): mlz 557.2 [M + Hf , Ή NMR (500 MHz, t/ DMSO): δ 8.51 (q, J ~ 4.0 Hz, 1 H), 8 00 ^«· 7 95 (m, 3H), 7,84 (s, I H), 7.59 (s, I H), 7.40 (t, J 8 5 Hz, 2H), 6.80 (t, J - 6.0 Hz, 1 H), 6.39 (m, 1 H). 6.31 (d. J ^s 1 .5 Hz, I H), 4.90 (q, J * 6 5 Hz, 1 H), 4 17 (m, I H), 4.08 (m, I H), 3.38 3.28 (m, 2H), 3.35 (s₅ 3H), 2.92 - 2 85 (m I H), 2.84 (d, J 4,5 Hz, 3H),

- 6.5 Hz, 3H) ppm.

10254| Synthesis of compound (5$,7Λ)-36Ιι-1 . Following the same procedure as that used for preparing compound (5S,7?)-36h-2 shown in Scheme 36h and replacing tert butyl thiazol 2 ylcarbamate with ierf-but l 4-c hloropyridin-2 -ylcarbamate, compound (SS R) 36h-l was obtained as a white solid. LC-MS (ESI): mlz 573.1 [M + H] ; Ή NMR (500 MHz, </~DMSO): δ 8.51 (q,J~ 4.0 Hz, I H), 7.97 - 7.92 (m, 3H), 7.84 (s, 1 H), 7.59 (s, 1 H), 740 (t, J - 9.0 Hz, 2H), 6.83 (m, 1 H).6.62 (d,J= 1.5 Hz, 1 H), 6.55 (dd, J, 55 Hz, J₂ 1.5 Hz, 1 H), 490 (q, J 6.0 Hz, 1H), 4.15 (m, 1H), 4.07 (m, IH), 3.40-3.27 (m, 2H), 335 (s, 3H), 2.89 2.85 (m 1H), 2.84 (d, J = - 6.5 Hz, 3H)ppm.

|0255| Synthesis of compound (5£,7i?)-36h-13. Following the same procedure as that used for preparing compound (5S,7?)-36h-2 shown in Scheme 36h and replacing teri-butyl thiazol-2- ylcarbamate with teri-butyl 5-trifluoromethylpyridin-2-ylcarbamate, compound (5S,7i?)-36h-13 was obtained as a white solid. LC-MS (ESI): mlz 6072 [M + Hf; Ή NMR (500 MHz, <^*- DMSO): 68.51 (q,J = 4.0 Hz, 1H), 8.20 (d, J - 5.0 Hz, I H), 7.95 (dd, J, = 9.0 Hz, J₂ 5.5 Hz, 2H), 7.84 (s, I H), 7.60 (s, 1 H), 7.40 (t, J - 8.5 Hz, 2H), 711 (t, J = 6.0 Hz, I H), 6.87 (s, 1 H), 6.72 (d,J=5.5 Hz, 1H), 4.90 (q,J=6.0 Hz, IH), 4.15 (m, IH), 4 i0(m, 1 H), 3.44 - 3.41 (m,

- 2.85 (m IH), 2.84 (d,J 5.0 Hz, 3H), 1.64 (d, J = 6.0 Hz, 3H) ppm.

102561 Synthesis of compound (5-?,7Λ)-36η-1 . Following the same procedure as that used for preparing compound (55,7/?)-36h-2 shown in Scheme 36h and replacing rerf-butyl thiazol-2- ylcarbamate with ieri-butyi pyridazin-3-ylcarbamate, compound (5S,7?)-36h-l4 was obtained as a white solid. LC-MS (ESI); mlz 540.2 [M + Hf ; Ή NMR (500 MHz, -DMSO): 58.51 (q,J 4.0 Hz, 1 H), 8.42 (d, J - 4.5 Hz, IH), 7.96 (dd, J_\ 9.0 Hz, J₂ 5.5 Hz, 2H), 7.84 (s, 1 H), 7.60 (s, IH), 7.40 (t,J=9.0 Hz, 2H), 7.21 (dd, J, * 9.0 Hz,J₂ 4.5 Hz, IH), 6,86 (d, J - 8,5 HZ, IH), 6.82 (m, IH), 4.91 (q,J=6.0 Hz, IH), 4.20-4.15 (m, 2H), 345- 3.42 (m, 2H), 3.35 (s, 3H), 2.89 - 2.85 (m 1 H), 2.84 (d, J - 4.5 Hz, 3H), 1.64 (d,J 6.0 Hz, 3H) ppm.

|0257| Synthesis of compound (&S,7i?)-36h-15. Following the same procedure as that used for preparing compound (5S,7/?)-36h-2 shown in Scheme 36h and replacing terf- butyl thiazol-2- ylcarbamate with feri-butyS S-chloropyrazin-2-ylcarbamate, compound (SS,7/?)-36h-15 was obtained as a white solid. LC-MS (ESI): mlz 574.1 [M + Hf; Ή NMR (500 MHz, ίΛ-DMSO): 5 8.51 (q, J = 4.0 Hz, I H), 8.05 (s, I H), 7.96 (dd. J, = 9.0 Hz, J₂ = 5.5 Hz, 2H), 7.84 (s, 1 H), 7.82 (s, 1 H), 7.40 (t, J = 9.0 Hz, 2H), 7.33 (t, J = 5.0 Hz, I H), 4.89 (q, J = 6.0 Hz, I H), 4.17 - 4.1 1 (m, 2H), 3.56 (s, 3H), 3.56 - 3.27 (m, 2H), 2.89 - 2.85 (m I H), 2.84 (d, J = 4.5 Hz, 3H), 1.64 (d, J 6.5 Hz, 3H) ppm.

|0258| Synthesis of (5S,7S)-36i-l Refer to Scheme 361, To a stirred suspension of Cs₃C0₃ (3 mg, 0 1 mmol) in dry DMF ( 1 mL) was added 4-fluorophenol (6 mg, 0.05 mmol) at rt under an atmosphere of Ar. After stirring at rt for 30 min, compound (55,75 -36e-l (30 mg, 0.05 mmol) was added. The resulting reaction mixture was stirred at 60 "C overnight and then diluted with water ( 10 mL). The mixture was adjusted pH value to 3-4 by adding 2 N aq. HCl solution The resulting suspention was filtered and the solid was collected and further purified by preparative HPLC to give compound (5S,7S>36.-1 ( 13 mg, 48% yield) as a white solid. LC MS (ESI): mlz 557.1 [M + Hf; Ή NMR (500 MHz, </ DMSO): δ 8 52 (q, J 4.5 Hz, I H), 7.97 (dd, J, - 8 0 Hz, J - 5 0 Hz, 2H), 7.86 (s, I H), 7 61 (s, I H), 7 40 (t, J 8.5 Hz, 2H), 7. l0 (t, J 9.0 Hz, 2H), 6.97 6 94 (m, 2H), 4.96 (q, J 6.0 Hz, 1 H), 4.27 {d, J ~ 1 1.0 Hz, 2H), 4.01 - 3.97 (m, 2H), 3 40 (s, 3H), 3 03 - 2.99 (m_f 1 H), 2.84 (d, J 5.0 Hz, 3H), 1.65 (d, J 5.0 Hz, 3H) ppm.

102591 Synthesis of compound (5S,75)-36i-2. Following the same procedure as that used for preparing compound (5S,7S)-36i-l shown in Scheme 36k and replacing 4-fluorophenol with 3- fluorophenol, compound (55,75)-36i-2 was obtained as a white solid. LC-MS (ESI): mlz 557.1 [M + H]⁺; Ή NMR (500 MHz, ( "-DMSO): δ 8.52 (q, J 5 0 Hz, 1 H), 7.97 (dd, J_s =5.5 Hz. J₂ = 9.0 Hz, 2H), 7.87 (s, I H), 7.61 (s, l H), 7.40 (t, J 8.5 Hz, 2H), 7.30 (q, 1 H), 6.84 - 6.74 (m, 3H), 4.97 (q, J = 6.5 Hz, I H), 4.29 - 4.25 (m, 2H), 4.07 4 01(m, 2H), 3.41 (s, 3H), 3.05 - 2.99 (m,

= 4.0 Hz, 3H), 1.65 (d, J- 6.0 Hz, 3H) ppm.

102601 Synthesis of compound (5&,7£)-36i-3. Following the same procedure as that used for preparing compound (55,75)-36i-l shown in Scheme 36i and replacing 4-fluorophenol with 3,4- difluorophenol, compound (55,75)-36I-3 was obtained as a white solid. LC-MS (ESI): mlz 575.1 [M + Hf; ¹ H NMR (500 MHz, d⁶-DMSO): δ 8.52 (q, J 5.0 Hz, I H), 7.98 (dd, J_t -5.5 Hz, - 9.0 Hz, 2H), 7.87 (s, I H), 7.61 (s, 1 H), 7.40 (t, J- 8 5 Hz, 2H), 7.33 (q, J = 10.0 Hz, 1 H), 7 1 1— 7.06 (m, l H), 6.78 ~ 6.77(d, J 9,0 Hz, I H), 4 96 (q, J^« 6 5 Hz, 1 H), 4.25 4.20 (m, 2H), 4.03 4.01(m, 2H), 3.40 (s. 3H), 3.05 - 2.99 (m, I H), 2.85 (d, J * 4.0 Hz, 3H), 1.64 (d, J - 6.0 Hz. 3H) ppm.

102611 Synthesis of compound (55,75 -36i-4. Following the same procedure as that used for preparing compound (55,75 36Ι~1 shown in Scheme 36i and replacing 4-fluorophenol with 2,4 difluorophenol, compound (55,75) -361-4 was obtained as a white solid. LC-MS (ESI): mlz 575.1 [M + Hf; Ή NMR (500 MHz, <f -DMSO): 6 8 52 (q, J 5.0 Hz, 1 H), 7.98 (dd, Ji ' 5.5 Hz, J₂ ^» 9.0 Hz, 2H), 7.87 (s, 1 H), 7 61 (s, I H), 7 40 (t, J - 9.0 Hz, 2H), 7.29 - 7.20 (m, 2H), 7 01 (t, J 9.0 Hz, I H), 4.96 (q, J 6 5 Hz, 1 H), 4.30 4 20 (m, 2H), 4.09 (d, J 4.5 Hz, 2H), 3.40 (s, 3H), 3.05 - 2.99 (m, I H), 2.85 (d, J 4.0 Hz, 3H), 1 64 (d, J - 6 5 Hz, 3H) ppm.

|02621 Synthesis of compounds (5S,7S)-36j-la and (5S,7#)-36j-ib. Refer to Scheme 36j. To a stirred suspension of NaH ( 10 mg, 0.4 mmol) in dry DMF ( I mL) was added 5-chloropyridin-2-ol (31 mg, 0.24 mmol) at rt under an atmosphere of Ar. After stirring at rt for 30 min, the reaction mixture was added compound (55,75)-36e-i (50 mg, 0.08 mmol). The resulting mixture was stirred at 60 °C for 4 hrs and added several drops of saturated aq, NH4CI solution to quench the reaction. Subsequently, the mixture was added water ( 10 mL). The resulting suspension was filtered and the solid was collected and further purified by preparative HPLC to give compounds (55,75)-36j-la ( 12 mg, 26% yield) and (5S,7/?)-36j-Ib (2 mg, 4% yield) as white solid. (55,75)- 36]- ί a: LC-MS (ESI): mlz 574.1 [M + Hf; Ή NMR (500 MHz, tADMSO): 6 8.52 (q, J= 4.0 Hz, 1 H), 8.21 (s, 1 H), 7.97 (t, J - 7.0 Hz, 2H), 7.86 (s, 1 H), 7.80 (d, J = 9.0 Hz, 1 H), 7.61 (s, 1 H). 7.40 (t, J = 9.0 Hz, 2H), 6.89 (d, J = 9.0 Hz , I H), 4.94 (q, J = 6.5 Hz, 1 H), 4.30 - 4.23 (m, 4H), 3.39 (s, 3H), 3.03 - 2.99 (m, 1 H), 2.84 (d, J = 4.0 Hz, 3H), 1.64 (d, J = 6.0 Hz, 3H) ppm. (55,7/?)- 36j-lb: LC-MS (ESI): mlz 574.1 [M + Hf; ¹ H NMR (500 MHz, cZ-DMSO): 6 8 50 (q, J - 4 5 Hz, 1 H), 7.97 (dd, J, = 5.0 Hz, J₂ = 9.0 Hz. 2H), 7.86 (s, I H), 7,74 (s, 1 H), 7.58 (s, 1 H), 7 51 (dd, J, = 3.0 Hz, Jj = 10.0 Hz, 2H), 7.40 (t, J = 9.0 Hz, 2H), 6.45 (d, J = 10.0 Hz ,1 H), 4.83 (q, J ^« 6.5 Hz, I H), 4.25 - 4.10 (m, 3H), 3.64 - 3.63 (m, 1 H), 3.38 (s, 3H), 2 84 (d, J - 5.0 Hz, 3H), 1 .52 (d, J - 6.5 Hz, 3H) ppm.

1026 1 Synthesis of compounds (55,75 -36j-2a and (55,7 ?)-36j-2b. Following the same procedure as that used for preparing compounds (55,75)-36j-la and (55,7 ?)-36j-ib shown in Scheme 36j and replacing 5-chloropyridin-2-ol with 5 trifiuoromethylpyridin-2-ol, compounds (55,75)-36j-2a and (55,7/?)-36j-2b were obtained as white solid. (55,75)-36j-2a. LC MS (ESI): mlz 608.1 [M + Hf; ¹ H NMR (500 MHz, c/^*-DMSO): δ 8 58 (s, 1 H), 8.52 (q, J - 4 0 Hz, 1 H), 8.07 (dd, J, = 9.0 Hz, J₂ = 2.5 Hz, I H), 7.97 (dd, J, - 9 0 Hz, J₂ 5.0 Hz, 2H), 7 87 (s, 1 H), 7 61 (s, 1 H), 7 42 0, J 9 0 Hz, 2H), 7.03 (d, J =^« 9 0 Hz, I H), 4.95 (q, J 6.5 Hz, 1 H), 4.39 4 24 (ra, 4H), 3 39 (s, 3H). 3 09 3 03 (m, 1 H), 2.84 (d, J 4.0 Hz, 3H), 1.64 (d, J 6.5 Hz, 3H) ppm, (55,7/?) 36j-2b LC MS (ESI): miz 608 I [M + Hf; Ή NMR (500 MHz, cZ-DMSO): δ 8.49 (q, J 4.0 Hz, 1H), 7 96 (dd, J_\ - 9.0 Hz, J₂ 5.5 Hz, 2H), 7.86 (s, 1 H), 7.78 (d, J ** 7.0 Hz, i H), 7.56 (s, 1 H), 7.40 (i, J 9 0 Hz, 2H), 6.80 (s, 1 H), 6.47 (dd, J, - 9.0 Hz, J₂ 2.5 Hz, I H), 4.83 (q, J - 6.5 Hz, 1 H), 4.28 4.21 (m, 3H), 3 76 3 71 (m, 1 H), 3 37 (s, 3H), 2.84 (d, J 4.5 Hz, 3H), 1.49 (d, J 6 5 Hz, 3H) ppm.

|0264| Synthesis of compounds (5_V,7S)-36j-3a and {5S,7i?)-36j-3b. Following the same procedure as that used for preparing compounds (5S,7S)-36j-la and (5S,7 ?)-36j-lb shown in

Scheme 36j and replacing 5-chloropyridin-2 ol with 4-tri fluoromethy lpyr idin 2-ol , compounds

(5S.7S) 36j-3a and (5S,7 ?)-36j-3b were obtained as white solid. (5S,7S)-36j-3a: LC-MS (ESI): miz 608.1 [M + H]⁺; ¹ H NMR (500 MHz, </-DMSO): 6 8.51 (q, J - 4.0 Hz, I H), 8.43 (d, j - 5.0

Hz, I H), 7.97 (dd, J, = 9.0 Hz, Ji = 5.0 Hz, 2H), 7.87 (s, I H), 7 61 (s, I H), 7.40 <t, J 9.0 Hz,

2H), 7.34 (d, i = 5.0 Hz, 1 H), 7.23 (s, 1 H), 4.96 (q, J = 6.5 Hz, 1 H), 4.41 - 4.26 (m, 4H), 3.40 (s,

3H), 3.09 - 3.03 (m, 1 H), 2.84 (d, J = 4.0 Hz, 3H), 1.64 (d, J - 6 5 Hz, 3H) ppm. (5S R) -36j~3b'

LC-MS (ESI), miz 608.1 [M + Hj⁺; Ή NMR (500 MHz, (f DMSO): δ 8 50 (q, J - 4.0 Hz, I H),

8.10 (s, 1 H), 7.96 (dd, J, = 9.0 Hz, J₂ = 5.5 Hz, 2H), 7.87 (s, 1 H), 7.70 (dd, A = 9 5 Hz, J₂ - 2 5

Hz, 1 H), 7.57 (d, J = 5.0 Hz, 1 H), 7.40 (t, J = 9.0 Hz, 2H), 6.57 (d, J 9 5 Hz, 1 H), 4 81 (q, J

5.5 Hz, I H), 4.38 (dd, J_\ = 13.5 Hz, j₂ = 3.0 Hz, I H), 4 27 - 4. l6 (m, 2H), 3.65 (m, I H), 3.38 (s,

3H), 2.87 (d, J^~ 4.5 Hz. 3H), 1.46 (d, J = 6.5 Hz, 3H) ppm.

Scheme 36k

10265| Synthesis of compound {5»S,7/f)-36k-l. Refer to Scheme 36k. A mixture of compound (5S,7/?)-36e-3 (30 mg, 0.065 mmol), 2-bromopyridine (20 mg, 0 13 mmol), Pd₂dba₃ (6.3 mg, 0.0065 mmol), Xantphos ( 1 1 mg, 0.13 mmol) and f BuONa ( 18 mg, 0.195 mmol) in dry DMF (8 ml) was stirred at 100 "C for 5 hrs under an atmosphere of N₂. The mixture was subsequently concentrated and the residue was diluted with water (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (20 mL x 3) and the combined organic extracts were washed with brine and dried over anhydrous NajSO . The solvent was removed and the residue was purified by preparative HPLC to give compound (5S,7 ?)-36k-l ( 13 mg, 24% yield) as a white solid. LC-MS (ESI): mlz 539.2 [M + Hf; Ή NMR (500 MHz, -DMSO): 5 8.51 (q, J = 5.0 Hz, 1 H), 7.98 - 7.95 (m, 3H), 7.83 (s, I H), 7.59 (s, 1 H), 7.37 (t, J - 6.0 Hz, 3H), 6.53(d, J = 8.5 Hz, 1 H), 6.47 (t, J = 5.5 Hz, 2H), 4.89 (q, J ^» 6.5 Hz, 1 H), 4.10 4.07 (m, 2H), 3.40 (s, 3H), 3.35 - 3.30 (m, 2H), 2.85 - 2.80 (m, 1 H), 2.84 (d, J- .5 Hz, 3H), 1.64 (d, J = 6.0 Hz, 3H) ppm.

|0266| Synthesis of compound (f¾7j?)-36h~8. Following the same procedure as that used for preparing compound ( 55,7/?) -36k- 1 shown in Scheme 36k and replacing 2-bromopyridine with 2- bromo-5-fluoropyridine, compound (55,7/?)-36h-8 was obtained as a white solid. LC-MS (ESI): mlz 557.2 [M + Hf .

|0267| Synthesis of compound (&S,7 ?)-36h-9. Following the same procedure as that used for preparing compound (55,7/?) 36k- 1 shown in Scheme 36k and replacing 2-bromopyridine with 2 bromo-5-chloropyridine, compound (55,7/?) 36h-9 was obtained as a white solid. LC-MS (ESI); mlz 557.2 [M + H]^T

Scheme 36.

|0268| Synthesis of compound (55,7fl)-36l-l. Refer to Scheme 361. To a stirred solution of compound (55,7/?) 36e-3 (45 mg, 0 1 mmol) in DMF (2 mL) was added 2-chloro-5- fluoropyrimidine (39 mg, 0 29 mmol) and DIPEA (51 mg, 0 39 mmol). After stirring at 120 "C for 3 hrs, the reaction mixture was concentrated and the residue was purified by preparative HPLC to give compound (55,7/?) 36Ϊ-1 (5 mg, 9% yield) as a white solid. LC-MS (ESI): mlz 558.2 [M + H] ; Ή NMR (500 MHz, tf DMSO): 6 8 51 (q, J - 4.5 Hz, 1 H), 8.37 (s, 1 H), 7.96 (dd, J _I - 8.8 Hz, Ji 5.5 Hz, 2H), 7 84 (s, 1 H), 7 59 (s, 1 H), 7.40 (t, J = 8.5 Hz, 2H), 7.21 (t, J 5.5 Hz, 1 H), 4.89 (q, J - 6,0 Hz, I H), 4.18 (d, J - 13.5 Hz, 1 H), 4.10 (br, 1 H), 3.34 (s, 3H), 3.26 3.18 (m, 2H), 2.84 (d, J = 4.0 Hz, 3H), 2.81 - 2.77 (m, 1 H), 1.62 <d, J 6.0 Hz, 3H) ppm.

|0269| Synthesis of compound (5S,7/?)-36h-7. Following the same procedure as that used for preparing compound (55,7Λ)-36Ι-Ι shown in Scheme 361 and replacing 2-chloro-5- fluoropyrimidine with 2-chloropyrimidine, compound (5S,7/?)-36h-7 was obtained as a white -MS (ESI): mlz 540.2 [M + Hf.

|0270| Synthesis of compound (5S,7J?)-36I-2. Following the same procedure as that used for preparing compound (5S,7 ?)- 361-1 shown in Scheme 361 and replacing 2-chloro-5- fluoropyrimidine with 2,5-dichloropyrimidine, compound (5-?,7/?)-36Ι-2 was obtained as a white solid. LC-MS (ESI): mlz 574.2 [M + Hf; Ή NMR (500 MHz, iZ-DMSO): S 8.50 (q, J- 5.5 Hz, 1 H), 8.35 (s, 2H), 7.97 (dd, J, = I I .O Hz, J₂ = 7.0 Hz, 2H), 7.84 (s, 1 H), 7.59 (s, 1 H), 7.46 (t, J = 7.5 Hz, 1 H), 7.40 (t, J = 1 1.0 Hz, 2H), 4.89 (q, J ~ 8.0 Hz, 1 H), 4.19 - 4.10 (m, 2H), 3.38 3.37 (m, 1 H), 3.35 (s, 3H), 3.28 - 3 21 (m, 1 H), 2.84 (d, J 5 5 Hz, 3H), 2.79 (m, 1 H), 1.62 (d, J - 8.0 Hz, 3H) ppm.

|02711 Synthesis of compound (&S",7 f)-36l-3 Following the same procedure as that used for preparing compound (55,7 ?) 361-1 shown in Scheme 361 and replacing 2-chloro-5- fluoropynmidine with 2-chloro-5 trifluoromethylpyrimidine, compound (5S,7/?)-361-3 was obtained as a white solid LC MS (ESI): mlz 608 2 [M + Hf, Ή NMR (500 MHz, ( -DMSO): δ 8.66 (s, 1 H), 8 63 (s. 1 H), 8 50 (q, J 5.0 Hz, I H), 8 09 (t, J 5.5 Hz, 1 H), 7.97 (dd, J_\ 9 0 Hz, J₂ - 5.5 Hz, 2H), 7.95 (s, 1 H), 7.59 (s. 1 H), 7.40 (t, J - 9.0 Hz, 2H), 4.90 (q, J 7.0 Hz, I H), 4.20 4.14 (m, 2H), 3.45 3 40 (m, I H), 3 32 (s, 3H), 2 85 ~ 2.80 (m, 1 H), 2.84 (d, J 4.5 Hz, 3H), 1.62 (d, J 6.5 Hz, 3H) ppm.

|0272| Synthesis of compound (&S,7i?)-361-4. Following the same procedure as that used for preparing compound (5-?,7/?)-361-l shown in Scheme 361 and replacing 2-chloro-5- fluoropyrimidine with 3,6-dichloropyridazine, compound (5-?,7Λ)-361-4 was obtained as a white solid. LC-MS (ESI): mlz 574.1 [M + Η]^τ; Ή NMR (500 MHz, </-DMSO): δ 8.52 (q, J 5.0 Hz, 1 H), 7.97 (dd, J, = 9.0 Hz, J₂ = 5.5 Hz, 2H), 7.85 (s, 1 H), 7.60 (s, 1 H), 7.43 - 7.36 (m, 3H), 7.15 (t, J= 5.0 Hz, 1 H), 7.00 (d, J- .0 Hz, I H), 4.92 (q, J= 6.5 Hz, 1 H), 4.22 - 4.10 (m, 2H), 3.50 ~

- 2.85 (m, 2H), 2.84 (d, J= 4.5 Hz, 3H), 1.65 (d, J= 6.0 Hz, 3H) ppm.

102731 Synthesis of compound (5£,7Ι?)-36Ι-5. Following the same procedure as that used for preparing compound (55,7 ?)-361-l shown in Scheme 361 and replacing 2-chloro-5- fluoropyrimidine with 3 -chloro-6-tri l uorome thylpyridazine, compound (55",7Λ) 361-5 was obtained as a white solid LC-MS (ES ): mlz 608.2 [M + Hf , Ή NMR (500 MHz, c DMSO): δ 8.52 (q, J= 5.0 Hz, 1 H), 7.97 (dd, J/ - 9,0 Hz, J₂ - 5.5 Hz, 2H), 7.85 (s, 1 H), 7.74 (m, 1 H), 7 70 (d, J - 9.0 Hz, 1 H), 7.60 (s, I H), 7 40 (t, J 8.5 Hz, I H), 7.08 (d, J 9.0 Hz, 1 H), 4 92 (q, J 6.5 Hz, I H), 4.22 - 4.10 (m, 2H), 3.50 {m, 2H), 3.37 (d, J · 5.5 Hz, 3H), 2.90 (m, I H), 2.84 (d, J- - 6.5 Hz, 3H) ppm.

102741 Synthesis of compound (5_S,7J?)-36Ms Following the same procedure as that used for preparing compound (55",7Λ)-361-1 shown in Scheme 361 and replacing 2-chloro-5- fluoropyrimidine with 4 chloroquinazoline, compound (55, 7Λ) 361-6 was obtained as a white solid. LC-MS (ESI): mlz 590.2 [M + Hf ; Ή NMR (500 MHz, i -DMSO): δ 8.52 (q, J 5 0 Hz, 1 H), 8.38 (s, I H), 8.34 (t, J - 15 Hz, I H), 8.29 (d, J - 8.5 Hz, 1 H), 7.97 (dd, J, ^» 9.0 Hz, J₂ - 5.5 Hz, 2H), 7.85 (s, I H), 7.78 (t, J 8.5 Hz, I H), 7 70 (d, J 8.0 Hz, I H), 7.60 (s, I H), 7 53 (t, J 7.0 Hz, 1H), 740 (t, J 85 Hz, 1H),493 (q, J* 6.5 Hz, 1H), 4.31 (m, 1H), 4.23 (m, IH), 3.66- (m, IH), 2.84 (d_tJ 40 Hz, 3H), 1.64 (d,J= 6.5 Hz, 3H) ppm.

|02751 Synthesis of compound (55,7Λ)-361-7. Following the same procedure as that used for preparing compound ( 55", 7Λ) 361-1 shown in Scheme 361 and replacing 2-chIoro-5- fluoropyrimidine with 2-chloroquinazoline, compound (55,7/?) 361-7 was obtained as a white solid. LC MS (ESI): m/z 5902 [M + Hf, Ή NMR (500 MHz, -DMSO): δ 9.16 (s, 1 H), 8.50 (q, J- 5.5 Hz, 1H),7.97 (dd,J,= 9.0 Hz, J₂ - 5.5 Hz, 2H), 7.84 (s, IH), 7.81 (d,J=6.5 Hz, 1H), 7.70 (m, 1 H), 760 (s, I H), 747 (d, J - 8.0 Hz, 1 H), 7.40 (t, J - 8.5 Hz, 1 H), 7.34 (m, 1 H), 7.24 (t, J = 8.0 Hz, IH), 4.92 (q, J 60 Hz, IH), 4.28 - 4.22 (m, 2H), 3.48 - 3.38 (m, 2H), 3.35 (s, 3H),

=4.0 Hz, 3H), l.64(d,J-6.0 Hz, 3H) ppm.

|0276| Synthesis of compound (5_ϊ,71?)-361-8. Following the same procedure as that used for preparing compound (55",7/?)-361-l shown in Scheme 361 and replacing 2-chloro-5

fluoropyrimidine with 4-chlorothieno[3,2-i]pyrimidine, compound (55,7Λ)-361-8 was obtained as a white solid. LC-MS (ESI): m/z 596.1 [M + Hf ; Ή NMR (500 MHz,

δ 8.50 (q, J* 5.5 Hz, IH), 8.45 (s, IH), 8.10 (d, J =5.5 Hz, IH), 7.98-7.94 (m, 3H),7.84 (s, IH), 759 (s, IH), 7.42 - 7.28 (m, 3H), 4.92 (q, J= 6.5 Hz, 1 H), 4.24 - 4.20 (m, 2H), 3.62 - 3.48 (m, 2H), 334 (s, 3H), 2.90- =4.5 Hz, 3H), 1.62 (d,J= 6.5 Hz, 3H) ppm.

4-F-PnO-, R

[02771 Synthesis of compound (&S,7-S)-37-3a-l. Refer to Scheme 37. To a stirred solution of compound (55,75)-37-1β (60 mg, 0. 1 15 mmol) in DCE (3 mL) was added PC1₅ (72 mg, 0.344 mmol) at rt. After refluxing for 3 hrs, the reaction mixture was cooled to rt. Subsequently,

NHjOH HC1 (23 mg, 0.344 mmol) and DIPEA (369 mg, 2.86 mmol) were added and the resulting mixture was re fluxed for 3 hrs. The mixture was concentrated and the residue was purified by preparative HPLC to give compound (5-?,75 37-3a-l (40 mg, 65% yield) as a white solid. LC-MS (ESI); m/z 540.1 [M + Hf; Ή NMR (500 MHz, i -DMSO): 6 9.81 (s, 1 H), 8.40 (s, 1 H), 7.94 - 7.97 (m, 2H), 7.90 (s, I H), 7.46 (s, 1 H), 7.37 - 7 44 (t, 2H), 6.25 (q, J = 5.0 Hz, 1 H), 4.99 (q, J = 6.5 Hz, 1 H), 4.40 (t, 7 = 6.5 Hz, 1 H), 4.20 4 22 (m, 1 H), 3.40 (s, 3H), 3.23 (br, 1 H), 3.04 (s, 3H), 2.92 - 2.97 (br, 1 H), 2.48 (d, J = 5.5 Hz, 3H), 1 64 (d, J - 6.5 Hz, 3H) ppm.

|0278| Synthesis of compound (55,75 7-3a-2. Following the same procedure as that used for the preparation of compound (55,7S)-37-3a-l and replacing NH₂OH HCl with NH₂OMe HCl, compound (5S,7S)-37«3a-2 (45 mg, 71 % yield) was obtained as a white solid. LC-MS (ESI): m/z 554.1 [M + Hf; Ή NMR (500 MHz,

δ 7.94 (m, 2H), 7.89 (s, 1 H), 7.47 (s, 1 H), 7.43 (m, 2H), 6.48 (q, J = 4.5 Hz, 1 H), 4.98 (m, 1 H), 4.39 (m, I H), 4.20 (m, 1 H), 3.72 (s, 3H), 3.39 (s, 3H), 3.23 3.30 m, 2H), 3.04 (s, 3H), 2.93 (m, 1 H), 2.45 (d, J = 6.5 Hz, 3H), 1.64 (d, J = 6.5 Hz, 3H) ppm.

Scheme 38

(0279] Synthesis of compounds 38-14a/b, 38-15a b and related derivatives. Refer to Scheme 38. Following the procedures described in a reported protocol (Aust, J. Chem. 1981, 34, 927) with some modification, compound 38-4 is obtained using commercially available compound 38-1 as the starting material. De-methylation of compound 38-4, followed by reduction of the -NO2 moiety and acylation of the resulting product gives compound 38-6. Sonogashira coupling of compound 38-6 with 4-fluorophenyl acetylene or 4-fluorophenoxyl-4-phenylacetylene, followed by soapnification, cyclization, and mesylation gives compound 38-9a or 38-9b, which is converted to compound 38- 10a or 38- 10b by a Pd-mediated vinylation. A-alkylation of compound 38- 10a or 38-10b with (/?)-(2,2-dimethyl-l,3-dioxolan-4-yl)methyl 4- methylbenzenesulfonate, followed by TsOH-mediated one-pot deprotection and cyclization gives compound 38-12a or 38-12b, which is converted to compound 38-13a or 38-13b by selective iodi nation, followed by a Pd-mediated carbonylation. Finally, following the procedures described for the preparation of those functionalized benzofuran derivatives described in Schemes 34a, 35, 35a, 35b, 36a, 36b, and 37 and using 38-13a or 38- 13b as the substrate, compounds 38-14a/b, 38- 15a b, O-alkylated or -acylated derivatives of 38-14a b, or W-hydroxy(or alkoxyl)-W- methylacetimidamide derivatives of 38-14a b or 38-15a/b are obtained.

Scheme 39

3S-12B-1 R = F. R" = -Me 3S-13S-1 R = F. " = -Me

39-12*-2 = F. R- = -OMe 39.13a.2 R = F. R- = -OMe

39-12b-1 R = 4-F-PhO-. R' 38-136-1 R ^F-PhO-. R"

39-12b-2 = 4-F-PhO-. R' 39.13b-2 R s4-F-PhO-. R-

[0280] Synthesis of compounds 39-12a b, 39-13a b and related derivatives. Refer to Scheme 39. Selective formylation of commercially available 39-1, followed by Baeyer-Villiger reaction and soapnification gives compound 39-3. De-methylation of compound 39-3 and acylation of the resulting phenol derivative give compound 39-4, which undergoes a Sonogashira coupling with 4- fluorophenylacetylene or 4-fluorophenoxyl-4-phenylacetylene to give compound 39-5a or 39-5b. One-pot benzofuran formation and carbonylation of compound 39-5a or 39-5b gives compound 39-6a or 39-6b, which is nitrated, followed by triflation and a Pd-mediated vinylation to give compound 39-8a or 39-8b. Finally, following the procedures described for the preparation of those functionalized benzofuran derivatives described in Schemes 29, 34a, 35, 35a, 35b, 36a, 36b, and 37 and using 39-8a or39-8b as the substrate, compounds 39-12a/b, 39-13a b, -alkylated or -acylated derivatives of 39-12a/b, orJV-hydroxy(or alkoxy.)-N-methylacetim idamide derivatives of 39-12a b or 39-13a/b are obtained

[0281] Step 1. Refer to Scheme 39a. To a stirred solution of compound 39a- 1 (5.1 g, 17 mmol) (prepared by following the procedure descried in WO200759421 with some modifications) in CH₃CN (300 mL) was added Selectfluor^® (7.25 g, 20.4 mmol) portion-wise at rt. After stirring at rt overnight, the reaction mixture was concentrated. The residue was added water (50 mL) and the resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether EtOAc = 9/1 (v V)) to give the desired regio- isomer compound 39a-2 (1.35 g, 25% yield) as a yellow solid. LC-MS (ESI): m/z 319.1 [M + H]⁺.

[0282] Step 2. To a stirred solution of H 0₃ (5 mL) in DCM (15 mL) at 0°C was added a solution of compound 39a-2 (954 mg, 3 mmol) in DCM (15 mL) dropwise (Caution: the reaction mixture must be kept around 0 °C). After stirring at 0 °C for 1 hr, the reaction mixture was slowly warmed to rt and diluted with ice-water (15 mL). The organic phase was washed with ¾0 (25 mL x 3), dried over anhydrous a₂S0₄, and concentrated. The residue was dried in vacuo to give crude compound 39a-3 (850 mg) as a dark yellow solid, which was used for the next step without further purification. LC-MS (ESI): m/z 364.1 [M + H .

[0283] Step 3. To a stirred solution of crude compound 39a-3 ( 1.24 g, about 3.4 mmol) in DCM (50 mL) was added DIPEA (1.7mL, 10.2 mmol) and DMAP (5 mg, 0.34 mmol), followed by Tf₂0 (0.86 mL, 5.1 mmol) at 0 °C. After stirring at rt for 5 hrs, the reaction mixture was diluted with water (50 mL) and DCM (50 mL). The organic phase was washed with brine (50 mL), dried over anhydrous Na2S0₄. and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether/EtOAc = 15/1 (v/v)) to give compound 39a-4 (850 mg, 51% yield) as a yellow solid. LC-MS (ESI): m/z 496.0 [M + H]⁺.

[0284] Step 4. To a solution of the compound 39a-4 (1.5 g, 3.0 mmol) in DME (50 mL) and 2 M Na₂C0₃ solution (4 mL) was added Pd(PPh₃)₂Cl2 (210 mg, 0.3 mmol), the resulting mixture was saturated with N2. Next, vinylboronic acid pinacol ester (0.6 mL, 4.5 mmol) was added and the resulting mixture was stirred at 80 °C for 4 hrs under an atmosphere of N₂. Subsequently, the mixture was concentrated and the residue was added water (50 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (25 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na₂S0₄, and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether/EtOAc = 15/1 (v/v)) to give compound 39a-5 (1.0 g, 89% yield) as a yellow solid. LC-MS (ESI): m/z 374.1 [M + H]⁺.

10285] Step 5. To a stirred solution of the compound 39a-5 (1.0 g, 2.7 mmol) in EtOAc (30 mL) was added SnC ₂-2H20 ( 1.22 g, 5.4 mmol) portion-wise. After refluxing for 1 hr under an atmosphere of N₂, the reaction mixture was cooled to rt and slowly added saturated aq. NaHC0₃ solution (20 mL). The mixture was filtered through Celite^® 545 and the filtered cake was washed with EtOAc (25 mL x 3). The organic phase of the filtrate was dried over anhydrous Na₂S0₄ and concentrated. The residue was dried in vacuo to give the amine as a light yellow solid, which was used for the next step without further purification. LC-MS (ESI): m/z 344.1 [M + H]⁺. Next, to a stirred solution of the crude amine in DCM (30 mL) was added TEA ( 1.8 mL, 13.5 mmol) and DMAP (50 mg), followed by MsCl (0.8 mL, 10 mmol) at 0 °C. After stirring at rt overnight, the reaction mixture was added saturated aq. NaHC0₃ solution (5 mL), water (25 mL), and DCM (50 mL). The organic phase was washed with brine (25 mL), dried over anhydrous NaiSG*, and concentrated. The residue was purified by silica gel column (Petroleum ether EtOAc = 2 1 (v/v)) to give compound 39a-6 (700 mg, 62% yield for two steps). LC-MS (ESI): mk 422.1 [M + H]⁺. (0286] Step 6. Following the same procedure as that used for preparing compound 34a-2 show in Scheme 34a and replacing compound 29-3 with 39a-6, compound 39a-7 (66 mg, 26% yield) was obtained as a yellow oil. LC-MS (ESI): mlz 536.1 [M + Hf.

[0287] Step 7. Following the same procedure as that used for preparing compound (55,75)-34-2a shown in Scheme 34a and replacing compound 34a-2 with 39a-7, compound 39a-8 (35 mg, 25% yield) was obtained as a white solid. LC-MS (ESI): mlz 518.1 [M + Na]⁺; Ή NMR (500 MHz, CDC1₃): δ 7.93 (dd, J,= 9.0 Hz, J₂ = 5.5 Hz, 2H), 7.32 (s, 1H), 7.17 (t, J= 9.0 Hz, 2H), 5.80 (q, J = 7.5 Hz, 1H), 4.40 (q, J= 7.0 Hz, 1H), 4.04 (d, J= 14.0 Hz, 1H), 3.76 - 3.61 (m, 2H), 3.25 (s, 3H), 3.30 - 3.20 (m, 1 H), 2.05 - 1.90 (m, 1H), 1.75 (d, J= 7.0 Hz, 3H), 1.36 (d, J = 7.5 Hz, 3H) ppm.

[0288] Step 8. Following the same procedure as that used for preparing compound 1-15 shown in Scheme 1 (WO2012/058125) and replacing compound 1-14 with 39a-8, compound 39a-9 was obtained as a light solid. LC-MS (ESI): mlz 490.0 [M + Na]⁺.

|0289] Step 9. Following the same procedure as that used for preparing compound 1-16 shown in Scheme 1 (WO2012/058125) and replacing compound 1-15 with 39a-9, compound 39-12a-l was obtained as a white solid. LC-MS (ESI): mlz =481.1 [M + H]⁺; Ή NMR (500 MHz, c -DMSO): δ 8.71 (q, J= 4.0 Hz, 1 H), 7.89 (dd, J, = 9.0 Hz, J₂ = 6.0 Hz, 2H), 7.73 (s, 1H), 7.42 (t, J= 9.0 Hz, 2H), 5.57 (q, J= 7.0 Hz, 1H), 4.83 (q, J= 5.5 Hz, 1H), 4.17 (d, J= 14.0 Hz, 1H), 3.48 - 3.43 (m, l H), 3.45 (s, 3H), 3.40 - 3.30 (m, 1 H), 2.93 - 2.92 (m, 1 H), 2.81 (d, J= 4.5 Hz, 3H), 1.61 (d,J= 7.0 Hz, 3H) ppm; ^!9F NMR (376 MHz, c -DMSO): δ -110.21 , -123.87 ppm.

Scheme 40

[0290 [ Step 1. Refer to Scheme 40. To a stirred solution of 6-amino-pyridin-2-ol (5g, 45.5 mmol) in acetic acid (50 mL) was added a solution of N-iodosuccinimide (20.45 g, 90.9 mmol) in acetic acid (90 mL). After stirring at rt for lhr, the resulting precipitate was collected by filtration, washed with acetic acid, and dried in vacuo to give compound 40-2 (12.5g, 84% yield) as yellow solid. LC-MS (ESI): m/z 462.7 [M + Hf.

[0291] Step 2. A solution of compound 40-2 (10 g, 27.6 mmol) in Ac₂0 (50 mL) was stirred at 90 °C for 1 hr and then concentrated. The residue was carefully added saturated aq. NaHCOj solution (100 mL) at 0 °C and the resulting mixture was extracted with DCM (150 mL x 3). The organic extracts were combined, dried over anhydrous Na₂S0₄, and concentrated. The residue was dried in vacuo to give compound 40-3 ( 15 g, 68 % yield) as a light yellow solid. LC-MS (ESI): m/z 510.5 [M + H]⁺. (0292] Step 3. To a stirred solution of compound 40-3 (10 g, 20.5 mmol) and EtjN (6 mL, 41 mmol) in THF (100 ml) were added Cul (0.18 g, 0.943 mmol) and Pd(PPh₃)₂Cl₂ (575 mg, 0.82 mmol) at 0 °C under an atmosphere of N₂. Subsequently, a solution of 4-fluorophenylacetylene (2.5 g, 20.5 mmol) in THF (80 mL) was added dropwise over a period of 2 hrs. After stirring at 0

°C for 5 hrs and then at rt overnight, the reaction mixture was filtered and the filtrate was concentrated. The residue was dried in vacuo to give crude compound 40-4a as a brown solid, which was used directly for the next step without further purification, LC-MS (ESI): mlz 502.6 [M + Hf.

[0293 [ Step 4. To a stirred solution of compound 40-4a (1.5 g, 3.1 mol) in MeOH (10 mL) was added K₂C0₃ ( 1.7 g, 12.4 mmol) at rt. After stirring at rt for 16 hrs, the reaction mixture was concentrated and the residue was diluted with THF (25 mL). The mixture was filtered through a Celite^®545 plug and the filtered cake was washed with THF (25 mL x 2). The filtrate was concentrated and the residue was dried in vacuo to give crude compound 40-5a (700 mg, 63% yield) as a yellow solid. LC-MS (ESI): mlz 354.8 [M + Hf.

10294] Step 5. To a stirred solution of compound 40-5a (5 g, 14.1 mol) in anhydrous THF (50 mL) was added 1 M TBAF in THF (14.1 mL). After refluxing for 16 hrs, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography

(DCM Petroleum ether = 1/1 (vV)) to give compound 40-6a (3.5 g, 70% yield) as a gray solid. LC-MS (ESI): m/z 354.7 [M + H]⁺.

[0295] Step 6. To a stirred solution of compound 40-6a (5.0 g, 14 mmol) and anhydrous Et₃N ( 11.6 mL, 85 mmol) in dry DCM (200 mL) at 0 °C was added MsCl (4.3 mL, 56 mmol) dropwise. After stirring at rt for 16 hrs, the reaction mixture was concentrated and the residue was diluted with water (100 mL). The mixture was extracted with EtOAc (100 mL x3). The organic extracts were combined, dried with anhydrous Na₂SC>4, and concentrated. The residue was dried in vacuo and then dissolved in MeOH (150 mL), followed by adding LiOH ( 1 M aq. solution, 25 mL). After stirring at rt for 1 hr, the reaction mixture was concentrated. The residue was added water ( 100 mL) and the mixture was extracted with ether (50 mL x 3). The aq. layer was adjusted to pH 6 with saturated aq. citric acid. The precipitate was collected by filtration, washed with water, and dried in a lyophilizerto give compound 40-7a (400 mg, 65% yield) as a brown solid. LC-MS

m (ESI): mlz 510.5 [M + H]⁺; Ή NMR (500 MHz, i/'-DMSO): δ 9.90 (br, 1H), 8.59 (s, 1 H), 8.00 (t, J= 5.5 Hz, 2H), 7.39 - 7.35 (m, 3H), 3.40 (s, 3H) ppm.

[0296] Step 7. To a stirred solution of the compound 40-7a (2.5 g, 5.8 mmol) in DME (30 mL) and 2 M aq. Na₂C0₃ solution (7.5 mL) was added Pd(PPh₃)₂Cl₂ (407 mg, 0.58 mmol), followed by vinylboronic acid pinacol ester (1.13 g, 8.7 mmol) under an atmosphere of N₂. After stirring at 80 °C for 4 hrs, the reaction mixture was concentrated and the residue was poured into water ( 100 mL). The mixture was extracted with EtOAc (50 mL x 3). The extracts were combined, washed with brine, dried with anhydrous Na₂S0₄, and concentrated. The residue was purified by silica gel column chromatography (DCM) to give compound 40-8a (900 mg, 47% yield) as a yellow solid. LC-MS (ESI): mJz 333.1 [M + Hf.

10297] Step 8. To a stirred solution of compound 40-8a (900 mg, 2.7 mmol) in dry DMF (5.4 mL) was added Cs₂C⁽¼ (3.52 g, 10.8 mmol). The mixture was stirred at rt for 30 min and then ( ?)-(2,2-dimethyl-l,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (3.1 1 g, 10.8 mmol) was added. After stirring at 1 10 °C for 48 hrs, the reaction mixture was concentrated. The residue was diluted with water (100 mL) and the resulting mixture was extracted with EtOAc (50 mL x 3). The extracts were combined, washed with brine, dried with anhydrous Na₂S0₄, and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether DCM = 2/1

(v/v)) to give compound 40-9a (600 mg, 50% yield) as a yellow solid. LC-MS (ESI): mlz 447.1

[0298 [ Step 9. To a stirred solution of compound 40-9a (800 mg, 1.76 mmol) in DCE ( 100 mL) at 90 °C was added TsOH (600 mg, 3.5 mmol). After re fluxing overnight, the reaction mixture was concentrated. The residue was dissolved in DCM (100 mL) and the resulting mixture was washed with water (25 mL x 2), dried with anhydrous Na₂SC>4, and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether/EtOAc = 2/1 (v/v) then

DCM acetone = 20/1 (v/v)) to give compound 40-10a (400 mg, 52%, yield; (5S, 7S)/(57?, 75) ~ 1/1) as a white solid. The desired diastereomer was isolated by chiral HPLC. LC-MS (ESI): mlz 407.1 [M + Hf; Ή NMR (500 MHz, cZ-DMSO): 5 8.19 (s, 1H), 8.03 (dd, J_/ = 5.5 Hz, J₂ = 8.5 Hz, 2H), 7.51 (s, 1H), 7.39 (t, J = 8.5 Hz, 2H), 4.86 (t, J= 6.0 Hz, 1H), 4.78 (q,J = 6.5 Hz, 1H), 4.19 (d, J= 13.0 Hz, 1H), 3.83 (t, J= 5.5 Hz, I H), 3.53 (s, 3H), 3.51- 3.49 (m, 1H), 3.30 - 3.26 (m, 1H), 2.85 - 2.81 (m, I H), 1.64 (d, J= 6.5 Hz, 3H) ppm. 10299] Step 10. To a solution of compound 40- 10a (200 mg, 0.5 mmol) and TFA (1 mL) in CH₂Cb (2 mL) was added NIS (160 mg, 0.60 mmol) portionwise at rt. After stirring at rt for 3 hrs, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (Petroleum ether/EtOAc = 4/1 (v/v)) to give compound 40-1 la (200 mg, 76% yield) as a yellow solid. LC-MS (ESI): mlz 533.0 [M + H]⁺.

[0300] Step 11. To a solution of compound 40- 11 a ( 100 mg, 0.19 mmol) and Et₃N (0.13 mL, 0.94 mmol) in DMF (3 mL) and MeOH (3 mL) was added

( 13 mg, 0.019 mmol) under an atmosphere of N₂. Subsequently, the reaction mixture was saturated with CO and stirred at 60 °C for 24 hrs under an atmosphere of CO. The reaction mixture was concentrated and the residue was diluted with water (25 mL). The mixture was extracted with EtOAc (25 mL x 4). The organic extracts were combined, washed with brine, dried with anhydrous a₂S0₄, and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether EtOAc = 8/1 (v v)) to give compound 40-12a (70 mg, 79% yield) as a yellow solid. LC-MS (ESI): mlz 465 Λ [M + H]⁺.

[0301] Synthesis of compound 40-14a. Following the same experimental procedures as described for the conversion of compound 1-14 to 1-16 in Scheme 1 (WO2012/058125) and replacing compound 1-14 with 40-12a, compound 40-14a was obtained as a white solid. LC-MS (ESI): mlz 464.1 [M + H]⁺; Ή NMR (500 MHz, i/-DMSO): δ 8.56 (q, J=5.0 Hz, 1 H), 8.09 (s, 1H), 8.03 (dd, J, = 5,0 Hz, J₂ = 9.0 Hz, 2H), 7.40 (t, J= 9.0 Hz, 2H), 4.87 (t, J= 7.0 Hz, 1H), 4.81 (q, J= 6.5 Hz, 1H), 4.21 (d, J= 13.5 Hz, 1 H), 3.84 (t, J= 7.0 Hz, 1H), 3.51 (s, 3H), 3.51- 3.49 (m, 1 H), 3.30 - 3.26 (m, 1 H), 2.85 (s, 3H), 2.85 -2.81 (m, 1 H), 1.65 (d, J = 6.5 Hz, 3H) ppm.

[0302] Synthesis of compound 40- 14b. Following the same experimental procedures as described for the conversion of compound 1-14 to 1-16 in Scheme 1 (WO2012/058125) and replacing compound 1-14 with 40-12a, and MeNH₂ HCl with MeONH₂ HCl, compound 40-14b was obtained as a white solid. LC-MS (ESI): mlz 479.4 [M + Hf. Ή NMR (500 MHz, ct- DMSO): δ 8.10 (s, 1H), 8.04 (dd, J_x = 5.0 Hz, J₂ = 8.5 Hz, 2H), 7.43 (t, J= 8.5 Hz, 2H), 4.87 (t, J = 7.0 Hz, 1H), 4.81 (q, J= 6.0 Hz, 1H), 4.21 (<L J = 13.5 Hz, 1 H), 3.85-3.83 (m, 1H), 3.78 (s, 3H), 3.54 (s, 3H), 3.50 - 3.49 (m, 1H), 2.86 - 2.81 (m, 1H), 1.65 (d, J= 6.5 Hz, 3H) ppm. [0303 J Synthesis of compound 40-15a. Following the same experimental procedures as described for the conversion of compound 28-1 lb to 28-13b in Scheme 28 and replacing compound 28-1 lb with 40-14a, compound 40-15a was obtained as a white solid. LC-MS (ESI): mlz 526.1 [M + H]⁺; Ή NMR (500 MHz, cZ-DMSO): δ 8.56 (q, J= 4.5 Hz, 1 H), 8.1 1 (s, 1H), 8.04 (dd, J i = 6.0 Hz, J₂ = 9.0 Hz, 2H), 7.41 (t, J = 9.0 Hz, 2H), 4.89 (q,J= 6.0 Hz, 1 H), 4.29 (t, J= 7.0 Hz, 1H), 4.19 (d, 7=14.0 Hz, 1H), 3.53 (s, 3H), 3.41- 3.36 (m, 2H), 3.05 (s, 3H), 2.97 (t, J= 12.5 Hz, 1H), 2.85 (d, J= 5.0 Hz, 3H), 1.69 (d, J = 6.5 Hz, 3H) ppm.

[0304] Synthesis of compound 40-15b. Following the same experimental procedures as described for the conversion of compound 28-1 lb to 28-13b in Scheme 28 and replacing compound 28-1 lb with 40-14b, compound 40-15b was obtained as a white solid. LC-MS (ESI): mlz 542.1 [M + H]⁺. Ή NMR (500 MHz, iZ-DMSO): δ 8.36 (s, 1H), 8.13 (s, 1H), 8.05 (m, 2H), 7.43 (t, 7 = 8.0 Hz, 2H), 4.90 (q, J= 6.5 Hz, 1 H), 4.30 (t, J = 6.0 Hz, 1H), 4.19 (d, J= 14.0 Hz, 1H), 3.78 (s, 3H), 3.75-3.73 (m, 1H), 3.53 (s, 3H), 3.54- 3.52 (m, 1 H), 3.05 (s, 3H), 2.97 (t, J=

= 6.0 Hz, 3H) ppm.

[0305] Step 1. Refer to Scheme 42a. To a stirred solution of sodium propane-2-thiolate (/-PrSNa) (120 mg, 1.22 mmol) in anhydrous DMF (8 mL) was added I (267 mg, 1.62 mmol) at rt under an atmosphere of N₂. After stirring at rt for 30 min, compound 36e-l (500 mg, 0.81 mmol) was added in small portions. The resulting mixture was stirred at rt overnight and then diluted with ice water. The suspension was filtered and the solid was washed with water and dried in vacuo to give crude compound 42a-l (450 mg, 67% purity based on LC-MS), which was used for the next step without further purification. LC-MS (ESI): mlz 521.2 [M + Hf.

[0306] Step 2. To a stirred solution of compound 42a-l (450 mg, 0.81 mmol) in acetone (50 mL) was added hydrogen peroxide (20 mL, 30 wt. % in H₂Q at rt. After stirring at 60 °C overnight, the reaction mixture was cooled to rt and quenched with saturated aq. Na₂S0₃ solution (20 mL). The mixture was concentrated to remove acetone and the resulting suspension was filtered. The solid was washed with water and purified by preparative HPLC to give compound 42a-2 (110 mg, 25% yield) as a white solid. LC-MS (ESI): mlz 553.1 [M + Hf; Ή NMR (500 MHz, t/-DMSO): δ 8.53 (d, J= 4.5 Hz, 1H), 7.98 (dd, Ji = 5.5 Hz, J₂= 8.5 Hz, 2H), 7.88 (s, 1H), 7.60 (s, 1H), 7.41 (t, J = 8.5 Hz, 2H), 4.97 (q, J= 6.5 Hz, 1H), 4.39 (t, J = 10.5 Hz, 1H), 4.21 (t, J = 14.5 Hz, 1H), 3.41 (s, 3 H), 3.41- 3.87 (m, 2H), 3.18 (dd. J, = 1.5 Hz, J₂ = 15.0 Hz, 1H), 2.94 (br, 1H), 2.85 (d, J = J = 6.0 Hz, 3H), 1.26 (d, J= 7.0 Hz, 3H), 1.23 (d, J = 7.0 Hz, 3H) ppm.

103071 Synthesis of compound 42a-3. Following the same procedure as that used for preparing compound 42a-2 shown in Scheme 42a and replacing i-PrSNa with EtSNa, compound 42a-3 was obtained as a white solid. LC-MS (ESI): mlz 539.1 [M + Hf.

103081 Synthesis of compound 42a-4. Following the same procedure as that used for preparing compound 42a-2 shown in Scheme 42a and replacing i-PrSNa with /-BuSNa, compound 42a-4 was obtained as a white solid. LC-MS (ESI): mlz 567.2 [M + Hf.

10309] Synthesis of compound 42a-5. Following the same procedure as that used for preparing compound 42a-2 shown in Scheme 42a and replacing /-PrSNa with 4-F-PhSNa, compound 42a-5 was obtained as a white solid. LC-MS (ESI): mlz 605.1 [M + Hf.

(03101 Synthesis of compound 42a-6. Following the same procedure as that used for preparing compound 42a-2 shown in Scheme 42a and replacing /-PrSNa with 4-F-BnSNa, compound 42a-6 was obtained as a white solid. LC-MS (ESI): mlz 619.1 [M + Hf.

1031 II Synthesis of compound 42a-7. Following the same procedure as that used for preparing compound 42a-2 shown in Scheme 42a and replacing i-PrSNa with HOCH2CH2SH under the condition of ^CCVanhydrous DMF/80 °C/overnight, the anticipated hydroxyethyl thiol ether was obtained. Subsequently, acylation of the hydroxyethylthiol ether under the condition of

Ac20/Et3N/DCM/rt/ovemight, followed by oxidation of the thioether moiety under the condition of H2<I)2/acetone/60 ⁰C/ovemight and soapnification of the acetate residue under the condition of 2C0₃ MeOH H₂0/rt 4 hr gave compound 42a-7 as a white solid. LC-MS (ESI): miz 555.1 [M + +.

]0312] Synthesis of compound 42a-8. Following the same procedure as that used for preparing compound 42a-7 described above and replacing HOCH2CH2SH with HOCH₂CH₂CH₂SH, compound 42a-8 as obtained a white solid. LC-MS (ESI): miz 569.1 [M + Hf.

Scheme 42b

J0313J Step 1. Refer to Scheme 42b. To a stirred solution of compound 36e-l (1.0 g, 1.62 mmol) in anhydrous DMF ( 10 mL) was added potassium ethanethioate (KSAc) (277 mg, 2.43 mmol) at rt under an atmosphere of Ar. After stirring at 90 °C for 3 hr, the reaction mixture was cooled to rt and added ice water (60 mL). The suspension was filtered and the solid was washed with water and dried in vacuo to give crude compound 42b-l (700 mg, 83% purity based on LC-MS) as a pale yellow solid, which was used for the next step without further purification. LC-MS (ESI): mlz 521.1 [M + H]\

I0314I Step 2. To a stirred solution of compound 42b-2 (100 mg, 0.192 mmol) and 4- chlorotetrahydro-2H-pyran (46 mg, 0.384 mmol) in anhydrous DMF/EtOH (2 rnL/l mL) was added NaOH (15 mg, 0.38 mmol) at 0 °C under an atmosphere of Ar. After stirring at 50 °C for 16 hr, the reaction mixture was cooled to rt and added ice water (30 mL). The mixture was extracted with EtOAc (30 mL x 3) and the combined organic extracts were washed with brine and dried over anhydrous Na₂S0₄. The solvent was removed and the residue was dried in vacuo to give crude compound 42b-2 (80 mg, 87% purity based on LC-MS) as a white solid, which was used for the next step without further purification. LC-MS (ESI): mlz 563.2 [M + H|\

103151 Step 3. To a stirred solution of compound 42b-2 (50 mg, 0.088 mmol) in AcOH (3 mL) was added H₂0₂ (3 mL, 30 wt.% in H₂0). After stirring at 50 °C for 3 hr, the reaction mixture was cooled to rt and added ice water (20 mL). The suspension was filtered and the solid was washed with water and purified by preparative HPLC to give compound 42b-3 (15 mg, 29% yield) as a white solid. LC-MS (ESI): mlz 595.2 [M + Hf; Ή NMR (500 MHz,

5 8.53 (q, J= 4.0 Hz, 1H), 7.97 (dd, J, = 8.5 Hz, J? = 5.5 Hz, 2H), 7.88 (s, 1 H), 7.61 (s, 1H), 7.41 (t, J= 8.5 Hz, 2H), 4.99 (q, J= 6.0 Hz, 1H), 4.41 (t, J = 10.5 Hz, 1H), 4.22 (d, J= 10.0 Hz, 1H), 4.04 - 3.93 (m, 2H), 3.52 (t, J = 11.5 Hz, 1H), 3.39 (s, 5H), 3.29 - 3.19 (m, 2H), 2.91 - 2.84 (m, 1 H), 2.84 (t, J = 4.5 Hz, I H), 1.96 - 1.90 (m, 1 H), 1.67 (m, J = 6.0 Hz, 1 H), 1.56 - 1.68 (m, 2H) ppm.

10316] Synthesis of compound 42b-4. Following the same procedure as that used for preparing compound 42b-3 shown in Scheme 42b and replacing 4-chlorotetrahydro-2/ -pyrane with bromocyclobutane, compound 42b-4 was obtained as a white solid. LC-MS (ESI): mlz 565.1 [M

+ Hf.

10317] Synthesis of compound 42b-5. Following the same procedure as that used for preparing compound 42b-3 shown in Scheme 42b and replacing 4-chlorotetrahydro-2H-pyrane with 3- bromooxetane, compound 42b-5 was obtained as a white solid. LC-MS (ESI): mlz 567.1 [M + +.

10318] Synthesis of compound 42b-6. Following the same procedure as that used for preparing compound 42b-3 shown in Scheme 42b and replacing 4-chlorotetrahydro-2H-pyrane with tert- butyl 3-bromoazetidine- 1 -carboxy late, compound 42b-6 was obtained as a white solid. LC-MS

+.

10319] Synthesis of compound 42b-7. Following the same procedure as that used for preparing compound 42b-3 shown in Scheme 42b and replacing 4-chlorotetrahydro-2H-pyrane with chlorocyclopentane, compound 42b-6 was obtained as a white solid. LC-MS (ESI): mlz 579.2 [M

|0320| Synthesis of compound 42b-8. Following the same procedure as that used for preparing compound 42b-3 shown in Scheme 42b and replacing 4-bromtetrahydro-2H-pyrane with tert- butyl 4-bromopiperidine- 1-carboxylate, compound 42b-8 was obtained as a white solid. LC-MS

(ESI): mlz 694.3 [M + Hf.

103211 Synthesis of compound 42b-9. Treatment of compound 42b-8 with 4.0 N HC1 in dioxane, followed by preparative HPLC purification gave compound 42b-9 as a white solid. LC-MS (ESI):

+.

103221 Synthesis of compound 42b-10. Treatment of compound 42b-9 with paraformalde in the presence of AcOH and NaBH₃CN in EtOH, followed by preparative HPLC purification gave

. LC-MS (ESI): mlz 608.2 [M + Hf.

I0323| Synthesis of compound 42b-l l. Treatment of compound 42b-9 with 2,2,2-trifluoroethyl trifluoromethanesulfonate in the presence of Et₃N in DCM at reflux, followed by preparative

42b- 11 as a white solid. LC-MS (ESI): mlz 676.2 [M + H]⁺.

103241 Synthesis of compound 42b-12. Treatment of compound 42b-9 with methyl

chloroformate in the presence of Et₃N in DCM at rt, followed by preparative HPLC purification gave compound 42b-12 as a white solid. LC-MS (ESI): mlz 652.2 [M + H]⁺.

J0325I Step 1. Refer to Scheme 42c. To a stirred solution of compound 36b-3b (3 g, 4.75 mmol) in anhydrous DMF (30 mL) was added KSAc (650 mg, 5.7 mmol) at rt under an atmosphere of AT. After stirring at 90 °C for 3 hr, the reaction mixture was cooled to rt and added ice water (100 mL), The resulting suspension was filtered and the solid was washed with water and dried in vacuo to give crude compound 42c-l (2.2 g, 86% purity based on LC-MS) as a white solid, which was used for the next step without further purification. LC-MS (ESI): mlz 558.1 [M + Naf.

103261 Step 2. To a stirred solution of hydrochloric acid (2 M aq. solution, 1 mL) in acetonitrile (20 mL) was added NCS (994 mg, 7.47 mmol), followed by a solution of compound 43c-l (1.0 g, 1.86 mmol) in acetonitrile (2 mL) at 0 °C. After stirring at 0 °C for 3 hr, the reaction mixture was diluted with water (20 mL) and concentrated. The residue was extracted with EtOAc (50 mL x 3) and the combined organic extracts were washed with brine and dried over anhydrous Na₂S0₄. The solvent was removed and the residue was dried in vacuo to give crude compound 42e-2 (600 mg, 87% purity based on LC-MS) as a white solid, which was used for the next step without further purification. LC-MS (ESI): mlz 582.1 [M + Naf.

I0327I Step 3. To a stirred solution of compound 42c-2 (150 mg, 0.26 mmol) in DCM (5 mL) was added methanamine hydrochloride (54 mg, 0.81 mmol), followed by an aqueous solution of 2CO3 (2 M, 0.5 mL) at 0 °C. After stirring at rt for 3 hr, the reaction mixture was diluted with water (5 mL). The mixture was extracted with DCM (20 mL x 3) and the combined organic extracts were washed with brine and dried over anhydrous Na₂S0₄. The solvent was removed and the residue was dried in vacuo to give crude compound 42c-3 (120 mg, 85% purity based on LC- MS) as a white solid, which was used for the next step without further purification. LC-MS (ESI): mlz 555.1 [M + H]⁺.

10328| Step 4. Following the same procedure used for preparing compound 4-9 shown in Scheme 4 and replacing compound 4-7 with 42c-3, compound 42c-5 was obtained as a white solid. LC- MS (ESI): mlz 540.1 [M + Hf; Ή NMR (500 MHz,

δ 8.53 (q, J= 4.5 Hz, I H), 7.95 - 7.98 (m, 2H), 7.87 (s, IH), 7.59 (s, IH), 7.40 (t, J= 9.0 Hz, 2H), 6.97 (q, J= 4.5 Hz, IH), 4.95 (q, J= 6.0 Hz, IH), 4.35 (m, IH), 4.18 (d, J = 18.0 Hz, IH), 3.39 (s, 3H), 3.09 - 3.20 (m, 2H), 2.89

= 4.5 Hz, 3H), 2.59 (d, J= 5.0 Hz, 3H), 1.64 (d, J = 6.5 Hz, 3H) ppm.

|0329] Synthesis of compound 42c-6. Following the same procedure as that used for preparing compound 42c-5 shown in Scheme 42c and replacing methylamine with ammonia, compound -6 was obtained as a white solid. LC-MS (ESI): mlz 526.6 [M + Hf .

103301 Synthesis of compound 42c-7. Following the same procedure as that used for preparing compound 42c-5 shown in Scheme 42c and replacing methylamine with dimethylamine, compound 42c-7 was obtained as a white solid. LC-MS (ESI): mlz 554.1 [M + Hf,

103311 Synthesis of compound 42c-8. Following the same procedure as that used for preparing compound 42c-5 shown in Scheme 42c and replacing methylamine with morpholine, compound 42c-8 was obtained as a white solid. LC-MS (ESI): mlz 596.1 [M + Hf.

103321 Step 1. Refer to Scheme 42d. To a stirred solution of compound 42b-l (300 mg, 0.58 mmol) in acetonitrile (10 mL) was added N-chlorosuccinimide (1 15 mg, 0.86 mmol) and hydrochloric acid aqueous solution (1 M, 2 mL) at 0 °C. After stirring at 0 °C for 3 hr, the reaction mixture was diluted with ice water (40 mL). The suspension was filtered and the solid was washed with water and dried in vacuo to give crude compound 42d~l (300 mg, 90% purity based on LC-MS) as a white solid, which was used for the next step without further purification. LC- MS (ESI): mlz 545.1 [M + H]⁺.

103331 Step 2. To a stirred solution of piperidine (19 mg, 0.2 mmol) in anhydrous DMF (2 mL) was added K₂C0₃ (28 mg, 0.2 mmol), followed by compound 42d-l (60 mg, 0.11 mmol) at rt. After stirring at rt for 2 hr, the reaction mixture was diluted with ice water (10 mL). The suspension was filtered and the solid was washed with water and purified by preparative HPLC to give compound 42d-2 (12 mg, 18.5% yield) as a white solid. LC-MS (ESI): mlz 594.2 [M + H ; Ή NMR (500 MHz, iZ-DMSO): δ 8.55 (q, J =5.0 Hz, 1H), 7.97 (dd, Ji = 5.5 Hz, J₂= 9.0 Hz, 2H), 7.86 (s, 1H), 7.60 (s, 1H), 7.41 (t, J= 9.0 Hz, 2H), 4.95 (q, J= 5.0 Hz, IH), 4.39 (t, J = 10.5 Hz, IH), 4.21 (t, J= 14.5 Hz, lH), 3.39 (s, 3H), 3.23 - 3.20 (m, IH), 3.20 - 3.10 (m, 5H), 2.89 - 2.84 (m, IH), 2.84 (<L J= 4.0 Hz, 3H), 1.65 (d, J= 6.5 Hz, 3H), 1.56 (m, 3H), 1.23 (d,J= 4.5 Hz, 3H) ppm.

10334] Synthesis of compound 42d-3. Following the same procedure as that used for preparing compound 42d-2 shown in Scheme 42d and repiacing piperidine with pyrrolidine, compound 42d-3 was obtained as a white solid. LC-MS (ESI): mlz 580.2 [M + H]⁺.

] 03351 Synthesis of compound 42d-4. Following the same procedure as that used for preparing compound 42d-2 shown in Scheme 42d and replacing piperidine with iV-methylpiperizine, s a white solid. LC-MS (ESI): mlz 609.2 [M + H]⁺.

10336] Synthesis of compound 42d-5. Following the same procedure as that used for preparing compound 42d-2 shown in Scheme 42d and replacing piperidine with thiomorphol ine-dioxane, compound 42d-5 was obtained as a white solid. LC-MS (ESI): mlz 644.1 [M + Hf .

10337 J Synthesis of compound 42d-4. Following the same procedure as that used for preparing compound 42d-2 shown in Scheme 42d and replacing piperidine with N-methy lpiperi zine, as a white solid. LC-MS (ESI): mlz 609.2 [M + Hf.

103381 Synthesis of compound 42d-5. Following the same procedure as that used for preparing compound 42d-2 shown in Scheme 42d and replacing piperidine with thiomorpholine-dioxane, compound 42d-5 was obtained as a white solid. LC-MS (ESI): mlz 644.1 [M + Hf. Scheme 42β

|0337J Synthesis of compound 42e-l. Amide coupling of compound 42c-6 with cyclopropyl carboxylic acid in the presence of EDCI, DMAP and EtjN in DCM gave compound 42e-l as a whilte solid. LC-MS (ESI): mlz 594.1 [M + H]⁺.

{03381 Synthesis of compound 42e-2. Amide coupling of compound 42c-6 with /-butyl carboxylic acid in the presence of EDCI, DMAP and Et3N in DCM gave compound 42e-2 as a whilte solid. LC-MS (ESI): mlz 610.2 [M + H]⁺.

10338| icai activity of the compounds of the invention was determined using an HCV replicon assay. The lb_Huh-Luc/Neo-ET cell line persistently expressing a bicistronic genotype lb replicon in Huh 7 cells was obtained from ReBLikon GMBH. This cell line was used to test compound inhibition using luciferase enzyme activity readout as a measurement of compound inhibition of replicon levels.

III. Biological A ci uvin

103391 Biological activity of the compounds of the invention was determined using an HCV replicon assay. The 1 b_Huh-Luc Neo-ET cell line persistently expressing a bicistronic genotype lb replicon in Huh 7 cells was obtained from ReBLikon GMBH. This cell line was used to test compound inhibition using luciferase enzyme activity readout as a measurement of compound inhibition of replicon levels.

10340 [ On Day 1 (the day after plating), each compound was added in triplicate to the cells. Plates were incubated for 72 hours prior to running the luciferase assay. Enzyme activity was measured using a Bright-Glo Kit (cat. number E2620) manufactured by Promega Corporation. The following equation was used to generate a percent control value for each compound.

% Control = (Average Compound Value/Average Control)* 100

10341] The EC» value was determined using GraphPad Prism and the following equation: Y ^« Bottom + (Top-Bottom)/ (1+10^Λ ((LogIC50-X)*HillSlope))

|0342] EC50 values of compounds were repeated several times in the replicon assay.

|0343] Compounds of the invention can inhibit multiple genotypes of HCV selected but not limited to la, l b, 2a, 3a, and 4a. The ECs₀s are measured in the corresponding replicon assays that are similar to HCV lb replicon assay as described above.

(03441 Exemplary compounds of the disclosed invention are illustrated in the Tables attached as Appendix A and Appendix B. Apendix A shows inhibitory activity of the compound against HCV lb. The biological activity against HCV lb is indicated as being *, **, ***, or ***^♦, which corresponds to EC*) ranges of EC50 > 1000 nM, 100 nM < EC₅₀≤ 1000 nM, 10 nM < ECso≤ 100 nM, or EC50≤ 10 nM, respectively.

10345J Appendix A shows structures of compounds of the invention identified by ID NOD B243- B577, and ECJO values determined for the compounds. Of these, all of compounds B243-B282, B285-B289, B292, B294-B426, B429-B438, B440-B443, B445-B469, B471-B540, B542-B549, B551 -B552, B554-B556, B558-B559, B561 -B575 had a measured activity of either 10 nM < EC50≤ 100 nM, or EC50≤ 10 nM.

IV. Pharmaceutical Compositions

103461 In another aspect, the invention includes a pharmaceutical composition comprising one or more of the compounds named above, together with one or more pharmaceutically acceptable excipients or vehicles, and optionally other therapeutic and/or prophylactic ingredients. The composition may further include one, two or three anti-HCV agent(s) selected from the group consisting of interferon-alpha, ribavirin, cyclosporine derivatives, NS3 protease inhibitors, NS4B inhibitors, NS5A inhibitors, NS5B polymerase inhibitors, and p7 inhibitors.

10347] The compounds described herein may be formulated in a pharmaceutical composition comprising one or more compounds, optionally together with one or more pharmaceutically acceptable excipients or vehicles, and optionally other therapeutic and/or prophylactic ingredients. Such excipients are known to those of skill in the art. Pharmaceutically acceptable salts can be used in the compositions of the present invention and include, for example, mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates and the like. A thorough discussion of pharmaceutically acceptable excipients and salts is available in Remington's Pharmaceutical Sciences, 18^th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990), and in

Handbook of Pharmaceutical Excipients, 6^lb Edition, Ed. R. C. Rowe, P. J. Sheskey, and M. E. Quinn (American Pharmacists Association, 2009).

{03481 Depending on the intended mode of administration, the pharmaceutical compositions may be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions or the like, preferably in unit dosage form suitable for single administration of a precise dosage. The compositions will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, may include other pharmaceutical agents, adjuvants, diluents, buffers, etc.

{0349| The compound comprised within the pharmaceutical composition includes isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof, together with one or more pharmaceutically acceptable carriers and optionally other therapeutic and/or prophylactic ingredients.

(03501 For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate and the like.

103511 For oral administration, the composition will generally take the form of a tablet, capsule, a softgel capsule nonaqueous solution, suspension or syrup. Tablets and capsules are preferred oral administration forms. Tablets and capsules for oral use will generally include one or more commonly used carriers such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. When liquid suspensions are used, the active agent may be combined with emulsifying and suspending agents. If desired, flavoring, coloring and/or sweetening agents may be added as well. Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents and the like.

{03521 In yet another aspect, provided herein is the use of the compounds of the invention in the manufacture of a medicament, e.g., for the treatment of hepatitis C.

m V. Method of Treating HCV

103531 Also provided is a method of treating hepatitis C. The method comprises administering to a subject in need thereof, a therapeutically effective amount of a compound of the invention, optionally contained in a pharmaceutical composition. A pharmaceutically or therapeutically effective amount of the composition will be delivered to the subject. The precise effective amount will vary from subject to subject and will depend upon the species, age, the subject's size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration. Thus, the effective amount for a given situation can be determined and optimized by routine experimentation. The subject may be administered as many doses as is required to reduce and/or alleviate the signs, symptoms or causes of the disorder in question, or bring about any other desired alteration of a biological system. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compounds of this invention for a given disease.

[0354] A treatment regimen using one or more of the compounds provided herein, optionally in combination with one or more anti-HCV agents, will generally involve administering a therapeutically effective dose of the compound, which can readily be determined by one skilled in the art taken into account variables as previously described. A typical dose of a compound as provided herein will generally range from about 10 mg to 1000 mg a day. Representative dosage ranges include from about 10 mg to 900 mg a day, or from about 30 mg to about 700 mg a day, from about 50 mg to about 600 mg a day. A therapeutically effective dosage amount will typically range from 0.1 mg kg body weight to about 30 mg/kg body weight, or from about 0.1 mg kg body weight to about 15 mg kg body weight. The compound may be administered once or multiple times (two to three times) daily, once a week, twice a week, three times a week, etc., over a time course effective to achieve a positive virologic response. Representative courses of treatment include but are not limited to 10 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, and the like. A positive virologic response generally refers to undetectable HCV RNA in serum as measured by PCR and a biochemical response (normalization of aminotransferase levels).

Although one may gauge success of treatment by a histologic response (e.g., pathology of liver biopsy), post-treatment biopsies are generally less preferable to an assessment based upon a virologic response.

10103] The treatment compound may be one or more of the compounds of B243, B244, B245, B246, B248, B249, B252, B253, B255, B256, B257, B258, B259, B260, B261, B262,B263, B264, B265, B266, B267, B268, B269, B270, B271, B272, B273, B274, B275, B276, B277, B278, B279, B280, B281, B282, B283, B284, B285, B286, B287, B288, B289, B290, B291, B293, B294, B295, B296, B297, B298, B299, B300, B301, B302, B303, B304, B305, B306, B307, B308, B309, B310, B31 1, B312, B313, B314, B315, B316, B317, B318, B319, B320, B321, B322, B323, B326, B327, B328, B329, B330, B333, B334, B335, B336, B337, B338, B339, B340, B341. B342, B343, B344, B345, B346, B347, B348, B349, B350, B351, B352, B353, B354, B355, B356, B357, B358, B360, B361, B362, B363, B364, B365, B366, B367, B368, B369, B370, B371, B372, B373, B374, B375, B376, B377, B378, B379, B380, B381, B382, B383, B384, B385, B386, B387, B388, B389, B390, B391, B392, B393, B394, B395, B396, B397, B398, B399, B400, B401, B402, B403, B404, B405, B406, B407, B408, B409, B410, B41 1, B412, B413, B414, B415, B416, B417, B418, B419, B420, B421, B422, B423, B424, B425, B426, B427, B428, B429, B430, B431, B432, B433, B434, B435, B436, B437, B438, B439, B440, B441, B442, B443, B444, B446, B447, B448, B449, B450, B451, B452, B453, B454, B455, B456, B457, B458, B459, B460, B461 , B462, B463, B464, B465, B466, B467, B468, B469, B470, B471, B472, B473, B474, B475, B476, B477, B478, B479, B480, B481, B482, B483, B484, B485, B486, B487, B488, B489, B490, B491, B492, B493, B494, B495, B496, B497, B498, B499, B500, B501, B502, B503, B504, B505, B506, B507, B508, B509, B510, B511, B512, B513, B514, B515, B516, B517, B518, B519, B520, B521, B522, B523, B524, B525, B526, B527, B528, B529, B530, B531, B532, B533, B534, B535, B536, B537, B538, B539, B540, B541, B542, B543, B544, B545, B546, B547, B548, B549, B550, B551, B552, B553, B554, B555, B556, B557, B558, B561, B562, B563, B564, B565, B566, B567, B568, B569, B570, B571, B572, B573, B574, B575, B576, and B577. Specific compounds include those from Group 1, Group 2, or Group 3 above.

103551 The administering may be by oral administration. Also disclosed is a compound as named above for use in treating HCV infection in an infected subject.

m 103561 Generally, treatment by administering a compound as provided herein is effective to result in at least a 2 log reduction in HCV RNA levels over the course of treatment. In some cases HCV RNA will still remain positive (detectable) after a course of treatment, although ideally, treatment is effective to achieve undetectable HCV RNA after completing a round of therapy. Subjects may also be assessed following completion of therapy to confirm maintenance of a positive and sustained virologic response (undetectable HCV RNA levels). Follow-up assessments may be carried out over the course of months or even years following treatment.

VI. ComblnationTheraDV

J0357[ The compounds of the present invention and their isomeric forms and pharmaceutically acceptable salts thereof are useful in treating and preventing HCV infection alone or when used in combination with other compounds targeting viral or cellular elements or functions involved in the HCV life cycle. Classes of compounds useful in the invention may include, without limitation, all classes of HCV an ivirals, both direct-acting and indirect-acting ('cell-targeted' inhibitors of HCV replication). For combination therapies, mechanistic classes of agents that may be useful when combined with the compounds of the present invention include, for example, nucleoside and non-nucleoside inhibitors of the HCV protease inhibitors, helicase inhibitors, NS5A inhibitors, NS4B inhibitors and medicinal agents that functionally inhibit the internal ribosomal entry site (IRES), other NS5B inhibitors and other medicaments that inhibit HCV cell attachment or virus entry, HCV RNA translation, HCV RNA transcription, replication or HCV maturation, assembly or virus release.

103581 Specific compounds in these classes and useful in the invention include, but are not limited to, linear, macrocyclic, and heterocyclic HCV protease inhibitors such as telaprevir (VX- 950), boceprevir (SCH-503034), narlaprevir (SCH-900518), ITMN-191 (R-7227), TMC-435350 (a.k.a. TMC-435), M -7009, M -5172, Bl-201335, BMS-650032, ACH- 1625, ACH-2784, ACH-1095 (HCV NS4A protease co-factor inhibitor), AVL-181, AVL-192, VX-813, PHX-1766, PHX-2054, 1DX-136, IDX-316, IDX-320, GS-9256, GS-9265, GS-9451, ABT-450, EP-013420 (and congeners) and VBY-376; the nucleosidic HCV polymerase (replicase) inhibitors useful in the invention include, but are not limited to, ALS2200, R7128, PSI-7851, PS1-7977 (GS-7977), PSI-938, PSI-879, PSI-6130, IDX-184, IDX-102, ΓΝΧ-189, R1479, R1626, UNX-08189, and various other nucleoside and nucleotide analogs and HCV inhibitors including, but not limited to, those derived from 2'-C-methyl modified nucleos(t)ides, 4'-aza modified nucleos(t)ides, and T- deaza modified nucleos(t)ides. NS5A inhibitors useful in the invention, include, but are not limited to, ΡΡΙ-46 , PPI-668, BMS-790052, BMS-824393, GS-5885, EDP-239, ACH-2928, AZD-7295, IDX-719, IDX-380, ABT-267, GS -2336805, CF-102, A-831 and ΓΓΜΝ-9916. Non-nucleosidic HCV polymerase (replicase) inhibitors useful in the invention, include, but are not limited to, VCH-759, VCH-916, VCH-222 (VX-222), ANA-598, M -3281, ABT-333, ABT- 072, PF-00868554 (filibuvir), BI-207127, GS-9190, A-837093, GS -625433, J T-109, GL- 59728 and GL-60667. HCV P7 inhibitors useful in the present invention include BIT-225 and other P7 inhibitors, as well as HCV NS4B inhibitors including but not limited to histamine agents that antagonize HCV NS4B function.

J0359I In addition, NS5B inhibitors of the present invention may be used in combination with cyclophyllin and immunophyllin antagonists (eg, without limitation, DEBIO compounds, NM- 81 1, SCY-635, EP-CyP282, as well as cyclosporine and its derivatives), kinase inhibitors, inhibitors of heat shock proteins (e.g., HSP90 and HSP70), other immunomodulatory agents that may include, without limitation, interferons (-alpha, -beta, -omega, -gamma, -lambda or synthetic) such as Intron A™, Roferon-A™, Canferon-A300™, Advaferon™, Infergen™, Humoferon™, Sumiferon MP™, Alfaferone™, IFN-β™, Feron™ and the like; polyethylene glycol derivatized (pegylated) interferon compounds, such as PEG interferon-a-2a (Pegasys™), PEG interferon-o-2b (PEGIntron™), pegylated IFN-a-conl and the like; long acting formulations and derivatizations of interferon compounds such as the albumin-fused interferon, Albuferon™ , Locteron™ and the like; interferons with various types of controlled delivery systems (e.g.

ITCA-638, omega-interferon delivered by the DUROS™ subcutaneous delivery system);

compounds that stimulate the synthesis of interferon in cells, such as resiquimod and the like; interleukins; compounds that enhance the development of type 1 helper T cell response, such as SCV-07 and the like; TOLL-like receptor agonists such as CpG-10101 (actilon), isotorabine, ANA773, SD-101, IMO-2125, and the like; thymosin a -1; ANA-245 and ANA-246; histamine dihydrochloride; propagerrnanium; tetrach lorodecaoxide; ampligen; IMP-321; KRN-7000:

antibodies, such as civacir, XTL-6865 and the like and prophylactic and therapeutic vaccines such as GI-5005, TG-4040, InnoVac C, HCV E1 E2/MF59 and the like. In addition, any of the above- described methods involving administering an NS5B inhibitor, a Type I interferon receptor agonist (e.g., an IFN-a) and a Type II interferon receptor agonist (e.g., an IFN-γ) can be augmented by administration of an effective amount of a TNF- antagonist Exemplary, non- limiting TNF-a antagonists that are suitable for use in such combination therapies include ENBREL™, REMICADE™ and HUMI A™.

J0360J NS5B inhibitors of the present invention may also be used with alternative forms of interferons and pegylated interferons, ribavirin or its analogs (e.g., tarabavarin, levoviron), microRNA, small interfering RNA compounds (e.g., S1RPLEX-140-N and the like) and microR A agents (such as micro-RNA-122), nucleotide or nucleoside analogs, multifunction inhibitors such as nitazoxanide, immunoglobulins, hepatoprotectants, anti-inflammatory agents and other direct and indirect inhibitors of HCV replication. Inhibitors of other targets in the HCV life cycle include NS3 helicase inhibitors; NS4A co- factor inhibitors; and sense oligonucleotide inhibitors, such as ISIS- 14803, ISlS-11, AVI-4065 and the like; vector-encoded short hairpin RNA (shRNA); HCV specific ribozymes such as heptazyme, RPI-13919 and the like; entry inhibitors such as HepeX-C, HuMax-HepC and the like; alpha glucosidase inhibitors such as celgosivir, UT-231B and the like; KPE-02003002 and BIVN 401 and IMPDH inhibitors.

J 0361 J Other illustrative HCV inhibitor compounds include those disclosed in the following publications: U.S. Pat. No. 5,807,876; U.S. Pat. No. 6,498,178; U.S. Pat. No. 6,344,465; U.S. Pat. No. 6,054,472; U.S. Pat. No. 7,759,495; U.S. Pat. No. 7,704,992; U.S. Pat. No. 7,741, 347; WO 02/04425; WO 03/007945; WO 03/010141; WO 03/000254; WO 03/037895; WO 02/100851; WO 02/100846; EP 1256628; WO 02/18369; WO 05/073216; WO 05/073195; WO 08/021927; US 20080050336; US 20080044379; US 2009004716; US 20090043107; US 20090202478; US 20090068140; WO 10/096302; US 20100068176; WO 10/094977; WO 07/138242; WO

10/096462; US 2010091413; WO 10/075380; WO 10/062821 ; WO 10/09677; WO 10/065681 and WO 10/065668.

103621 Additionally, combinations of, for example, ribavirin a NS3 protease inhibitor, a replicase inhibitor and interferon, may be administered as multiple combination therapy with at least one of the compounds of the present invention. The present invention is not limited to the

aforementioned classes or compounds and contemplates known and new compounds and combinations of biologically active agents (see, for example, lebl et al. "Host cell targets in HCV therapy: novel strategy or proven practice, Antiviral Chemistry & Chemotherapy 16:69-90, which is incorporated by reference herein). It is intended that combination therapies of the present invention include any chemically compatible combination of a compound of this inventive group with other compounds of the inventive group or other compounds outside of the inventive group, as long as the combination does not eliminate the anti-viral activity of the compound of this inventive group or the anti-viral activity of the pharmaceutical composition itself

[0363 J Combination therapy can be sequential, that is treatment with one agent first and then a second agent (for example, where each treatment comprises a different compound of the invention or where one treatment comprises a compound of the invention and the other comprises one or more biologically active agents) or it can be treatment with both agents at the same time (concurrently). Sequential therapy can include a reasonable time after the completion of the first therapy before beginning the second therapy. Treatment with both agents at the same time can be in the same daily dose or in separate doses. The dosages for both concurrent and sequential combination therapy will depend on absorption, distribution, metabolism and excretion rates of the components of the combination therapy as well as other factors known to one of skill in the art. Dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules may be adjusted over time according to the individual's need.

[0364| All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.

10365] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to one of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the invention as defined in the appended claims.

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Appendix A Page 2

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Appendix B

Claims

IT IS CLAIMED:

1. A com ound havin the structural formula:

21}

214

216

117

°c ¾ O^' o TT¾

s _and r¾

X' is selected from =0, =N-OH, .23CH₃, and R'3 is selected from -CH₃ and -OCH3.

2. The compound of claim 1, wherein: R'| is para-Y, X' is =0, and R'₃ is -CH3.

3. The compound of claim I, selected from the group consisting of B243, B244, B245, B246, B248, B249, B252, B253, B255, B256, B257, B258, B259, B260, B261, B262.B263, B264, B265, B266, B267, B268, B269, B270, B271, B272, B273, B274, B275, B276, B277, B278, B279, B280, B281, B282, B283, B284, B285, B286, B287, B288, B289, B290, B291, B293, B294, B295, B296, B297, B298, B299, B300, B301, B302, B303, B304, B305, B306, B307, B308, B309, B310, B31 1 , B312, B313, B314, B315, B316, B317, B3 18, B319, B320, B321 , B322, B323, B326, B327, B328, B329, B330, B333, B334, B335, B336, B337, B338, B339, B340, B341 , B342, B343, B344, B345, B346, B347, B348, B349, B350, B351 , B352, B353, B354, B355, B356, B357, B358, B360, B361, B362, B363, B364, B365, B366, B367, B368, B369, B370, B371, B372, B373, B374, B375, B376, B377, B378, B379, B380, B381 , B382, B383, B384, B385, B386, B387, B388, B389, B390, B391 , B392, B393, B394, B395, B396, B397, B398, B399, B400, B401, B402, B403, B404, B405, B406, B407, B408, B409, B410, B41 1, B412, B413, B414, B 15, B416, B417, B418, B419, B420, B421, B422, B423, B424, B425, B426, B427, B428, B429, B430, B431 , B432, B433, B434, B435, B436, B437, B438, B439, B440, B441, B442, B443, B444, B446, B447, B448, B449, B450, B451 , B452, B453, B454, B455, B456, B457, B458, B459, B460, B461, B462, B463, B464, B465, B466, B467, B468, B469, B470, B471, B472, B473, B474, B475, B476, B477, B478, B479, B480, B48 I , B482, B483, B484, B485, B486, B487, B488, B489, B490, B491 , B492, B493, B494, B495, B496, B497, B498, B499, B500, B501 , B502, B503, B504, B505, B506, B507, B508, B509, B510, B51 1 , B512, B513, B514, B515, B516, B517, B518, B519, B520, B521 , B522, B523, B524, B525, B526, B527, B528, B529, B530, B531 , B532, B533, B534, B535, B536, B537, B538, B539, B540, B541, B542, B543, B544, B545, B546, B547, B548, B549, B550, B551, B552, B553, B554, B555, B556, B557, B558, B561, B562, B563, B564, B565, B566, B567, B568, B569, B570, B571, B572, B573, B574, B575, B576, and B577.

4. The compound of claim 1,

5. The compound of claim 1, compound having the structural formula:

wherein:

R'i is selected from -H, -F, -C

I, -Br, -1, and

221

X' is selected from =0, =N-OH, =N-0(CH₂CH₂0)o.gCH,, and =N-0(CH₂)] 23CH3, and R'₃ is selected from -CH₃ and -OCH3.

6. The compound of claim 5, wherein: R'i is para-?, X' is =0, and R'₃ is -CHj.

7. The compound of claim 5, selected from the group consisting of B243, B244, B245, B246, B248, B249, B252, B253, B255, B256, B257, B258, B259, B260, B261 , B262.B263, B264, B265, B266, B267, B268, B269, B270, B27I, B272, B273, B274, B275, B276, B277, B278, B279, B280, B281, B282, B285, B286, B289, B300, B302, B306, B307, B308, B309, B310, B31 1, B314, B316, B317, B318, B319, B320, B333, B335, B336, B337, B338, B343, B344, B345, B346, B347, B348, B349, B350, B351 , B352, B353, B354, B373, B378, B379, B381, B383, B384, B385, B386, B388, B389, B390, B391 , B392, B394, B395, B397, B399, B400, B401 , B402, B404, B405, and B409.

8. The compound of claim 1, compound having the structural formula:

wherein:

M io ^F_- > o X #,

234

H⁰ Δ ₀¾ - j o¾ ^H0 j¾ ^H0 I ₀¾ <U o

X' is selected from -O, =N-OH,

and R'i is selected from -CH3 and -OCH3.

9. The compound of claim 8, wherein: 1 is para-F, X' is =0, and R'₃ is -CH3.

10. The compound of claim 8, selected from the group consisting of B283, B284, B287, B288,

1 1. The compound of claim 1 , compound having the structural formula:

wherein:

selected from -H, -F, -CI, -Br, -I,

Χ' is selected from =0, =N-OH,

and R'₃ is selected from -CH₃ and -OCH₃.

12. The compound of claim 1 1, wherein: R'i is para-F, X' is =0, and R'₃ is -CH₃.

13. The compound of claim 1 1, selected from the group consisting of B294, B295, B296, B297, B298, B299, B301 , B303, B304, B305, B312, B313, B315, B321, B322, B323, B326, B327, B328, B329, B330, B334, B339, B340, B341, B342, B355, B356, B357, B358, B360, B361, B362, B363, B364, B365, B366, B367, B368, B369, B370, B371, B372, B374, B375, B376, B377, B380, B382, B387, B393, B396, B398, B403, B406, B407, B408, B410, B41 1, B412, B413, B414, B415, B416, B417, B418, B419, B420, B421, B425, B427, B428, B429, B430, B431, B433, B434, B435, B436, B437, B438, B439, B440, B441, B442, B444, B448, B449, B450, B451, B452, B453, B454, B457, B458, B460, B461, B462, B465, B468, B471, B472, B473, B474, B475, B476, B477, B480, B481, B482, B483, B484, B485, B486, and B490.

14. A compound having the structural formula:

m 0'-¾'CH₃

o

wherein:

R'i is selected from para-Έ

;

R'2 is selected from -OH and -SOjMe; and

R'i is selected from -CH₃ and -OCH3, as exemplified by B324, B325, B331, and B332.

15. A compound having the structural formula:

wherein:

R'i is selected from para-F

R*2 is selected from -OH and -SOjMe; and

R'3 is selected from -CH3 and -OCH3, as exemplified by compound B359.

16. A pharmaceutical composition comprising a compound of any one of claims 1-15 or its pharmaceutically acceptable salts, together with one or more pharmaceutically acceptable excipients or vehicles, and optionally other therapeutic and/or prophylactic ingredients.

17. The composition of claim 16, with further comprises additional one, two or three anti-HCV agent(s) selected from the group consisting of interferon-alpha, ribavirin, cyclosporine derivatives, HCV NS3 protease inhibitors, HCV NS4B inhibitors, HCV NS5A inhibitors, HCV NS5B polymerase inhibitors, and p7 inhibitors.

18. A method of treating HCV infection in a subject comprising administering to the subject, a pharmaceutically acceptable dose of the compound of any one of claims 1-15, and continuing the administering until a selected reduction in the subject's HCV titer is achieved.

1 . The method of claim 18, wherein the compound is selected from the group consisting of B243, B244, B245, B246, B248, B249, B252, B253, B255, B256, B257, B258, B259, B260, B261, B262,B263, B264, B265, B266, B267, B268, B269, B270, B271, B272, B273, B274, B275, B276, B277, B278, B279, B280, B281, B282, B283, B284, B285, B286, B287, B288, B289, B290, B291, B293, B294, B295, B296, B297, B298, B299, B300, B301, B302, B303, B304, B305, B306, B307, B308, B309, B310, B31 1, B312, B313, B314, B315, B316, B317, B318, B319, B320, B321, B322, B323, B326, B327, B328, B329, B330, B333, B334, B335, B336, B337, B338, B339, B340, B341, B342, B343, B344, B345, B346, B347, B348, B349, B350, B351 , B352, B353, B354, B355, B356, B357, B358, B360, B361, B362, B363, B364, B365, B366, B367, B368, B369, B370, B371, B372, B373, B374, B375, B376, B377, B378, B379, B380, B381, B382, B383, B384, B385, B386, B387, B388, B389, B390, B391, B392, B393, B394, B395, B396, B397, B398, B399, B400, B401, B402, B403, B404, B405, B406, B407, B408, B409, B410, B41 1, B412, B413, B414, B415, B416, B417, B418, B419, B420, B421, B422, B423, B424, B425, B426, B427, B428, B429, B430, B431, B432, B433, B434, B435, B436, B437, B438, B439, B440, B441, B442, B443, B444, B446, B447, B448, B449, B450, B451, B452, B453, B454, B455, B456, B457, B458, B459, B460, B461, B462, B463, B464, B465, B466, B467, B468, B469, B470, B471, B472, B473, B474, B475, B476, B477, B478, B479, B480, B481, B482, B483, B484, B485, B486, B487, B488, B489, B490, B491, B492, B493, B494, B495, B496, B497, B498, B499, B500, B501, B502, B503, B504, B505, B506, B507, B508, B509, B510, B51 1, B512, B5 I 3, B514, B515, B516, B517, B518, B519, B520, B521 , B522, B523, B524, B525, B526, B527, B528, B529, B530, B531 , B532, B533, B534, B535, B536, B537, B538, B539, B540, B541, B542, B543, B544, B545, B546, B547, B548, B549, B550, B551, B552, B553, B554, B555, B556, B557, B558, B561, B562, B563, B564, B565, B566, B567, B568, B569, B570, B571 , B572, B573, B574, B575, B576, and B577.

2M

20. The method of claim 18, wherein the compound is selected from the group consisting of B243, B244, B245, B246, B248, B249, B252, B253, B255, B256, B257, B258, B259, B260, B261, B262.B263, B264, B265, B266, B267, B268, B269, B270, B271, B272, B273, B274, B275, B276, B277, B278, B279, B280, B281, B282, B285, B286, B289, B300, B302, B306, B307, B308, B309, B310, B31 1, B314, B316, B317, B318, B319, B320, B333, B335, B336, B337, B338, B343, B344, B345, B346, B347, B348, B349, B350, B351, B352, B353, B354, B373, B378, B379, B381, B383, B384, B385, B386, B388, B389, B390, B391, B392, B394, B395, B397, B399, B400, B401, B402, B404, B405, and B409.

21. The method of claim 18, wherein the compound is selected from the group consisting of B283, B284, B287, B288, B290, B291, B293, B422, B423, B424, B426, B432, B443, B446, B447, B455, B456, B459, B463, B464, B466, B467, B470, B478, B479, B487, B488, B489, B491, B492, B493, B494, B495, B496, B497, B498, B499, B500, B501, B502, B503, B504, B505, B506, B507, B508, B509, B510, BS 1 1, B512, B513, B514, B515, B516, B517, B518, B519, B520, B521, B522, B523, B524, B525, B526, B527, B528, B529, B530, B531, B532, B533, B534, B535, B536, B537, B538, B539, B540, B541, B542, B543, B544, B545, B546, B547, B548, B549, B550, B551, B552, B553, B554, B555, B556, B557, B558, B561, B562, B563, B564, B565, B566, B567, B568, B569, B570, B571, B572, B573, B574, B575, B576, and B577.

22. The method of claim 18, wherein the compound is selected from the group consisting of B294, B295, B296, B297, B298, B299, B301, B303, B304, B305, B312, B313, B315, B321, B322, B323, B326, B327, B328, B329, B330, B334, B339, B340, B341, B342, B355, B356, B357, B358, B360, B361, B362, B363, B364, B365, B366, B367, B368, B369, B370, B371, B372, B374, B375, B376, B377, B380, B382, B387, B393, B396, B398, B403, B406, B407, B408, B410, B41 1, B412, B413, B414, B415, B416, B417, B418, B419, B420, B421, B425, B427, B428, B429, B430, B431, B433, B434, B435, B436, B437, B438, B439, B440, B441 , B442, B444, B448, B449, B450, B451, B452, B453, B454, B457, B458, B460, B461, B462, B465, B468, B471, B472, B473, B474, B475, B476, B477, B480, B481, B482, B483, B484, B485, B486, and B490.

23i

23. The method of claim 18, wherein the administering is by oral administration.

24. A compound of any one of claims 1-15 for use in treating HCV infection in an infected subject.